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Sample records for acute lung inflammation

  1. Inhibition of lipopolysaccharide induced acute inflammation in lung by chlorination

    Energy Technology Data Exchange (ETDEWEB)

    Zhang, Jinshan; Xue, Jinling; Xu, Bi; Xie, Jiani [Environmental Simulation and Pollution Control State Key Joint Laboratory, School of Environment, Tsinghua University, Beijing 100084 (China); Qiao, Juan, E-mail: qjuan@tsinghua.edu.cn [Department of Chemistry, Tsinghua University, Beijing 100084 (China); Lu, Yun, E-mail: luyun@tsinghua.edu.cn [Environmental Simulation and Pollution Control State Key Joint Laboratory, School of Environment, Tsinghua University, Beijing 100084 (China)

    2016-02-13

    Highlights: • Chlorination is effective to reduce the inflammation inducing capacity of LPS in lung. • LAL-detected endotoxin activity is not correlated to the potency of inflammation induction. • Alkyl chain of LPS was chlorinated in chlorination process. • LPS aggregate size decreases after chlorination. - Abstract: Lipopolysaccharide (LPS, also called endotoxin) is a pro-inflammatory constituent of gram negative bacteria and cyanobacteria, which causes a potential health risk in the process of routine urban application of reclaimed water, such as car wash, irrigation, scenic water refilling, etc. Previous studies indicated that the common disinfection treatment, chlorination, has little effect on endotoxin activity removal measured by Limulus amebocyte lysate (LAL) assay. However, in this study, significant decrease of acute inflammatory effects was observed in mouse lung, while LAL assay still presented a moderate increase of endotoxin activity. To explore the possible mechanisms, the nuclear magnetic resonance (NMR) results showed the chlorination happened in alkyl chain of LPS molecules, which could affect the interaction between LPS and LPS-binding protein. Also the size of LPS aggregates was found to drop significantly after treatment, which could be another results of chlorination caused polarity change. In conclusion, our observation demonstrated that chlorination is effective to reduce the LPS induced inflammation in lung, and it is recommended to use health effect-based methods to assess risk removal of water treatment technologies.

  2. Inhibition of lipopolysaccharide induced acute inflammation in lung by chlorination

    International Nuclear Information System (INIS)

    Zhang, Jinshan; Xue, Jinling; Xu, Bi; Xie, Jiani; Qiao, Juan; Lu, Yun

    2016-01-01

    Highlights: • Chlorination is effective to reduce the inflammation inducing capacity of LPS in lung. • LAL-detected endotoxin activity is not correlated to the potency of inflammation induction. • Alkyl chain of LPS was chlorinated in chlorination process. • LPS aggregate size decreases after chlorination. - Abstract: Lipopolysaccharide (LPS, also called endotoxin) is a pro-inflammatory constituent of gram negative bacteria and cyanobacteria, which causes a potential health risk in the process of routine urban application of reclaimed water, such as car wash, irrigation, scenic water refilling, etc. Previous studies indicated that the common disinfection treatment, chlorination, has little effect on endotoxin activity removal measured by Limulus amebocyte lysate (LAL) assay. However, in this study, significant decrease of acute inflammatory effects was observed in mouse lung, while LAL assay still presented a moderate increase of endotoxin activity. To explore the possible mechanisms, the nuclear magnetic resonance (NMR) results showed the chlorination happened in alkyl chain of LPS molecules, which could affect the interaction between LPS and LPS-binding protein. Also the size of LPS aggregates was found to drop significantly after treatment, which could be another results of chlorination caused polarity change. In conclusion, our observation demonstrated that chlorination is effective to reduce the LPS induced inflammation in lung, and it is recommended to use health effect-based methods to assess risk removal of water treatment technologies.

  3. Inhibition of lipopolysaccharide induced acute inflammation in lung by chlorination.

    Science.gov (United States)

    Zhang, Jinshan; Xue, Jinling; Xu, Bi; Xie, Jiani; Qiao, Juan; Lu, Yun

    2016-02-13

    Lipopolysaccharide (LPS, also called endotoxin) is a pro-inflammatory constituent of gram negative bacteria and cyanobacteria, which causes a potential health risk in the process of routine urban application of reclaimed water, such as car wash, irrigation, scenic water refilling, etc. Previous studies indicated that the common disinfection treatment, chlorination, has little effect on endotoxin activity removal measured by Limulus amebocyte lysate (LAL) assay. However, in this study, significant decrease of acute inflammatory effects was observed in mouse lung, while LAL assay still presented a moderate increase of endotoxin activity. To explore the possible mechanisms, the nuclear magnetic resonance (NMR) results showed the chlorination happened in alkyl chain of LPS molecules, which could affect the interaction between LPS and LPS-binding protein. Also the size of LPS aggregates was found to drop significantly after treatment, which could be another results of chlorination caused polarity change. In conclusion, our observation demonstrated that chlorination is effective to reduce the LPS induced inflammation in lung, and it is recommended to use health effect-based methods to assess risk removal of water treatment technologies. Copyright © 2015 Elsevier B.V. All rights reserved.

  4. Titanium Dioxide Exposure Induces Acute Eosinophilic Lung Inflammation in Rabbits

    Science.gov (United States)

    CHOI, Gil Soon; OAK, Chulho; CHUN, Bong-Kwon; WILSON, Donald; JANG, Tae Won; KIM, Hee-Kyoo; JUNG, Mannhong; TUTKUN, Engin; PARK, Eun-Kee

    2014-01-01

    Titanium dioxide (TiO2) is increasingly widely used in industrial, commercial and home products. TiO2 aggravates respiratory symptoms by induction of pulmonary inflammation although the mechanisms have not been well investigated. We aimed to investigate lung inflammation in rabbits after intratracheal instillation of P25 TiO2. One ml of 10, 50 and 250 µg of P25 TiO2 was instilled into one of the lungs of rabbits, chest computed-tomography was performed, and bronchoalveolar lavage (BAL) fluid was collected before, at 1 and 24 h after P25 TiO2 exposure. Changes in inflammatory cells in the BAL fluids were measured. Lung pathological assay was also carried out at 24 h after P25 TiO2 exposure. Ground glass opacities were noted in both lungs 1 h after P25 TiO2 and saline (control) instillation. Although the control lung showed complete resolution at 24 h, the lung exposed to P25 TiO2 showed persistent ground glass opacities at 24 h. The eosinophil counts in BAL fluid were significantly increased after P25 TiO2 exposure. P25 TiO2 induced a dose dependent increase of eosinophils in BAL fluid but no significant differences in neutrophil and lymphocyte cell counts were detected. The present findings suggest that P25 TiO2 induces lung inflammation in rabbits which is associated with eosinophilic inflammation. PMID:24705802

  5. Punica granatum L. Leaf Extract Attenuates Lung Inflammation in Mice with Acute Lung Injury

    Science.gov (United States)

    Pinheiro, Aruanã Joaquim Matheus Costa Rodrigues; Gonçalves, Jaciara Sá; Dourado, Ádylla Wilenna Alves; de Sousa, Eduardo Martins; Brito, Natilene Mesquita; Silva, Lanna Karinny; Batista, Marisa Cristina Aranha; de Sá, Joicy Cortez; Monteiro, Cinara Regina Aragão Vieira; Fernandes, Elizabeth Soares; Campbell, Lee Ann; Zago, Patrícia Maria Wiziack

    2018-01-01

    The hydroalcoholic extract of Punica granatum (pomegranate) leaves was previously demonstrated to be anti-inflammatory in a rat model of lipopolysaccharide- (LPS-) induced acute peritonitis. Here, we investigated the anti-inflammatory effects of the ethyl acetate fraction obtained from the pomegranate leaf hydroalcoholic extract (EAFPg) on the LPS-induced acute lung injury (ALI) mouse model. Male Swiss mice received either EAFPg at different doses or dexamethasone (per os) prior to LPS intranasal instillation. Vehicle-treated mice were used as controls. Animals were culled at 4 h after LPS challenge, and the bronchoalveolar lavage fluid (BALF) and lung samples were collected for analysis. EAFPg and kaempferol effects on NO and cytokine production by LPS-stimulated RAW 264.7 macrophages were also investigated. Pretreatment with EAFPg (100–300 mg/kg) markedly reduced cell accumulation (specially neutrophils) and collagen deposition in the lungs of ALI mice. The same animals presented with reduced lung and BALF TNF-α and IL-1β expression in comparison with vehicle controls (p < 0.05). Additionally, incubation with either EAFPg or kaempferol (100 μg/ml) reduced NO production and cytokine gene expression in cultured LPS-treated RAW 264.7 macrophages. Overall, these results demonstrate that the prophylactic treatment with EAFPg attenuates acute lung inflammation. We suggest this fraction may be useful in treating ALI. PMID:29675437

  6. Punica granatum L. Leaf Extract Attenuates Lung Inflammation in Mice with Acute Lung Injury.

    Science.gov (United States)

    Pinheiro, Aruanã Joaquim Matheus Costa Rodrigues; Gonçalves, Jaciara Sá; Dourado, Ádylla Wilenna Alves; de Sousa, Eduardo Martins; Brito, Natilene Mesquita; Silva, Lanna Karinny; Batista, Marisa Cristina Aranha; de Sá, Joicy Cortez; Monteiro, Cinara Regina Aragão Vieira; Fernandes, Elizabeth Soares; Monteiro-Neto, Valério; Campbell, Lee Ann; Zago, Patrícia Maria Wiziack; Lima-Neto, Lidio Gonçalves

    2018-01-01

    The hydroalcoholic extract of Punica granatum (pomegranate) leaves was previously demonstrated to be anti-inflammatory in a rat model of lipopolysaccharide- (LPS-) induced acute peritonitis. Here, we investigated the anti-inflammatory effects of the ethyl acetate fraction obtained from the pomegranate leaf hydroalcoholic extract (EAFPg) on the LPS-induced acute lung injury (ALI) mouse model. Male Swiss mice received either EAFPg at different doses or dexamethasone (per os) prior to LPS intranasal instillation. Vehicle-treated mice were used as controls. Animals were culled at 4 h after LPS challenge, and the bronchoalveolar lavage fluid (BALF) and lung samples were collected for analysis. EAFPg and kaempferol effects on NO and cytokine production by LPS-stimulated RAW 264.7 macrophages were also investigated. Pretreatment with EAFPg (100-300 mg/kg) markedly reduced cell accumulation (specially neutrophils) and collagen deposition in the lungs of ALI mice. The same animals presented with reduced lung and BALF TNF- α and IL-1 β expression in comparison with vehicle controls ( p < 0.05). Additionally, incubation with either EAFPg or kaempferol (100  μ g/ml) reduced NO production and cytokine gene expression in cultured LPS-treated RAW 264.7 macrophages. Overall, these results demonstrate that the prophylactic treatment with EAFPg attenuates acute lung inflammation. We suggest this fraction may be useful in treating ALI.

  7. Intratracheal IL-6 protects against lung inflammation in direct, but not indirect, causes of acute lung injury in mice.

    Science.gov (United States)

    Bhargava, Rhea; Janssen, William; Altmann, Christopher; Andrés-Hernando, Ana; Okamura, Kayo; Vandivier, R William; Ahuja, Nilesh; Faubel, Sarah

    2013-01-01

    Serum and bronchoalveolar fluid IL-6 are increased in patients with acute respiratory distress syndrome (ARDS) and predict prolonged mechanical ventilation and poor outcomes, although the role of intra-alveolar IL-6 in indirect lung injury is unknown. We investigated the role of endogenous and exogenous intra-alveolar IL-6 in AKI-mediated lung injury (indirect lung injury), intraperitoneal (IP) endotoxin administration (indirect lung injury) and, for comparison, intratracheal (IT) endotoxin administration (direct lung injury) with the hypothesis that IL-6 would exert a pro-inflammatory effect in these causes of acute lung inflammation. Bronchoalveolar cytokines (IL-6, CXCL1, TNF-α, IL-1β, and IL-10), BAL fluid neutrophils, lung inflammation (lung cytokines, MPO activity [a biochemical marker of neutrophil infiltration]), and serum cytokines were determined in adult male C57Bl/6 mice with no intervention or 4 hours after ischemic AKI (22 minutes of renal pedicle clamping), IP endotoxin (10 µg), or IT endotoxin (80 µg) with and without intratracheal (IT) IL-6 (25 ng or 200 ng) treatment. Lung inflammation was similar after AKI, IP endotoxin, and IT endotoxin. BAL fluid IL-6 was markedly increased after IT endotoxin, and not increased after AKI or IP endotoxin. Unexpectedly, IT IL-6 exerted an anti-inflammatory effect in healthy mice characterized by reduced BAL fluid cytokines. IT IL-6 also exerted an anti-inflammatory effect in IT endotoxin characterized by reduced BAL fluid cytokines and lung inflammation; IT IL-6 had no effect on lung inflammation in AKI or IP endotoxin. IL-6 exerts an anti-inflammatory effect in direct lung injury from IT endotoxin, yet has no role in the pathogenesis or treatment of indirect lung injury from AKI or IP endotoxin. Since intra-alveolar inflammation is important in the pathogenesis of direct, but not indirect, causes of lung inflammation, IT anti-inflammatory treatments may have a role in direct, but not indirect, causes of ARDS.

  8. Spred-2 deficiency exacerbates lipopolysaccharide-induced acute lung inflammation in mice.

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    Yang Xu

    Full Text Available BACKGROUND: Acute respiratory distress syndrome (ARDS is a severe and life-threatening acute lung injury (ALI that is caused by noxious stimuli and pathogens. ALI is characterized by marked acute inflammation with elevated alveolar cytokine levels. Mitogen-activated protein kinase (MAPK pathways are involved in cytokine production, but the mechanisms that regulate these pathways remain poorly characterized. Here, we focused on the role of Sprouty-related EVH1-domain-containing protein (Spred-2, a negative regulator of the Ras-Raf-extracellular signal-regulated kinase (ERK-MAPK pathway, in lipopolysaccharide (LPS-induced acute lung inflammation. METHODS: Wild-type (WT mice and Spred-2(-/- mice were exposed to intratracheal LPS (50 µg in 50 µL PBS to induce pulmonary inflammation. After LPS-injection, the lungs were harvested to assess leukocyte infiltration, cytokine and chemokine production, ERK-MAPK activation and immunopathology. For ex vivo experiments, alveolar macrophages were harvested from untreated WT and Spred-2(-/- mice and stimulated with LPS. In in vitro experiments, specific knock down of Spred-2 by siRNA or overexpression of Spred-2 by transfection with a plasmid encoding the Spred-2 sense sequence was introduced into murine RAW264.7 macrophage cells or MLE-12 lung epithelial cells. RESULTS: LPS-induced acute lung inflammation was significantly exacerbated in Spred-2(-/- mice compared with WT mice, as indicated by the numbers of infiltrating leukocytes, levels of alveolar TNF-α, CXCL2 and CCL2 in a later phase, and lung pathology. U0126, a selective MEK/ERK inhibitor, reduced the augmented LPS-induced inflammation in Spred-2(-/- mice. Specific knock down of Spred-2 augmented LPS-induced cytokine and chemokine responses in RAW264.7 cells and MLE-12 cells, whereas Spred-2 overexpression decreased this response in RAW264.7 cells. CONCLUSIONS: The ERK-MAPK pathway is involved in LPS-induced acute lung inflammation. Spred-2 controls

  9. Intratracheal IL-6 protects against lung inflammation in direct, but not indirect, causes of acute lung injury in mice.

    Directory of Open Access Journals (Sweden)

    Rhea Bhargava

    Full Text Available Serum and bronchoalveolar fluid IL-6 are increased in patients with acute respiratory distress syndrome (ARDS and predict prolonged mechanical ventilation and poor outcomes, although the role of intra-alveolar IL-6 in indirect lung injury is unknown. We investigated the role of endogenous and exogenous intra-alveolar IL-6 in AKI-mediated lung injury (indirect lung injury, intraperitoneal (IP endotoxin administration (indirect lung injury and, for comparison, intratracheal (IT endotoxin administration (direct lung injury with the hypothesis that IL-6 would exert a pro-inflammatory effect in these causes of acute lung inflammation.Bronchoalveolar cytokines (IL-6, CXCL1, TNF-α, IL-1β, and IL-10, BAL fluid neutrophils, lung inflammation (lung cytokines, MPO activity [a biochemical marker of neutrophil infiltration], and serum cytokines were determined in adult male C57Bl/6 mice with no intervention or 4 hours after ischemic AKI (22 minutes of renal pedicle clamping, IP endotoxin (10 µg, or IT endotoxin (80 µg with and without intratracheal (IT IL-6 (25 ng or 200 ng treatment.Lung inflammation was similar after AKI, IP endotoxin, and IT endotoxin. BAL fluid IL-6 was markedly increased after IT endotoxin, and not increased after AKI or IP endotoxin. Unexpectedly, IT IL-6 exerted an anti-inflammatory effect in healthy mice characterized by reduced BAL fluid cytokines. IT IL-6 also exerted an anti-inflammatory effect in IT endotoxin characterized by reduced BAL fluid cytokines and lung inflammation; IT IL-6 had no effect on lung inflammation in AKI or IP endotoxin.IL-6 exerts an anti-inflammatory effect in direct lung injury from IT endotoxin, yet has no role in the pathogenesis or treatment of indirect lung injury from AKI or IP endotoxin. Since intra-alveolar inflammation is important in the pathogenesis of direct, but not indirect, causes of lung inflammation, IT anti-inflammatory treatments may have a role in direct, but not indirect, causes of

  10. Endothelial Semaphorin 7A promotes inflammation in seawater aspiration-induced acute lung injury.

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    Zhang, Minlong; Wang, Li; Dong, Mingqing; Li, Zhichao; Jin, Faguang

    2014-10-28

    Inflammation is involved in the pathogenesis of seawater aspiration-induced acute lung injury (ALI). Although several studies have shown that Semaphorin 7A (SEMA7A) promotes inflammation, there are limited reports regarding immunological function of SEMA7A in seawater aspiration-induced ALI. Therefore, we investigated the role of SEMA7A during seawater aspiration-induced ALI. Male Sprague-Dawley rats were underwent seawater instillation. Then, lung samples were collected at an indicated time for analysis. In addition, rat pulmonary microvascular endothelial cells (RPMVECs) were cultured and then stimulated with 25% seawater for indicated time point. After these treatments, cells samples were collected for analysis. In vivo, seawater instillation induced lung histopathologic changes, pro-inflammation cytokines release and increased expression of SEMA7A. In vitro, seawater stimulation led to pro-inflammation cytokine release, cytoskeleton remodeling and increased monolayer permeability in pulmonary microvascular endothelial cells. In addition, knockdown of hypoxia-inducible factor (HIF)-1α inhibited the seawater induced increase expression of SEMA7A. Meanwhile, knockdown of SEMA7A by specific siRNA inhibited the seawater induced aberrant inflammation, endothelial cytoskeleton remodeling and endothelial permeability. These results suggest that SEMA7A is critical in the development of lung inflammation and pulmonary edema in seawater aspiration-induced ALI, and may be a therapeutic target for this disease.

  11. Inhibition of Pyk2 blocks lung inflammation and injury in a mouse model of acute lung injury

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    Duan Yingli

    2012-01-01

    Full Text Available Abstract Background Proline-rich tyrosine kinase 2 (Pyk2 is essential in neutrophil degranulation and chemotaxis in vitro. However, its effect on the process of lung inflammation and edema formation during LPS induced acute lung injury (ALI remains unknown. The goal of the present study was to determine the effect of inhibiting Pyk2 on LPS-induced acute lung inflammation and injury in vivo. Methods C57BL6 mice were given either 10 mg/kg LPS or saline intratracheally. Inhibition of Pyk2 was effected by intraperitoneal administration TAT-Pyk2-CT 1 h before challenge. Bronchoalveolar lavage analysis of cell counts, lung histology and protein concentration in BAL were analyzed at 18 h after LPS treatment. KC and MIP-2 concentrations in BAL were measured by a mouse cytokine multiplex kit. The static lung compliance was determined by pressure-volume curve using a computer-controlled small animal ventilator. The extravasated Evans blue concentration in lung homogenate was determined spectrophotometrically. Results Intratracheal instillation of LPS induced significant neutrophil infiltration into the lung interstitium and alveolar space, which was attenuated by pre-treatment with TAT-Pyk2-CT. TAT-Pyk2-CT pretreatment also attenuated 1 myeloperoxidase content in lung tissues, 2 vascular leakage as measured by Evans blue dye extravasation in the lungs and the increase in protein concentration in bronchoalveolar lavage, and 3 the decrease in lung compliance. In each paradigm, treatment with control protein TAT-GFP had no blocking effect. By contrast, production of neutrophil chemokines MIP-2 and keratinocyte-derived chemokine in the bronchoalveolar lavage was not reduced by TAT-Pyk2-CT. Western blot analysis confirmed that tyrosine phosphorylation of Pyk2 in LPS-challenged lungs was reduced to control levels by TAT-Pyk2-CT pretreatment. Conclusions These results suggest that Pyk2 plays an important role in the development of acute lung injury in mice and

  12. Hypertonic saline reduces inflammation and enhances the resolution of oleic acid induced acute lung injury

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    Costello Joseph F

    2008-07-01

    Full Text Available Abstract Background Hypertonic saline (HTS reduces the severity of lung injury in ischemia-reperfusion, endotoxin-induced and ventilation-induced lung injury. However, the potential for HTS to modulate the resolution of lung injury is not known. We investigated the potential for hypertonic saline to modulate the evolution and resolution of oleic acid induced lung injury. Methods Adult male Sprague Dawley rats were used in all experiments. Series 1 examined the potential for HTS to reduce the severity of evolving oleic acid (OA induced acute lung injury. Following intravenous OA administration, animals were randomized to receive isotonic (Control, n = 12 or hypertonic saline (HTS, n = 12, and the extent of lung injury assessed after 6 hours. Series 2 examined the potential for HTS to enhance the resolution of oleic acid (OA induced acute lung injury. Following intravenous OA administration, animals were randomized to receive isotonic (Control, n = 6 or hypertonic saline (HTS, n = 6, and the extent of lung injury assessed after 6 hours. Results In Series I, HTS significantly reduced bronchoalveolar lavage (BAL neutrophil count compared to Control [61.5 ± 9.08 versus 102.6 ± 11.89 × 103 cells.ml-1]. However, there were no between group differences with regard to: A-a O2 gradient [11.9 ± 0.5 vs. 12.0 ± 0.5 KPa]; arterial PO2; static lung compliance, or histologic injury. In contrast, in Series 2, hypertonic saline significantly reduced histologic injury and reduced BAL neutrophil count [24.5 ± 5.9 versus 46.8 ± 4.4 × 103 cells.ml-1], and interleukin-6 levels [681.9 ± 190.4 versus 1365.7 ± 246.8 pg.ml-1]. Conclusion These findings demonstrate, for the first time, the potential for HTS to reduce pulmonary inflammation and enhance the resolution of oleic acid induced lung injury.

  13. Myricetin attenuates lung inflammation and provides protection ...

    African Journals Online (AJOL)

    stress in lungs ... Table 1: Effect of myricetin on oxidative stress biomarkers in the lung; mean ± SEM (n = 20); # compared with .... known to release MPO during acute inflammation .... on acute hypoxia-induced exercise intolerance and.

  14. Role of Quzhou Fructus Aurantii Extract in Preventing and Treating Acute Lung Injury and Inflammation.

    Science.gov (United States)

    Li, Lili; Zhang, Sheng; Xin, Yanfei; Sun, Junying; Xie, Feng; Yang, Lin; Chen, Zhiqin; Chen, Hao; Liu, Fang; Xuan, Yaoxian; You, Zhenqiang

    2018-01-26

    Quzhou Fructus Aurantii (QFA) is an authentic herb of local varieties in Zhejiang, China, which is usually used to treat gastrointestinal illnesses, but its effects on respiratory inflammation have not been reported yet. In our study, the anti-inflammatory activity of QFA extract (QFAE) was evaluated on copper sulfate pentahydrate (CuSO 4 ·5H 2 O)-induced transgenic neutrophil fluorescent zebrafish model. QFAE showed a significant effect of anti-inflammation in CuSO 4 ·5H 2 O-induced zebrafish by reducing the neutrophil number in the inflammatory site. We investigated the anti-inflammatory activity of QFAE on lipopolysaccharide (LPS)-induced acute lung injury (ALI) mice models and RAW 264.7 cells. QFAE had an anti-inflammatory effect on reducing total cells, neutrophils, and macrophages in BALF and attenuated alveolus collapse, neutrophils infiltration, lung W/D ratio, myeloperoxidase (MPO) protein expression and other pulmonary histological changes in lung tissues, as well as hematological changes. Levels of pro-inflammatory cytokines, including TNF, IL-6, IFN-γ, MCP-1, and IL-12p70, were decreased, whereas anti-inflammatory cytokine IL-10 was increased after treatment with QFAE both in vivo and in vitro. In summary, our results suggested that QFAE had apparent anti-inflammatory effects on CuSO 4 ·5H 2 O-induced zebrafish, LPS-induced ALI mice, and RAW 264.7 cells. Furthermore, QFAE may be a therapeutic drug to treat ALI/ARDS and other respiratory inflammations.

  15. RGD-tagged helical rosette nanotubes aggravate acute lipopolysaccharide-induced lung inflammation

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    Suri SS

    2011-12-01

    Full Text Available Sarabjeet Singh Suri1, Steven Mills1, Gurpreet Kaur Aulakh1, Felaniaina Rakotondradany2, Hicham Fenniri2, Baljit Singh11Department of Veterinary Biomedical Sciences, University of Saskatchewan, Saskatoon; 2National Institute for Nanotechnology and Department of Chemistry, Edmonton, CanadaAbstract: Rosette nanotubes (RNT are a novel class of self-assembled biocompatible nanotubes that offer a built-in strategy for engineering structure and function through covalent tagging of synthetic self-assembling modules (G∧C motif. In this report, the G∧C motif was tagged with peptide Arg-Gly-Asp-Ser-Lys (RGDSK-G∧C and amino acid Lys (K-G∧C which, upon co-assembly, generate RNTs featuring RGDSK and K on their surface in predefined molar ratios. These hybrid RNTs, referred to as Kx/RGDSKy-RNT, where x and y refer to the molar ratios of K-G∧C and RGDSK–G∧C, were designed to target neutrophil integrins. A mouse model was used to investigate the effects of intravenous Kx/RGDSKy-RNT on acute lipopolysaccharide (LPS-induced lung inflammation. Healthy male C57BL/6 mice were treated intranasally with Escherichia coli LPS 80 µg and/or intravenously with K90/RGDSK10-RNT. Here we provide the first evidence that intravenous administration of K90/RGDSK10-RNT aggravates the proinflammatory effect of LPS in the mouse. LPS and K90/RGDSK10-RNT treatment groups showed significantly increased infiltration of polymorphonuclear cells in bronchoalveolar lavage fluid at all time points compared with the saline control. The combined effect of LPS and K90/RGDSK10-RNT was more pronounced than LPS alone, as shown by a significant increase in the expression of interleukin-1ß, MCP-1, MIP-1, and KC-1 in the bronchoalveolar lavage fluid and myeloperoxidase activity in the lung tissues. We conclude that K90/RGDSK10-RNT promotes acute lung inflammation, and when used along with LPS, leads to exaggerated immune response in the lung.Keywords: RGD peptide, helical rosette

  16. Angiotensin II type 2 receptor agonist Compound 21 attenuates pulmonary inflammation in a model of acute lung injury

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    Menk M

    2018-05-01

    Full Text Available Mario Menk, Jan Adriaan Graw, Clarissa von Haefen, Hendrik Steinkraus, Burkhard Lachmann, Claudia D Spies, David Schwaiberger Department of Anesthesiology and Operative Intensive Care Medicine, Charité – University Medicine Berlin, FreieUniversität Berlin, Humboldt-Universitätzu Berlin, and Berlin Institute of Health, Germany Purpose: Although the role of the angiotensin II type 2 (AT2 receptor in acute lung injury is not yet completely understood, a protective role of this receptor subtype has been suggested. We hypothesized that, in a rodent model of acute lung injury, stimulation of the AT2 receptor with the direct agonist Compound 21 (C21 might have a beneficial effect on pulmonary inflammation and might improve pulmonary gas exchange. Materials and methods: Male adult rats were divided into a treatment group that received pulmonary lavage followed by mechanical ventilation (LAV, n=9, a group receiving pulmonary lavage, mechanical ventilation, and direct stimulation of the AT2 receptor with C21 (LAV+C21, n=9, and a control group that received mechanical ventilation only (control, n=9. Arterial blood gas analysis was performed every 30 min throughout the 240-min observation period. Lung tissue and plasma samples were obtained at 240 min after the start of mechanical ventilation. Protein content and surface activity of bronchoalveolar lavage fluid were assessed and the wet/dry-weight ratio of lungs was determined. Transcriptional and translational regulation of pro- and antiinflammatory cytokines IL-1β, tumor necrosis factor-alpha, IL-6, IL-10, and IL-4 was determined in lungs and in plasma. Results: Pulmonary lavage led to a significant impairment of gas exchange, the formation of lung edema, and the induction of pulmonary inflammation. Protein content of lavage fluid was increased and contained washed-out surfactant. Direct AT2 receptor stimulation with C21 led to a significant inhibition of tumor necrosis factor-alpha and IL-6

  17. Attenuation of acute nitrogen mustard-induced lung injury, inflammation and fibrogenesis by a nitric oxide synthase inhibitor

    Energy Technology Data Exchange (ETDEWEB)

    Malaviya, Rama; Venosa, Alessandro [Department of Pharmacology and Toxicology, Ernest Mario School of Pharmacy, Rutgers University, Piscataway, NJ 08854 (United States); Hall, LeRoy [Drug Safety Sciences, Johnson and Johnson, Raritan, NJ 08869 (United States); Gow, Andrew J. [Department of Pharmacology and Toxicology, Ernest Mario School of Pharmacy, Rutgers University, Piscataway, NJ 08854 (United States); Sinko, Patrick J. [Department of Pharmaceutics, Ernest Mario School of Pharmacy, Rutgers University, Piscataway, NJ 08854 (United States); Laskin, Jeffrey D. [Department of Environmental and Occupational Medicine, UMDNJ-Robert Wood Johnson Medical School, Piscataway, NJ 08854 (United States); Laskin, Debra L., E-mail: laskin@eohsi.rutgers.edu [Department of Pharmacology and Toxicology, Ernest Mario School of Pharmacy, Rutgers University, Piscataway, NJ 08854 (United States)

    2012-12-15

    Nitrogen mustard (NM) is a toxic vesicant known to cause damage to the respiratory tract. Injury is associated with increased expression of inducible nitric oxide synthase (iNOS). In these studies we analyzed the effects of transient inhibition of iNOS using aminoguanidine (AG) on NM-induced pulmonary toxicity. Rats were treated intratracheally with 0.125 mg/kg NM or control. Bronchoalveolar lavage fluid (BAL) and lung tissue were collected 1 d–28 d later and lung injury, oxidative stress and fibrosis assessed. NM exposure resulted in progressive histopathological changes in the lung including multifocal lesions, perivascular and peribronchial edema, inflammatory cell accumulation, alveolar fibrin deposition, bronchiolization of alveolar septal walls, and fibrosis. This was correlated with trichrome staining and expression of proliferating cell nuclear antigen (PCNA). Expression of heme oxygenase (HO)-1 and manganese superoxide dismutase (Mn-SOD) was also increased in the lung following NM exposure, along with levels of protein and inflammatory cells in BAL, consistent with oxidative stress and alveolar-epithelial injury. Both classically activated proinflammatory (iNOS{sup +} and cyclooxygenase-2{sup +}) and alternatively activated profibrotic (YM-1{sup +} and galectin-3{sup +}) macrophages appeared in the lung following NM administration; this was evident within 1 d, and persisted for 28 d. AG administration (50 mg/kg, 2 ×/day, 1 d–3 d) abrogated NM-induced injury, oxidative stress and inflammation at 1 d and 3 d post exposure, with no effects at 7 d or 28 d. These findings indicate that nitric oxide generated via iNOS contributes to acute NM-induced lung toxicity, however, transient inhibition of iNOS is not sufficient to protect against pulmonary fibrosis. -- Highlights: ► Nitrogen mustard (NM) induces acute lung injury and fibrosis. ► Pulmonary toxicity is associated with increased expression of iNOS. ► Transient inhibition of iNOS attenuates acute

  18. Does Regional Lung Strain Correlate With Regional Inflammation in Acute Respiratory Distress Syndrome During Nonprotective Ventilation? An Experimental Porcine Study.

    Science.gov (United States)

    Retamal, Jaime; Hurtado, Daniel; Villarroel, Nicolás; Bruhn, Alejandro; Bugedo, Guillermo; Amato, Marcelo Britto Passos; Costa, Eduardo Leite Vieira; Hedenstierna, Göran; Larsson, Anders; Borges, João Batista

    2018-06-01

    It is known that ventilator-induced lung injury causes increased pulmonary inflammation. It has been suggested that one of the underlying mechanisms may be strain. The aim of this study was to investigate whether lung regional strain correlates with regional inflammation in a porcine model of acute respiratory distress syndrome. Retrospective analysis of CT images and positron emission tomography images using [F]fluoro-2-deoxy-D-glucose. University animal research laboratory. Seven piglets subjected to experimental acute respiratory distress syndrome and five ventilated controls. Acute respiratory distress syndrome was induced by repeated lung lavages, followed by 210 minutes of injurious mechanical ventilation using low positive end-expiratory pressures (mean, 4 cm H2O) and high inspiratory pressures (mean plateau pressure, 45 cm H2O). All animals were subsequently studied with CT scans acquired at end-expiration and end-inspiration, to obtain maps of volumetric strain (inspiratory volume - expiratory volume)/expiratory volume, and dynamic positron emission tomography imaging. Strain maps and positron emission tomography images were divided into 10 isogravitational horizontal regions-of-interest, from which spatial correlation was calculated for each animal. The acute respiratory distress syndrome model resulted in a decrease in respiratory system compliance (20.3 ± 3.4 to 14.0 ± 4.9 mL/cm H2O; p < 0.05) and oxygenation (PaO2/FIO2, 489 ± 80 to 92 ± 59; p < 0.05), whereas the control animals did not exhibit changes. In the acute respiratory distress syndrome group, strain maps showed a heterogeneous distribution with a greater concentration in the intermediate gravitational regions, which was similar to the distribution of [F]fluoro-2-deoxy-D-glucose uptake observed in the positron emission tomography images, resulting in a positive spatial correlation between both variables (median R = 0.71 [0.02-0.84]; p < 0.05 in five of seven animals

  19. Mast cell stabilization alleviates acute lung injury after orthotopic autologous liver transplantation in rats by downregulating inflammation.

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    Ailan Zhang

    Full Text Available BACKGROUND: Acute lung injury (ALI is one of the most severe complications after orthotopic liver transplantation. Amplified inflammatory response after transplantation contributes to the process of ALI, but the mechanism underlying inflammation activation is not completely understood. We have demonstrated that mast cell stabilization attenuated inflammation and ALI in a rodent intestine ischemia/reperfusion model. We hypothesized that upregulation of inflammation triggered by mast cell activation may be involve in ALI after liver transplantation. METHODS: Adult male Sprague-Dawley rats received orthotopic autologous liver transplantation (OALT and were executed 4, 8, 16, and 24 h after OALT. The rats were pretreated with the mast cell stabilizers cromolyn sodium or ketotifen 15 min before OALT and executed 8 h after OALT. Lung tissues and arterial blood were collected to evaluate lung injury. β-hexosaminidase and mast cell tryptase levels were assessed to determine the activation of mast cells. Tumor necrosis factor α (TNF-α, interleukin (IL-1β and IL-6 in serum and lung tissue were analyzed by enzyme-linked immunosorbent assay. Nuclear factor-kappa B (NF-κB p65 translocation was assessed by Western blot. RESULTS: The rats that underwent OALT exhibited severe pulmonary damage with a high wet-to-dry ratio, low partial pressure of oxygen, and low precursor surfactant protein C levels, which corresponded to the significant elevation of pro-inflammatory cytokines, β-hexosaminidase, and tryptase levels in serum and lung tissues. The severity of ALI progressed and maximized 8 h after OALT. Mast cell stabilization significantly inhibited the activation of mast cells, downregulated pro-inflammatory cytokine levels and translocation of NF-κB, and attenuated OALT-induced ALI. CONCLUSIONS: Mast cell activation amplified inflammation and played an important role in the process of post-OALT related ALI.

  20. Human umbilical cord mesenchymal stem cells reduce systemic inflammation and attenuate LPS-induced acute lung injury in rats

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    Li Jianjun

    2012-09-01

    Full Text Available Abstract Background Mesenchymal stem cells (MSCs possess potent immunomodulatory properties and simultaneously lack the ability to illicit immune responses. Hence, MSCs have emerged as a promising candidate for cellular therapeutics for inflammatory diseases. Within the context of this study, we investigated whether human umbilical cord-derived mesenchymal stem cells (UC-MSCs could ameliorate lipopolysaccharide- (LPS- induced acute lung injury (ALI in a rat model. Methods ALI was induced via injection of LPS. Rats were divided into three groups: (1 saline group(control, (2 LPS group, and (3 MSC + LPS group. The rats were sacrificed at 6, 24, and 48 hours after injection. Serum, bronchoalveolar lavage fluid (BALF, and lungs were collected for cytokine concentration measurements, assessment of lung injury, and histology. Results UC-MSCs increased survival rate and suppressed LPS-induced increase of serum concentrations of pro-inflammatory mediators TNF-α, IL-1β, and IL-6 without decreasing the level of anti-inflammatory cytokine IL-10. The MSC + LPS group exhibited significant improvements in lung inflammation, injury, edema, lung wet/dry ratio, protein concentration, and neutrophil counts in the BALF, as well as improved myeloperoxidase (MPO activity in the lung tissue. Furthermore, UC-MSCs decreased malondialdehyde (MDA production and increased Heme Oxygenase-1 (HO-1 protein production and activity in the lung tissue. Conclusion UC-MSCs noticeably increased the survival rate of rats suffering from LPS-induced lung injury and significantly reduced systemic and pulmonary inflammation. Promoting anti-inflammatory homeostasis and reducing oxidative stress might be the therapeutic basis of UC-MSCs.

  1. H2S Attenuates LPS-Induced Acute Lung Injury by Reducing Oxidative/Nitrative Stress and Inflammation

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    Hong-Xia Zhang

    2016-12-01

    Full Text Available Background: Hydrogen sulfide (H2S, known as the third endogenous gaseous transmitter, has received increasing attention because of its diverse effects, including angiogenesis, vascular relaxation and myocardial protection.We aimed to investigate the role of H2S in oxidative/nitrative stress and inflammation in acute lung injury (ALI induced by endotoxemia. Methods: Male ICR mice were divided in six groups: (1 Control group; (2 GYY4137treatment group; (3 L-NAME treatment group; (4 lipopolysaccharide (LPS treatment group; (5 LPS with GYY4137 treatment group; and (6 LPS with L-NAME treatment group. The lungs were analysed by histology, NO production in the mouse lungs determined by modified Griess (Sigma-Aldrich reaction, cytokine levels utilizing commercialkits, and protein abundance by Western blotting. Results: GYY4137, a slowly-releasing H2S donor, improved the histopathological changes in the lungs of endotoxemic mice. Treatment with NG-nitro-L-arginine methyl ester (L-NAME, a nitric oxide synthase (NOS inhibitor, increased anti-oxidant biomarkers such as thetotal antioxidant capacity (T-AOC and theactivities of catalase (CAT and superoxide dismutase (SOD but decreased a marker of peroxynitrite (ONOO- action and 3-nitrotyrosine (3-NT in endotoxemic lung. L-NAME administration also suppressed inflammation in endotoxemic lung, as evidenced by the decreased pulmonary levels of interleukin (IL-6, IL-8, and myeloperoxidase (MPO and the increased level of anti-inflammatory cytokine IL-10. GYY4137 treatment reversed endotoxin-induced oxidative/nitrative stress, as evidenced by a decrease in malondialdehyde (MDA, hydrogenperoxide (H2O2 and 3-NT and an increase in the antioxidant biomarker ratio of reduced/oxidized glutathione(GSH/GSSG ratio and T-AOC, CAT and SOD activity. GYY4137 also attenuated endotoxin-induced lung inflammation. Moreover, treatment with GYY4137 inhibited inducible NOS (iNOS expression and nitric oxide (NO production in the

  2. Endogenous PGI2 signaling through IP inhibits neutrophilic lung inflammation in LPS-induced acute lung injury mice model.

    Science.gov (United States)

    Toki, Shinji; Zhou, Weisong; Goleniewska, Kasia; Reiss, Sara; Dulek, Daniel E; Newcomb, Dawn C; Lawson, William E; Peebles, R Stokes

    2018-04-13

    Endogenous prostaglandin I 2 (PGI 2 ) has inhibitory effects on immune responses against pathogens or allergens; however, the immunomodulatory activity of endogenous PGI 2 signaling in endotoxin-induced inflammation is unknown. To test the hypothesis that endogenous PGI 2 down-regulates endotoxin-induced lung inflammation, C57BL/6 wild type (WT) and PGI 2 receptor (IP) KO mice were challenged intranasally with LPS. Urine 6-keto-PGF 1α , a stable metabolite of PGI 2, was significantly increased following the LPS-challenge, suggesting that endogenous PGI 2 signaling modulates the host response to LPS-challenge. IPKO mice had a significant increase in neutrophils in the BAL fluid as well as increased proteins of KC, LIX, and TNF-α in lung homogenates compared with WT mice. In contrast, IL-10 was decreased in LPS-challenged IPKO mice compared with WT mice. The PGI 2 analog cicaprost significantly decreased LPS-induced KC, and TNF-α, but increased IL-10 and AREG in bone marrow-derived dendritic cells (BMDCs) and bone marrow-derived macrophages (BMMs) compared with vehicle-treatment. These results indicated that endogenous PGI 2 signaling attenuated neutrophilic lung inflammation through the reduced inflammatory cytokine and chemokine and enhanced IL-10. Copyright © 2018. Published by Elsevier Inc.

  3. LPS-induced lung inflammation in marmoset monkeys - an acute model for anti-inflammatory drug testing.

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    Sophie Seehase

    Full Text Available Increasing incidence and substantial morbidity and mortality of respiratory diseases requires the development of new human-specific anti-inflammatory and disease-modifying therapeutics. Therefore, new predictive animal models that closely reflect human lung pathology are needed. In the current study, a tiered acute lipopolysaccharide (LPS-induced inflammation model was established in marmoset monkeys (Callithrix jacchus to reflect crucial features of inflammatory lung diseases. Firstly, in an ex vivo approach marmoset and, for the purposes of comparison, human precision-cut lung slices (PCLS were stimulated with LPS in the presence or absence of the phosphodiesterase-4 (PDE4 inhibitor roflumilast. Pro-inflammatory cytokines including tumor necrosis factor-alpha (TNF-α and macrophage inflammatory protein-1 beta (MIP-1β were measured. The corticosteroid dexamethasone was used as treatment control. Secondly, in an in vivo approach marmosets were pre-treated with roflumilast or dexamethasone and unilaterally challenged with LPS. Ipsilateral bronchoalveolar lavage (BAL was conducted 18 hours after LPS challenge. BAL fluid was processed and analyzed for neutrophils, TNF-α, and MIP-1β. TNF-α release in marmoset PCLS correlated significantly with human PCLS. Roflumilast treatment significantly reduced TNF-α secretion ex vivo in both species, with comparable half maximal inhibitory concentration (IC(50. LPS instillation into marmoset lungs caused a profound inflammation as shown by neutrophilic influx and increased TNF-α and MIP-1β levels in BAL fluid. This inflammatory response was significantly suppressed by roflumilast and dexamethasone. The close similarity of marmoset and human lungs regarding LPS-induced inflammation and the significant anti-inflammatory effect of approved pharmaceuticals assess the suitability of marmoset monkeys to serve as a promising model for studying anti-inflammatory drugs.

  4. LFG-500, a newly synthesized flavonoid, attenuates lipopolysaccharide-induced acute lung injury and inflammation in mice.

    Science.gov (United States)

    Li, Chenglin; Yang, Dan; Cao, Xin; Wang, Fan; Jiang, Haijing; Guo, Hao; Du, Lei; Guo, Qinglong; Yin, Xiaoxing

    2016-08-01

    Acute lung injury (ALI) often causes significant morbidity and mortality worldwide. Improved treatment and effective strategies are still required for ALI patients. Our previous studies demonstrated that LFG-500, a novel synthesized flavonoid, has potent anti-cancer activities, while its anti-inflammatory effect has not been revealed. In the present study, the in vivo protective effect of LFG-500 on the amelioration of lipopolysaccharide (LPS)-induced ALI and inflammation was detected. LFG-500 attenuated LPS-induced histological alterations, suppressed the infiltration of inflammatory cells in lung tissues and bronchoalveolar lavage fluid, as well as inhibited the secretion of several inflammatory cytokines, such as tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and IL-6 in lung tissues after LPS challenge. In addition, the in vitro effects and mechanisms were studied in LPS stimulated RAW 264.7 cells and THP-1 cells. LFG-500 significantly decreased the secretion and expression of TNF-α, IL-1β, and IL-6 through inhibiting the transcriptional activation of NF-κB. Moreover, overexpression of NF-κB p65 reversed the inhibitory effect of LFG-500 on LPS-induced NF-κB activation and inflammatory cytokine secretion. Further elucidation of the mechanism revealed that p38 and JNK MAPK pathways were involved in the anti-inflammation effect of LFG-500, through which LFG-500 inhibited the classical IKK-dependent pathway and led to inactivation of NF-κB. More importantly, LFG-500 suppressed the expression and nuclear localization of NF-κB in LPS-induced ALI mice. Taken together, these results demonstrated that LFG-500 could attenuate LPS-induced ALI and inflammation by suppressing NF-κB activation, which provides new evidence for the anti-inflammation activity of LFG-500. Copyright © 2016 Elsevier Inc. All rights reserved.

  5. Lung function and airway inflammation in rats following exposure to combustion products of carbon-graphite/epoxy composite material: comparison to a rodent model of acute lung injury.

    Science.gov (United States)

    Whitehead, Gregory S; Grasman, Keith A; Kimmel, Edgar C

    2003-02-01

    Pulmonary function and inflammation in the lungs of rodents exposed by inhalation to carbon/graphite/epoxy advanced composite material (ACM) combustion products were compared to that of a rodent model of acute lung injury (ALI) produced by pneumotoxic paraquat dichloride. This investigation was undertaken to determine if short-term exposure to ACM smoke induces ALI; and to determine if smoke-related responses were similar to the pathogenic mechanisms of a model of lung vascular injury. We examined the time-course for mechanical lung function, infiltration of inflammatory cells into the lung, and the expression of three inflammatory cytokines, tumor necrosis factor-alpha (TNF-alpha), macrophage inflammatory protein-2 (MIP-2) and interferon-gamma (IFN-gamma). Male Fischer-344 rats were either exposed to 26.8-29.8 g/m(3) nominal concentrations of smoke or were given i.p. injections of paraquat dichloride. Measurements were determined at 1, 2, 3, and 7 days post exposure. In the smoke-challenged rats, there were no changes in lung function indicative of ALI throughout the 7-day observation period, despite the acute lethality of the smoke atmosphere. However, the animals showed signs of pulmonary inflammation. The expression of TNF-alpha was significantly increased in the lavage fluid 1 day following exposure, which preceded the maximum leukocyte infiltration. MIP-2 levels were significantly increased in lavage fluid at days 2, 3, and 7. This followed the leukocyte infiltration. IFN-gamma was significantly increased in the lung tissue at day 7, which occurred during the resolution of the inflammatory response. The paraquat, which was also lethal to a small percentage of the animals, caused several physiologic changes characteristic of ALI, including significant decreases in lung compliance, lung volumes/capacities, distribution of ventilation, and gas exchange capacity. The expression of TNF-alpha and MIP-2 increased significantly in the lung tissue as well as in the

  6. Proteomic Analysis of Lung Tissue in a Rat Acute Lung Injury Model: Identification of PRDX1 as a Promoter of Inflammation

    Directory of Open Access Journals (Sweden)

    Dongdong Liu

    2014-01-01

    Full Text Available Acute respiratory distress syndrome (ARDS remains a high morbidity and mortality disease entity in critically ill patients, despite decades of numerous investigations into its pathogenesis. To obtain global protein expression changes in acute lung injury (ALI lung tissues, we employed a high-throughput proteomics method to identify key components which may be involved in the pathogenesis of ALI. In the present study, we analyzed lung tissue proteomes of Pseudomonas aeruginosa-induced ALI rats and identified eighteen proteins whose expression levels changed more than twofold as compared to normal controls. In particular, we found that PRDX1 expression in culture medium was elevated by a lipopolysaccharide (LPS challenge in airway epithelial cells in vitro. Furthermore, overexpression of PRDX1 increased the expression of proinflammatory cytokines interleukin-6 (IL-6, interleukin-8 (IL-8, and tumor necrosis factor-α (TNF-α, whereas knockdown of PRDX1 led to downregulated expression of cytokines induced by LPS. In conclusion, our findings provide a global alteration in the proteome of lung tissues in the ALI rat model and indicate that PRDX1 may play a critical role in the pathogenesis of ARDS by promoting inflammation and represent a novel strategy for the development of new therapies against ALI.

  7. Lung Neutrophilia in Myeloperoxidase Deficient Mice during the Course of Acute Pulmonary Inflammation

    Czech Academy of Sciences Publication Activity Database

    Kremserová, Silvie; Perečko, Tomáš; Souček, Karel; Klinke, A.; Baldus, S.; Eiserich, J.P.; Kubala, Lukáš

    2016-01-01

    Roč. 2016, Č. 2016 (2016), č. článku 5219056. ISSN 1942-0900 R&D Projects: GA ČR GCP305/12/J038 Institutional support: RVO:68081707 Keywords : nitrotyrosine formation * airway inflammation * mouse neutrophils * apoptosis Subject RIV: BO - Biophysics Impact factor: 4.593, year: 2016

  8. Extracellular histones are essential effectors of C5aR- and C5L2-mediated tissue damage and inflammation in acute lung injury.

    Science.gov (United States)

    Bosmann, Markus; Grailer, Jamison J; Ruemmler, Robert; Russkamp, Norman F; Zetoune, Firas S; Sarma, J Vidya; Standiford, Theodore J; Ward, Peter A

    2013-12-01

    We investigated how complement activation promotes tissue injury and organ dysfunction during acute inflammation. Three models of acute lung injury (ALI) induced by LPS, IgG immune complexes, or C5a were used in C57BL/6 mice, all models requiring availability of both C5a receptors (C5aR and C5L2) for full development of ALI. Ligation of C5aR and C5L2 with C5a triggered the appearance of histones (H3 and H4) in bronchoalveolar lavage fluid (BALF). BALF from humans with ALI contained H4 histone. Histones were absent in control BALF from healthy volunteers. In mice with ALI, in vivo neutralization of H4 with IgG antibody reduced the intensity of ALI. Neutrophil depletion in mice with ALI markedly reduced H4 presence in BALF and was highly protective. The direct lung damaging effects of extracellular histones were demonstrated by airway administration of histones into mice and rats (Sprague-Dawley), which resulted in ALI that was C5a receptor-independent, and associated with intense inflammation, PMN accumulation, damage/destruction of alveolar epithelial cells, together with release into lung of cytokines/chemokines. High-resolution magnetic resonance imaging demonstrated lung damage, edema and consolidation in histone-injured lungs. These studies confirm the destructive C5a-dependent effects in lung linked to appearance of extracellular histones.

  9. Regulatory T Cells Contribute to the Inhibition of Radiation-Induced Acute Lung Inflammation via Bee Venom Phospholipase A₂ in Mice.

    Science.gov (United States)

    Shin, Dasom; Lee, Gihyun; Sohn, Sung-Hwa; Park, Soojin; Jung, Kyung-Hwa; Lee, Ji Min; Yang, Jieun; Cho, Jaeho; Bae, Hyunsu

    2016-04-30

    Bee venom has long been used to treat various inflammatory diseases, such as rheumatoid arthritis and multiple sclerosis. Previously, we reported that bee venom phospholipase A₂ (bvPLA₂) has an anti-inflammatory effect through the induction of regulatory T cells. Radiotherapy is a common anti-cancer method, but often causes adverse effects, such as inflammation. This study was conducted to evaluate the protective effects of bvPLA₂ in radiation-induced acute lung inflammation. Mice were focally irradiated with 75 Gy of X-rays in the lung and administered bvPLA₂ six times after radiation. To evaluate the level of inflammation, the number of immune cells, mRNA level of inflammatory cytokine, and histological changes in the lung were measured. BvPLA₂ treatment reduced the accumulation of immune cells, such as macrophages, neutrophils, lymphocytes, and eosinophils. In addition, bvPLA₂ treatment decreased inflammasome-, chemokine-, cytokine- and fibrosis-related genes' mRNA expression. The histological results also demonstrated the attenuating effect of bvPLA₂ on radiation-induced lung inflammation. Furthermore, regulatory T cell depletion abolished the therapeutic effects of bvPLA₂ in radiation-induced pneumonitis, implicating the anti-inflammatory effects of bvPLA₂ are dependent upon regulatory T cells. These results support the therapeutic potential of bvPLA₂ in radiation pneumonitis and fibrosis treatments.

  10. Acute respiratory changes and pulmonary inflammation involving a pathway of TGF-β1 induction in a rat model of chlorine-induced lung injury

    Energy Technology Data Exchange (ETDEWEB)

    Wigenstam, Elisabeth; Elfsmark, Linda; Koch, Bo [Swedish Defence Research Agency, CBRN Defence and Security, Umeå (Sweden); Bucht, Anders [Swedish Defence Research Agency, CBRN Defence and Security, Umeå (Sweden); Department of Public Health and Clinical Medicine, Unit of Respiratory Medicine, Umeå University, Umeå (Sweden); Jonasson, Sofia, E-mail: sofia.jonasson@foi.se [Swedish Defence Research Agency, CBRN Defence and Security, Umeå (Sweden)

    2016-10-15

    We investigated acute and delayed respiratory changes after inhalation exposure to chlorine (Cl{sub 2}) with the aim to understand the pathogenesis of the long-term sequelae of Cl{sub 2}-induced lung-injury. In a rat model of nose-only exposure we analyzed changes in airway hyperresponsiveness (AHR), inflammatory responses in airways, expression of pro-inflammatory markers and development of lung fibrosis during a time-course from 5 h up to 90 days after a single inhalation of Cl{sub 2}. A single dose of dexamethasone (10 mg/kg) was administered 1 h following Cl{sub 2}-exposure. A 15-min inhalation of 200 ppm Cl{sub 2} was non-lethal in Sprague-Dawley rats. At 24 h post exposure, Cl{sub 2}-exposed rats displayed elevated numbers of leukocytes with an increase of neutrophils and eosinophils in bronchoalveolar lavage (BAL) and edema was shown both in lung tissue and the heart. At 24 h, the inflammasome-associated cytokines IL-1β and IL-18 were detected in BAL. Concomitant with the acute inflammation a significant AHR was detected. At the later time-points, a delayed inflammatory response was observed together with signs of lung fibrosis as indicated by increased pulmonary macrophages, elevated TGF-β expression in BAL and collagen deposition around airways. Dexamethasone reduced the numbers of neutrophils in BAL at 24 h but did not influence the AHR. Inhalation of Cl{sub 2} in rats leads to acute respiratory and cardiac changes as well as pulmonary inflammation involving induction of TGF-β1. The acute inflammatory response was followed by sustained macrophage response and lack of tissue repair. It was also found that pathways apart from the acute inflammatory response contribute to the Cl{sub 2}-induced respiratory dysfunction. - Highlights: • Inhalation of Cl{sub 2} leads to acute lung inflammation and airway hyperreactivity. • Cl{sub 2} activates an inflammasome pathway of TGF-β induction. • Cl{sub 2} leads to a fibrotic respiratory disease. • Treatment

  11. Effects of acteoside on lipopolysaccharide-induced inflammation in acute lung injury via regulation of NF-κB pathway in vivo and in vitro

    Energy Technology Data Exchange (ETDEWEB)

    Jing, Wang; Chunhua, Ma, E-mail: machunhuabest@126.com; Shumin, Wang, E-mail: wangshuminch@126.com

    2015-06-01

    The purpose of the present study was to investigate the protective role of acteoside (AC) on lipopolysaccharide (LPS)-induced acute lung injury (ALI). BalB/c mice intraperitoneally received AC (30, and 60 mg/kg) or dexamethasone (2 mg/kg) 2 h prior to or after intratracheal instillation of LPS. Treatment with AC significantly decreased lung wet-to-dry weight (W/D) ratio and lung myeloperoxidase (MPO) activity and ameliorated LPS-induced lung histopathological changes. In addition, AC increased super oxide dismutase (SOD) level and inhibited malondialdehyde (MDA) content, total cell and neutrophil infiltrations, and levels of proinflammatory cytokines including tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β) and interleukin-6 (IL-6) in bronchoalveolar lavage fluid (BALF) in LPS-stimulated mice. Furthermore, we demonstrated that AC inhibited the phosphorylation of IκBα, nuclear factor-κB (NF-κB) p65, inhibitor of nuclear factor kappa-B kinase-α (IKK-α) and inhibitor of nuclear factor kappa-B kinase-β (IKKβ) in LPS-induced inflammation in A549 cells. Our data suggested that LPS evoked the inflammatory response in lung epithelial cells A549. The experimental results indicated that the protective mechanism of AC might be attributed partly to the inhibition of proinflammatory cytokine production and NF-κB activation. - Highlights: • Acteoside inhibited inflammation in LPS-induced lung injury in mice. • Acteoside inhibited inflammation in lung epithelial cells A549. • Acteoside inhibited NF-kB activation in LPS-induced mice and lung epithelial cells A549.

  12. Blockage of glycolysis by targeting PFKFB3 alleviates sepsis-related acute lung injury via suppressing inflammation and apoptosis of alveolar epithelial cells.

    Science.gov (United States)

    Gong, Yuanqi; Lan, Haibing; Yu, Zhihong; Wang, Meng; Wang, Shu; Chen, Yu; Rao, Haiwei; Li, Jingying; Sheng, Zhiyong; Shao, Jianghua

    2017-09-16

    Sepsis-related acute lung injury (ALI) is characterized by excessive lung inflammation and apoptosis of alveolar epithelial cells resulting in acute hypoxemic respiratory failure. Recent studies indicated that anaerobic glycolysis play an important role in sepsis. However, whether inhibition of aerobic glycolysis exhibits beneficial effect on sepsis-induced ALI is not known. In vivo, a cecal ligation and puncture (CLP)-induced ALI mouse model was set up and mice treated with glycolytic inhibitor 3PO after CLP. The mice treated with the 3PO ameliorated the survival rate, histopathological changes, lung inflammation, lactate increased and lung apoptosis of mice with CLP-induced sepsis. In vitro, the exposure of human alveolar epithelial A549 cells to lipopolysaccharide (LPS) resulted in cell apoptosis, inflammatory cytokine production, enhanced glycolytic flux and reactive oxygen species (ROS) increased. While these changes were attenuated by 3PO treatment. Sequentially, treatment of A549 cells with lactate caused cell apoptosis and enhancement of ROS. Pretreatment with N-acetylcysteine (NAC) significantly lowered LPS and lactate-induced the generation of ROS and cell apoptosis in A549 cells. Therefore, these results indicate that anaerobic glycolysis may be an important contributor in cell apoptosis of sepsis-related ALI. Moreover, LPS specifically induces apoptotic insults to A549 cell through lactate-mediated enhancement of ROS. Copyright © 2017 Elsevier Inc. All rights reserved.

  13. Anti-inflammatory effects of eugenol on lipopolysaccharide-induced inflammatory reaction in acute lung injury via regulating inflammation and redox status.

    Science.gov (United States)

    Huang, Xianfeng; Liu, Yuanyuan; Lu, Yingxun; Ma, Chunhua

    2015-05-01

    Acute lung injury (ALI) represents a clinical syndrome that results from complex responses of the lung to a multitude of direct and indirect insults. This study aims to evaluate the possible mechanisms responsible for the anti-inflammatory effects of eugenol (EUL) on lipopolysaccharide (LPS)-induced inflammatory reaction in ALI. ALI was induced in mice by intratracheal instillation of LPS (0.5 mg/kg), and EUL (5, and 10 mg/kg) was injected intraperitoneally 1h prior to LPS administration. After 6h, bronchoalveolar lavage fluid (BALF) and lung tissue were collected. The findings suggest that the protective mechanism of EUL may be attributed partly to decreased production of proinflammatory cytokines through the regulating inflammation and redox status. The results support that use of EUL is beneficial in the treatment of ALI. Copyright © 2015 Elsevier B.V. All rights reserved.

  14. Preventative effect of OMZ-SPT on lipopolysaccharide-induced acute lung injury and inflammation via nuclear factor-kappa B signaling in mice

    International Nuclear Information System (INIS)

    Wang, Ting; Hou, Wanru; Fu, Zhou

    2017-01-01

    Acute lung injury (ALI) is an early pathophysiologic change in acute respiratory distress syndrome and its management can be challenging. Omalizumab (Xolair™) is a recombinant DNA-derived, humanized antibody. OMZ-SPT is a polypeptide on the heavy chain of omalizumab monoclonal antibody. Here, we found that intramuscular administration of OMZ-SPT significantly improved survival and attenuated lung inflammation in female C57BL/6 mice suffering from lipopolysaccharide (LPS)-induced ALI. We also demonstrated that OMZ-SPT can inhibit expression of the inflammatory cytokines tumor necrosis factor-α, interleukin-1β and interleukin-6 by ELISA in mice suffering from LPS-induced ALI and a mouse macrophage line (RAW264.7 cells). In addition, we showed that OMZ-SPT inhibited LPS-induced activation of nuclear factor-kappa B (NF-κB) signaling and total expression of NF-κB by western blotting. These data suggest that OMZ-SPT could be a novel therapeutic choice for ALI. - Highlights: • OMZ-SPT is a polypeptide on the heavy chain of omalizumab monoclonal antibody. • Omalizumab (Xolair™) have anti-inflammatory effects. • OMZ-SPT can inhibit inflammatory responses and lung injury in LPS-induced ALI mice. • Protective effect of OMZ-SPT on ALI is due to inhibition of NF-κB signaling. • OMZ-SPT could be a novel therapeutic choice for ALI.

  15. Qi-Dong-Huo-Xue-Yin Inhibits Inflammation in Acute Lung Injury in Mice via Toll-Like Receptor 4/Caveolin-1 Signaling

    Directory of Open Access Journals (Sweden)

    Li-Ying Xu

    2018-01-01

    Full Text Available Acute lung injury (ALI is a critical illness with no current effective treatment. Caveolin-1 indirectly activates inflammation-associated signaling pathways by inhibiting endothelial nitric oxide synthase (eNOS. This induces an imbalance between pro- and anti-inflammatory cytokine levels, which are involved in the pathogenesis of ALI. The compound Chinese prescription Qi-Dong-Huo-Xue-Yin (QDHXY is efficacious for ALI treatment via an anti-inflammatory effect; however, the exact underlying mechanism is unknown. Therefore, we explored the protective effect of QDHXY against lipopolysaccharide- (LPS- induced ALI in mice. Histopathological changes in mouse lung tissues were studied. Furthermore, alterations in the serum levels of pro- and anti-inflammatory cytokines were investigated. The levels of tumor necrosis factor- (TNF-α, interleukin- (IL- 6, IL-1β, and interferon-γ-induced protein 10 in bronchoalveolar lavage fluid were measured. Additionally, the expression levels of myeloid differentiation factor 88 (MyD88, caveolin-1, and eNOS were assessed. QDHXY significantly reduced lung infiltration with inflammatory cells and the production of serum pro- and anti-inflammatory cytokines and inhibited the expression of TNF-α, IL-1β, caveolin-1, and MyD88 but not eNOS. These indicate that QDHXY significantly improved the balance between pro- and anti-inflammatory cytokine levels, possibly by inhibiting the caveolin-1 signaling pathway. Therefore, QDHXY may be a potential treatment for ALI.

  16. Pediatric acute lung injury

    NARCIS (Netherlands)

    Dahlem, P.; van Aalderen, W. M. C.; Bos, A. P.

    2007-01-01

    Among ventilated children, the incidence of acute lung injury (ALI) was 9%; of that latter group 80% developed the acute respiratory distress syndrome (ARDS). The population-based prevalence of pediatric ARDS was 5.5 cases/100.000 inhabitants. Underlying diseases in children were septic shock (34%),

  17. Extravascular Lung Water and Acute Lung Injury

    Directory of Open Access Journals (Sweden)

    Ritesh Maharaj

    2012-01-01

    Full Text Available Acute lung injury carries a high burden of morbidity and mortality and is characterised by nonhydrostatic pulmonary oedema. The aim of this paper is to highlight the role of accurate quantification of extravascular lung water in diagnosis, management, and prognosis in “acute lung injury” and “acute respiratory distress syndrome”. Several studies have verified the accuracy of both the single and the double transpulmonary thermal indicator techniques. Both experimental and clinical studies were searched in PUBMED using the term “extravascular lung water” and “acute lung injury”. Extravascular lung water measurement offers information not otherwise available by other methods such as chest radiography, arterial blood gas, and chest auscultation at the bedside. Recent data have highlighted the role of extravascular lung water in response to treatment to guide fluid therapy and ventilator strategies. The quantification of extravascular lung water may predict mortality and multiorgan dysfunction. The limitations of the dilution method are also discussed.

  18. Acute lung injury induces cardiovascular dysfunction

    DEFF Research Database (Denmark)

    Suda, Koichi; Tsuruta, Masashi; Eom, Jihyoun

    2011-01-01

    Acute lung injury (ALI) is associated with systemic inflammation and cardiovascular dysfunction. IL-6 is a biomarker of this systemic response and a predictor of cardiovascular events, but its possible causal role is uncertain. Inhaled corticosteroids and long-acting β2 agonists (ICS/LABA) down-r...

  19. Amount of Pneumocystis carinii and degree of acute lung inflammation in HIV-associated P carinii pneumonia

    DEFF Research Database (Denmark)

    Vestbo, Jørgen; Nielsen, T L; Junge, Jette

    1993-01-01

    ) was examined. In the TBB the amount of PC correlated strongly with overall inflammation in the interstitium (Kendall correlation coefficient [Kcc] = 0.59; p type 2 pneumocyte proliferation, and edema formation. The amount of PC in the TBB also correlated with interstitial accumulation of neutrophils...... (Kcc = 0.54; p = 0.0001), lymphocytes, and macrophages. In BALF the amount of PC correlated with edema formation and type 2 pneumocyte proliferation in the TBB but not with the percentage of neutrophils, lymphocytes, or macrophages in BALF. The amount of PC in the BALF and the percentage of neutrophils...

  20. Contribution of neutrophils to acute lung injury.

    Science.gov (United States)

    Grommes, Jochen; Soehnlein, Oliver

    2011-01-01

    Treatment of acute lung injury (ALI) and its most severe form, acute respiratory distress syndrome (ARDS), remain unsolved problems of intensive care medicine. ALI/ARDS are characterized by lung edema due to increased permeability of the alveolar-capillary barrier and subsequent impairment of arterial oxygenation. Lung edema, endothelial and epithelial injury are accompanied by an influx of neutrophils into the interstitium and broncheoalveolar space. Hence, activation and recruitment of neutrophils are regarded to play a key role in progression of ALI/ARDS. Neutrophils are the first cells to be recruited to the site of inflammation and have a potent antimicrobial armour that includes oxidants, proteinases and cationic peptides. Under pathological circumstances, however, unregulated release of these microbicidal compounds into the extracellular space paradoxically can damage host tissues. This review focuses on the mechanisms of neutrophil recruitment into the lung and on the contribution of neutrophils to tissue damage in ALI.

  1. Acute effects of cigarette smoke on inflammation and oxidative stress : a review

    NARCIS (Netherlands)

    van der Vaart, H; Postma, DS; Timens, W; Ten Hacken, NHT

    Compared with the effects of chronic smoke exposure on lung function and airway inflammation, there are few data on the acute effects of smoking. A review of the literature identified 123 studies investigating the acute effects of cigarette smoking on inflammation and oxidative stress in human,

  2. Alveolar recruitment of ficolin-3 in response to acute pulmonary inflammation in humans

    DEFF Research Database (Denmark)

    Plovsing, Ronni R; Berg, Ronan M G; Munthe-Fog, Lea

    2016-01-01

    acute lung and systemic inflammation induce recruitment of lectins in humans. METHODS: Fifteen healthy volunteers received LPS intravenously (IV) or in a lung subsegment on two different occasions. Volunteers were evaluated by consecutive blood samples and by bronchoalveolar lavage 2, 4, 6, 8, or 24h...... acute phase response with an increase in CRP (precruitment...

  3. G-CSF maintains controlled neutrophil mobilization during acute inflammation by negatively regulating CXCR2 signaling

    Science.gov (United States)

    Bajrami, Besnik; Zhu, Haiyan; Zhang, Yu C.

    2016-01-01

    Cytokine-induced neutrophil mobilization from the bone marrow to circulation is a critical event in acute inflammation, but how it is accurately controlled remains poorly understood. In this study, we report that CXCR2 ligands are responsible for rapid neutrophil mobilization during early-stage acute inflammation. Nevertheless, although serum CXCR2 ligand concentrations increased during inflammation, neutrophil mobilization slowed after an initial acute fast phase, suggesting a suppression of neutrophil response to CXCR2 ligands after the acute phase. We demonstrate that granulocyte colony-stimulating factor (G-CSF), usually considered a prototypical neutrophil-mobilizing cytokine, was expressed later in the acute inflammatory response and unexpectedly impeded CXCR2-induced neutrophil mobilization by negatively regulating CXCR2-mediated intracellular signaling. Blocking G-CSF in vivo paradoxically elevated peripheral blood neutrophil counts in mice injected intraperitoneally with Escherichia coli and sequestered large numbers of neutrophils in the lungs, leading to sterile pulmonary inflammation. In a lipopolysaccharide-induced acute lung injury model, the homeostatic imbalance caused by G-CSF blockade enhanced neutrophil accumulation, edema, and inflammation in the lungs and ultimately led to significant lung damage. Thus, physiologically produced G-CSF not only acts as a neutrophil mobilizer at the relatively late stage of acute inflammation, but also prevents exaggerated neutrophil mobilization and the associated inflammation-induced tissue damage during early-phase infection and inflammation. PMID:27551153

  4. Differential Role of the Fas/Fas Ligand Apoptotic Pathway in Inflammation and Lung Fibrosis Associated with Reovirus 1/L-Induced Bronchiolitis Obliterans Organizing Pneumonia and Acute Respiratory Distress Syndrome1

    Science.gov (United States)

    Lopez, Andrea D.; Avasarala, Sreedevi; Grewal, Suman; Murali, Anuradha K.; London, Lucille

    2010-01-01

    Bronchiolitis obliterans organizing pneumonia (BOOP) and acute respiratory distress syndrome (ARDS) are two clinically and histologically distinct syndromes sharing the presence of an inflammatory and fibrotic component. Apoptosis via the Fas/Fas ligand (FasL) pathway plays an important role in the development of acute lung injury and fibrosis characteristic of these and other pulmonary inflammatory and fibrotic syndromes. We evaluated the role of apoptosis via the Fas/FasL pathway in the development of pulmonary inflammation and fibrosis in reovirus 1/L-induced BOOP and ARDS. CBA/J mice were intranasally inoculated with saline, 1 × 106 (BOOP), or 1 × 107 (ARDS) PFU reovirus 1/L, and evaluated at various days postinoculation for in situ apoptosis by TUNEL analysis and Fas/FasL expression. Our results demonstrate the presence of apoptotic cells and up-regulation of Fas/FasL expression in alveolar epithelium and in infiltrating cells during the inflammatory and fibrotic stages of both reovirus 1/L-induced ARDS and BOOP. Treatment of mice with the caspase 8 inhibitor, zIETD-fmk, inhibited apoptosis, inflammation, and fibrotic lesion development in reovirus 1/L-induced BOOP and ARDS. However, CBA/KlJms-Faslpr-cg/J mice, which carry a point mutation in the Fas cytoplasmic region that abolishes the ability of Fas to transduce an apoptotic signal, do not develop pulmonary inflammation and fibrotic lesions associated with reovirus 1/L-induced BOOP, but still develop inflammation and fibrotic lesions associated with reovirus 1/L-induced ARDS. These results suggest a differential role for the Fas/FasL apoptotic pathway in the development of inflammation and fibrotic lesions associated with BOOP and ARDS. PMID:20007588

  5. Differential role of the Fas/Fas ligand apoptotic pathway in inflammation and lung fibrosis associated with reovirus 1/L-induced bronchiolitis obliterans organizing pneumonia and acute respiratory distress syndrome.

    Science.gov (United States)

    Lopez, Andrea D; Avasarala, Sreedevi; Grewal, Suman; Murali, Anuradha K; London, Lucille

    2009-12-15

    Bronchiolitis obliterans organizing pneumonia (BOOP) and acute respiratory distress syndrome (ARDS) are two clinically and histologically distinct syndromes sharing the presence of an inflammatory and fibrotic component. Apoptosis via the Fas/Fas ligand (FasL) pathway plays an important role in the development of acute lung injury and fibrosis characteristic of these and other pulmonary inflammatory and fibrotic syndromes. We evaluated the role of apoptosis via the Fas/FasL pathway in the development of pulmonary inflammation and fibrosis in reovirus 1/L-induced BOOP and ARDS. CBA/J mice were intranasally inoculated with saline, 1 x 10(6) (BOOP), or 1 x 10(7) (ARDS) PFU reovirus 1/L, and evaluated at various days postinoculation for in situ apoptosis by TUNEL analysis and Fas/FasL expression. Our results demonstrate the presence of apoptotic cells and up-regulation of Fas/FasL expression in alveolar epithelium and in infiltrating cells during the inflammatory and fibrotic stages of both reovirus 1/L-induced ARDS and BOOP. Treatment of mice with the caspase 8 inhibitor, zIETD-fmk, inhibited apoptosis, inflammation, and fibrotic lesion development in reovirus 1/L-induced BOOP and ARDS. However, CBA/KlJms-Fas(lpr-cg)/J mice, which carry a point mutation in the Fas cytoplasmic region that abolishes the ability of Fas to transduce an apoptotic signal, do not develop pulmonary inflammation and fibrotic lesions associated with reovirus 1/L-induced BOOP, but still develop inflammation and fibrotic lesions associated with reovirus 1/L-induced ARDS. These results suggest a differential role for the Fas/FasL apoptotic pathway in the development of inflammation and fibrotic lesions associated with BOOP and ARDS.

  6. Inflammation and angiogenesis in fibrotic lung disease.

    Science.gov (United States)

    Keane, Michael P; Strieter, Robert M; Lynch, Joseph P; Belperio, John A

    2006-12-01

    The pathogenesis of pulmonary fibrosis is poorly understood. Although inflammation has been presumed to have an important role in the development of fibrosis this has been questioned recently, particularly with regard to idiopathic pulmonary fibrosis (IPF). It is, however, increasingly recognized that the polarization of the inflammatory response toward a type 2 phenotype supports fibroproliferation. Increased attention has been on the role of noninflammatory structural cells such as the fibroblast, myofibroblast, epithelial cell, and endothelial cells. Furthermore, the origin of these cells appears to be multifactorial and includes resident cells, bone marrow-derived cells, and epithelial to mesenchymal transition. Increasing evidence supports the presence of vascular remodeling in fibrotic lung disease, although the precise role in the pathogenesis of fibrosis remains to be determined. Therefore, the pathogenesis of pulmonary fibrosis is complex and involves the interaction of multiple cell types and compartments within the lung.

  7. Effects of positive end-expiratory pressure titration and recruitment maneuver on lung inflammation and hyperinflation in experimental acid aspiration-induced lung injury.

    Science.gov (United States)

    Ambrosio, Aline M; Luo, Rubin; Fantoni, Denise T; Gutierres, Claudia; Lu, Qin; Gu, Wen-Jie; Otsuki, Denise A; Malbouisson, Luiz M S; Auler, Jose O C; Rouby, Jean-Jacques

    2012-12-01

    In acute lung injury positive end-expiratory pressure (PEEP) and recruitment maneuver are proposed to optimize arterial oxygenation. The aim of the study was to evaluate the impact of such a strategy on lung histological inflammation and hyperinflation in pigs with acid aspiration-induced lung injury. Forty-seven pigs were randomly allocated in seven groups: (1) controls spontaneously breathing; (2) without lung injury, PEEP 5 cm H2O; (3) without lung injury, PEEP titration; (4) without lung injury, PEEP titration + recruitment maneuver; (5) with lung injury, PEEP 5 cm H2O; (6) with lung injury, PEEP titration; and (7) with lung injury, PEEP titration + recruitment maneuver. Acute lung injury was induced by intratracheal instillation of hydrochloric acid. PEEP titration was performed by incremental and decremental PEEP from 5 to 20 cm H2O for optimizing arterial oxygenation. Three recruitment maneuvers (pressure of 40 cm H2O maintained for 20 s) were applied to the assigned groups at each PEEP level. Proportion of lung inflammation, hemorrhage, edema, and alveolar wall disruption were recorded on each histological field. Mean alveolar area was measured in the aerated lung regions. Acid aspiration increased mean alveolar area and produced alveolar wall disruption, lung edema, alveolar hemorrhage, and lung inflammation. PEEP titration significantly improved arterial oxygenation but simultaneously increased lung inflammation in juxta-diaphragmatic lung regions. Recruitment maneuver during PEEP titration did not induce additional increase in lung inflammation and alveolar hyperinflation. In a porcine model of acid aspiration-induced lung injury, PEEP titration aimed at optimizing arterial oxygenation, substantially increased lung inflammation. Recruitment maneuvers further improved arterial oxygenation without additional effects on inflammation and hyperinflation.

  8. Inflammation: a trigger for acute coronary syndrome

    International Nuclear Information System (INIS)

    SAGER, Hendrik B.; NAHRENDORF, Matthias

    2016-01-01

    Atherosclerosis is a chronic inflammatory disease of the vessel wall and a major cause of death worldwide. One of atherosclerosis’ most dreadful complications are acute coronary syndromes that comprise ST-segment elevation myocardial infarction, non-ST-segment elevation myocardial infarction, and unstable angina. We now understand that inflammation substantially contributes to the initiation, progression, and destabilization of atherosclerosis. In this review, we will focus on the role of inflammatory leukocytes, which are the cellular protagonists of vascular inflammation, in triggering disease progression and, ultimately, the destabilization that causes acute coronary syndromes.

  9. Low Tidal Volume Reduces Lung Inflammation Induced by Liquid Ventilation in Piglets With Severe Lung Injury.

    Science.gov (United States)

    Jiang, Lijun; Feng, Huizhen; Chen, Xiaofan; Liang, Kaifeng; Ni, Chengyao

    2017-05-01

    Total liquid ventilation (TLV) is an alternative treatment for severe lung injury. High tidal volume is usually required for TLV to maintain adequate CO 2 clearance. However, high tidal volume may cause alveolar barotrauma. We aim to investigate the effect of low tidal volume on pulmonary inflammation in piglets with lung injury and under TLV. After the establishment of acute lung injury model by infusing lipopolysaccharide, 12 piglets were randomly divided into two groups, TLV with high tidal volume (25 mL/kg) or with low tidal volume (6 mL/kg) for 240 min, respectively. Extracorporeal CO 2 removal was applied in low tidal volume group to improve CO 2 clearance and in high tidal volume group as sham control. Gas exchange and hemodynamic status were monitored every 30 min during TLV. At the end of the study, pulmonary mRNA expression and plasmatic concentration of interleukin-6 (IL-6) and interleukin-8 (IL-8) were measured by collecting lung tissue and blood samples from piglets. Arterial blood pressure, PaO 2 , and PaCO 2 showed no remarkable difference between groups during the observation period. Compared with high tidal volume strategy, low tidal volume resulted in 76% reduction of minute volume and over 80% reduction in peak inspiratory pressure during TLV. In addition, low tidal volume significantly diminished pulmonary mRNA expression and plasmatic level of IL-6 and IL-8. We conclude that during TLV, low tidal volume reduces lung inflammation in piglets with acute lung injury without compromising gas exchange. © 2016 International Center for Artificial Organs and Transplantation and Wiley Periodicals, Inc.

  10. Non-Invasive Detection of Lung Inflammation by Near-Infrared Fluorescence Imaging Using Bimodal Liposomes.

    Science.gov (United States)

    Desu, Hari R; Wood, George C; Thoma, Laura A

    2016-01-01

    Acute lung injury (ALI) and its more severe form, acute respiratory distress syndrome results in respiratory obstruction and severe lung inflammation. Critical characteristics of ALI are alveolar edema, infiltration of leukocytes (neutrophils and monocytes), release of pro-inflammatory cytokines and chemokines into broncho-alveolar lavage fluid, and activation of integrin receptors. The purpose of the study was to demonstrate non-invasive detection of lung inflammation using integrin receptor targeted fluorescence liposomes. An inflammation similar to that observed in ALI was elicited in rodents by intra-tracheal instillation of interleukin-1beta (IL-1beta). Cyclic arginine glycine-(D)-aspartic acid-peptide (cRGD-peptide) grafted fluorescence liposomes were administered to ALI induced male Sprague-Dawley rats for targeting lung integrin receptors. Near-infrared fluorescence imaging (NIRFI) was applied for visualization and quantitation of lung inflammation. NIRFI signals were correlated with inflammatory cellular and biochemical markers of lungs. A positive correlation was observed between NIRF signals and lung inflammation markers. Compared to control group, an intense NIRF signal was observed in ALI induced rats in the window 6-24 h post-IL-1beta instillation. Interaction of integrin receptors with targeted liposomes was assumed to contribute to intense NIRF signal. RT-PCR studies showed an elevated lung expression of alphavbeta5 integrin receptors, 12 h post-IL-1beta instillation. In vitro studies demonstrated integrin receptor specificity of targeted liposomes. These targeted liposomes showed binding to alphavbeta5 integrin receptors expressed on alveolar cells. Non-invasive detection of lung inflammation was demonstrated using a combination of integrin receptor targeting and NIRFI.

  11. Lung inflammation caused by inhaled toxicants: a review

    Directory of Open Access Journals (Sweden)

    Wong J

    2016-06-01

    Full Text Available John Wong, Bruce E Magun, Lisa J Wood School of Nursing, MGH Institute of Health Professions, Boston, MA, USA Abstract: Exposure of the lungs to airborne toxicants from different sources in the environment may lead to acute and chronic pulmonary or even systemic inflammation. Cigarette smoke is the leading cause of chronic obstructive pulmonary disease, although wood smoke in urban areas of underdeveloped countries is now recognized as a leading cause of respiratory disease. Mycotoxins from fungal spores pose an occupational risk for respiratory illness and also present a health hazard to those living in damp buildings. Microscopic airborne particulates of asbestos and silica (from building materials and those of heavy metals (from paint are additional sources of indoor air pollution that contributes to respiratory illness and is known to cause respiratory illness in experimental animals. Ricin in aerosolized form is a potential bioweapon that is extremely toxic yet relatively easy to produce. Although the aforementioned agents belong to different classes of toxic chemicals, their pathogenicity is similar. They induce the recruitment and activation of macrophages, activation of mitogen-activated protein kinases, inhibition of protein synthesis, and production of interleukin-1 beta. Targeting either macrophages (using nanoparticles or the production of interleukin-1 beta (using inhibitors against protein kinases, NOD-like receptor protein-3, or P2X7 may potentially be employed to treat these types of lung inflammation without affecting the natural immune response to bacterial infections. Keywords: cigarette, mycotoxin, trichothecene, ricin, inflammasome, macrophage, inhibitors

  12. Important role of platelets in modulating endotoxin-induced lung inflammation in CFTR-deficient mice.

    Directory of Open Access Journals (Sweden)

    Caiqi Zhao

    Full Text Available Mutation of CFTR (cystic fibrosis transmembrane conductance regulator leads to cystic fibrosis (CF. Patients with CF develop abnormalities of blood platelets and recurrent lung inflammation. However, whether CFTR-mutated platelets play a role in the development of lung inflammation is elusive. Therefore, we intratracheally challenged wildtype and F508del (a common type of CFTR mutation mice with LPS to observe changes of F508del platelets in the peripheral blood and indexes of lung inflammation (BAL neutrophils and protein levels. Furthermore, we investigated whether or not and how F508del platelets modulate the LPS-induced acute lung inflammation by targeting anti-platelet aggregation, depletion of neutrophils, reconstitution of bone marrow or neutrophils, blockade of P-selectin glycoprotein ligand-1 (PSGL-1, platelet activating factor (PAF, and correction of mutated CFTR trafficking. We found that LPS-challenged F508del mice developed severe thrombocytopenia and had higher levels of plasma TXB2 coincided with neutrophilic lung inflammation relative to wildtype control. Inhibition of F508del platelet aggregation or depletion of F508del neutrophils diminished the LPS-induced lung inflammation in the F508del mice. Moreover, wildtype mice reconstituted with either F508del bone marrow or neutrophils developed worse thrombocytopenia. Blocking PSGL-1, platelet activating factor (PAF, or rectifying trafficking of mutated CFTR in F508del mice diminished and alveolar neutrophil transmigration in the LPS-challenged F508del mice. These findings suggest that F508del platelets and their interaction with neutrophils are requisite for the development of LPS-induced lung inflammation and injury. As such, targeting platelets might be an emerging strategy for dampening recurrent lung inflammation in cystic fibrosis patients.

  13. Human models of acute lung injury

    Directory of Open Access Journals (Sweden)

    Alastair G. Proudfoot

    2011-03-01

    Full Text Available Acute lung injury (ALI is a syndrome that is characterised by acute inflammation and tissue injury that affects normal gas exchange in the lungs. Hallmarks of ALI include dysfunction of the alveolar-capillary membrane resulting in increased vascular permeability, an influx of inflammatory cells into the lung and a local pro-coagulant state. Patients with ALI present with severe hypoxaemia and radiological evidence of bilateral pulmonary oedema. The syndrome has a mortality rate of approximately 35% and usually requires invasive mechanical ventilation. ALI can follow direct pulmonary insults, such as pneumonia, or occur indirectly as a result of blood-borne insults, commonly severe bacterial sepsis. Although animal models of ALI have been developed, none of them fully recapitulate the human disease. The differences between the human syndrome and the phenotype observed in animal models might, in part, explain why interventions that are successful in models have failed to translate into novel therapies. Improved animal models and the development of human in vivo and ex vivo models are therefore required. In this article, we consider the clinical features of ALI, discuss the limitations of current animal models and highlight how emerging human models of ALI might help to answer outstanding questions about this syndrome.

  14. Comparison of lung protective ventilation strategies in a rabbit model of acute lung injury.

    Science.gov (United States)

    Rotta, A T; Gunnarsson, B; Fuhrman, B P; Hernan, L J; Steinhorn, D M

    2001-11-01

    To determine the impact of different protective and nonprotective mechanical ventilation strategies on the degree of pulmonary inflammation, oxidative damage, and hemodynamic stability in a saline lavage model of acute lung injury. A prospective, randomized, controlled, in vivo animal laboratory study. Animal research facility of a health sciences university. Forty-six New Zealand White rabbits. Mature rabbits were instrumented with a tracheostomy and vascular catheters. Lavage-injured rabbits were randomized to receive conventional ventilation with either a) low peak end-expiratory pressure (PEEP; tidal volume of 10 mL/kg, PEEP of 2 cm H2O); b) high PEEP (tidal volume of 10 mL/kg, PEEP of 10 cm H2O); c) low tidal volume with PEEP above Pflex (open lung strategy, tidal volume of 6 mL/kg, PEEP set 2 cm H2O > Pflex); or d) high-frequency oscillatory ventilation. Animals were ventilated for 4 hrs. Lung lavage fluid and tissue samples were obtained immediately after animals were killed. Lung lavage fluid was assayed for measurements of total protein, elastase activity, tumor necrosis factor-alpha, and malondialdehyde. Lung tissue homogenates were assayed for measurements of myeloperoxidase activity and malondialdehyde. The need for inotropic support was recorded. Animals that received a lung protective strategy (open lung or high-frequency oscillatory ventilation) exhibited more favorable oxygenation and lung mechanics compared with the low PEEP and high PEEP groups. Animals ventilated by a lung protective strategy also showed attenuation of inflammation (reduced tracheal fluid protein, tracheal fluid elastase, tracheal fluid tumor necrosis factor-alpha, and pulmonary leukostasis). Animals treated with high-frequency oscillatory ventilation had attenuated oxidative injury to the lung and greater hemodynamic stability compared with the other experimental groups. Both lung protective strategies were associated with improved oxygenation, attenuated inflammation, and

  15. Glutamine Attenuates Acute Lung Injury Caused by Acid Aspiration

    Directory of Open Access Journals (Sweden)

    Chih-Cheng Lai

    2014-08-01

    Full Text Available Inadequate ventilator settings may cause overwhelming inflammatory responses associated with ventilator-induced lung injury (VILI in patients with acute respiratory distress syndrome (ARDS. Here, we examined potential benefits of glutamine (GLN on a two-hit model for VILI after acid aspiration-induced lung injury in rats. Rats were intratracheally challenged with hydrochloric acid as a first hit to induce lung inflammation, then randomly received intravenous GLN or lactated Ringer’s solution (vehicle control thirty min before different ventilator strategies. Rats were then randomized to receive mechanical ventilation as a second hit with a high tidal volume (TV of 15 mL/kg and zero positive end-expiratory pressure (PEEP or a low TV of 6 mL/kg with PEEP of 5 cm H2O. We evaluated lung oxygenation, inflammation, mechanics, and histology. After ventilator use for 4 h, high TV resulted in greater lung injury physiologic and biologic indices. Compared with vehicle treated rats, GLN administration attenuated lung injury, with improved oxygenation and static compliance, and decreased respiratory elastance, lung edema, extended lung destruction (lung injury scores and lung histology, neutrophil recruitment in the lung, and cytokine production. Thus, GLN administration improved the physiologic and biologic profiles of this experimental model of VILI based on the two-hit theory.

  16. Caffeine Mitigates Lung Inflammation Induced by Ischemia-Reperfusion of Lower Limbs in Rats

    Directory of Open Access Journals (Sweden)

    Wei-Chi Chou

    2015-01-01

    Full Text Available Reperfusion of ischemic limbs can induce inflammation and subsequently cause acute lung injury. Caffeine, a widely used psychostimulant, possesses potent anti-inflammatory capacity. We elucidated whether caffeine can mitigate lung inflammation caused by ischemia-reperfusion (IR of the lower limbs. Adult male Sprague-Dawley rats were randomly allocated to receive IR, IR plus caffeine (IR + Caf group, sham-operation (Sham, or sham plus caffeine (n=12 in each group. To induce IR, lower limbs were bilaterally tied by rubber bands high around each thigh for 3 hours followed by reperfusion for 3 hours. Caffeine (50 mg/kg, intraperitoneal injection was administered immediately after reperfusion. Our histological assay data revealed characteristics of severe lung inflammation in the IR group and mild to moderate characteristic of lung inflammation in the IR + Caf group. Total cells number and protein concentration in bronchoalveolar lavage fluid of the IR group were significantly higher than those of the IR + Caf group (P<0.001 and P=0.008, resp.. Similarly, pulmonary concentrations of inflammatory mediators (tumor necrosis factor-α, interleukin-1β, and macrophage inflammatory protein-2 and pulmonary myeloperoxidase activity of the IR group were significantly higher than those of the IR + Caf group (all P<0.05. These data clearly demonstrate that caffeine could mitigate lung inflammation induced by ischemia-reperfusion of the lower limbs.

  17. Modeling and Hemofiltration Treatment of Acute Inflammation

    Directory of Open Access Journals (Sweden)

    Robert S. Parker

    2016-10-01

    Full Text Available The body responds to endotoxins by triggering the acute inflammatory response system to eliminate the threat posed by gram-negative bacteria (endotoxin and restore health. However, an uncontrolled inflammatory response can lead to tissue damage, organ failure, and ultimately death; this is clinically known as sepsis. Mathematical models of acute inflammatory disease have the potential to guide treatment decisions in critically ill patients. In this work, an 8-state (8-D differential equation model of the acute inflammatory response system to endotoxin challenge was developed. Endotoxin challenges at 3 and 12 mg/kg were administered to rats, and dynamic cytokine data for interleukin (IL-6, tumor necrosis factor (TNF, and IL-10 were obtained and used to calibrate the model. Evaluation of competing model structures was performed by analyzing model predictions at 3, 6, and 12 mg/kg endotoxin challenges with respect to experimental data from rats. Subsequently, a model predictive control (MPC algorithm was synthesized to control a hemoadsorption (HA device, a blood purification treatment for acute inflammation. A particle filter (PF algorithm was implemented to estimate the full state vector of the endotoxemic rat based on time series cytokine measurements. Treatment simulations show that: (i the apparent primary mechanism of HA efficacy is white blood cell (WBC capture, with cytokine capture a secondary benefit; and (ii differential filtering of cytokines and WBC does not provide substantial improvement in treatment outcomes vs. existing HA devices.

  18. Lung Surfactant Protein D (SP-D) Response and Regulation During Acute and Chronic Lung Injury

    DEFF Research Database (Denmark)

    Gaunsbaek, Maria Quisgaard; Rasmussen, Karina Juhl; Beers, Michael F.

    2013-01-01

    in three murine models of lung injury, using a validated ELISA technology for estimation of SP-D levels. METHODS: Mice were exposed to lipopolysaccharide, bleomycin, or Pneumocystis carinii (Pc) and sacrificed at different time points. RESULTS: In lipopolysaccharide-challenged mice, the level of SP...... injury, with a sustained increment during chronic inflammation compared with acute inflammation. A quick upregulation of SP-D in serum in response to acute airway inflammation supports the notion that SP-D translocates from the airways into the vascular system, in favor of being synthesized systemically....... The study also confirms the concept of using increased SP-D serum levels as a biomarker of especially chronic airway inflammation....

  19. PET imaging of lung inflammation with [18F]FEDAC, a radioligand for translocator protein (18 kDa.

    Directory of Open Access Journals (Sweden)

    Akiko Hatori

    Full Text Available PURPOSE: The translocator protein (18 kDa (TSPO is highly expressed on the bronchial and bronchiole epithelium, submucosal glands in intrapulmonary bronchi, pneumocytes and alveolar macrophages in human lung. This study aimed to perform positron emission tomography (PET imaging of lung inflammation with [(18F]FEDAC, a specific TSPO radioligand, and to determine cellular sources enriching TSPO expression in the lung. METHODS: An acute lung injury model was prepared by intratracheal administration of lipopolysaccharide (LPS to rat. Uptake of radioactivity in the rat lungs was measured with small-animal PET after injection of [(18F]FEDAC. Presence of TSPO was examined in the lung tissue using Western blot and immunohistochemical assays. RESULTS: The uptake of [(18F]FEDAC increased in the lung with the progress of inflammation by treatment with LPS. Pretreatment with a TSPO-selective ligand PK11195 showed a significant decrease in the lung uptake of [(18F]FEDAC due to competitive binding to TSPO. TSPO expression was elevated in the inflamed lung section and its level responded to the [(18F]FEDAC uptake and severity of inflammation. Increase of TSPO expression was mainly found in the neutrophils and macrophages of inflamed lungs. CONCLUSION: From this study we conclude that PET with [(18F]FEDAC may be a useful tool for imaging TSPO expression and evaluating progress of lung inflammation. Study on human lung using [(18F]FEDAC-PET is promising.

  20. Acute respiratory distress syndrome and acute lung injury.

    Science.gov (United States)

    Dushianthan, A; Grocott, M P W; Postle, A D; Cusack, R

    2011-09-01

    Acute respiratory distress syndrome (ARDS) is a life threatening respiratory failure due to lung injury from a variety of precipitants. Pathologically ARDS is characterised by diffuse alveolar damage, alveolar capillary leakage, and protein rich pulmonary oedema leading to the clinical manifestation of poor lung compliance, severe hypoxaemia, and bilateral infiltrates on chest radiograph. Several aetiological factors associated with the development of ARDS are identified with sepsis, pneumonia, and trauma with multiple transfusions accounting for most cases. Despite the absence of a robust diagnostic definition, extensive epidemiological investigations suggest ARDS remains a significant health burden with substantial morbidity and mortality. Improvements in outcome following ARDS over the past decade are in part due to improved strategies of mechanical ventilation and advanced support of other failing organs. Optimal treatment involves judicious fluid management, protective lung ventilation with low tidal volumes and moderate positive end expiratory pressure, multi-organ support, and treatment where possible of the underlying cause. Moreover, advances in general supportive measures such as appropriate antimicrobial therapy, early enteral nutrition, prophylaxis against venous thromboembolism and gastrointestinal ulceration are likely contributory reasons for the improved outcomes. Although therapies such as corticosteroids, nitric oxide, prostacyclins, exogenous surfactants, ketoconazole and antioxidants have shown promising clinical effects in animal models, these have failed to translate positively in human studies. Most recently, clinical trials with β2 agonists aiding alveolar fluid clearance and immunonutrition with omega-3 fatty acids have also provided disappointing results. Despite these negative studies, mortality seems to be in decline due to advances in overall patient care. Future directions of research are likely to concentrate on identifying potential

  1. Contribution of Neutrophils to Acute Lung Injury

    OpenAIRE

    Grommes, Jochen; Soehnlein, Oliver

    2010-01-01

    Treatment of acute lung injury (ALI) and its most severe form, acute respiratory distress syndrome (ARDS), remain unsolved problems of intensive care medicine. ALI/ARDS are characterized by lung edema due to increased permeability of the alveolar-capillary barrier and subsequent impairment of arterial oxygenation. Lung edema, endothelial and epithelial injury are accompanied by an influx of neutrophils into the interstitium and broncheoalveolar space. Hence, activation and recruitment of neut...

  2. Lung injury, inflammation and Akt signaling following inhalation of particulate hexavalent chromium

    International Nuclear Information System (INIS)

    Beaver, Laura M.; Stemmy, Erik J.; Constant, Stephanie L.; Schwartz, Arnold; Little, Laura G.; Gigley, Jason P.; Chun, Gina; Sugden, Kent D.

    2009-01-01

    Certain particulate hexavalent chromium [Cr(VI)] compounds are human respiratory carcinogens that release genotoxic soluble chromate, and are associated with fibrosis, fibrosarcomas, adenocarcinomas and squamous cell carcinomas of the lung. We postulate that inflammatory processes and mediators may contribute to the etiology of Cr(VI) carcinogenesis, however the immediate (0-24 h) pathologic injury and immune responses after exposure to particulate chromates have not been adequately investigated. Our aim was to determine the nature of the lung injury, inflammatory response, and survival signaling responses following intranasal exposure of BALB/c mice to particulate basic zinc chromate. Factors associated with lung injury, inflammation and survival signaling were measured in airway lavage fluid and in lung tissue. A single chromate exposure induced an acute immune response in the lung, characterized by a rapid and significant increase in IL-6 and GRO-α levels, an influx of neutrophils, and a decline in macrophages in lung airways. Histological examination of lung tissue in animals challenged with a single chromate exposure revealed an increase in bronchiolar cell apoptosis and mucosal injury. Furthermore, chromate exposure induced injury and inflammation that progressed to alveolar and interstitial pneumonitis. Finally, a single Cr(VI) challenge resulted in a rapid and persistent increase in the number of airways immunoreactive for phosphorylation of the survival signaling protein Akt, on serine 473. These data illustrate that chromate induces both survival signaling and an inflammatory response in the lung, which we postulate may contribute to early oncogenesis

  3. Inflammation-induced preterm lung maturation: lessons from animal experimentation.

    Science.gov (United States)

    Moss, Timothy J M; Westover, Alana J

    2017-06-01

    Intrauterine inflammation, or chorioamnionitis, is a major contributor to preterm birth. Prematurity per se is associated with considerable morbidity and mortality resulting from lung immaturity but exposure to chorioamnionitis reduces the risk of neonatal respiratory distress syndrome (RDS) in preterm infants. Animal experiments have identified that an increase in pulmonary surfactant production by the preterm lungs likely underlies this decreased risk of RDS in infants exposed to chorioamnionitis. Further animal experimentation has shown that infectious or inflammatory agents in amniotic fluid exert their effects on lung development by direct effects within the developing respiratory tract, and probably not by systemic pathways. Differences in the effects of intrauterine inflammation and glucocorticoids demonstrate that canonical glucocorticoid-mediated lung maturation is not responsible for inflammation-induced changes in lung development. Animal experimentation is identifying alternative lung maturational pathways, and transgenic animals and cell culture techniques will allow identification of novel mechanisms of lung maturation that may lead to new treatments for the prevention of RDS. Copyright © 2016. Published by Elsevier Ltd.

  4. Transfusion related acute lung injury

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    Sharma Ratti

    2009-10-01

    Full Text Available Transfusion related acute lung injury (TRALI is an uncommon but potentially fatal adverse reaction to transfusion of plasma containing blood components. We describe a case of 10-year-old male child with aplastic anemia, platelet count of 7800/΅l, B positive blood group who developed fever (39.2΀C, difficulty in breathing and cyanosis within 2 hrs after transfusion of a random platelet concentrate. Despite the best resuscitative efforts, the child died within next 24 hrs. The present case highlights the fact that TRALI should be kept as a differential diagnosis in all patients developing acute respiratory discomfort within 6 hrs of transfusion. Without a ′gold standard′ the diagnosis of TRALI relies on a high index of suspicion and on excluding other types of transfusion reactions. Notification to transfusion services is crucial to ensure that a proper investigation is carried out and at-risk donor and recipients can be identified, and risk reduction measures can be adopted.

  5. Protective effect of Arbutus unedo aqueous extract in carrageenan-induced lung inflammation in mice.

    Science.gov (United States)

    Mariotto, Sofia; Esposito, Emanuela; Di Paola, Rosanna; Ciampa, Anna; Mazzon, Emanuela; de Prati, Alessandra Carcereri; Darra, Elena; Vincenzi, Simone; Cucinotta, Giovanni; Caminiti, Rocco; Suzuki, Hisanori; Cuzzocrea, Salvatore

    2008-02-01

    In the present study, we show that an aqueous extract of Arbutus unedo L. (AuE), a Mediterranean endemic plant widely employed as an astringent, diuretic and urinary anti-septic, in vitro down-regulates the expression of some inflammatory genes, such as those encoding inducible nitric oxide synthase (iNOS) and intracellular adhesion molecule-(ICAM)-1, exerting a inhibitory action on both IFN-gamma-elicited STAT1 activation and IL-6-elicited STAT3 activation. To evaluate further the effect of AuE in animal models of acute inflammation, we examined whether AuE administration attenuates inflammatory response of murine induced by intrapleural injection of carrageenan. For this purpose we studied: (1) STAT1/3 activation, (2) TNF-alpha, IL-1beta and IL-6 production in pleural exudate, (3) lung iNOS, COX-2 and ICAM-1 expression, (4) neutrophil infiltration, (5) the nitration of cellular proteins by peroxynitrite, (6) lipid peroxidation, (7) prostaglandin E2 and nitrite/nitrate levels and (8) lung injury. We show that AuE strongly down-regulates STAT3 activation induced in the lung by carrageenan with concomitant attenuation of all parameters examined associated with inflammation, suggesting that STAT3 should be a new molecular target for anti-inflammatory treatment. This study demonstrates that acute lung inflammation is significantly attenuated by the treatment with AuE.

  6. Alternative and Natural Therapies for Acute Lung Injury and Acute Respiratory Distress Syndrome

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    Vipul J. Patel

    2018-01-01

    Full Text Available Introduction. Acute respiratory distress syndrome (ARDS is a complex clinical syndrome characterized by acute inflammation, microvascular damage, and increased pulmonary vascular and epithelial permeability, frequently resulting in acute respiratory failure and death. Current best practice for ARDS involves “lung-protective ventilation,” which entails low tidal volumes and limiting the plateau pressures in mechanically ventilated patients. Although considerable progress has been made in understanding the pathogenesis of ARDS, little progress has been made in the development of specific therapies to combat injury and inflammation. Areas Covered. In recent years, several natural products have been studied in experimental models and have been shown to inhibit multiple inflammatory pathways associated with acute lung injury and ARDS at a molecular level. Because of the pleiotropic effects of these agents, many of them also activate antioxidant pathways through nuclear factor erythroid-related factor 2, thereby targeting multiple pathways. Several of these agents are prescribed for treatment of inflammatory conditions in the Asian subcontinent and have shown to be relatively safe. Expert Commentary. Here we review natural remedies shown to attenuate lung injury and inflammation in experimental models. Translational human studies in patients with ARDS may facilitate treatment of this devastating disease.

  7. Size effects of latex nanomaterials on lung inflammation in mice

    International Nuclear Information System (INIS)

    Inoue, Ken-ichiro; Takano, Hirohisa; Yanagisawa, Rie; Koike, Eiko; Shimada, Akinori

    2009-01-01

    Effects of nano-sized materials (nanomaterials) on sensitive population have not been well elucidated. This study examined the effects of pulmonary exposure to (latex) nanomaterials on lung inflammation related to lipopolysaccharide (LPS) or allergen in mice, especially in terms of their size-dependency. In protocol 1, ICR male mice were divided into 8 experimental groups that intratracheally received a single exposure to vehicle, latex nanomaterials (250 μg/animal) with three sizes (25, 50, and 100 nm), LPS (75 μg/animal), or LPS plus latex nanomaterials. In protocol 2, ICR male mice were divided into 8 experimental groups that intratracheally received repeated exposure to vehicle, latex nanomaterials (100 μg/animal), allergen (ovalbumin: OVA; 1 μg/animal), or allergen plus latex nanomaterials. In protocol 1, latex nanomaterials with all sizes exacerbated lung inflammation elicited by LPS, showing an overall trend of amplified lung expressions of proinflammatory cytokines. Furthermore, LPS plus nanomaterials, especially with size less than 50 nm, significantly elevated circulatory levels of fibrinogen, macrophage chemoattractant protein-1, and keratinocyte-derived chemoattractant, and von Willebrand factor as compared with LPS alone. The enhancement tended overall to be greater with the smaller nanomaterials than with the larger ones. In protocol 2, latex nanomaterials with all sizes did not significantly enhance the pathophysiology of allergic asthma, characterized by eosinophilic lung inflammation and Igs production, although latex nanomaterials with less than 50 nm significantly induced/enhanced neutrophilic lung inflammation. These results suggest that latex nanomaterials differentially affect two types of (innate and adaptive immunity-dominant) lung inflammation

  8. [The use of Timalin in the treatment of the acute lung abscess].

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    Tsybikov, M N; Likhanov, I D; Borshchevskiĭ, V S; Kuznik, B I; Tsepelev, V L; Maslo, E Iu; Tsybikov, N N

    2012-01-01

    The study was aimed to research levels of main acute inflammation phase peptides, coagulative and fibrinolitic plasma activity on the background of traditional treatment and with addition of Timalin in patients with acute lung abscess. The study demonstrated that induction of bioregulative therapy leads to faster normalization of main indicators of SIRS and plasma fibrinolitic activity and eliminates hypercoagulation.

  9. The Murine Lung Microbiome Changes During Lung Inflammation and Intranasal Vancomycin Treatment

    Science.gov (United States)

    Barfod, Kenneth Klingenberg; Vrankx, Katleen; Mirsepasi-Lauridsen, Hengameh Chloé; Hansen, Jitka Stilund; Hougaard, Karin Sørig; Larsen, Søren Thor; Ouwenhand, Arthur C.; Krogfelt, Karen Angeliki

    2015-01-01

    Most microbiome research related to airway diseases has focused on the gut microbiome. This is despite advances in culture independent microbial identification techniques revealing that even healthy lungs possess a unique dynamic microbiome. This conceptual change raises the question; if lung diseases could be causally linked to local dysbiosis of the local lung microbiota. Here, we manipulate the murine lung and gut microbiome, in order to show that the lung microbiota can be changed experimentally. We have used four different approaches: lung inflammation by exposure to carbon nano-tube particles, oral probiotics and oral or intranasal exposure to the antibiotic vancomycin. Bacterial DNA was extracted from broncho-alveolar and nasal lavage fluids, caecum samples and compared by DGGE. Our results show that: the lung microbiota is sex dependent and not just a reflection of the gut microbiota, and that induced inflammation can change lung microbiota. This change is not transferred to offspring. Oral probiotics in adult mice do not change lung microbiome detectible by DGGE. Nasal vancomycin can change the lung microbiome preferentially, while oral exposure does not. These observations should be considered in future studies of the causal relationship between lung microbiota and lung diseases. PMID:26668669

  10. Modulation of lung inflammation by vessel dilator in a mouse model of allergic asthma

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    Cormier Stephania A

    2009-07-01

    Full Text Available Abstract Background Atrial natriuretic peptide (ANP and its receptor, NPRA, have been extensively studied in terms of cardiovascular effects. We have found that the ANP-NPRA signaling pathway is also involved in airway allergic inflammation and asthma. ANP, a C-terminal peptide (amino acid 99–126 of pro-atrial natriuretic factor (proANF and a recombinant peptide, NP73-102 (amino acid 73–102 of proANF have been reported to induce bronchoprotective effects in a mouse model of allergic asthma. In this report, we evaluated the effects of vessel dilator (VD, another N-terminal natriuretic peptide covering amino acids 31–67 of proANF, on acute lung inflammation in a mouse model of allergic asthma. Methods A549 cells were transfected with pVD or the pVAX1 control plasmid and cells were collected 24 hrs after transfection to analyze the effect of VD on inactivation of the extracellular-signal regulated receptor kinase (ERK1/2 through western blot. Luciferase assay, western blot and RT-PCR were also performed to analyze the effect of VD on NPRA expression. For determination of VD's attenuation of lung inflammation, BALB/c mice were sensitized and challenged with ovalbumin and then treated intranasally with chitosan nanoparticles containing pVD. Parameters of airway inflammation, such as airway hyperreactivity, proinflammatory cytokine levels, eosinophil recruitment and lung histopathology were compared with control mice receiving nanoparticles containing pVAX1 control plasmid. Results pVD nanoparticles inactivated ERK1/2 and downregulated NPRA expression in vitro, and intranasal treatment with pVD nanoparticles protected mice from airway inflammation. Conclusion VD's modulation of airway inflammation may result from its inactivation of ERK1/2 and downregulation of NPRA expression. Chitosan nanoparticles containing pVD may be therapeutically effective in preventing allergic airway inflammation.

  11. Regulation of Endothelial Cell Inflammation and Lung PMN Infiltration by Transglutaminase 2

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    Bijli, Kaiser M.; Kanter, Bryce G.; Minhajuddin, Mohammad; Leonard, Antony; Xu, Lei; Fazal, Fabeha; Rahman, Arshad

    2014-01-01

    We addressed the role of transglutaminase2 (TG2), a calcium-dependent enzyme that catalyzes crosslinking of proteins, in the mechanism of endothelial cell (EC) inflammation and lung PMN infiltration. Exposure of EC to thrombin, a procoagulant and proinflammatory mediator, resulted in activation of the transcription factor NF-κB and its target genes, VCAM-1, MCP-1, and IL-6. RNAi knockdown of TG2 inhibited these responses. Analysis of NF-κB activation pathway showed that TG2 knockdown was associated with inhibition of thrombin-induced DNA binding as well as serine phosphorylation of RelA/p65, a crucial event that controls transcriptional capacity of the DNA-bound RelA/p65. These results implicate an important role for TG2 in mediating EC inflammation by promoting DNA binding and transcriptional activity of RelA/p65. Because thrombin is released in high amounts during sepsis and its concentration is elevated in plasma and lavage fluids of patients with Acute Respiratory Distress Syndrome (ARDS), we determined the in vivo relevance of TG2 in a mouse model of sepsis-induced lung PMN recruitment. A marked reduction in NF-κB activation, adhesion molecule expression, and lung PMN sequestration was observed in TG2 knockout mice compared to wild type mice exposed to endotoxemia. Together, these results identify TG2 as an important mediator of EC inflammation and lung PMN sequestration associated with intravascular coagulation and sepsis. PMID:25057925

  12. Inhibiting Bruton's Tyrosine Kinase Rescues Mice from Lethal Influenza Induced Acute Lung Injury.

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    Florence, Jon M; Krupa, Agnieszka; Booshehri, Laela M; Davis, Sandra A; Matthay, Michael A; Kurdowska, Anna K

    2018-03-08

    Infection with seasonal influenza A virus (IAV) leads to lung inflammation and respiratory failure, a main cause of death in influenza infected patients. Previous experiments in our laboratory indicated that Bruton's tyrosine kinase (Btk) plays a substantial role in regulating inflammation in the respiratory region during acute lung injury (ALI) in mice, therefore we sought to determine if blocking Btk activity had a protective effect in the lung during influenza induced inflammation. A Btk inhibitor (Btk Inh.) Ibrutinib (also known as PCI-32765) was administered intranasally to mice starting 72h after lethal infection with IAV. Our data indicates that treatment with the Btk inhibitor not only reduced weight loss and led to survival, but had a dramatic effect on morphological changes to the lungs of IAV infected mice. Attenuation of lung inflammation indicative of ALI such as alveolar hemorrhage, interstitial thickening, and the presence of alveolar exudate, together with reduced levels of inflammatory mediators TNFα, IL-1β, IL-6, KC, and MCP-1 strongly suggest amelioration of the pathological immune response in the lungs to promote resolution of the infection. Finally, we observed that blocking Btk specifically in the alveolar compartment led to significant attenuation of neutrophil extracellular traps (NET)s released into the lung in vivo, and NET formation in vitro. Our innovative findings suggest that Btk may be a new drug target for influenza induced lung injury, and in general immunomodulatory treatment may be key in treating lung dysfunction driven by excessive inflammation.

  13. Polyhexamethyleneguanidine phosphate induces severe lung inflammation, fibrosis, and thymic atrophy.

    Science.gov (United States)

    Song, Jeong Ah; Park, Hyun-Ju; Yang, Mi-Jin; Jung, Kyung Jin; Yang, Hyo-Seon; Song, Chang-Woo; Lee, Kyuhong

    2014-07-01

    Polyhexamethyleneguanidine phosphate (PHMG-P) has been widely used as a disinfectant because of its strong bactericidal activity and low toxicity. However, in 2011, the Korea Centers for Disease Control and Prevention and the Ministry of Health and Welfare reported that a suspicious outbreak of pulmonary disease might have originated from humidifier disinfectants. The purpose of this study was to assess the toxicity of PHMG-P following direct exposure to the lung. PHMG-P (0.3, 0.9, or 1.5 mg/kg) was instilled into the lungs of mice. The levels of proinflammatory markers and fibrotic markers were quantified in lung tissues and flow cytometry was used to evaluate T cell distribution in the thymus. Administration of PHMG-P induced proinflammatory cytokines elevation and infiltration of immune cells into the lungs. Histopathological analysis revealed a dose-dependent exacerbation of both inflammation and pulmonary fibrosis on day 14. PHMG-P also decreased the total cell number and the CD4(+)/CD8(+) cell ratio in the thymus, with the histopathological examination indicating severe reduction of cortex and medulla. The mRNA levels of biomarkers associated with T cell development also decreased markedly. These findings suggest that exposure of lung tissue to PHMG-P leads to pulmonary inflammation and fibrosis as well as thymic atrophy. Copyright © 2014 Elsevier Ltd. All rights reserved.

  14. Apocynin and ebselen reduce influenza A virus-induced lung inflammation in cigarette smoke-exposed mice.

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    Oostwoud, L C; Gunasinghe, P; Seow, H J; Ye, J M; Selemidis, S; Bozinovski, S; Vlahos, R

    2016-02-15

    Influenza A virus (IAV) infections are a common cause of acute exacerbations of chronic obstructive pulmonary disease (AECOPD). Oxidative stress is increased in COPD, IAV-induced lung inflammation and AECOPD. Therefore, we investigated whether targeting oxidative stress with the Nox2 oxidase inhibitors and ROS scavengers, apocynin and ebselen could ameliorate lung inflammation in a mouse model of AECOPD. Male BALB/c mice were exposed to cigarette smoke (CS) generated from 9 cigarettes per day for 4 days. On day 5, mice were infected with 1 × 10(4.5) PFUs of the IAV Mem71 (H3N1). BALF inflammation, viral titers, superoxide production and whole lung cytokine, chemokine and protease mRNA expression were assessed 3 and 7 days post infection. IAV infection resulted in a greater increase in BALF inflammation in mice that had been exposed to CS compared to non-smoking mice. This increase in BALF inflammation in CS-exposed mice caused by IAV infection was associated with elevated gene expression of pro-inflammatory cytokines, chemokines and proteases, compared to CS alone mice. Apocynin and ebselen significantly reduced the exacerbated BALF inflammation and pro-inflammatory cytokine, chemokine and protease expression caused by IAV infection in CS mice. Targeting oxidative stress using apocynin and ebselen reduces IAV-induced lung inflammation in CS-exposed mice and may be therapeutically exploited to alleviate AECOPD.

  15. Time course of polyhexamethyleneguanidine phosphate-induced lung inflammation and fibrosis in mice.

    Science.gov (United States)

    Song, Jeongah; Kim, Woojin; Kim, Yong-Bum; Kim, Bumseok; Lee, Kyuhong

    2018-04-15

    Pulmonary fibrosis is a chronic progressive disease with unknown etiology and has poor prognosis. Polyhexamethyleneguanidine phosphate (PHMG-P) causes acute interstitial pneumonia and pulmonary fibrosis in humans when it exposed to the lung. In a previous study, when rats were exposed to PHMG-P through inhalation for 3 weeks, lung inflammation and fibrosis was observed even after 3 weeks of recovery. In this study, we aimed to determine the time course of PHMG-P-induced lung inflammation and fibrosis. We compared pathological action of PHMG-P with that of bleomycin (BLM) and investigated the mechanism underlying PHMG-P-induced lung inflammation and fibrosis. PHMG-P (0.9 mg/kg) or BLM (1.5 mg/kg) was intratracheally administered to mice. At weeks 1, 2, 4 and 10 after instillation, the levels of inflammatory and fibrotic markers and the expression of inflammasome proteins were measured. The inflammatory and fibrotic responses were upregulated until 10 and 4 weeks in the PHMG-P and BLM groups, respectively. Immune cell infiltration and considerable collagen deposition in the peribronchiolar and interstitial areas of the lungs, fibroblast proliferation, and hyperplasia of type II epithelial cells were observed. NALP3 inflammasome activation was detected in the PHMG-P group until 4 weeks, which is suspected to be the main reason for the persistent inflammatory response and exacerbation of fibrotic changes. Most importantly, the pathological changes in the PHMG-P group were similar to those observed in humidifier disinfectant-associated patients. A single exposure of PHMG-P led to persistent pulmonary inflammation and fibrosis for at least 10 weeks. Copyright © 2018. Published by Elsevier Inc.

  16. Impact of interleukin-6 on hypoxia-induced pulmonary hypertension and lung inflammation in mice

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    Izziki Mohamed

    2009-01-01

    Full Text Available Abstract Background Inflammation may contribute to the pathogenesis of various forms of pulmonary hypertension (PH. Recent studies in patients with idiopathic PH or PH associated with underlying diseases suggest a role for interleukin-6 (IL-6. Methods To determine whether endogenous IL-6 contributes to mediate hypoxic PH and lung inflammation, we studied IL-6-deficient (IL-6-/- and wild-type (IL-6+/+ mice exposed to hypoxia for 2 weeks. Results Right ventricular systolic pressure, right ventricle hypertrophy, and the number and media thickness of muscular pulmonary vessels were decreased in IL-6-/- mice compared to wild-type controls after 2 weeks' hypoxia, although the pressure response to acute hypoxia was similar in IL-6+/+ and IL-6-/- mice. Hypoxia exposure of IL-6+/+ mice led to marked increases in IL-6 mRNA and protein levels within the first week, with positive IL-6 immunostaining in the pulmonary vessel walls. Lung IL-6 receptor and gp 130 (the IL-6 signal transducer mRNA levels increased after 1 and 2 weeks' hypoxia. In vitro studies of cultured human pulmonary-artery smooth-muscle-cells (PA-SMCs and microvascular endothelial cells revealed prominent synthesis of IL-6 by PA-SMCs, with further stimulation by hypoxia. IL-6 also markedly stimulated PA-SMC migration without affecting proliferation. Hypoxic IL-6-/- mice showed less inflammatory cell recruitment in the lungs, compared to hypoxic wild-type mice, as assessed by lung protein levels and immunostaining for the specific macrophage marker F4/80, with no difference in lung expression of adhesion molecules or cytokines. Conclusion These data suggest that IL-6 may be actively involved in hypoxia-induced lung inflammation and pulmonary vascular remodeling in mice.

  17. Sub-chronic lung inflammation after airway exposures to Bacillus thuringiensis biopesticides in mice

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    Barfod Kenneth K

    2010-09-01

    Full Text Available Abstract Background The aim of the present study was to assess possible health effects of airway exposures to Bacillus thuringiensis (Bt based biopesticides in mice. Endpoints were lung inflammation evaluated by presence of inflammatory cells in bronchoalveolar lavage fluid (BALF, clearance of bacteria from the lung lumen and histological alterations of the lungs. Hazard identifications of the biopesticides were carried out using intratracheal (i.t. instillation, followed by an inhalation study. The two commercial biopesticides used were based on the Bt. subspecies kurstaki and israelensis, respectively. Groups of BALB/c mice were i.t instilled with one bolus (3.5 × 105 or 3.4 × 106 colony forming units (CFU per mouse of either biopesticide. Control mice were instilled with sterile water. BALFs were collected and the inflammatory cells were counted and differentiated. The BALFs were also subjected to CFU counts. Results BALF cytology showed an acute inflammatory response dominated by neutrophils 24 hours after instillation of biopesticide. Four days after instillation, the neutrophil number was normalised and inflammation was dominated by lymphocytes and eosinophils, whereas 70 days after instillation, the inflammation was interstitially located with few inflammatory cells present in the lung lumen. Half of the instilled mice had remaining CFU recovered from BALF 70 days after exposure. To gain further knowledge with relevance for risk assessment, mice were exposed to aerosols of biopesticide one hour per day for 2 × 5 days. Each mouse received 1.9 × 104 CFU Bt israelensis or 2.3 × 103 CFU Bt kurstaki per exposure. Seventy days after end of the aerosol exposures, 3 out of 17 mice had interstitial lung inflammation. CFU could be recovered from 1 out of 10 mice 70 days after exposure to aerosolised Bt kurstaki. Plethysmography showed that inhalation of Bt aerosol did not induce airway irritation. Conclusions Repeated low dose aerosol

  18. Aspirin-triggered resolvin D1 reduces pneumococcal lung infection and inflammation in a viral and bacterial coinfection pneumonia model.

    Science.gov (United States)

    Wang, Hao; Anthony, Desiree; Yatmaz, Selcuk; Wijburg, Odilia; Satzke, Catherine; Levy, Bruce; Vlahos, Ross; Bozinovski, Steven

    2017-09-15

    Formyl peptide receptor 2/lipoxin A 4 (LXA 4 ) receptor (Fpr2/ALX) co-ordinates the transition from inflammation to resolution during acute infection by binding to distinct ligands including serum amyloid A (SAA) and Resolvin D1 (RvD1). Here, we evaluated the proresolving actions of aspirin-triggered RvD1 (AT-RvD1) in an acute coinfection pneumonia model. Coinfection with Streptococcus pneumoniae and influenza A virus (IAV) markedly increased pneumococcal lung load and neutrophilic inflammation during the resolution phase. Fpr2/ALX transcript levels were increased in the lungs of coinfected mice, and immunohistochemistry identified prominent Fpr2/ALX immunoreactivity in bronchial epithelial cells and macrophages. Levels of circulating and lung SAA were also highly increased in coinfected mice. Therapeutic treatment with exogenous AT-RvD1 during the acute phase of infection (day 4-6 post-pneumococcal inoculation) significantly reduced the pneumococcal load. AT-RvD1 also significantly reduced neutrophil elastase (NE) activity and restored total antimicrobial activity in bronchoalveolar lavage (BAL) fluid (BALF) of coinfected mice. Pneumonia severity, as measured by quantitating parenchymal inflammation or alveolitis was significantly reduced with AT-RvD1 treatment, which also reduced the number of infiltrating lung neutrophils and monocytes/macrophages as assessed by flow cytometry. The reduction in distal lung inflammation in AT-RvD1-treated mice was not associated with a significant reduction in inflammatory and chemokine mediators. In summary, we demonstrate that in the coinfection setting, SAA levels were persistently increased and exogenous AT-RvD1 facilitated more rapid clearance of pneumococci in the lungs, while concurrently reducing the severity of pneumonia by limiting excessive leukocyte chemotaxis from the infected bronchioles to distal areas of the lungs. © 2017 The Author(s).

  19. Hypercapnic acidosis modulates inflammation, lung mechanics, and edema in the isolated perfused lung.

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    De Smet, Hilde R; Bersten, Andrew D; Barr, Heather A; Doyle, Ian R

    2007-12-01

    Low tidal volume (V(T)) ventilation strategies may be associated with permissive hypercapnia, which has been shown by ex vivo and in vivo studies to have protective effects. We hypothesized that hypercapnic acidosis may be synergistic with low V(T) ventilation; therefore, we studied the effects of hypercapnia and V(T) on unstimulated and lipopolysaccharide-stimulated isolated perfused lungs. Isolated perfused rat lungs were ventilated for 2 hours with low (7 mL/kg) or moderately high (20 mL/kg) V(T) and 5% or 20% CO(2), with lipopolysaccharide or saline added to the perfusate. Hypercapnia resulted in reduced pulmonary edema, lung stiffness, tumor necrosis factor alpha (TNF-alpha) and interleukin 6 (IL-6) in the lavage and perfusate. The moderately high V(T) did not cause lung injury but increased lavage IL-6 and perfusate IL-6 as well as TNF-alpha. Pulmonary edema and respiratory mechanics improved, possibly as a result of a stretch-induced increase in surfactant turnover. Lipopolysaccharide did not induce significant lung injury. We conclude that hypercapnia exerts a protective effect by modulating inflammation, lung mechanics, and edema. The moderately high V(T) used in this study stimulated inflammation but paradoxically improved edema and lung mechanics with an associated increase in surfactant release.

  20. Aging, not age-associated inflammation, determines blood pressure and endothelial responses to acute inflammation.

    Science.gov (United States)

    Lane-Cordova, Abbi D; Ranadive, Sushant M; Kappus, Rebecca M; Cook, Marc D; Phillips, Shane A; Woods, Jeffrey A; Wilund, Kenneth R; Baynard, Tracy; Fernhall, Bo

    2016-12-01

    Aging is characterized by a state of chronic, low-grade inflammation that impairs vascular function. Acute inflammation causes additional decrements in vascular function, but these responses are not uniform in older compared with younger adults. We sought to determine if older adults with low levels of baseline inflammation respond to acute inflammation in a manner similar to younger adults. We hypothesized age-related differences in the vascular responses to acute inflammation, but that older adults with low baseline inflammation would respond similarly to younger adults. Inflammation was induced with an influenza vaccine in 96 participants [older = 67 total, 38 with baseline C-reactive protein (CRP) > 1.5 mg/l and 29 with CRP < 1.5 mg/l; younger = 29]; serum inflammatory markers IL-6 and CRP, blood pressure and flow-mediated dilation (FMD) were measured 24 and 48 h later. Younger adults increased IL-6 and CRP more than the collective older adult group and increased pulse pressure, whereas older adults decreased SBP and reduced pulse pressure. The entire cohort decreased FMD from 11.3 ± 0.8 to 8.3 ± 0.7 to 8.7 ± 0.7% in younger and from 5.8 ± 0.3 to 5.0 ± 0.4 to 4.7 ± 0.4% in older adults, P less than 0.05 for main effect. Older adult groups with differing baseline CRP had the same IL-6, blood pressure, and FMD response to acute inflammation, P less than 0.05 for all interactions, but the low-CRP group increased CRP at 24 and 48 h (from 0.5 ± 0.1 to 1.4 ± 0.2 to 1.7 ± 0.3 mg/l), whereas the high-CRP group did not (from 4.8 ± 0.5 to 5.4 ± 0.5 to 5.4 ± 0.6 mg/l), P less than 0.001 for interaction. Aging, not age-related chronic, low-grade inflammation, determines the vascular responses to acute inflammation.

  1. Iron supplementation decreases severity of allergic inflammation in murine lung.

    Directory of Open Access Journals (Sweden)

    Laura P Hale

    Full Text Available The incidence and severity of allergic asthma have increased over the last century, particularly in the United States and other developed countries. This time frame was characterized by marked environmental changes, including enhanced hygiene, decreased pathogen exposure, increased exposure to inhaled pollutants, and changes in diet. Although iron is well-known to participate in critical biologic processes such as oxygen transport, energy generation, and host defense, iron deficiency remains common in the United States and world-wide. The purpose of these studies was to determine how dietary iron supplementation affected the severity of allergic inflammation in the lungs, using a classic model of IgE-mediated allergy in mice. Results showed that mice fed an iron-supplemented diet had markedly decreased allergen-induced airway hyperreactivity, eosinophil infiltration, and production of pro-inflammatory cytokines, compared with control mice on an unsupplemented diet that generated mild iron deficiency but not anemia. In vitro, iron supplementation decreased mast cell granule content, IgE-triggered degranulation, and production of pro-inflammatory cytokines post-degranulation. Taken together, these studies show that iron supplementation can decrease the severity of allergic inflammation in the lung, potentially via multiple mechanisms that affect mast cell activity. Further studies are indicated to determine the potential of iron supplementation to modulate the clinical severity of allergic diseases in humans.

  2. Nebulized hyaluronan ameliorates lung inflammation in cystic fibrosis mice.

    Science.gov (United States)

    Gavina, Manuela; Luciani, Alessandro; Villella, Valeria R; Esposito, Speranza; Ferrari, Eleonora; Bressani, Ilaria; Casale, Alida; Bruscia, Emanuela M; Maiuri, Luigi; Raia, Valeria

    2013-08-01

    Chronic lung inflammation with increased susceptibility to bacterial infections cause much of the morbidity and mortality in patients with cystic fibrosis (CF), the most common severe, autosomal recessively inherited disease in the Caucasian population. Exogenous inhaled hyaluronan (HA) can exert a protective effect against injury and beneficial effects of HA have been shown in experimental models of chronic respiratory diseases. Our objective was to examine whether exogenous administration of nebulized HA might interfere with lung inflammation in CF. F508del homozygous mice (Cftr(F508del) ) and transgenic mice overexpressing the ENaC channel β-subunit (Scnn1b-Tg) were treated with nebulized HA (0.5 mg/mouse/day for 7 days). Tumor necrosis factor-alpha (TNFα), macrophage inflammatory protein-2 (MIP-2), myeloperoxidase (MPO) levels, and macrophage infiltration were assessed on lung tissues. IB3-1 and CFBE41o-epithelial cell lines were cultured with HA (24 hr, 100 µg/ml) and Reactive Oxygen Species (ROS), Tissue Transglutaminase (TG2) SUMOylation and Peroxisome Proliferator Activated Receptor gamma (PPARγ) and phospho-p42/p44 levels were measured by dichlorodihydrofluorescein assay, or fluorescence resonance energy transfer (FRET) microscopy or immunoblots. Nebulized HA reduced TNFα expression (P < 0.005); TNFα, MIP-2, and MPO protein levels (P < 0.05); MPO activity (P < 0.05); and CD68+ cells counts (P < 0.005) in lung tissues of Cftr(F508del) and Scnn1b-Tg mice, compared with saline-treated mice. HA reduced ROS, TG2 SUMOylation, TG2 activity, phospho-p42-44, and increased PPARγ protein in both IB3-1 and CFBE41o cells (P < 0.05). Nebulized HA is effective in controlling inflammation in vivo in mice CF airways and in vitro in human airway epithelial cells. We provide the proof of concept for the use of inhaled HA as a potential anti-inflammatory drug in CF therapy. Copyright © 2012 Wiley Periodicals, Inc.

  3. Role of glutathione in immunity and inflammation in the lung

    Directory of Open Access Journals (Sweden)

    Pietro Ghezzi

    2011-01-01

    Full Text Available Pietro GhezziBrighton and Sussex Medical School, Trafford Centre, Falmer, Brighton, UKAbstract: Reactive oxygen species and thiol antioxidants, including glutathione (GSH, regulate innate immunity at various levels. This review outlines the redox-sensitive steps of the cellular mechanisms implicated in inflammation and host defense against infection, and describes how GSH is not only important as an antioxidant but also as a signaling molecule. There is an extensive literature of the role of GSH in immunity. Most reviews are biased by an oversimplified picture where “bad” free radicals cause all sorts of diseases and “good” antioxidants protect from them and prevent oxidative stress. While this may be the case in certain fields (eg, toxicology, the role of thiols (the topic of this review in immunity certainly requires wearing scientist’s goggles and being prepared to accept a more complex picture. This review aims at describing the role of GSH in the lung in the context of immunity and inflammation. The first part summarizes the history and basic concepts of this picture. The second part focuses on GSH metabolism/levels in pathology, the third on the role of GSH in innate immunity and inflammation, and the fourth gives 4 examples describing the importance of GSH in the response to infections.Keywords: antioxidants, oxidative stress, sepsis, infection, cysteine

  4. The axonal guidance receptor neogenin promotes acute inflammation.

    Directory of Open Access Journals (Sweden)

    Klemens König

    Full Text Available Neuronal guidance proteins (NGP were originally described in the context of axonal growth and migration. Yet recent work has demonstrated that NGPs also serve as guidance cues for immune competent cells. A crucial target receptor for NGPs during embryonic development is the neogenin receptor, however its role during acute inflammation is unknown. We report here that neogenin is abundantly expressed outside the nervous system and that animals with endogenous repression of neogenin (Neo1(-/- demonstrate attenuated changes of acute inflammation. Studies using functional inhibition of neogenin resulted in a significant attenuation of inflammatory peritonitis. In studies employing bone marrow chimeric animals we found the hematopoietic presence of Neo1(-/- to be responsible for the attenuated inflammatory response. Taken together our studies suggest that the guidance receptor neogenin holds crucial importance for the propagation of an acute inflammatory response and further define mechanisms shared between the nervous and the immune system.

  5. Acute lung injury and acute respiratory distress syndrome

    Directory of Open Access Journals (Sweden)

    Ragaller Maximillian

    2010-01-01

    Full Text Available Every year, more information accumulates about the possibility of treating patients with acute lung injury or acute respiratory distress syndrome with specially designed mechanical ventilation strategies. Ventilator modes, positive end-expiratory pressure settings, and recruitment maneuvers play a major role in these strategies. However, what can we take from these experimental and clinical data to the clinical practice? In this article, we discuss substantial options of mechanical ventilation together with some adjunctive therapeutic measures, such as prone positioning and inhalation of nitric oxide.

  6. The effects of exogenous surfactant administration on ventilation-induced inflammation in mouse models of lung injury.

    Science.gov (United States)

    Puntorieri, Valeria; Hiansen, Josh Qua; McCaig, Lynda A; Yao, Li-Juan; Veldhuizen, Ruud A W; Lewis, James F

    2013-11-20

    Mechanical ventilation (MV) is an essential supportive therapy for acute lung injury (ALI); however it can also contribute to systemic inflammation. Since pulmonary surfactant has anti-inflammatory properties, the aim of the study was to investigate the effect of exogenous surfactant administration on ventilation-induced systemic inflammation. Mice were randomized to receive an intra-tracheal instillation of a natural exogenous surfactant preparation (bLES, 50 mg/kg) or no treatment as a control. MV was then performed using the isolated and perfused mouse lung (IPML) set up. This model allowed for lung perfusion during MV. In experiment 1, mice were exposed to mechanical ventilation only (tidal volume =20 mL/kg, 2 hours). In experiment 2, hydrochloric acid or air was instilled intra-tracheally four hours before applying exogenous surfactant and ventilation (tidal volume =5 mL/kg, 2 hours). For both experiments, exogenous surfactant administration led to increased total and functional surfactant in the treated groups compared to the controls. Exogenous surfactant administration in mice exposed to MV only did not affect peak inspiratory pressure (PIP), lung IL-6 levels and the development of perfusate inflammation compared to non-treated controls. Acid injured mice exposed to conventional MV showed elevated PIP, lung IL-6 and protein levels and greater perfusate inflammation compared to air instilled controls. Instillation of exogenous surfactant did not influence the development of lung injury. Moreover, exogenous surfactant was not effective in reducing the concentration of inflammatory cytokines in the perfusate. The data indicates that exogenous surfactant did not mitigate ventilation-induced systemic inflammation in our models. Future studies will focus on altering surfactant composition to improve its immuno-modulating activity.

  7. A PAF receptor antagonist inhibits acute airway inflammation and late-phase responses but not chronic airway inflammation and hyperresponsiveness in a primate model of asthma

    Directory of Open Access Journals (Sweden)

    R. H. Gundel

    1992-01-01

    Full Text Available We have examined the effects of a PAF receptor antagonist, WEB 2170, on several indices of acute and chronic airway inflammation and associated changes in lung function in a primate model of allergic asthma. A single oral administration WEB 2170 provided dose related inhibition of the release of leukotriene C4 (LTC4 and prostaglandin D2 (PGD2 recovered and quantified in bronchoalveolar lavage (BAL fluid obtained during the acute phase response to inhaled antigen. In addition, oral WEB 2170 treatment in dual responder primates blocked the acute influx of neutrophils into the airways as well as the associated late-phase airway obstruction occurring 6 h after antigen inhalation. In contrast, a multiple dosing regime with WEB 2170 (once a day for 7 consecutive days failed to reduce the chronic airway inflammation (eosinophilic and associated airway hyperresponsiveness to inhaled methacholine that is characteristic of dual responder monkeys. Thus, we conclude that the generation of PAF following antigen inhalation contributes to the development of lipid mediators, acute airway inflammation and associated late-phase airway obstruction in dual responder primates; however, PAF does not play a significant role in the maintenance of chronic airway inflammation and associated airway hyperresponsiveness in this primate model.

  8. Critical role of non-muscle myosin light chain kinase in thrombin-induced endothelial cell inflammation and lung PMN infiltration.

    Science.gov (United States)

    Fazal, Fabeha; Bijli, Kaiser M; Murrill, Matthew; Leonard, Antony; Minhajuddin, Mohammad; Anwar, Khandaker N; Finkelstein, Jacob N; Watterson, D Martin; Rahman, Arshad

    2013-01-01

    The pathogenesis of acute lung injury (ALI) involves bidirectional cooperation and close interaction between inflammatory and coagulation pathways. A key molecule linking coagulation and inflammation is the procoagulant thrombin, a serine protease whose concentration is elevated in plasma and lavage fluids of patients with ALI and acute respiratory distress syndrome (ARDS). However, little is known about the mechanism by which thrombin contributes to lung inflammatory response. In this study, we developed a new mouse model that permits investigation of lung inflammation associated with intravascular coagulation. Using this mouse model and in vitro approaches, we addressed the role of non-muscle myosin light chain kinase (nmMLCK) in thrombin-induced endothelial cell (EC) inflammation and lung neutrophil (PMN) infiltration. Our in vitro experiments revealed a key role of nmMLCK in ICAM-1 expression by its ability to control nuclear translocation and transcriptional capacity of RelA/p65 in EC. When subjected to intraperitoneal thrombin challenge, wild type mice showed a marked increase in lung PMN infiltration via expression of ICAM-1. However, these responses were markedly attenuated in mice deficient in nmMLCK. These results provide mechanistic insight into lung inflammatory response associated with intravascular coagulation and identify nmMLCK as a critical target for modulation of lung inflammation.

  9. Creatine kinase activity in dogs with experimentally induced acute inflammation

    Directory of Open Access Journals (Sweden)

    Dimitrinka Zapryanova

    2013-01-01

    Full Text Available The main purpose of this study was to investigate the effect of acute inflammation on total creatine kinase (CK activity in dogs. In these animals, CK is an enzyme found predominantly in skeletal muscle and significantly elevated serum activity is largely associated with muscle damage. Plasma increases in dogs are associated with cell membrane leakage and will therefore be seen in any condition associated with muscular inflammation. The study was induced in 15 mongrel male dogs (n=9 in experimental group and n=6 in control group at the age of two years and body weight 12-15 kg. The inflammation was reproduced by inoculation of 2 ml turpentine oil subcutaneously in lumbar region. The plasma activity of creatine kinase was evaluated at 0, 6, 24, 48, 72 hours after inoculation and on days 7, 14 and 21 by a kit from Hospitex Diagnostics. In the experimental group, the plasma concentrations of the CK-activity were increased at the 48th hour (97.48±6.92 U/L and remained significantly higher (p<0.05 at the 72 hour (97.43±2.93 U/L compared to the control group (77.08±5.27 U/L. The results of this study suggest that the evaluation of creatine kinase in dogs with experimentally induced acute inflammation has a limited diagnostic value. It was observed that the creatine kinase activity is slightly affected by the experimentally induced acute inflammation in dogs.

  10. The novel cytokine interleukin-33 activates acinar cell proinflammatory pathways and induces acute pancreatic inflammation in mice.

    Directory of Open Access Journals (Sweden)

    Duraisamy Kempuraj

    Full Text Available Acute pancreatitis is potentially fatal but treatment options are limited as disease pathogenesis is poorly understood. IL-33, a novel IL-1 cytokine family member, plays a role in various inflammatory conditions but its role in acute pancreatitis is not well understood. Specifically, whether pancreatic acinar cells produce IL-33 when stressed or respond to IL-33 stimulation, and whether IL-33 exacerbates acute pancreatic inflammation is unknown.In duct ligation-induced acute pancreatitis in mice and rats, we found that (a IL-33 concentration was increased in the pancreas; (b mast cells, which secrete and also respond to IL-33, showed degranulation in the pancreas and lung; (c plasma histamine and pancreatic substance P concentrations were increased; and (d pancreatic and pulmonary proinflammatory cytokine concentrations were increased. In isolated mouse pancreatic acinar cells, TNF-α stimulation increased IL-33 release while IL-33 stimulation increased proinflammatory cytokine release, both involving the ERK MAP kinase pathway; the flavonoid luteolin inhibited IL-33-stimulated IL-6 and CCL2/MCP-1 release. In mice without duct ligation, exogenous IL-33 administration induced pancreatic inflammation without mast cell degranulation or jejunal inflammation; pancreatic changes included multifocal edema and perivascular infiltration by neutrophils and some macrophages. ERK MAP kinase (but not p38 or JNK and NF-kB subunit p65 were activated in the pancreas of mice receiving exogenous IL-33, and acinar cells isolated from the pancreas of these mice showed increased spontaneous cytokine release (IL-6, CXCL2/MIP-2α. Also, IL-33 activated ERK in human pancreatic tissue.As exogenous IL-33 does not induce jejunal inflammation in the same mice in which it induces pancreatic inflammation, we have discovered a potential role for an IL-33/acinar cell axis in the recruitment of neutrophils and macrophages and the exacerbation of acute pancreatic inflammation

  11. Cell kinetics and acute lung injury

    International Nuclear Information System (INIS)

    Witschi, H.P.; Whitaker, M.S.

    1987-01-01

    In order to estimate whether acute lung injury is followed by a stereotype pattern of cell proliferation in the lungs, mice were treated with three cytostatic drugs: cyclophosphamide, busulfan, or 1,3-Bis(2-chloroethyl)-1-nitrosourea (BCNU). The alveolar labeling index was measured following drug administration with a pulse of 3 H-labeled thymidine and autoradiography. In cyclophosphamide treated animals, peak alveolar cell proliferation was seen 5 days after injection of the drug. In animals treated with busulfan or BCNU, proliferation was even more delayed (occurring 2 to 3 wks after administration). In contrast, with oleic acid, the highest alveolar cell labeling was found 2 days after intravenous administration. In animals exposed to a cytostatic drug, proliferation of type II alveolar cells was never a prominent feature; whereas, in animals treated with oleic acid there was an initial burst of type II cell proliferation. It was concluded that the patterns of pulmonary repair vary between chemical designed to interfere with DNA replication as compared to agents which produce acute lung damage such as oleic acid

  12. Aerobic Exercise Decreases Lung Inflammation by IgE Decrement in an OVA Mice Model.

    Science.gov (United States)

    Camargo Hizume-Kunzler, Deborah; Greiffo, Flavia R; Fortkamp, Bárbara; Ribeiro Freitas, Gabriel; Keller Nascimento, Juliana; Regina Bruggemann, Thayse; Melo Avila, Leonardo; Perini, Adenir; Bobinski, Franciane; Duarte Silva, Morgana; Rocha Lapa, Fernanda; Paula Vieira, Rodolfo; Vargas Horewicz, Verônica; Soares Dos Santos, Adair Roberto; Cattelan Bonorino, Kelly

    2017-06-01

    Aerobic exercise (AE) reduces lung function decline and risk of exacerbations in asthmatic patients. However, the inflammatory lung response involved in exercise during the sensitization remains unclear. Therefore, we evaluated the effects of exercise for 2 weeks in an experimental model of sensitization and single ovalbumin-challenge. Mice were divided into 4 groups: mice non-sensitized and not submitted to exercise (Sedentary, n=10); mice non-sensitized and submitted to exercise (Exercise, n=10); mice sensitized and exposed to ovalbumin (OVA, n=10); and mice sensitized, submitted to exercise and exposed to OVA (OVA+Exercise, n=10). 24 h after the OVA/saline exposure, we counted inflammatory cells from bronchoalveolar fluid (BALF), lung levels of total IgE, IL-4, IL-5, IL-10 and IL-1ra, measurements of OVA-specific IgG1 and IgE, and VEGF and NOS-2 expression via western blotting. AE reduced cell counts from BALF in the OVA group (p<0.05), total IgE, IL-4 and IL-5 lung levels and OVA-specific IgE and IgG1 titers (p<0.05). There was an increase of NOS-2 expression, IL-10 and IL-1ra lung levels in the OVA groups (p<0.05). Our results showed that AE attenuated the acute lung inflammation, suggesting immunomodulatory properties on the sensitization process in the early phases of antigen presentation in asthma. © Georg Thieme Verlag KG Stuttgart · New York.

  13. Silica-induced Chronic Inflammation Promotes Lung Carcinogenesis in the Context of an Immunosuppressive Microenvironment

    Directory of Open Access Journals (Sweden)

    Javier Freire

    2013-08-01

    Full Text Available The association between inflammation and lung tumor development has been clearly demonstrated. However, little is known concerning the molecular events preceding the development of lung cancer. In this study, we characterize a chemically induced lung cancer mouse model in which lung cancer developed in the presence of silicotic chronic inflammation. Silica-induced lung inflammation increased the incidence and multiplicity of lung cancer in mice treated with N-nitrosodimethylamine, a carcinogen found in tobacco smoke. Histologic and molecular analysis revealed that concomitant chronic inflammation contributed to lung tumorigenesis through induction of preneoplastic changes in lung epithelial cells. In addition, silica-mediated inflammation generated an immunosuppressive microenvironment in which we observed increased expression of programmed cell death protein 1 (PD-1, transforming growth factor-β1, monocyte chemotactic protein 1 (MCP-1, lymphocyte-activation gene 3 (LAG3, and forkhead box P3 (FOXP3, as well as the presence of regulatory T cells. Finally, the K-RAS mutational profile of the tumors changed from Q61R to G12D mutations in the inflammatory milieu. In summary, we describe some of the early molecular changes associated to lung carcinogenesis in a chronic inflammatory microenvironment and provide novel information concerning the mechanisms underlying the formation and the fate of preneoplastic lesions in the silicotic lung.

  14. Nanosilver induces minimal lung toxicity or inflammation in a subacute murine inhalation model

    Directory of Open Access Journals (Sweden)

    O'Shaughnessy Patrick T

    2011-01-01

    Full Text Available Abstract Background There is increasing interest in the environmental and health consequences of silver nanoparticles as the use of this material becomes widespread. Although human exposure to nanosilver is increasing, only a few studies address possible toxic effect of inhaled nanosilver. The objective of this study was to determine whether very small commercially available nanosilver induces pulmonary toxicity in mice following inhalation exposure. Results In this study, mice were exposed sub-acutely by inhalation to well-characterized nanosilver (3.3 mg/m3, 4 hours/day, 10 days, 5 ± 2 nm primary size. Toxicity was assessed by enumeration of total and differential cells, determination of total protein, lactate dehydrogenase activity and inflammatory cytokines in bronchoalveolar lavage fluid. Lungs were evaluated for histopathologic changes and the presence of silver. In contrast to published in vitro studies, minimal inflammatory response or toxicity was found following exposure to nanosilver in our in vivo study. The median retained dose of nanosilver in the lungs measured by inductively coupled plasma - optical emission spectroscopy (ICP-OES was 31 μg/g lung (dry weight immediately after the final exposure, 10 μg/g following exposure and a 3-wk rest period and zero in sham-exposed controls. Dissolution studies showed that nanosilver did not dissolve in solutions mimicking the intracellular or extracellular milieu. Conclusions Mice exposed to nanosilver showed minimal pulmonary inflammation or cytotoxicity following sub-acute exposures. However, longer term exposures with higher lung burdens of nanosilver are needed to ensure that there are no chronic effects and to evaluate possible translocation to other organs.

  15. Linking Inflammation, Cardiorespiratory Variability, and Neural Control in Acute Inflammation via Computational Modeling.

    Science.gov (United States)

    Dick, Thomas E; Molkov, Yaroslav I; Nieman, Gary; Hsieh, Yee-Hsee; Jacono, Frank J; Doyle, John; Scheff, Jeremy D; Calvano, Steve E; Androulakis, Ioannis P; An, Gary; Vodovotz, Yoram

    2012-01-01

    Acute inflammation leads to organ failure by engaging catastrophic feedback loops in which stressed tissue evokes an inflammatory response and, in turn, inflammation damages tissue. Manifestations of this maladaptive inflammatory response include cardio-respiratory dysfunction that may be reflected in reduced heart rate and ventilatory pattern variabilities. We have developed signal-processing algorithms that quantify non-linear deterministic characteristics of variability in biologic signals. Now, coalescing under the aegis of the NIH Computational Biology Program and the Society for Complexity in Acute Illness, two research teams performed iterative experiments and computational modeling on inflammation and cardio-pulmonary dysfunction in sepsis as well as on neural control of respiration and ventilatory pattern variability. These teams, with additional collaborators, have recently formed a multi-institutional, interdisciplinary consortium, whose goal is to delineate the fundamental interrelationship between the inflammatory response and physiologic variability. Multi-scale mathematical modeling and complementary physiological experiments will provide insight into autonomic neural mechanisms that may modulate the inflammatory response to sepsis and simultaneously reduce heart rate and ventilatory pattern variabilities associated with sepsis. This approach integrates computational models of neural control of breathing and cardio-respiratory coupling with models that combine inflammation, cardiovascular function, and heart rate variability. The resulting integrated model will provide mechanistic explanations for the phenomena of respiratory sinus-arrhythmia and cardio-ventilatory coupling observed under normal conditions, and the loss of these properties during sepsis. This approach holds the potential of modeling cross-scale physiological interactions to improve both basic knowledge and clinical management of acute inflammatory diseases such as sepsis and trauma.

  16. Acute lung injury and persistent small airway disease in a rabbit model of chlorine inhalation

    Energy Technology Data Exchange (ETDEWEB)

    Musah, Sadiatu; Schlueter, Connie F.; Humphrey, David M. [Department of Environmental and Occupational Health Sciences, School of Public Health and Information Sciences, University of Louisville, Louisville, KY (United States); Powell, Karen S. [Research Resource Facilities, University of Louisville, Louisville, KY (United States); Roberts, Andrew M. [Department of Physiology, University of Louisville, Louisville, KY (United States); Hoyle, Gary W., E-mail: Gary.Hoyle@louisville.edu [Department of Environmental and Occupational Health Sciences, School of Public Health and Information Sciences, University of Louisville, Louisville, KY (United States)

    2017-01-15

    Chlorine is a pulmonary toxicant to which humans can be exposed through accidents or intentional releases. Acute effects of chlorine inhalation in humans and animal models have been well characterized, but less is known about persistent effects of acute, high-level chlorine exposures. In particular, animal models that reproduce the long-term effects suggested to occur in humans are lacking. Here, we report the development of a rabbit model in which both acute and persistent effects of chlorine inhalation can be assessed. Male New Zealand White rabbits were exposed to chlorine while the lungs were mechanically ventilated. After chlorine exposure, the rabbits were extubated and were allowed to survive for up to 24 h after exposure to 800 ppm chlorine for 4 min to study acute effects or up to 7 days after exposure to 400 ppm for 8 min to study longer term effects. Acute effects observed 6 or 24 h after inhalation of 800 ppm chlorine for 4 min included hypoxemia, pulmonary edema, airway epithelial injury, inflammation, altered baseline lung mechanics, and airway hyperreactivity to inhaled methacholine. Seven days after recovery from inhalation of 400 ppm chlorine for 8 min, rabbits exhibited mild hypoxemia, increased area of pressure–volume loops, and airway hyperreactivity. Lung histology 7 days after chlorine exposure revealed abnormalities in the small airways, including inflammation and sporadic bronchiolitis obliterans lesions. Immunostaining showed a paucity of club and ciliated cells in the epithelium at these sites. These results suggest that small airway disease may be an important component of persistent respiratory abnormalities that occur following acute chlorine exposure. This non-rodent chlorine exposure model should prove useful for studying persistent effects of acute chlorine exposure and for assessing efficacy of countermeasures for chlorine-induced lung injury. - Highlights: • A novel rabbit model of chlorine-induced lung disease was developed.

  17. Lung inflammation biomarkers and lung function in children chronically exposed to arsenic

    Energy Technology Data Exchange (ETDEWEB)

    Olivas-Calderón, Edgar, E-mail: edgar_olivascalderon@hotmail.com [Department of Environmental Health, Biomedical Research Center, School of Medicine, University of Coahuila, Torreon, Coahuila (Mexico); School of Medicine, University Juarez of Durango, Gomez Palacio, Durango (Mexico); Recio-Vega, Rogelio, E-mail: rrecio@yahoo.com [Department of Environmental Health, Biomedical Research Center, School of Medicine, University of Coahuila, Torreon, Coahuila (Mexico); Gandolfi, A. Jay, E-mail: gandolfi@pharmacy.arizona.edu [Southwest Environmental Health Science Center, University of Arizona, Tucson, AZ (United States); Department of Cellular and Molecular Medicine, University of Arizona, Tucson, AZ (United States); Lantz, R. Clark, E-mail: lantz@email.arizona.edu [Department of Cellular and Molecular Medicine, University of Arizona, Tucson, AZ (United States); Department of Pharmacology and Toxicology, University of Arizona, Tucson, AZ (United States); González-Cortes, Tania, E-mail: taniagc2201@hotmail.com [Department of Environmental Health, Biomedical Research Center, School of Medicine, University of Coahuila, Torreon, Coahuila (Mexico); Gonzalez-De Alba, Cesar, E-mail: cesargonzalezalba@hotmail.com [Department of Environmental Health, Biomedical Research Center, School of Medicine, University of Coahuila, Torreon, Coahuila (Mexico); Froines, John R., E-mail: jfroines@ucla.edu [Center for Environmental and Occupational Health, School of Public Health, University of California at Los Angeles, Los Angeles, CA (United States); Espinosa-Fematt, Jorge A., E-mail: dr.jorge.espinosa@gmail.com [School of Medicine, University Juarez of Durango, Gomez Palacio, Durango (Mexico)

    2015-09-01

    Evidence suggests that exposure to arsenic in drinking water during early childhood or in utero has been associated with an increase in respiratory symptoms or diseases in the adulthood, however only a few studies have been carried out during those sensitive windows of exposure. Recently our group demonstrated that the exposure to arsenic during early childhood or in utero in children was associated with impairment in the lung function and suggested that this adverse effect could be due to a chronic inflammation response to the metalloid. Therefore, we designed this cross-sectional study in a cohort of children associating lung inflammatory biomarkers and lung function with urinary As levels. A total of 275 healthy children were partitioned into four study groups according with their arsenic urinary levels. Inflammation biomarkers were measured in sputum by ELISA and the lung function was evaluated by spirometry. Fifty eight percent of the studied children were found to have a restrictive spirometric pattern. In the two highest exposed groups, the soluble receptor for advanced glycation end products' (sRAGE) sputum level was significantly lower and matrix metalloproteinase-9 (MMP-9) concentration was higher. When the biomarkers were correlated to the urinary arsenic species, negative associations were found between dimethylarsinic (DMA), monomethylarsonic percentage (%MMA) and dimethylarsinic percentage (%DMA) with sRAGE and positive associations between %DMA with MMP-9 and with the MMP-9/tissue inhibitor of metalloproteinase (TIMP-1) ratio. In conclusion, chronic arsenic exposure of children negatively correlates with sRAGE, and positively correlated with MMP-9 and MMP-9/TIMP-1 levels, and increases the frequency of an abnormal spirometric pattern. Arsenic-induced alterations in inflammatory biomarkers may contribute to the development of restrictive lung diseases. - Highlights: • First study in children evaluating lung inflammatory biomarkers and As levels

  18. Lung inflammation and genotoxicity in mice lungs after pulmonary exposure to candle light combustion particles

    DEFF Research Database (Denmark)

    Skovmand, Astrid; Damiao Gouveia, Ana Cecilia; Koponen, Ismo Kalevi

    2017-01-01

    Candle burning produces a large amount of particles that contribute substantially to the exposure to indoor particulate matter. The exposures to various types of combustion particles, such as diesel exhaust particles, have been associated with increased risk of lung cancer by mechanisms that invo......Candle burning produces a large amount of particles that contribute substantially to the exposure to indoor particulate matter. The exposures to various types of combustion particles, such as diesel exhaust particles, have been associated with increased risk of lung cancer by mechanisms...... that involve oxidative stress, inflammation and genotoxicity. The aim of this study was to compare pulmonary effects of candle light combustion particles (CP) with two benchmark diesel exhaust particles (A-DEP and SRM2975). Intratracheal (i.t.) instillation of CP (5mg/kg bodyweight) in C57BL/6n mice produced......-DEP or SRM2975. The i.t. instillation of CP did not generate oxidative damage to DNA in lung tissue, measured as DNA strand breaks and human 8-oxoguanine glycosylase-sensitive sites by the comet assay. The lack of genotoxic response was confirmed in lung epithelial (A549) cells, although the exposure to CP...

  19. Allicin Protects against Lipopolysaccharide-Induced Acute Lung ...

    African Journals Online (AJOL)

    Purpose: To investigate the effect of allicin, an active component of garlic, on lipopolysaccharide (LPS)- induced acute lung injury. Methods: Wistar rats were subjected to LPS intravenous injection with or without allicin treatment to induce acute lung injury (ALI) model. Also, A549 cells were stimulated with LPS in the ...

  20. Protective mechanical ventilation does not exacerbate lung function impairment or lung inflammation following influenza A infection.

    Science.gov (United States)

    Zosky, Graeme R; Cannizzaro, Vincenzo; Hantos, Zoltan; Sly, Peter D

    2009-11-01

    The degree to which mechanical ventilation induces ventilator-associated lung injury is dependent on the initial acute lung injury (ALI). Viral-induced ALI is poorly studied, and this study aimed to determine whether ALI induced by a clinically relevant infection is exacerbated by protective mechanical ventilation. Adult female BALB/c mice were inoculated with 10(4.5) plaque-forming units of influenza A/Mem/1/71 in 50 microl of medium or medium alone. This study used a protective ventilation strategy, whereby mice were anesthetized, tracheostomized, and mechanically ventilated for 2 h. Lung mechanics were measured periodically throughout the ventilation period using a modification of the forced oscillation technique to obtain measures of airway resistance and coefficients of tissue damping and tissue elastance. Thoracic gas volume was measured and used to obtain specific airway resistance, tissue damping, and tissue elastance. At the end of the ventilation period, a bronchoalveolar lavage sample was collected to measure inflammatory cells, macrophage inflammatory protein-2, IL-6, TNF-alpha, and protein leak. Influenza infection caused significant increases in inflammatory cells, protein leak, and deterioration in lung mechanics that were not exacerbated by mechanical ventilation, in contrast to previous studies using bacterial and mouse-specific viral infection. This study highlighted the importance of type and severity of lung injury in determining outcome following mechanical ventilation.

  1. Deciphering the complexity of acute inflammation using mathematical models.

    Science.gov (United States)

    Vodovotz, Yoram

    2006-01-01

    Various stresses elicit an acute, complex inflammatory response, leading to healing but sometimes also to organ dysfunction and death. We constructed both equation-based models (EBM) and agent-based models (ABM) of various degrees of granularity--which encompass the dynamics of relevant cells, cytokines, and the resulting global tissue dysfunction--in order to begin to unravel these inflammatory interactions. The EBMs describe and predict various features of septic shock and trauma/hemorrhage (including the response to anthrax, preconditioning phenomena, and irreversible hemorrhage) and were used to simulate anti-inflammatory strategies in clinical trials. The ABMs that describe the interrelationship between inflammation and wound healing yielded insights into intestinal healing in necrotizing enterocolitis, vocal fold healing during phonotrauma, and skin healing in the setting of diabetic foot ulcers. Modeling may help in understanding the complex interactions among the components of inflammation and response to stress, and therefore aid in the development of novel therapies and diagnostics.

  2. Cyclooxygenase-2 Regulates Th17 Cell Differentiation during Allergic Lung Inflammation

    OpenAIRE

    Li, Hong; Bradbury, J. Alyce; Dackor, Ryan T.; Edin, Matthew L.; Graves, Joan P.; DeGraff, Laura M.; Wang, Ping Ming; Bortner, Carl D.; Maruoka, Shuichiro; Lih, Fred B.; Cook, Donald N.; Tomer, Kenneth B.; Jetten, Anton M.; Zeldin, Darryl C.

    2011-01-01

    Rationale: Th17 cells comprise a distinct lineage of proinflammatory T helper cells that are major contributors to allergic responses. It is unknown whether cyclooxygenase (COX)-derived eicosanoids regulate Th17 cells during allergic lung inflammation.

  3. A dual role for the immune response in a mouse model of inflammation-associated lung cancer

    OpenAIRE

    Dougan, Michael; Li, Danan; Neuberg, Donna; Mihm, Martin; Googe, Paul; Wong, Kwok-Kin; Dranoff, Glenn

    2011-01-01

    Lung cancer is the leading cause of cancer death worldwide. Both principal factors known to cause lung cancer, cigarette smoke and asbestos, induce pulmonary inflammation, and pulmonary inflammation has recently been implicated in several murine models of lung cancer. To further investigate the role of inflammation in the development of lung cancer, we generated mice with combined loss of IFN-γ and the β-common cytokines GM-CSF and IL-3. These immunodeficient mice develop chronic pulmonary in...

  4. Agmatine Protects against Zymosan-Induced Acute Lung Injury in Mice by Inhibiting NF-κB-Mediated Inflammatory Response

    Directory of Open Access Journals (Sweden)

    Xuanfei Li

    2014-01-01

    Full Text Available Acute lung injury (ALI is characterized by overwhelming lung inflammation and anti-inflammation treatment is proposed to be a therapeutic strategy for ALI. Agmatine, a cationic polyamine formed by decarboxylation of L-arginine, is an endogenous neuromodulator that plays protective roles in diverse central nervous system (CNS disorders. Consistent with its neuromodulatory and neuroprotective properties, agmatine has been reported to have beneficial effects on depression, anxiety, hypoxic ischemia, Parkinson’s disease, and gastric disorder. In this study, we tested the effect of agmatine on the lung inflammation induced by Zymosan (ZYM challenge in mice. We found that agmatine treatment relieved ZYM-induced acute lung injury, as evidenced by the reduced histological scores, wet/dry weight ratio, and myeloperoxidase activity in the lung tissue. This was accompanied by reduced levels of TNF-α, IL-1β, and IL-6 in lung and bronchoalveolar lavage fluid and decreased iNOS expression in lung. Furthermore, agmatine inhibited the phosphorylation and degradation of IκB and subsequently blocked the activation of nuclear factor (NF-κB induced by Zymosan. Taken together, our results showed that agmatine treatment inhibited NF-κB signaling in lungs and protected mice against ALI induced by Zymosan, suggesting agmatine may be a potential safe and effective approach for the treatment of ALI.

  5. Agmatine protects against zymosan-induced acute lung injury in mice by inhibiting NF-κB-mediated inflammatory response.

    Science.gov (United States)

    Li, Xuanfei; Liu, Zheng; Jin, He; Fan, Xia; Yang, Xue; Tang, Wanqi; Yan, Jun; Liang, Huaping

    2014-01-01

    Acute lung injury (ALI) is characterized by overwhelming lung inflammation and anti-inflammation treatment is proposed to be a therapeutic strategy for ALI. Agmatine, a cationic polyamine formed by decarboxylation of L-arginine, is an endogenous neuromodulator that plays protective roles in diverse central nervous system (CNS) disorders. Consistent with its neuromodulatory and neuroprotective properties, agmatine has been reported to have beneficial effects on depression, anxiety, hypoxic ischemia, Parkinson's disease, and gastric disorder. In this study, we tested the effect of agmatine on the lung inflammation induced by Zymosan (ZYM) challenge in mice. We found that agmatine treatment relieved ZYM-induced acute lung injury, as evidenced by the reduced histological scores, wet/dry weight ratio, and myeloperoxidase activity in the lung tissue. This was accompanied by reduced levels of TNF-α, IL-1β, and IL-6 in lung and bronchoalveolar lavage fluid and decreased iNOS expression in lung. Furthermore, agmatine inhibited the phosphorylation and degradation of IκB and subsequently blocked the activation of nuclear factor (NF)-κB induced by Zymosan. Taken together, our results showed that agmatine treatment inhibited NF-κB signaling in lungs and protected mice against ALI induced by Zymosan, suggesting agmatine may be a potential safe and effective approach for the treatment of ALI.

  6. Low Level Laser Therapy Reduces the Development of Lung Inflammation Induced by Formaldehyde Exposure.

    Directory of Open Access Journals (Sweden)

    Cristiane Miranda da Silva

    Full Text Available Lung diseases constitute an important public health problem and its growing level of concern has led to efforts for the development of new therapies, particularly for the control of lung inflammation. Low Level Laser Therapy (LLLT has been highlighted as a non-invasive therapy with few side effects, but its mechanisms need to be better understood and explored. Considering that pollution causes several harmful effects on human health, including lung inflammation, in this study, we have used formaldehyde (FA, an environmental and occupational pollutant, for the induction of neutrophilic lung inflammation. Our objective was to investigate the local and systemic effects of LLLT after FA exposure. Male Wistar rats were exposed to FA (1% or vehicle (distillated water during 3 consecutive days and treated or not with LLLT (1 and 5 hours after each FA exposure. Non-manipulated rats were used as control. 24 h after the last FA exposure, we analyzed the local and systemic effects of LLLT. The treatment with LLLT reduced the development of neutrophilic lung inflammation induced by FA, as observed by the reduced number of leukocytes, mast cells degranulated, and a decreased myeloperoxidase activity in the lung. Moreover, LLLT also reduced the microvascular lung permeability in the parenchyma and the intrapulmonary bronchi. Alterations on the profile of inflammatory cytokines were evidenced by the reduced levels of IL-6 and TNF-α and the elevated levels of IL-10 in the lung. Together, our results showed that LLLT abolishes FA-induced neutrophilic lung inflammation by a reduction of the inflammatory cytokines and mast cell degranulation. This study may provide important information about the mechanisms of LLLT in lung inflammation induced by a pollutant.

  7. Open lung approach vs acute respiratory distress syndrome network ventilation in experimental acute lung injury.

    Science.gov (United States)

    Spieth, P M; Güldner, A; Carvalho, A R; Kasper, M; Pelosi, P; Uhlig, S; Koch, T; Gama de Abreu, M

    2011-09-01

    Setting and strategies of mechanical ventilation with positive end-expiratory pressure (PEEP) in acute lung injury (ALI) remains controversial. This study compares the effects between lung-protective mechanical ventilation according to the Acute Respiratory Distress Syndrome Network recommendations (ARDSnet) and the open lung approach (OLA) on pulmonary function and inflammatory response. Eighteen juvenile pigs were anaesthetized, mechanically ventilated, and instrumented. ALI was induced by surfactant washout. Animals were randomly assigned to mechanical ventilation according to the ARDSnet protocol or the OLA (n=9 per group). Gas exchange, haemodynamics, pulmonary blood flow (PBF) distribution, and respiratory mechanics were measured at intervals and the lungs were removed after 6 h of mechanical ventilation for further analysis. PEEP and mean airway pressure were higher in the OLA than in the ARDSnet group [15 cmH(2)O, range 14-18 cmH(2)O, compared with 12 cmH(2)O; 20.5 (sd 2.3) compared with 18 (1.4) cmH(2)O by the end of the experiment, respectively], and OLA was associated with improved oxygenation compared with the ARDSnet group after 6 h. OLA showed more alveolar overdistension, especially in gravitationally non-dependent regions, while the ARDSnet group was associated with more intra-alveolar haemorrhage. Inflammatory mediators and markers of lung parenchymal stress did not differ significantly between groups. The PBF shifted from ventral to dorsal during OLA compared with ARDSnet protocol [-0.02 (-0.09 to -0.01) compared with -0.08 (-0.12 to -0.06), dorsal-ventral gradients after 6 h, respectively]. According to the OLA, mechanical ventilation improved oxygenation and redistributed pulmonary perfusion when compared with the ARDSnet protocol, without differences in lung inflammatory response.

  8. Acute Lung Injury Results from Innate Sensing of Viruses by an ER Stress Pathway

    Directory of Open Access Journals (Sweden)

    Eike R. Hrincius

    2015-06-01

    Full Text Available Incursions of new pathogenic viruses into humans from animal reservoirs are occurring with alarming frequency. The molecular underpinnings of immune recognition, host responses, and pathogenesis in this setting are poorly understood. We studied pandemic influenza viruses to determine the mechanism by which increasing glycosylation during evolution of surface proteins facilitates diminished pathogenicity in adapted viruses. ER stress during infection with poorly glycosylated pandemic strains activated the unfolded protein response, leading to inflammation, acute lung injury, and mortality. Seasonal strains or viruses engineered to mimic adapted viruses displaying excess glycans on the hemagglutinin did not cause ER stress, allowing preservation of the lungs and survival. We propose that ER stress resulting from recognition of non-adapted viruses is utilized to discriminate “non-self” at the level of protein processing and to activate immune responses, with unintended consequences on pathogenesis. Understanding this mechanism should improve strategies for treating acute lung injury from zoonotic viral infections.

  9. Lipoxin A4 and platelet activating factor are involved in E. coli or LPS-induced lung inflammation in CFTR-deficient mice.

    Directory of Open Access Journals (Sweden)

    Haiya Wu

    Full Text Available CFTR (cystic fibrosis transmembrane conductance regulator is expressed by both neutrophils and platelets. Lack of functional CFTR could lead to severe lung infection and inflammation. Here, we found that mutation of CFTR (F508del or inhibition of CFTR in mice led to more severe thrombocytopenia, alveolar neutrocytosis and bacteriosis, and lower lipoxin A4/MIP-2 (macrophage inhibitory protein-2 or lipoxin A4/neutrophil ratios in the BAL (bronchoalveolar lavage during acute E. coli pneumonia. In vitro, inhibition of CFTR promotes MIP-2 production in LPS-stimulated neutrophils; however, lipoxin A4 could dose-dependently suppress this effect. In LPS-induced acute lung inflammation, blockade of PSGL-1 (P-selectin glycoprotein ligand-1 or P-selectin, antagonism of PAF by WEB2086, or correction of mutated CFTR trafficking by KM11060 could significantly increase plasma lipoxin A4 levels in F508del relevant to wildtype mice. Concurrently, F508del mice had higher plasma platelet activating factor (PAF levels and PAF-AH activity compared to wildtype under LPS challenge. Inhibiting hydrolysis of PAF by a specific PAF-AH (PAF-acetylhydrolase inhibitor, MAFP, could worsen LPS-induced lung inflammation in F508del mice compared to vehicle treated F508del group. Particularly, depletion of platelets in F508del mice could significantly decrease plasma lipoxin A4 and PAF-AH activity and deteriorate LPS-induced lung inflammation compared to control F508del mice. Taken together, lipoxin A4 and PAF are involved in E. coli or LPS-induced lung inflammation in CFTR-deficient mice, suggesting that lipoxin A4 and PAF might be therapeutic targets for ameliorating CFTR-deficiency deteriorated lung inflammation.

  10. New perspectives in monitoring lung inflammation: analysis of exhaled breath condensate

    National Research Council Canada - National Science Library

    Montuschi, Paolo

    2005-01-01

    ... diseases might be relevant to differential diagnosis. Given its noninvasiveness, this method might be suitable for longitudinal studies in patients with lung disease, including children. This book provides an introduction to the analysis of exhaled breath condensate. To provide an overview of lung inflammation, basic and clinical pharmacology of leukotrie...

  11. STING Signaling Promotes Inflammation in Experimental Acute Pancreatitis.

    Science.gov (United States)

    Zhao, Qinglan; Wei, Yi; Pandol, Stephen J; Li, Lingyin; Habtezion, Aida

    2018-05-01

    Acute pancreatitis (AP) is characterized by severe inflammation and acinar cell death. Transmembrane protein 173 (TMEM173 or STING) is a DNA sensor adaptor protein on immune cells that recognizes cytosolic nucleic acids and transmits signals that activate production of interferons and the innate immune response. We investigated whether leukocyte STING signaling mediates inflammation in mice with AP. We induced AP in C57BL/6J mice (control) and C57BL/6J-Tmem173gt/J mice (STING-knockout mice) by injection of cerulein or placement on choline-deficient DL-ethionine supplemented diet. In some mice, STING signaling was induced by administration of a pharmacologic agonist. AP was also induced in C57BL/6J mice with bone marrow transplants from control or STING-knockout mice and in mice with disruption of the cyclic GMP-AMP synthase (Cgas) gene. Pancreata were collected, analyzed by histology, and acini were isolated and analyzed by flow cytometry, quantitative polymerase chain reaction, immunoblots, and enzyme-linked immunosorbent assay. Bone-marrow-derived macrophages were collected from mice and tested for their ability to detect DNA from dying acinar cells in the presence and absence of deoxyribonuclease (DNaseI). STING signaling was activated in pancreata from mice with AP but not mice without AP. STING-knockout mice developed less severe AP (less edema, inflammation, and markers of pancreatic injury) than control mice, whereas mice given a STING agonist developed more severe AP than controls. In immune cells collected from pancreata, STING was expressed predominantly in macrophages. Levels of cGAS were increased in mice with vs without AP, and cGAS-knockout mice had decreased edema, inflammation, and other markers of pancreatic injury upon induction of AP than control mice. Wild-type mice given bone marrow transplants from STING-knockout mice had less pancreatic injury and lower serum levels of lipase and pancreatic trypsin activity following induction of AP than

  12. Mechanisms of decreased intestinal epithelial proliferation and increased apoptosis in murine acute lung injury.

    Science.gov (United States)

    Husain, Kareem D; Stromberg, Paul E; Woolsey, Cheryl A; Turnbull, Isaiah R; Dunne, W Michael; Javadi, Pardis; Buchman, Timothy G; Karl, Irene E; Hotchkiss, Richard S; Coopersmith, Craig M

    2005-10-01

    The aim of this study was to determine the effects of acute lung injury on the gut epithelium and examine mechanisms underlying changes in crypt proliferation and apoptosis. The relationship between severity and timing of lung injury to intestinal pathology was also examined. Randomized, controlled study. University research laboratory. Genetically inbred mice. Following induction of acute lung injury, gut epithelial proliferation and apoptosis were assessed in a) C3H/HeN wild-type and C3H/HeJ mice, which lack functional Toll-like receptor 4 (n = 17); b) C57Bl/6 mice that received monoclonal anti-tumor necrosis factor-alpha or control antibody (n = 22); and c) C57Bl/6 wild-type and transgenic mice that overexpress Bcl-2 in their gut epithelium (n = 21). Intestinal epithelial proliferation and death were also examined in animals with differing degrees of lung inflammation (n = 24) as well as in a time course analysis following a fixed injury (n = 18). Acute lung injury caused decreased proliferation and increased apoptosis in crypt epithelial cells in all animals studied. C3H/HeJ mice had higher levels of proliferation than C3H/HeN animals without additional changes in apoptosis. Anti-tumor necrosis factor-alpha antibody had no effect on gut epithelial proliferation or death. Overexpression of Bcl-2 did not change proliferation despite decreasing gut apoptosis. Proliferation and apoptosis were not correlated to severity of lung injury, as gut alterations were lost in mice with more severe acute lung injury. Changes in both gut epithelial proliferation and death were apparent within 12 hrs, but proliferation was decreased 36 hrs following acute lung injury while apoptosis returned to normal. Acute lung injury causes disparate effects on crypt proliferation and apoptosis, which occur, at least in part, through differing mechanisms involving Toll-like receptor 4 and Bcl-2. Severity of lung injury does not correlate with perturbations in proliferation or death in the

  13. Low power infrared laser modifies the morphology of lung affected with acute injury induced by sepsis

    Science.gov (United States)

    Sergio, L. P. S.; Trajano, L. A. S. N.; Thomé, A. M. C.; Mencalha, A. L.; Paoli, F.; Fonseca, A. S.

    2018-06-01

    Acute lung injury (ALI) is a potentially fatal disease characterized by uncontrolled hyperinflammatory responses in the lungs as a consequence of sepsis. ALI is divided into two sequential and time-dependent phases, exudative and fibroproliferative phases, with increased permeability of the alveolar barrier, causing edema and inflammation. However, there are no specific treatments for ALI. Low-power lasers have been successfully used in the resolution of acute inflammatory processes. The aim of this study was to evaluate the effects of low-power infrared laser exposure on alveolus and interalveolar septa of Wistar rats affected by ALI-induced by sepsis. Laser fluences, power, and the emission mode were those used in clinical protocols for the treatment of acute inflammation. Adult male Wistar rats were randomized into six groups: control, 10 J cm‑2, 20 J cm‑2, ALI, ALI  +  10 J cm‑2, and ALI  +  20 J cm‑2. ALI was induced by intraperitoneal Escherichia coli lipopolysaccharide (LPS). Lungs were removed and processed for hematoxylin–eosin staining. Morphological alterations induced by LPS in lung tissue were quantified by morphometry with a 32-point cyclic arcs test system in Stepanizer. Data showed that exposure to low-power infrared laser in both fluences reduced the thickening of interalveolar septa in lungs affected by ALI, increasing the alveolar space; however, inflammatory infiltrate was still observed. Our research showed that exposure to low-power infrared laser improves the lung parenchyma in Wistar rats affected by ALI, which could be an alternative approach for treatment of inflammatory lung injuries.

  14. Aerosolized prostacyclin for acute lung injury (ALI) and acute respiratory distress syndrome (ARDS)

    DEFF Research Database (Denmark)

    Afshari, Arash; Brok, Jesper; Møller, Ann

    2010-01-01

    Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are critical conditions that are associated with high mortality and morbidity. Aerosolized prostacyclin has been used to improve oxygenation despite the limited evidence available so far.......Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are critical conditions that are associated with high mortality and morbidity. Aerosolized prostacyclin has been used to improve oxygenation despite the limited evidence available so far....

  15. Arterial Carboxyhemoglobin Measurement Is Useful for Evaluating Pulmonary Inflammation in Subjects with Interstitial Lung Disease.

    Science.gov (United States)

    Hara, Yu; Shinkai, Masaharu; Kanoh, Soichiro; Fujikura, Yuji; K Rubin, Bruce; Kawana, Akihiko; Kaneko, Takeshi

    2017-01-01

    Objective The arterial concentration of carboxyhemoglobin (CO-Hb) in subjects with inflammatory pulmonary disease is higher than that in healthy individuals. We retrospectively analyzed the relationship between the CO-Hb concentration and established markers of disease severity in subjects with interstitial lung disease (ILD). Methods The CO-Hb concentration was measured in subjects with newly diagnosed or untreated ILD and the relationships between the CO-Hb concentration and the serum biomarker levels, lung function, high-resolution CT (HRCT) findings, and the uptake in gallium-67 ( 67 Ga) scintigraphy were evaluated. Results Eighty-one non-smoking subjects were studied (mean age, 67 years). Among these subjects, (A) 17 had stable idiopathic pulmonary fibrosis (IPF), (B) 9 had an acute exacerbation of IPF, (C) 44 had stable non-IPF, and (D) 11 had an exacerbation of non-IPF. The CO-Hb concentrations of these subjects were (A) 1.5±0.5%, (B) 2.1±0.5%, (C) 1.2±0.4%, and (D) 1.7±0.5%. The CO-Hb concentration was positively correlated with the serum levels of surfactant protein (SP)-A (r=0.38), SP-D (r=0.39), and the inflammation index (calculated from HRCT; r=0.57) and was negatively correlated with the partial pressure of oxygen in the arterial blood (r=-0.56) and the predicted diffusion capacity of carbon monoxide (r=-0.61). The CO-Hb concentrations in subjects with a negative heart sign on 67 Ga scintigraphy were higher than those in subjects without a negative heart sign (1.4±0.5% vs. 1.1±0.3%, p=0.018). Conclusion The CO-Hb levels of subjects with ILD were increased, particularly during an exacerbation, and were correlated with the parameters that reflect pulmonary inflammation.

  16. Lung injury in acute pancreatitis: mechanisms, prevention, and therapy.

    LENUS (Irish Health Repository)

    Shields, Conor J

    2012-02-03

    Lung injury is the most pertinent manifestation of extra-abdominal organ dysfunction in pancreatitis. The propensity of this retroperitoneal inflammatory condition to engender a diffuse and life-threatening lung injury is significant. Approximately one third of patients will develop acute lung injury and acute respiratory distress syndrome, which account for 60% of all deaths within the first week. The variability in the clinical course of pancreatitis renders it a vexing entity and makes demonstration of the efficacy of any specific intervention difficult. The distinct pathologic entity of pancreatitis-associated lung injury is reviewed with a focus on etiology and potential therapeutic maneuvers.

  17. Glufosinate aerogenic exposure induces glutamate and IL-1 receptor dependent lung inflammation.

    Science.gov (United States)

    Maillet, Isabelle; Perche, Olivier; Pâris, Arnaud; Richard, Olivier; Gombault, Aurélie; Herzine, Ameziane; Pichon, Jacques; Huaux, Francois; Mortaud, Stéphane; Ryffel, Bernhard; Quesniaux, Valérie F J; Montécot-Dubourg, Céline

    2016-11-01

    Glufosinate-ammonium (GLA), the active component of an herbicide, is known to cause neurotoxicity. GLA shares structural analogy with glutamate. It is a powerful inhibitor of glutamine synthetase (GS) and may bind to glutamate receptors. Since these potentials targets of GLA are present in lung and immune cells, we asked whether airway exposure to GLA may cause lung inflammation in mice. A single GLA exposure (1 mg/kg) induced seizures and inflammatory cell recruitment in the broncho-alveolar space, and increased myeloperoxidase (MPO), inducible NO synthase (iNOS), interstitial inflammation and disruption of alveolar septae within 6-24 h. Interleukin 1β (IL-1β) was increased and lung inflammation depended on IL-1 receptor 1 (IL-1R1). We demonstrate that glutamate receptor pathway is central, since the N-methyl-D-aspartate (NMDA) receptor inhibitor MK-801 prevented GLA-induced lung inflammation. Chronic exposure (0.2 mg/kg 3× per week for 4 weeks) caused moderate lung inflammation and enhanced airway hyperreactivity with significant increased airway resistance. In conclusion, GLA aerosol exposure causes glutamate signalling and IL-1R-dependent pulmonary inflammation with airway hyperreactivity in mice. © 2016 The Author(s). published by Portland Press Limited on behalf of the Biochemical Society.

  18. Neonates with reduced neonatal lung function have systemic low-grade inflammation

    DEFF Research Database (Denmark)

    Chawes, Bo L.K.; Stokholm, Jakob; Bønnelykke, Klaus

    2015-01-01

    Background: Children and adults with asthma and impaired lung function have been reported to have low-grade systemic inflammation, but it is unknown whether this inflammation starts before symptoms and in particular whether low-grade inflammation is present in asymptomatic neonates with reduced...... lung function. ObjectiveWe sought to investigate the possible association between neonatal lung function and biomarkers of systemic inflammation.  Methods: Plasma levels of high-sensitivity C-reactive protein (hs-CRP), IL-1β, IL-6, TNF-α, and CXCL8 (IL-8) were measured at age 6 months in 300 children.......  Results: The neonatal forced expiratory volume at 0.5 seconds was inversely associated with hs-CRP (β-coefficient, −0.12; 95% CI, −0.21 to −0.04; P approach, including hs-CRP, IL-6...

  19. X-ray characteristics of acute lung abscess

    International Nuclear Information System (INIS)

    Churilyin, R.Yu.; Kramnij, Yi.O.

    2007-01-01

    The analysis of x-ray investigation of 35 patients with lung abscess reported. Our data allow to determine the early sings, to define the nature of radiological peculiarities of acute and chronic abscess and carry out differential diagnosis

  20. Influence of pre-existing inflammation on the outcome of acute coronary syndrome

    DEFF Research Database (Denmark)

    Odeberg, J.; Freitag, M.; Forssell, Henrik

    2016-01-01

    Objectives: Inflammation is a well-established risk factor for the development of coronary artery disease (CAD) and acute coronary syndrome (ACS). However, less is known about its influence on the outcome of ACS. The aim of this study was to determine if blood biomarkers of inflammation were...... that a pre-existing low-grade inflammation may dispose towards MI over UA....

  1. Transfusion related acute lung injury presenting with acute dyspnoea: a case report

    Directory of Open Access Journals (Sweden)

    Haji Altaf

    2008-10-01

    Full Text Available Abstract Introduction Transfusion-related acute lung injury is emerging as a common cause of transfusion-related adverse events. However, awareness about this entity in the medical fraternity is low and it, consequently, remains a very under-reported and often an under-diagnosed complication of transfusion therapy. Case presentation We report a case of a 46-year old woman who developed acute respiratory and hemodynamic instability following a single unit blood transfusion in the postoperative period. Investigation results were non-specific and a diagnosis of transfusion-related acute lung injury was made after excluding other possible causes of acute lung injury. She responded to symptomatic management with ventilatory and vasopressor support and recovered completely over the next 72 hours. Conclusion The diagnosis of transfusion-related acute lung injury relies on excluding other causes of acute pulmonary edema following transfusion, such as sepsis, volume overload, and cardiogenic pulmonary edema. All plasma containing blood products have been implicated in transfusion-related acute lung injury, with the majority being linked to whole blood, packed red blood cells, platelets, and fresh-frozen plasma. The pathogenesis of transfusion-related acute lung injury may be explained by a "two-hit" hypothesis, involving priming of the inflammatory machinery and then activation of this primed mechanism. Treatment is supportive, with prognosis being substantially better than for most other causes of acute lung injury.

  2. Acute and chronic effects of treatment with mesenchymal stromal cells on LPS-induced pulmonary inflammation, emphysema and atherosclerosis development.

    Directory of Open Access Journals (Sweden)

    P Padmini S J Khedoe

    Full Text Available COPD is a pulmonary disorder often accompanied by cardiovascular disease (CVD, and current treatment of this comorbidity is suboptimal. Systemic inflammation in COPD triggered by smoke and microbial exposure is suggested to link COPD and CVD. Mesenchymal stromal cells (MSC possess anti-inflammatory capacities and MSC treatment is considered an attractive treatment option for various chronic inflammatory diseases. Therefore, we investigated the immunomodulatory properties of MSC in an acute and chronic model of lipopolysaccharide (LPS-induced inflammation, emphysema and atherosclerosis development in APOE*3-Leiden (E3L mice.Hyperlipidemic E3L mice were intranasally instilled with 10 μg LPS or vehicle twice in an acute 4-day study, or twice weekly during 20 weeks Western-type diet feeding in a chronic study. Mice received 0.5x106 MSC or vehicle intravenously twice after the first LPS instillation (acute study or in week 14, 16, 18 and 20 (chronic study. Inflammatory parameters were measured in bronchoalveolar lavage (BAL and lung tissue. Emphysema, pulmonary inflammation and atherosclerosis were assessed in the chronic study.In the acute study, intranasal LPS administration induced a marked systemic IL-6 response on day 3, which was inhibited after MSC treatment. Furthermore, MSC treatment reduced LPS-induced total cell count in BAL due to reduced neutrophil numbers. In the chronic study, LPS increased emphysema but did not aggravate atherosclerosis. Emphysema and atherosclerosis development were unaffected after MSC treatment.These data show that MSC inhibit LPS-induced pulmonary and systemic inflammation in the acute study, whereas MSC treatment had no effect on inflammation, emphysema and atherosclerosis development in the chronic study.

  3. Occurrence of hypermutable Pseudomonas aeruginosa in cystic fibrosis patients is associated with the oxidative stress caused by chronic lung inflammation

    DEFF Research Database (Denmark)

    Ciofu, Oana; Riis, Bente; Pressler, Tacjana

    2005-01-01

    Oxidative stress caused by chronic lung inflammation in patients with cystic fibrosis (CF) and chronic lung infection with Pseudomonas aeruginosa is characterized by the reactive oxygen species (ROS) liberated by polymorphonuclear leukocytes (PMNs). We formulated the hypothesis that oxidation...

  4. Preventing cleavage of Mer promotes efferocytosis and suppresses acute lung injury in bleomycin treated mice

    International Nuclear Information System (INIS)

    Lee, Ye-Ji; Lee, Seung-Hae; Youn, Young-So; Choi, Ji-Yeon; Song, Keung-Sub; Cho, Min-Sun; Kang, Jihee Lee

    2012-01-01

    Mer receptor tyrosine kinase (Mer) regulates macrophage activation and promotes apoptotic cell clearance. Mer activation is regulated through proteolytic cleavage of the extracellular domain. To determine if membrane-bound Mer is cleaved during bleomycin-induced lung injury, and, if so, how preventing the cleavage of Mer enhances apoptotic cell uptake and down-regulates pulmonary immune responses. During bleomycin-induced acute lung injury in mice, membrane-bound Mer expression decreased, but production of soluble Mer and activity as well as expression of disintegrin and metalloproteinase 17 (ADAM17) were enhanced . Treatment with the ADAM inhibitor TAPI-0 restored Mer expression and diminished soluble Mer production. Furthermore, TAPI-0 increased Mer activation in alveolar macrophages and lung tissue resulting in enhanced apoptotic cell clearance in vivo and ex vivo by alveolar macrophages. Suppression of bleomycin-induced pro-inflammatory mediators, but enhancement of hepatocyte growth factor induction were seen after TAPI-0 treatment. Additional bleomycin-induced inflammatory responses reduced by TAPI-0 treatment included inflammatory cell recruitment into the lungs, levels of total protein and lactate dehydrogenase activity in bronchoalveolar lavage fluid, as well as caspase-3 and caspase-9 activity and alveolar epithelial cell apoptosis in lung tissue. Importantly, the effects of TAPI-0 on bleomycin-induced inflammation and apoptosis were reversed by coadministration of specific Mer-neutralizing antibodies. These findings suggest that restored membrane-bound Mer expression by TAPI-0 treatment may help resolve lung inflammation and apoptosis after bleomycin treatment. -- Highlights: ►Mer expression is restored by TAPI-0 treatment in bleomycin-stimulated lung. ►Mer signaling is enhanced by TAPI-0 treatment in bleomycin-stimulated lung. ►TAPI-0 enhances efferocytosis and promotes resolution of lung injury.

  5. Induced hypernatraemia is protective in acute lung injury.

    Science.gov (United States)

    Bihari, Shailesh; Dixon, Dani-Louise; Lawrence, Mark D; Bersten, Andrew D

    2016-06-15

    Sucrose induced hyperosmolarity is lung protective but the safety of administering hyperosmolar sucrose in patients is unknown. Hypertonic saline is commonly used to produce hyperosmolarity aimed at reducing intra cranial pressure in patients with intracranial pathology. Therefore we studied the protective effects of 20% saline in a lipopolysaccharide lung injury rat model. 20% saline was also compared with other commonly used fluids. Following lipopolysaccharide-induced acute lung injury, male Sprague Dawley rats received either 20% hypertonic saline, 0.9% saline, 4% albumin, 20% albumin, 5% glucose or 20% albumin with 5% glucose, i.v. During 2h of non-injurious mechanical ventilation parameters of acute lung injury were assessed. Hypertonic saline resulted in hypernatraemia (160 (1) mmol/l, mean (SD)) maintained through 2h of ventilation, and in amelioration of lung oedema, myeloperoxidase, bronchoalveolar cell infiltrate, total soluble protein and inflammatory cytokines, and lung histological injury score, compared with positive control and all other fluids (p ≤ 0.001). Lung physiology was maintained (conserved PaO2, elastance), associated with preservation of alveolar surfactant (p ≤ 0.0001). Independent of fluid or sodium load, induced hypernatraemia is lung protective in lipopolysaccharide-induced acute lung injury. Copyright © 2016 Elsevier B.V. All rights reserved.

  6. Effect of acute moderate exercise on induced inflammation and arterial function in older adults.

    Science.gov (United States)

    Ranadive, Sushant Mohan; Kappus, Rebecca Marie; Cook, Marc D; Yan, Huimin; Lane, Abbi Danielle; Woods, Jeffrey A; Wilund, Kenneth R; Iwamoto, Gary; Vanar, Vishwas; Tandon, Rudhir; Fernhall, Bo

    2014-04-01

    Acute inflammation reduces flow-mediated vasodilatation and increases arterial stiffness in young healthy individuals. However, this response has not been studied in older adults. The aim of this study, therefore, was to evaluate the effect of acute induced systemic inflammation on endothelial function and wave reflection in older adults. Furthermore, an acute bout of moderate-intensity aerobic exercise can be anti-inflammatory. Taken together, we tested the hypothesis that acute moderate-intensity endurance exercise, immediately preceding induced inflammation, would be protective against the negative effects of acute systemic inflammation on vascular function. Fifty-nine healthy volunteers between 55 and 75 years of age were randomized to an exercise or a control group. Both groups received a vaccine (induced inflammation) and sham (saline) injection in a counterbalanced crossover design. Inflammatory markers, endothelial function (flow-mediated vasodilatation) and measures of wave reflection and arterial stiffness were evaluated at baseline and at 24 and 48 h after injections. There were no significant differences in endothelial function and arterial stiffness between the exercise and control group after induced inflammation. The groups were then analysed together, and we found significant differences in the inflammatory markers 24 and 48 h after induction of acute inflammation compared with sham injection. However, flow-mediated vasodilatation, augmentation index normalized for heart rate (AIx75) and β-stiffness did not change significantly. Our results suggest that acute inflammation induced by influenza vaccination did not affect endothelial function in older adults.

  7. Soyabean oil supplementation effects on perivascular inflammation in lungs induced by bisphenol a: a histological study

    International Nuclear Information System (INIS)

    Shaukat, S.; Hamid, S.; Umbreen, F.

    2017-01-01

    To determine the effect of soyabean oil supplementation on perivascular inflammation in lungs of adult mice induced by Bisphenol A (BPA). Study Design: An experimental study. Place and Duration of Study: Department of Anatomy, Army Medical College, Rawalpindi, in collaboration with the Animal House, National Institute of Health, Islamabad, from June to November 2016. Methodology:Thirty male and female BALB/c mice were divided into three groups, of 10 animals each. Group A animals served as control. Group B animals were given BPA at a dose of 50 mg/Kg body weight/day. Group C animals were given BPA and soyabean oil at doses of 50 mg/Kg body weight/day and 500 mg/day, respectively. All treatments were given once daily for a period of eight weeks. Animals were dissected 24 hours after receiving the last dose. Lung tissue specimen processing and H and E staining was carried out for routine histological study. Perivascular inflammation was morphometrically graded and statistically analysed using Chi-square test with p<0.05. Results: Grade 2 inflammation was recorded in two (20%) animals and grade 3 perivascular inflammation in 80% specimens in Group B; whereas 20% specimens of Group C had grade 2 inflammation and eight (80%) showed grade 1 inflammation. None of the control animals showed any inflammation. All groups were significantly different at p<0.001. Conclusion: BPA produced perivascular inflammation and con-commitant administration of soyabean oil diet protected against it in rodent. (author)

  8. Aspiration, Localized Pulmonary Inflammation, and Predictors of Early-Onset Bronchiolitis Obliterans Syndrome after Lung Transplantation

    Science.gov (United States)

    Fisichella, P Marco; Davis, Christopher S; Lowery, Erin; Ramirez, Luis; Gamelli, Richard L; Kovacs, Elizabeth J

    2014-01-01

    BACKGROUND We hypothesized that immune mediator concentrations in the bronchoalveolar fluid (BALF) are predictive of bronchiolitis obliterans syndrome (BOS) and demonstrate specific patterns of dysregulation, depending on the presence of acute cellular rejection, BOS, aspiration, and timing of lung transplantation. STUDY DESIGN We prospectively collected 257 BALF samples from 105 lung transplant recipients. The BALF samples were assessed for absolute and differential white blood cell counts and 34 proteins implicated in pulmonary immunity, inflammation, fibrosis, and aspiration. RESULTS There were elevated BALF concentrations of interleukin (IL)-15, IL-17, basic fibroblast growth factor, tumor necrosis factor–α, and myeloperoxidase, and reduced concentrations of α1-antitrypsin, which were predictive of early-onset BOS. Patients with BOS had an increased percentage of BALF lymphocytes and neutrophils, with a reduced percentage of macrophages (p < 0.05). The BALF concentrations of IL-1β; IL-8; interferon-γ–induced protein 10; regulated upon activation, normal T-cell expressed and secreted; neutrophil elastase; and pepsin were higher in patients with BOS (p < 0.05). Among those with BOS, BALF concentrations of IL-1RA; IL-8; eotaxin; interferon-γ–induced protein 10; regulated upon activation, normal T-cell expressed and secreted; myeloperoxidase; and neutrophil elastase were positively correlated with time since transplantation (p < 0.01). Those with worse grades of acute cellular rejection had an increased percentage of lymphocytes in their BALF (p < 0.0001) and reduced BALF concentrations of IL-1β, IL-7, IL-9, IL-12, granulocyte colony-stimulating factor, granulocyte-macrophage colony-stimulating factor, interferon-γ, and vascular endothelial growth factor (p ≤ 0.001). Patients with aspiration based on detectable pepsin had increased percentage of neutrophils (p < 0.001) and reduced BALF concentrations of IL-12 (p < 0.001). CONCLUSIONS The BALF levels

  9. Synchrotron microradiography study on acute lung injury of mouse caused by PM2.5 aerosols

    International Nuclear Information System (INIS)

    Tong Yongpeng; Zhang Guilin; Li Yan; Tan Mingguan; Wang Wei; Chen Jianmin; Hwu Yeukuang; Hsu, Pei-Chebg; Je, Jung Ho; Margaritondo, Giorgio; Song Weiming; Jiang, Rongfang; Jiang Zhihai

    2006-01-01

    In order to investigate FeSO 4 , ZnSO 4 (the two of main metal compositions of Shanghai PM 2.5 (particle matter with those aerodynamical diameter 2.5 aerosol particles, FeSO 4 , ZnSO 4 and their mixtures were instilled intratracheally into mouse lungs for experiment. By 2 days after instillation, the live mice were checked in vivo by synchrotron refractive index microradiography. In addition after extracted and examined by dissection, the right lobes of lung were fixed by formalin, then imaged by synchrotron microradiography again. Corresponding parts of those lung tissues were embedded in paraffin for histopathologic study. The synchrotron X-ray microradiographs of live mouse lung showed different lung texture changes after instilled with different toxic solutions. Hemorrhage points in lung were observed more from those mice instilled by FeSO 4 contained toxin solutions groups. Bronchial epithelial hyperplasia can be observed in ZnSO 4 contained solution-instilled groups from histopathologic analysis. It was found that the acute lung injury of mice caused by solution of PM 2.5 + FeSO 4 + ZnSO 4 was more serious than other toxin solutions. Results suggested that FeSO 4 mainly induced hemorrhage and ZnSO 4 mainly induced inflammation and bronchiolar epithelial hyperplasia in the early toxicological effects of PM 2.5

  10. Nox1 oxidase suppresses influenza a virus-induced lung inflammation and oxidative stress.

    Directory of Open Access Journals (Sweden)

    Stavros Selemidis

    Full Text Available Influenza A virus infection is an ongoing clinical problem and thus, there is an urgent need to understand the mechanisms that regulate the lung inflammation in order to unravel novel generic pharmacological strategies. Evidence indicates that the Nox2-containing NADPH oxidase enzyme promotes influenza A virus-induced lung oxidative stress, inflammation and dysfunction via ROS generation. In addition, lung epithelial and endothelial cells express the Nox1 isoform of NADPH oxidase, placing this enzyme at key sites to regulate influenza A virus-induced lung inflammation. The aim of this study was to investigate whether Nox1 oxidase regulates the inflammatory response and the oxidative stress to influenza infection in vivo in mice. Male WT and Nox1-deficient (Nox1(-/y mice were infected with the moderately pathogenic HkX-31 (H3N2, 1×10(4 PFU influenza A virus for analysis of bodyweight, airways inflammation, oxidative stress, viral titre, lung histopathology, and cytokine/chemokine expression at 3 and 7 days post infection. HkX-31 virus infection of Nox1(-/y mice resulted in significantly greater: loss of bodyweight (Day 3; BALF neutrophilia, peri-bronchial, peri-vascular and alveolar inflammation; Nox2-dependent inflammatory cell ROS production and peri-bronchial, epithelial and endothelial oxidative stress. The expression of pro-inflammatory cytokines including CCL2, CCL3, CXCL2, IL-1β, IL-6, GM-CSF and TNF-α was higher in Nox1(-/y lungs compared to WT mice at Day 3, however, the expression of CCL2, CCL3, CXCL2, IFN-γ and the anti-inflammatory cytokine IL-10 were lower in lungs of Nox1(-/y mice vs. WT mice at Day 7. Lung viral titre, and airways infiltration of active CD8(+ and CD4(+ T lymphocytes, and of Tregs were similar between WT and Nox1(-/y mice. In conclusion, Nox1 oxidase suppresses influenza A virus induced lung inflammation and oxidative stress in mice particularly at the early phases of the infection. Nox1 and Nox2 oxidases appear

  11. Qingfei Xiaoyan Wan, a traditional Chinese medicine formula, ameliorates Pseudomonas aeruginosa–induced acute lung inflammation by regulation of PI3K/AKT and Ras/MAPK pathways

    Directory of Open Access Journals (Sweden)

    Yuanyuan Hou

    2016-05-01

    Full Text Available Gram-negative pathogen–induced nosocomial infections and resistance are a most serious menace to global public health. Qingfei Xiaoyan Wan (QF, a traditional Chinese medicine (TCM formula, has been used clinically in China for the treatment of upper respiratory tract infections, acute or chronic bronchitis and pulmonary infection. In this study, the effects of QF on Pseudomonas aeruginosa–induced acute pneumonia in mice were evaluated. The mechanisms by which four typical anti-inflammatory ingredients from QF, arctigenin (ATG, cholic acid (CLA, chlorogenic acid (CGA and sinapic acid (SPA, regulate anti-inflammatory signaling pathways and related targets were investigated using molecular biology and molecular docking techniques. The results showed that pretreatment with QF significantly inhibits the release of cytokines (TNF-α and IL-6 and chemokines (IL-8 and RANTES, reduces leukocytes recruitment into inflamed tissues and ameliorates pulmonary edema and necrosis. In addition, ATG was identified as the primary anti-inflammatory agent with action on the PI3K/AKT and Ras/MAPK pathways. CLA and CGA enhanced the actions of ATG and exhibited synergistic NF-κB inactivation effects possibly via the Ras/MAPK signaling pathway. Moreover, CLA is speculated to target FGFR and MEK firstly. Overall, QF regulated the PI3K/AKT and Ras/MAPK pathways to inhibit pathogenic bacterial infections effectively.

  12. Activation of PPARα by Wy-14643 ameliorates systemic lipopolysaccharide-induced acute lung injury

    International Nuclear Information System (INIS)

    Yoo, Seong Ho; Abdelmegeed, Mohamed A.; Song, Byoung-Joon

    2013-01-01

    Highlights: •Activation of PPARα attenuated LPS-mediated acute lung injury. •Pretreatment with Wy-14643 decreased the levels of IFN-γ and IL-6 in ALI. •Nitrosative stress and lipid peroxidation were downregulated by PPARα activation. •PPARα agonists may be potential therapeutic targets for acute lung injury. -- Abstract: Acute lung injury (ALI) is a major cause of mortality and morbidity worldwide. The activation of peroxisome proliferator-activated receptor-α (PPARα) by its ligands, which include Wy-14643, has been implicated as a potential anti-inflammatory therapy. To address the beneficial efficacy of Wy-14643 for ALI along with systemic inflammation, the in vivo role of PPARα activation was investigated in a mouse model of lipopolysaccharide (LPS)-induced ALI. Using age-matched Ppara-null and wild-type mice, we demonstrate that the activation of PPARα by Wy-14643 attenuated LPS-mediated ALI. This was evidenced histologically by the significant alleviation of inflammatory manifestations and apoptosis observed in the lung tissues of wild-type mice, but not in the corresponding Ppara-null mice. This protective effect probably resulted from the inhibition of LPS-induced increases in pro-inflammatory cytokines and nitroxidative stress levels. These results suggest that the pharmacological activation of PPARα might have a therapeutic effect on LPS-induced ALI

  13. Activation of PPARα by Wy-14643 ameliorates systemic lipopolysaccharide-induced acute lung injury

    Energy Technology Data Exchange (ETDEWEB)

    Yoo, Seong Ho, E-mail: yoosh@snu.ac.kr [Seoul National University Hospital, Biomedical Research Institute and Institute of Forensic Medicine, Seoul National University College of Medicine, Seoul (Korea, Republic of); Abdelmegeed, Mohamed A. [Laboratory of Membrane Biochemistry and Biophysics, National Institute on Alcohol Abuse and Alcoholism, Bethesda, MD (United States); Song, Byoung-Joon, E-mail: bj.song@nih.gov [Laboratory of Membrane Biochemistry and Biophysics, National Institute on Alcohol Abuse and Alcoholism, Bethesda, MD (United States)

    2013-07-05

    Highlights: •Activation of PPARα attenuated LPS-mediated acute lung injury. •Pretreatment with Wy-14643 decreased the levels of IFN-γ and IL-6 in ALI. •Nitrosative stress and lipid peroxidation were downregulated by PPARα activation. •PPARα agonists may be potential therapeutic targets for acute lung injury. -- Abstract: Acute lung injury (ALI) is a major cause of mortality and morbidity worldwide. The activation of peroxisome proliferator-activated receptor-α (PPARα) by its ligands, which include Wy-14643, has been implicated as a potential anti-inflammatory therapy. To address the beneficial efficacy of Wy-14643 for ALI along with systemic inflammation, the in vivo role of PPARα activation was investigated in a mouse model of lipopolysaccharide (LPS)-induced ALI. Using age-matched Ppara-null and wild-type mice, we demonstrate that the activation of PPARα by Wy-14643 attenuated LPS-mediated ALI. This was evidenced histologically by the significant alleviation of inflammatory manifestations and apoptosis observed in the lung tissues of wild-type mice, but not in the corresponding Ppara-null mice. This protective effect probably resulted from the inhibition of LPS-induced increases in pro-inflammatory cytokines and nitroxidative stress levels. These results suggest that the pharmacological activation of PPARα might have a therapeutic effect on LPS-induced ALI.

  14. Allergic Lung Inflammation Aggravates Angiotensin II-Induced Abdominal Aortic Aneurysms in Mice

    DEFF Research Database (Denmark)

    Liu, Cong-Lin; Wang, Yi; Liao, Mengyang

    2016-01-01

    sensitization and challenge in mice led to the development of allergic lung inflammation (ALI). Subcutaneous infusion of angiotensin II into mice produced AAA. Simultaneous production of ALI in AAA mice doubled abdominal aortic diameter and increased macrophage and mast cell content, arterial media smooth...... and reduced lesion inflammation, plasma IgE, and bronchioalveolar inflammation. Pre-establishment of ALI also increased AAA lesion size, lesion accumulation of macrophages and mast cells, media smooth muscle cell loss, and plasma IgE, reduced plasma interleukin-5, interleukin-13, and transforming growth...... factor-β, and increased bronchioalveolar inflammation. Consequent production of ALI also doubled lesion size of pre-established AAA and increased lesion mast cell and T-cell accumulation, media smooth muscle cell loss, lesion cell proliferation and apoptosis, plasma IgE, and bronchioalveolar inflammation...

  15. HMGB1 and Extracellular Histones Significantly Contribute to Systemic Inflammation and Multiple Organ Failure in Acute Liver Failure.

    Science.gov (United States)

    Yang, Runkuan; Zou, Xiaoping; Tenhunen, Jyrki; Tønnessen, Tor Inge

    2017-01-01

    Acute liver failure (ALF) is the culmination of severe liver cell injury from a variety of causes. ALF occurs when the extent of hepatocyte death exceeds the hepatic regenerative capacity. ALF has a high mortality that is associated with multiple organ failure (MOF) and sepsis; however, the underlying mechanisms are still not clear. Emerging evidence shows that ALF patients/animals have high concentrations of circulating HMGB1, which can contribute to multiple organ injuries and mediate gut bacterial translocation (BT). BT triggers/induces systemic inflammatory responses syndrome (SIRS), which can lead to MOF in ALF. Blockade of HMGB1 significantly decreases BT and improves hepatocyte regeneration in experimental acute fatal liver injury. Therefore, HMGB1 seems to be an important factor that links BT and systemic inflammation in ALF. ALF patients/animals also have high levels of circulating histones, which might be the major mediators of systemic inflammation in patients with ALF. Extracellular histones kill endothelial cells and elicit immunostimulatory effect to induce multiple organ injuries. Neutralization of histones can attenuate acute liver, lung, and brain injuries. In conclusion, HMGB1 and histones play a significant role in inducing systemic inflammation and MOF in ALF.

  16. HMGB1 and Extracellular Histones Significantly Contribute to Systemic Inflammation and Multiple Organ Failure in Acute Liver Failure

    Directory of Open Access Journals (Sweden)

    Runkuan Yang

    2017-01-01

    Full Text Available Acute liver failure (ALF is the culmination of severe liver cell injury from a variety of causes. ALF occurs when the extent of hepatocyte death exceeds the hepatic regenerative capacity. ALF has a high mortality that is associated with multiple organ failure (MOF and sepsis; however, the underlying mechanisms are still not clear. Emerging evidence shows that ALF patients/animals have high concentrations of circulating HMGB1, which can contribute to multiple organ injuries and mediate gut bacterial translocation (BT. BT triggers/induces systemic inflammatory responses syndrome (SIRS, which can lead to MOF in ALF. Blockade of HMGB1 significantly decreases BT and improves hepatocyte regeneration in experimental acute fatal liver injury. Therefore, HMGB1 seems to be an important factor that links BT and systemic inflammation in ALF. ALF patients/animals also have high levels of circulating histones, which might be the major mediators of systemic inflammation in patients with ALF. Extracellular histones kill endothelial cells and elicit immunostimulatory effect to induce multiple organ injuries. Neutralization of histones can attenuate acute liver, lung, and brain injuries. In conclusion, HMGB1 and histones play a significant role in inducing systemic inflammation and MOF in ALF.

  17. Increased alveolar soluble Annexin V promotes lung inflammation and fibrosis

    OpenAIRE

    Buckley, S.; Shi, W.; Xu, W.; Frey, M.R.; Moats, R.; Pardo, A.; Selman, M.; Warburton, D.

    2015-01-01

    The causes underlying the self-perpetuating nature of idiopathic pulmonary fibrosis (IPF), a progressive and usually lethal disease, remain unknown. We hypothesized that alveolar soluble Annexin V contributes to lung fibrosis, based on the observation that human IPF BALF containing high Annexin V levels promoted fibroblast involvement in alveolar epithelial wound healing that was reduced when Annexin V was depleted from the BALF.

  18. Killing of Pseudomonas aeruginosa by Chicken Cathelicidin-2 Is Immunogenically Silent, Preventing Lung Inflammation In Vivo

    Science.gov (United States)

    Coorens, Maarten; Banaschewski, Brandon J. H.; Baer, Brandon J.; Yamashita, Cory; van Dijk, Albert; Veldhuizen, Ruud A. W.; Veldhuizen, Edwin J. A.

    2017-01-01

    ABSTRACT The development of antibiotic resistance by Pseudomonas aeruginosa is a major concern in the treatment of bacterial pneumonia. In the search for novel anti-infective therapies, the chicken-derived peptide cathelicidin-2 (CATH-2) has emerged as a potential candidate, with strong broad-spectrum antimicrobial activity and the ability to limit inflammation by inhibiting Toll-like receptor 2 (TLR2) and TLR4 activation. However, as it is unknown how CATH-2 affects inflammation in vivo, we investigated how CATH-2-mediated killing of P. aeruginosa affects lung inflammation in a murine model. First, murine macrophages were used to determine whether CATH-2-mediated killing of P. aeruginosa reduced proinflammatory cytokine production in vitro. Next, a murine lung model was used to analyze how CATH-2-mediated killing of P. aeruginosa affects neutrophil and macrophage recruitment as well as cytokine/chemokine production in the lung. Our results show that CATH-2 kills P. aeruginosa in an immunogenically silent manner both in vitro and in vivo. Treatment with CATH-2-killed P. aeruginosa showed reduced neutrophil recruitment to the lung as well as inhibition of cytokine and chemokine production, compared to treatment with heat- or gentamicin-killed bacteria. Together, these results show the potential for CATH-2 as a dual-activity antibiotic in bacterial pneumonia, which can both kill P. aeruginosa and prevent excessive inflammation. PMID:28947647

  19. Cordycepin alleviates lipopolysaccharide-induced acute lung injury via Nrf2/HO-1 pathway.

    Science.gov (United States)

    Qing, Rui; Huang, Zezhi; Tang, Yufei; Xiang, Qingke; Yang, Fan

    2018-04-24

    The present study is to investigate the protective effect of cordycepin on inflammatory reactions in rats with acute lung injury (ALI) induced by lipopolysaccharide (LPS), as well as the underlying mechanism. Wistar rat model of ALI was induced by intravenous injection of LPS (30 mg/kg body weight). One hour later, intravenous injection of cordycepin (1, 10 or 30 mg/kg body weight) was administered. The wet-to-dry weight ratio of lung tissues and myeloperoxidase activity in the lung tissues were measured. The contents of nitrite and nitrate were measured by reduction method, while chemiluminescence was used to determine the content of superoxide. Quantitative real-time polymerase chain reaction and Western blotting were used to determine the expression of mRNA and protein, respectively. Colorimetry was performed to determine the enzymatic activity of heme oxygenase-1 (HO-1). Nuclear translocation of Nrf2 was identified by Western blotting. The plasma contents of cytokines were measured by enzyme-linked immunosorbent assay. Cordycepin enhanced the expression and enzymatic activity of HO-1 in ALI rats, and activated Nrf2 by inducing the translocation of Nrf2 from cytoplasm to nucleus. In addition, cordycepin regulated the secretion of TNF-α, IL-6 and IL-10 via HO-1, and suppressed inflammation in lung tissues of ALI rats by inducing the expression of HO-1. HO-1 played important roles in the down-regulation of superoxide levels in lung tissues by cordycepin, and HO-1 expression induced by cordycepin affected nitrite and nitrate concentrations in plasma and iNOS protein expression in lung tissues. Cordycepin showed protective effect on injuries in lung tissues. The present study demonstrates that cordycepin alleviates inflammation induced by LPS via the activation of Nrf2 and up-regulation of HO-1 expression. Copyright © 2018. Published by Elsevier B.V.

  20. Acute lung injury and the acute respiratory distress syndrome in the injured patient

    Directory of Open Access Journals (Sweden)

    Bakowitz Magdalena

    2012-08-01

    Full Text Available Abstract Acute lung injury and acute respiratory distress syndrome are clinical entities of multi-factorial origin frequently seen in traumatically injured patients requiring intensive care. We performed an unsystematic search using PubMed and the Cochrane Database of Systematic Reviews up to January 2012. The purpose of this article is to review recent evidence for the pathophysiology and the management of acute lung injury/acute respiratory distress syndrome in the critically injured patient. Lung protective ventilation remains the most beneficial therapy. Future trials should compare intervention groups to controls receiving lung protective ventilation, and focus on relevant outcome measures such as duration of mechanical ventilation, length of intensive care unit stay, and mortality.

  1. Acute Lung Injury during Antithymocyte Globulin Therapy for Aplastic Anemia

    Directory of Open Access Journals (Sweden)

    Ewan Christopher Goligher

    2009-01-01

    Full Text Available The case of a 33-year-old man with aplastic anemia who experienced recurrent episodes of hypoxemia and pulmonary infiltrates during infusions of antithymocyte globulin (ATG is described. With the use of high-dose corticosteroids, the patient’s original episodes resolved, and were subsequently prevented before additional administrations of ATG. Rare reports of an association between ATG and acute lung injury are found in the literature, but this is the first report of successful steroid-supported re-exposure. Although the mechanism of ATG-related acute lung injury remains uncertain, it may be parallel to the mechanism of transfusion-related acute lung injury because the pathogenesis of the latter relies, in part, on antileukocyte antibodies. ATG-related toxicity should be included in the differential diagnosis of new, infusion-associated pulmonary infiltrates, and corticosteroids may be a useful therapeutic consideration in the management.

  2. Protease Inhibitors Extracted from Caesalpinia echinata Lam. Affect Kinin Release during Lung Inflammation

    Directory of Open Access Journals (Sweden)

    Ilana Cruz-Silva

    2016-01-01

    Full Text Available Inflammation is an essential process in many pulmonary diseases in which kinins are generated by protease action on kininogen, a phenomenon that is blocked by protease inhibitors. We evaluated kinin release in an in vivo lung inflammation model in rats, in the presence or absence of CeKI (C. echinata kallikrein inhibitor, a plasma kallikrein, cathepsin G, and proteinase-3 inhibitor, and rCeEI (recombinant C. echinata elastase inhibitor, which inhibits these proteases and also neutrophil elastase. Wistar rats were intravenously treated with buffer (negative control or inhibitors and, subsequently, lipopolysaccharide was injected into their lungs. Blood, bronchoalveolar lavage fluid (BALF, and lung tissue were collected. In plasma, kinin release was higher in the LPS-treated animals in comparison to CeKI or rCeEI groups. rCeEI-treated animals presented less kinin than CeKI-treated group. Our data suggest that kinins play a pivotal role in lung inflammation and may be generated by different enzymes; however, neutrophil elastase seems to be the most important in the lung tissue context. These results open perspectives for a better understanding of biological process where neutrophil enzymes participate and indicate these plant inhibitors and their recombinant correlates for therapeutic trials involving pulmonary diseases.

  3. Bone-marrow-derived mesenchymal stem cells inhibit gastric aspiration lung injury and inflammation in rats.

    Science.gov (United States)

    Zhou, Jing; Jiang, Liyan; Long, Xuan; Fu, Cuiping; Wang, Xiangdong; Wu, Xiaodan; Liu, Zilong; Zhu, Fen; Shi, Jindong; Li, Shanqun

    2016-09-01

    Gastric aspiration lung injury is one of the most common clinical events. This study investigated the effects of bone-marrow-derived mesenchymal stem cells (BMSCs) on combined acid plus small non-acidified particle (CASP)-induced aspiration lung injury. Enhanced green fluorescent protein (EGFP(+) ) or EGFP(-) BMSCs or 15d-PGJ2 were injected via the tail vein into rats immediately after CASP-induced aspiration lung injury. Pathological changes in lung tissues, blood gas analysis, the wet/dry weight ratio (W/D) of the lung, levels of total proteins and number of total cells and neutrophils in bronchoalveolar lavage fluid (BALF) were determined. The cytokine levels were measured using ELISA. Protein expression was determined by Western blot. Bone-marrow-derived mesenchymal stem cells treatment significantly reduced alveolar oedema, exudation and lung inflammation; increased the arterial partial pressure of oxygen; and decreased the W/D of the lung, the levels of total proteins and the number of total cells and neutrophils in BALF in the rats with CASP-induced lung injury. Bone-marrow-derived mesenchymal stem cells treatment decreased the levels of tumour necrosis factor-α and Cytokine-induced neutrophil chemoattractant (CINC)-1 and the expression of p-p65 and increased the levels of interleukin-10 and 15d-PGJ2 and the expression of peroxisome proliferator-activated receptor (PPAR)-γ in the lung tissue in CASP-induced rats. Tumour necrosis factor-α stimulated BMSCs to secrete 15d-PGJ2 . A tracking experiment showed that EGFP(+) BMSCs were able to migrate to local lung tissues. Treatment with 15d-PGJ2 also significantly inhibited CASP-induced lung inflammation and the production of pro-inflammatory cytokines. Our results show that BMSCs can protect lung tissues from gastric aspiration injury and inhibit lung inflammation in rats. A beneficial effect might be achieved through BMSC-derived 15d-PGJ2 activation of the PPAR-γ receptor, reducing the production of

  4. Mesenchymal stromal cell treatment prevents H9N2 avian influenza virus-induced acute lung injury in mice

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    Yan Li

    2016-10-01

    Full Text Available Abstract Background The avian influenza virus (AIV can cross species barriers and expand its host range from birds to mammals, even humans. Avian influenza is characterized by pronounced activation of the proinflammatory cytokine cascade, which perpetuates the inflammatory response, leading to persistent systemic inflammatory response syndrome and pulmonary infection in animals and humans. There are currently no specific treatment strategies for avian influenza. Methods We hypothesized that mesenchymal stromal cells (MSCs would have beneficial effects in the treatment of H9N2 AIV-induced acute lung injury in mice. Six- to 8-week-old C57BL/6 mice were infected intranasally with 1 × 104 MID50 of A/HONG KONG/2108/2003 [H9N2 (HK] H9N2 virus to induce acute lung injury. After 30 min, syngeneic MSCs were delivered through the caudal vein. Three days after infection, we measured the survival rate, lung weight, arterial blood gas, and cytokines in both bronchoalveolar lavage fluid (BALF and serum, and assessed pathological changes to the lungs. Results MSC administration significantly palliated H9N2 AIV-induced pulmonary inflammation by reducing chemokines and proinflammatory cytokines levels, as well as reducing inflammatory cell recruit into the lungs. Thus, H9N2 AIV-induced lung injury was markedly alleviated in mice treated with MSCs. Lung histopathology and arterial blood gas analysis were improved in mice with H9N2 AIV-induced lung injury following MSC treatment. Conclusions MSC treatment significantly reduces H9N2 AIV-induced acute lung injury in mice and is associated with reduced pulmonary inflammation. These results indicate a potential role for MSC therapy in the treatment of clinical avian influenza.

  5. Using bosentan to treat paraquat poisoning-induced acute lung injury in rats.

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    Zhongchen Zhang

    Full Text Available BACKGROUND: Paraquat poisoning is well known for causing multiple organ function failure (MODS and high mortality. Acute lung injury and advanced pulmonary fibrosis are the most serious complications. Bosentan is a dual endothelin receptor antagonist. It plays an important role in treating PF. There is no related literature on the use of bosentan therapy for paraquat poisoning. OBJECTIVE: To study the use of bosentan to treat acute lung injury and pulmonary fibrosis as induced by paraquat. METHOD: A total of 120 adult Wister male rats were randomly assigned to three groups: the paraquat poisoning group (rats were intragastrically administered with paraquat at 50 mg/kg body weight once at the beginning; the bosentan therapy group (rats were administered bosentan at 100 mg/kg body weight by intragastric administration half an hour after paraquat was administered, then the same dose was administered once a day; and a control group (rats were administered intragastric physiological saline. On the 3rd, 7th, 14th, and 21st days following paraquat exposure, rats were sacrificed, and samples of lung tissue and venous blood were collected. The levels of transforming growth factor-β1 (TGF-β1, endothelin-1 (ET-1, and hydroxyproline (HYP in the plasma and lung homogenate were determined. Optical and electronic microscopes were used to examine pathological changes. RESULT: The TGF-β1, ET-1, and HYP of the paraquat poisoning group were significantly higher than in the control group, and they were significantly lower in the 21st day therapy group than in the paraquat poisoning group on the same day. Under the optical and electronic microscopes, lung tissue damage was observed to be more severe but was then reduced after bosentan was administered. CONCLUSION: Bosentan can reduce inflammation factor release. It has a therapeutic effect on acute lung injury as induced by paraquat.

  6. Obesity-Induced Endoplasmic Reticulum Stress Causes Lung Endothelial Dysfunction and Promotes Acute Lung Injury.

    Science.gov (United States)

    Shah, Dilip; Romero, Freddy; Guo, Zhi; Sun, Jianxin; Li, Jonathan; Kallen, Caleb B; Naik, Ulhas P; Summer, Ross

    2017-08-01

    Obesity is a significant risk factor for acute respiratory distress syndrome. The mechanisms underlying this association are unknown. We recently showed that diet-induced obese mice exhibit pulmonary vascular endothelial dysfunction, which is associated with enhanced susceptibility to LPS-induced acute lung injury. Here, we demonstrate that lung endothelial dysfunction in diet-induced obese mice coincides with increased endoplasmic reticulum (ER) stress. Specifically, we observed enhanced expression of the major sensors of misfolded proteins, including protein kinase R-like ER kinase, inositol-requiring enzyme α, and activating transcription factor 6, in whole lung and in primary lung endothelial cells isolated from diet-induced obese mice. Furthermore, we found that primary lung endothelial cells exposed to serum from obese mice, or to saturated fatty acids that mimic obese serum, resulted in enhanced expression of markers of ER stress and the induction of other biological responses that typify the lung endothelium of diet-induced obese mice, including an increase in expression of endothelial adhesion molecules and a decrease in expression of endothelial cell-cell junctional proteins. Similar changes were observed in lung endothelial cells and in whole-lung tissue after exposure to tunicamycin, a compound that causes ER stress by blocking N-linked glycosylation, indicating that ER stress causes endothelial dysfunction in the lung. Treatment with 4-phenylbutyric acid, a chemical protein chaperone that reduces ER stress, restored vascular endothelial cell expression of adhesion molecules and protected against LPS-induced acute lung injury in diet-induced obese mice. Our work indicates that fatty acids in obese serum induce ER stress in the pulmonary endothelium, leading to pulmonary endothelial cell dysfunction. Our work suggests that reducing protein load in the ER of pulmonary endothelial cells might protect against acute respiratory distress syndrome in obese

  7. Does advanced lung inflammation index (ALI) have prognostic significance in metastatic non-small cell lung cancer?

    Science.gov (United States)

    Ozyurek, Berna Akinci; Ozdemirel, Tugce Sahin; Ozden, Sertac Buyukyaylaci; Erdoğan, Yurdanur; Ozmen, Ozlem; Kaplan, Bekir; Kaplan, Tugba

    2018-01-22

    Lung cancer is the most commonly diagnosed and death-related cancer type and is more frequent in males. Non-small-cell lung cancer (NSCLC) accounts for about 85% of all case. In this study, it was aimed to research the relationship between advanced lung inflammation index (ALI) and the primary mass maximum standardized uptake value (SUVmax) and C-reactive protein (CRP) at initial diagnosis and the prognostic value of ALI in determining the survival in metastatic NSCLC. A total of 112 patients diagnosed as stage 4 non-small-lung cancer in our hospital between January 2006 and December 2013 were included in this study. ALI was calculated as body mass index (BMI) × serum albumin/neutrophil-to-lymphocyte ratio (NLR). The patients were divided into two groups as ALI ALI ≥ 18 (low inflammation). The log-rank test and Cox proportional hazard model were used to identify predictors of mortality. Evaluation was made of 94 male and 18 female patients with a mean age of 59.7 ± 9.9 years. A statistically significant negative relationship was determined between ALI and CRP values (P ALI and SUVmax values (P = .436). The median survival time in patients with ALI ALI ≥ 18, it was 16 months (P = .095). ALI is an easily calculated indicator of inflammation in lung cancer patients. Values <18 can be considered to predict a poor prognosis. © 2018 John Wiley & Sons Ltd.

  8. Intratracheal synthetic CpG oligodeoxynucleotide causes acute lung injury with systemic inflammatory response

    Directory of Open Access Journals (Sweden)

    Hasegawa Naoki

    2009-09-01

    Full Text Available Abstract Bacterial genome is characterized by frequent unmethylated cytosine-phosphate-guanine (CpG motifs. Deleterious effects can occur when synthetic oligodeoxynucleotides (ODN with unmethylated CpG dinucleotides (CpG-ODN are administered in a systemic fashion. We aimed to evaluate the effect of intratracheal CpG-ODN on lung inflammation and systemic inflammatory response. C57BL/6J mice received intratracheal administration of CpG-ODN (0.01, 0.1, 1.0, 10, or 100 μM or control ODN without CpG motif. Bronchoalveolar lavage (BAL fluid was obtained 3 or 6 h or 1, 2, 7, or 14 days after the instillation and subjected to a differential cell count and cytokine measurement. Lung permeability was evaluated as the BAL fluid-to-plasma ratio of the concentration of human serum albumin that was injected 1 h before euthanasia. Nuclear factor (NF-κB DNA binding activity was also evaluated in lung homogenates. Intratracheal administration of 10 μM or higher concentration of CpG-ODN induced significant inflammatory cell accumulation into the airspace. The peak accumulation of neutrophils and lymphocytes occurred 1 and 2 days after the CpG-ODN administration, respectively. Lung permeability was increased 1 day after the 10 μM CpG-ODN challenge. CpG-ODN also induced nuclear translocation of NF-κB and upregulation of various inflammatory cytokines in BAL fluid and plasma. Histopathology of the lungs and liver revealed acute lung injury and liver damage with necrosis, respectively. Control ODN without CpG motif did not induce any inflammatory change. Since intratracheal CpG-ODN induced acute lung injury as well as systemic inflammatory response, therapeutic strategies to neutralize bacterial DNA that is released after administration of bactericidal agents should be considered.

  9. Lung pathology in case of acute radiation injury

    International Nuclear Information System (INIS)

    Vlasov, P.A.; Kvacheva, Yu.V.

    1998-01-01

    Results of pathomorphological studies of 27 patients exposed to total external γ- and β-radiation resulted from the Chernobyl accident and lost due to the acute radiation disease in the first weeks following radiation exposure are discussed. Dose range is 3.7-13.7 Gy. Two groups of pathological changes in lungs are revealed, those are: infection (bacterial, viral and fungous) ones caused by acute radiation disease and signs of respiratory distress-syndrome in adults [ru

  10. Acute exacerbation of idiopathic interstitial pneumonia complicated by lung cancer, caused by treatment for lung cancer

    International Nuclear Information System (INIS)

    Takenaka, Kiyoshi; Okano, Tetsuya; Yoshimura, Akinobu

    1999-01-01

    In 64 patients with lung cancer complicated by idiopathic interstitial pneumonia (IIP), we retrospectively studied the outcome of the treatment for lung cancer and clinical features of acute exacerbation of IIP after treatment for lung cancer. The incidence of acute exacerbation of IIP was 8.7% (2 of 23 patients) after anticancer chemotherapy, 14.3% (2 of 14 patients) after operation, and 25% (2 of 8 patients) after radiation therapy. Serum C-reactive protein level was significantly higher in the patients who developed acute exacerbation of IIP than in those who did not (CRP=5.12±2.27, 2.26±2.29, respectively). On the contrary, there were no differences in the levels of serum lactate dehydrogenase, white blood cell count, erythrocyte sedimentation rate, PaO 2 , and %VC between the two groups. Pathologic presentations of surgically resected lungs did not show significant differences in the activity of IIP between the two groups. Five of 6 patients who developed acute exacerbation of IIP died within 3 months after the treatment for lung cancer. We conclude that we should evaluate the activity of IIP more precisely using new markers for activity of IIP and on that basis select patients to be treated for lung cancer. (author)

  11. Prostaglandin D2 Attenuates Bleomycin-Induced Lung Inflammation and Pulmonary Fibrosis.

    Science.gov (United States)

    Kida, Taiki; Ayabe, Shinya; Omori, Keisuke; Nakamura, Tatsuro; Maehara, Toko; Aritake, Kosuke; Urade, Yoshihiro; Murata, Takahisa

    2016-01-01

    Pulmonary fibrosis is a progressive and fatal lung disease with limited therapeutic options. Although it is well known that lipid mediator prostaglandins are involved in the development of pulmonary fibrosis, the role of prostaglandin D2 (PGD2) remains unknown. Here, we investigated whether genetic disruption of hematopoietic PGD synthase (H-PGDS) affects the bleomycin-induced lung inflammation and pulmonary fibrosis in mouse. Compared with H-PGDS naïve (WT) mice, H-PGDS-deficient mice (H-PGDS-/-) represented increased collagen deposition in lungs 14 days after the bleomycin injection. The enhanced fibrotic response was accompanied by an increased mRNA expression of inflammatory mediators, including tumor necrosis factor-α, monocyte chemoattractant protein-1, and cyclooxygenase-2 on day 3. H-PGDS deficiency also increased vascular permeability on day 3 and infiltration of neutrophils and macrophages in lungs on day 3 and 7. Immunostaining showed that the neutrophils and macrophages expressed H-PGDS, and its mRNA expression was increased on day 3and 7 in WT lungs. These observations suggest that H-PGDS-derived PGD2 plays a protective role in bleomycin-induced lung inflammation and pulmonary fibrosis.

  12. Histologic and biochemical alterations predict pulmonary mechanical dysfunction in aging mice with chronic lung inflammation.

    Science.gov (United States)

    Massa, Christopher B; Groves, Angela M; Jaggernauth, Smita U; Laskin, Debra L; Gow, Andrew J

    2017-08-01

    Both aging and chronic inflammation produce complex structural and biochemical alterations to the lung known to impact work of breathing. Mice deficient in surfactant protein D (Sftpd) develop progressive age-related lung pathology characterized by tissue destruction/remodeling, accumulation of foamy macrophages and alteration in surfactant composition. This study proposes to relate changes in tissue structure seen in normal aging and in chronic inflammation to altered lung mechanics using a computational model. Alterations in lung function in aging and Sftpd -/- mice have been inferred from fitting simple mechanical models to respiratory impedance data (Zrs), however interpretation has been confounded by the simultaneous presence of multiple coexisting pathophysiologic processes. In contrast to the inverse modeling approach, this study uses simulation from experimental measurements to recapitulate how aging and inflammation alter Zrs. Histologic and mechanical measurements were made in C57BL6/J mice and congenic Sftpd-/- mice at 8, 27 and 80 weeks of age (n = 8/group). An anatomic computational model based on published airway morphometry was developed and Zrs was simulated between 0.5 and 20 Hz. End expiratory pressure dependent changes in airway caliber and recruitment were estimated from mechanical measurements. Tissue elements were simulated using the constant phase model of viscoelasticity. Baseline elastance distribution was estimated in 8-week-old wild type mice, and stochastically varied for each condition based on experimentally measured alteration in elastic fiber composition, alveolar geometry and surfactant composition. Weighing reduction in model error against increasing model complexity allowed for identification of essential features underlying mechanical pathology and their contribution to Zrs. Using a maximum likelihood approach, alteration in lung recruitment and diminished elastic fiber density were shown predictive of mechanical alteration at

  13. Histologic and biochemical alterations predict pulmonary mechanical dysfunction in aging mice with chronic lung inflammation.

    Directory of Open Access Journals (Sweden)

    Christopher B Massa

    2017-08-01

    Full Text Available Both aging and chronic inflammation produce complex structural and biochemical alterations to the lung known to impact work of breathing. Mice deficient in surfactant protein D (Sftpd develop progressive age-related lung pathology characterized by tissue destruction/remodeling, accumulation of foamy macrophages and alteration in surfactant composition. This study proposes to relate changes in tissue structure seen in normal aging and in chronic inflammation to altered lung mechanics using a computational model. Alterations in lung function in aging and Sftpd -/- mice have been inferred from fitting simple mechanical models to respiratory impedance data (Zrs, however interpretation has been confounded by the simultaneous presence of multiple coexisting pathophysiologic processes. In contrast to the inverse modeling approach, this study uses simulation from experimental measurements to recapitulate how aging and inflammation alter Zrs. Histologic and mechanical measurements were made in C57BL6/J mice and congenic Sftpd-/- mice at 8, 27 and 80 weeks of age (n = 8/group. An anatomic computational model based on published airway morphometry was developed and Zrs was simulated between 0.5 and 20 Hz. End expiratory pressure dependent changes in airway caliber and recruitment were estimated from mechanical measurements. Tissue elements were simulated using the constant phase model of viscoelasticity. Baseline elastance distribution was estimated in 8-week-old wild type mice, and stochastically varied for each condition based on experimentally measured alteration in elastic fiber composition, alveolar geometry and surfactant composition. Weighing reduction in model error against increasing model complexity allowed for identification of essential features underlying mechanical pathology and their contribution to Zrs. Using a maximum likelihood approach, alteration in lung recruitment and diminished elastic fiber density were shown predictive of mechanical

  14. Cell Origin Dictates Programming of Resident versus Recruited Macrophages during Acute Lung Injury.

    Science.gov (United States)

    Mould, Kara J; Barthel, Lea; Mohning, Michael P; Thomas, Stacey M; McCubbrey, Alexandra L; Danhorn, Thomas; Leach, Sonia M; Fingerlin, Tasha E; O'Connor, Brian P; Reisz, Julie A; D'Alessandro, Angelo; Bratton, Donna L; Jakubzick, Claudia V; Janssen, William J

    2017-09-01

    Two populations of alveolar macrophages (AMs) coexist in the inflamed lung: resident AMs that arise during embryogenesis, and recruited AMs that originate postnatally from circulating monocytes. The objective of this study was to determine whether origin or environment dictates the transcriptional, metabolic, and functional programming of these two ontologically distinct populations over the time course of acute inflammation. RNA sequencing demonstrated marked transcriptional differences between resident and recruited AMs affecting three main areas: proliferation, inflammatory signaling, and metabolism. Functional assays and metabolomic studies confirmed these differences and demonstrated that resident AMs proliferate locally and are governed by increased tricarboxylic acid cycle and amino acid metabolism. Conversely, recruited AMs produce inflammatory cytokines in association with increased glycolytic and arginine metabolism. Collectively, the data show that even though they coexist in the same environment, inflammatory macrophage subsets have distinct immunometabolic programs and perform specialized functions during inflammation that are associated with their cellular origin.

  15. Eosinophils in the lung – modulating apoptosis and efferocytosis in airway inflammation

    Directory of Open Access Journals (Sweden)

    Jennifer M Felton

    2014-07-01

    Full Text Available Due to the key role of the lung in efficient transfer of oxygen in exchange for carbon dioxide, a controlled inflammatory response is essential for restoration of tissue homeostasis following airway exposure to bacterial pathogens or environmental toxins. Unregulated or prolonged inflammatory responses in the lungs can lead to tissue damage, disrupting normal tissue architecture and consequently compromising efficient gaseous exchange. Failure to resolve inflammation underlies the development and/or progression of a number of inflammatory lung diseases including asthma. Eosinophils, granulocytic cells of the innate immune system, are primarily involved in defence against parasitic infections. However, the propagation of the allergic inflammatory response in chronic asthma is thought to involve excessive recruitment and impaired apoptosis of eosinophils together with defective phagocytic clearance of apoptotic cells (efferocytosis. In terms of therapeutic approaches for treatment of asthma, the widespread use of glucocorticoids is associated with a number of adverse health consequences after long-term use, while some patients suffer from steroid-resistant disease. A new approach for therapeutic intervention would be to promote the resolution of inflammation via modulation of eosinophil apoptosis and the phagocytic clearance of apoptotic cells. This review focuses on the mechanisms underpinning eosinophil-mediated lung damage, currently available treatments and therapeutic targets that might in future be harnessed to facilitate inflammation resolution by the manipulation of cell survival and clearance pathways.

  16. Euthanasia and Lavage Mediated Effects on Bronchoalveolar Measures of Lung Injury and Inflammation.

    Science.gov (United States)

    Tighe, Robert M; Birukova, Anastasiya; Yeager, Michael J; Reece, Sky W; Gowdy, Kymberly M

    2018-02-26

    Accurate and reproducible assessments of experimental lung injury and inflammation are critical to basic and translational research. In particular, investigators use varied methods of bronchoalveolar lavage and euthanasia but their impact to assessments of injury and inflammation are unknown. To define potential effects, we compared methods of lavage and euthanasia in uninjured mice and following a mild lung injury model (ozone). C57BL/6J male mice age 8-10 weeks underwent BAL following euthanasia with ketamine/xylazine, carbon dioxide (C0 2 ), or isoflurane. BAL methods included 800-μL instilled and withdrawn three times, and 1 or 3 passive fill(s) and drainage to 20cm H20. Parallel experiments were performed 24hr following 3hr of ozone (O 3 ) exposure at 2 parts per million (ppm). BAL total cell counts/differentials and total protein/albumin were determined. Lung histology was evaluated for lung inflammation/injury. BAL cells were cultured and stimulated with PBS, phorbol myristate acetate (PMA) or lipopolysaccharide (LPS) for 4hr and supernatants were evaluated for cytokine content. In uninjured mice, we observed differences due to the lavage and euthanasia methods. The lavage method increased uninjured and O 3 exposure total cells and total protein/albumin with 800-μL instillation having the highest values. Isoflurane increased uninjured total BAL cells, while C0 2 euthanasia increased the uninjured total protein/albumin levels. These effects limited the ability to detect differences in BAL injury measures following O 3 exposure. In conclusion, the method of lavage and euthanasia affects measures of lung inflammation/injury and should be considered a variable in model assessment.

  17. Stem cells in sepsis and acute lung injury.

    Science.gov (United States)

    Cribbs, Sushma K; Matthay, Michael A; Martin, Greg S

    2010-12-01

    Sepsis and acute lung injury continue to be major causes of morbidity and mortality worldwide despite advances in our understanding of pathophysiology and the discovery of new management strategies. Recent investigations show that stem cells may be beneficial as prognostic biomarkers and novel therapeutic strategies in these syndromes. This article reviews the potential use of endogenous adult tissue-derived stem cells in sepsis and acute lung injury as prognostic markers and also as exogenous cell-based therapy. A directed systematic search of the medical literature using PubMed and OVID, with particular emphasis on the time period after 2002, was done to evaluate topics related to 1) the epidemiology and pathophysiology of sepsis and acute lung injury; and 2) the definition, characterization, and potential use of stem cells in these diseases. DATA SYNTHESIS AND FINDINGS: When available, preferential consideration was given to prospective nonrandomized clinical and preclinical studies. Stem cells have shown significant promise in the field of critical care both for 1) prognostic value and 2) treatment strategies. Although several recent studies have identified the potential benefit of stem cells in sepsis and acute lung injury, further investigations are needed to more completely understand stem cells and their potential prognostic and therapeutic value.

  18. Transfusion-related acute lung injury: a change of perspective

    NARCIS (Netherlands)

    Vlaar, A. P.; Schultz, M. J.; Juffermans, N. P.

    2009-01-01

    Two decades ago, transfusion-related acute lung injury (TRALI) was considered a rare complication of transfusion medicine. Nowadays, TRALI has emerged as the leading cause of transfusion-related mortality, presumably as a consequence of reaching international agreement on defining TRALI with

  19. Age-related ventricular-vascular coupling during acute inflammation in humans: Effect of physical activity.

    Science.gov (United States)

    Lane, Abbi D; Kappus, Rebecca M; Bunsawat, Kanokwan; Ranadive, Sushant M; Yan, Huimin; Phillips, Shane; Baynard, Tracy; Woods, Jeffrey A; Motl, Robert; Fernhall, Bo

    2015-07-01

    Aging is commonly accompanied by increased arterial and ventricular stiffness (determined by arterial elastance (Ea) and ventricular elastance (Elv)), augmented ventricular-vascular coupling ratios (Ea/Elv) and systemic inflammation. Acute inflammation may impact ventricular-vascular coupling and predispose older adults to cardiovascular events. However, physically active older adults have more compliant large arteries and left ventricles and lower inflammation than sedentary older adults. We hypothesized that acute inflammation would alter Ea, Elv, and Ea/Elv more in older versus younger adults but that higher levels of physical activity would attenuate inflammation-induced changes. End-systolic and central blood pressures were obtained using applanation tonometry before and at 24 and 48 h post-influenza vaccination in 24 older and 38 younger adults. Ultrasonography was used to measure ventricular volumes and other indices of cardiac performance. Physical activity was measured with accelerometry. Ea and Ea/Elv were maintained (p > 0.05), but Elv was reduced (p  0.05) except in the most active group of seniors (p < 0.05). Aging did not affect the elastance responses but did affect central blood pressure and other ventricular systolic responses to acute inflammation. Aging, not physical activity, appears to modulate cardiovascular responses to acute inflammation, except in the most active older adults. © The European Society of Cardiology 2014 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav.

  20. Genomic instability in quartz dust exposed rat lungs: Is inflammation responsible?

    Energy Technology Data Exchange (ETDEWEB)

    Albrecht, C; Schins, R P F [Institut fuer Umweltmedizinische Forschung (IUF) at the Heinrich Heine University Duesseldorf (Germany); Demircigil, G Cakmak; Coskun, Erdem [Gazi University, Faculty of Pharmacy, Department of Toxicology, Ankara (Turkey); Schooten, F J van [Nutrition and Toxicology Research Institute Maastricht (NUTRIM), Department of Health Risk Analysis and Toxicology, University of Maastricht (Netherlands); Borm, P J A [Centre of Expertise in Life Sciences (Cel), Hogeschool Zuyd, Heerlen (Netherlands); Knaapen, A M, E-mail: catrin.albrecht@uni-duesseldorf.d

    2009-02-01

    Exposure to quartz dusts has been associated with lung cancer and fibrosis. Although the responsible mechanisms are not completely understood, progressive inflammation with associated induction of persistent oxidative stress has been discussed as a key event for these diseases. Previously we have evaluated the kinetics of pulmonary inflammation in the rat model following a single intratracheal instillation of 2mg DQ12 quartz, either in its native form or upon its surface modification with polyvinylpyridine-N-oxide or aluminium lactate. This model has been applied now to evaluate the role of inflammation in the kinetics of induction of DNA damage and response at 3, 7, 28, and 90 days after treatment. Bronchoalveolar lavage (BAL) cell counts and differentials as well as BAL fluid myeloperoxidase activity were used as markers of inflammation. Whole lung homogenate was investigated to determine the induction of the oxidative and pre-mutagenic DNA lesion 8-hydroxy-2-deoxy-guanosine (8-OHdG) by HPLC/ECD, while mRNA and protein expression of oxidative stress and DNA damage response genes including hemeoxygenase-1 (HO-1) and apurinic/apyrimidinic endonuclease (APE/Ref-1) were evaluated using Western blotting and real time PCR. Isolated lung epithelial cells from the treated rats were used for DNA strand breakage analysis using the alkaline comet assay as well as for micronucleus scoring in May-Gruenwald-Giemsa stained cytospin preparations. In the rats that were treated with quartz, no increased 8-OHdG levels were observed, despite the presence of a marked and persistent inflammation. However, DNA strand breakage in the lung epithelial cells of the quartz treated rats was significantly enhanced at 3 days, but not at 28 days. Moreover, significantly enhanced micronucleus frequencies were observed for all four time points investigated. In the animals that were treated with the PVNO modified quartz, micronuclei scores did not differ from controls, while in those treated with

  1. March1 E3 Ubiquitin Ligase Modulates Features of Allergic Asthma in an Ovalbumin-Induced Mouse Model of Lung Inflammation

    Directory of Open Access Journals (Sweden)

    Osama A. Kishta

    2018-01-01

    Full Text Available Membrane-associated RING-CH-1 (March1 is a member of the March family of E3 ubiquitin ligases. March1 downregulates cell surface expression of MHC II and CD86 by targeting them to lysosomal degradation. Given the key roles of MHC class II and CD86 in T cell activation and to get further insights into the development of allergic inflammation, we asked whether March1 deficiency exacerbates or attenuates features of allergic asthma in mice. Herein, we used an acute model of allergy to compare the asthmatic phenotype of March1-deficient and -sufficient mice immunized with ovalbumin (OVA and later challenged by intranasal instillation of OVA in the lungs. We found that eosinophilic inflammation in airways and lung tissue was similar between WT and March1−/− allergic mice, whereas neutrophilic inflammation was significant only in March1−/− mice. Airway hyperresponsiveness as well as levels of IFN-γ, IL-13, IL-6, and IL-10 was lower in the lungs of asthmatic March1−/− mice compared to WT, whereas lung levels of TNF-α, IL-4, and IL-5 were not significantly different. Interestingly, in the serum, levels of total and ova-specific IgE were reduced in March1-deficient mice as compared to WT mice. Taken together, our results demonstrate a role of March1 E3 ubiquitin ligase in modulating allergic responses.

  2. Overexpression of IL-38 protein in anticancer drug-induced lung injury and acute exacerbation of idiopathic pulmonary fibrosis.

    Science.gov (United States)

    Tominaga, Masaki; Okamoto, Masaki; Kawayama, Tomotaka; Matsuoka, Masanobu; Kaieda, Shinjiro; Sakazaki, Yuki; Kinoshita, Takashi; Mori, Daisuke; Inoue, Akira; Hoshino, Tomoaki

    2017-09-01

    Interleukin (IL)-38, a member of the IL-1 family, shows high homology to IL-1 receptor antagonist (IL-1Ra) and IL-36 receptor antagonist (IL-36Ra). Its function in interstitial lung disease (ILD) is still unknown. To determine the expression pattern of IL-38 mRNA, a panel of cDNAs derived from various tissues was analyzed by quantitative real-time PCR. Immunohistochemical reactivity with anti-human IL-38 monoclonal antibody (clone H127C) was evaluated semi-quantitatively in lung tissue samples from 12 patients with idiopathic pulmonary fibrosis/usual interstitial pneumonia (IPF/UIP), 5 with acute exacerbation of IPF, and 10 with anticancer drug-induced ILD (bleomycin in 5 and epidermal growth factor receptor-tyrosine kinase inhibitor in 5). Control lung tissues were obtained from areas of normal lung in 22 lung cancer patients who underwent extirpation surgery. IL-38 transcripts were strongly expressed in the lung, spleen, synoviocytes, and peripheral blood mononuclear cells, and at a lower level in pancreas and muscle. IL-38 protein was not strongly expressed in normal pulmonary alveolar tissues in all 22 control lungs. In contrast, IL-38 was overexpressed in the lungs of 4 of 5 (80%) patients with acute IPF exacerbation and 100% (10/10) of the patients with drug-induced ILD. IL-38 overexpression was limited to hyperplastic type II pneumocytes, which are considered to reflect regenerative change following diffuse alveolar damage in ILD. IL-38 may play an important role in acute and/or chronic inflammation in anticancer drug-induced lung injury and acute exacerbation of IPF. Copyright © 2017 The Japanese Respiratory Society. Published by Elsevier B.V. All rights reserved.

  3. Efficacy and safety of lung recruitment in pediatric patients with acute lung injury.

    Science.gov (United States)

    Boriosi, Juan P; Sapru, Anil; Hanson, James H; Asselin, Jeanette; Gildengorin, Ginny; Newman, Vivienne; Sabato, Katie; Flori, Heidi R

    2011-07-01

    To assess the safety and efficacy of a recruitment maneuver, the Open Lung Tool, in pediatric patients with acute lung injury and acute respiratory distress syndrome. Prospective cohort study using a repeated-measures design. Pediatric intensive care unit at an urban tertiary children's hospital. Twenty-one ventilated pediatric patients with acute lung injury. Recruitment maneuver using incremental positive end-expiratory pressure. The ratio of partial pressure of arterial oxygen over fraction of inspired oxygen (Pao2/Fio2 ratio) increased 53% immediately after the recruitment maneuver. The median Pao2/Fio2 ratio increased from 111 (interquartile range, 73-266) prerecruitment maneuver to 170 (interquartile range, 102-341) immediately postrecruitment maneuver (p interquartile range, 116-257) 4 hrs postrecruitment maneuver (p interquartile range, 127-236) 12 hrs postrecruitment maneuver (p interquartile range, 44-60) prerecruitment maneuver compared with 48 torr (interquartile range, 43-50) immediately postrecruitment maneuver (p = .69), 45 torr (interquartile range, 41-50) at 4 hrs postrecruitment maneuver (p interquartile range, 38-51) at 12 hrs postrecruitment maneuver. Recruitment maneuvers were well tolerated except for significant increase in Paco2 in three patients. There were no serious adverse events related to the recruitment maneuver. Using the modified open lung tool recruitment maneuver, pediatric patients with acute lung injury may safely achieve improved oxygenation and ventilation with these benefits potentially lasting up to 12 hrs postrecruitment maneuver.

  4. The role of the acute phase protein PTX3 in the ventilator-induced lung injury

    Directory of Open Access Journals (Sweden)

    JM Real

    2008-06-01

    Full Text Available The pentraxin 3 (PTX3 is an acute phase proinflammatory protein produced by fibroblasts and alveolar epithelial cells. We have previously demonstrated that PTX3 is a key modulator of inflammation. Mechanical ventilation (MV is a life saving therapeutic approach for patients with acute lung injury that, nevertheless could lead to an inflammatory response and tissue injury (ventilator-induced lung injury: VILI, representing a major cause of iatrogenic lung damage in intensive units. Our objective was to investigate the role of PTX3 in VILI. PTX3 transgenic, knockout and Wt control mice (n = 12/group were ventilated (45ml·kg–1 until respiratory system Elastance increased 50% (Ers150%, an indicator of VILI. Histological analysis demonstrated that using a Ers150% was appropriate for our analysis since identical degrees of inflammation were observed in Tg, KO and Wt mice as assessed by leukocyte infiltration, oedema, alveolar collapse and number of breaks in alveolar septa. However, Tg mice reached Ers150% faster than Wt controls (p = 0.0225. We also showed that the lack of PTX3 does not abolish the occurrence of VILI in KOs. Gene expression profile of PTX3, IL-1beta, IL-6, KC, IFNgamma, TGFbeta and PCIII were investigated by QPCR. MV drastically up modulated PTX3 as well as IL-1beta, IL-6, IFNgamma and KC. Alternatively, mice were ventilated for 20, 40 and 60 min. The faster kinetics of Tg mice to reach Ers150% was accompanied by an earlier augmentation of IL-1b and PTX3 expression. The kinetics of local PTX3 expression in the lungs of ventilated mice strongly suggests the involvement of this pentraxin in the pathogenesis of VILI.

  5. Pulmonary stromal cells induce the generation of regulatory DC attenuating T-cell-mediated lung inflammation.

    Science.gov (United States)

    Li, Qian; Guo, Zhenhong; Xu, Xiongfei; Xia, Sheng; Cao, Xuetao

    2008-10-01

    The tissue microenvironment may affect the development and function of immune cells such as DC. Whether and how the pulmonary stromal microenvironment can affect the development and function of lung DC need to be investigated. Regulatory DC (DCreg) can regulate T-cell response. We wondered whether such regulatory DC exist in the lung and what is the effect of the pulmonary stromal microenvironment on the generation of DCreg. Here we demonstrate that murine pulmonary stromal cells can drive immature DC, which are regarded as being widely distributed in the lung, to proliferate and differentiate into a distinct subset of DCreg, which express high levels of CD11b but low levels of MHC class II (I-A), CD11c, secrete high amounts of IL-10, NO and prostaglandin E2 (PGE2) and suppress T-cell proliferation. The natural counterpart of DCreg in the lung with similar phenotype and regulatory function has been identified. Pulmonary stroma-derived TGF-beta is responsible for the differentiation of immature DC to DCreg, and DCreg-derived PGE2 contributes to their suppression of T-cell proliferation. Moreover, DCreg can induce the generation of CD4+CD25+Foxp3+ Treg. Importantly, infusion with DCreg attenuates T-cell-mediated eosinophilic airway inflammation in vivo. Therefore, the pulmonary microenvironment may drive the generation of DCreg, thus contributing to the maintenance of immune homoeostasis and the control of inflammation in the lung.

  6. Increased lung neutrophil apoptosis and inflammation resolution in nonresponding pneumonia.

    Science.gov (United States)

    Moret, I; Lorenzo, M J; Sarria, B; Cases, E; Morcillo, E; Perpiñá, M; Molina, J M; Menéndez, R

    2011-11-01

    Neutrophil activation state and its relationship with an inflammatory environment in community-acquired pneumonia (CAP) remain insufficiently elucidated. We aimed to evaluate the neutrophil apoptosis and cytokine pattern in CAP patients after 72 h of treatment, and their impact on infection resolution. Apoptosis of blood and bronchoalveolar lavage (BAL) neutrophils was measured in nonresponding CAP (NCAP), in responding CAP (blood only) and in patients without infection (control). Pro-inflammatory (interleukin (IL)-6, IL-8) and anti-inflammatory (IL-10) cytokines were measured. Main outcomes were clinical stability and days of hospitalisation. Basal neutrophil apoptosis was higher in the BAL and blood of NCAP, whereas spontaneous apoptosis (after 24 h culture) was lower. Cytokines in NCAP were higher than in responding CAP and control: IL-6 was increased in BAL and blood, IL-8 in BAL and IL-10 in blood. An increased basal apoptosis (≥20%) in BAL of NCAP was associated with lower systemic IL-10 (p<0.01), earlier clinical stability (p=0.05) and shorter hospital stay (p=0.02). A significant correlation was found for systemic IL-6 and IL-10 with days to reach stability and length of stay. After 72 h of treatment, an increased basal alveolar neutrophil apoptosis might contribute to downregulation of inflammation and to faster clinical stability.

  7. Inflammation of vertebral bone associated with acute calcific tendinitis of the longus colli muscle

    Energy Technology Data Exchange (ETDEWEB)

    Mihmanli, I.; Kanberoglu, K. [Dept. of Radiology, Istanbul Univ. (Turkey); Karaarslan, E. [Intermed Medical Center, Nisantasi, Istanbul (Turkey)

    2001-12-01

    We present a case of acute retropharyngeal calcific tendinitis with characteristic findings on radiographic, computed tomography, and magnetic resonance imaging (MRI). To our knowledge, this is the first acute retropharyngeal calcific tendinitis report having inflammation of both the vertebra itself and the longus colli muscle diagnosed on MRI. In patients with neck pain, acute retropharyngeal calcific tendinitis should be kept in mind in the differential diagnosis, even if these patients had vertebral pathological signals on MRI. (orig.)

  8. Inflammation of vertebral bone associated with acute calcific tendinitis of the longus colli muscle

    International Nuclear Information System (INIS)

    Mihmanli, I.; Kanberoglu, K.; Karaarslan, E.

    2001-01-01

    We present a case of acute retropharyngeal calcific tendinitis with characteristic findings on radiographic, computed tomography, and magnetic resonance imaging (MRI). To our knowledge, this is the first acute retropharyngeal calcific tendinitis report having inflammation of both the vertebra itself and the longus colli muscle diagnosed on MRI. In patients with neck pain, acute retropharyngeal calcific tendinitis should be kept in mind in the differential diagnosis, even if these patients had vertebral pathological signals on MRI. (orig.)

  9. Familial idiopathic pulmonary fibrosis. Evidence of lung inflammation in unaffected family members

    International Nuclear Information System (INIS)

    Bitterman, P.B.; Rennard, S.I.; Keogh, B.A.; Wewers, M.D.; Adelberg, S.; Crystal, R.G.

    1986-01-01

    We evaluated 17 clinically unaffected members of three families with an autosomal dominant form of idiopathic pulmonary fibrosis for evidence of alveolar inflammation. Each person in the study was examined by gallium-67 scanning for a general estimate of pulmonary inflammation, and by bronchoalveolar lavage for characterization of the types of recovered cells and their state of activation. Eight of the 17 subjects had evidence of alveolar inflammation on the lavage studies. Supporting data included increased numbers of neutrophils and activated macrophages that released one or more neutrophil chemoattractants, and growth factors for lung fibroblasts--findings similar to those observed in patients with overt idiopathic pulmonary fibrosis. Four of these eight also had a positive gallium scan; in all the other clinically unaffected subjects the scan was normal. During a follow-up of two to four years in seven of the eight subjects who had evidence of inflammation, no clinical evidence of pulmonary fibrosis has appeared. These results indicate that alveolar inflammation occurs in approximately half the clinically unaffected family members at risk of inheriting autosomal dominant idiopathic pulmonary fibrosis. Whether these persons with evidence of pulmonary inflammation but no fibrosis will proceed to have clinically evident pulmonary fibrosis is not yet known

  10. Acute inflammation in horizontal incompletely impacted third molar with radiolucency in the elderly

    Directory of Open Access Journals (Sweden)

    Minoru Yamaoka

    2009-07-01

    Full Text Available Minoru Yamaoka, Yusuke Ono, Masahiro Takahashi, Masahide Ishizuka, Takayuki Uchihashi, Kouichi Yasuda, Takashi Uematsu, Kiyofumi FurusawaMatsumoto Dental University, Oral and Maxillofacial Surgery, Shiojiri, Nagano, JapanAbstract: Although radiolucency has been shown as a risk of infection, the poorly understood effects of aging on radiolucency correlate with acute pericoronitis, which has a high risk of infection extending any complications. We reviewed the records of 346 consecutive patients aged more than 41 years to evaluate whether pericoronal radiolucency below the crown in mandibular horizontal incompletely impacted third molars is related to acute inflammation. The frequency of acute inflammation in teeth with pericoronal radiolucency below the crown was similar to that in teeth without; however, the odds ratio of acute inflammation exhibited in women aged more than 61 years compared to women aged 41–50 years was 9.77 (95% confidence interval [CI]: 1.67–57.29; P <<0.05, and in women aged more than 61 years compared to women aged 51–60 years was 26.25 (95% CI: 2.94–234.38; P < 0.01. The odds ratio of severe acute inflammation exhibited in men aged more than 61 years compared to men aged 41–50 years was 16.67 (95% CI: 1.76–158.27; P < 0.01. These odds ratios indicate an association of acute pericoronitis, including the severe forms of acute inflammation that result from pericoronitis, with pericoronal radiolucency below the crown in the elderly.Keywords: radiolucency, mandible, third molar, acute inflammation, aging

  11. Hydroxysafflor yellow A suppress oleic acid-induced acute lung injury via protein kinase A

    International Nuclear Information System (INIS)

    Wang, Chaoyun; Huang, Qingxian; Wang, Chunhua; Zhu, Xiaoxi; Duan, Yunfeng; Yuan, Shuai; Bai, Xianyong

    2013-01-01

    Inflammation response and oxidative stress play important roles in acute lung injury (ALI). Activation of the cAMP/protein kinase A (PKA) signaling pathway may attenuate ALI by suppressing immune responses and inhibiting the generation of reactive oxygen species (ROS). Hydroxysafflor yellow A (HSYA) is a natural flavonoid compound that reduces oxidative stress and inflammatory cytokine-mediated damage. In this study, we examined whether HSYA could protect the lungs from oleic acid (OA)-induced injury, which was used to mimic ALI, and determined the role of the cAMP/PKA signaling pathway in this process. Arterial oxygen tension (PaO 2 ), carbon dioxide tension, pH, and the PaO 2 /fraction of inspired oxygen ratio in the blood were detected using a blood gas analyzer. We measured wet/dry lung weight ratio and evaluated tissue morphology. The protein and inflammatory cytokine levels in the bronchoalveolar lavage fluid and serum were determined using enzyme-linked immunoassay. The activities of superoxide dismutase, glutathione peroxidase, PKA, and nicotinamide adenine dinucleotide phosphate oxidase, and the concentrations of cAMP and malondialdehyde in the lung tissue were detected using assay kits. Bcl-2, Bax, caspase 3, and p22 phox levels in the lung tissue were analyzed using Western blotting. OA increased the inflammatory cytokine and ROS levels and caused lung dysfunction by decreasing cAMP synthesis, inhibiting PKA activity, stimulating caspase 3, and reducing the Bcl-2/Bax ratio. H-89 increased these effects. HSYA significantly increased the activities of antioxidant enzymes, inhibited the inflammatory response via cAMP/PKA pathway activation, and attenuated OA-induced lung injury. Our results show that the cAMP/PKA signaling pathway is required for the protective effect of HSYA against ALI. - Highlights: • Oleic acid (OA) cause acute lung injury (ALI) via inhibiting cAMP/PKA signal pathway. • Blocking protein kinase A (PKA) activation may enhance Cytokine

  12. Platelet serotonin promotes the recruitment of neutrophils to sites of acute inflammation in mice

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    Suidan, Georgette L.; Demers, Melanie; Herr, Nadine; Carbo, Carla; Brill, Alexander; Cifuni, Stephen M.; Mauler, Maximilian; Cicko, Sanja; Bader, Michael; Idzko, Marco; Bode, Christoph

    2013-01-01

    The majority of peripheral serotonin is stored in platelets, which secrete it on activation. Serotonin releases Weibel-Palade bodies (WPBs) and we asked whether absence of platelet serotonin affects neutrophil recruitment in inflammatory responses. Tryptophan hydroxylase (Tph)1–deficient mice, lacking non-neuronal serotonin, showed mild leukocytosis compared with wild-type (WT), primarily driven by an elevated neutrophil count. Despite this, 50% fewer leukocytes rolled on unstimulated mesenteric venous endothelium of Tph1−/− mice. The velocity of rolling leukocytes was higher in Tph1−/− mice, indicating fewer selectin-mediated interactions with endothelium. Stimulation of endothelium with histamine, a secretagogue of WPBs, or injection of serotonin normalized the rolling in Tph1−/− mice. Diminished rolling in Tph1−/− mice resulted in reduced firm adhesion of leukocytes after lipopolysaccharide treatment. Blocking platelet serotonin uptake with fluoxetine in WT mice reduced serum serotonin by > 80% and similarly reduced leukocyte rolling and adhesion. Four hours after inflammatory stimulation, neutrophil extravasation into lung, peritoneum, and skin wounds was reduced in Tph1−/− mice, whereas in vitro neutrophil chemotaxis was independent of serotonin. Survival of lipopolysaccharide-induced endotoxic shock was improved in Tph1−/− mice. In conclusion, platelet serotonin promotes the recruitment of neutrophils in acute inflammation, supporting an important role for platelet serotonin in innate immunity. PMID:23243271

  13. Milano summer particulate matter (PM10 triggers lung inflammation and extra pulmonary adverse events in mice.

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    Francesca Farina

    Full Text Available Recent studies have suggested a link between particulate matter (PM exposure and increased mortality and morbidity associated with pulmonary and cardiovascular diseases; accumulating evidences point to a new role for air pollution in CNS diseases. The purpose of our study is to investigate PM10sum effects on lungs and extra pulmonary tissues. Milano PM10sum has been intratracheally instilled into BALB/c mice. Broncho Alveolar Lavage fluid, lung parenchyma, heart and brain were screened for markers of inflammation (cell counts, cytokines, ET-1, HO-1, MPO, iNOS, cytotoxicity (LDH, ALP, Hsp70, Caspase8-p18, Caspase3-p17 for a putative pro-carcinogenic marker (Cyp1B1 and for TLR4 pathway activation. Brain was also investigated for CD68, TNF-α, GFAP. In blood, cell counts were performed while plasma was screened for endothelial activation (sP-selectin, ET-1 and for inflammation markers (TNF-α, MIP-2, IL-1β, MPO. Genes up-regulation (HMOX1, Cyp1B1, IL-1β, MIP-2, MPO and miR-21 have been investigated in lungs and blood. Inflammation in the respiratory tract of PM10sum-treated mice has been confirmed in BALf and lung parenchyma by increased PMNs percentage, increased ET-1, MPO and cytokines levels. A systemic spreading of lung inflammation in PM10sum-treated mice has been related to the increased blood total cell count and neutrophils percentage, as well as to increased blood MPO. The blood-endothelium interface activation has been confirmed by significant increases of plasma ET-1 and sP-selectin. Furthermore PM10sum induced heart endothelial activation and PAHs metabolism, proved by increased ET-1 and Cyp1B1 levels. Moreover, PM10sum causes an increase in brain HO-1 and ET-1. These results state the translocation of inflammation mediators, ultrafine particles, LPS, metals associated to PM10sum, from lungs to bloodstream, thus triggering a systemic reaction, mainly involving heart and brain. Our results provided additional insight into the toxicity

  14. Simulating Sleep Apnea by Exposure to Intermittent Hypoxia Induces Inflammation in the Lung and Liver

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    da Rosa, Darlan Pase; Forgiarini, Luiz Felipe; Baronio, Diego; Feijó, Cristiano Andrade; Martinez, Dênis; Marroni, Norma Possa

    2012-01-01

    Sleep apnea is a breathing disorder that results from momentary and cyclic collapse of the upper airway, leading to intermittent hypoxia (IH). IH can lead to the formation of free radicals that increase oxidative stress, and this mechanism may explain the association between central sleep apnea and nonalcoholic steatohepatitis. We assessed the level of inflammation in the lung and liver tissue from animals subjected to intermittent hypoxia and simulated sleep apnea. A total of 12 C57BL/6 mice...

  15. Rac1 signaling regulates cigarette smoke-induced inflammation in the lung via the Erk1/2 MAPK and STAT3 pathways.

    Science.gov (United States)

    Jiang, Jun-Xia; Zhang, Shui-Juan; Shen, Hui-Juan; Guan, Yan; Liu, Qi; Zhao, Wei; Jia, Yong-Liang; Shen, Jian; Yan, Xiao-Feng; Xie, Qiang-Min

    2017-07-01

    Cigarette smoke (CS) is a major risk factor for the development of chronic obstructive pulmonary disease (COPD). Our previous studies have indicated that Rac1 is involved in lipopolysaccharide-induced pulmonary injury and CS-mediated epithelial-mesenchymal transition. However, the contribution of Rac1 activity to CS-induced lung inflammation remains not fully clear. In this study, we investigated the regulation of Rac1 in CS-induced pulmonary inflammation. Mice or 16HBE cells were exposed to CS or cigarette smoke extract (CSE) to induce acute inflammation. The lungs of mice exposed to CS showed an increase in the release of interleukin-6 (IL-6) and keratinocyte-derived chemokine (KC), as well as an accumulation of inflammatory cells, indicating high Rac1 activity. The exposure of 16HBE cells to CSE resulted in elevated Rac1 levels, as well as increased release of IL-6 and interleukin-8 (IL-8). Selective inhibition of Rac1 ameliorated the release of IL-6 and KC as well as inflammation in the lungs of CS-exposed mice. Histological assessment showed that treatment with a Rac1 inhibitor, NSC23766, led to a decrease in CD68 and CD11b positive cells and the infiltration of neutrophils and macrophages into the alveolar spaces. Selective inhibition or knockdown of Rac1 decreased IL-6 and IL-8 release in 16HBE cells induced by CSE, which correlated with CSE-induced Rac1-regulated Erk1/2 mitogen-activated protein kinase (MAPK) and signal transducer and activator of transcription-3 (STAT3) signaling. Our data suggest an important role for Rac1 in the pathological alterations associated with CS-mediated inflammation. Rac1 may be a promising therapeutic target for the treatment of CS-induced pulmonary inflammation. Copyright © 2017 Elsevier B.V. All rights reserved.

  16. Vildagliptin-induced acute lung injury: a case report.

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    Ohara, Nobumasa; Kaneko, Masanori; Sato, Kazuhiro; Maruyama, Ryoko; Furukawa, Tomoyasu; Tanaka, Junta; Kaneko, Kenzo; Kamoi, Kyuzi

    2016-08-12

    Dipeptidyl peptidase-4 inhibitors are a class of oral hypoglycemic drugs and are used widely to treat type 2 diabetes mellitus in many countries. Adverse effects include nasopharyngitis, headache, elevated serum pancreatic enzymes, and gastrointestinal symptoms. In addition, a few cases of interstitial pneumonia associated with their use have been reported in the Japanese literature. Here we describe a patient who developed drug-induced acute lung injury shortly after the administration of the dipeptidyl peptidase-4 inhibitor vildagliptin. A 38-year-old Japanese woman with diabetes mellitus developed acute respiratory failure 1 day after administration of vildagliptin. Chest computed tomography revealed nonsegmental ground-glass opacities in her lungs. There was no evidence of bacterial pneumonia or any other cause of her respiratory manifestations. After discontinuation of vildagliptin, she recovered fully from her respiratory disorder. She received insulin therapy for her diabetes mellitus, and her subsequent clinical course has been uneventful. The period of drug exposure in previously reported cases of patients with drug-induced interstitial pneumonia caused by dipeptidyl peptidase-4 inhibitor varied from several days to over 6 months. In the present case, our patient developed interstitial pneumonia only 1 day after the administration of vildagliptin. The precise mechanism of her vildagliptin-induced lung injury remains uncertain, but physicians should consider that dipeptidyl peptidase-4 inhibitor-induced lung injury, although rare, may appear acutely, even within days after administration of this drug.

  17. The LIM-only protein FHL2 attenuates lung inflammation during bleomycin-induced fibrosis.

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    Abdulaleem Alnajar

    Full Text Available Fibrogenesis is usually initiated when regenerative processes have failed and/or chronic inflammation occurs. It is characterised by the activation of tissue fibroblasts and dysregulated synthesis of extracellular matrix proteins. FHL2 (four-and-a-half LIM domain protein 2 is a scaffolding protein that interacts with numerous cellular proteins, regulating signalling cascades and gene transcription. It is involved in tissue remodelling and tumour progression. Recent data suggest that FHL2 might support fibrogenesis by maintaining the transcriptional expression of alpha smooth muscle actin and the excessive synthesis and assembly of matrix proteins in activated fibroblasts. Here, we present evidence that FHL2 does not promote bleomycin-induced lung fibrosis, but rather suppresses this process by attenuating lung inflammation. Loss of FHL2 results in increased expression of the pro-inflammatory matrix protein tenascin C and downregulation of the macrophage activating C-type lectin receptor DC-SIGN. Consequently, FHL2 knockout mice developed a severe and long-lasting lung pathology following bleomycin administration due to enhanced expression of tenascin C and impaired activation of inflammation-resolving macrophages.

  18. Helminth-induced arginase-1 exacerbates lung inflammation and disease severity in tuberculosis

    Science.gov (United States)

    Monin, Leticia; Griffiths, Kristin L.; Lam, Wing Y.; Gopal, Radha; Kang, Dongwan D.; Ahmed, Mushtaq; Rajamanickam, Anuradha; Cruz-Lagunas, Alfredo; Zúñiga, Joaquín; Babu, Subash; Kolls, Jay K.; Mitreva, Makedonka; Rosa, Bruce A.; Ramos-Payan, Rosalio; Morrison, Thomas E.; Murray, Peter J.; Rangel-Moreno, Javier; Pearce, Edward J.; Khader, Shabaana A.

    2015-01-01

    Parasitic helminth worms, such as Schistosoma mansoni, are endemic in regions with a high prevalence of tuberculosis (TB) among the population. Human studies suggest that helminth coinfections contribute to increased TB susceptibility and increased rates of TB reactivation. Prevailing models suggest that T helper type 2 (Th2) responses induced by helminth infection impair Th1 immune responses and thereby limit Mycobacterium tuberculosis (Mtb) control. Using a pulmonary mouse model of Mtb infection, we demonstrated that S. mansoni coinfection or immunization with S. mansoni egg antigens can reversibly impair Mtb-specific T cell responses without affecting macrophage-mediated Mtb control. Instead, S. mansoni infection resulted in accumulation of high arginase-1–expressing macrophages in the lung, which formed type 2 granulomas and exacerbated inflammation in Mtb-infected mice. Treatment of coinfected animals with an antihelminthic improved Mtb-specific Th1 responses and reduced disease severity. In a genetically diverse mouse population infected with Mtb, enhanced arginase-1 activity was associated with increased lung inflammation. Moreover, in patients with pulmonary TB, lung damage correlated with increased serum activity of arginase-1, which was elevated in TB patients coinfected with helminths. Together, our data indicate that helminth coinfection induces arginase-1–expressing type 2 granulomas, thereby increasing inflammation and TB disease severity. These results also provide insight into the mechanisms by which helminth coinfections drive increased susceptibility, disease progression, and severity in TB. PMID:26571397

  19. Inducible Bronchus-Associated Lymphoid Tissue: Taming Inflammation in the Lung.

    Science.gov (United States)

    Hwang, Ji Young; Randall, Troy D; Silva-Sanchez, Aaron

    2016-01-01

    Following pulmonary inflammation, leukocytes that infiltrate the lung often assemble into structures known as inducible Bronchus-Associated Lymphoid Tissue (iBALT). Like conventional lymphoid organs, areas of iBALT have segregated B and T cell areas, specialized stromal cells, high endothelial venules, and lymphatic vessels. After inflammation is resolved, iBALT is maintained for months, independently of inflammation. Once iBALT is formed, it participates in immune responses to pulmonary antigens, including those that are unrelated to the iBALT-initiating antigen, and often alters the clinical course of disease. However, the mechanisms that govern immune responses in iBALT and determine how iBALT impacts local and systemic immunity are poorly understood. Here, we review our current understanding of iBALT formation and discuss how iBALT participates in pulmonary immunity.

  20. Supernatant of stored platelets causes lung inflammation and coagulopathy in a novel in vivo transfusion model

    NARCIS (Netherlands)

    Vlaar, Alexander P. J.; Hofstra, Jorrit J.; Kulik, Wim; van Lenthe, Henk; Nieuwland, Rienk; Schultz, Marcus J.; Levi, Marcel M.; Roelofs, Joris J. T. H.; Tool, Anton T. J.; de Korte, Dirk; Juffermans, Nicole P.

    2010-01-01

    Transfusion-related acute lung injury is suggested to be a "2-hit" event resulting from priming and activation of pulmonary neutrophils. Activation may result from infusion of lysophosphatidylcholines (LysoPCs), which accumulate during storage of blood products. In the present study, we developed a

  1. Peripheral inflammation acutely impairs human spatial memory via actions on medial temporal lobe glucose metabolism.

    Science.gov (United States)

    Harrison, Neil A; Doeller, Christian F; Voon, Valerie; Burgess, Neil; Critchley, Hugo D

    2014-10-01

    Inflammation impairs cognitive performance and is implicated in the progression of neurodegenerative disorders. Rodent studies demonstrated key roles for inflammatory mediators in many processes critical to memory, including long-term potentiation, synaptic plasticity, and neurogenesis. They also demonstrated functional impairment of medial temporal lobe (MTL) structures by systemic inflammation. However, human data to support this position are limited. Sequential fluorodeoxyglucose positron emission tomography together with experimentally induced inflammation was used to investigate effects of a systemic inflammatory challenge on human MTL function. Fluorodeoxyglucose positron emission tomography scanning was performed in 20 healthy participants before and after typhoid vaccination and saline control injection. After each scanning session, participants performed a virtual reality spatial memory task analogous to the Morris water maze and a mirror-tracing procedural memory control task. Fluorodeoxyglucose positron emission tomography data demonstrated an acute reduction in human MTL glucose metabolism after inflammation. The inflammatory challenge also selectively compromised human spatial, but not procedural, memory; this effect that was independent of actions on motivation or psychomotor response. Effects of inflammation on parahippocampal and rhinal glucose metabolism directly mediated actions of inflammation on spatial memory. These data demonstrate acute sensitivity of human MTL to mild peripheral inflammation, giving rise to associated functional impairment in the form of reduced spatial memory performance. Our findings suggest a mechanism for the observed epidemiologic link between inflammation and risk of age-related cognitive decline and progression of neurodegenerative disorders including Alzheimer's disease. Copyright © 2014 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.

  2. Prevention of LPS-Induced Acute Lung Injury in Mice by Progranulin

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    Zhongliang Guo

    2012-01-01

    Full Text Available The acute respiratory distress syndrome (ARDS, a clinical complication of severe acute lung injury (ALI in humans, is a leading cause of morbidity and mortality in critically ill patients. Despite decades of research, few therapeutic strategies for clinical ARDS have emerged. Here we carefully evaluated the effect of progranulin (PGRN in treatment of ARDS using the murine model of lipopolysaccharide (LPS-induced ALI. We reported that administration of PGRN maintained the body weight and survival of ALI mice. We revealed that administration of PGRN significantly reduced LPS-induced pulmonary inflammation, as reflected by reductions in total cell and neutrophil counts, proinflammatory cytokines, as well as chemokines in bronchoalveolar lavage (BAL fluid. Furthermore, administration of PGRN resulted in remarkable reversal of LPS-induced increases in lung permeability as assessed by reductions in total protein, albumin, and IgM in BAL fluid. Consistently, we revealed a significant reduction of histopathology changes of lung in mice received PGRN treatment. Finally, we showed that PGRN/TNFR2 interaction was crucial for the protective effect of PGRN on the LPS-induced ALI. Our findings strongly demonstrated that PGRN could effectively ameliorate the LPS-induced ALI in mice, suggesting a potential application for PGRN-based therapy to treat clinical ARDS.

  3. Double-hit mouse model of cigarette smoke priming for acute lung injury.

    Science.gov (United States)

    Sakhatskyy, Pavlo; Wang, Zhengke; Borgas, Diana; Lomas-Neira, Joanne; Chen, Yaping; Ayala, Alfred; Rounds, Sharon; Lu, Qing

    2017-01-01

    Epidemiological studies indicate that cigarette smoking (CS) increases the risk and severity of acute lung injury (ALI)/acute respiratory distress syndrome (ARDS). The mechanism is not understood, at least in part because of lack of animal models that reproduce the key features of the CS priming process. In this study, using two strains of mice, we characterized a double-hit mouse model of ALI induced by CS priming of injury caused by lipopolysaccharide (LPS). C57BL/6 and AKR mice were preexposed to CS briefly (3 h) or subacutely (3 wk) before intratracheal instillation of LPS and ALI was assessed 18 h after LPS administration by measuring lung static compliance, lung edema, vascular permeability, inflammation, and alveolar apoptosis. We found that as little as 3 h of exposure to CS enhanced LPS-induced ALI in both strains of mice. Similar exacerbating effects were observed after 3 wk of preexposure to CS. However, there was a strain difference in susceptibility to CS priming for ALI, with a greater effect in AKR mice. The key features we observed suggest that 3 wk of CS preexposure of AKR mice is a reproducible, clinically relevant animal model that is useful for studying mechanisms and treatment of CS priming for a second-hit-induced ALI. Our data also support the concept that increased susceptibility to ALI/ARDS is an important adverse health consequence of CS exposure that needs to be taken into consideration when treating critically ill individuals.

  4. Independent lung ventilation in a newborn with asymmetric acute lung injury due to respiratory syncytial virus: a case report

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    Di Nardo Matteo

    2008-06-01

    Full Text Available Abstract Introduction Independent lung ventilation is a form of protective ventilation strategy used in adult asymmetric acute lung injury, where the application of conventional mechanical ventilation can produce ventilator-induced lung injury and ventilation-perfusion mismatch. Only a few experiences have been published on the use of independent lung ventilation in newborn patients. Case presentation We present a case of independent lung ventilation in a 16-day-old infant of 3.5 kg body weight who had an asymmetric lung injury due to respiratory syncytial virus bronchiolitis. We used independent lung ventilation applying conventional protective pressure controlled ventilation to the less-compromised lung, with a respiratory frequency proportional to the age of the patient, and a pressure controlled high-frequency ventilation to the atelectatic lung. This was done because a single tube conventional ventilation protective strategy would have exposed the less-compromised lung to a high mean airways pressure. The target of independent lung ventilation is to provide adequate gas exchange at a safe mean airways pressure level and to expand the atelectatic lung. Independent lung ventilation was accomplished for 24 hours. Daily chest radiograph and gas exchange were used to evaluate the efficacy of independent lung ventilation. Extubation was performed after 48 hours of conventional single-tube mechanical ventilation following independent lung ventilation. Conclusion This case report demonstrates the feasibility of independent lung ventilation with two separate tubes in neonates as a treatment of an asymmetric acute lung injury.

  5. Lung function evaluation in acute postradiation pneumonitis

    International Nuclear Information System (INIS)

    Jassem, E.; Zandwijk, N. van; Jassem, J.; Badzio, A.

    1997-01-01

    The aim of this study was pulmonary function evaluation in patients with radiation pneumonitis (rp). Study group included 18 patients with symptomatic rp (8 with breast cancer, 6 with Hodgkin's disease and 4 with lung cancer) treated at the Netherland s Cancer inst. In Amsterdam between 1988 and 1994. The lung function tests were performed at the time of rp presentation and monthly thereafter and consisted of a standard spirometry: forced expiratory volume in 1 sec. (FEV1), vital capacity (VC) and diffusing capacity for carbon monoxide (DLCO) performed with the use of a single breath technique. The mean values of DLCO, VC, FEV1 and TLC at the time of rp presentation were 72.2%, 91.0% and 85.8% of predicted value (pv), respectively. The results of the a bone tests at the last examination (66.4%, 85.6%, 77.2% and 76.2% of pv), respectively, were lower than those registered at the time of rp presentation. The highest degree of functional deterioration included diffusion capacity; the mean of the lowest values of DLCO was 56.4% of pv. Usually the lowest value of DLCO accompanied the exacerbation of clinical symptoms. The results of this study demonstrated pulmonary function deterioration in patients with rp. (author)

  6. Inhibitory effect of kefiran on ovalbumin-induced lung inflammation in a murine model of asthma.

    Science.gov (United States)

    Kwon, Ok-Kyoung; Ahn, Kyung-Seop; Lee, Mee-Young; Kim, So-Young; Park, Bo-Young; Kim, Mi-Kyoung; Lee, In-Young; Oh, Sei-Ryang; Lee, Hyeong-Kyu

    2008-12-01

    Kefiran is a major component of kefir which is a microbial symbiont mixture that produces jelly-like grains. This study aimed to evaluate the therapeutic availability of kefiran on the ovalbumin-induced asthma mouse model in which airway inflammation and airway hyper-responsiveness were found in the lung. BALB/c mice sensitized and challenged to ovalbumin were treated intra-gastrically with kefiran 1 hour before the ovalbumin challenge. Kefiran significantly suppressed ovalbumin-induced airway hyper-responsiveness (AHR) to inhaled methacholine. Administration of kefiran significantly inhibited the release of both eosinophils and other inflammatory cells into bronchoalveolar lavage (BAL) fluid and lung tissue which was measured by Diff-Quik. Interleukin-4 (IL-4) and interleukin-5 (IL-5) were also reduced to normal levels after administration of kefiran in BAL fluid. Histological studies demonstrate that kefiran substantially inhibited ovalbumin-induced eosinophilia in lung tissue by H&E staining and goblet cell hyperplasia in the airway by PAS staining. Taken above data, kefiran may be useful for the treatment of inflammation of lung tissue and airway hyper-responsiveness in a murine model and may have therapeutic potential for the treatment of allergic bronchial asthma.

  7. Systemic Inflammation and Lung Function Impairment in Morbidly Obese Subjects with the Metabolic Syndrome

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    Astrid van Huisstede

    2013-01-01

    Full Text Available Background. Obesity and asthma are associated. There is a relationship between lung function impairment and the metabolic syndrome. Whether this relationship also exists in the morbidly obese patients is still unknown. Hypothesis. Low-grade systemic inflammation associated with the metabolic syndrome causes inflammation in the lungs and, hence, lung function impairment. Methods. This is cross-sectional study of morbidly obese patients undergoing preoperative screening for bariatric surgery. Metabolic syndrome was assessed according to the revised NCEP-ATP III criteria. Results. A total of 452 patients were included. Patients with the metabolic syndrome (n=293 had significantly higher blood monocyte (mean 5.3 versus 4.9, P=0.044 and eosinophil percentages (median 1.0 versus 0.8, P=0.002, while the total leukocyte count did not differ between the groups. The FEV1/FVC ratio was significantly lower in patients with the metabolic syndrome (76.7% versus 78.2%, P=0.032. Blood eosinophils were associated with FEV1/FVC ratio (adj. B −0.113, P=0.018. Conclusion. Although the difference in FEV1/FVC ratio between the groups is relatively small, in this cross-sectional study, and its clinical relevance may be limited, these data indicate that the presence of the metabolic syndrome may influence lung function impairment, through the induction of relative eosinophilia.

  8. COPD and squamous cell lung cancer: aberrant inflammation and immunity is the common link.

    Science.gov (United States)

    Bozinovski, Steven; Vlahos, Ross; Anthony, Desiree; McQualter, Jonathan; Anderson, Gary; Irving, Louis; Steinfort, Daniel

    2016-02-01

    Cigarette smoking has reached epidemic proportions within many regions of the world and remains the highest risk factor for chronic obstructive pulmonary disease (COPD) and lung cancer. Squamous cell lung cancer is commonly detected in heavy smokers, where the risk of developing lung cancer is not solely defined by tobacco consumption. Although therapies that target common driver mutations in adenocarcinomas are showing some promise, they are proving ineffective in smoking-related squamous cell lung cancer. Since COPD is characterized by an excessive inflammatory and oxidative stress response, this review details how aberrant innate, adaptive and systemic inflammatory processes can contribute to lung cancer susceptibility in COPD. Activated leukocytes release increasing levels of proteases and free radicals as COPD progresses and tertiary lymphoid aggregates accumulate with increasing severity. Reactive oxygen species promote formation of reactive carbonyls that are not only tumourigenic through initiating DNA damage, but can directly alter the function of regulatory proteins involved in host immunity and tumour suppressor functions. Systemic inflammation is also markedly increased during infective exacerbations in COPD and the interplay between tumour-promoting serum amyloid A (SAA) and IL-17A is discussed. SAA is also an endogenous allosteric modifier of FPR2 expressed on immune and epithelial cells, and the therapeutic potential of targeting this receptor is proposed as a novel strategy for COPD-lung cancer overlap. © 2015 The British Pharmacological Society.

  9. Lung sound analysis helps localize airway inflammation in patients with bronchial asthma

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    Shimoda T

    2017-03-01

    Full Text Available Terufumi Shimoda,1 Yasushi Obase,2 Yukio Nagasaka,3 Hiroshi Nakano,1 Akiko Ishimatsu,1 Reiko Kishikawa,1 Tomoaki Iwanaga1 1Clinical Research Center, Fukuoka National Hospital, Fukuoka, 2Second Department of Internal Medicine, School of Medicine, Nagasaki University, Nagasaki, 3Kyoto Respiratory Center, Otowa Hospital, Kyoto, Japan Purpose: Airway inflammation can be detected by lung sound analysis (LSA at a single point in the posterior lower lung field. We performed LSA at 7 points to examine whether the technique could identify the location of airway inflammation in patients with asthma. Patients and methods: Breath sounds were recorded at 7 points on the body surface of 22 asthmatic subjects. Inspiration sound pressure level (ISPL, expiration sound pressure level (ESPL, and the expiration-to-inspiration sound pressure ratio (E/I were calculated in 6 frequency bands. The data were analyzed for potential correlation with spirometry, airway hyperresponsiveness (PC20, and fractional exhaled nitric oxide (FeNO. Results: The E/I data in the frequency range of 100–400 Hz (E/I low frequency [LF], E/I mid frequency [MF] were better correlated with the spirometry, PC20, and FeNO values than were the ISPL or ESPL data. The left anterior chest and left posterior lower recording positions were associated with the best correlations (forced expiratory volume in 1 second/forced vital capacity: r=–0.55 and r=–0.58; logPC20: r=–0.46 and r=–0.45; and FeNO: r=0.42 and r=0.46, respectively. The majority of asthmatic subjects with FeNO ≥70 ppb exhibited high E/I MF levels in all lung fields (excluding the trachea and V50%pred <80%, suggesting inflammation throughout the airway. Asthmatic subjects with FeNO <70 ppb showed high or low E/I MF levels depending on the recording position, indicating uneven airway inflammation. Conclusion: E/I LF and E/I MF are more useful LSA parameters for evaluating airway inflammation in bronchial asthma; 7-point lung

  10. Importance of surface characteristics of QUARTZ DQ 12 for acute inflammation

    Energy Technology Data Exchange (ETDEWEB)

    Albrecht, C.; Becher, A.; Scins, R.P.F.; Hoehr, D.; Unfried, K.; Knaapen, A.M.; Borm, P.J.A. [Institut fuer medizinische Forschung (IUF), Duesseldorf (Germany)

    2004-07-01

    Although quartz is known to induce inflammation in rat lungs, mechanisms are not yet fully understood. The importance of particle surface characteristics was investigated in vivo after intratracheal instillation of different preparations of quartz in rat lungs. Three days after instillation of 2 mg DQ12 quartz, or DQ12 coated with polyvinylpyridine-N-oxide (PVNO) or Aluminium lactate (AL), lungs of female Wistar rats were lavaged in situ to determine markers of inflammation. Control rats received saline or the coating substances alone. DQ12 induced a marked inflammatory response, as indicated by a significant increase in the number of neutrophils and macrophages, as well as in the levels of b-glucuronidase and myeloperoxidase. None of these inflammatory markers was increased for both coated quartz preparations, with the exception of neutrophil influx which was also increased after treatment with AL quartz. Our results indicate that surface characteristics are important in the onset of quartz-induced lung inflammation which could imply a different development of persistent inflammation. This will be investigated in later follow-up time points of the same animal study. (orig.)

  11. Mechanical ventilation with lower tidal volumes and positive end-expiratory pressure prevents pulmonary inflammation in patients without preexisting lung injury.

    Science.gov (United States)

    Wolthuis, Esther K; Choi, Goda; Dessing, Mark C; Bresser, Paul; Lutter, Rene; Dzoljic, Misa; van der Poll, Tom; Vroom, Margreeth B; Hollmann, Markus; Schultz, Marcus J

    2008-01-01

    Mechanical ventilation with high tidal volumes aggravates lung injury in patients with acute lung injury or acute respiratory distress syndrome. The authors sought to determine the effects of short-term mechanical ventilation on local inflammatory responses in patients without preexisting lung injury. Patients scheduled to undergo an elective surgical procedure (lasting > or = 5 h) were randomly assigned to mechanical ventilation with either higher tidal volumes of 12 ml/kg ideal body weight and no positive end-expiratory pressure (PEEP) or lower tidal volumes of 6 ml/kg and 10 cm H2O PEEP. After induction of anesthesia and 5 h thereafter, bronchoalveolar lavage fluid and/or blood was investigated for polymorphonuclear cell influx, changes in levels of inflammatory markers, and nucleosomes. Mechanical ventilation with lower tidal volumes and PEEP (n = 21) attenuated the increase of pulmonary levels of interleukin (IL)-8, myeloperoxidase, and elastase as seen with higher tidal volumes and no PEEP (n = 19). Only for myeloperoxidase, a difference was found between the two ventilation strategies after 5 h of mechanical ventilation (P volumes and PEEP may limit pulmonary inflammation in mechanically ventilated patients without preexisting lung injury. The specific contribution of both lower tidal volumes and PEEP on the protective effects of the lung should be further investigated.

  12. DNA repair is indispensable for survival after acute inflammation

    Science.gov (United States)

    Calvo, Jennifer A.; Meira, Lisiane B.; Lee, Chun-Yue I.; Moroski-Erkul, Catherine A.; Abolhassani, Nona; Taghizadeh, Koli; Eichinger, Lindsey W.; Muthupalani, Sureshkumar; Nordstrand, Line M.; Klungland, Arne; Samson, Leona D.

    2012-01-01

    More than 15% of cancer deaths worldwide are associated with underlying infections or inflammatory conditions, therefore understanding how inflammation contributes to cancer etiology is important for both cancer prevention and treatment. Inflamed tissues are known to harbor elevated etheno-base (ε-base) DNA lesions induced by the lipid peroxidation that is stimulated by reactive oxygen and nitrogen species (RONS) released from activated neutrophils and macrophages. Inflammation contributes to carcinogenesis in part via RONS-induced cytotoxic and mutagenic DNA lesions, including ε-base lesions. The mouse alkyl adenine DNA glycosylase (AAG, also known as MPG) recognizes such base lesions, thus protecting against inflammation-associated colon cancer. Two other DNA repair enzymes are known to repair ε-base lesions, namely ALKBH2 and ALKBH3; thus, we sought to determine whether these DNA dioxygenase enzymes could protect against chronic inflammation-mediated colon carcinogenesis. Using established chemically induced colitis and colon cancer models in mice, we show here that ALKBH2 and ALKBH3 provide cancer protection similar to that of the DNA glycosylase AAG. Moreover, Alkbh2 and Alkbh3 each display apparent epistasis with Aag. Surprisingly, deficiency in all 3 DNA repair enzymes confers a massively synergistic phenotype, such that animals lacking all 3 DNA repair enzymes cannot survive even a single bout of chemically induced colitis. PMID:22684101

  13. Lung protective mechanical ventilation and two year survival in patients with acute lung injury: prospective cohort study.

    Science.gov (United States)

    Needham, Dale M; Colantuoni, Elizabeth; Mendez-Tellez, Pedro A; Dinglas, Victor D; Sevransky, Jonathan E; Dennison Himmelfarb, Cheryl R; Desai, Sanjay V; Shanholtz, Carl; Brower, Roy G; Pronovost, Peter J

    2012-04-05

    To evaluate the association of volume limited and pressure limited (lung protective) mechanical ventilation with two year survival in patients with acute lung injury. Prospective cohort study. 13 intensive care units at four hospitals in Baltimore, Maryland, USA. 485 consecutive mechanically ventilated patients with acute lung injury. Two year survival after onset of acute lung injury. 485 patients contributed data for 6240 eligible ventilator settings, as measured twice daily (median of eight eligible ventilator settings per patient; 41% of which adhered to lung protective ventilation). Of these patients, 311 (64%) died within two years. After adjusting for the total duration of ventilation and other relevant covariates, each additional ventilator setting adherent to lung protective ventilation was associated with a 3% decrease in the risk of mortality over two years (hazard ratio 0.97, 95% confidence interval 0.95 to 0.99, P=0.002). Compared with no adherence, the estimated absolute risk reduction in two year mortality for a prototypical patient with 50% adherence to lung protective ventilation was 4.0% (0.8% to 7.2%, P=0.012) and with 100% adherence was 7.8% (1.6% to 14.0%, P=0.011). Lung protective mechanical ventilation was associated with a substantial long term survival benefit for patients with acute lung injury. Greater use of lung protective ventilation in routine clinical practice could reduce long term mortality in patients with acute lung injury. Clinicaltrials.gov NCT00300248.

  14. Acute chlorine gas exposure produces transient inflammation and a progressive alteration in surfactant composition with accompanying mechanical dysfunction

    Energy Technology Data Exchange (ETDEWEB)

    Massa, Christopher B.; Scott, Pamela; Abramova, Elena; Gardner, Carol; Laskin, Debra L.; Gow, Andrew J., E-mail: Gow@rci.rutgers.edu

    2014-07-01

    Acute Cl{sub 2} exposure following industrial accidents or military/terrorist activity causes pulmonary injury and severe acute respiratory distress. Prior studies suggest that antioxidant depletion is important in producing dysfunction, however a pathophysiologic mechanism has not been elucidated. We propose that acute Cl{sub 2} inhalation leads to oxidative modification of lung lining fluid, producing surfactant inactivation, inflammation and mechanical respiratory dysfunction at the organ level. C57BL/6J mice underwent whole-body exposure to an effective 60 ppm-hour Cl{sub 2} dose, and were euthanized 3, 24 and 48 h later. Whereas pulmonary architecture and endothelial barrier function were preserved, transient neutrophilia, peaking at 24 h, was noted. Increased expression of ARG1, CCL2, RETLNA, IL-1b, and PTGS2 genes was observed in bronchoalveolar lavage (BAL) cells with peak change in all genes at 24 h. Cl{sub 2} exposure had no effect on NOS2 mRNA or iNOS protein expression, nor on BAL NO{sub 3}{sup −} or NO{sub 2}{sup −}. Expression of the alternative macrophage activation markers, Relm-α and mannose receptor was increased in alveolar macrophages and pulmonary epithelium. Capillary surfactometry demonstrated impaired surfactant function, and altered BAL phospholipid and surfactant protein content following exposure. Organ level respiratory function was assessed by forced oscillation technique at 5 end expiratory pressures. Cl{sub 2} exposure had no significant effect on either airway or tissue resistance. Pulmonary elastance was elevated with time following exposure and demonstrated PEEP refractory derecruitment at 48 h, despite waning inflammation. These data support a role for surfactant inactivation as a physiologic mechanism underlying respiratory dysfunction following Cl{sub 2} inhalation. - Highlights: • Effect of 60 ppm*hr Cl{sub 2} gas on lung inflammation and mechanical function examined. • Pulmonary inflammation is transient and minor.

  15. Effects of acute systemic inflammation on the interplay between sad mood and affective cognition.

    Science.gov (United States)

    Benson, Sven; Brinkhoff, Alexandra; Lueg, Larissa; Roderigo, Till; Kribben, Andreas; Wilde, Benjamin; Witzke, Oliver; Engler, Harald; Schedlowski, Manfred; Elsenbruch, Sigrid

    2017-12-11

    Experimental endotoxemia is a translational model to study inflammatory mechanisms involved in the pathophysiology of mood disorders including depression. Disturbed affective cognition constitutes a core aspect in depression, but has never been studied in the context of inflammation. We combined experimental endotoxemia with an established experimental mood induction procedure to assess the interaction between acute inflammation and sad mood and their effects on affective cognition. In this randomized cross-over study, N = 15 healthy males received endotoxin (0.8 ng/kg lipopolysaccharide iv) on one study day and placebo an otherwise identical study day. The affective Go/Nogo task was conducted after experimental induction of neutral and sad mood. Inflammatory markers were assessed hourly. Endotoxin application induced a transient systemic inflammation, characterized by increased leukocyte counts, TNF-alpha and interleukin-6 plasma concentrations (all p sadness ratings, with highest ratings when sad mood was induced during inflammation (p sad vs. neutral mood) × 2 (sad vs. happy Go/Nogo target words) factorial design, we observed a significant target × endotoxin condition interaction (p sad targets during endotoxemia. Additionally, we found a valence × mood interaction (p sad targets in sad mood. In summary, acute inflammation and sad mood are risk factors for disturbed affective cognition. The results may reflect a mood-congruency effect, with prolonged and sustained processing of mood-congruent information during acute inflammation, which may contribute to depression risk.

  16. Acute Abdomen: A Rare Presentation of Lung Cancer Metastasis

    OpenAIRE

    Guérin, E.; Gilbert, O.; Dequanter, D.

    2009-01-01

    Surgical emergencies caused by bowel metastases from carcinoma of the lung are very rare. We describe two cases of symptomatic gastrointestinal metastatic small cell carcinoma: the first one concerns a 69-year-old man with an acute abdomen and the second is a 72-year-old man complaining of a gastric ulcer symptoms. We also discuss the current management and the prognosis of these patients.

  17. Cerium oxide nanoparticles protect rodent lungs from hypobaric hypoxia-induced oxidative stress and inflammation

    Directory of Open Access Journals (Sweden)

    Arya A

    2013-11-01

    intraperitoneal injections of low micromole concentration, we successfully localized the nanoceria in rodent lung without any inflammatory response. The lung-deposited nanoceria limited ROS formation, lipid peroxidation, and glutathione oxidation, and prevented oxidative protein modifications like nitration and carbonyl formation during hypobaric hypoxia. We also observed reduced lung inflammation in the nanoceria-injected lungs, supporting the anti-inflammatory properties of nanoceria. Conclusion: Cumulatively, these results suggest nanoceria deposit in lungs, confer protection by quenching noxious free radicals during hypobaric hypoxia, and do not evoke any inflammatory response. Keywords: nanoceria, high altitude, nanomedicine

  18. Limonene and its ozone-initiated reaction products attenuate allergic lung inflammation in mice.

    Science.gov (United States)

    Hansen, Jitka S; Nørgaard, Asger W; Koponen, Ismo K; Sørli, Jorid B; Paidi, Maya D; Hansen, Søren W K; Clausen, Per Axel; Nielsen, Gunnar D; Wolkoff, Peder; Larsen, Søren Thor

    2016-11-01

    Inhalation of indoor air pollutants may cause airway irritation and inflammation and is suspected to worsen allergic reactions. Inflammation may be due to mucosal damage, upper (sensory) and lower (pulmonary) airway irritation due to activation of the trigeminal and vagal nerves, respectively, and to neurogenic inflammation. The terpene, d-limonene, is used as a fragrance in numerous consumer products. When limonene reacts with the pulmonary irritant ozone, a complex mixture of gas and particle phase products is formed, which causes sensory irritation. This study investigated whether limonene, ozone or the reaction mixture can exacerbate allergic lung inflammation and whether airway irritation is enhanced in allergic BALB/cJ mice. Naïve and allergic (ovalbumin sensitized) mice were exposed via inhalation for three consecutive days to clean air, ozone, limonene or an ozone-limonene reaction mixture. Sensory and pulmonary irritation was investigated in addition to ovalbumin-specific antibodies, inflammatory cells, total protein and surfactant protein D in bronchoalveolar lavage fluid and hemeoxygenase-1 and cytokines in lung tissue. Overall, airway allergy was not exacerbated by any of the exposures. In contrast, it was found that limonene and the ozone-limonene reaction mixture reduced allergic inflammation possibly due to antioxidant properties. Ozone induced sensory irritation in both naïve and allergic mice. However, allergic but not naïve mice were protected from pulmonary irritation induced by ozone. This study showed that irritation responses might be modulated by airway allergy. However, aggravation of allergic symptoms was observed by neither exposure to ozone nor exposure to ozone-initiated limonene reaction products. In contrast, anti-inflammatory properties of the tested limonene-containing pollutants might attenuate airway allergy.

  19. Mechanisms of alveolar fibrosis after acute lung injury.

    Science.gov (United States)

    Marinelli, W A; Henke, C A; Harmon, K R; Hertz, M I; Bitterman, P B

    1990-12-01

    In patients who die after severe acute lung injury, a dramatic fibroproliferative response occurs within the alveolar air space, interstitium, and microvessels. Profound shunt physiology, dead space ventilation, and pulmonary hypertension are the physiologic consequences of this fibroproliferative response. The anatomic pattern of the response is unique within each alveolar compartment. For example, the air space is obliterated by granulation tissue, with replicating mesenchymal cells, their connective tissue products, and an expanding network of intra-alveolar capillaries. In contrast, the vascular fibroproliferative response is dominated by mesenchymal cell replication and connective tissue deposition within the walls of microvessels. Despite the unique anatomic features of these fibroproliferative processes, the regulatory signals involved are likely to be similar. Although our current understanding of the signals regulating the fibroproliferative response to acute lung injury is limited, inferences can be made from in vitro studies of mesenchymal cell behavior and several better understood fibroproliferative processes, including wound healing and chronic fibrotic lung diseases. As clinicians, our future ability to enhance effective lung repair will likely utilize therapeutic strategies specifically targeted to the signals that regulate the fibroproliferative process within the alveolar microenvironment.

  20. Impact of food supplements on hemoglobin, iron status, and inflammation in children with moderate acute malnutrition

    DEFF Research Database (Denmark)

    Cichon, Bernardette; Fabiansen, Christian; Iuel-Brockdorf, Ann-Sophie Julie D

    2018-01-01

    Background: Children with moderate acute malnutrition (MAM) are treated with lipid-based nutrient supplements (LNSs) or corn-soy blends (CSBs) but little is known about the impact of these supplements on hemoglobin, iron status, and inflammation. Objective: The objective of this study was to inve......Background: Children with moderate acute malnutrition (MAM) are treated with lipid-based nutrient supplements (LNSs) or corn-soy blends (CSBs) but little is known about the impact of these supplements on hemoglobin, iron status, and inflammation. Objective: The objective of this study...

  1. Mesoporous carbon nanomaterials induced pulmonary surfactant inhibition, cytotoxicity, inflammation and lung fibrosis.

    Science.gov (United States)

    Chen, Yunan; Yang, Yi; Xu, Bolong; Wang, Shunhao; Li, Bin; Ma, Juan; Gao, Jie; Zuo, Yi Y; Liu, Sijin

    2017-12-01

    Environmental exposure and health risk upon engineered nanomaterials are increasingly concerned. The family of mesoporous carbon nanomaterials (MCNs) is a rising star in nanotechnology for multidisciplinary research with versatile applications in electronics, energy and gas storage, and biomedicine. Meanwhile, there is mounting concern on their environmental health risks due to the growing production and usage of MCNs. The lung is the primary site for particle invasion under environmental exposure to nanomaterials. Here, we studied the comprehensive toxicological profile of MCNs in the lung under the scenario of moderate environmental exposure. It was found that at a low concentration of 10μg/mL MCNs induced biophysical inhibition of natural pulmonary surfactant. Moreover, MCNs at similar concentrations reduced viability of J774A.1 macrophages and lung epithelial A549 cells. Incubating with nature pulmonary surfactant effectively reduced the cytotoxicity of MCNs. Regarding the pro-inflammatory responses, MCNs activated macrophages in vitro, and stimulated lung inflammation in mice after inhalation exposure, associated with lung fibrosis. Moreover, we found that the size of MCNs played a significant role in regulating cytotoxicity and pro-inflammatory potential of this nanomaterial. In general, larger MCNs induced more pronounced cytotoxic and pro-inflammatory effects than their smaller counterparts. Our results provided valuable information on the toxicological profile and environmental health risks of MCNs, and suggested that fine-tuning the size of MCNs could be a practical precautionary design strategy to increase safety and biocompatibility of this nanomaterial. Copyright © 2017. Published by Elsevier B.V.

  2. Niacinamide mitigated the acute lung injury induced by phorbol myristate acetate in isolated rat's lungs

    Directory of Open Access Journals (Sweden)

    Lin Chia-Chih

    2012-03-01

    Full Text Available Abstract Background Phorbol myristate acetate (PMA is a strong neutrophil activator and has been used to induce acute lung injury (ALI. Niacinamide (NAC is a compound of B complex. It exerts protective effects on the ALI caused by various challenges. The purpose was to evaluate the protective effects of niacinamide (NAC on the PMA-induced ALI and associated changes. Methods The rat's lungs were isolated in situ and perfused with constant flow. A total of 60 isolated lungs were randomized into 6 groups to received Vehicle (DMSO 100 μg/g, PMA 4 μg/g (lung weight, cotreated with NAC 0, 100, 200 and 400 mg/g (lung weight. There were 10 isolated lungs in each group. We measured the lung weight and parameters related to ALI. The pulmonary arterial pressure and capillary filtration coefficient (Kfc were determined in isolated lungs. ATP (adenotriphosphate and PARP [poly(adenosine diphophate-ribose polymerase] contents in lung tissues were detected. Real-time PCR was employed to display the expression of inducible and endothelial NO synthases (iNOS and eNOS. The neutrophil-derived mediators in lung perfusate were determined. Results PMA caused increases in lung weight parameters. This agent produced pulmonary hypertension and increased microvascular permeability. It resulted in decrease in ATP and increase in PARP. The expression of iNOS and eNOS was upregulated following PMA. PMA increased the neutrophil-derived mediators. Pathological examination revealed lung edema and hemorrhage with inflammatory cell infiltration. Immunohistochemical stain disclosed the presence of iNOS-positive cells in macrophages and endothelial cells. These pathophysiological and biochemical changes were diminished by NAC treatment. The NAC effects were dose-dependent. Conclusions Our results suggest that neutrophil activation and release of neutrophil-derived mediators by PMA cause ALI and associated changes. NO production through the iNOS-producing cells plays a detrimental

  3. Niacinamide mitigated the acute lung injury induced by phorbol myristate acetate in isolated rat's lungs.

    Science.gov (United States)

    Lin, Chia-Chih; Hsieh, Nan-Kuang; Liou, Huey Ling; Chen, Hsing I

    2012-03-01

    Phorbol myristate acetate (PMA) is a strong neutrophil activator and has been used to induce acute lung injury (ALI). Niacinamide (NAC) is a compound of B complex. It exerts protective effects on the ALI caused by various challenges. The purpose was to evaluate the protective effects of niacinamide (NAC) on the PMA-induced ALI and associated changes. The rat's lungs were isolated in situ and perfused with constant flow. A total of 60 isolated lungs were randomized into 6 groups to received Vehicle (DMSO 100 μg/g), PMA 4 μg/g (lung weight), cotreated with NAC 0, 100, 200 and 400 mg/g (lung weight). There were 10 isolated lungs in each group. We measured the lung weight and parameters related to ALI. The pulmonary arterial pressure and capillary filtration coefficient (Kfc) were determined in isolated lungs. ATP (adenotriphosphate) and PARP [poly(adenosine diphophate-ribose) polymerase] contents in lung tissues were detected. Real-time PCR was employed to display the expression of inducible and endothelial NO synthases (iNOS and eNOS). The neutrophil-derived mediators in lung perfusate were determined. PMA caused increases in lung weight parameters. This agent produced pulmonary hypertension and increased microvascular permeability. It resulted in decrease in ATP and increase in PARP. The expression of iNOS and eNOS was upregulated following PMA. PMA increased the neutrophil-derived mediators. Pathological examination revealed lung edema and hemorrhage with inflammatory cell infiltration. Immunohistochemical stain disclosed the presence of iNOS-positive cells in macrophages and endothelial cells. These pathophysiological and biochemical changes were diminished by NAC treatment. The NAC effects were dose-dependent. Our results suggest that neutrophil activation and release of neutrophil-derived mediators by PMA cause ALI and associated changes. NO production through the iNOS-producing cells plays a detrimental role in the PMA-induced lung injury. ATP is beneficial

  4. Pathogenic TH17 inflammation is sustained in the lungs by conventional dendritic cells and Toll-like receptor 4 signaling.

    Science.gov (United States)

    Shalaby, Karim H; Lyons-Cohen, Miranda R; Whitehead, Gregory S; Thomas, Seddon Y; Prinz, Immo; Nakano, Hideki; Cook, Donald N

    2017-11-14

    Mechanisms that elicit mucosal T H 17 cell responses have been described, yet how these cells are sustained in chronically inflamed tissues remains unclear. We sought to understand whether maintenance of lung T H 17 inflammation requires environmental agents in addition to antigen and to identify the lung antigen-presenting cell (APC) types that sustain the self-renewal of T H 17 cells. Animals were exposed repeatedly to aspiration of ovalbumin alone or together with environmental adjuvants, including common house dust extract (HDE), to test their role in maintaining lung inflammation. Alternatively, antigen-specific effector/memory T H 17 cells, generated in culture with CD4 + T cells from Il17a fate-mapping mice, were adoptively transferred to assess their persistence in genetically modified animals lacking distinct lung APC subsets or cell-specific Toll-like receptor (TLR) 4 signaling. T H 17 cells were also cocultured with lung APC subsets to determine which of these could revive their expansion and activation. T H 17 cells and the consequent neutrophilic inflammation were poorly sustained by inhaled antigen alone but were augmented by inhalation of antigen together with HDE. This was associated with weight loss and changes in lung physiology consistent with interstitial lung disease. The effect of HDE required TLR4 signaling predominantly in lung hematopoietic cells, including CD11c + cells. CD103 + and CD11b + conventional dendritic cells interacted directly with T H 17 cells in situ and revived the clonal expansion of T H 17 cells both ex vivo and in vivo, whereas lung macrophages and B cells could not. T H 17-dependent inflammation in the lungs can be sustained by persistent TLR4-mediated activation of lung conventional dendritic cells. Published by Elsevier Inc.

  5. Protective ventilation of preterm lambs exposed to acute chorioamnionitis does not reduce ventilation-induced lung or brain injury.

    Science.gov (United States)

    Barton, Samantha K; Moss, Timothy J M; Hooper, Stuart B; Crossley, Kelly J; Gill, Andrew W; Kluckow, Martin; Zahra, Valerie; Wong, Flora Y; Pichler, Gerhard; Galinsky, Robert; Miller, Suzanne L; Tolcos, Mary; Polglase, Graeme R

    2014-01-01

    The onset of mechanical ventilation is a critical time for the initiation of cerebral white matter (WM) injury in preterm neonates, particularly if they are inadvertently exposed to high tidal volumes (VT) in the delivery room. Protective ventilation strategies at birth reduce ventilation-induced lung and brain inflammation and injury, however its efficacy in a compromised newborn is not known. Chorioamnionitis is a common antecedent of preterm birth, and increases the risk and severity of WM injury. We investigated the effects of high VT ventilation, after chorioamnionitis, on preterm lung and WM inflammation and injury, and whether a protective ventilation strategy could mitigate the response. Pregnant ewes (n = 18) received intra-amniotic lipopolysaccharide (LPS) 2 days before delivery, instrumentation and ventilation at 127±1 days gestation. Lambs were either immediately euthanased and used as unventilated controls (LPSUVC; n = 6), or were ventilated using an injurious high VT strategy (LPSINJ; n = 5) or a protective ventilation strategy (LPSPROT; n = 7) for a total of 90 min. Mean arterial pressure, heart rate and cerebral haemodynamics and oxygenation were measured continuously. Lungs and brains underwent molecular and histological assessment of inflammation and injury. LPSINJ lambs had poorer oxygenation than LPSPROT lambs. Ventilation requirements and cardiopulmonary and systemic haemodynamics were not different between ventilation strategies. Compared to unventilated lambs, LPSINJ and LPSPROT lambs had increases in pro-inflammatory cytokine expression within the lungs and brain, and increased astrogliosis (pVentilation after acute chorioamnionitis, irrespective of strategy used, increases haemodynamic instability and lung and cerebral inflammation and injury. Mechanical ventilation is a potential contributor to WM injury in infants exposed to chorioamnionitis.

  6. Higher levels of spontaneous breathing reduce lung injury in experimental moderate acute respiratory distress syndrome.

    Science.gov (United States)

    Carvalho, Nadja C; Güldner, Andreas; Beda, Alessandro; Rentzsch, Ines; Uhlig, Christopher; Dittrich, Susanne; Spieth, Peter M; Wiedemann, Bärbel; Kasper, Michael; Koch, Thea; Richter, Torsten; Rocco, Patricia R; Pelosi, Paolo; de Abreu, Marcelo Gama

    2014-11-01

    To assess the effects of different levels of spontaneous breathing during biphasic positive airway pressure/airway pressure release ventilation on lung function and injury in an experimental model of moderate acute respiratory distress syndrome. Multiple-arm randomized experimental study. University hospital research facility. Thirty-six juvenile pigs. Pigs were anesthetized, intubated, and mechanically ventilated. Moderate acute respiratory distress syndrome was induced by repetitive saline lung lavage. Biphasic positive airway pressure/airway pressure release ventilation was conducted using the airway pressure release ventilation mode with an inspiratory/expiratory ratio of 1:1. Animals were randomly assigned to one of four levels of spontaneous breath in total minute ventilation (n = 9 per group, 6 hr each): 1) biphasic positive airway pressure/airway pressure release ventilation, 0%; 2) biphasic positive airway pressure/airway pressure release ventilation, > 0-30%; 3) biphasic positive airway pressure/airway pressure release ventilation, > 30-60%, and 4) biphasic positive airway pressure/airway pressure release ventilation, > 60%. The inspiratory effort measured by the esophageal pressure time product increased proportionally to the amount of spontaneous breath and was accompanied by improvements in oxygenation and respiratory system elastance. Compared with biphasic positive airway pressure/airway pressure release ventilation of 0%, biphasic positive airway pressure/airway pressure release ventilation more than 60% resulted in lowest venous admixture, as well as peak and mean airway and transpulmonary pressures, redistributed ventilation to dependent lung regions, reduced the cumulative diffuse alveolar damage score across lungs (median [interquartile range], 11 [3-40] vs 18 [2-69]; p ventilation more than 0-30% and more than 30-60% showed a less consistent pattern of improvement in lung function, inflammation, and damage compared with biphasic positive airway

  7. Radiolucency below the crown of mandibular horizontal incompletely impacted third molars and acute inflammation in men with diabetes

    Directory of Open Access Journals (Sweden)

    Minoru Yamaoka

    2009-05-01

    Full Text Available Minoru Yamaoka, Yusuke Ono, Masahide Ishizuka, Kouichi Yasuda, Takashi Uematsu, Kiyofumi FurusawaOral and Maxillofacial Surgery, Matsumoto Dental University, Shiojiri, Nagano 399-0781, JapanAbstract: Although mandibular third molar has a high risk of infection extending any complications, the influence of diabetes on radiolucency and acute inflammation in pericoronitis remains unclear. The present study was to evaluate whether radiolucency below the crown is related to acute inflammation in mandibular horizontal incompletely impacted third molars and to review the records of 140 men more than 45 years with and without diabetes. The odds ratio of exhibiting acute inflammation was 3.38 (95% CI: 1.13–10.16, p < 0.05 and that of exhibiting severe acute inflammation was 15.38 (95% CI: 3.56–66.49, p < 0.0001, indicating an association of acute pericoronitis in diabetes. The frequency of radiolucency below the crown and below the root in diabetics was similar to that in nondiabetics. However, the odds ratio of exhibiting both radiolucency below the crown and acute inflammation under the diabetic condition was 4.85 (95% CI: 1.60–14.73, p < 0.01, whereas that of diabetics showing both radiolucency below the root and acute inflammation was 0.46 (95% CI: 0.06–3.74, p = 0.74. Radiolucency below the crown and acute inflammation were associated with diabetes, but that below root and acute inflammation were not associated with diabetes, indicating that the region below the crown carries susceptibility to acute pericoronitis, whereas the periodontium shows a protective effect against acute pericoronitis.Keywords: radiolucency, acute inflammation, mandible, third molar, diabetes, periodontium

  8. Endogenous expression pattern of resolvin D1 in a rat model of self-resolution of lipopolysaccharide-induced acute respiratory distress syndrome and inflammation.

    Science.gov (United States)

    Sun, Wei; Wang, Zai-ping; Gui, Ping; Xia, Weiyi; Xia, Zhengyuan; Zhang, Xing-cai; Deng, Qing-zhu; Xuan, Wei; Marie, Christelle; Wang, Lin-lin; Wu, Qing-ping; Wang, Tingting; Lin, Yun

    2014-11-01

    Resolvin D1 (RvD1), an endogenous lipid mediator derived from docosahexaenoic acid, has been reported to promote a biphasic activity in anti-inflammatory response and regulate inflammatory resolution. The present study aimed to determine the endogenous expression pattern of RvD1 in a rat model of self-resolution of lipopolysaccharide (LPS)-induced acute respiratory distress syndrome (ARDS) and inflammation. The ARDS model was induced by administrating LPS (2mg/kg) via tracheotomy in 138 male Sprague-Dawley rats. At specified time points, lung injury and inflammation were respectively assessed by lung histology and analysis of bronchoalveolar lavage fluid and cytokine levels. The expression of endogenous RvD1 was detected by high performance liquid chromatography and tandem mass spectrometry. The results showed that histological lung injury peaked between 6h (LPS6h) and day 3, followed by recovery over 4-10 days after LPS administration. Lung tissue polymorph nuclear cell (PMN) was significantly increased at LPS6h, and peaked between 6h to day 2. The levels of interleukin (IL)-6 and IL-10 were significantly increased at LPS6h and remained higher over day 10 as compared to baseline. Intriguingly, the endogenous RvD1 expression was decreased gradually during the first 3 days, followed by almost completely recovery over days 9-10. The finding indicated that endogenous RvD1 underwent a decrease in expression followed by gradual increase that was basically coincident with the lung injury recovery in a rat model of self-resolution LPS-induced ARDS and inflammation. Our results may help define the optimal therapeutic window for endogenous RvD1 to prevent or treat LPS-induced ARDS and inflammation. Copyright © 2014 Elsevier B.V. All rights reserved.

  9. Seawater-drowning-induced acute lung injury: From molecular mechanisms to potential treatments.

    Science.gov (United States)

    Jin, Faguang; Li, Congcong

    2017-06-01

    Drowning is a crucial public safety problem and is the third leading cause of accidental fatality, claiming ~372,000 lives annually, worldwide. In near-drowning patients, acute lung injury (ALI) or acute respiratory distress syndrome (ARDS) is one of the most common complications. Approximately 1/3 of near-drowning patients fulfill the criteria for ALI or ARDS. In the present article, the current literature of near-drowning, pathophysiologic changes and the molecular mechanisms of seawater-drowning-induced ALI and ARDS was reviewed. Seawater is three times more hyperosmolar than plasma, and following inhalation of seawater the hyperosmotic seawater may cause serious injury in the lung and alveoli. The perturbing effects of seawater may be primarily categorized into insufficiency of pulmonary surfactant, blood-air barrier disruption, formation of pulmonary edema, inflammation, oxidative stress, autophagy, apoptosis and various other hypertonic stimulation. Potential treatments for seawater-induced ALI/ARDS were also presented, in addition to suggestions for further studies. A total of nine therapeutic strategies had been tested and all had focused on modulating the over-activated immunoreactions. In conclusion, seawater drowning is a complex injury process and the exact mechanisms and potential treatments require further exploration.

  10. Seawater-drowning-induced acute lung injury: From molecular mechanisms to potential treatments

    Science.gov (United States)

    Jin, Faguang; Li, Congcong

    2017-01-01

    Drowning is a crucial public safety problem and is the third leading cause of accidental fatality, claiming ~372,000 lives annually, worldwide. In near-drowning patients, acute lung injury (ALI) or acute respiratory distress syndrome (ARDS) is one of the most common complications. Approximately 1/3 of near-drowning patients fulfill the criteria for ALI or ARDS. In the present article, the current literature of near-drowning, pathophysiologic changes and the molecular mechanisms of seawater-drowning-induced ALI and ARDS was reviewed. Seawater is three times more hyperosmolar than plasma, and following inhalation of seawater the hyperosmotic seawater may cause serious injury in the lung and alveoli. The perturbing effects of seawater may be primarily categorized into insufficiency of pulmonary surfactant, blood-air barrier disruption, formation of pulmonary edema, inflammation, oxidative stress, autophagy, apoptosis and various other hypertonic stimulation. Potential treatments for seawater-induced ALI/ARDS were also presented, in addition to suggestions for further studies. A total of nine therapeutic strategies had been tested and all had focused on modulating the over-activated immunoreactions. In conclusion, seawater drowning is a complex injury process and the exact mechanisms and potential treatments require further exploration. PMID:28587319

  11. Up-Regulation of Claudin-6 in the Distal Lung Impacts Secondhand Smoke-Induced Inflammation

    Directory of Open Access Journals (Sweden)

    Joshua B. Lewis

    2016-10-01

    Full Text Available It has long been understood that increased epithelial permeability contributes to inflammation observed in many respiratory diseases. Recently, evidence has revealed that environmental exposure to noxious material such as cigarette smoke reduces tight junction barrier integrity, thus enhancing inflammatory conditions. Claudin-6 (Cldn6 is a tetraspanin transmembrane protein found within the tight junctional complex and is implicated in maintaining lung epithelial barriers. To test the hypothesis that increased Cldn6 ameliorates inflammation at the respiratory barrier, we utilized the Tet-On inducible transgenic system to conditionally over-express Clnd6 in the distal lung. Cldn6 transgenic (TG and control mice were continuously provided doxycycline from postnatal day (PN 30 until euthanasia date at PN90. A subset of Cldn6 TG and control mice were also subjected to daily secondhand tobacco smoke (SHS via a nose only inhalation system from PN30-90 and compared to room air (RA controls. Animals were euthanized on PN90 and lungs were harvested for histological and molecular characterization. Bronchoalveolar lavage fluid (BALF was procured for the assessment of inflammatory cells and molecules. Quantitative RT-PCR and immunoblotting revealed increased Cldn6 expression in TG vs. control animals and SHS decreased Cldn6 expression regardless of genetic up-regulation. Histological evaluations revealed no adverse pulmonary remodeling via Hematoxylin and Eosin (H&E staining or any qualitative alterations in the abundance of type II pneumocytes or proximal non-ciliated epithelial cells via staining for cell specific propeptide of Surfactant Protein-C (proSP-C or Club Cell Secretory Protein (CCSP, respectively. Immunoblotting and qRT-PCR confirmed the differential expression of Cldn6 and the pro-inflammatory cytokines TNF-α and IL-1β. As a general theme, inflammation induced by SHS exposure was influenced by the availability of Cldn6. These data reveal

  12. Acrolein induced both pulmonary inflammation and the death of lung epithelial cells.

    Science.gov (United States)

    Sun, Yang; Ito, Sachiko; Nishio, Naomi; Tanaka, Yuriko; Chen, Nana; Isobe, Ken-Ichi

    2014-09-02

    Acrolein, a compound found in cigarette smoke, is a major risk factor for respiratory diseases. Previous research determined that both acrolein and cigarette smoke produced reactive oxygen species (ROS). As many types of pulmonary injuries are associated with inflammation, this study sought to ascertain the extent to which exposure to acrolein advanced inflammatory state in the lungs. Our results showed that intranasal exposure of mice to acrolein increased CD11c(+)F4/80(high) macrophages in the lungs and increased ROS formation via induction of NF-κB signaling. Treatment with acrolein activated macrophages and led to their increased production of ROS and expression of several key pro-inflammatory cytokines. In in vitro studies, acrolein treatment of bone marrow-derived GM-CSF-dependent immature macrophages (GM-IMs), activated the cells and led to their increased production of ROS and expression of several key pro-inflammatory cytokines. Acrolein treatment of macrophages induced apoptosis of lung epithelial cells. Inclusion of an inhibitor of ROS formation markedly decreased acrolein-mediated macrophage activation and reduced the extent of epithelial cell death. These results indicate that acrolein can cause lung damage, in great part by mediating the increased release of pro-inflammatory cytokines/factors by macrophages. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

  13. Factors secreted from dental pulp stem cells show multifaceted benefits for treating acute lung injury in mice.

    Science.gov (United States)

    Wakayama, Hirotaka; Hashimoto, Naozumi; Matsushita, Yoshihiro; Matsubara, Kohki; Yamamoto, Noriyuki; Hasegawa, Yoshinori; Ueda, Minoru; Yamamoto, Akihito

    2015-08-01

    Acute respiratory distress syndrome (ARDS) is a severe inflammatory disorder characterized by acute respiratory failure, resulting from severe, destructive lung inflammation and irreversible lung fibrosis. We evaluated the use of stem cells derived from human exfoliated deciduous teeth (SHEDs) or SHED-derived serum-free conditioned medium (SHED-CM) as treatments for bleomycin (BLM)-induced mice acute lung injury (ALI), exhibiting several pathogenic features associated with the human disease ARDS. Mice with BLM-induced ALI with or without SHED or SHED-CM treatment were examined for weight loss and survival. The lung tissue was characterized by histological and real-time quantitative polymerase chain reaction analysis. The effects of SHED-CM on macrophage differentiation in vitro were also assessed. A single intravenous administration of either SHEDs or SHED-CM attenuated the lung injury and weight loss in BLM-treated mice and improved their survival rate. Similar recovery levels were seen in the SHEDs and SHED-CM treatment groups, suggesting that SHED improves ALI by paracrine mechanisms. SHED-CM contained multiple therapeutic factors involved in lung-regenerative mechanisms. Importantly, SHED-CM attenuated the BLM-induced pro-inflammatory response and generated an anti-inflammatory/tissue-regenerating environment, accompanied by the induction of anti-inflammatory M2-like lung macrophages. Furthermore, SHED-CM promoted the in vitro differentiation of bone marrow-derived macrophages into M2-like cells, which expressed high levels of Arginase1, CD206 and Ym-1. Our results suggest that SHED-secreted factors provide multifaceted therapeutic effects, including a strong M2-inducing activity, for treating BLM-induced ALI. This work may open new avenues for research on stem cell-based ARDS therapies. Copyright © 2015 International Society for Cellular Therapy. Published by Elsevier Inc. All rights reserved.

  14. The clinical significance of lung hypoexpansion in acute childhood asthma

    International Nuclear Information System (INIS)

    Spottswood, Stephanie E.; Allison, Kelley Z.; Narla, Lakshmana D.; Lowry, Patricia A.; Lopatina, Olga A.; Sethi, Narinder N.; Nettleman, Mary D.

    2004-01-01

    Many children experiencing acute asthmatic episodes have chest radiographs, which may show lung hyperinflation, hypoinflation, or normal inflation. Lung hypoinflation may be a sign of respiratory fatigue and poor prognosis. To compare the clinical course in children with asthma according to the degree of lung inflation on chest radiographs. We conducted a retrospective study during a 24-month period (from July 1999 to July 2001) of children aged 0-17 years, who presented to a pediatric emergency department or outpatient clinic with an asthma exacerbation. Chest radiographs obtained at presentation were reviewed independently by three pediatric radiologists who were blinded to the admission status of the patient. The correlation between hypoinflation and hospital admission was assessed in three age groups: 0-2 years, 3-5 years, and 6-17 years. Hypoinflation on chest radiographs was significantly correlated with hospital admission for children aged 6-17 years (odds ratio 16.00, 95% confidence interval 1.89-135.43). The inter-reader agreement for interpretation of these radiographs was strong, with a kappa score of 0.76. Hypoinflation was not correlated with admission in younger children. Lung hypoinflation is associated with a greater likelihood of hospital admission in children aged 6 years or older. Therefore, hypoinflation was a poor prognostic sign and may warrant more aggressive therapy. (orig.)

  15. The clinical significance of lung hypoexpansion in acute childhood asthma

    Energy Technology Data Exchange (ETDEWEB)

    Spottswood, Stephanie E. [Department of Radiology, Medical College of Virginia, Virginia Commonwealth University Health System, Box 980615, 23298-0615, Richmond, VA (United States); Department of Radiology, The Children' s Hospital of the King' s Daughters, 601 Children' s Lane, Norfolk, VA 23507 (United States); Allison, Kelley Z.; Narla, Lakshmana D.; Lowry, Patricia A. [Department of Radiology, Medical College of Virginia, Virginia Commonwealth University Health System, Box 980615, 23298-0615, Richmond, VA (United States); Lopatina, Olga A.; Sethi, Narinder N. [School of Medicine, Medical College of Virginia, Virginia Commonwealth University Health System, Richmond, VA (United States); Nettleman, Mary D. [Department of Internal Medicine, B-427 Clinical Center, Michigan State University, East Lansing, MI 48824 (United States)

    2004-04-01

    Many children experiencing acute asthmatic episodes have chest radiographs, which may show lung hyperinflation, hypoinflation, or normal inflation. Lung hypoinflation may be a sign of respiratory fatigue and poor prognosis. To compare the clinical course in children with asthma according to the degree of lung inflation on chest radiographs. We conducted a retrospective study during a 24-month period (from July 1999 to July 2001) of children aged 0-17 years, who presented to a pediatric emergency department or outpatient clinic with an asthma exacerbation. Chest radiographs obtained at presentation were reviewed independently by three pediatric radiologists who were blinded to the admission status of the patient. The correlation between hypoinflation and hospital admission was assessed in three age groups: 0-2 years, 3-5 years, and 6-17 years. Hypoinflation on chest radiographs was significantly correlated with hospital admission for children aged 6-17 years (odds ratio 16.00, 95% confidence interval 1.89-135.43). The inter-reader agreement for interpretation of these radiographs was strong, with a kappa score of 0.76. Hypoinflation was not correlated with admission in younger children. Lung hypoinflation is associated with a greater likelihood of hospital admission in children aged 6 years or older. Therefore, hypoinflation was a poor prognostic sign and may warrant more aggressive therapy. (orig.)

  16. Pulmonary Surfactants for Acute and Chronic Lung Diseases (Part II

    Directory of Open Access Journals (Sweden)

    O. A. Rozenberg

    2014-01-01

    Full Text Available Part 2 of the review considers the problem of surfactant therapy for acute respiratory distress syndrome (ARDS in adults and young and old children. It gives information on the results of surfactant therapy and prevention of ARDS in patients with severe concurrent trauma, inhalation injuries, complications due to complex expanded chest surgery, or severe pneumonias, including bilateral pneumonia in the presence of A/H1N1 influenza. There are data on the use of a surfactant in obstetric care and prevention of primary graft dysfunction during lung transplantation. The results of longterm use of surfactant therapy in Russia, suggesting that death rates from ARDS may be substantially reduced (to 20% are discussed. Examples of surfactant therapy for other noncritical lung diseases, such as permanent athelectasis, chronic obstructive pulmonary diseases, and asthma, as well tuberculosis, are also considered.

  17. Cleaved caspase-3 in lung epithelium of children who died with acute respiratory distress syndrome

    NARCIS (Netherlands)

    Bem, Reinout A.; van der Loos, Chris M.; van Woensel, Job B. M.; Bos, Albert P.

    2010-01-01

    OBJECTIVE: To investigate the extent of cleaved caspase-3 immunostaining in lung epithelial cells in children with acute respiratory distress syndrome. DESIGN: Observational study in sixteen children who died with acute respiratory distress syndrome and diffuse alveolar damage. SETTING: Pediatric

  18. Simulating sleep apnea by exposure to intermittent hypoxia induces inflammation in the lung and liver.

    Science.gov (United States)

    da Rosa, Darlan Pase; Forgiarini, Luiz Felipe; Baronio, Diego; Feijó, Cristiano Andrade; Martinez, Dênis; Marroni, Norma Possa

    2012-01-01

    Sleep apnea is a breathing disorder that results from momentary and cyclic collapse of the upper airway, leading to intermittent hypoxia (IH). IH can lead to the formation of free radicals that increase oxidative stress, and this mechanism may explain the association between central sleep apnea and nonalcoholic steatohepatitis. We assessed the level of inflammation in the lung and liver tissue from animals subjected to intermittent hypoxia and simulated sleep apnea. A total of 12 C57BL/6 mice were divided into two groups and then exposed to IH (n = 6) or a simulated IH (SIH) (n = 6) for 35 days. We observed an increase in oxidative damage and other changes to endogenous antioxidant enzymes in mice exposed to IH. Specifically, the expression of multiple transcription factors, including hypoxia inducible factor (HIF-1α), nuclear factor kappa B (NF-κB), and tumor necrosis factor (TNF-α), inducible NO synthase (iNOS), vascular endothelial growth factor (VEGF), and cleaved caspase 3 were shown to be increased in the IH group. Overall, we found that exposure to intermittent hypoxia for 35 days by simulating sleep apnea leads to oxidative stress, inflammation, and increased activity of caspase 3 in the liver and lung.

  19. Simulating Sleep Apnea by Exposure to Intermittent Hypoxia Induces Inflammation in the Lung and Liver

    Directory of Open Access Journals (Sweden)

    Darlan Pase da Rosa

    2012-01-01

    Full Text Available Sleep apnea is a breathing disorder that results from momentary and cyclic collapse of the upper airway, leading to intermittent hypoxia (IH. IH can lead to the formation of free radicals that increase oxidative stress, and this mechanism may explain the association between central sleep apnea and nonalcoholic steatohepatitis. We assessed the level of inflammation in the lung and liver tissue from animals subjected to intermittent hypoxia and simulated sleep apnea. A total of 12 C57BL/6 mice were divided into two groups and then exposed to IH (n=6 or a simulated IH (SIH (n=6 for 35 days. We observed an increase in oxidative damage and other changes to endogenous antioxidant enzymes in mice exposed to IH. Specifically, the expression of multiple transcription factors, including hypoxia inducible factor (HIF-1α, nuclear factor kappa B (NF-κB, and tumor necrosis factor (TNF-α, inducible NO synthase (iNOS, vascular endothelial growth factor (VEGF, and cleaved caspase 3 were shown to be increased in the IH group. Overall, we found that exposure to intermittent hypoxia for 35 days by simulating sleep apnea leads to oxidative stress, inflammation, and increased activity of caspase 3 in the liver and lung.

  20. Synchrotron microradiography study on acute lung injury of mouse caused by PM{sub 2.5} aerosols

    Energy Technology Data Exchange (ETDEWEB)

    Tong Yongpeng [Shanghai Institute of Applied Physics, Chinese Academy of Sciences, Shanghai 201800 (China); Zhang Guilin [Shanghai Institute of Applied Physics, Chinese Academy of Sciences, Shanghai 201800 (China)]. E-mail: glzhang@sinap.ac.cn; Li Yan [Shanghai Institute of Applied Physics, Chinese Academy of Sciences, Shanghai 201800 (China); Tan Mingguan [Shanghai Institute of Applied Physics, Chinese Academy of Sciences, Shanghai 201800 (China); Wang Wei [Shanghai Institute of Applied Physics, Chinese Academy of Sciences, Shanghai 201800 (China); Chen Jianmin [Shanghai Institute of Applied Physics, Chinese Academy of Sciences, Shanghai 201800 (China); Hwu Yeukuang [Institute of Physics, Academia Sinica, Nankang, Taipei (China); Hsu, Pei-Chebg [Institute of Physics, Academia Sinica, Nankang, Taipei, Taiwan (China); Je, Jung Ho [Department of Material Science and Engineering, Pohang University of Science and Technology, Pohang (Korea, Republic of); Margaritondo, Giorgio [Faculte des sciences de base, CH-1015 Lausanne, Ecole Polytechnique Federale de Lausanne (EPFL) (Switzerland); Song Weiming [School of Public Health, Fudan University, Shanghai 200032 (China); Jiang, Rongfang [School of Public Health, Fudan University, Shanghai 200032 (China); Jiang Zhihai [School of Public Health, Fudan University, Shanghai 200032 (China)

    2006-05-15

    In order to investigate FeSO{sub 4}, ZnSO{sub 4} (the two of main metal compositions of Shanghai PM{sub 2.5} (particle matter with those aerodynamical diameter <2.5 {mu}m)) effects on acute lung injury, six solutions contained PM{sub 2.5} aerosol particles, FeSO{sub 4}, ZnSO{sub 4} and their mixtures were instilled intratracheally into mouse lungs for experiment. By 2 days after instillation, the live mice were checked in vivo by synchrotron refractive index microradiography. In addition after extracted and examined by dissection, the right lobes of lung were fixed by formalin, then imaged by synchrotron microradiography again. Corresponding parts of those lung tissues were embedded in paraffin for histopathologic study. The synchrotron X-ray microradiographs of live mouse lung showed different lung texture changes after instilled with different toxic solutions. Hemorrhage points in lung were observed more from those mice instilled by FeSO{sub 4} contained toxin solutions groups. Bronchial epithelial hyperplasia can be observed in ZnSO{sub 4} contained solution-instilled groups from histopathologic analysis. It was found that the acute lung injury of mice caused by solution of PM{sub 2.5} + FeSO{sub 4} + ZnSO{sub 4} was more serious than other toxin solutions. Results suggested that FeSO{sub 4} mainly induced hemorrhage and ZnSO{sub 4} mainly induced inflammation and bronchiolar epithelial hyperplasia in the early toxicological effects of PM{sub 2.5}.

  1. Genetic Deletion and Pharmacological Inhibition of PI3Kγ Reduces Neutrophilic Airway Inflammation and Lung Damage in Mice with Cystic Fibrosis-Like Lung Disease

    Directory of Open Access Journals (Sweden)

    Maria Galluzzo

    2015-01-01

    Full Text Available Purpose. Neutrophil-dominated airway inflammation is a key feature of progressive lung damage in cystic fibrosis (CF. Thus, reducing airway inflammation is a major goal to prevent lung damage in CF. However, current anti-inflammatory drugs have shown several limits. PI3Kγ plays a pivotal role in leukocyte recruitment and activation; in the present study we determined the effects of genetic deletion and pharmacologic inhibition of PI3Kγ on airway inflammation and structural lung damage in a mouse model of CF lung disease. Methods. βENaC overexpressing mice (βENaC-Tg were backcrossed with PI3Kγ-deficient (PI3KγKO mice. Tissue damage was assessed by histology and morphometry and inflammatory cell number was evaluated in bronchoalveolar lavage fluid (BALF. Furthermore, we assessed the effect of a specific PI3Kγ inhibitor (AS-605240 on inflammatory cell number in BALF. Results. Genetic deletion of PI3Kγ decreased neutrophil numbers in BALF of PI3KγKO/βENaC-Tg mice, and this was associated with reduced emphysematous changes. Treatment with the PI3Kγ inhibitor AS-605240 decreased the number of neutrophils in BALF of βENaC-Tg mice, reproducing the effect observed with genetic deletion of the enzyme. Conclusions. These results demonstrate the biological efficacy of both genetic deletion and pharmacological inhibition of PI3Kγ in reducing chronic neutrophilic inflammation in CF-like lung disease in vivo.

  2. Proposed revised nomenclature for transfusion-related acute lung injury.

    Science.gov (United States)

    Toy, Pearl; Kleinman, Steven H; Looney, Mark R

    2017-03-01

    A decade ago, definitions of "transfusionߚrelated acute lung injury (TRALI)" and "possible TRALI" were standardized for research and clinical diagnosis. Since then, evidence has confirmed that TRALI is often due to transfusion of white blood cell antibodies to at-risk patients, and the term "TRALI, antibody mediated" is appropriate for such cases. Other TRALI cases are non-antibody mediated. Because specific, nonantibody transfusion factors have not yet been confirmed to cause TRALI in humans, the general term "TRALI, non-antibody mediated" is appropriate for such cases. In contrast, evidence is against possible TRALI being due to transfusion with the more likely cause of the acute respiratory distress syndrome (ARDS) being the alternative ARDS risk factor present in these patients. We propose to drop the misleading term "possible TRALI" and to rename this category of cases as "transfused ARDS." These nomenclature updates will more accurately categorize ARDS cases that develop after transfusion. © 2016 AABB.

  3. Loss of hypoxia-inducible factor 2 alpha in the lung alveolar epithelium of mice leads to enhanced eosinophilic inflammation in cobalt-induced lung injury.

    Science.gov (United States)

    Proper, Steven P; Saini, Yogesh; Greenwood, Krista K; Bramble, Lori A; Downing, Nathaniel J; Harkema, Jack R; Lapres, John J

    2014-02-01

    Hard metal lung disease (HMLD) is an occupational lung disease specific to inhalation of cobalt-containing particles whose mechanism is largely unknown. Cobalt is a known hypoxia mimic and stabilizer of the alpha subunits of hypoxia-inducible factors (HIFs). Previous work revealed that though HIF1α contrib utes to cobalt toxicity in vitro, loss of HIF1α in the alveolar epithelial cells does not provide in vivo protection from cobalt-induced lung inflammation. HIF1α and HIF2α show unique tissue expression profiles, and HIF2α is known to be the predominant HIF mRNA isoform in the adult lung. Thus, if HIF2α activation by cobalt contributes to pathophysiology of HMLD, we hypothesized that loss of HIF2α in lung epithelium would provide protection from cobalt-induced inflammation. Mice with HIF2α-deficiency in Club and alveolar type II epithelial cells (ATIIs) (HIF2α(Δ/Δ)) were exposed to cobalt (60 µg/day) or saline using a subacute occupational exposure model. Bronchoalveolar lavage cellularity, cytokines, qRT-PCR, and histopathology were analyzed. Results show that loss of HIF2α leads to enhanced eosinophilic inflammation and increased goblet cell metaplasia. Additionally, control mice demonstrated a mild recovery from cobalt-induced lung injury compared with HIF2α(Δ/Δ) mice, suggesting a role for epithelial HIF2α in repair mechanisms. The expression of important cytokines, such as interleukin (IL)-5 and IL-10, displayed significant differences following cobalt exposure when HIF2α(Δ/Δ) and control mice were compared. In summary, our data suggest that although loss of HIF2α does not afford protection from cobalt-induced lung inflammation, epithelial HIF2α signaling does play an important role in modulating the inflammatory and repair response in the lung.

  4. Inhaled nitric oxide for acute respiratory distress syndrome (ARDS) and acute lung injury in children and adults

    DEFF Research Database (Denmark)

    Afshari, Arash; Brok, Jesper; Møller, Ann

    2010-01-01

    Acute hypoxaemic respiratory failure (AHRF), defined as acute lung injury (ALI) and acute respiratory distress syndrome (ARDS), are critical conditions. AHRF results from a number of systemic conditions and is associated with high mortality and morbidity in all ages. Inhaled nitric oxide (INO) has...

  5. How inflammation underlies physical and organ function in acutely admitted older medical patients

    DEFF Research Database (Denmark)

    Klausen, Henrik Hedegaard; Bodilsen, Ann Christine; Petersen, Janne

    2017-01-01

    OBJECTIVES: To investigate whether systemic inflammation in acutely admitted older medical patients (age >65 years) is associated with physical performance and organ dysfunction. Organ dysfunction´s association with physical performance, and whether these associations are mediated by systemic...... inflammation was assessed by suPAR, TNFα, and IL-6. Associations were investigated by regression analyses adjusted for age, sex, cognitive impairment, CRP, and VitalPAC Modified Early Warning Score. RESULTS: A total of 369 patients were evaluated. In adjusted analyses, suPAR and TNFα was associated with both...

  6. Preemptive mechanical ventilation can block progressive acute lung injury.

    Science.gov (United States)

    Sadowitz, Benjamin; Jain, Sumeet; Kollisch-Singule, Michaela; Satalin, Joshua; Andrews, Penny; Habashi, Nader; Gatto, Louis A; Nieman, Gary

    2016-02-04

    Mortality from acute respiratory distress syndrome (ARDS) remains unacceptable, approaching 45% in certain high-risk patient populations. Treating fulminant ARDS is currently relegated to supportive care measures only. Thus, the best treatment for ARDS may lie with preventing this syndrome from ever occurring. Clinical studies were examined to determine why ARDS has remained resistant to treatment over the past several decades. In addition, both basic science and clinical studies were examined to determine the impact that early, protective mechanical ventilation may have on preventing the development of ARDS in at-risk patients. Fulminant ARDS is highly resistant to both pharmacologic treatment and methods of mechanical ventilation. However, ARDS is a progressive disease with an early treatment window that can be exploited. In particular, protective mechanical ventilation initiated before the onset of lung injury can prevent the progression to ARDS. Airway pressure release ventilation (APRV) is a novel mechanical ventilation strategy for delivering a protective breath that has been shown to block progressive acute lung injury (ALI) and prevent ALI from progressing to ARDS. ARDS mortality currently remains as high as 45% in some studies. As ARDS is a progressive disease, the key to treatment lies with preventing the disease from ever occurring while it remains subclinical. Early protective mechanical ventilation with APRV appears to offer substantial benefit in this regard and may be the prophylactic treatment of choice for preventing ARDS.

  7. VEGF Promotes Malaria-Associated Acute Lung Injury in Mice

    Science.gov (United States)

    Carapau, Daniel; Pena, Ana C.; Ataíde, Ricardo; Monteiro, Carla A. A.; Félix, Nuno; Costa-Silva, Artur; Marinho, Claudio R. F.; Dias, Sérgio; Mota, Maria M.

    2010-01-01

    The spectrum of the clinical presentation and severity of malaria infections is broad, ranging from uncomplicated febrile illness to severe forms of disease such as cerebral malaria (CM), acute lung injury (ALI), acute respiratory distress syndrome (ARDS), pregnancy-associated malaria (PAM) or severe anemia (SA). Rodent models that mimic human CM, PAM and SA syndromes have been established. Here, we show that DBA/2 mice infected with P. berghei ANKA constitute a new model for malaria-associated ALI. Up to 60% of the mice showed dyspnea, airway obstruction and hypoxemia and died between days 7 and 12 post-infection. The most common pathological findings were pleural effusion, pulmonary hemorrhage and edema, consistent with increased lung vessel permeability, while the blood-brain barrier was intact. Malaria-associated ALI correlated with high levels of circulating VEGF, produced de novo in the spleen, and its blockage led to protection of mice from this syndrome. In addition, either splenectomization or administration of the anti-inflammatory molecule carbon monoxide led to a significant reduction in the levels of sera VEGF and to protection from ALI. The similarities between the physiopathological lesions described here and the ones occurring in humans, as well as the demonstration that VEGF is a critical host factor in the onset of malaria-associated ALI in mice, not only offers important mechanistic insights into the processes underlying the pathology related with malaria but may also pave the way for interventional studies. PMID:20502682

  8. Lung inflammation and genotoxicity following pulmonary exposure to nanoparticles in ApoE-/- mice

    Directory of Open Access Journals (Sweden)

    Ladefoged Ole

    2009-01-01

    Full Text Available Abstract Background The toxic and inflammatory potential of 5 different types of nanoparticles were studied in a sensitive model for pulmonary effects in apolipoprotein E knockout mice (ApoE-/-. We studied the effects instillation or inhalation Printex 90 of carbon black (CB and compared CB instillation in ApoE-/- and C57 mice. Three and 24 h after pulmonary exposure, inflammation was assessed by mRNA levels of cytokines in lung tissue, cell composition, genotoxicity, protein and lactate dehydrogenase activity in broncho-alveolar lavage (BAL fluid. Results Firstly, we found that intratracheal instillation of CB caused far more pulmonary toxicity in ApoE-/- mice than in C57 mice. Secondly, we showed that instillation of CB was more toxic than inhalation of a presumed similar dose with respect to inflammation in the lungs of ApoE-/- mice. Thirdly, we compared effects of instillation in ApoE-/- mice of three carbonaceous particles; CB, fullerenes C60 (C60 and single walled carbon nanotubes (SWCNT as well as gold particles and quantum dots (QDs. Characterization of the instillation media revealed that all particles were delivered as agglomerates and aggregates. Significant increases in Il-6, Mip-2 and Mcp-1 mRNA were detected in lung tissue, 3 h and 24 h following instillation of SWCNT, CB and QDs. DNA damage in BAL cells, the fraction of neutrophils in BAL cells and protein in BAL fluid increased statistically significantly. Gold and C60 particles caused much weaker inflammatory responses. Conclusion Our data suggest that ApoE-/- model is sensitive for evaluating particle induced inflammation. Overall QDs had greatest effects followed by CB and SWCNT with C60 and gold being least inflammatory and DNA-damaging. However the gold was used at a much lower mass dose than the other particles. The strong effects of QDs were likely due to Cd release. The surface area of the instilled dose correlated well the inflammatory response for low toxicity particles.

  9. Receptor Interacting Protein 3-Mediated Necroptosis Promotes Lipopolysaccharide-Induced Inflammation and Acute Respiratory Distress Syndrome in Mice.

    Directory of Open Access Journals (Sweden)

    Linlin Wang

    Full Text Available Necrosis amplifies inflammation and plays important roles in acute respiratory distress syndrome (ARDS. Necroptosis is a newly identified programmed necrosis that is mediated by receptor interacting protein 3 (RIP3. However, the potential involvement and impact of necroptosis in lipopolysaccharide (LPS-induced ARDS remains unknown. We therefore explored the role and mechanism of RIP3-mediated necroptosis in LPS-induced ARDS. Mice were instilled with increasing doses of LPS intratracheally to induce different degrees of ARDS. Lung tissues were harvested for histological and TUNEL staining and western blot for RIP3, p-RIP3, X-linked inhibitor of apoptosis protein (XIAP, mixed lineage kinase domain-like protein (MLKL, total and cleaved caspases-3/8. Then, wild-type and RIP3 knock-out mice were induced ARDS with 30 mg/kg LPS. Pulmonary cellular necrosis was labeled by the propidium Iodide (PI staining. Levels of TNF-a, Interleukin (IL-1β, IL-6, IL-1α, IL-10 and HMGB1, tissue myeloperoxidase (MPO activity, neutrophil counts and total protein concentration were measured. Results showed that in high dose LPS (30mg/kg and 40mg/kg -induced severe ARDS, RIP3 protein was increased significantly, accompanied by increases of p-RIP3 and MLKL, while in low dose LPS (10mg/kg and 20mg/kg -induced mild ARDS, apoptosis was remarkably increased. In LPS-induced severe ARDS, RIP3 knock-out alleviated the hypothermia symptom, increased survival rate and ameliorated the lung tissue injury RIP3 depletion also attenuated LPS-induced increase in IL-1α/β, IL-6 and HMGB1 release, decreased tissue MPO activity, and reduced neutrophil influx and total protein concentration in BALF in severe ARDS. Further, RIP3 depletion reduced the necrotic cells in the lung and decreased the expression of MLKL, but had no impact on cleaved caspase-3 in LPS-induced ARDS. It is concluded that RIP3-mediated necroptosis is a major mechanism of enhanced inflammation and lung tissue injury in

  10. Role of PGC-1α in acute and low-grade inflammation

    DEFF Research Database (Denmark)

    Olesen, Jesper

    The aim of the present thesis was to examine the role of the exercise-induced transcriptional co-activator, PGC-1α, in acute and low-grade inflammation. To investigate this, the following three hypotheses were tested: 1) Skeletal muscle PGC-1α plays an important role in acute LPS-induced systemic...... in skeletal muscle showed a greater fold increase in plasma TNFα than WT mice, when stimulated with LPS. Taken together, these results suggest that skeletal muscle PGC-1α is required for a robust LPS-induced TNFα response. Study II demonstrated that plasma TNFα and IL-6 as well as liver TNFα mRNA and protein...

  11. Relationship between natriuretic peptides and inflammation: proteomic evidence obtained during acute cellular cardiac allograft rejection in humans.

    Science.gov (United States)

    Meirovich, Yael F; Veinot, John P; de Bold, Mercedes L Kuroski; Haddad, Haissam; Davies, Ross A; Masters, Roy G; Hendry, Paul J; de Bold, Adolfo J

    2008-01-01

    Cardiac natriuretic peptides (NPs) atrial natriuretic factor (ANF) and brain natriuretic peptide (BNP) are polypeptide hormones secreted by the heart. Previously, we found that BNP, but not ANF, plasma levels may increase during an acute cellular cardiac allograft rejection episode. In vitro, the pro-inflammatory cytokines interleukin-1beta (IL-1beta) and tumor necrosis factor-alpha (TNF-alpha) produced a selective increase of BNP gene expression and secretion. Other pro-inflammatory cytokines had no such effects. We identified cytokines associated with the selective upregulation of BNP during cardiac allograft rejection using a proteomics approach to measure 120 cytokines and related substances in the plasma of 16 transplant patients before, during and after an acute rejection episode. The values obtained were correlated with BNP plasma levels. Cytokines identified as being significantly related to BNP plasma levels were tested in neonatal rat ventricular cardiocytes in culture for their ability to selectively promote BNP secretion. The signaling pathway related to this phenomenon was pharmacologically characterized. Regulated-on-activation, normal T-expressed and secreted (RANTES), neutrophil-activating protein-2 (NAP-2) and insulin growth factor binding protein-1 (IGFBP-1) had significant correlations with BNP plasma levels during Grade 3A (Grade 2 revised [2R]) or above rejection as diagnosed by endomyocardial biopsy score according to the International Society for Heart and Lung Transplantation (ISHLT) grading system. In rat neonatal ventricular cardiocyte cultures, IGFBP-1 and RANTES were capable of promoting BNP, but not ANF secretion, as observed in rejecting patients. The BNP-promoting secretion activity of the identified cytokines was abolished by SB203580, a specific p38 MAP kinase inhibitor. This work shows that cytokines other than pro-inflammatory cytokines correlate with BNP plasma levels observed during acute cardiac allograft rejection, and that

  12. [Expression of various matrix metalloproteinases in mice with hyperoxia-induced acute lung injury].

    Science.gov (United States)

    Zhang, Xiang-feng; Ding, Shao-fang; Gao, Yuan-ming; Liang, Ying; Foda, Hussein D

    2006-08-01

    To investigate the role of matrix metalloproteinases (MMPs) and extracellular matrix metalloproteinase inducer (EMMPRIN) in the pathogenesis of acute lung injury induced by hyperoxia. Fifty four mice were exposed in sealed cages to >98% oxygen (for 24-72 hours), and another 18 mice to room air. The severity of lung injury was assessed, and the expression of mRNA and protein of MMP-2, MMP-9 and EMMPRIN in lung tissue, after exposure for 24, 48 and 72 hours of hyperoxia were studied by reverse transcription-polymerase chain reaction (RT-PCR) and immunohistochemistry. Hyperoxia caused acute lung injury; this was accompanied by increased expression of an upregulation of MMP-2, MMP-9 and EMMPRIN mRNA and protein in lung tissues. Hyperoxia causes acute lung injury in mice; increases in MMP-2, MMP-9 and EMMPRIN may play an important role in the development of hyperoxia induced lung injury in mice.

  13. Guidance Cue Netrin-1 and the Regulation of Inflammation in Acute and Chronic Kidney Disease

    Directory of Open Access Journals (Sweden)

    Punithavathi Ranganathan

    2014-01-01

    Full Text Available Acute kidney injury (AKI is a common problem in the hospital setting and intensive care unit. Despite improved understanding, there are no effective therapies available to treat AKI. A large body of evidence strongly suggests that ischemia reperfusion injury is an inflammatory disease mediated by both adaptive and innate immune systems. Cell migration also plays an important role in embryonic development and inflammation, and this process is highly regulated to ensure tissue homeostasis. One such paradigm exists in the developing nervous system, where neuronal migration is mediated by a balance between chemoattractive and chemorepulsive signals. The ability of the guidance molecule netrin-1 to repulse or abolish attraction of neuronal cells expressing the UNC5B receptor makes it an attractive candidate for the regulation of inflammatory cell migration. Recent identification of netrin-1 as regulators of immune cell migration has led to a large number of studies looking into how netrin-1 controls inflammation and inflammatory cell migration. This review will focus on recent advances in understanding netrin-1 mediated regulation of inflammation during acute and chronic kidney disease and whether netrin-1 and its receptor activation can be used to treat acute and chronic kidney disease.

  14. The central role of hypothalamic inflammation in the acute illness response and cachexia.

    Science.gov (United States)

    Burfeind, Kevin G; Michaelis, Katherine A; Marks, Daniel L

    2016-06-01

    When challenged with a variety of inflammatory threats, multiple systems across the body undergo physiological responses to promote defense and survival. The constellation of fever, anorexia, and fatigue is known as the acute illness response, and represents an adaptive behavioral and physiological reaction to stimuli such as infection. On the other end of the spectrum, cachexia is a deadly and clinically challenging syndrome involving anorexia, fatigue, and muscle wasting. Both of these processes are governed by inflammatory mediators including cytokines, chemokines, and immune cells. Though the effects of cachexia can be partially explained by direct effects of disease processes on wasting tissues, a growing body of evidence shows the central nervous system (CNS) also plays an essential mechanistic role in cachexia. In the context of inflammatory stress, the hypothalamus integrates signals from peripheral systems, which it translates into neuroendocrine perturbations, altered neuronal signaling, and global metabolic derangements. Therefore, we will discuss how hypothalamic inflammation is an essential driver of both the acute illness response and cachexia, and why this organ is uniquely equipped to generate and maintain chronic inflammation. First, we will focus on the role of the hypothalamus in acute responses to dietary and infectious stimuli. Next, we will discuss the role of cytokines in driving homeostatic disequilibrium, resulting in muscle wasting, anorexia, and weight loss. Finally, we will address mechanisms and mediators of chronic hypothalamic inflammation, including endothelial cells, chemokines, and peripheral leukocytes. Copyright © 2015 Elsevier Ltd. All rights reserved.

  15. Acute secondhand smoke-induced pulmonary inflammation is diminished in RAGE knockout mice.

    Science.gov (United States)

    Wood, Tyler T; Winden, Duane R; Marlor, Derek R; Wright, Alex J; Jones, Cameron M; Chavarria, Michael; Rogers, Geraldine D; Reynolds, Paul R

    2014-11-15

    The receptor for advanced glycation end-products (RAGE) has increasingly been demonstrated to be an important modulator of inflammation in cases of pulmonary disease. Published reports involving tobacco smoke exposure have demonstrated increased expression of RAGE, its participation in proinflammatory signaling, and its role in irreversible pulmonary remodeling. The current research evaluated the in vivo effects of short-term secondhand smoke (SHS) exposure in RAGE knockout and control mice compared with identical animals exposed to room air only. Quantitative PCR, immunoblotting, and immunohistochemistry revealed elevated RAGE expression in controls after 4 wk of SHS exposure and an anticipated absence of RAGE expression in RAGE knockout mice regardless of smoke exposure. Ras activation, NF-κB activity, and cytokine elaboration were assessed to characterize the molecular basis of SHS-induced inflammation in the mouse lung. Furthermore, bronchoalveolar lavage fluid was procured from RAGE knockout and control animals for the assessment of inflammatory cells and molecules. As a general theme, inflammation coincident with leukocyte recruitment was induced by SHS exposure and significantly influenced by the availability of RAGE. These data reveal captivating information suggesting a role for RAGE signaling in lungs exposed to SHS. However, ongoing research is still warranted to fully explain roles for RAGE and other receptors in cells coping with involuntary smoke exposure for prolonged periods of time. Copyright © 2014 the American Physiological Society.

  16. Protocols to Evaluate Cigarette Smoke-Induced Lung Inflammation and Pathology in Mice.

    Science.gov (United States)

    Vlahos, Ross; Bozinovski, Steven

    2018-01-01

    Cigarette smoking is a major cause of chronic obstructive pulmonary disease (COPD). Inhalation of cigarette smoke causes inflammation of the airways, airway wall remodelling, mucus hypersecretion and progressive airflow limitation. Much of the disease burden and health care utilisation in COPD is associated with the management of its comorbidities and infectious (viral and bacterial) exacerbations (AECOPD). Comorbidities, in particular skeletal muscle wasting, cardiovascular disease and lung cancer markedly impact on disease morbidity, progression and mortality. The mechanisms and mediators underlying COPD and its comorbidities are poorly understood and current COPD therapy is relatively ineffective. Many researchers have used animal modelling systems to explore the mechanisms underlying COPD, AECOPD and comorbidities of COPD with the goal of identifying novel therapeutic targets. Here we describe a mouse model that we have developed to define the cellular, molecular and pathological consequences of cigarette smoke exposure and the development of comorbidities of COPD.

  17. Lung inflammation and genotoxicity following pulmonary exposure to nanoparticles in ApoE-/- mice

    DEFF Research Database (Denmark)

    Raun Jacobsen, Nicklas; Møller, Peter; Alstrup Jensen, Keld

    2009-01-01

    of three carbonaceous particles; CB, fullerenes C-60 (C-60) and single walled carbon nanotubes (SWCNT) as well as gold particles and quantum dots (QDs). Characterization of the instillation media revealed that all particles were delivered as agglomerates and aggregates. Significant increases in Il-6, Mip-2...... and Mcp-1 mRNA were detected in lung tissue, 3 h and 24 h following instillation of SWCNT, CB and QDs. DNA damage in BAL cells, the fraction of neutrophils in BAL cells and protein in BAL fluid increased statistically significantly. Gold and C-60 particles caused much weaker inflammatory responses....... Conclusion: Our data suggest that ApoE(-/-) model is sensitive for evaluating particle induced inflammation. Overall QDs had greatest effects followed by CB and SWCNT with C-60 and gold being least inflammatory and DNA-damaging. However the gold was used at a much lower mass dose than the other particles...

  18. Metabolic pathways of lung inflammation revealed by high-resolution metabolomics (HRM) of H1N1 influenza virus infection in mice.

    Science.gov (United States)

    Chandler, Joshua D; Hu, Xin; Ko, Eun-Ju; Park, Soojin; Lee, Young-Tae; Orr, Michael; Fernandes, Jolyn; Uppal, Karan; Kang, Sang-Moo; Jones, Dean P; Go, Young-Mi

    2016-11-01

    Influenza is a significant health concern worldwide. Viral infection induces local and systemic activation of the immune system causing attendant changes in metabolism. High-resolution metabolomics (HRM) uses advanced mass spectrometry and computational methods to measure thousands of metabolites inclusive of most metabolic pathways. We used HRM to identify metabolic pathways and clusters of association related to inflammatory cytokines in lungs of mice with H1N1 influenza virus infection. Infected mice showed progressive weight loss, decreased lung function, and severe lung inflammation with elevated cytokines [interleukin (IL)-1β, IL-6, IL-10, tumor necrosis factor (TNF)-α, and interferon (IFN)-γ] and increased oxidative stress via cysteine oxidation. HRM showed prominent effects of influenza virus infection on tryptophan and other amino acids, and widespread effects on pathways including purines, pyrimidines, fatty acids, and glycerophospholipids. A metabolome-wide association study (MWAS) of the aforementioned inflammatory cytokines was used to determine the relationship of metabolic responses to inflammation during infection. This cytokine-MWAS (cMWAS) showed that metabolic associations consisted of distinct and shared clusters of 396 metabolites highly correlated with inflammatory cytokines. Strong negative associations of selected glycosphingolipid, linoleate, and tryptophan metabolites with IFN-γ contrasted strong positive associations of glycosphingolipid and bile acid metabolites with IL-1β, TNF-α, and IL-10. Anti-inflammatory cytokine IL-10 had strong positive associations with vitamin D, purine, and vitamin E metabolism. The detailed metabolic interactions with cytokines indicate that targeted metabolic interventions may be useful during life-threatening crises related to severe acute infection and inflammation. Copyright © 2016 the American Physiological Society.

  19. Influence of fitness and age on the endothelial response to acute inflammation.

    Science.gov (United States)

    Schroeder, Elizabeth C; Lane-Cordova, Abbi D; Ranadive, Sushant M; Baynard, Tracy; Fernhall, Bo

    2018-04-16

    What is the central question of the study? The purpose of this study was to determine the effect of age and fitness on the vascular response to acute inflammation in younger and older adults. What is the main finding and its importance? In older adults, cardiorespiratory fitness level has a differential impact on endothelial function following acute inflammation: older moderately fit adults have a greater decrease in endothelial function, similar to that of younger adults. These findings have important implications of further supporting the beneficial effects of higher cardiorespiratory fitness in maintaining vascular reactivity and the ability to respond to stressors. Inflammation is associated with greater risk of cardiovascular events and reduced vascular function with aging. Higher cardiorespiratory fitness is associated with lower risk of cardiovascular events and better vascular function. We evaluated the role of fitness in the vascular response to acute inflammation in 26 younger (YA) and 62 older (OA) adults. We used an influenza vaccine to induce acute inflammation. Blood pressure, flow-mediated dilation (FMD), augmentation index (AIx@75), carotid elastic modulus (Ep) and inflammatory markers were measured before and 24-hours after vaccination. VO 2 peak was measured via a treadmill test. Fit was defined as a VO 2 peak greater than the age- and sex-determined 50 th percentile according to the American College of Sports Medicine. An interaction effect existed for the FMD response during acute inflammation (p fit: 11.5 ± 1.8 to 9.2 ± 1.3%; moderately fit: 11.9 ± 0.8 to 9.0 ± 0.8%) and moderately fit OA (7.5 ± 1.0 to 3.9 ± 0.8%) had similar reductions in FMD at 24h (p fit OA did not reduce FMD at 24h (5.5 ± 0.4 to 5.2 ± 0.5%, p > 0.05). The reduction in FMD in YA was similar between fitness groups (p > 0.05). All groups had similar reductions in mean arterial pressure and increases in inflammatory markers. AIx@75 and Ep did not

  20. Rabdosia japonica var. glaucocalyx Flavonoids Fraction Attenuates Lipopolysaccharide-Induced Acute Lung Injury in Mice

    Directory of Open Access Journals (Sweden)

    Chun-jun Chu

    2014-01-01

    Full Text Available Rabdosia japonica var. glaucocalyx (Maxim. Hara, belonging to the Labiatae family, is widely used as an anti-inflammatory and antitumor drug for the treatment of different inflammations and cancers. Aim of the Study. To investigate therapeutic effects and possible mechanism of the flavonoids fraction of Rabdosia japonica var. glaucocalyx (Maxim. Hara (RJFs in acute lung injury (ALI mice induced by lipopolysaccharide (LPS. Materials and Methods. Mice were orally administrated with RJFs (6.4, 12.8, and 25.6 mg/kg per day for 7 days, consecutively, before LPS challenge. Lung specimens and the bronchoalveolar lavage fluid (BALF were isolated for histopathological examinations and biochemical analysis. The level of complement 3 (C3 in serum was quantified by a sandwich ELISA kit. Results. RJFs significantly attenuated LPS-induced ALI via reducing productions of the level of inflammatory mediators (TNF-α, IL-6, and IL-1β, and significantly reduced complement deposition with decreasing the level of C3 in serum, which was exhibited together with the lowered myeloperoxidase (MPO activity and nitric oxide (NO and protein concentration in BALF. Conclusions. RJFs significantly attenuate LPS-induced ALI via reducing productions of proinflammatory mediators, decreasing the level of complement, and reducing radicals.

  1. Grain dust-induced lung inflammation is reduced by Rhodobacter sphaeroides diphosphoryl lipid A.

    Science.gov (United States)

    Jagielo, P J; Quinn, T J; Qureshi, N; Schwartz, D A

    1998-01-01

    To further determine the importance of endotoxin in grain dust-induced inflammation of the lower respiratory tract, we evaluated the efficacy of pentaacylated diphosphoryl lipid A derived from the lipopolysaccharide of Rhodobacter sphaeroides (RsDPLA) as a partial agonist of grain dust-induced airway inflammation. RsDPLA is a relatively inactive compound compared with lipid A derived from Escherichia coli (LPS) and has been demonstrated to act as a partial agonist of LPS-induced inflammation. To assess the potential stimulatory effect of RsDPLA in relation to LPS, we incubated THP-1 cells with RsDPLA (0.001-100 micrograms/ml), LPS (0.02 microgram endotoxin activity/ml), or corn dust extract (CDE; 0.02 microgram endotoxin activity/ml). Incubation with RsDPLA revealed a tumor necrosis factor (TNF)-alpha stimulatory effect at 100 micrograms/ml. In contrast, incubation with LPS or CDE resulted in TNF-alpha release at 0.02 microgram/ml. Pretreatment of THP-1 cells with varying concentrations of RsDPLA before incubation with LPS or CDE (0.02 microgram endotoxin activity/ml) resulted in a dose-dependent reduction in the LPS- or CDE-induced release of TNF-alpha with concentrations of RsDPLA of up to 10 micrograms/ml but not at 100 micrograms/ml. To further understand the role of endotoxin in grain dust-induced airway inflammation, we utilized the unique LPS inhibitory property of RsDPLA to determine the inflammatory response to inhaled CDE in mice in the presence of RsDPLA. Ten micrograms of RsDPLA intratracheally did not cause a significant inflammatory response compared with intratracheal saline. However, pretreatment of mice with 10 micrograms of RsDPLA intratracheally before exposure to CDE (5.4 and 0.2 micrograms/m3) or LPS (7.2 and 0.28 micrograms/m3) resulted in significant reductions in the lung lavage concentrations of total cells, neutrophils, and specific proinflammatory cytokines compared with mice pretreated with sterile saline. These results confirm the LPS

  2. Obeticholic acid protects against carbon tetrachloride-induced acute liver injury and inflammation

    International Nuclear Information System (INIS)

    Zhang, Da-Gang; Zhang, Cheng; Wang, Jun-Xian; Wang, Bi-Wei; Wang, Hua; Zhang, Zhi-Hui; Chen, Yuan-Hua; Lu, Yan; Tao, Li; Wang, Jian-Qing; Chen, Xi; Xu, De-Xiang

    2017-01-01

    The farnesoid X receptor (FXR) is a ligand-activated transcription factor that plays important roles in regulating bile acid homeostasis. The aim of the present study was to investigate the effects of obeticholic acid (OCA), a novel synthetic FXR agonist, carbon tetrachloride (CCl 4 )-induced acute liver injury. Mice were intraperitoneally injected with CCl 4 (0.15 ml/kg). In CCl 4 + OCA group, mice were orally with OCA (5 mg/kg) 48, 24 and 1 h before CCl 4 . As expected, hepatic FXR was activated by OCA. Interestingly, OCA pretreatment alleviated CCl 4 -induced elevation of serum ALT and hepatic necrosis. Moreover, OCA pretreatment inhibited CCl 4 -induced hepatocyte apoptosis. Additional experiment showed that OCA inhibits CCl 4 -induced hepatic chemokine gene Mcp-1, Mip-2 and Kc. Moreover, OCA inhibits CCl 4 -induced hepatic pro-inflammatory gene Tnf-α and Il-1β. By contrast, OCA pretreatment elevated hepatic anti-inflammatory gene Il-4. Further analysis showed that OCA pretreatment inhibited hepatic IκB phosphorylation and blocked nuclear translocation of NF-κB p65 and p50 subunits during CCl 4 -induced acute liver injury. In addition, OCA pretreatment inhibited hepatic Akt, ERK and p38 phosphorylation in CCl 4 -induced acute liver injury. These results suggest that OCA protects against CCl 4 -induced acute liver injury and inflammation. Synthetic FXR agonists may be effective antidotes for hepatic inflammation during acute liver injury. - Highlights: • OCA pretreatment activates hepatic FXR. • FXR activation protects against CCl 4 -induced acute liver injury. • FXR activation inhibits hepatocyte apoptosis during CCl 4 -induced liver injury. • FXR activation differentially regulates hepatic inflammatory genes. • Synthetic FXR agonists are effective antidotes for acute liver injury.

  3. Obeticholic acid protects against carbon tetrachloride-induced acute liver injury and inflammation

    Energy Technology Data Exchange (ETDEWEB)

    Zhang, Da-Gang [First Affiliated Hospital, Anhui Medical University, Hefei 230022 (China); Zhang, Cheng [Department of Toxicology, Anhui Medical University, Hefei 230032 (China); Wang, Jun-Xian [First Affiliated Hospital, Anhui Medical University, Hefei 230022 (China); Wang, Bi-Wei; Wang, Hua; Zhang, Zhi-Hui; Chen, Yuan-Hua [Department of Toxicology, Anhui Medical University, Hefei 230032 (China); Lu, Yan; Tao, Li; Wang, Jian-Qing [Second Affiliated Hospital, Anhui Medical University, Hefei 230601 (China); Chen, Xi [First Affiliated Hospital, Anhui Medical University, Hefei 230022 (China); Xu, De-Xiang, E-mail: xudex@126.com [Department of Toxicology, Anhui Medical University, Hefei 230032 (China)

    2017-01-01

    The farnesoid X receptor (FXR) is a ligand-activated transcription factor that plays important roles in regulating bile acid homeostasis. The aim of the present study was to investigate the effects of obeticholic acid (OCA), a novel synthetic FXR agonist, carbon tetrachloride (CCl{sub 4})-induced acute liver injury. Mice were intraperitoneally injected with CCl{sub 4} (0.15 ml/kg). In CCl{sub 4} + OCA group, mice were orally with OCA (5 mg/kg) 48, 24 and 1 h before CCl{sub 4}. As expected, hepatic FXR was activated by OCA. Interestingly, OCA pretreatment alleviated CCl{sub 4}-induced elevation of serum ALT and hepatic necrosis. Moreover, OCA pretreatment inhibited CCl{sub 4}-induced hepatocyte apoptosis. Additional experiment showed that OCA inhibits CCl{sub 4}-induced hepatic chemokine gene Mcp-1, Mip-2 and Kc. Moreover, OCA inhibits CCl{sub 4}-induced hepatic pro-inflammatory gene Tnf-α and Il-1β. By contrast, OCA pretreatment elevated hepatic anti-inflammatory gene Il-4. Further analysis showed that OCA pretreatment inhibited hepatic IκB phosphorylation and blocked nuclear translocation of NF-κB p65 and p50 subunits during CCl{sub 4}-induced acute liver injury. In addition, OCA pretreatment inhibited hepatic Akt, ERK and p38 phosphorylation in CCl{sub 4}-induced acute liver injury. These results suggest that OCA protects against CCl{sub 4}-induced acute liver injury and inflammation. Synthetic FXR agonists may be effective antidotes for hepatic inflammation during acute liver injury. - Highlights: • OCA pretreatment activates hepatic FXR. • FXR activation protects against CCl{sub 4}-induced acute liver injury. • FXR activation inhibits hepatocyte apoptosis during CCl{sub 4}-induced liver injury. • FXR activation differentially regulates hepatic inflammatory genes. • Synthetic FXR agonists are effective antidotes for acute liver injury.

  4. Postmortem changes in lungs in severe closed traumatic brain injury complicated by acute respiratory failure

    Directory of Open Access Journals (Sweden)

    V. A. Tumanskiy

    2013-08-01

    Full Text Available V.А. Tumanskіy, S.І. Ternishniy, L.M. Tumanskaya Pathological changes in the lungs were studied in the work of 42 patiens who died from severe closed intracranial injury (SCII. It was complicated with acute respiratory insufficient (ARI. The most modified subpleural areas were selected from every lobe of the lungs for pathological studies. Prepared histological sections were stained by means of hemotoxylin and eosin and by Van Giеson for light microscopy. The results of the investigation have shown absence of the significant difference of pathological changes in the lungs of patients who died from ARI because of severe brain injury and traumatic intracranial hemorrhage. Pathognomic pathological changes in the lungs as a result of acute lung injury syndrome (ALIS were found in deceased patients on the third day since the SCII (n=8. There was a significant bilateral interstitial edema and mild alveolar edema with the presence of red and blood cells in the alveoli, vascular plethora of the septum interalveolar and stasis of blood in the capillaries, the slight pericapillary leukocyte infiltration, subpleural hemorrhage and laminar pulmonary atelectasis. In deceased patients on 4-6 days after SCII that was complicated with ARI (n=14, morphological changes had been detected in the lungs. It was pathognomic for acute respiratory distress syndrome (ARDS with local pneumonic to be layered. A significant interstitial pulmonary edema was observed in the respiratory part of the lungs. The edema has spread from the walls of the alveoli into the interstitial spaces of the bronchioles and blood vessels, and also less marked serous-hemorrhagic alveolar edema with presence of the fibrin in the alveoli and macrophages. The ways of intrapleural lymphatic drainage were dilatated. Histopathological changes in the lungs of those who died on the 7-15th days after severe closed craniocerebral injury with ARI to be complicated (n=12 have been indicative of two

  5. Porous Se@SiO2 nanospheres treated paraquat-induced acute lung injury by resisting oxidative stress

    Directory of Open Access Journals (Sweden)

    Zhu Y

    2017-09-01

    Full Text Available Yong Zhu,1,* Guoying Deng,2,* Anqi Ji,2 Jiayi Yao,1 Xiaoxiao Meng,1 Jinfeng Wang,1 Qian Wang,2 Qiugen Wang,2 Ruilan Wang1 1Department of Critical Care Medicine, Shanghai General Hospital, Shanghai Jiaotong University, School of Medicine, 2Trauma Center, Shanghai General Hospital, Shanghai Jiaotong University, School of Medicine, Shanghai, China *These authors contributed equally to this work Abstract: Acute paraquat (PQ poisoning is one of the most common forms of pesticide poisoning. Oxidative stress and inflammation are thought to be important mechanisms in PQ-induced acute lung injury (ALI. Selenium (Se can scavenge intracellular free radicals directly or indirectly. In this study, we investigated whether porous Se@SiO2 nanospheres could alleviate oxidative stress and inflammation in PQ-induced ALI. Male Sprague Dawley rats and RLE-6TN cells were used in this study. Rats were categorized into 3 groups: control (n=6, PQ (n=18, and PQ + Se@SiO2 (n=18. The PQ and PQ + Se@SiO2 groups were randomly and evenly divided into 3 sub-groups according to different time points (24, 48 and 72 h after PQ treatment. Porous Se@SiO2 nanospheres 1 mg/kg (in the PQ + Se@SiO2 group were administered via intraperitoneal injection every 24 h. Expression levels of reduced glutathione, malondialdehyde, superoxide dismutase, reactive oxygen species (ROS, nuclear factor-κB (NF-κB, phosphorylated NF-κB (p-NF-κB, tumor necrosis factor-α and interleukin-1β were detected, and a histological analysis of rat lung tissues was performed. The results showed that the levels of ROS, malondialdehyde, NF-κB, p-NF-κB, tumor necrosis factor-α and interleukin-1β were markedly increased after PQ treatment. Glutathione and superoxide dismutase levels were reduced. However, treatment with porous Se@SiO2 nanospheres markedly alleviated PQ-induced oxidative stress and inflammation. Additionally, the results from histological examinations and wet-to-dry weight ratios of rat lung

  6. Inflammatory mechanisms in the lung

    Directory of Open Access Journals (Sweden)

    B Moldoveanu

    2008-12-01

    Full Text Available B Moldoveanu1, P Otmishi1, P Jani1, J Walker1,2, X Sarmiento3, J Guardiola1, M Saad1, Jerry Yu11Department of Medicine, University of Louisville, Louisville, KY, USA, 40292; 2Department of Respiratory Therapy, Bellarmine University, Louisville, KY, USA, 40205; 3Intensive Care Medicine Service, University Hospital Germans Trias i Pujol, Badalona, Spain 08916Abstract: Inflammation is the body’s response to insults, which include infection, trauma, and hypersensitivity. The inflammatory response is complex and involves a variety of mechanisms to defend against pathogens and repair tissue. In the lung, inflammation is usually caused by pathogens or by exposure to toxins, pollutants, irritants, and allergens. During inflammation, numerous types of inflammatory cells are activated. Each releases cytokines and mediators to modify activities of other inflammatory cells. Orchestration of these cells and molecules leads to progression of inflammation. Clinically, acute inflammation is seen in pneumonia and acute respiratory distress syndrome (ARDS, whereas chronic inflammation is represented by asthma and chronic obstructive pulmonary disease (COPD. Because the lung is a vital organ for gas exchange, excessive inflammation can be life threatening. Because the lung is constantly exposed to harmful pathogens, an immediate and intense defense action (mainly inflammation is required to eliminate the invaders as early as possible. A delicate balance between inflammation and anti-inflammation is essential for lung homeostasis. A full understanding of the underlying mechanisms is vital in the treatment of patients with lung inflammation. This review focuses on cellular and molecular aspects of lung inflammation during acute and chronic inflammatory states.Keywords: inflammation, lung, inflammatory mediators, cytokines

  7. Impact of lipopolysaccharide-induced acute inflammation on baroreflex-controlled sympathetic arterial pressure regulation.

    Directory of Open Access Journals (Sweden)

    Takeshi Tohyama

    Full Text Available Lipopolysaccharide (LPS induces acute inflammation, activates sympathetic nerve activity (SNA and alters hemodynamics. Since the arterial baroreflex is a negative feedback system to stabilize arterial pressure (AP, examining the arterial baroreflex function is a prerequisite to understanding complex hemodynamics under LPS challenge. We investigated the impact of LPS-induced acute inflammation on SNA and AP regulation by performing baroreflex open-loop analysis.Ten anesthetized Sprague-Dawley rats were used. Acute inflammation was induced by an intravenous injection of LPS (60 μg/kg. We isolated the carotid sinuses from the systemic circulation and controlled carotid sinus pressure (CSP by a servo-controlled piston pump. We matched CSP to AP to establish the baroreflex closed-loop condition, whereas we decoupled CSP from AP to establish the baroreflex open-loop condition and changed CSP stepwise to evaluate the baroreflex open-loop function. We recorded splanchnic SNA and hemodynamic parameters under baroreflex open- and closed-loop conditions at baseline and at 60 and 120 min after LPS injection.In the baroreflex closed-loop condition, SNA continued to increase after LPS injection, reaching three-fold the baseline value at 120 min (baseline: 94.7 ± 3.6 vs. 120 min: 283.9 ± 31.9 a.u.. In contrast, AP increased initially (until 75 min, then declined to the baseline level. In the baroreflex open-loop condition, LPS reset the neural arc (CSP-SNA relationship upward to higher SNA, while shifted the peripheral arc (SNA-AP relationship downward at 120 min after the injection. As a result, the operating point determined by the intersection between function curves of neural arc and peripheral arc showed marked sympatho-excitation without substantial changes in AP.LPS-induced acute inflammation markedly increased SNA via resetting of the baroreflex neural arc, and suppressed the peripheral arc. The balance between the augmented neural arc and

  8. Impact of lipopolysaccharide-induced acute inflammation on baroreflex-controlled sympathetic arterial pressure regulation.

    Science.gov (United States)

    Tohyama, Takeshi; Saku, Keita; Kawada, Toru; Kishi, Takuya; Yoshida, Keimei; Nishikawa, Takuya; Mannoji, Hiroshi; Kamada, Kazuhiro; Sunagawa, Kenji; Tsutsui, Hiroyuki

    2018-01-01

    Lipopolysaccharide (LPS) induces acute inflammation, activates sympathetic nerve activity (SNA) and alters hemodynamics. Since the arterial baroreflex is a negative feedback system to stabilize arterial pressure (AP), examining the arterial baroreflex function is a prerequisite to understanding complex hemodynamics under LPS challenge. We investigated the impact of LPS-induced acute inflammation on SNA and AP regulation by performing baroreflex open-loop analysis. Ten anesthetized Sprague-Dawley rats were used. Acute inflammation was induced by an intravenous injection of LPS (60 μg/kg). We isolated the carotid sinuses from the systemic circulation and controlled carotid sinus pressure (CSP) by a servo-controlled piston pump. We matched CSP to AP to establish the baroreflex closed-loop condition, whereas we decoupled CSP from AP to establish the baroreflex open-loop condition and changed CSP stepwise to evaluate the baroreflex open-loop function. We recorded splanchnic SNA and hemodynamic parameters under baroreflex open- and closed-loop conditions at baseline and at 60 and 120 min after LPS injection. In the baroreflex closed-loop condition, SNA continued to increase after LPS injection, reaching three-fold the baseline value at 120 min (baseline: 94.7 ± 3.6 vs. 120 min: 283.9 ± 31.9 a.u.). In contrast, AP increased initially (until 75 min), then declined to the baseline level. In the baroreflex open-loop condition, LPS reset the neural arc (CSP-SNA relationship) upward to higher SNA, while shifted the peripheral arc (SNA-AP relationship) downward at 120 min after the injection. As a result, the operating point determined by the intersection between function curves of neural arc and peripheral arc showed marked sympatho-excitation without substantial changes in AP. LPS-induced acute inflammation markedly increased SNA via resetting of the baroreflex neural arc, and suppressed the peripheral arc. The balance between the augmented neural arc and suppressed

  9. Prone positioning ventilation for treatment of acute lung injury and acute respiratory distress syndrome.

    Science.gov (United States)

    Lan, Mei-juan; He, Xiao-di

    2009-08-01

    Patients who are diagnosed with acute lung injury/acute respiratory distress syndrome (ALI/ARDS) usually have ventilation-perfusion mismatch, severe decrease in lung capacity, and gas exchange abnormalities. Health care workers have implemented various strategies in an attempt to compensate for these pathological alterations. By rotating patients with ALI/ARDS between the supine and prone position, it is possible to achieve a significant improvement in PaO2/FiO2, decrease shunting and therefore improve oxygenation without use of expensive, invasive and experimental procedures. Prone positioning is a safe and effective way to improve ventilation when conventional strategies fail to initiate a patient response. Because a specific cure for ARDS is not available, the goal is to support the patients with therapies that cause the least amount of injury while the lungs have an opportunity to heal. Based on current data, a trial of prone positioning ventilation should be offered to the patients who have ALI/ARDS in the early course of the disease. Published studies exhibit substantial heterogeneity in clinical results, suggesting that an adequately sized study optimizing the duration of proning ventilation strategy is warranted to enable definitive conclusions to be drawn.

  10. Biomarkers of acute lung injury: worth their salt?

    Directory of Open Access Journals (Sweden)

    Proudfoot Alastair G

    2011-12-01

    Full Text Available Abstract The validation of biomarkers has become a key goal of translational biomedical research. The purpose of this article is to discuss the role of biomarkers in the management of acute lung injury (ALI and related research. Biomarkers should be sensitive and specific indicators of clinically important processes and should change in a relevant timeframe to affect recruitment to trials or clinical management. We do not believe that they necessarily need to reflect pathogenic processes. We critically examined current strategies used to identify biomarkers and which, owing to expedience, have been dominated by reanalysis of blood derived markers from large multicenter Phase 3 studies. Combining new and existing validated biomarkers with physiological and other data may add predictive power and facilitate the development of important aids to research and therapy.

  11. The role of inflammation and interleukin-1 in acute cerebrovascular disease

    Directory of Open Access Journals (Sweden)

    Galea J

    2013-08-01

    Full Text Available James Galea,1 David Brough21Manchester Academic Health Sciences Center, Brain Injury Research Group, Clinical Sciences Building, Salford Royal Foundation Trust, Salford, UK; 2Faculty of Life Sciences, University of Manchester, AV Hill Building, Manchester, UKAbstract: Acute cerebrovascular disease can affect people at all stages of life, from neonates to the elderly, with devastating consequences. It is responsible for up to 10% of deaths worldwide, is a major cause of disability, and represents an area of real unmet clinical need. Acute cerebrovascular disease is multifactorial with many mechanisms contributing to a complex pathophysiology. One of the major processes worsening disease severity and outcome is inflammation. Pro-inflammatory cytokines of the interleukin (IL-1 family are now known to drive damaging inflammatory processes in the brain. The aim of this review is to discuss the recent literature describing the role of IL-1 in acute cerebrovascular disease and to provide an update on our current understanding of the mechanisms of IL-1 production. We also discuss the recent literature where the effects of IL-1 have been targeted in animal models, thus reviewing potential future strategies that may limit the devastating effects of acute cerebrovascular disease.Keywords: cerebral ischemia, stroke, inflammation, microglia, interleukin-1, caspase-1

  12. Vitamin K3 attenuates lipopolysaccharide-induced acute lung injury through inhibition of nuclear factor-κB activation

    Science.gov (United States)

    Tanaka, S; Nishiumi, S; Nishida, M; Mizushina, Y; Kobayashi, K; Masuda, A; Fujita, T; Morita, Y; Mizuno, S; Kutsumi, H; Azuma, T; Yoshida, M

    2010-01-01

    Vitamin K is a family of fat-soluble compounds including phylloquinone (vitamin K1), menaquinone (vitamin K2) and menadione (vitamin K3). Recently, it was reported that vitamin K, especially vitamins K1 and K2, exerts a variety of biological effects, and these compounds are expected to be candidates for therapeutic agents against various diseases. In this study, we investigated the anti-inflammatory effects of vitamin K3 in in vitro cultured cell experiments and in vivo animal experiments. In human embryonic kidney (HEK)293 cells, vitamin K3 inhibited the tumour necrosis factor (TNF)-α-evoked translocation of nuclear factor (NF)-κB into the nucleus, although vitamins K1 and K2 did not. Vitamin K3 also suppressed the lipopolysaccharide (LPS)-induced nuclear translocation of NF-κB and production of TNF-α in mouse macrophage RAW264·7 cells. Moreover, the addition of vitamin K3 before and after LPS administration attenuated the severity of lung injury in an animal model of acute lung injury/acute respiratory distress syndrome (ARDS), which occurs in the setting of acute severe illness complicated by systemic inflammation. In the ARDS model, vitamin K3 also suppressed the LPS-induced increase in the serum TNF-α level and inhibited the LPS-evoked nuclear translocation of NF-κB in lung tissue. Despite marked efforts, little therapeutic progress has been made, and the mortality rate of ARDS remains high. Vitamin K3 may be an effective therapeutic strategy against acute lung injury including ARDS. PMID:20030669

  13. Vitamin K3 attenuates lipopolysaccharide-induced acute lung injury through inhibition of nuclear factor-kappaB activation.

    Science.gov (United States)

    Tanaka, S; Nishiumi, S; Nishida, M; Mizushina, Y; Kobayashi, K; Masuda, A; Fujita, T; Morita, Y; Mizuno, S; Kutsumi, H; Azuma, T; Yoshida, M

    2010-05-01

    Vitamin K is a family of fat-soluble compounds including phylloquinone (vitamin K1), menaquinone (vitamin K2) and menadione (vitamin K3). Recently, it was reported that vitamin K, especially vitamins K1 and K2, exerts a variety of biological effects, and these compounds are expected to be candidates for therapeutic agents against various diseases. In this study, we investigated the anti-inflammatory effects of vitamin K3 in in vitro cultured cell experiments and in vivo animal experiments. In human embryonic kidney (HEK)293 cells, vitamin K3 inhibited the tumour necrosis factor (TNF)-alpha-evoked translocation of nuclear factor (NF)-kappaB into the nucleus, although vitamins K1 and K2 did not. Vitamin K3 also suppressed the lipopolysaccharide (LPS)-induced nuclear translocation of NF-kappaB and production of TNF-alpha in mouse macrophage RAW264.7 cells. Moreover, the addition of vitamin K3 before and after LPS administration attenuated the severity of lung injury in an animal model of acute lung injury/acute respiratory distress syndrome (ARDS), which occurs in the setting of acute severe illness complicated by systemic inflammation. In the ARDS model, vitamin K3 also suppressed the LPS-induced increase in the serum TNF-alpha level and inhibited the LPS-evoked nuclear translocation of NF-kappaB in lung tissue. Despite marked efforts, little therapeutic progress has been made, and the mortality rate of ARDS remains high. Vitamin K3 may be an effective therapeutic strategy against acute lung injury including ARDS.

  14. Local and Systemic Inflammation May Mediate Diesel Engine Exhaust-Induced Lung Function Impairment in a Chinese Occupational Cohort.

    Science.gov (United States)

    Wang, Haitao; Duan, Huawei; Meng, Tao; Yang, Mo; Cui, Lianhua; Bin, Ping; Dai, Yufei; Niu, Yong; Shen, Meili; Zhang, Liping; Zheng, Yuxin; Leng, Shuguang

    2018-04-01

    Diesel exhaust (DE) as the major source of vehicle-emitted particle matter in ambient air impairs lung function. The objectives were to assess the contribution of local (eg, the fraction of exhaled nitric oxide [FeNO] and serum Club cell secretory protein [CC16]) and systemic (eg, serum C-reaction protein [CRP] and interleukin-6 [IL-6]) inflammation to DE-induced lung function impairment using a unique cohort of diesel engine testers (DETs, n = 137) and non-DETs (n = 127), made up of current and noncurrent smokers. Urinary metabolites, FeNO, serum markers, and spirometry were assessed. A 19% reduction in CC16 and a 94% increase in CRP were identified in DETs compared with non-DETs (all p values regulatory risk assessment. Local and systemic inflammation may be key processes that contribute to the subsequent development of obstructive lung disease in DE-exposed populations.

  15. Rheumatoid arthritis-associated interstitial lung disease: lung inflammation evaluated with high resolution computed tomography scan is correlated to rheumatoid arthritis disease activity.

    Science.gov (United States)

    Pérez-Dórame, Renzo; Mejía, Mayra; Mateos-Toledo, Heidegger; Rojas-Serrano, Jorge

    2015-01-01

    To describe the association between rheumatoid arthritis disease activity (RA) and interstitial lung damage (inflammation and fibrosis), in a group of patients with rheumatoid arthritis-associated interstitial lung disease (RA-ILD). A retrospective study of RA patients with interstitial lung disease (restrictive pattern in lung function tests and evidence of interstitial lung disease in high resolution computed tomography (HRCT)). Patients were evaluated to exclude other causes of pulmonary disease. RA disease activity was measured with the CDAI index. Interstitial lung inflammation and fibrosis were determined by Kazerooni scale. We compared Kazerooni ground-glass score with the nearest CDAI score to HRCT date scan of the first medical evaluation at our institution. In nine patients, we compared the first ground-glass score with a second one after treatment with DMARDs and corticosteroids. Spearman's rank correlation coefficient was used to evaluate association between RA disease activity and the Kazerooni ground-glass and fibrosis scores. Thirty-four patients were included. A positive correlation between CDAI and ground-glass scores was found (rs=0.3767, P<0.028). Fibrosis and CDAI scores were not associated (rs=-0.0747, P<0.6745). After treatment, a downward tendency in the ground-glass score was observed (median [IQR]): (2.33 [2,3] vs. 2 [1.33-2.16]), P<0.056, along with a lesser CDAI score (27 [8-43] vs. 9 [5-12]), P<0.063. There is a correlation between RA disease activity and ground-glass appearance in the HRCT of RA-ILD patients. These results suggest a positive association between RA disease activity and lung inflammation in RA-ILD. Copyright © 2013 Elsevier España, S.L.U. All rights reserved.

  16. Bilirubin nanoparticles ameliorate allergic lung inflammation in a mouse model of asthma.

    Science.gov (United States)

    Kim, Dong Eon; Lee, Yonghyun; Kim, MinGyo; Lee, Soyoung; Jon, Sangyong; Lee, Seung-Hyo

    2017-09-01

    Although asthma, a chronic inflammatory airway disease, is relatively well-managed by inhaled corticosteroids, the side effects associated with the long-term use of these agents precipitate the need for alternative therapeutic options based on differing modes of action. Bilirubin, a potent endogenous antioxidant, and anti-inflammatory molecule have been shown to ameliorate asthmatic symptoms; however, its clinical translation has been limited owing to its water insolubility and associated potential toxicity. Here we report the first application of bilirubin-based nanoparticles (BRNPs) as a nanomedicine for the treatment of allergic lung inflammatory disease. BRNPs were prepared directly from self-assembly of PEGylated bilirubin in aqueous solution and had a hydrodynamic diameter of ∼100 nm. Because allergen-specific type 2 T-helper (Th2) cells play a key role in the pathogenesis and progression of allergic asthma, the effects of BRNPs on Th2 immune responses were investigated both in vivo and in vitro. BRNPs after intravenous injection (i.v.) showed much higher serum concentration and a longer circulation time of bilirubin than the intraperitoneal injection (i.p.) of BRNPs or unconjugated bilirubin (UCB). The anti-asthmatic effects of BRNPs were assessed in a mouse model of allergen-induced asthma. Compared with UCB, treatment with BRNPs suppressed the symptoms of experimental allergic asthma and dramatically ameliorated Th2-related allergic lung inflammation. Consistent with these results, BRNPs caused a reduction of Th2 cell populations and the expression of related cytokines by antibody-stimulated CD4 + T cells in vitro. Therefore, our results establish BRNPs as an important immunomodulatory agent that may be useful as a therapeutic for allergic lung inflammatory disease and other immune-mediated disorders. Copyright © 2017 Elsevier Ltd. All rights reserved.

  17. Inflammation and Rupture of a Congenital Pericardial Cyst Manifesting Itself as an Acute Chest Pain Syndrome.

    Science.gov (United States)

    Aertker, Robert A; Cheong, Benjamin Y C; Lufschanowski, Roberto

    2016-12-01

    We present the case of a 63-year-old woman with a remote history of supraventricular tachycardia and hyperlipidemia, who presented with recurrent episodes of acute-onset chest pain. An electrocardiogram showed no evidence of acute coronary syndrome. A chest radiograph revealed a prominent right-sided heart border. A suspected congenital pericardial cyst was identified on a computed tomographic chest scan, and stranding was noted around the cyst. The patient was treated with nonsteroidal anti-inflammatory drugs, and the pain initially abated. Another flare-up was treated similarly. Cardiac magnetic resonance imaging was then performed after symptoms had resolved, and no evidence of the cyst was seen. The suspected cause of the patient's chest pain was acute inflammation of a congenital pericardial cyst with subsequent rupture and resolution of symptoms.

  18. Dual pancreas- and lung-targeting therapy for local and systemic complications of acute pancreatitis mediated by a phenolic propanediamine moiety.

    Science.gov (United States)

    Li, Jianbo; Zhang, Jinjie; Fu, Yao; Sun, Xun; Gong, Tao; Jiang, Jinghui; Zhang, Zhirong

    2015-08-28

    To inhibit both the local and systemic complications with acute pancreatitis, an effective therapy requires a drug delivery system that can efficiently overcome the blood-pancreas barrier while achieving lung-specific accumulation. Here, we report the first dual pancreas- and lung-targeting therapeutic strategy mediated by a phenolic propanediamine moiety for the treatment of acute pancreatitis. Using the proposed dual-targeting ligand, an anti-inflammatory compound Rhein has been tailored to preferentially accumulate in the pancreas and lungs with rapid distribution kinetics, excellent tissue-penetrating properties and minimum toxicity. Accordingly, the drug-ligand conjugate remarkably downregulated the proinflammatory cytokines in the target organs thus effectively inhibiting local pancreatic and systemic inflammation in rats. The dual-specific targeting therapeutic strategy may help pave the way for targeted drug delivery to treat complicated inflammatory diseases. Copyright © 2015 Elsevier B.V. All rights reserved.

  19. [Clinical features and management of acute myositis in idiopathic orbital inflammation].

    Science.gov (United States)

    Halimi, E; Rosenberg, R; Wavreille, O; Bouckehove, S; Franquet, N; Labalette, P

    2013-09-01

    Acute myositis is the second most common component of non-specific orbital inflammation. We will describe its clinical features and natural history. This is a retrospective study of 10 cases. The diagnosis of acute myositis was based on clinical and imaging criteria. Our study includes five men and five women. The average age was 35.8 years (17-59 years). Clinical symptoms were: pain increased on eye movement (10/10), diplopia (4/10), proptosis (6/10), visual loss (3/10), lid edema (6/10), conjunctival hyperemia (7/10), anterior scleritis (2/10), episcleritis (2/10), chemosis (4/10), upper lid retraction (1/10), limitation of eye movement (3/10), fundus abnormalities (2/10). Imaging showed thickening of one or more extraocular muscles (10/10). Recovery was complete with anti-inflammatory therapy in six patients. Three patients experienced recurrence, and one patient had a clinical rebound upon tapering the treatment. Acute myositis can be defined by pain on eye movement, signs of inflammation, and extraocular muscle thickening on imaging. If the clinical presentation is typical, histopathological analysis can be deferred but remains necessary in cases of poor response to treatment, chronic duration or suspicion of tumor infiltration. The diagnosis of acute myositis may be suspected in the presence of consistent, well-defined clinical signs. Contiguous inflammation is often associated. Treatment is based on steroids or non-steroidal treatment anti-inflammatory therapy, administered alone or consecutively. Recurrences are frequent but do not alter the final prognosis. Copyright © 2013 Elsevier Masson SAS. All rights reserved.

  20. Andrographolide sulfonate ameliorates lipopolysaccharide-induced acute lung injury in mice by down-regulating MAPK and NF-κB pathways.

    Science.gov (United States)

    Peng, Shuang; Hang, Nan; Liu, Wen; Guo, Wenjie; Jiang, Chunhong; Yang, Xiaoling; Xu, Qiang; Sun, Yang

    2016-05-01

    Acute lung injury (ALI) or acute respiratory distress syndrome (ARDS) is a severe, life-threatening medical condition characterized by widespread inflammation in the lungs, and is a significant source of morbidity and mortality in the patient population. New therapies for the treatment of ALI are desperately needed. In the present study, we examined the effect of andrographolide sulfonate, a water-soluble form of andrographolide (trade name: Xi-Yan-Ping Injection), on lipopolysaccharide (LPS)-induced ALI and inflammation. Andrographolide sulfonate was administered by intraperitoneal injection to mice with LPS-induced ALI. LPS-induced airway inflammatory cell recruitment and lung histological alterations were significantly ameliorated by andrographolide sulfonate. Protein levels of pro-inflammatory cytokines in bronchoalveolar lavage fluid (BALF) and serum were reduced by andrographolide sulfonate administration. mRNA levels of pro-inflammatory cytokines in lung tissue were also suppressed. Moreover, andrographolide sulfonate markedly suppressed the activation of mitogen-activated protein kinase (MAPK) as well as p65 subunit of nuclear factor-κB (NF-κB). In summary, these results suggest that andrographolide sulfonate ameliorated LPS-induced ALI in mice by inhibiting NF-κB and MAPK-mediated inflammatory responses. Our study shows that water-soluble andrographolide sulfonate may represent a new therapeutic approach for treating inflammatory lung disorders.

  1. Andrographolide sulfonate ameliorates lipopolysaccharide-induced acute lung injury in mice by down-regulating MAPK and NF-κB pathways

    Directory of Open Access Journals (Sweden)

    Shuang Peng

    2016-05-01

    Full Text Available Acute lung injury (ALI or acute respiratory distress syndrome (ARDS is a severe, life-threatening medical condition characterized by widespread inflammation in the lungs, and is a significant source of morbidity and mortality in the patient population. New therapies for the treatment of ALI are desperately needed. In the present study, we examined the effect of andrographolide sulfonate, a water-soluble form of andrographolide (trade name: Xi-Yan-Ping Injection, on lipopolysaccharide (LPS-induced ALI and inflammation. Andrographolide sulfonate was administered by intraperitoneal injection to mice with LPS-induced ALI. LPS-induced airway inflammatory cell recruitment and lung histological alterations were significantly ameliorated by andrographolide sulfonate. Protein levels of pro-inflammatory cytokines in bronchoalveolar lavage fluid (BALF and serum were reduced by andrographolide sulfonate administration. mRNA levels of pro-inflammatory cytokines in lung tissue were also suppressed. Moreover, andrographolide sulfonate markedly suppressed the activation of mitogen-activated protein kinase (MAPK as well as p65 subunit of nuclear factor-κB (NF-κB. In summary, these results suggest that andrographolide sulfonate ameliorated LPS-induced ALI in mice by inhibiting NF-κB and MAPK-mediated inflammatory responses. Our study shows that water-soluble andrographolide sulfonate may represent a new therapeutic approach for treating inflammatory lung disorders.

  2. Acute and repeated inhalation lung injury by 3-methoxybutyl chloroformate in rats: CT-pathologic correlation

    Energy Technology Data Exchange (ETDEWEB)

    Lim, Yeon Soo [Department of Radiology, Holy Family Hospital, College of Medicine, Catholic University of Korea, 2, Sosa-dong, Wonmi-gu, Pucheon, Kyung gi-do 420-717 (Korea, Republic of); Chung, Myung Hee [Department of Radiology, Holy Family Hospital, College of Medicine, Catholic University of Korea, 2, Sosa-dong, Wonmi-gu, Pucheon, Kyung gi-do 420-717 (Korea, Republic of)]. E-mail: mhchung@catholic.ac.kr; Park, Seog Hee [Department of Radiology, Kangnam St. Mary Hospital, Catholic University of Korea, 505 Banpo-dong, Seocho-gu, Seoul 137-040 (Korea, Republic of); Kim, Hyeon-Yeong [Industrial Chemicals Research Center, Industrial Safety and Health Research Institute KISCO, 104-8, Moonji-dong, Yusong-gu, Taejon-si 305-380 (Korea, Republic of); Choi, Byung Gil [Department of Radiology, Kangnam St. Mary Hospital, Catholic University of Korea, 505 Banpo-dong, Seocho-gu, Seoul 137-040 (Korea, Republic of); Lim, Hyun Wook [Department of Radiology, Holy Family Hospital, College of Medicine, Catholic University of Korea, 2, Sosa-dong, Wonmi-gu, Pucheon, Kyung gi-do 420-717 (Korea, Republic of); Kim, Jin Ah [Department of Pathology, Holy Family Hospital, Catholic University of Korea, 2, Sosa-dong, Wonmi-gu, Pucheon-si, Kyung gi-do 420-717 (Korea, Republic of); Yoo, Won Jong [Department of Radiology, Holy Family Hospital, College of Medicine, Catholic University of Korea, 2, Sosa-dong, Wonmi-gu, Pucheon, Kyung gi-do 420-717 (Korea, Republic of)

    2007-05-15

    Objectives: To investigate the acute and repeated pulmonary damage in Sprague-Dawley rats caused by the inhalation of 3-methoxybutyl chloroformate (3-MBCF) using computed tomography (CT), and to correlate these results with those obtained from a pathological study. Methods: Sixty, 7-week-old rats were exposed to 3-MBCF vapor via inhalation (6 h/day) for 1 day (N = 20), 3 days (N = 20), and 28 days (5 days/week) (N = 20) using whole body exposure chambers at a concentration of 0 (control), 3, 6 and 12 ppm. CT examinations including densitometry and histopathologic studies were carried out. For the follow-up study, the rats exposed for 3 days were scanned using CT and their pathology was examined at 7, 14, and 28 days. Results: There was a significant decrease in the parenchymal density in the groups exposed to the 3-MBCF vapors for 1 day at 3 ppm (p = 0.022) or 6 ppm (p = 0.010), compared with the control. The parenchymal density of the rats exposed to12 ppm was significantly higher. The pathological findings in this period, the grades of vascular congestion, tracheobronchial exfoliation, and alveolar rupture were significant. In the groups exposed for 3 days, there was a large decrease in the parenchymal density with increasing dose (control: -675.48 {+-} 32.82 HU, 3 ppm: -720.65 {+-} 34.21 HU, 6 ppm: -756.41 {+-} 41.68 HU, 12 ppm: -812.56 {+-} 53.48 HU) (p = 0.000). There were significant density differences between each dose in the groups exposed for 28 days (p = 0.000). The CT findings include an irregular lung surface, areas of multifocal, wedge-shaped increased density, a heterogeneous lung density, bronchial dilatation, and axial peribronchovascular bundle thickening. The histopathology examination revealed the development of alveolar interstitial thickening and vasculitis, and an aggravation of the mainstem bronchial exudates and bronchial inflammation. The alveolar wall ruptures and bronchial dilatation became severe during this period. On the follow

  3. Acute and repeated inhalation lung injury by 3-methoxybutyl chloroformate in rats: CT-pathologic correlation

    International Nuclear Information System (INIS)

    Lim, Yeon Soo; Chung, Myung Hee; Park, Seog Hee; Kim, Hyeon-Yeong; Choi, Byung Gil; Lim, Hyun Wook; Kim, Jin Ah; Yoo, Won Jong

    2007-01-01

    Objectives: To investigate the acute and repeated pulmonary damage in Sprague-Dawley rats caused by the inhalation of 3-methoxybutyl chloroformate (3-MBCF) using computed tomography (CT), and to correlate these results with those obtained from a pathological study. Methods: Sixty, 7-week-old rats were exposed to 3-MBCF vapor via inhalation (6 h/day) for 1 day (N = 20), 3 days (N = 20), and 28 days (5 days/week) (N = 20) using whole body exposure chambers at a concentration of 0 (control), 3, 6 and 12 ppm. CT examinations including densitometry and histopathologic studies were carried out. For the follow-up study, the rats exposed for 3 days were scanned using CT and their pathology was examined at 7, 14, and 28 days. Results: There was a significant decrease in the parenchymal density in the groups exposed to the 3-MBCF vapors for 1 day at 3 ppm (p = 0.022) or 6 ppm (p = 0.010), compared with the control. The parenchymal density of the rats exposed to12 ppm was significantly higher. The pathological findings in this period, the grades of vascular congestion, tracheobronchial exfoliation, and alveolar rupture were significant. In the groups exposed for 3 days, there was a large decrease in the parenchymal density with increasing dose (control: -675.48 ± 32.82 HU, 3 ppm: -720.65 ± 34.21 HU, 6 ppm: -756.41 ± 41.68 HU, 12 ppm: -812.56 ± 53.48 HU) (p = 0.000). There were significant density differences between each dose in the groups exposed for 28 days (p = 0.000). The CT findings include an irregular lung surface, areas of multifocal, wedge-shaped increased density, a heterogeneous lung density, bronchial dilatation, and axial peribronchovascular bundle thickening. The histopathology examination revealed the development of alveolar interstitial thickening and vasculitis, and an aggravation of the mainstem bronchial exudates and bronchial inflammation. The alveolar wall ruptures and bronchial dilatation became severe during this period. On the follow-up study, the

  4. Propofol attenuates oxidant-induced acute lung injury in an isolated perfused rabbit-lung model.

    Science.gov (United States)

    Yumoto, Masato; Nishida, Osamu; Nakamura, Fujio; Katsuya, Hirotada

    2005-01-01

    Reactive oxygen species have been strongly implicated in the pathogenesis of acute lung injury (ALI). Some animal studies suggest that free radical scavengers inhibit the onset of oxidant-induced ALI. Propofol (2,6-diisopropylphenol) is chemically similar to phenol-based free radical scavengers such as the endogenous antioxidant vitamin E. Both in vivo and in vitro studies have suggested that propofol has antioxidant potential. We hypothesized that propofol may attenuate ALI by acting as a free-radical scavenger. We investigated the effects of propofol on oxidant-induced ALI induced by purine and xanthine oxidase (XO), in isolated perfused rabbit lung, in two series of experiments. In series 1, we examined the relationship between the severity of ALI and the presence of hydrogen peroxide (H2O2). In series 2, we evaluated the effects of propofol on attenuating ALI and the dose dependence of these effects. The lungs were perfused for 90 min, and we evaluated the effects on the severity of ALI by monitoring the pulmonary capillary filtration coefficient (Kfc), pulmonary arterial pressure (Ppa), and the pulmonary capillary hydrostatic pressure (Ppc). In series 1, treatment with catalase (an H2O2 scavenger) prior to the addition of purine and XO resulted in complete prevention of ALI, suggesting that H2O2 may be involved closely in the pathogenesis of ALI. In series 2, pretreatment with propofol at concentrations in excess of 0.5 mM significantly inhibited the increases in the Kfc values, and that in excess of 0.75 mM significantly inhibited the increase in the Ppa values. Propofol attenuates oxidant-induced ALI in an isolated perfused rabbit lung model, probably due to its antioxidant action.

  5. Irgm1-deficient mice exhibit Paneth cell abnormalities and increased susceptibility to acute intestinal inflammation.

    Science.gov (United States)

    Liu, Bo; Gulati, Ajay S; Cantillana, Viviana; Henry, Stanley C; Schmidt, Elyse A; Daniell, Xiaoju; Grossniklaus, Emily; Schoenborn, Alexi A; Sartor, R Balfour; Taylor, Gregory A

    2013-10-15

    Crohn's disease (CD) is a chronic, immune-mediated, inflammatory disorder of the intestine that has been linked to numerous susceptibility genes, including the immunity-related GTPase (IRG) M (IRGM). IRGs comprise a family of proteins known to confer resistance to intracellular infections through various mechanisms, including regulation of phagosome processing, cell motility, and autophagy. However, despite its association with CD, the role of IRGM and other IRGs in regulating intestinal inflammation is unclear. We investigated the involvement of Irgm1, an ortholog of IRGM, in the genesis of murine intestinal inflammation. After dextran sodium sulfate exposure, Irgm1-deficient [Irgm1 knockout (KO)] mice showed increased acute inflammation in the colon and ileum, with worsened clinical responses. Marked alterations of Paneth cell location and granule morphology were present in Irgm1 KO mice, even without dextran sodium sulfate exposure, and were associated with impaired mitophagy and autophagy in Irgm1 KO intestinal cells (including Paneth cells). This was manifested by frequent tubular and swollen mitochondria and increased LC3-positive autophagic structures. Interestingly, these LC3-positive structures often contained Paneth cell granules. These results suggest that Irgm1 modulates acute inflammatory responses in the mouse intestine, putatively through the regulation of gut autophagic processes, that may be pivotal for proper Paneth cell functioning.

  6. Detection of acute inflammation with 111In-labeled nonspecific polyclonal IgG

    International Nuclear Information System (INIS)

    Fischman, A.J.; Rubin, R.H.; Khaw, B.A.

    1988-01-01

    The detection of focal sites of inflammation is an integral part of the clinical evaluation of the febrile patient. When anatomically distinct abscesses are present, lesion detection can be accomplished by standard radiographic techniques, particularly in patients with normal anatomy. At the phlegmon stage, however, and in patients who have undergone surgery, these techniques are considerably less effective. While radionuclide methods, such as Gallium-67 (67Ga)-citrate and Indium-111 (111In)-labeled WBCs have been relatively successful for the detection of early inflammation, neither approach is ideal. In the course of studies addressing the use of specific organism-directed antibodies for imaging experimental infections in animals, we observed that nonspecific polyclonal immunoglobulin G (IgG) localized as well as specific antibodies. Preliminary experiments suggested that the Fc portion of IgG is necessary for effective inflammation localization. Since polyclonal IgG in gram quantities has been safely used for therapy in patients with immune deficiency states, we decided to test whether milligram quantities of radiolabeled IgG could image focal sites of inflammation in humans. Thus far, we have studied a series of 84 patients with suspected lesions in the abdomen, pelvis, vascular grafts, lungs, or bones/joints. In 48 of 52 patients with focal lesions detected by surgery, computed tomography (CT), magnetic resonance imaging (MRI), or ultrasound (US), the IgG scan correctly localized the site, while 31 patients without focal inflammation had no abnormal focal localization of the radiopharmaceutical. Four patients had false negative scans and one patient had a false positive scan. For this small series, the overall sensitivity and specificity were 92% and 95%, respectively. In this report, we review our experience with this exciting new agent

  7. Low triiodothyronine: A new facet of inflammation in acute ischemic stroke.

    Science.gov (United States)

    Ma, Lili; Zhu, Dongliang; Jiang, Ying; Liu, Yingying; Ma, Xiaomeng; Liu, Mei; Chen, Xiaohong

    2016-07-01

    Patients with acute ischemic stroke (AIS) frequently experience low free triiodothyronine (fT3) concentrations. Inflammation is recognized as a key contributor to the pathophysiology of stroke. Previous studies, however, did not simultaneously evaluate fT3 and inflammation biomarkers in AIS patients. Markers of inflammation, including serum concentrations of C-reactive protein (CRP) and albumin, and fT3 were assessed retrospectively in 117 patients. Stroke severity was measured on the National Institutes of Health Stroke Scale (NIHSS). Regression analyses were performed to adjust for confounders. Serum fT3 concentrations were significantly lower in moderate AIS patients than those in mild AIS patients (P<0.001). fT3 concentration also positively correlated with serum albumin concentration (r=0.358, P<0.001) and negatively correlated with log10CRP concentration (r=-0.341, P<0.001), NIHSS score (r=-0.384, P<0.001). Multiple regression analysis showed that CRP, albumin concentrations and NIHSS score were independently correlated with fT3 concentration. Binary logistic regression analysis showed that fT3 concentration was an independent factor correlated with NIHSS score, the area under the receiver operating characteristic curve was 0.712 (95% CI, 0.618-0.805). Low fT3 concentrations may be involved in the pathogenic pathway linking inflammation to stroke severity in AIS patients. Copyright © 2016 Elsevier B.V. All rights reserved.

  8. Tobacco smoke exposure suppresses radiation-induced inflammation in the lung

    International Nuclear Information System (INIS)

    Bjermer, L.; Cai, Y.; Nilsson, K.; Hellstroem, S.; Henriksson, R.

    1993-01-01

    Previous studies on patients with breast cancer, who received postsurgical irradiation, displayed a markedly suppressed inflammatory response in the lung of smoking patients compared to nonsmokers. The aim of the present study was to investigate further the effect of exposure to tobacco smoke on the development of irradiation-induced pneumonitis in the rat. Four groups of animals were used: controls (C); those exposed to tobacco smoke (S); those irradiated but not exposed to smoke (RNS); and those irradiated and exposed to tobacco smoke (RS). The rats were exposed to a diluted main stream of cigarette smoke, at a concentration of about 0.4 mgxl -1 , in a nose-only exposure system for 1 hxday -1 , 5 daysxweek -1 for 10 weeks. Exposure to tobacco smoke started 3 weeks before irradiation. The basal one third of both lungs was exposed to a single radiation dose of 28 Gy (6 MeV photons). All animals were killed 7 weeks after irradiation. We compared findings in bronchoalveolar lavage (BAL) and tissue morphology. The alveolar tissue showed less inflammation in the RS-group than in the RNS-group. Most strikingly, mast cells were increased one hundredfold in the lung interstitium and thirty fold in the peribronchial area in the RNS-group, whereas no increase was found in the RS-group or in the controls. The alveolar septa of the RNS-group were thickened, with occurrence of inflammatory cells and mast cells, whereas the RS-group displayed no difference as compared to the non-irradiated, nonsmoking group (C). There was a marked discrepancy between the findings in BAL and tissue of the alveolar space or lung interstitium. In BAL, neutrophils, and to a lesser extent lymphocytes, were increased both in the RS- and RNS-group; however, with significantly higher numbers in the RNS-group. In contrast, the cells in the alveolar space and interstitium were dominated by mononuclear cells, mainly macrophages. Moreover, a more than twenty fold increase in total cells in the alveolar

  9. Dynamic expression of leukocyte innate immune genes in whole blood from horses with lipopolysaccharide-induced acute systemic inflammation

    DEFF Research Database (Denmark)

    Vinther, Anne Mette L.; Skovgaard, Kerstin; Heegaard, Peter M. H.

    2015-01-01

    Background: In horses, insights into the innate immune processes in acute systemic inflammation are limited even though these processes may be highly important for future diagnostic and therapeutic advances in high-mortality disease conditions as the systemic inflammatory response syndrome (SIRS......) and sepsis. Therefore, the aim of this study was to investigate the expression of 31 selected blood leukocyte immune genes in an equine model of acute systemic inflammation to identify significantly regulated genes and to describe their expression dynamics during a 24-h experimental period. Systemic...... expressions in blood leukocytes during equine acute LPS-induced systemic inflammation thoroughly characterized a highly regulated and dynamic innate immune response. These results provide new insights into the molecular mechanisms of equine systemic inflammation....

  10. Involvement of prostaglandins and histamine in nickel wire-induced acute inflammation in mice.

    Science.gov (United States)

    Hirasawa, Noriyasu; Goi, Yoshiaki; Tanaka, Rina; Ishihara, Kenji; Ohtsu, Hiroshi; Ohuchi, Kazuo

    2010-06-15

    The irritancy of Nickel (Ni) ions has been well documented clinically. However, the chemical mediators involved in the acute inflammation induced by solid Ni are not fully understood. We used the Ni wire-implantation model in mice and examined roles of prostaglandins and histamine in plasma leakage in the acute phase. The subcutaneous implantation of a Ni wire into the back of mice induced plasma leakage from 8 to 24 h and tissue necrosis around the wire at 3 days, whereas the implantation of an aluminum wire induced no such inflammatory responses. An increase in the mRNA for cyclooxygenase (COX)-2 and HDC in cells around the Ni wire was detected 4 h after the implantation. The leakage of plasma at 8 h was inhibited by indomethacin in a dose-dependent manner. Dexamethasone and the p38 MAP kinase inhibitor SB203580 also inhibited the exudation of plasma consistent with the inhibition of the expression of COX-2 mRNA. Furthermore, plasma leakage was partially but siginificantly reduced in histamine H1 receptor knockout mice and histidine decarboxylase (HDC) knockout mice but not in H2 receptor knockout mice. These results suggested that the Ni ions released from the wire induced the expression of COX-2 and HDC, resulting in an increase in vascular permeability during the acute phase of inflammation. (c) 2009 Wiley Periodicals, Inc.

  11. Acute hyperammonemia and systemic inflammation is associated with increased extracellular brain adenosine in rats

    DEFF Research Database (Denmark)

    Bjerring, Peter Nissen; Dale, Nicholas; Larsen, Fin Stolze

    2015-01-01

    ) and cerebral blood flow (CBF). We measured the adenosine concentration with biosensors in rat brain slices exposed to ammonia and in a rat model with hyperammonemia and systemic inflammation. Exposure to ammonia in concentrations from 0.15-10 mM led to increases in the cortical adenosine concentration up to 18......Acute liver failure (ALF) can lead to brain edema, cerebral hyperperfusion and intracranial hypertension. These complications are thought to be mediated by hyperammonemia and inflammation leading to altered brain metabolism. As increased levels of adenosine degradation products have been found...... in brain tissue of patients with ALF we investigated whether hyperammonemia could induce adenosine release in brain tissue. Since adenosine is a potent vasodilator and modulator of cerebral metabolism we furthermore studied the effect of adenosine receptor ligands on intracranial pressure (ICP...

  12. Fetal inflammation associated with minimal acute morbidity in moderate/late preterm infants.

    Science.gov (United States)

    Gisslen, Tate; Alvarez, Manuel; Wells, Casey; Soo, Man-Ting; Lambers, Donna S; Knox, Christine L; Meinzen-Derr, Jareen K; Chougnet, Claire A; Jobe, Alan H; Kallapur, Suhas G

    2016-03-23

    To determine whether exposure to acute chorioamnionitis and fetal inflammation caused short-term adverse outcomes. This is a prospective observational study: subjects were mothers delivering at 32-36 weeks gestation and their preterm infants at a large urban tertiary level III perinatal unit (N=477 infants). Placentae and fetal membranes were scored for acute histological chorioamnionitis based on the Redline criteria. Fetal inflammation was characterised by histological diagnosis of funisitis (umbilical cord inflammation), increased cord blood cytokines measured by ELISA, and activation of the inflammatory cells infiltrating the placenta and fetal membranes measured by immunohistology. Maternal and infant data were collected. Twenty-four per cent of 32-36-week infants were exposed to histological chorioamnionitis and 6.9% had funisitis. Immunostaining for leucocyte subsets showed selective infiltration of the placenta and fetal membranes with activated neutrophils and macrophages with chorioamnionitis. Interleukin (IL) 6, IL-8 and granulocyte colony-stimulating factor were selectively increased in the cord blood of preterm infants with funisitis. Compared with infants without chorioamnionitis, funisitis was associated with increased ventilation support during resuscitation (43.8% vs 15.4%) and more respiratory distress syndrome postnatally (27.3% vs 10.2%) in univariate analysis. However, these associations disappeared after adjusting for prematurity. Despite fetal exposure to funisitis, increased cord blood cytokines and activated placental inflammatory cells, we could not demonstrate neonatal morbidity specifically attributable to fetal inflammation after adjusting for gestational age in moderate and late preterm infants. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/

  13. Electroacupuncture Alleviates Pain Responses and Inflammation in a Rat Model of Acute Gout Arthritis

    Directory of Open Access Journals (Sweden)

    Wenxin Chai

    2018-01-01

    Full Text Available Acute gout arthritis is one of the most painful inflammatory conditions. Treatments for gout pain are limited to colchicine, nonsteroidal anti-inflammatory drugs, and corticosteroids, which oftentimes result in severe adverse effects. Electroacupuncture (EA has been proved to be effective in relieving many inflammatory pain conditions with few side effects. Here, we aim to investigate the therapeutic potentials of EA on pain and inflammation of a rat model of acute gout arthritis and underlying mechanisms. We found that 2/100 Hz EA produced the most robust analgesic effect on mechanical hyperalgesia of acute gout arthritis rat model compared with 2 and 100 Hz. EA produced similar analgesic effect compared with indomethacin. 2/100 Hz EA also significantly alleviates the ongoing pain behavior, thermal hyperalgesia, and ankle edema. Locally applied μ and κ-opioid receptor antagonists but not adenosine A1 receptor antagonist significantly abolished the analgesic effect of EA. Locally applied μ and κ-opioid receptor agonists produced significant antiallodynia on acute gout arthritis rats, mimicking EA. Furthermore, 2/100 Hz EA upregulated β-endorphin expression in inflamed ankle skin tissue. Our results demonstrated, for the first time, that EA can be used for relieving acute gout arthritis with effect dependent on peripheral opioid system and comparable with the one obtained with indomethacin.

  14. Oxidative stress and inflammation: liver responses and adaptations to acute and regular exercise.

    Science.gov (United States)

    Pillon Barcelos, Rômulo; Freire Royes, Luiz Fernando; Gonzalez-Gallego, Javier; Bresciani, Guilherme

    2017-02-01

    The liver is remarkably important during exercise outcomes due to its contribution to detoxification, synthesis, and release of biomolecules, and energy supply to the exercising muscles. Recently, liver has been also shown to play an important role in redox status and inflammatory modulation during exercise. However, while several studies have described the adaptations of skeletal muscles to acute and chronic exercise, hepatic changes are still scarcely investigated. Indeed, acute intense exercise challenges the liver with increased reactive oxygen species (ROS) and inflammation onset, whereas regular training induces hepatic antioxidant and anti-inflammatory improvements. Acute and regular exercise protocols in combination with antioxidant and anti-inflammatory supplementation have been also tested to verify hepatic adaptations to exercise. Although positive results have been reported in some acute models, several studies have shown an increased exercise-related stress upon liver. A similar trend has been observed during training: while synergistic effects of training and antioxidant/anti-inflammatory supplementations have been occasionally found, others reported a blunting of relevant adaptations to exercise, following the patterns described in skeletal muscles. This review discusses current data regarding liver responses and adaptation to acute and regular exercise protocols alone or combined with antioxidant and anti-inflammatory supplementation. The understanding of the mechanisms behind these modulations is of interest for both exercise-related health and performance outcomes.

  15. Effects of mycobacteria major secretion protein, Ag85B, on allergic inflammation in the lung.

    Directory of Open Access Journals (Sweden)

    Yusuke Tsujimura

    Full Text Available Many epidemiological studies have suggested that the recent increase in prevalence and severity of allergic diseases such as asthma is inversely correlated with Mycobacterium bovis bacillus Calmette Guerin (BCG vaccination. However, the underlying mechanisms by which mycobacterial components suppress allergic diseases are not yet fully understood. Here we showed the inhibitory mechanisms for development of allergic airway inflammation by using highly purified recombinant Ag85B (rAg85B, which is one of the major protein antigens secreted from M. tuberculosis. Ag85B is thought to be a single immunogenic protein that can elicit a strong Th1-type immune response in hosts infected with mycobacteria, including individuals vaccinated with BCG. Administration of rAg85B showed a strong inhibitory effect on the development of allergic airway inflammation with induction of Th1-response and IL-17and IL-22 production. Both cytokines induced by rAg85B were involved in the induction of Th17-related cytokine-production innate immune cells in the lung. Administration of neutralizing antibodies to IL-17 or IL-22 in rAg85B-treated mice revealed that IL-17 induced the infiltration of neutrophils in BAL fluid and that allergen-induced bronchial eosinophilia was inhibited by IL-22. Furthermore, enhancement of the expression of genes associated with tissue homeostasis and wound healing was observed in bronchial tissues after rAg85B administration in a Th17-related cytokine dependent manner. The results of this study provide evidence for the potential usefulness of rAg85B as a novel approach for anti-allergic effect and tissue repair other than the role as a conventional TB vaccine.

  16. β-Catenin is required for the differentiation of iNKT2 and iNKT17 cells that augment IL-25-dependent lung inflammation

    OpenAIRE

    Berga-Bolaños, Rosa; Sharma, Archna; Steinke, Farrah C.; Pyaram, Kalyani; Kim, Yeung-Hyen; Sultana, Dil A.; Fang, Jessie X.; Chang, Cheong-Hee; Xue, Hai-Hui; Heller, Nicola M.; Sen, Jyoti Misra

    2015-01-01

    Background Invariant Natural Killer T (iNKT) cells have been implicated in lung inflammation in humans and also shown to be a key cell type in inducing allergic lung inflammation in mouse models. iNKT cells differentiate and acquire functional characteristics during development in the thymus. However, the correlation between development of iNKT cells in the thymus and role in lung inflammation remains unknown. In addition, transcriptional control of differentiation of iNKT cells into iNKT cel...

  17. Lung Transcriptomics during Protective Ventilatory Support in Sepsis-Induced Acute Lung Injury.

    Directory of Open Access Journals (Sweden)

    Marialbert Acosta-Herrera

    Full Text Available Acute lung injury (ALI is a severe inflammatory process of the lung. The only proven life-saving support is mechanical ventilation (MV using low tidal volumes (LVT plus moderate to high levels of positive end-expiratory pressure (PEEP. However, it is currently unknown how they exert the protective effects. To identify the molecular mechanisms modulated by protective MV, this study reports transcriptomic analyses based on microarray and microRNA sequencing in lung tissues from a clinically relevant animal model of sepsis-induced ALI. Sepsis was induced by cecal ligation and puncture (CLP in male Sprague-Dawley rats. At 24 hours post-CLP, septic animals were randomized to three ventilatory strategies: spontaneous breathing, LVT (6 ml/kg plus 10 cmH2O PEEP and high tidal volume (HVT, 20 ml/kg plus 2 cmH2O PEEP. Healthy, non-septic, non-ventilated animals served as controls. After 4 hours of ventilation, lung samples were obtained for histological examination and gene expression analysis using microarray and microRNA sequencing. Validations were assessed using parallel analyses on existing publicly available genome-wide association study findings and transcriptomic human data. The catalogue of deregulated processes differed among experimental groups. The 'response to microorganisms' was the most prominent biological process in septic, non-ventilated and in HVT animals. Unexpectedly, the 'neuron projection morphogenesis' process was one of the most significantly deregulated in LVT. Further support for the key role of the latter process was obtained by microRNA studies, as four species targeting many of its genes (Mir-27a, Mir-103, Mir-17-5p and Mir-130a were found deregulated. Additional analyses revealed 'VEGF signaling' as a central underlying response mechanism to all the septic groups (spontaneously breathing or mechanically ventilated. Based on this data, we conclude that a co-deregulation of 'VEGF signaling' along with 'neuron projection

  18. Lung Transcriptomics during Protective Ventilatory Support in Sepsis-Induced Acute Lung Injury

    Science.gov (United States)

    Acosta-Herrera, Marialbert; Lorenzo-Diaz, Fabian; Pino-Yanes, Maria; Corrales, Almudena; Valladares, Francisco; Klassert, Tilman E.; Valladares, Basilio; Slevogt, Hortense; Ma, Shwu-Fan

    2015-01-01

    Acute lung injury (ALI) is a severe inflammatory process of the lung. The only proven life-saving support is mechanical ventilation (MV) using low tidal volumes (LVT) plus moderate to high levels of positive end-expiratory pressure (PEEP). However, it is currently unknown how they exert the protective effects. To identify the molecular mechanisms modulated by protective MV, this study reports transcriptomic analyses based on microarray and microRNA sequencing in lung tissues from a clinically relevant animal model of sepsis-induced ALI. Sepsis was induced by cecal ligation and puncture (CLP) in male Sprague-Dawley rats. At 24 hours post-CLP, septic animals were randomized to three ventilatory strategies: spontaneous breathing, LVT (6 ml/kg) plus 10 cmH2O PEEP and high tidal volume (HVT, 20 ml/kg) plus 2 cmH2O PEEP. Healthy, non-septic, non-ventilated animals served as controls. After 4 hours of ventilation, lung samples were obtained for histological examination and gene expression analysis using microarray and microRNA sequencing. Validations were assessed using parallel analyses on existing publicly available genome-wide association study findings and transcriptomic human data. The catalogue of deregulated processes differed among experimental groups. The ‘response to microorganisms’ was the most prominent biological process in septic, non-ventilated and in HVT animals. Unexpectedly, the ‘neuron projection morphogenesis’ process was one of the most significantly deregulated in LVT. Further support for the key role of the latter process was obtained by microRNA studies, as four species targeting many of its genes (Mir-27a, Mir-103, Mir-17-5p and Mir-130a) were found deregulated. Additional analyses revealed 'VEGF signaling' as a central underlying response mechanism to all the septic groups (spontaneously breathing or mechanically ventilated). Based on this data, we conclude that a co-deregulation of 'VEGF signaling' along with 'neuron projection

  19. Total ginsenosides synergize with ulinastatin against septic acute lung injury and acute respir atory distress syndrome

    Science.gov (United States)

    Sun, Rongju; Li, Yana; Chen, Wei; Zhang, Fei; Li, Tanshi

    2015-01-01

    Total ginsenosides synergize with ulinastatin (UTI) against septic acute lung injury (ALI) and acute respiratory distress syndrome (ARDS). We randomly divided 80 cases of severe sepsis-induced ALI and ARDS into a UTI group and a ginsenosides (GS)+UTI group. Continuous electrocardiac monitoring of pulse, respiratory rate, blood pressure, and heart rate; invasive hemodynamic monitoring; ventilator-assisted breathing and circulation support; and anti-infection as well as UTI treatment were given in the UTI group with GS treatment added for 7 consecutive days in the GS+UTI group. The indicators of pulmonary vascular permeability, pulmonary circulation, blood gases, and hemodynamics as well as APACHE II and ALI scores were detected on days 1, 3, and 7. The ALI score in the GS+UTI group was significantly decreased (P UTI group, and the indicators of pulmonary capillary permeability such as pulmonary vascular permeability index, extravascular lung water index, and oxygenation index, in the GS+UTI group improved significantly more than that of the UTI group. The indicators of hemodynamics and pulmonary circulation such as cardiac index, intrathoracic blood volume index, and central venous pressure improved significantly (P UTI group was lower than that of the UTI group. GS can effectively collaborate with UTI against ALI and/or ARDS. PMID:26261640

  20. S1P-induced airway smooth muscle hyperresponsiveness and lung inflammation in vivo: molecular and cellular mechanisms.

    Science.gov (United States)

    Roviezzo, F; Sorrentino, R; Bertolino, A; De Gruttola, L; Terlizzi, M; Pinto, A; Napolitano, M; Castello, G; D'Agostino, B; Ianaro, A; Sorrentino, R; Cirino, G

    2015-04-01

    Sphingosine-1-phosphate (S1P) has been shown to be involved in the asthmatic disease as well in preclinical mouse experimental models of this disease. The aim of this study was to understand the mechanism(s) underlying S1P effects on the lung. BALB/c, mast cell-deficient and Nude mice were injected with S1P (s.c.) on days 0 and 7. Functional, molecular and cellular studies were performed. S1P administration to BALB/c mice increased airway smooth muscle reactivity, mucus production, PGD2 , IgE, IL-4 and IL-13 release. These features were associated to a higher recruitment of mast cells to the lung. Mast cell-deficient Kit (W) (-sh/) (W) (-sh) mice injected with S1P did not display airway smooth muscle hyper-reactivity. However, lung inflammation and IgE production were still present. Treatment in vivo with the anti-CD23 antibody B3B4, which blocks IgE production, inhibited both S1P-induced airway smooth muscle reactivity in vitro and lung inflammation. S1P administration to Nude mice did not elicit airway smooth muscle hyper-reactivity and lung inflammation. Naïve (untreated) mice subjected to the adoptive transfer of CD4+ T-cells harvested from S1P-treated mice presented all the features elicited by S1P in the lung. S1P triggers a cascade of events that sequentially involves T-cells, IgE and mast cells reproducing several asthma-like features. This model may represent a useful tool for defining the role of S1P in the mechanism of action of currently-used drugs as well as in the development of new therapeutic approaches for asthma-like diseases. © 2014 The British Pharmacological Society.

  1. Validation of an electronic surveillance system for acute lung injury.

    Science.gov (United States)

    Herasevich, Vitaly; Yilmaz, Murat; Khan, Hasrat; Hubmayr, Rolf D; Gajic, Ognjen

    2009-06-01

    Early detection of acute lung injury (ALI) is essential for timely implementation of evidence-based therapies and enrollment into clinical trials. We aimed to determine the accuracy of computerized syndrome surveillance for detection of ALI in hospitalized patients and compare it with routine clinical assessment. Using a near-real time copy of the electronic medical records, we developed and validated a custom ALI electronic alert (ALI "sniffer") based on the European-American Consensus Conference Definition and compared its performance against provider-derived documentation. A total of 3,795 consecutive critically ill patients admitted to nine multidisciplinary intensive care units (ICUs) of a tertiary care teaching institution were included. ALI developed in 325 patients and was recognized by bedside clinicians in only 86 (26.5%). Under-recognition of ALI was associated with not implementing protective mechanical ventilation (median tidal volumes of 9.2 vs. 8.0 ml/kg predicted body weight, P sniffer" demonstrated excellent sensitivity of 96% (95% CI 94-98) and moderate specificity of 89% (95% CI 88-90) with a positive predictive value ranging from 24% (95% CI 13-40) in the heart-lung transplant ICU to 64% (95% CI 55-71) in the medical ICU. The computerized surveillance system accurately identifies critically ill patients who develop ALI syndrome. Since the lack of ALI recognition is a barrier to the timely implementation of best practices and enrollment into research studies, computerized syndrome surveillance could be a useful tool to enhance patient safety and clinical research.

  2. Inflammation Activation Contributes to Adipokine Imbalance in Patients with Acute Coronary Syndrome.

    Directory of Open Access Journals (Sweden)

    Rong Li

    Full Text Available Inflammation can be activated as a defensive response by the attack of acute coronary syndrome (ACS for ischemic tissue injury. The aim of the present study was to investigate the impact of ACS-activated inflammation on adipokine imbalance and the effects of statins on the crosstalk between inflammation and adipokine imbalance during ACS. In this study, 586 subjects were categorized into: (1 control group; (2 SA (stable angina group; and (3 ACS group. Circulating levels of hs-CRP, adiponectin and resistin were measured by ELISA. Furthermore, forty C57BL/6 mice were randomized into: sham, AMI, low-statin (atorvastatin, 2 mg/kg/day and high-statin (atorvastatin, 20 mg/kg/day group. After 3 weeks, AMI models were established by surgical coronary artery ligation. Circulating levels and adipose expressions of adiponectin and resistin were assessed in animals. Besides, we investigate the effects of atorvastatin on ox-LDL-induced adipokine imbalance in vitro. As a result, we found that ACS patients had higher hs-CRP and resistin levels and lower adiponectin levels. Our correlation analysis demonstrated hs-CRP concentrations were positively correlated with resistin but negatively with adiponectin levels in humans. Our animal findings indicated higher circulating hs-CRP and resistin levels and lower adiponectin levels in AMI mice. Atorvastatin pre-treatment dose-dependently decreased hs-CRP and resistin levels but increased adiponectin levels in mice. The consistent findings were observed about the adipose expressions of resistin and adiponectin in mice. In study in vitro, ox-LDL increased cellular resistin expressions and otherwise for adiponectin expressions, which dose-dependently reversed by the addition of atorvastatin. Therefore, our study indicates that the ACS attack activates inflammation leading to adipokine imbalance that can be ameliorated by anti-inflammation of atorvastatin.

  3. Effectiveness of Alveolar Opening in Patients with Acute Lung Injury and Concomitant Pneumothorax

    Directory of Open Access Journals (Sweden)

    Yu. V. Marchenkov

    2009-01-01

    Full Text Available Objective: to study the efficiency of a lung opening maneuver in patients with acute lung injury (ALI and concomitant pneumothorax, who were on biphasic positive airway pressure ventilation (BIPAP and synchronized intermittent mandatory ventilation. Subject and methods. Seventy-three patients with acute lung injury and concomitant pneumoth-orax resulting from blunt chest trauma were examined. Their condition was an APACHE II of 18—24 scores. After elimination of pneumothorax, an open lung maneuver was made using different modes of lung support 3—5 times daily. Results. The study has shown that BIPAP used in patients with ALI and concomitant pneumothorax reduces the time of pleural cavity drainage, which allows the lung opening maneuver to be applied earlier. The employment of the latter in patients with ALI and pneumothorax permits a prompter recovery of lung function during different types of respiratory support, which is attended by reductions in the number of complications, artificial ventilation, and mortality. When the lung opening maneuver is combined with BIPAP, its efficiency considerably increases. Key words: acute lung injury, pneumothorax, BIPAP, lung opening maneuver.

  4. Smart imaging of acute lung injury: exploration of myeloperoxidase activity using in vivo endoscopic confocal fluorescence microscopy.

    Science.gov (United States)

    Chagnon, Frédéric; Bourgouin, Alexandra; Lebel, Réjean; Bonin, Marc-André; Marsault, Eric; Lepage, Martin; Lesur, Olivier

    2015-09-15

    The pathophysiology of acute lung injury (ALI) is well characterized, but its real-time assessment at bedside remains a challenge. When patients do not improve after 1 wk despite supportive therapies, physicians have to consider open lung biopsy (OLB) to identify the process(es) at play. Sustained inflammation and inadequate repair are often observed in this context. OLB is neither easy to perform in a critical setting nor exempt from complications. Herein, we explore intravital endoscopic confocal fluorescence microscopy (ECFM) of the lung in vivo combined with the use of fluorescent smart probe(s) activated by myeloperoxidase (MPO). MPO is a granular enzyme expressed by polymorphonuclear neutrophils (PMNs) and alveolar macrophages (AMs), catalyzing the synthesis of hypoclorous acid, a by-product of hydrogen peroxide. Activation of these probes was first validated in vitro in relevant cells (i.e., AMs and PMNs) and on MPO-non-expressing cells (as negative controls) and then tested in vivo using three rat models of ALI and real-time intravital imaging with ECFM. Semiquantitative image analyses revealed that in vivo probe-related cellular/background fluorescence was associated with corresponding enhanced lung enzymatic activity and was partly prevented by specific MPO inhibition. Additional ex vivo phenotyping was performed, confirming that fluorescent cells were neutrophil elastase(+) (PMNs) or CD68(+) (AMs). This work is a first step toward "virtual biopsy" of ALI without OLB. Copyright © 2015 the American Physiological Society.

  5. 1α,25-Dihydroxyvitamin D3 Ameliorates Seawater Aspiration-Induced Acute Lung Injury via NF-κB and RhoA/Rho Kinase Pathways

    Science.gov (United States)

    Liu, Wei; Wang, Li; Luo, Ying; Li, Zhichao; Jin, Faguang

    2014-01-01

    Introduction Inflammation and pulmonary edema are involved in the pathogenesis of seawater aspiration-induced acute lung injury (ALI). Although several studies have reported that 1α,25-Dihydroxyvitamin D3 (calcitriol) suppresses inflammation, it has not been confirmed to be effective in seawater aspiration-induced ALI. Thus, we investigated the effect of calcitriol on seawater aspiration-induced ALI and explored the probable mechanism. Methods Male SD rats receiving different doses of calcitriol or not, underwent seawater instillation. Then lung samples were collected at 4 h for analysis. In addition, A549 cells and rat pulmonary microvascular endothelial cells (RPMVECs) were cultured with calcitriol or not and then stimulated with 25% seawater for 40 min. After these treatments, cells samples were collected for analysis. Results Results from real-time PCR showed that seawater stimulation up-regulated the expression of vitamin D receptor in lung tissues, A549 cells and RPMVECs. Seawater stimulation also activates NF-κB and RhoA/Rho kinase pathways. However, we found that pretreatment with calcitriol significantly inhibited the activation of NF-κB and RhoA/Rho kinase pathways. Meanwhile, treatment of calcitriol also improved lung histopathologic changes, reduced inflammation, lung edema and vascular leakage. Conclusions These results demonstrated that NF-κB and RhoA/Rho kinase pathways are critical in the development of lung inflammation and pulmonary edema and that treatment with calcitriol could ameliorate seawater aspiration-induced ALI, which was probably through the inhibition of NF-κB and RhoA/Rho kinase pathways. PMID:25118599

  6. Angiotensin-(1?7) inhibits inflammation and oxidative stress to relieve lung injury induced by chronic intermittent hypoxia in rats

    OpenAIRE

    Lu, W.; Kang, J.; Hu, K.; Tang, S.; Zhou, X.; Yu, S.; Li, Y.; Xu, L.

    2016-01-01

    Obstructive sleep apnea is associated with inflammation and oxidative stress in lung tissues and can lead to metabolic abnormalities. We investigated the effects of angiotensin1–7 [Ang-(1–7)] on lung injury in rats induced by chronic intermittent hypoxia (CIH). We randomly assigned 32 male Sprague-Dawley rats (180–200 g) to normoxia control (NC), CIH-untreated (uCIH), Ang-(1–7)-treated normoxia control (N-A), and Ang-(1–7)-treated CIH (CIH-A) groups. Oxidative stress biomarkers were measured ...

  7. Erythropoietin augments the cytokine response to acute endotoxin-induced inflammation in humans

    DEFF Research Database (Denmark)

    Hojman, Pernille; Taudorf, Sarah; Lundby, Carsten

    2009-01-01

    in a human in vivo model of acute systemic low-grade inflammation, we measured circulating inflammatory mediators after intravenous administration of Escherichia coli endotoxin (LPS) bolus injection (0.1 ng/kg of body weight) in young healthy male subjects. The subjects were divided into three groups...... receiving either (1) LPS alone, (2) EPO alone (15,000 IE of rHuEPO) or (3) EPO and LPS. Endotoxin administration alone induced a 3-, 12- and 5-fold increase in plasma concentrations of TNF-alpha, IL-6 and IL-10, respectively, 3h after LPS challenge. When EPO was given prior to a bolus injection...... with endotoxin, the levels of TNF-alpha and IL-6 were enhanced by 5- and 40-fold, respectively, whereas the endotoxin-induced increase in IL-10 response was not influenced by EPO. In contrast to our hypothesis, we find that EPO augments the acute inflammatory effect....

  8. Effects of Mikania glomerata Spreng. and Mikania laevigata Schultz Bip. ex Baker (Asteraceae) extracts on pulmonary inflammation and oxidative stress caused by acute coal dust exposure

    Energy Technology Data Exchange (ETDEWEB)

    Freitas, T.P.; Silveira, P.C.; Rocha, L.G.; Rezin, G.T.; Rocha, J.; Citadini-Zanette, V.; Romao, P.T.; Dal-Pizzol, F.; Pinho, R.A.; Andrade, V.M.; Streck, E.L. [University Extremo Catarinense, Criciuma (Brazil)

    2008-12-15

    Several studies have reported biological effects of Mikania glomerata and Mikania laevigata, used in Brazilian folk medicine for respiratory diseases. Pneumoconiosis is characterized by pulmonary inflammation caused by coal dust exposure. In this work, we evaluated the effect of pretreatment with M. glomerata and M. laevigata extracts (MGE and MLE, respectively) (100 mg/kg, s.c.) on inflammatory and oxidative stress parameters in lung of rats subjected to a single coal dust intratracheal instillation. Rats were pretreated for 2 weeks with saline solution, MGE, or MLE. On day 15, the animals were anesthetized, and gross mineral coal dust or saline solutions were administered directly in the lung by intratracheal instillation. Fifteen days after coal dust instillation, the animals were killed. Bronchoalveolar lavage (BAL) was obtained; total cell count and lactate dehydrogenase (LDH) activity were determined. In the lung, myeloperoxidase activity, thiobarbituric acid-reactive substances (TBARS) level, and protein carbonyl and sulfhydryl contents were evaluated. In BAL of treated animals, we verified an increased total cell count and LDH activity. MGE and MLE prevented the increase in cell count, but only MLE prevented the increase in LDH. Myeloperoxidase and TBARS levels were not affected, protein carbonylation was increased, and the protein thiol levels were decreased by acute coal dust intratracheal administration. The findings also suggest that both extracts present an important protective effect on the oxidation of thiol groups. Moreover, pretreatment with MGE and MLE also diminished lung inflammatory infiltration induced by coal dust, as assessed by histopathologic analyses.

  9. VEGF controls lung Th2 inflammation via the miR-1–Mpl (myeloproliferative leukemia virus oncogene)–P-selectin axis

    Science.gov (United States)

    Vasavada, Hema; Zhang, Jian-ge; Ahangari, Farida; Niu, Naiqian; Liu, Qing; Lee, Chun Geun; Cohn, Lauren

    2013-01-01

    Asthma, the prototypic Th2-mediated inflammatory disorder of the lung, is an emergent disease worldwide. Vascular endothelial growth factor (VEGF) is a critical regulator of pulmonary Th2 inflammation, but the underlying mechanism and the roles of microRNAs (miRNAs) in this process have not been defined. Here we show that lung-specific overexpression of VEGF decreases miR-1 expression in the lung, most prominently in the endothelium, and a similar down-regulation occurs in lung endothelium in Th2 inflammation models. Intranasal delivery of miR-1 inhibited inflammatory responses to ovalbumin, house dust mite, and IL-13 overexpression. Blocking VEGF inhibited Th2-mediated lung inflammation, and this was restored by antagonizing miR-1. Using mRNA arrays, Argonaute pull-down assays, luciferase expression assays, and mutational analysis, we identified Mpl as a direct target of miR-1 and showed that VEGF controls the expression of endothelial Mpl during Th2 inflammation via the regulation of miR-1. In vivo knockdown of Mpl inhibited Th2 inflammation and indirectly inhibited the expression of P-selectin in lung endothelium. These experiments define a novel VEGF–miR-1–Mpl–P-selectin effector pathway in lung Th2 inflammation and herald the utility of miR-1 and Mpl as potential therapeutic targets for asthma. PMID:24043765

  10. VEGF controls lung Th2 inflammation via the miR-1-Mpl (myeloproliferative leukemia virus oncogene)-P-selectin axis.

    Science.gov (United States)

    Takyar, Seyedtaghi; Vasavada, Hema; Zhang, Jian-ge; Ahangari, Farida; Niu, Naiqian; Liu, Qing; Lee, Chun Geun; Cohn, Lauren; Elias, Jack A

    2013-09-23

    Asthma, the prototypic Th2-mediated inflammatory disorder of the lung, is an emergent disease worldwide. Vascular endothelial growth factor (VEGF) is a critical regulator of pulmonary Th2 inflammation, but the underlying mechanism and the roles of microRNAs (miRNAs) in this process have not been defined. Here we show that lung-specific overexpression of VEGF decreases miR-1 expression in the lung, most prominently in the endothelium, and a similar down-regulation occurs in lung endothelium in Th2 inflammation models. Intranasal delivery of miR-1 inhibited inflammatory responses to ovalbumin, house dust mite, and IL-13 overexpression. Blocking VEGF inhibited Th2-mediated lung inflammation, and this was restored by antagonizing miR-1. Using mRNA arrays, Argonaute pull-down assays, luciferase expression assays, and mutational analysis, we identified Mpl as a direct target of miR-1 and showed that VEGF controls the expression of endothelial Mpl during Th2 inflammation via the regulation of miR-1. In vivo knockdown of Mpl inhibited Th2 inflammation and indirectly inhibited the expression of P-selectin in lung endothelium. These experiments define a novel VEGF-miR-1-Mpl-P-selectin effector pathway in lung Th2 inflammation and herald the utility of miR-1 and Mpl as potential therapeutic targets for asthma.

  11. [Lung Abscess with Acute Empyema Which Improved after Performing by Video Assissted Thoracic Surgery( Including Pneumonotomy and Lung Abscess Drainage);Report of a Case].

    Science.gov (United States)

    Gabe, Atsushi; Nagamine, Naoji

    2017-05-01

    We herein report the case of a patient demonstrating a lung abscess with acute empyema which improved after performing pnemumonotomy and lung abscess drainage. A 60-year-old male was referred to our hospital to receive treatment for a lung abscess with acute empyema. At surgery, the lung parenchyma was slightly torn with pus leakage. After drainage of lung abscess by enlarging the injured part, curettage in the thoracic cavity and decortication were performed. The postoperative course was uneventful. Direct drainage of an abscess into the thoracic cavity is thought to be a choice for the treatment of lung abscesses.

  12. Targeting Extracellular Histones with Novel RNA Bio drugs for the Treatment of Acute Lung Injury

    Science.gov (United States)

    2017-10-01

    AWARD NUMBER: W81XWH-16-1-0179 TITLE: Targeting Extracellular Histones with Novel RNA Bio -drugs for the Treatment of Acute Lung Injury...4. TITLE AND SUBTITLE Targeting Extracellular Histones with Novel RNA Bio -drugs for the Treatment of Acute Lung Injury 5a. CONTRACT NUMBER 5b...and field situations. To accomplish this goal, we developed novel bio -reagents (RNA aptamers) that bind to those histones known to cause MODS/ARDS and

  13. Exposure to low doses of formaldehyde during pregnancy suppresses the development of allergic lung inflammation in offspring

    International Nuclear Information System (INIS)

    Maiellaro, Marília; Correa-Costa, Matheus; Vitoretti, Luana Beatriz; Gimenes Júnior, João Antônio; Câmara, Niels Olsen Saraiva; Tavares-de-Lima, Wothan; Farsky, Sandra Helena Poliselli; Lino-dos-Santos-Franco, Adriana

    2014-01-01

    Formaldehyde (FA) is an environmental and occupational pollutant, and its toxic effects on the immune system have been shown. Nevertheless, no data are available regarding the programming mechanisms after FA exposure and its repercussions for the immune systems of offspring. In this study, our objective was to investigate the effects of low-dose exposure of FA on pregnant rats and its repercussion for the development of allergic lung inflammation in offspring. Pregnant Wistar rats were assigned in 3 groups: P (rats exposed to FA (0.75 ppm, 1 h/day, 5 days/week, for 21 days)), C (rats exposed to vehicle of FA (distillated water)) and B (rats non-manipulated). After 30 days of age, the offspring was sensitised with ovalbumin (OVA)-alum and challenged with aerosolized OVA (1%, 15 min, 3 days). After 24 h the OVA challenge the parameters were evaluated. Our data showed that low-dose exposure to FA during pregnancy induced low birth weight and suppressed the development of allergic lung inflammation and tracheal hyperresponsiveness in offspring by mechanisms mediated by reduced anaphylactic antibodies synthesis, IL-6 and TNF-alpha secretion. Elevated levels of IL-10 were found. Any systemic alteration was detected in the exposed pregnant rats, although oxidative stress in the uterine environment was evident at the moment of the delivery based on elevated COX-1 expression and reduced cNOS and SOD-2 in the uterus. Therefore, we show the putative programming mechanisms induced by FA on the immune system for the first time and the mechanisms involved may be related to oxidative stress in the foetal microenvironment. - Highlights: • Formaldehyde exposure does not cause lung inflammation in pregnant rats. • Formaldehyde exposure suppresses allergic lung inflammation in the offspring. • Formaldehyde exposure induces oxidative stress in uterine environment

  14. Exposure to low doses of formaldehyde during pregnancy suppresses the development of allergic lung inflammation in offspring

    Energy Technology Data Exchange (ETDEWEB)

    Maiellaro, Marília [Department of Clinical and Toxicological Analyses, Faculty of Pharmaceutical Sciences, University of São Paulo, São Paulo (Brazil); Correa-Costa, Matheus [Department of Immunology, Institute of Biomedical Sciences, University of São Paulo, São Paulo (Brazil); Vitoretti, Luana Beatriz; Gimenes Júnior, João Antônio [Department of Pharmacology, Institute of Biomedical Sciences, University of São Paulo, São Paulo (Brazil); Câmara, Niels Olsen Saraiva [Department of Immunology, Institute of Biomedical Sciences, University of São Paulo, São Paulo (Brazil); Tavares-de-Lima, Wothan [Department of Pharmacology, Institute of Biomedical Sciences, University of São Paulo, São Paulo (Brazil); Farsky, Sandra Helena Poliselli [Department of Clinical and Toxicological Analyses, Faculty of Pharmaceutical Sciences, University of São Paulo, São Paulo (Brazil); Lino-dos-Santos-Franco, Adriana, E-mail: adrilino@usp.br [Department of Clinical and Toxicological Analyses, Faculty of Pharmaceutical Sciences, University of São Paulo, São Paulo (Brazil)

    2014-08-01

    Formaldehyde (FA) is an environmental and occupational pollutant, and its toxic effects on the immune system have been shown. Nevertheless, no data are available regarding the programming mechanisms after FA exposure and its repercussions for the immune systems of offspring. In this study, our objective was to investigate the effects of low-dose exposure of FA on pregnant rats and its repercussion for the development of allergic lung inflammation in offspring. Pregnant Wistar rats were assigned in 3 groups: P (rats exposed to FA (0.75 ppm, 1 h/day, 5 days/week, for 21 days)), C (rats exposed to vehicle of FA (distillated water)) and B (rats non-manipulated). After 30 days of age, the offspring was sensitised with ovalbumin (OVA)-alum and challenged with aerosolized OVA (1%, 15 min, 3 days). After 24 h the OVA challenge the parameters were evaluated. Our data showed that low-dose exposure to FA during pregnancy induced low birth weight and suppressed the development of allergic lung inflammation and tracheal hyperresponsiveness in offspring by mechanisms mediated by reduced anaphylactic antibodies synthesis, IL-6 and TNF-alpha secretion. Elevated levels of IL-10 were found. Any systemic alteration was detected in the exposed pregnant rats, although oxidative stress in the uterine environment was evident at the moment of the delivery based on elevated COX-1 expression and reduced cNOS and SOD-2 in the uterus. Therefore, we show the putative programming mechanisms induced by FA on the immune system for the first time and the mechanisms involved may be related to oxidative stress in the foetal microenvironment. - Highlights: • Formaldehyde exposure does not cause lung inflammation in pregnant rats. • Formaldehyde exposure suppresses allergic lung inflammation in the offspring. • Formaldehyde exposure induces oxidative stress in uterine environment.

  15. Blood transfusion : Transfusion-related acute lung injury: back to basics

    NARCIS (Netherlands)

    Peters, A.L.

    2017-01-01

    Transfusion-related acute lung injury (TRALI) is a life-threatening disease affecting the lungs. TRALI can develop within 6 hours after transfusion and almost all patients with TRALI require mechanical ventilation at the intensive care department. Nevertheless up to 40% of patients do not recover

  16. Regional pressure volume curves by electrical impedance tomography in a model of acute lung injury

    NARCIS (Netherlands)

    Kunst, P. W.; Böhm, S. H.; Vazquez de Anda, G.; Amato, M. B.; Lachmann, B.; Postmus, P. E.; de Vries, P. M.

    2000-01-01

    OBJECTIVE: A new noninvasive method, electrical impedance tomography (EIT), was used to make pressure-impedance (PI) curves in a lung lavage model of acute lung injury in pigs. The lower inflection point (LIP) and the upper deflection point (UDP) were determined from these curves and from the

  17. Lung tissue remodeling in the acute respiratory distress syndrome

    Directory of Open Access Journals (Sweden)

    Souza Alba Barros de

    2003-01-01

    Full Text Available Acute respiratory distress syndrome (ARDS is characterized by diffuse alveolar damage, and evolves progressively with three phases: exsudative, fibroproliferative, and fibrotic. In the exudative phase, there are interstitial and alveolar edemas with hyaline membrane. The fibropro­liferative phase is characterized by exudate organization and fibroelastogenesis. There is proliferation of type II pneumocytes to cover the damaged epithelial surface, followed by differentiation into type I pneumocytes. The fibroproliferative phase starts early, and its severity is related to the patient?s prognosis. The alterations observed in the phenotype of the pulmonary parenchyma cells steer the tissue remodeling towards either progressive fibrosis or the restoration of normal alveolar architecture. The fibrotic phase is characterized by abnormal and excessive deposition of extracellular matrix proteins, mainly collagen. The dynamic control of collagen deposition and degradation is regulated by metalloproteinases and their tissular regulators. The deposition of proteoglycans in the extracellular matrix of ARDS patients needs better study. The regulation of extracellular matrix remodeling, in normal conditions or in several pulmonary diseases, such as ARDS, results from a complex mechanism that integrate the transcription of elements that destroy the matrix protein and produce activation/inhibition of several cellular types of lung tissue. This review article will analyze the ECM organization in ARDS, the different pulmonary parenchyma remodeling mechanisms, and the role of cytokines in the regulation of the different matrix components during the remodeling process.

  18. Andrographolide protects against LPS-induced acute lung injury by inactivation of NF-κB.

    Directory of Open Access Journals (Sweden)

    Tao Zhu

    Full Text Available Nuclear factor-κB (NF-κB is a central transcriptional factor and a pleiotropic regulator of many genes involved in acute lung injury. Andrographolide is found in the plant of Andrographis paniculata and widely used in Traditional Chinese Medicine, exhibiting potently anti-inflammatory property by inhibiting NF-κB activity. The purpose of our investigation was designed to reveal the effect of andrographolide on various aspects of LPS induced inflammation in vivo and in vitro.In vivo, BALB/C mice were subjected to LPS injection with or without andrographolide treatments to induce ALI model. In vitro, MLE-12 cells were stimulated with LPS in the presence and absence of andrographolide. In vivo, pulmonary inflammation, pulmonary edema, ultrastructure changes of type II alveolar epithelial cells, MPO activity, total cells, neutrophils, macrophages, TNF-α, IL-6 and IL-1β in BALF, along with the expression of VCAM-1 and VEGF were dose-dependently attenuated by andrographolide. Meanwhile, in vitro, the expression of VCAM-1 and VEGF was also reduced by andrographolide. Moreover, our data showed that andrographolide significantly inhibited the ratios of phospho-IKKβ/total IKKβ, phospho-IκBα/total IκBα and phospho-NF-κB p65/total NF-κB p65, and NF-κB p65 DNA binding activities, both in vivo and in vitro.These results indicate that andrographolide dose-dependently suppressed the severity of LPS-induced ALI, more likely by virtue of andrographolide-mediated NF-κB inhibition at the level of IKKβ activation. These results suggest andrographolide may be considered as an effective and safe drug for the potential treatment of ALI.

  19. Andrographolide Protects against LPS-Induced Acute Lung Injury by Inactivation of NF-κB

    Science.gov (United States)

    Zhu, Tao; Wang, Dao-xin; Zhang, Wei; Liao, Xiu-qing; Guan, Xian; Bo, Hong; Sun, Jia-yang; Huang, Ni-wen; He, Jing; Zhang, Yun-kun; Tong, Jing; Li, Chang-yi

    2013-01-01

    Background Nuclear factor-κB (NF-κB) is a central transcriptional factor and a pleiotropic regulator of many genes involved in acute lung injury. Andrographolide is found in the plant of Andrographis paniculata and widely used in Traditional Chinese Medicine, exhibiting potently anti-inflammatory property by inhibiting NF-κB activity. The purpose of our investigation was designed to reveal the effect of andrographolide on various aspects of LPS induced inflammation in vivo and in vitro. Methods and Results In vivo, BALB/C mice were subjected to LPS injection with or without andrographolide treatments to induce ALI model. In vitro, MLE-12 cells were stimulated with LPS in the presence and absence of andrographolide. In vivo, pulmonary inflammation, pulmonary edema, ultrastructure changes of type II alveolar epithelial cells, MPO activity, total cells, neutrophils, macrophages, TNF-α, IL-6 and IL-1β in BALF, along with the expression of VCAM-1 and VEGF were dose-dependently attenuated by andrographolide. Meanwhile, in vitro, the expression of VCAM-1 and VEGF was also reduced by andrographolide. Moreover, our data showed that andrographolide significantly inhibited the ratios of phospho-IKKβ/total IKKβ, phospho-IκBα/total IκBα and phospho-NF-κB p65/total NF-κB p65, and NF-κB p65 DNA binding activities, both in vivo and in vitro. Conclusions These results indicate that andrographolide dose-dependently suppressed the severity of LPS-induced ALI, more likely by virtue of andrographolide-mediated NF-κB inhibition at the level of IKKβ activation. These results suggest andrographolide may be considered as an effective and safe drug for the potential treatment of ALI. PMID:23437127

  20. Reversal of acute and chronic synovial inflammation by anti-transforming growth factor beta.

    Science.gov (United States)

    Wahl, S M; Allen, J B; Costa, G L; Wong, H L; Dasch, J R

    1993-01-01

    Transforming growth factor beta (TGF-beta) induces leukocyte recruitment and activation, events central to an inflammatory response. In this study, we demonstrate that antagonism of TGF-beta with a neutralizing antibody not only blocks inflammatory cell accumulation, but also tissue pathology in an experimental model of chronic erosive polyarthritis. Intraarticular injection of monoclonal antibody 1D11.16, which inhibits both TGF-beta 1 and TGF-beta 2 bioactivity, into animals receiving an arthropathic dose of bacterial cell walls significantly inhibits arthritis. Inhibition was observed with a single injection of 50 micrograms antibody, and a 1-mg injection blocked acute inflammation > 75% compared with the contralateral joints injected with an irrelevant isotype control antibody (MOPC21) as quantitated by an articular index (AI = 0.93 +/- 0.23 for 1D11.16, and AI = 4.0 +/- 0 on day 4; p histopathologic and radiologic evidence of a therapeutic response. These data implicate TGF-beta as a profound agonist not only in the early events responsible for synovial inflammation, but also in the chronicity of streptococcal cell wall fragment-induced inflammation culminating in destructive pathology. Interrupting the cycle of leukocyte recruitment and activation with TGF-beta antagonists may provide a mechanism for resolution of chronic destructive lesions.

  1. MMP-3 Deficiency Alleviates Endotoxin-Induced Acute Inflammation in the Posterior Eye Segment

    Directory of Open Access Journals (Sweden)

    Inge Van Hove

    2016-11-01

    Full Text Available Matrix metalloproteinase-3 (MMP-3 is known to mediate neuroinflammatory processes by activating microglia, disrupting blood–central nervous system barriers and supporting neutrophil influx into the brain. In addition, the posterior part of the eye, more specifically the retina, the retinal pigment epithelium (RPE and the blood–retinal barrier, is affected upon neuroinflammation, but a role for MMP-3 during ocular inflammation remains elusive. We investigated whether MMP-3 contributes to acute inflammation in the eye using the endotoxin-induced uveitis (EIU model. Systemic administration of lipopolysaccharide induced an increase in MMP-3 mRNA and protein expression level in the posterior part of the eye. MMP-3 deficiency or knockdown suppressed retinal leukocyte adhesion and leukocyte infiltration into the vitreous cavity in mice subjected to EIU. Moreover, retinal and RPE mRNA levels of intercellular adhesion molecule 1 (Icam1, interleukin 6 (Il6, cytokine-inducible nitrogen oxide synthase (Nos2 and tumor necrosis factor α (Tnfα, which are key molecules involved in EIU, were clearly reduced in MMP-3 deficient mice. In addition, loss of MMP-3 repressed the upregulation of the chemokines monocyte chemoattractant protein (MCP-1 and (C-X-C motif ligand 1 (CXCL1. These findings suggest a contribution of MMP-3 during EIU, and its potential use as a therapeutic drug target in reducing ocular inflammation.

  2. HELICOBACTER PYLORI-ASSOCIATED INFLAMMATION IN PATIENTS WITH ACUTE CORONARY SYNDROME

    Directory of Open Access Journals (Sweden)

    O. N. Pavlov

    2014-07-01

    Full Text Available The aim – assessment of the prevalence of seropositivity to Helicobacter pylori infection and laboratory comparative study of the peripheralblood in patients depending on the course of coronary heart disease (CHD.Materials and methods. Observation of 100 patients with coronary artery disease and 40 control patients is presented. Investigation indicatorsof clinical blood tests, biochemical blood analysis and determination of immunoglobulin antibody titer against Helicobacter pylori.Results. In patients with coronary artery disease signs of systemic inflammation associated with the development of acute coronary syndrome are marked with increased antibody titers to infection Helicobacter pylori.Conclusion. A history of coronary artery disease in patients with Helicobacter pylori-associated gastroduodenal pathology should be considered as a factor that increases the likelihood of unstable coronary desease course. Detected in patients with coronary artery disease signs of systemic inflammation with an increase in titer of antibodies to Helicobacter pylori infection associated with development of acute coronary syndrome.

  3. Xanthohumol ameliorates lipopolysaccharide (LPS-induced acute lung injury via induction of AMPK/GSK3β-Nrf2 signal axis

    Directory of Open Access Journals (Sweden)

    Hongming Lv

    2017-08-01

    Full Text Available Abundant natural flavonoids can induce nuclear factor-erythroid 2 related factor 2 (Nrf2 and/or AMP-activated protein kinase (AMPK activation, which play crucial roles in the amelioration of various inflammation- and oxidative stress-induced diseases, including acute lung injury (ALI. Xanthohumol (Xn, a principal prenylflavonoid, possesses anti-inflammation and anti-oxidant activities. However, whether Xn could protect from LPS-induced ALI through inducing AMPK/Nrf2 activation and its downstream signals, are still poorly elucidated. Accordingly, we focused on exploring the protective effect of Xn in the context of ALI and the involvement of underlying molecular mechanisms. Our findings indicated that Xn effectively alleviated lung injury by reduction of lung W/D ratio and protein levels, neutrophil infiltration, MDA and MPO formation, and SOD and GSH depletion. Meanwhile, Xn significantly lessened histopathological changes, reactive oxygen species (ROS generation, several cytokines secretion, and iNOS and HMGB1 expression, and inhibited Txnip/NLRP3 inflammasome and NF-κB signaling pathway activation. Additionally, Xn evidently decreased t-BHP-stimulated cell apoptosis, ROS generation and GSH depletion but increased various anti-oxidative enzymes expression regulated by Keap1-Nrf2/ARE activation, which may be associated with AMPK and GSK3β phosphorylation. However, Xn-mediated inflammatory cytokines and ROS production, histopathological changes, Txnip/NLRP3 inflammasome and NF-κB signaling pathway in WT mice were remarkably abrogated in Nrf2-/- mice. Our experimental results firstly provided a support that Xn effectively protected LPS-induced ALI against oxidative stress and inflammation damage which are largely dependent upon upregulation of the Nrf2 pathway via activation of AMPK/GSK3β, thereby suppressing LPS-activated Txnip/NLRP3 inflammasome and NF-κB signaling pathway. Keywords: Xanthohumol, Acute lung injury, Oxidative stress

  4. Combined effects of sivelestat and resveratrol on severe acute pancreatitis-associated lung injury in rats.

    Science.gov (United States)

    Wang, Houhong; Wang, Shuai; Tang, Amao; Gong, Huihui; Ma, Panpan; Chen, Li

    2014-08-01

    Despite extensive research and clinical efforts made in the management of acute pancre-atitis during the past few decades, to date no effective cure is available and the mortality from severe acute pancre-atitis remains high. Given that lung is the primary cause of early death in acute pancreatitis patients, novel therapeutic approaches aiming to prevent lung injury have become a subject of intensive investigation. In a previous study, we demonstrated that sivelestat, a specific inhibitor of neutrophil elastase, is effective in protecting against lung failure in rats with taurocholate-induced acute pancreatitis. As part of the analyses extended from that study, the present study aimed to evaluate the role of sivelestat and/or resveratrol in the protection against acute pancreatitis-associated lung injury. The extended analyses demonstrated the following: (1) sodium taurocholate induced apparent lung injury and dysfunction manifested by histological anomalies, including vacuolization and apoptosis of the cells in the lung, as well as biochemical aberrations in the blood (an increase in amylase concentration and a decrease in partial arterial oxygen pressure) and increases in activities of reactive oxygen species, interleukin 6, myeloperoxidase, neutrophil elastase, lung edema, bronchotracho alveolar lavage protein concentration, and bronchotracho alveolar lavage cell infiltration in the lung; and (2) in lung tissues, either sivelestat or resveratrol treatment effectively attenuated the taurocholate-induced abnormalities in all parameters analyzed except for serum amylase concentration. In addition, combined treatment with both sivelestat and resveratrol demonstrated additive protective effects on pancreatitis-associated lung injury compared with single treatment.

  5. Violacein Treatment Modulates Acute and Chronic Inflammation through the Suppression of Cytokine Production and Induction of Regulatory T Cells.

    Directory of Open Access Journals (Sweden)

    Liana Verinaud

    Full Text Available Inflammation is a necessary process to control infection. However, exacerbated inflammation, acute or chronic, promotes deleterious effects in the organism. Violacein (viola, a quorum sensing metabolite from the Gram-negative bacterium Chromobacterium violaceum, has been shown to protect mice from malaria and to have beneficial effects on tumors. However, it is not known whether this drug possesses anti-inflammatory activity. In this study, we investigated whether viola administration is able to reduce acute and chronic autoimmune inflammation. For that purpose, C57BL/6 mice were intraperitoneally injected with 1 μg of LPS and were treated with viola (3.5mg/kg via i.p. at the same time-point. Three hours later, the levels of inflammatory cytokines in the sera and phenotypical characterization of leukocytes were determined. Mice treated with viola presented a significant reduction in the production of inflammatory cytokines compared with untreated mice. Interestingly, although viola is a compound derived from bacteria, it did not induce inflammation upon administration to naïve mice. To test whether viola would protect mice from an autoimmune inflammation, Experimental Autoimmune Encephalomyelitis (EAE-inflicted mice were given viola i.p. at disease onset, at the 10th day from immunization. Viola-treated mice developed mild EAE disease in contrast with placebo-treated mice. The frequencies of dendritic cells and macrophages were unaltered in EAE mice treated with viola. However, the sole administration of viola augmented the levels of splenic regulatory T cells (CD4+Foxp3+. We also found that adoptive transfer of viola-elicited regulatory T cells significantly reduced EAE. Our study shows, for the first time, that violacein is able to modulate acute and chronic inflammation. Amelioration relied in suppression of cytokine production (in acute inflammation and stimulation of regulatory T cells (in chronic inflammation. New studies must be

  6. Biodiesel versus diesel exposure: Enhanced pulmonary inflammation, oxidative stress, and differential morphological changes in the mouse lung

    International Nuclear Information System (INIS)

    Yanamala, Naveena; Hatfield, Meghan K.; Farcas, Mariana T.; Schwegler-Berry, Diane; Hummer, Jon A.; Shurin, Michael R.; Birch, M. Eileen; Gutkin, Dmitriy W.; Kisin, Elena; Kagan, Valerian E.; Bugarski, Aleksandar D.; Shvedova, Anna A.

    2013-01-01

    The use of biodiesel (BD) or its blends with petroleum diesel (D) is considered to be a viable approach to reduce occupational and environmental exposures to particulate matter (PM). Due to its lower particulate mass emissions compared to D, use of BD is thought to alleviate adverse health effects. Considering BD fuel is mainly composed of unsaturated fatty acids, we hypothesize that BD exhaust particles could induce pronounced adverse outcomes, due to their ability to readily oxidize. The main objective of this study was to compare the effects of particles generated by engine fueled with neat BD and neat petroleum-based D. Biomarkers of tissue damage and inflammation were significantly elevated in lungs of mice exposed to BD particulates. Additionally, BD particulates caused a significant accumulation of oxidatively modified proteins and an increase in 4-hydroxynonenal. The up-regulation of inflammatory cytokines/chemokines/growth factors was higher in lungs upon BD particulate exposure. Histological evaluation of lung sections indicated presence of lymphocytic infiltrate and impaired clearance with prolonged retention of BD particulate in pigment laden macrophages. Taken together, these results clearly indicate that BD exhaust particles could exert more toxic effects compared to D. - Highlights: • Exposure of mice to BDPM caused higher pulmonary toxicity compared to DPM. • Oxidative stress and inflammation were higher in BD vs to D exposed mice. • Inflammatory lymphocyte infiltrates were seen only in lungs of mice exposed to BD. • Ineffective clearance, prolonged PM retention was present only after BD exposure

  7. Biodiesel versus diesel exposure: Enhanced pulmonary inflammation, oxidative stress, and differential morphological changes in the mouse lung

    Energy Technology Data Exchange (ETDEWEB)

    Yanamala, Naveena, E-mail: wqu1@cdc.gov [Pathology and Physiology Research Branch/NIOSH/CDC, Morgantown, WV 26505 (United States); Hatfield, Meghan K., E-mail: wla4@cdc.gov [Pathology and Physiology Research Branch/NIOSH/CDC, Morgantown, WV 26505 (United States); Farcas, Mariana T., E-mail: woe7@cdc.gov [Pathology and Physiology Research Branch/NIOSH/CDC, Morgantown, WV 26505 (United States); Schwegler-Berry, Diane [Pathology and Physiology Research Branch/NIOSH/CDC, Morgantown, WV 26505 (United States); Hummer, Jon A., E-mail: qzh3@cdc.gov [Office of Mine Safety and Health Research/NIOSH/CDC, Pittsburgh, PA 15236 (United States); Shurin, Michael R., E-mail: shurinmr@upmc.edu [Department of Pathology, University of Pittsburgh Medical Center, Pittsburgh, PA (United States); Birch, M. Eileen, E-mail: mib2@cdc.gov [NIOSH/CDC, 4676 Columbia Parkway, Cincinnati, OH 45226 (United States); Gutkin, Dmitriy W., E-mail: dwgutkin@hotmail.com [Department of Pathology, University of Pittsburgh Medical Center, Pittsburgh, PA (United States); Kisin, Elena, E-mail: edk8@cdc.gov [Pathology and Physiology Research Branch/NIOSH/CDC, Morgantown, WV 26505 (United States); Kagan, Valerian E., E-mail: kagan@pitt.edu [Department of Environmental and Occupational Health, University of Pittsburgh, PA (United States); Bugarski, Aleksandar D., E-mail: zjl1@cdc.gov [Office of Mine Safety and Health Research/NIOSH/CDC, Pittsburgh, PA 15236 (United States); Shvedova, Anna A., E-mail: ats1@cdc.gov [Pathology and Physiology Research Branch/NIOSH/CDC, Morgantown, WV 26505 (United States); Department Physiology and Pharmacology, WVU, Morgantown, WV 26505 (United States)

    2013-10-15

    The use of biodiesel (BD) or its blends with petroleum diesel (D) is considered to be a viable approach to reduce occupational and environmental exposures to particulate matter (PM). Due to its lower particulate mass emissions compared to D, use of BD is thought to alleviate adverse health effects. Considering BD fuel is mainly composed of unsaturated fatty acids, we hypothesize that BD exhaust particles could induce pronounced adverse outcomes, due to their ability to readily oxidize. The main objective of this study was to compare the effects of particles generated by engine fueled with neat BD and neat petroleum-based D. Biomarkers of tissue damage and inflammation were significantly elevated in lungs of mice exposed to BD particulates. Additionally, BD particulates caused a significant accumulation of oxidatively modified proteins and an increase in 4-hydroxynonenal. The up-regulation of inflammatory cytokines/chemokines/growth factors was higher in lungs upon BD particulate exposure. Histological evaluation of lung sections indicated presence of lymphocytic infiltrate and impaired clearance with prolonged retention of BD particulate in pigment laden macrophages. Taken together, these results clearly indicate that BD exhaust particles could exert more toxic effects compared to D. - Highlights: • Exposure of mice to BDPM caused higher pulmonary toxicity compared to DPM. • Oxidative stress and inflammation were higher in BD vs to D exposed mice. • Inflammatory lymphocyte infiltrates were seen only in lungs of mice exposed to BD. • Ineffective clearance, prolonged PM retention was present only after BD exposure.

  8. Evidence for chronic inflammation as a component of the interstitial lung disease associated with progressive systemic sclerosis

    International Nuclear Information System (INIS)

    Rossi, G.A.; Bitterman, P.B.; Rennard, S.I.; Ferrans, V.J.; Crystal, R.G.

    1985-01-01

    Progressive systemic sclerosis (PSS) is a generalized disorder characterized by fibrosis of many organs including the lung parenchyma. Unlike most other interstitial disorders, traditional concepts of the interstitial lung disease associated with PSS have held it to be a ''pure'' fibrotic disorder without a significant inflammatory component. To directly evaluate whether an active alveolitis is associated with this disorder, patients with chronic interstitial lung disease and PSS were studied by open lung biopsy, gallium-67 scanning, and bronchoalveolar lavage. Histologic evaluation of the biopsies demonstrated that the interstitial fibrosis of PSS is clearly associated with the presence of macrophages, lymphocytes, and polymorphonuclear leukocytes, both in the interstitium and on the alveolar epithelial surface. Gallium-67 scans were positive in 77% of the patients, showing diffuse, primarily lower zone uptake, suggestive of active inflammation. Consistent with the histologic findings, bronchoalveolar lavage studies demonstrated a mild increase in the proportions of neutrophils and eosinophils with occasional increased numbers of lymphocytes. Importantly, alveolar macrophages from patients with PSS showed increased release of fibronectin and alveolar-macrophage-derived growth factor, mediators that together stimulate lung fibroblasts to proliferate, thus suggesting at least one mechanism modulating the lung fibrosis of these patients

  9. Role of reactive nitrogen species generated via inducible nitric oxide synthase in vesicant-induced lung injury, inflammation and altered lung functioning

    Energy Technology Data Exchange (ETDEWEB)

    Sunil, Vasanthi R., E-mail: sunilvr@eohsi.rutgers.edu [Department of Pharmacology and Toxicology, Rutgers University, Ernest Mario School of Pharmacy Piscataway, NJ (United States); Shen, Jianliang; Patel-Vayas, Kinal; Gow, Andrew J. [Department of Pharmacology and Toxicology, Rutgers University, Ernest Mario School of Pharmacy Piscataway, NJ (United States); Laskin, Jeffrey D. [Department of Environmental and Occupational Medicine, University of Medicine and Dentistry of New Jersey, Robert Wood Johnson Medical School, Piscataway, NJ (United States); Laskin, Debra L. [Department of Pharmacology and Toxicology, Rutgers University, Ernest Mario School of Pharmacy Piscataway, NJ (United States)

    2012-05-15

    Pulmonary toxicity induced by sulfur mustard and related vesicants is associated with oxidative stress. In the present studies we analyzed the role of reactive nitrogen species (RNS) generated via inducible nitric oxide synthase (iNOS) in lung injury and inflammation induced by vesicants using 2-chloroethyl ethyl sulfide (CEES) as a model. C57Bl/6 (WT) and iNOS −/− mice were sacrificed 3 days or 14 days following intratracheal administration of CEES (6 mg/kg) or control. CEES intoxication resulted in transient (3 days) increases in bronchoalveolar lavage (BAL) cell and protein content in WT, but not iNOS −/− mice. This correlated with expression of Ym1, a marker of oxidative stress in alveolar macrophages and epithelial cells. In contrast, in iNOS −/− mice, Ym1 was only observed 14 days post-exposure in enlarged alveolar macrophages, suggesting that they are alternatively activated. This is supported by findings that lung tumor necrosis factor and lipocalin Lcn2 expression, mediators involved in tissue repair were also upregulated at this time in iNOS −/− mice. Conversely, CEES-induced increases in the proinflammatory genes, monocyte chemotactic protein-1 and cyclooxygenase-2, were abrogated in iNOS −/− mice. In WT mice, CEES treatment also resulted in increases in total lung resistance and decreases in compliance in response to methacholine, effects blunted by loss of iNOS. These data demonstrate that RNS, generated via iNOS play a role in the pathogenic responses to CEES, augmenting oxidative stress and inflammation and suppressing tissue repair. Elucidating inflammatory mechanisms mediating vesicant-induced lung injury is key to the development of therapeutics to treat mustard poisoning. -- Highlights: ► Lung injury, inflammation and oxidative stress are induced by the model vesicant CEES ► RNS generated via iNOS are important in the CEES-induced pulmonary toxicity ► iNOS −/− mice are protected from CEES-induced lung toxicity and

  10. Transfusion-related acute lung injury: Current understanding and preventive strategies

    NARCIS (Netherlands)

    Vlaar, A. P. J.

    2012-01-01

    Transfusion-related acute lung injury (TRALI) is the most serious complication of transfusion medicine. TRALI is defined as the onset of acute hypoxia within 6 hours of a blood transfusion in the absence of hydrostatic pulmonary oedema. The past decades have resulted in a better understanding of the

  11. Cross Cancer Genomic Investigation of Inflammation Pathway for Five Common Cancers: Lung, Ovary, Prostate, Breast, and Colorectal Cancer.

    Science.gov (United States)

    Hung, Rayjean J; Ulrich, Cornelia M; Goode, Ellen L; Brhane, Yonathan; Muir, Kenneth; Chan, Andrew T; Marchand, Loic Le; Schildkraut, Joellen; Witte, John S; Eeles, Rosalind; Boffetta, Paolo; Spitz, Margaret R; Poirier, Julia G; Rider, David N; Fridley, Brooke L; Chen, Zhihua; Haiman, Christopher; Schumacher, Fredrick; Easton, Douglas F; Landi, Maria Teresa; Brennan, Paul; Houlston, Richard; Christiani, David C; Field, John K; Bickeböller, Heike; Risch, Angela; Kote-Jarai, Zsofia; Wiklund, Fredrik; Grönberg, Henrik; Chanock, Stephen; Berndt, Sonja I; Kraft, Peter; Lindström, Sara; Al Olama, Ali Amin; Song, Honglin; Phelan, Catherine; Wentzensen, Nicholas; Peters, Ulrike; Slattery, Martha L; Sellers, Thomas A; Casey, Graham; Gruber, Stephen B; Hunter, David J; Amos, Christopher I; Henderson, Brian

    2015-11-01

    Inflammation has been hypothesized to increase the risk of cancer development as an initiator or promoter, yet no large-scale study of inherited variation across cancer sites has been conducted. We conducted a cross-cancer genomic analysis for the inflammation pathway based on 48 genome-wide association studies within the National Cancer Institute GAME-ON Network across five common cancer sites, with a total of 64 591 cancer patients and 74 467 control patients. Subset-based meta-analysis was used to account for possible disease heterogeneity, and hierarchical modeling was employed to estimate the effect of the subcomponents within the inflammation pathway. The network was visualized by enrichment map. All statistical tests were two-sided. We identified three pleiotropic loci within the inflammation pathway, including one novel locus in Ch12q24 encoding SH2B3 (rs3184504), which reached GWAS significance with a P value of 1.78 x 10(-8), and it showed an association with lung cancer (P = 2.01 x 10(-6)), colorectal cancer (GECCO P = 6.72x10(-6); CORECT P = 3.32x10(-5)), and breast cancer (P = .009). We also identified five key subpathway components with genetic variants that are relevant for the risk of these five cancer sites: inflammatory response for colorectal cancer (P = .006), inflammation related cell cycle gene for lung cancer (P = 1.35x10(-6)), and activation of immune response for ovarian cancer (P = .009). In addition, sequence variations in immune system development played a role in breast cancer etiology (P = .001) and innate immune response was involved in the risk of both colorectal (P = .022) and ovarian cancer (P = .003). Genetic variations in inflammation and its related subpathway components are keys to the development of lung, colorectal, ovary, and breast cancer, including SH2B3, which is associated with lung, colorectal, and breast cancer. © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please e

  12. Mechanical ventilation with lower tidal volumes and positive end-expiratory pressure prevents pulmonary inflammation in patients without preexisting lung injury

    NARCIS (Netherlands)

    Wolthuis, Esther K.; Choi, Goda; Dessing, Mark C.; Bresser, Paul; Lutter, Rene; Dzoljic, Misa; van der Poll, Tom; Vroom, Margreeth B.; Hollmann, Markus; Schultz, Marcus J.

    2008-01-01

    Background: Mechanical ventilation with high tidal volumes aggravates lung injury in patients with acute lung injury or acute respiratory distress syndrome. The authors sought to determine the effects of short-term mechanical ventilation on local inflammatory responses in patients without

  13. Protective Effect of the Fruit Hull of Gleditsia sinensis on LPS-Induced Acute Lung Injury Is Associated with Nrf2 Activation

    Directory of Open Access Journals (Sweden)

    Jun-Young Choi

    2012-01-01

    Full Text Available The fruit hull of Gleditsia sinensis (FGS has been prescribed as a traditional eastern Asian medicinal remedy for the treatment of various respiratory diseases, but the efficacy and underlying mechanisms remain poorly characterized. Here, we explored a potential usage of FGS for the treatment of acute lung injury (ALI, a highly fatal inflammatory lung disease that urgently needs effective therapeutics, and investigated a mechanism for the anti-inflammatory activity of FGS. Pretreatment of C57BL/6 mice with FGS significantly attenuated LPS-induced neutrophilic lung inflammation compared to sham-treated, inflamed mice. Reporter assays, semiquantitative RT-PCR, and Western blot analyses show that while not affecting NF-κB, FGS activated Nrf2 and expressed Nrf2-regulated genes including GCLC, NQO-1, and HO-1 in RAW 264.7 cells. Furthermore, pretreatment of mice with FGS enhanced the expression of GCLC and HO-1 but suppressed that of proinflammatory cytokines in including TNF-α and IL-1β in the inflamed lungs. These results suggest that FGS effectively suppresses neutrophilic lung inflammation, which can be associated with, at least in part, FGS-activating anti-inflammatory factor Nrf2. Our results suggest that FGS can be developed as a therapeutic option for the treatment of ALI.

  14. Influenza Virus-Induced Lung Inflammation Was Modulated by Cigarette Smoke Exposure in Mice

    Science.gov (United States)

    Han, Yan; Ling, Man To; Mao, Huawei; Zheng, Jian; Liu, Ming; Lam, Kwok Tai; Liu, Yuan; Tu, Wenwei; Lau, Yu-Lung

    2014-01-01

    Although smokers have increased susceptibility and severity of seasonal influenza virus infection, there is no report about the risk of 2009 pandemic H1N1 (pdmH1N1) or avian H9N2 (H9N2/G1) virus infection in smokers. In our study, we used mouse model to investigate the effect of cigarette smoke on pdmH1N1 or H9N2 virus infection. Mice were exposed to cigarette smoke for 21 days and then infected with pdmH1N1 or H9N2 virus. Control mice were exposed to air in parallel. We found that cigarette smoke exposure alone significantly upregulated the lung inflammation. Such prior cigarette smoke exposure significantly reduced the disease severity of subsequent pdmH1N1 or H9N2 virus infection. For pdmH1N1 infection, cigarette smoke exposed mice had significantly lower mortality than the control mice, possibly due to the significantly decreased production of inflammatory cytokines and chemokines. Similarly, after H9N2 infection, cigarette smoke exposed mice displayed significantly less weight loss, which might be attributed to lower cytokines and chemokines production, less macrophages, neutrophils, CD4+ and CD8+ T cells infiltration and reduced lung damage compared to the control mice. To further investigate the underlying mechanism, we used nicotine to mimic the effect of cigarette smoke both in vitro and in vivo. Pre-treating the primary human macrophages with nicotine for 72 h significantly decreased their expression of cytokines and chemokines after pdmH1N1 or H9N2 infection. The mice subcutaneously and continuously treated with nicotine displayed significantly less weight loss and lower inflammatory response than the control mice upon pdmH1N1 or H9N2 infection. Moreover, α7 nicotinic acetylcholine receptor knockout mice had more body weight loss than wild-type mice after cigarette smoke exposure and H9N2 infection. Our study provided the first evidence that the pathogenicity of both pdmH1N1 and H9N2 viruses was alleviated in cigarette smoke exposed mice, which might

  15. Influenza virus-induced lung inflammation was modulated by cigarette smoke exposure in mice.

    Directory of Open Access Journals (Sweden)

    Yan Han

    Full Text Available Although smokers have increased susceptibility and severity of seasonal influenza virus infection, there is no report about the risk of 2009 pandemic H1N1 (pdmH1N1 or avian H9N2 (H9N2/G1 virus infection in smokers. In our study, we used mouse model to investigate the effect of cigarette smoke on pdmH1N1 or H9N2 virus infection. Mice were exposed to cigarette smoke for 21 days and then infected with pdmH1N1 or H9N2 virus. Control mice were exposed to air in parallel. We found that cigarette smoke exposure alone significantly upregulated the lung inflammation. Such prior cigarette smoke exposure significantly reduced the disease severity of subsequent pdmH1N1 or H9N2 virus infection. For pdmH1N1 infection, cigarette smoke exposed mice had significantly lower mortality than the control mice, possibly due to the significantly decreased production of inflammatory cytokines and chemokines. Similarly, after H9N2 infection, cigarette smoke exposed mice displayed significantly less weight loss, which might be attributed to lower cytokines and chemokines production, less macrophages, neutrophils, CD4+ and CD8+ T cells infiltration and reduced lung damage compared to the control mice. To further investigate the underlying mechanism, we used nicotine to mimic the effect of cigarette smoke both in vitro and in vivo. Pre-treating the primary human macrophages with nicotine for 72 h significantly decreased their expression of cytokines and chemokines after pdmH1N1 or H9N2 infection. The mice subcutaneously and continuously treated with nicotine displayed significantly less weight loss and lower inflammatory response than the control mice upon pdmH1N1 or H9N2 infection. Moreover, α7 nicotinic acetylcholine receptor knockout mice had more body weight loss than wild-type mice after cigarette smoke exposure and H9N2 infection. Our study provided the first evidence that the pathogenicity of both pdmH1N1 and H9N2 viruses was alleviated in cigarette smoke exposed

  16. Neutralization of interleukin-17A delays progression of silica-induced lung inflammation and fibrosis in C57BL/6 mice

    International Nuclear Information System (INIS)

    Chen, Ying; Li, Cuiying; Weng, Dong; Song, Laiyu; Tang, Wen; Dai, Wujing; Yu, Ye; Liu, Fangwei; Zhao, Ming; Lu, Chunwei; Chen, Jie

    2014-01-01

    Silica exposure can cause lung inflammation and fibrosis, known as silicosis. Interleukin-17A (IL-17A) and Th17 cells play a pivotal role in controlling inflammatory diseases. However, the roles of IL-17A and Th17 cells in the progress of silica-induced inflammation and fibrosis are poorly understood. This study explored the effects of IL-17A on silica-induced inflammation and fibrosis. We used an anti-mouse IL-17A antibody to establish an IL-17A-neutralized mice model, and mice were exposed to silica to establish an experimental silicosis model. We showed that IL-17A neutralization delayed neutrophil accumulation and progression of silica-induced lung inflammation and fibrosis. IL-17A neutralization reduced the percentage of Th17 in CD4 + T cells, decreased IL-6 and IL-1β expression, and increased Tregs at an early phase of silica-induced inflammation. Neutralization of IL-17A delayed silica-induced Th1/Th2 immune and autoimmune responses. These results suggest that IL-17A neutralization alleviates early stage silica-induced lung inflammation and delays progression of silica-induced lung inflammation and fibrosis. Neutralization of IL-17A suppressed Th17 cell development by decreasing IL-6 and/or IL-1β and increased Tregs at an early phase of silica-induced inflammation. Neutralization of IL-17A also delayed the Th1/Th2 immune response during silica-induced lung inflammation and fibrosis. IL-17A may play a pivotal role in the early phase of silica-induced inflammation and may mediate the Th immune response to influence silica-induced lung inflammation and fibrosis in mice. - Highlights: • Neutralization of IL-17A alleviated silica-induced lung inflammation of early stage. • Neutralization of IL-17A decreased Th17 cells and increased Tregs. • IL-17A mediated the reciprocal relationship of Th17/Tregs by IL-6 and/or IL-1β. • Neutralization of IL-17A delayed silica-induced Th1/Th2 immune response. • Neutralization of IL-17A delayed silica-induced lung

  17. Neutralization of interleukin-17A delays progression of silica-induced lung inflammation and fibrosis in C57BL/6 mice

    Energy Technology Data Exchange (ETDEWEB)

    Chen, Ying; Li, Cuiying [Division of Pneumoconiosis, School of Public Health, China Medical University, Shenyang, Liaoning (China); Weng, Dong [Division of Pneumoconiosis, School of Public Health, China Medical University, Shenyang, Liaoning (China); Clinical Translational Research Center, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai (China); Song, Laiyu; Tang, Wen; Dai, Wujing; Yu, Ye; Liu, Fangwei; Zhao, Ming; Lu, Chunwei [Division of Pneumoconiosis, School of Public Health, China Medical University, Shenyang, Liaoning (China); Chen, Jie, E-mail: chenjie@mail.cmu.edu.cn [Division of Pneumoconiosis, School of Public Health, China Medical University, Shenyang, Liaoning (China)

    2014-02-15

    Silica exposure can cause lung inflammation and fibrosis, known as silicosis. Interleukin-17A (IL-17A) and Th17 cells play a pivotal role in controlling inflammatory diseases. However, the roles of IL-17A and Th17 cells in the progress of silica-induced inflammation and fibrosis are poorly understood. This study explored the effects of IL-17A on silica-induced inflammation and fibrosis. We used an anti-mouse IL-17A antibody to establish an IL-17A-neutralized mice model, and mice were exposed to silica to establish an experimental silicosis model. We showed that IL-17A neutralization delayed neutrophil accumulation and progression of silica-induced lung inflammation and fibrosis. IL-17A neutralization reduced the percentage of Th17 in CD4 + T cells, decreased IL-6 and IL-1β expression, and increased Tregs at an early phase of silica-induced inflammation. Neutralization of IL-17A delayed silica-induced Th1/Th2 immune and autoimmune responses. These results suggest that IL-17A neutralization alleviates early stage silica-induced lung inflammation and delays progression of silica-induced lung inflammation and fibrosis. Neutralization of IL-17A suppressed Th17 cell development by decreasing IL-6 and/or IL-1β and increased Tregs at an early phase of silica-induced inflammation. Neutralization of IL-17A also delayed the Th1/Th2 immune response during silica-induced lung inflammation and fibrosis. IL-17A may play a pivotal role in the early phase of silica-induced inflammation and may mediate the Th immune response to influence silica-induced lung inflammation and fibrosis in mice. - Highlights: • Neutralization of IL-17A alleviated silica-induced lung inflammation of early stage. • Neutralization of IL-17A decreased Th17 cells and increased Tregs. • IL-17A mediated the reciprocal relationship of Th17/Tregs by IL-6 and/or IL-1β. • Neutralization of IL-17A delayed silica-induced Th1/Th2 immune response. • Neutralization of IL-17A delayed silica-induced lung

  18. Acute phase response, inflammation and metabolic syndrome biomarkers of Libby asbestos exposure

    Energy Technology Data Exchange (ETDEWEB)

    Shannahan, Jonathan H. [Curriculum in Toxicology, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC 27599 (United States); Alzate, Oscar [Systems Proteomics Center, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC 27599 (United States); Winnik, Witold M.; Andrews, Debora [Proteomics Core, Research Core Unit, National Health and Environmental Effects Research Laboratory, Office of Research and Development, U.S. Environmental Protection Agency, Research Triangle Park, NC 27711 (United States); Schladweiler, Mette C. [Cardiopulmonary and Immunotoxicology Branch, Environmental Public Health Division, National Health and Environmental Effects Research Laboratory, Office of Research and Development, U.S. Environmental Protection Agency, Research Triangle Park, NC 27711 (United States); Ghio, Andrew J. [Clinical Research Branch, Environmental Public Health Division, National Health and Environmental Effects Research Laboratory, Office of Research and Development, U.S. Environmental Protection Agency, Chapel Hill, NC 27599 (United States); Gavett, Stephen H. [Cardiopulmonary and Immunotoxicology Branch, Environmental Public Health Division, National Health and Environmental Effects Research Laboratory, Office of Research and Development, U.S. Environmental Protection Agency, Research Triangle Park, NC 27711 (United States); Kodavanti, Urmila P., E-mail: Kodavanti.Urmila@epa.gov [Cardiopulmonary and Immunotoxicology Branch, Environmental Public Health Division, National Health and Environmental Effects Research Laboratory, Office of Research and Development, U.S. Environmental Protection Agency, Research Triangle Park, NC 27711 (United States)

    2012-04-15

    Identification of biomarkers assists in the diagnosis of disease and the assessment of health risks from environmental exposures. We hypothesized that rats exposed to Libby amphibole (LA) would present with a unique serum proteomic profile which could help elucidate epidemiologically-relevant biomarkers. In four experiments spanning varied protocols and temporality, healthy (Wistar Kyoto, WKY; and F344) and cardiovascular compromised (CVD) rat models (spontaneously hypertensive, SH; and SH heart failure, SHHF) were intratracheally instilled with saline (control) or LA. Serum biomarkers of cancer, inflammation, metabolic syndrome (MetS), and the acute phase response (APR) were analyzed. All rat strains exhibited acute increases in α-2-macroglobulin, and α1-acid glycoprotein. Among markers of inflammation, lipocalin-2 was induced in WKY, SH and SHHF and osteopontin only in WKY after LA exposure. While rat strain- and age-related changes were apparent in MetS biomarkers, no LA effects were evident. The cancer marker mesothelin was increased only slightly at 1 month in WKY in one of the studies. Quantitative Intact Proteomic profiling of WKY serum at 1 day or 4 weeks after 4 weekly LA instillations indicated no oxidative protein modifications, however APR proteins were significantly increased. Those included serine protease inhibitor, apolipoprotein E, α-2-HS-glycoprotein, t-kininogen 1 and 2, ceruloplasmin, vitamin D binding protein, serum amyloid P, and more 1 day after last LA exposure. All changes were reversible after a short recovery regardless of the acute or long-term exposures. Thus, LA exposure induces an APR and systemic inflammatory biomarkers that could have implications in systemic and pulmonary disease in individuals exposed to LA. -- Highlights: ► Biomarkers of asbestos exposure are required for disease diagnosis. ► Libby amphibole exposure is associated with increased human mortality. ► Libby amphibole increases circulating proteins involved

  19. Effects of acute and chronic administration of methylprednisolone on oxidative stress in rat lungs

    Directory of Open Access Journals (Sweden)

    Ronaldo Lopes Torres

    2014-06-01

    Full Text Available Objective: To determine the effects of acute and chronic administration of methylprednisolone on oxidative stress, as quantified by measuring lipid peroxidation (LPO and total reactive antioxidant potential (TRAP, in rat lungs. Methods: Forty Wistar rats were divided into four groups: acute treatment, comprising rats receiving a single injection of methylprednisolone (50 mg/kg i.p.; acute control, comprising rats i.p. injected with saline; chronic treatment, comprising rats receiving methylprednisolone in drinking water (6 mg/kg per day for 30 days; and chronic control, comprising rats receiving normal drinking water. Results: The levels of TRAP were significantly higher in the acute treatment group rats than in the acute control rats, suggesting an improvement in the pulmonary defenses of the former. The levels of lung LPO were significantly higher in the chronic treatment group rats than in the chronic control rats, indicating oxidative damage in the lung tissue of the former. Conclusions: Our results suggest that the acute use of corticosteroids is beneficial to lung tissue, whereas their chronic use is not. The chronic use of methylprednisolone appears to increase lung LPO levels.

  20. Effects of personal air pollution exposure on asthma symptoms, lung function and airway inflammation.

    Science.gov (United States)

    Chambers, L; Finch, J; Edwards, K; Jeanjean, A; Leigh, R; Gonem, S

    2018-03-11

    There is evidence that air pollution increases the risk of asthma hospitalizations and healthcare utilization, but the effects on day-to-day asthma control are not fully understood. We undertook a prospective single-centre panel study to test the hypothesis that personal air pollution exposure is associated with asthma symptoms, lung function and airway inflammation. Thirty-two patients with a clinical diagnosis of asthma were provided with a personal air pollution monitor (Cairclip NO 2 /O 3 ) which was kept on or around their person throughout the 12-week follow-up period. Ambient levels of NO 2 and particulate matter were modelled based upon satellite imaging data. Directly measured ozone, NO 2 and particulate matter levels were obtained from a monitoring station in central Leicester. Participants made daily electronic records of asthma symptoms, peak expiratory flow and exhaled nitric oxide. Spirometry and asthma symptom questionnaires were completed at fortnightly study visits. Data were analysed using linear mixed effects models and cross-correlation. Cairclip exposure data were of good quality with clear evidence of diurnal variability and a missing data rate of approximately 20%. We were unable to detect consistent relationships between personal air pollution exposure and clinical outcomes in the group as a whole. In an exploratory subgroup analysis, total oxidant exposure was associated with increased daytime symptoms in women but not men. We did not find compelling evidence that air pollution exposure impacts on day-to-day clinical control in an unselected asthma population, but further studies are required in larger populations with higher exposure levels. Women may be more susceptible than men to the effects of air pollution, an observation which requires confirmation in future studies. © 2018 John Wiley & Sons Ltd.

  1. Melatonin attenuates inflammation of acute pulpitis subjected to dental pulp injury

    Science.gov (United States)

    Li, Ji-Guo; Lin, Jia-Ji; Wang, Zhao-Ling; Cai, Wen-Ke; Wang, Pei-Na; Jia, Qian; Zhang, An-Sheng; Wu, Gao-Yi; Zhu, Guo-Xiong; Ni, Long-Xing

    2015-01-01

    Acute pulpitis (AP), one of the most common diseases in the endodontics, usually causes severe pain to the patients, which makes the search for therapeutic target of AP essential in clinic. Toll-like receptor 4 (TLR4) signaling is widely involved in the mechanism of pulp inflammation, while melatonin has been reported to have an inhibition for a various kinds of inflammation. We hereby studied whether melatonin can regulate the expression of TLR4/NF-ĸB signaling in the pulp tissue of AP and in human dental pulp cells (HDPCs). Two left dental pulps of the adult rat were drilled open to establish the AP model, and the serum levels of melatonin and pro-inflammatory cytokines, including interleukin 1β (IL-1β), interleukin 18 (IL-18) and tumor necrosis factor α (TNF-α), were assessed at 1, 3 and 5 d post injury. At the same time points, the expression of TLR4 signaling in the pulp was explored by quantitative real-time PCR and immunohistochemistry. The AP rats were administered an abdominal injection of melatonin to assess whether melatonin rescued AP and TLR4/NF-ĸB signaling. Dental pulp injury led to an approximately five-day period acute pulp inflammation and necrosis in the pulp and a significant up-regulation of IL-1β, IL-18 and TNF-α in the serum. ELISA results showed that the level of melatonin in the serum decreased due to AP, while an abdominal injection of melatonin suppressed the increase in serum cytokines and the percentage of necrosis at the 5 d of the injured pulp. Consistent with the inflammation in AP rats, TLR4, NF-ĸB, TNF-α and IL-1β in the pulp were increased post AP compared with the baseline expression. And melatonin showed an inhibition on TLR4/NF-ĸB signaling as well as IL-1β and TNF-α production in the pulp of AP rats. Furthermore, melatonin could also regulate the expression of TLR4/NF-ĸB signaling in LPS-stimulated HDPCs. These data suggested that dental pulp injury induced AP and reduced the serum level of melatonin and that

  2. Are there differences in acute phase inflammation markers regarding the type of heart failure?

    Directory of Open Access Journals (Sweden)

    Jaime Agüero-Ramón-Llin

    2011-09-01

    Full Text Available This study aimed to determine if there are differences in inflammatory markers in the acute phase between systolic heart failure and heart failure with preserved systolic function. One hundred and thirty-one patients with acute heart failure were recruited consecutively. At admission, plasma fibrinogen, Creactive protein, sialic acid, von Willebrand factor, vascular endothelial growth factor, interleukin-6 and NTproBNP were all evaluated. If the ejection fraction was 45% or over patients were included in the HF-PSF group; the remaining patients were included in the SHF group. The HF-PSF patients were older (72±10 vs 63±12 years, P<0.001, presented a higher rate of atrial fibrillation (56.1 vs 21.3%, P<0.001, and had a lower rate of hemoglobin (12.2±2 vs 13.3±2.1 g/dL, P<0.01. No significant differences were observed in the inflammation markers analyzed among SHF and HFPSF groups. In the acute phase of heart failure there is a marked elevation of inflammatory markers but there are no differences in the inflammatory markers analyzed between the two different types of heart failure

  3. Dynamic FDG-PET Imaging to Differentiate Malignancies from Inflammation in Subcutaneous and In Situ Mouse Model for Non-Small Cell Lung Carcinoma (NSCLC).

    Science.gov (United States)

    Yang, Zhen; Zan, Yunlong; Zheng, Xiujuan; Hai, Wangxi; Chen, Kewei; Huang, Qiu; Xu, Yuhong; Peng, Jinliang

    2015-01-01

    [18F]fluoro-2-deoxy-D-glucose positron emission tomography (FDG-PET) has been widely used in oncologic procedures such as tumor diagnosis and staging. However, false-positive rates have been high, unacceptable and mainly caused by inflammatory lesions. Misinterpretations take place especially when non-subcutaneous inflammations appear at the tumor site, for instance in the lung. The aim of the current study is to evaluate the use of dynamic PET imaging procedure to differentiate in situ and subcutaneous non-small cell lung carcinoma (NSCLC) from inflammation, and estimate the kinetics of inflammations in various locations. Dynamic FDG-PET was performed on 33 female mice inoculated with tumor and/or inflammation subcutaneously or inside the lung. Standardized Uptake Values (SUVs) from static imaging (SUVmax) as well as values of influx rate constant (Ki) of compartmental modeling from dynamic imaging were obtained. Static and kinetic data from different lesions (tumor and inflammations) or different locations (subcutaneous, in situ and spontaneous group) were compared. Values of SUVmax showed significant difference in subcutaneous tumor and inflammation (pPET based SUVmax, both subcutaneous and in situ inflammations and malignancies can be differentiated via dynamic FDG-PET based Ki. Moreover, Values of influx rate constant Ki from compartmental modeling can offer an assessment for inflammations at different locations of the body, which also implies further validation is necessary before the replacement of in situ inflammation with its subcutaneous counterpart in animal experiments.

  4. Performance of an automated electronic acute lung injury screening system in intensive care unit patients.

    Science.gov (United States)

    Koenig, Helen C; Finkel, Barbara B; Khalsa, Satjeet S; Lanken, Paul N; Prasad, Meeta; Urbani, Richard; Fuchs, Barry D

    2011-01-01

    Lung protective ventilation reduces mortality in patients with acute lung injury, but underrecognition of acute lung injury has limited its use. We recently validated an automated electronic acute lung injury surveillance system in patients with major trauma in a single intensive care unit. In this study, we assessed the system's performance as a prospective acute lung injury screening tool in a diverse population of intensive care unit patients. Patients were screened prospectively for acute lung injury over 21 wks by the automated system and by an experienced research coordinator who manually screened subjects for enrollment in Acute Respiratory Distress Syndrome Clinical Trials Network (ARDSNet) trials. Performance of the automated system was assessed by comparing its results with the manual screening process. Discordant results were adjudicated blindly by two physician reviewers. In addition, a sensitivity analysis using a range of assumptions was conducted to better estimate the system's performance. The Hospital of the University of Pennsylvania, an academic medical center and ARDSNet center (1994-2006). Intubated patients in medical and surgical intensive care units. None. Of 1270 patients screened, 84 were identified with acute lung injury (incidence of 6.6%). The automated screening system had a sensitivity of 97.6% (95% confidence interval, 96.8-98.4%) and a specificity of 97.6% (95% confidence interval, 96.8-98.4%). The manual screening algorithm had a sensitivity of 57.1% (95% confidence interval, 54.5-59.8%) and a specificity of 99.7% (95% confidence interval, 99.4-100%). Sensitivity analysis demonstrated a range for sensitivity of 75.0-97.6% of the automated system under varying assumptions. Under all assumptions, the automated system demonstrated higher sensitivity than and comparable specificity to the manual screening method. An automated electronic system identified patients with acute lung injury with high sensitivity and specificity in diverse

  5. A study of the protective effect and mechanism of ketamine on acute lung injury induced by mechanical ventilation.

    Science.gov (United States)

    Wang, W-F; Liu, S; Xu, B

    2017-03-01

    To investigate the protective effects and mechanism of ketamine on acute lung injury induced by mechanical ventilation. 63 patients with acute lung injury caused by mechanical ventilation in our hospital between June 2014 and May 2015 were chosen and divided into three groups: group A, B, and C. Group A (20 cases) received conventional treatment. Group B (21 cases) was treated with propofol and group C (22 cases) with ketamine. The ventilator application time, the success rate of weaning, the mortality rate, inflammation index (IL-1, Caspase-1, and NF-κB), pulmonary function index and oxygen saturation were compared. The ventilator application time and the mortality rate of group B and group C were significantly (p 0.05). After the intervention, the levels of FEV1, FEV1/FVC, FVC and PEER in the three groups increased, but more remarkably in group B and group C (p mechanical ventilation. They shorten the application time of ventilator, improve the success rate of weaning and reduce the mortality rate which is probably related to the reduction of the degree of inflammatory reaction. Ketamine is more effective in reducing inflammatory factors including IL-1β, Caspase-1, and NF-κB than propofol.

  6. Kaempferol attenuates acute lung injury in caecal ligation and puncture model of sepsis in mice.

    Science.gov (United States)

    Rabha, Dipankar Jyoti; Singh, Thakur Uttam; Rungsung, Soya; Kumar, Tarun; Parida, Subhashree; Lingaraju, Madhu Cholenahalli; Paul, Avishek; Sahoo, Monalisa; Kumar, Dinesh

    2018-03-01

    Kaempferol is a flavonoid and important part of the diet. Kaempferol has shown antioxidant, antiinflammatory and antidiabetic activities in various studies. However, protective potential of kaempferol in acute lung injury induced by sepsis and its mechanism remains unclear. The present study was undertaken to evaluate the effect of kaempferol in sepsis-induced acute lung injury in mice and its possible mechanism of action. Acute lung injury was induced by CLP surgery in mice. Kaempferol (100 mg/kg bw) was administered orally one hour before caecal ligation and puncture surgery in mice. Mice were divided into four groups sham, KEM+sham, sepsis (CLP), and KEM+sepsis. Assessment of lung injury was done by estimation of protein content in lung tissue, lung edema, proinflammatory cytokines in plasma and lung tissue, oxidative stress, antioxidant enzymes, nitrite production, and histopathology. Kaempferol pretreated mice showed significant (P Kaempferol pretreatment showed reduction in cytokines IL-6, IL-1β, and TNF-α in plasma as well as in lung tissue in comparison with septic mice without pretreatment. Pretreatment with kaempferol did not show any reduction in MDA level in comparison with septic mice. Antioxidant enzymes SOD and catalase and nonenzymatic antioxidant GSH activities were also increased with kaempferol pretreatment in septic mice. Further, kaempferol pretreatment reduced the lung tissue nitrite level (P Kaempferol pretreatment did not decrease bacterial load in septic mice. Mice pretreated with kaempferol followed by sepsis showed lesser infiltration of cells and more arranged alveolar structure in histopathological analysis. The study suggests that kaempferol showed attenuation in sepsis-induced acute lung injury in mice through suppression of oxidative stress, iNOS, and ICAM-1 pathways.

  7. Bradykinin-induced lung inflammation and bronchoconstriction: role in parainfluenze-3 virus-induced inflammation and airway hyperreactivity.

    Science.gov (United States)

    Broadley, Kenneth J; Blair, Alan E; Kidd, Emma J; Bugert, Joachim J; Ford, William R

    2010-12-01

    Inhaled bradykinin causes bronchoconstriction in asthmatic subjects but not nonasthmatics. To date, animal studies with inhaled bradykinin have been performed only in anesthetized guinea pigs and rats, where it causes bronchoconstriction through sensory nerve pathways. In the present study, airway function was recorded in conscious guinea pigs by whole-body plethysmography. Inhaled bradykinin (1 mM, 20 s) caused bronchoconstriction and influx of inflammatory cells to the lungs, but only when the enzymatic breakdown of bradykinin by angiotensin-converting enzyme and neutral endopeptidase was inhibited by captopril (1 mg/kg i.p.) and phosphoramidon (10 mM, 20-min inhalation), respectively. The bronchoconstriction and cell influx were antagonized by the B(2) kinin receptor antagonist 4-(S)-amino-5-(4-{4-[2,4-dichloro-3-(2,4-dimethyl-8-quinolyloxymethyl)phenylsulfonamido]-tetrahydro-2H-4-pyranylcarbonyl}piperazino)-5-oxopentyl](trimethyl)ammonium chloride hydrochloride (MEN16132) when given by inhalation (1 and 10 μM, 20 min) and are therefore mediated via B(2) kinin receptors. However, neither intraperitioneal MEN16132 nor the peptide B(2) antagonist icatibant, by inhalation, antagonized these bradykinin responses. Sensitization of guinea pigs with ovalbumin was not sufficient to induce airway hyperreactivity (AHR) to the bronchoconstriction by inhaled bradykinin. However, ovalbumin challenge of sensitized guinea pigs caused AHR to bradykinin and histamine. Infection of guinea pigs by nasal instillation of parainfluenza-3 virus produced AHR to inhaled histamine and lung influx of inflammatory cells. These responses were attenuated by the bradykinin B(2) receptor antagonist MEN16132 and H-(4-chloro)DPhe-2'(1-naphthylalanine)-(3-aminopropyl)guanidine (VA999024), an inhibitor of tissue kallikrein, the enzyme responsible for lung synthesis of bradykinin. These results suggest that bradykinin is involved in virus-induced inflammatory cell influx and AHR.

  8. Effects of a Natural Prolyl Oligopeptidase Inhibitor, Rosmarinic Acid, on Lipopolysaccharide-Induced Acute Lung Injury in Mice

    Directory of Open Access Journals (Sweden)

    Miaomiao Wei

    2012-03-01

    Full Text Available Rosmarinic acid (RA, a polyphenolic phytochemical, is a natural prolyl oligopeptidase inhibitor. In the present study, we found that RA exerted potent anti-inflammatory effects in in vivo models of acute lung injury (ALI induced by lipopolysaccharide (LPS. Mice were pretreated with RA one hour before challenge with a dose of 0.5 mg/kg LPS. Twenty-four hours after LPS was given, bronchoalveolar lavage fluid (BALF was obtained to measure pro-inflammatory mediator and total cell counts. RA significantly decreased the production of LPS-induced TNF-a, IL-6, and IL-1β compare with the LPS group. When pretreated with RA (5, 10, or 20 mg/kg the lung wet-to-dry weight (W/D ratio of the lung tissue and the number of total cells, neutrophils and macrophages in the BALF were decreased significantly. Furthermore, RA may enhance oxidase dimutase (SOD activity during the inflammatory response to LPS-induced ALI. And we further demonstrated that RA exerts anti-inflammation effect in vivo models of ALI through suppresses ERK/MAPK signaling in a dose dependent manner. These studies have important implications for RA administration as a potential treatment for ALI.

  9. A unified approach for EIT imaging of regional overdistension and atelectasis in acute lung injury.

    Science.gov (United States)

    Gómez-Laberge, Camille; Arnold, John H; Wolf, Gerhard K

    2012-03-01

    Patients with acute lung injury or acute respiratory distress syndrome (ALI/ARDS) are vulnerable to ventilator-induced lung injury. Although this syndrome affects the lung heterogeneously, mechanical ventilation is not guided by regional indicators of potential lung injury. We used electrical impedance tomography (EIT) to estimate the extent of regional lung overdistension and atelectasis during mechanical ventilation. Techniques for tidal breath detection, lung identification, and regional compliance estimation were combined with the Graz consensus on EIT lung imaging (GREIT) algorithm. Nine ALI/ARDS patients were monitored during stepwise increases and decreases in airway pressure. Our method detected individual breaths with 96.0% sensitivity and 97.6% specificity. The duration and volume of tidal breaths erred on average by 0.2 s and 5%, respectively. Respiratory system compliance from EIT and ventilator measurements had a correlation coefficient of 0.80. Stepwise increases in pressure could reverse atelectasis in 17% of the lung. At the highest pressures, 73% of the lung became overdistended. During stepwise decreases in pressure, previously-atelectatic regions remained open at sub-baseline pressures. We recommend that the proposed approach be used in collaborative research of EIT-guided ventilation strategies for ALI/ARDS.

  10. Acute Pancreatitis as a Model to Predict Transition of Systemic Inflammation to Organ Failure in Trauma and Critical Illness

    Science.gov (United States)

    2017-10-01

    models ); • clinical interventions; • new business creation; and • other. Nothing to report. Nothing to report. Nothing to report. 17...AWARD NUMBER: W81XWH-14-1-0376 TITLE: Acute Pancreatitis as a Model to Predict Transition of Systemic Inflammation to Organ Failgure in Trauma...COVERED 22 Sep 2016 - 21 Sep 2017 4. TITLE AND SUBTITLE 5a. CONTRACT NUMBER Acute Pancreatitis as a Model to Predict Transition of Systemic

  11. Regulation of Lipolysis and Adipose Tissue Signaling during Acute Endotoxin-Induced Inflammation

    DEFF Research Database (Denmark)

    Rittig, Nikolaj; Bach, Ermina; Thomsen, Henrik Holm

    2016-01-01

    BACKGROUND: Lipolysis is accelerated during the acute phase of inflammation, a process being regulated by pro-inflammatory cytokines (e.g. TNF-α), stress-hormones, and insulin. The intracellular mechanisms remain elusive and we therefore measured pro- and anti-lipolytic signaling pathways...... to measure palmitate rate of appearance (Rapalmitate) and indirect calorimetry was performed to measure energy expenditures and lipid oxidation rates. A subcutaneous abdominal fat biopsy was obtained during both interventions and subjected to western blotting and qPCR quantifications. RESULTS: LPS caused...... a mean increase in serum free fatty acids (FFA) concentrations of 90% (CI-95%: 37-142, p = 0.005), a median increase in Rapalmitate of 117% (CI-95%: 77-166, penergy expenditure of 28% (CI-95%: 16-42, p...

  12. mTOR regulates metabolic adaptation of APCs in the lung and controls the outcome of allergic inflammation.

    Science.gov (United States)

    Sinclair, Charles; Bommakanti, Gayathri; Gardinassi, Luiz; Loebbermann, Jens; Johnson, Matthew Joseph; Hakimpour, Paul; Hagan, Thomas; Benitez, Lydia; Todor, Andrei; Machiah, Deepa; Oriss, Timothy; Ray, Anuradha; Bosinger, Steven; Ravindran, Rajesh; Li, Shuzhao; Pulendran, Bali

    2017-09-08

    Antigen-presenting cells (APCs) occupy diverse anatomical tissues, but their tissue-restricted homeostasis remains poorly understood. Here, working with mouse models of inflammation, we found that mechanistic target of rapamycin (mTOR)-dependent metabolic adaptation was required at discrete locations. mTOR was dispensable for dendritic cell (DC) homeostasis in secondary lymphoid tissues but necessary to regulate cellular metabolism and accumulation of CD103 + DCs and alveolar macrophages in lung. Moreover, while numbers of mTOR-deficient lung CD11b + DCs were not changed, they were metabolically reprogrammed to skew allergic inflammation from eosinophilic T helper cell 2 (T H 2) to neutrophilic T H 17 polarity. The mechanism for this change was independent of translational control but dependent on inflammatory DCs, which produced interleukin-23 and increased fatty acid oxidation. mTOR therefore mediates metabolic adaptation of APCs in distinct tissues, influencing the immunological character of allergic inflammation. Copyright © 2017 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.

  13. [The influnence of dachengqi tang on acute lung injury and intra abdominal hypertension in rats with acute pancreatitis].

    Science.gov (United States)

    Wan, Mei-Hua; Li, Juan; Tang, Wen-Fu; Gong, Han-Lin; Chen, Guang-Yuan; Xue, Ping; Zhao, Xian-Lin; Xia, Qing

    2011-09-01

    To test the hypothesis "lung and large intestine are interior exteriorly related" through investgating into the effect of Dacheng qi tang (DCQT) on intra abdominal hypertension (IAH) and acute lung injury (ALI) in rats with acute pancreatitis. Male SD rats were randomly divided into three groups with ten rats for each group: rats with sham-operations (SO); rats with acute necrosis pancreatitis (ANP); rats with ANP plus DCQT treatment. ANP was induced by retrograde infusion of 5% taurocholic acid into pancreatic duct. Two hours after operations, 10 mL/kg of normal saline was orally adminstered to the rats in both SO and ANP groups, whereas 10 mL/kg DCQT was adminstered to the rats in the treatment group. Aterial blood, pancreas and lung tissues were collected for biomarkers and histopathology 24 hours after operations. Intra-abdominal pressure and intestinal propulsion rate were also measured. RESULTS; DCQT treatment reduced intra-abdominal pressure and improved intestinal propulsion rate compared with those treated with saline (P 0.05). Only two rats in the ANP group died. DCQT can effectively relieve IAH and cure ALI at the same time in rats with acute pancreatitis. The result provides evidence to support the hypothesis "lung and large intestine are interior exteriorly related".

  14. Dexamethasone attenuates VEGF expression and inflammation but not barrier dysfunction in a murine model of ventilator-induced lung injury.

    Directory of Open Access Journals (Sweden)

    Maria A Hegeman

    Full Text Available BACKGROUND: Ventilator-induced lung injury (VILI is characterized by vascular leakage and inflammatory responses eventually leading to pulmonary dysfunction. Vascular endothelial growth factor (VEGF has been proposed to be involved in the pathogenesis of VILI. This study examines the inhibitory effect of dexamethasone on VEGF expression, inflammation and alveolar-capillary barrier dysfunction in an established murine model of VILI. METHODS: Healthy male C57Bl/6 mice were anesthetized, tracheotomized and mechanically ventilated for 5 hours with an inspiratory pressure of 10 cmH2O ("lower" tidal volumes of ∼7.5 ml/kg; LVT or 18 cmH2O ("higher" tidal volumes of ∼15 ml/kg; HVT. Dexamethasone was intravenously administered at the initiation of HVT-ventilation. Non-ventilated mice served as controls. Study endpoints included VEGF and inflammatory mediator expression in lung tissue, neutrophil and protein levels in bronchoalveolar lavage fluid, PaO2 to FiO2 ratios and lung wet to dry ratios. RESULTS: Particularly HVT-ventilation led to alveolar-capillary barrier dysfunction as reflected by reduced PaO2 to FiO2 ratios, elevated alveolar protein levels and increased lung wet to dry ratios. Moreover, VILI was associated with enhanced VEGF production, inflammatory mediator expression and neutrophil infiltration. Dexamethasone treatment inhibited VEGF and pro-inflammatory response in lungs of HVT-ventilated mice, without improving alveolar-capillary permeability, gas exchange and pulmonary edema formation. CONCLUSIONS: Dexamethasone treatment completely abolishes ventilator-induced VEGF expression and inflammation. However, dexamethasone does not protect against alveolar-capillary barrier dysfunction in an established murine model of VILI.

  15. Angiotensin-(1–7 inhibits inflammation and oxidative stress to relieve lung injury induced by chronic intermittent hypoxia in rats

    Directory of Open Access Journals (Sweden)

    W. Lu

    2016-01-01

    Full Text Available Obstructive sleep apnea is associated with inflammation and oxidative stress in lung tissues and can lead to metabolic abnormalities. We investigated the effects of angiotensin1–7 [Ang-(1–7] on lung injury in rats induced by chronic intermittent hypoxia (CIH. We randomly assigned 32 male Sprague-Dawley rats (180–200 g to normoxia control (NC, CIH-untreated (uCIH, Ang-(1–7-treated normoxia control (N-A, and Ang-(1–7-treated CIH (CIH-A groups. Oxidative stress biomarkers were measured in lung tissues, and expression of NADPH oxidase 4 (Nox4 and Nox subunits (p22phox, and p47phox was determined by Western blot and reverse transcription-polymerase chain reaction. Pulmonary pathological changes were more evident in the uCIH group than in the other groups. Enzyme-linked immunosorbent assays and immunohistochemical staining showed that inflammatory factor concentrations in serum and lung tissues in the uCIH group were significantly higher than those in the NC and N-A groups. Expression of inflammatory factors was significantly higher in the CIH-A group than in the NC and N-A groups, but was lower than in the uCIH group (P<0.01. Oxidative stress was markedly higher in the uCIH group than in the NC and N-A groups. Expression of Nox4 and its subunits was also increased in the uCIH group. These changes were attenuated upon Ang-(1–7 treatment. In summary, treatment with Ang-(1-7 reversed signs of CIH-induced lung injury via inhibition of inflammation and oxidative stress.

  16. Identification of distinct genes associated with seawater aspiration-induced acute lung injury by gene expression profile analysis

    Science.gov (United States)

    Liu, Wei; Pan, Lei; Zhang, Minlong; Bo, Liyan; Li, Congcong; Liu, Qingqing; Wang, Li; Jin, Faguang

    2016-01-01

    Seawater aspiration-induced acute lung injury (ALI) is a syndrome associated with a high mortality rate, which is characterized by severe hypoxemia, pulmonary edema and inflammation. The present study is the first, to the best of our knowledge, to analyze gene expression profiles from a rat model of seawater aspiration-induced ALI. Adult male Sprague-Dawley rats were instilled with seawater (4 ml/kg) in the seawater aspiration-induced ALI group (S group) or with distilled water (4 ml/kg) in the distilled water negative control group (D group). In the blank control group (C group) the rats' tracheae were exposed without instillation. Subsequently, lung samples were examined by histopathology; total protein concentration was detected in bronchoalveolar lavage fluid (BALF); lung wet/dry weight ratios were determined; and transcript expression was detected by gene sequencing analysis. The results demonstrated that histopathological alterations, pulmonary edema and total protein concentrations in BALF were increased in the S group compared with in the D group. Analysis of differential gene expression identified up and downregulated genes in the S group compared with in the D and C groups. A gene ontology analysis of the differential gene expression revealed enrichment of genes in the functional pathways associated with neutrophil chemotaxis, immune and defense responses, and cytokine activity. Kyoto Encyclopedia of Genes and Genomes analysis revealed that the cytokine-cytokine receptor interaction pathway was one of the most important pathways involved in seawater aspiration-induced ALI. In conclusion, activation of the cytokine-cytokine receptor interaction pathway may have an essential role in the progression of seawater aspiration-induced ALI, and the downregulation of tumor necrosis factor superfamily member 10 may enhance inflammation. Furthermore, IL-6 may be considered a biomarker in seawater aspiration-induced ALI. PMID:27509884

  17. CMV driven CD8(+) T-cell activation is associated with acute rejection in lung transplantation.

    Science.gov (United States)

    Roux, Antoine; Mourin, Gisèle; Fastenackels, Solène; Almeida, Jorge R; Iglesias, Maria Candela; Boyd, Anders; Gostick, Emma; Larsen, Martin; Price, David A; Sacre, Karim; Douek, Daniel C; Autran, Brigitte; Picard, Clément; Miranda, Sandra de; Sauce, Delphine; Stern, Marc; Appay, Victor

    2013-07-01

    Lung transplantation is the definitive treatment for terminal respiratory disease, but the associated mortality rate is high. Acute rejection of the transplanted lung is a key determinant of adverse prognosis. Furthermore, an epidemiological relationship has been established between the occurrence of acute lung rejection and cytomegalovirus infection. However, the reasons for this association remain unclear. Here, we performed a longitudinal characterization of CMV-specific T-cell responses and immune activation status in the peripheral blood and bronchoalveolar lavage fluid of forty-four lung transplant patients. Acute rejection was associated with high levels of cellular activation in the periphery, reflecting strong CMV-specific CD8(+) T-cell activity post-transplant. Peripheral and lung CMV-specific CD8(+) T-cell responses were very similar, and related to the presence of CMV in the transplanted organ. These findings support that activated CMV-specific CD8(+) T-cells in the lung may play a role in promoting acute rejection. Copyright © 2013 Elsevier Inc. All rights reserved.

  18. Diagnostic and Therapeutic Aspects of Acute Lung Injury: empirical studies

    NARCIS (Netherlands)

    R.A. Lachmann

    2006-01-01

    textabstractThe thesis emphases research on prognostic markers as well as on different approaches for treating lung injury. Thereby, the prevention and treatment of pneumonia and possible ventilation induced bacterial translocation from the lung into the blood represents the main focus of

  19. Ventilator induced lung injury (VILI) in acute respiratory distress ...

    African Journals Online (AJOL)

    The lung protective ventilation strategy- Low tidal volume ventilation has shown some reduction in mortality in patients with ARDS but mortality is still high in patient with severe ARDS secondary to Pneumocystis jiroveci pneumonia (PJP) despite of lung protective ventilation strategy. In patients with Severe ARDS due to PJP ...

  20. Acute Respiratory Distress Syndrome Caused by Leukemic Infiltration of the Lung

    Directory of Open Access Journals (Sweden)

    Yao-Kuang Wu

    2008-05-01

    Full Text Available Respiratory distress syndrome resulting from leukemic pulmonary infiltrates is seldom diagnosed antemortem. Two 60- and 80-year-old women presented with general malaise, progressive shortness of breath, and hyperleukocytosis, which progressed to acute respiratory distress syndrome (ARDS after admission. Acute leukemia with pulmonary infection was initially diagnosed, but subsequent examinations including open lung biopsy revealed leukemic pulmonary infiltrates without infection. In one case, the clinical condition and chest radiography improved initially after combination therapy with chemotherapy for leukemia and aggressive pulmonary support. However, new pulmonary infiltration on chest radiography and hypoxemia recurred, which was consistent with acute lysis pneumopathy. Despite aggressive treatment, both patients died due to rapidly deteriorating condition. Leukemic pulmonary involvement should be considered in acute leukemia patients with non-infectious diffusive lung infiltration, especially in acute leukemia with a high blast count.

  1. Dynamic expression of leukocyte innate immune genes in whole blood from horses with lipopolysaccharide-induced acute systemic inflammation

    DEFF Research Database (Denmark)

    Vinther, Anne Mette L.; Skovgaard, Kerstin; Heegaard, Peter M. H.

    2015-01-01

    Background: In horses, insights into the innate immune processes in acute systemic inflammation are limited even though these processes may be highly important for future diagnostic and therapeutic advances in high-mortality disease conditions as the systemic inflammatory response syndrome (SIRS......) and sepsis. Therefore, the aim of this study was to investigate the expression of 31 selected blood leukocyte immune genes in an equine model of acute systemic inflammation to identify significantly regulated genes and to describe their expression dynamics during a 24-h experimental period. Systemic...... were compared with baseline levels. Results: Systemic inflammation was confirmed by the presence of clinical and hematological changes which were consistent with SIRS. The clinical response to LPS was transient and brief as all horses except one showed unaltered general demeanor after 24 h. Twenty...

  2. Acute inflammation reduces kisspeptin immunoreactivity at the arcuate nucleus and decreases responsiveness to kisspeptin independently of its anorectic effects

    DEFF Research Database (Denmark)

    Castellano, J M; Bentsen, A H; Romero, M

    2010-01-01

    , was suggested as potential target for transmitting immune-mediated repression of the gonadotropic axis during acute inflammation, and yet key facets of such a phenomenon remain ill defined. Using lipopolysaccharide S (LPS)-treated male rats as model of inflammation, we document herein the pattern......-IR in the arcuate nucleus (ARC) that was not observed under conditions of metabolic stress induced by 48-h fasting. In addition, absolute responses to kisspeptin-10 (Kp-10), in terms of LH and testosterone secretion, were significantly attenuated in LPS-treated males that also displayed a decrease in food intake...... and body weight. Yet pair-fed males did not show similar alterations in LH and testosterone secretory responses to Kp-10, whose magnitude was preserved, if not augmented, during food restriction. In summary, our data document the impact of acute inflammation on kisspeptin content at the ARC as key center...

  3. Chikungunya Arthritis: Implications of Acute and Chronic Inflammation Mechanisms on Disease Management.

    Science.gov (United States)

    Zaid, Ali; Gérardin, Patrick; Taylor, Adam; Mostafavi, Helen; Malvy, Denis; Mahalingam, Suresh

    2018-04-01

    In the past decade, arboviruses-arthropod-borne viruses-have been the focus of public health institutions worldwide following a spate of devastating outbreaks. Chikungunya virus, an arbovirus that belongs to the alphavirus genus, is a reemerging arthritogenic virus that has caused explosive outbreaks since 2006, notably on Réunion Island, and more recently in the Caribbean, South America, India, and Southeast Asia. The severity of arthritic disease caused by chikungunya virus has prompted public health authorities in affected countries to develop specific guidelines to tackle this pathogen. Chikungunya virus disease manifests first as an acute stage of severe joint inflammation and febrile illness, which later progresses to a chronic stage, during which patients may experience debilitating and persisting articular pain for extended periods. This review aims to provide a broad perspective on current knowledge of chikungunya virus pathogenesis by identifying key clinical and experimental studies that have contributed to our understanding of chikungunya virus to date. In addition, the review explores the practical aspects of treatment and management of both acute and chronic chikungunya virus based on clinical experience during chikungunya virus outbreaks. Finally, recent findings on potential therapeutic solutions-from antiviral agents to immunomodulators-are reviewed to provide both viral immunologists and clinical rheumatologists with a balanced perspective on the nature of a reemerging arboviral disease of significant public health concern, and insight into future therapeutic approaches to better address the treatment and management of chikungunya virus. © 2017, American College of Rheumatology.

  4. Small RNA-seq during acute maximal exercise reveal RNAs involved in vascular inflammation and cardiometabolic health: brief report.

    Science.gov (United States)

    Shah, Ravi; Yeri, Ashish; Das, Avash; Courtright-Lim, Amanda; Ziegler, Olivia; Gervino, Ernest; Ocel, Jeffrey; Quintero-Pinzon, Pablo; Wooster, Luke; Bailey, Cole Shields; Tanriverdi, Kahraman; Beaulieu, Lea M; Freedman, Jane E; Ghiran, Ionita; Lewis, Gregory D; Van Keuren-Jensen, Kendall; Das, Saumya

    2017-12-01

    Exercise improves cardiometabolic and vascular function, although the mechanisms remain unclear. Our objective was to demonstrate the diversity of circulating extracellular RNA (ex-RNA) release during acute exercise in humans and its relevance to exercise-mediated benefits on vascular inflammation. We performed plasma small RNA sequencing in 26 individuals undergoing symptom-limited maximal treadmill exercise, with replication of our top candidate miRNA in a separate cohort of 59 individuals undergoing bicycle ergometry. We found changes in miRNAs and other ex-RNAs with exercise (e.g., Y RNAs and tRNAs) implicated in cardiovascular disease. In two independent cohorts of acute maximal exercise, we identified miR-181b-5p as a key ex-RNA increased in plasma after exercise, with validation in a separate cohort. In a mouse model of acute exercise, we found significant increases in miR-181b-5p expression in skeletal muscle after acute exercise in young (but not older) mice. Previous work revealed a strong role for miR-181b-5p in vascular inflammation in obesity, insulin resistance, sepsis, and cardiovascular disease. We conclude that circulating ex-RNAs were altered in plasma after acute exercise target pathways involved in inflammation, including miR-181b-5p. Further investigation into the role of known (e.g., miRNA) and novel (e.g., Y RNAs) RNAs is warranted to uncover new mechanisms of vascular inflammation on exercise-mediated benefits on health. NEW & NOTEWORTHY How exercise provides benefits to cardiometabolic health remains unclear. We performed RNA sequencing in plasma during exercise to identify the landscape of small noncoding circulating transcriptional changes. Our results suggest a link between inflammation and exercise, providing rich data on circulating noncoding RNAs for future studies by the scientific community. Copyright © 2017 the American Physiological Society.

  5. The effects of acute inflammation on cognitive functioning and emotional processing in humans: A systematic review of experimental studies.

    Science.gov (United States)

    Bollen, Jessica; Trick, Leanne; Llewellyn, David; Dickens, Chris

    2017-03-01

    The cognitive neuropsychological model of depression proposes that negative biases in the processing of emotionally salient information have a central role in the development and maintenance of depression. We have conducted a systematic review to determine whether acute experimental inflammation is associated with changes to cognitive and emotional processing that are thought to cause and maintain depression. We identified experimental studies in which healthy individuals were administered an acute inflammatory challenge (bacterial endotoxin/vaccination) and standardised tests of cognitive function were performed. Fourteen references were identified, reporting findings from 12 independent studies on 345 participants. Methodological quality was rated strong or moderate for 11 studies. Acute experimental inflammation was triggered using a variety of agents (including endotoxin from E. coli, S. typhi, S. abortus Equi and Hepatitis B vaccine) and cognition was assessed over hours to months, using cognitive tests of i) attention/executive functioning, ii) memory and iii) social/emotional processing. Studies found mixed evidence that acute experimental inflammation caused changes to attention/executive functioning (2 of 6 studies showed improvements in attention executive function compared to control), changes in memory (3 of 5 studies; improved reaction time: reduced memory for object proximity: poorer immediate and delayed memory) and changes to social/emotional processing (4 of 5 studies; reduced perception of emotions, increased avoidance of punishment/loss experiences, and increased social disconnectedness). Acute experimental inflammation causes negative biases in social and emotional processing that could explain observed associations between inflammation and depression. Copyright © 2017 Elsevier Inc. All rights reserved.

  6. Casticin, an active compound isolated from Vitex Fructus, ameliorates the cigarette smoke-induced acute lung inflammatory response in a murine model.

    Science.gov (United States)

    Lee, Hyeonhoon; Jung, Kyung-Hwa; Lee, Hangyul; Park, Soojin; Choi, Woosung; Bae, Hyunsu

    2015-10-01

    The aim of this study was to determine of the effect of casticin, as an anti-inflammatory agent, on an acute lung inflammation in vivo model established through exposure to cigarette smoke (CS). Casticin is a phytochemical from Vitex species such as Vitex rotundifolia and Vitex agnus-castus that was recently shown to exert an anti-inflammatory effect in vivo. To demonstrate the effects of casticin, C57BL/6 mice were whole-body exposed to mainstream CS or fresh air for two weeks and treated with 1, 2, and 10mg/kg casticin via an i.p. injection. Immune cell infiltrations and cytokine productions were assessed from bronchoalveolar lavage Fluid (BALF), and lung histological analysis was performed. Treatment with casticin was observed to significantly inhibit the numbers of total cells, neutrophils, macrophages, and lymphocytes and reduce the levels of proinflammatory cytokines and chemokines in the BALF. In addition, casticin significantly decreased the infiltration of peribronchial and perivascular inflammatory cells and the epithelium thickness. The results of this study indicate that casticin has significant effects on the lung inflammation induced by CS in a mouse model. According to these outcomes, casticin may have therapeutic potential in inflammatory lung diseases, such as chronic obstructive pulmonary disease (COPD). Copyright © 2015 Elsevier B.V. All rights reserved.

  7. Respiratory Therapy for Acute Lung Lesion, by Using Biphasic Positive Pressure Ventilation

    Directory of Open Access Journals (Sweden)

    Yu. V. Marchenkov

    2005-01-01

    Full Text Available Objective. To comparatively study the efficiency of respiratory support in patients with acute lung lesion, by applying BIPAP, SIMV, and aIPPV.Subjects. Twenty-six patients with acute lung lesion whose pattern included acute respiratory distress syndrome (n=16, pneumonia (и=6, and pneumonitis (n=4 were examined. The severity of disease was 18 to 21 APACHE II scale score.Results. The use of BIPAP leads to a better adaptation of a patient to respiratory support, to a reduction in the number of used myorelaxants and sedatives, and to improvement of gas exchange in the lung and diminishes the negative impact of artificial ventilation on hemodynamics. As compared with other types of assisted ventilation, BIPAP accelerates transfer from total respiratory support to spontaneous breathing.

  8. Design, synthesis, and structure–activity relationships of 2-benzylidene-1-indanone derivatives as anti-inflammatory agents for treatment of acute lung injury

    Directory of Open Access Journals (Sweden)

    Xiao S

    2018-04-01

    Full Text Available Siyang Xiao,1,* Wenxin Zhang,1,* Hongjin Chen,1 Bo Fang,1 Yinda Qiu,2 Xianxin Chen,1 Lingfeng Chen,1 Sheng Shu,1 Yunjie Zhao,1 Zhiguo Liu,1 Guang Liang1 1Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, China; 2College of Life and Environmental Science, Wenzhou University, Wenzhou, Zhejiang, China *These authors contributed equally to this work Purpose: The purpose of this study was to design and synthesize novel 2-benzylidene-1-indanone derivatives for treatment of acute lung injury. Methods: A series of 39 novel 2-benzylidene-indanone structural derivatives were synthesized and evaluated for anti-inflammatory activity in lipopolysaccharide (LPS-stimulated murine primary macrophages. Results: Most of the obtained compounds effectively inhibited the LPS-induced expression of IL-6 and TNF-α. The most active compound, 8f, was found to significantly reduce LPS-induced pulmonary inflammation, as reflected by reductions in the concentration of total protein, inflammatory cell count, as well as the lung wet/dry ratio in bronchoalveolar lavage (BAL fluid. Furthermore, 8f effectively inhibited mRNA expression of several inflammatory cytokines after LPS challenge in vitro and in vivo. Administration of 8f also blocked LPS-induced activation of the proinflammatory NF-κB/MAPK signaling pathway. Conclusion: The simple synthetic preparation and biological properties of these derivatives make these 2-benzylidene-indanone scaffolds promising new entities for the development of anti-inflammatory therapeutics for the treatment of acute lung injury. Keywords: indanone, acute lung injury, drug design, anti-inflammation, synthesis

  9. X-ray varieties of acute lung abscess course

    International Nuclear Information System (INIS)

    Churilyin, R.Yu.

    2009-01-01

    Chest of x-ray films of 52 patients with lung abscess aged of 18-78 were analyzed. Eight patients were performed radiography in 2 projections, liner and computed tomography. All patients underwent dynamic investigation.

  10. Vitamin D supplementation of initially vitamin D-deficient mice diminishes lung inflammation with limited effects on pulmonary epithelial integrity.

    Science.gov (United States)

    Gorman, Shelley; Buckley, Alysia G; Ling, Kak-Ming; Berry, Luke J; Fear, Vanessa S; Stick, Stephen M; Larcombe, Alexander N; Kicic, Anthony; Hart, Prue H

    2017-08-01

    In disease settings, vitamin D may be important for maintaining optimal lung epithelial integrity and suppressing inflammation, but less is known of its effects prior to disease onset. Female BALB/c dams were fed a vitamin D 3 -supplemented (2280 IU/kg, VitD + ) or nonsupplemented (0 IU/kg, VitD - ) diet from 3 weeks of age, and mated at 8 weeks of age. Male offspring were fed the same diet as their mother. Some offspring initially fed the VitD - diet were switched to a VitD + diet from 8 weeks of age (VitD -/+ ). At 12 weeks of age, signs of low-level inflammation were observed in the bronchoalveolar lavage fluid (BALF) of VitD - mice (more macrophages and neutrophils), which were suppressed by subsequent supplementation with vitamin D 3 There was no difference in the level of expression of the tight junction proteins occludin or claudin-1 in lung epithelial cells of VitD + mice compared to VitD - mice; however, claudin-1 levels were reduced when initially vitamin D-deficient mice were fed the vitamin D 3 -containing diet (VitD -/+ ). Reduced total IgM levels were detected in BALF and serum of VitD -/+ mice compared to VitD + mice. Lung mRNA levels of the vitamin D receptor (VDR) were greatest in VitD -/+ mice. Total IgG levels in BALF were greater in mice fed the vitamin D 3 -containing diet, which may be explained by increased activation of B cells in airway-draining lymph nodes. These findings suggest that supplementation of initially vitamin D-deficient mice with vitamin D 3 suppresses signs of lung inflammation but has limited effects on the epithelial integrity of the lungs. © 2017 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of The Physiological Society and the American Physiological Society.

  11. Long-term activation of TLR3 by Poly(I:C induces inflammation and impairs lung function in mice

    Directory of Open Access Journals (Sweden)

    Alexopoulou Lena

    2009-06-01

    Full Text Available Abstract Background The immune mechanisms associated with infection-induced disease exacerbations in asthma and COPD are not fully understood. Toll-like receptor (TLR 3 has an important role in recognition of double-stranded viral RNA, which leads to the production of various inflammatory mediators. Thus, an understanding of TLR3 activation should provide insight into the mechanisms underlying virus-induced exacerbations of pulmonary diseases. Methods TLR3 knock-out (KO mice and C57B6 (WT mice were intranasally administered repeated doses of the synthetic double stranded RNA analog poly(I:C. Results There was a significant increase in total cells, especially neutrophils, in BALF samples from poly(I:C-treated mice. In addition, IL-6, CXCL10, JE, KC, mGCSF, CCL3, CCL5, and TNFα were up regulated. Histological analyses of the lungs revealed a cellular infiltrate in the interstitium and epithelial cell hypertrophy in small bronchioles. Associated with the pro-inflammatory effects of poly(I:C, the mice exhibited significant impairment of lung function both at baseline and in response to methacholine challenge as measured by whole body plethysmography and an invasive measure of airway resistance. Importantly, TLR3 KO mice were protected from poly(I:C-induced changes in lung function at baseline, which correlated with milder inflammation in the lung, and significantly reduced epithelial cell hypertrophy. Conclusion These findings demonstrate that TLR3 activation by poly(I:C modulates the local inflammatory response in the lung and suggest a critical role of TLR3 activation in driving lung function impairment. Thus, TLR3 activation may be one mechanism through which viral infections contribute toward exacerbation of respiratory disease.

  12. Sildenafil attenuates pulmonary inflammation and fibrin deposition, mortality and right ventricular hypertrophy in neonatal hyperoxic lung injury

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    Boersma Hester

    2009-04-01

    Full Text Available Abstract Background Phosphodiesterase-5 inhibition with sildenafil has been used to treat severe pulmonary hypertension and bronchopulmonary dysplasia (BPD, a chronic lung disease in very preterm infants who were mechanically ventilated for respiratory distress syndrome. Methods Sildenafil treatment was investigated in 2 models of experimental BPD: a lethal neonatal model, in which rat pups were continuously exposed to hyperoxia and treated daily with sildenafil (50–150 mg/kg body weight/day; injected subcutaneously and a neonatal lung injury-recovery model in which rat pups were exposed to hyperoxia for 9 days, followed by 9 days of recovery in room air and started sildenafil treatment on day 6 of hyperoxia exposure. Parameters investigated include survival, histopathology, fibrin deposition, alveolar vascular leakage, right ventricular hypertrophy, and differential mRNA expression in lung and heart tissue. Results Prophylactic treatment with an optimal dose of sildenafil (2 × 50 mg/kg/day significantly increased lung cGMP levels, prolonged median survival, reduced fibrin deposition, total protein content in bronchoalveolar lavage fluid, inflammation and septum thickness. Treatment with sildenafil partially corrected the differential mRNA expression of amphiregulin, plasminogen activator inhibitor-1, fibroblast growth factor receptor-4 and vascular endothelial growth factor receptor-2 in the lung and of brain and c-type natriuretic peptides and the natriuretic peptide receptors NPR-A, -B, and -C in the right ventricle. In the lethal and injury-recovery model we demonstrated improved alveolarization and angiogenesis by attenuating mean linear intercept and arteriolar wall thickness and increasing pulmonary blood vessel density, and right ventricular hypertrophy (RVH. Conclusion Sildenafil treatment, started simultaneously with exposure to hyperoxia after birth, prolongs survival, increases pulmonary cGMP levels, reduces the pulmonary

  13. Pretreatment advanced lung cancer inflammation index (ALI) for predicting early progression in nivolumab-treated patients with advanced non-small cell lung cancer.

    Science.gov (United States)

    Shiroyama, Takayuki; Suzuki, Hidekazu; Tamiya, Motohiro; Tamiya, Akihiro; Tanaka, Ayako; Okamoto, Norio; Nakahama, Kenji; Taniguchi, Yoshihiko; Isa, Shun-Ichi; Inoue, Takako; Imamura, Fumio; Atagi, Shinji; Hirashima, Tomonori

    2018-01-01

    Programmed death-ligand 1 (PD-L1) expression status is inadequate for indicating nivolumab in patients with non-small cell lung cancer (NSCLC). Because the baseline advanced lung cancer inflammation index (ALI) is reportedly associated with patient outcomes, we investigated whether the pretreatment ALI is prognostic in NSCLC patients treated with nivolumab. We retrospectively reviewed the medical records of all patients treated with nivolumab for advanced NSCLC between December 2015 and May 2016 at three Japanese institutes. Multivariate logistic regression and Cox proportional hazards models were used to assess the impact of the pretreatment ALI (and other inflammation-related parameters) on progression-free survival (PFS) and early progression (i.e., within 8 weeks after starting nivolumab). A total of 201 patients were analyzed; their median age was 68 years (range, 27-87 years), 67% were men, and 24% had an Eastern Cooperative Oncology Group (ECOG) performance status of 2 or higher. An ECOG performance status ≥2, serum albumin ALI ALI ALI was found to be a significant independent predictor of early progression in patients with advanced NSCLC receiving nivolumab, and may help identify patients likely to benefit from continued nivolumab treatment in routine clinical practice. © 2017 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.

  14. Inhibition of c-Jun N-terminal Kinase Signaling Pathway Alleviates Lipopolysaccharide-induced Acute Respiratory Distress Syndrome in Rats

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    Jian-Bo Lai

    2016-01-01

    Conclusions: Inhibiting JNK alleviated LPS-induced acute lung inflammation and had no effects on pulmonary edema and fibrosis. JNK inhibitor might be a potential therapeutic medication in ARDS, in the context of reducing lung inflammatory.

  15. Nebulized anticoagulants limit pulmonary coagulopathy, but not inflammation, in a model of experimental lung injury

    NARCIS (Netherlands)

    Hofstra, Jorrit J; Vlaar, Alexander P; Cornet, Alexander D; Dixon, Barry; Roelofs, Joris J; Choi, Goda; van der Poll, Tom; Levi, Marcel; Schultz, Marcus J

    BACKGROUND: Pulmonary coagulopathy may contribute to an adverse outcome in lung injury. We assessed the effects of local anticoagulant therapy on bronchoalveolar and systemic haemostasis in a rat model of endotoxemia-induced lung injury. METHODS: Male Sprague-Dawley rats were intravenously

  16. Alda-1 Protects Against Acrolein-Induced Acute Lung Injury and Endothelial Barrier Dysfunction.

    Science.gov (United States)

    Lu, Qing; Mundy, Miles; Chambers, Eboni; Lange, Thilo; Newton, Julie; Borgas, Diana; Yao, Hongwei; Choudhary, Gaurav; Basak, Rajshekhar; Oldham, Mahogany; Rounds, Sharon

    2017-12-01

    Inhalation of acrolein, a highly reactive aldehyde, causes lung edema. The underlying mechanism is poorly understood and there is no effective treatment. In this study, we demonstrated that acrolein not only dose-dependently induced lung edema but also promoted LPS-induced acute lung injury. Importantly, acrolein-induced lung injury was prevented and rescued by Alda-1, an activator of mitochondrial aldehyde dehydrogenase 2. Acrolein also dose-dependently increased monolayer permeability, disrupted adherens junctions and focal adhesion complexes, and caused intercellular gap formation in primary cultured lung microvascular endothelial cells (LMVECs). These effects were attenuated by Alda-1 and the antioxidant N-acetylcysteine, but not by the NADPH inhibitor apocynin. Furthermore, acrolein inhibited AMP-activated protein kinase (AMPK) and increased mitochondrial reactive oxygen species levels in LMVECs-effects that were associated with impaired mitochondrial respiration. AMPK total protein levels were also reduced in lung tissue of mice and LMVECs exposed to acrolein. Activation of AMPK with 5-aminoimidazole-4-carboxamide-1-β-4-ribofuranoside blunted an acrolein-induced increase in endothelial monolayer permeability, but not mitochondrial oxidative stress or inhibition of mitochondrial respiration. Our results suggest that acrolein-induced mitochondrial dysfunction may not contribute to endothelial barrier dysfunction. We speculate that detoxification of acrolein by Alda-1 and activation of AMPK may be novel approaches to prevent and treat acrolein-associated acute lung injury, which may occur after smoke inhalation.

  17. Interleukin-33 from Monocytes Recruited to the Lung Contributes to House Dust Mite-Induced Airway Inflammation in a Mouse Model.

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    Hiroki Tashiro

    Full Text Available Interleukin-33 (IL-33 activates group 2 innate lymphoid cells (ILC2, resulting in T-helper-2 inflammation in bronchial asthma. Airway epithelial cells were reported as sources of IL-33 during apoptosis and necrosis. However, IL-33 is known to be from sources other than airway epithelial cells such as leukocytes, and the mechanisms of IL-33 production and release are not fully understood. The aim of this study was to clarify the role of IL-33 production by monocytes in airway inflammation.BALB/c mice were sensitized and challenged with a house dust mite (HDM preparation. Airway inflammation was assessed by quantifying inflammatory cells in bronchoalveolar lavage (BAL fluid, and IL-25, IL-33, and thymic stromal lymphopoietin (TSLP levels in lung. Immunohistochemistry for IL-33 in lung sections was also performed. Ly6c, CD11b, and CD11c expression was examined by flow cytometry. Clodronate liposomes were used in the HDM-airway inflammation model to deplete circulating monocytes.The IL-33, but not IL-25 or TSLP, level in lung homogenates was markedly increased in HDM mice compared to control mice. IL-33-positive cells in the lungs were identified using immunohistochemistry and were increased in areas surrounding bronchi and vasculature. Furthermore, IL-33 levels were increased in mononuclear cells derived from lungs of HDM mice compared to controls. The expression of Ly6c in mononuclear cells was significantly higher in HDM mice than in controls. Treatment with clodronate liposomes led to inhibition of not only inflammatory cells in BAL fluid, airway hyper reactivity and Th2 cytokines in lung, but also IL-33 in lung.IL-33 from monocytes recruited to the lung may contribute to the pathogenesis of HDM-induced airway inflammation.

  18. Lung recruitment maneuver effects on respiratory mechanics and extravascular lung water index in patients with acute respiratory distress syndrome.

    Science.gov (United States)

    Zhang, Jian-Guo; Chen, Xiao-Juan; Liu, Fen; Zeng, Zhen-Guo; Qian, Ke-Jian

    2011-01-01

    Animal experiments showed that recruitment maneuver (RM) and protective ventilation strategy of the lung could improve oxygenation and reduce extravascular lung water. This study was to investigate the effects of RM on respiratory mechanics and extravascular lung water index (EVLWI) in patients with acute respiratory distress syndrome (ARDS). Thirty patients with ARDS were randomized into a RM group and a non-RM group. In the RM group, after basic mechanical ventilation stabilized for 30 minutes, RM was performed and repeated once every 12 hours for 3 days. In the non-RM group, lung protective strategy was conducted without RM. Oxygenation index (PaO2/FiO2), peak inspiratory pressure (PIP), Plateau pressure (Pplat), static pulmonary compliance (Cst) and EVLWI of patients before treatment and at 12, 24, 48, 72 hours after the treatment were measured and compared between the groups. Hemodynamic changes were observed before and after RM. One-way ANOVA, Student's t test and Fisher's exact test were used to process the data. The levels of PaO2/FiO2 and Cst increased after treatment in the two groups, but they were higher in the RM group than in the non-RM group (P0.05). RM could reduce EVLWI, increase oxygenation and lung compliance. The effect of RM on hemodynamics was transient.

  19. Effects of High-Intensity Swimming on Lung Inflammation and Oxidative Stress in a Murine Model of DEP-Induced Injury.

    Science.gov (United States)

    Ávila, Leonardo C M; Bruggemann, Thayse R; Bobinski, Franciane; da Silva, Morgana Duarte; Oliveira, Regiane Carvalho; Martins, Daniel Fernandes; Mazzardo-Martins, Leidiane; Duarte, Marta Maria Medeiros Frescura; de Souza, Luiz Felipe; Dafre, Alcir; Vieira, Rodolfo de Paula; Santos, Adair Roberto Soares; Bonorino, Kelly Cattelan; Hizume Kunzler, Deborah de C

    2015-01-01

    Studies have reported that exposure to diesel exhaust particles (DEPs) induces lung inflammation and increases oxidative stress, and both effects are susceptible to changes via regular aerobic exercise in rehabilitation programs. However, the effects of exercise on lungs exposed to DEP after the cessation of exercise are not clear. Therefore, the aim of this study was to evaluate the effects of high-intensity swimming on lung inflammation and oxidative stress in mice exposed to DEP concomitantly and after exercise cessation. Male Swiss mice were divided into 4 groups: Control (n = 12), Swimming (30 min/day) (n = 8), DEP (3 mg/mL-10 μL/mouse) (n = 9) and DEP+Swimming (n = 8). The high-intensity swimming was characterized by an increase in blood lactate levels greater than 1 mmoL/L between 10th and 30th minutes of exercise. Twenty-four hours after the final exposure to DEP, the anesthetized mice were euthanized, and we counted the number of total and differential inflammatory cells in the bronchoalveolar fluid (BALF), measured the lung homogenate levels of IL-1β, TNF-α, IL-6, INF-ϫ, IL-10, and IL-1ra using ELISA, and measured the levels of glutathione, non-protein thiols (GSH-t and NPSH) and the antioxidant enzymes catalase and glutathione peroxidase (GPx) in the lung. Swimming sessions decreased the number of total cells (pswimming groups compared with the control groups, as did the CAT lung levels (p = 0.0001). Simultaneously, swimming resulted in an increase in the GSH-t and NPSH lung levels in the DEP group (p = 0.0001 and pswimming sessions decreased the lung inflammation and oxidative stress status during DEP-induced lung inflammation in mice.

  20. Iron supplementation at high altitudes induces inflammation and oxidative injury to lung tissues in rats

    Energy Technology Data Exchange (ETDEWEB)

    Salama, Samir A., E-mail: salama.3@buckeyemail.osu.edu [High Altitude Research Center, Taif University, Al-Haweiah, Taif 21974 (Saudi Arabia); Department of Biochemistry, Faculty of Pharmacy, Al-Azhar University, Cairo 11751 (Egypt); Department of Pharmacology and GTMR Unit, College of Clinical Pharmacy, Taif University, Al-Haweiah, Taif 21974 (Saudi Arabia); Omar, Hany A. [Department of Pharmacology, Faculty of Pharmacy, Beni-Suef University, Beni-Suef 62514 (Egypt); Maghrabi, Ibrahim A. [Department of Clinical Pharmacy, College of Clinical Pharmacy, Taif University, Al-Haweiah, Taif 21974 (Saudi Arabia); AlSaeed, Mohammed S. [Department of Surgery, College of Medicine, Taif University, Al-Haweiah, Taif 21974 (Saudi Arabia); EL-Tarras, Adel E. [High Altitude Research Center, Taif University, Al-Haweiah, Taif 21974 (Saudi Arabia)

    2014-01-01

    Exposure to high altitudes is associated with hypoxia and increased vulnerability to oxidative stress. Polycythemia (increased number of circulating erythrocytes) develops to compensate the high altitude associated hypoxia. Iron supplementation is, thus, recommended to meet the demand for the physiological polycythemia. Iron is a major player in redox reactions and may exacerbate the high altitudes-associated oxidative stress. The aim of this study was to explore the potential iron-induced oxidative lung tissue injury in rats at high altitudes (6000 ft above the sea level). Iron supplementation (2 mg elemental iron/kg, once daily for 15 days) induced histopathological changes to lung tissues that include severe congestion, dilatation of the blood vessels, emphysema in the air alveoli, and peribronchial inflammatory cell infiltration. The levels of pro-inflammatory cytokines (IL-1β, IL-6, and TNF-α), lipid peroxidation product and protein carbonyl content in lung tissues were significantly elevated. Moreover, the levels of reduced glutathione and total antioxidant capacity were significantly reduced. Co-administration of trolox, a water soluble vitamin E analog (25 mg/kg, once daily for the last 7 days of iron supplementation), alleviated the lung histological impairments, significantly decreased the pro-inflammatory cytokines, and restored the oxidative stress markers. Together, our findings indicate that iron supplementation at high altitudes induces lung tissue injury in rats. This injury could be mediated through excessive production of reactive oxygen species and induction of inflammatory responses. The study highlights the tissue injury induced by iron supplementation at high altitudes and suggests the co-administration of antioxidants such as trolox as protective measures. - Highlights: • Iron supplementation at high altitudes induced lung histological changes in rats. • Iron induced oxidative stress in lung tissues of rats at high altitudes. • Iron

  1. Iron supplementation at high altitudes induces inflammation and oxidative injury to lung tissues in rats

    International Nuclear Information System (INIS)

    Salama, Samir A.; Omar, Hany A.; Maghrabi, Ibrahim A.; AlSaeed, Mohammed S.; EL-Tarras, Adel E.

    2014-01-01

    Exposure to high altitudes is associated with hypoxia and increased vulnerability to oxidative stress. Polycythemia (increased number of circulating erythrocytes) develops to compensate the high altitude associated hypoxia. Iron supplementation is, thus, recommended to meet the demand for the physiological polycythemia. Iron is a major player in redox reactions and may exacerbate the high altitudes-associated oxidative stress. The aim of this study was to explore the potential iron-induced oxidative lung tissue injury in rats at high altitudes (6000 ft above the sea level). Iron supplementation (2 mg elemental iron/kg, once daily for 15 days) induced histopathological changes to lung tissues that include severe congestion, dilatation of the blood vessels, emphysema in the air alveoli, and peribronchial inflammatory cell infiltration. The levels of pro-inflammatory cytokines (IL-1β, IL-6, and TNF-α), lipid peroxidation product and protein carbonyl content in lung tissues were significantly elevated. Moreover, the levels of reduced glutathione and total antioxidant capacity were significantly reduced. Co-administration of trolox, a water soluble vitamin E analog (25 mg/kg, once daily for the last 7 days of iron supplementation), alleviated the lung histological impairments, significantly decreased the pro-inflammatory cytokines, and restored the oxidative stress markers. Together, our findings indicate that iron supplementation at high altitudes induces lung tissue injury in rats. This injury could be mediated through excessive production of reactive oxygen species and induction of inflammatory responses. The study highlights the tissue injury induced by iron supplementation at high altitudes and suggests the co-administration of antioxidants such as trolox as protective measures. - Highlights: • Iron supplementation at high altitudes induced lung histological changes in rats. • Iron induced oxidative stress in lung tissues of rats at high altitudes. • Iron

  2. Suscetibilidade genética na lesão pulmonar aguda e síndrome da angústia respiratória aguda Genetic susceptibility in acute lung injury and acute respiratory distress syndrome

    Directory of Open Access Journals (Sweden)

    Fernando Suparregui Dias

    2009-12-01

    Full Text Available A lesão pulmonar aguda e sua forma mais grave, a síndrome da angústia respiratória aguda, são o denominador comum de várias doenças que podem provocar uma inflamação exagerada nos pulmões. Nos últimos anos, essa variabilidade tem sido atribuída, pelo menos em parte, a fatores genéticos. O presente estudo tem por objetivos revisar o papel dos principais genes envolvidos na suscetibilidade, morbidade e mortalidade na lesão pulmonar aguda e na síndrome da angústia respiratória aguda. Através de pesquisa nas bases de dados PubMed e LiLACS, empregando-se os unitermos lesão pulmonar aguda, síndrome da angústia respiratória aguda e síndrome da angústia respiratória do adulto em combinação com polimorfismos genéticos, foram selecionados 69 artigos, dos quais 38 foram incluídos nesta revisão. Foram também considerados artigos relevantes extraídos das referências bibliográficas nos artigos selecionados das bases de dados. Os polimorfismos genéticos são variantes gênicas presentes em pelo menos 1% da população. A presença destas variantes genéticas pode influenciar a expressão de mediadores da resposta inflamatória, afetando diretamente a suscetibilidade à lesão pulmonar aguda, a intensidade da inflamação no parênquima pulmonar, a evolução e o desfecho destes pacientes. Estudos de associação com grandes populações e passíveis de reprodução permitirão de modo definitivo a inclusão da genômica no arsenal diagnóstico, prognóstico e terapêutico de pacientes com lesão pulmonar aguda/síndrome da angústia respiratória agudaAcute lung injury and its most severe presentation, acute respiratory distress syndrome, are a common denominator for several diseases which can lead to exaggerated lung inflammation. In the last years this variability has been ascribed, at least partially, to genetic issues. This study aims to review the role of the main genes involved in acute lung injury and acute respiratory

  3. Systemic inflammation, nutritional status and tumor immune microenvironment determine outcome of resected non-small cell lung cancer.

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    Marco Alifano

    Full Text Available BACKGROUND: Hypothesizing that nutritional status, systemic inflammation and tumoral immune microenvironment play a role as determinants of lung cancer evolution, the purpose of this study was to assess their respective impact on long-term survival in resected non-small cell lung cancers (NSCLC. METHODS AND FINDINGS: Clinical, pathological and laboratory data of 303 patients surgically treated for NSCLC were retrospectively analyzed. C-reactive protein (CRP and prealbumin levels were recorded, and tumoral infiltration by CD8+ lymphocytes and mature dendritic cells was assessed. We observed that factors related to nutritional status, systemic inflammation and tumoral immune microenvironment were correlated; significant correlations were also found between these factors and other relevant clinical-pathological parameters. With respect to outcome, at univariate analysis we found statistically significant associations between survival and the following variables: Karnofsky index, American Society of Anesthesiologists (ASA class, CRP levels, prealbumin concentrations, extent of resection, pathologic stage, pT and pN parameters, presence of vascular emboli, and tumoral infiltration by either CD8+ lymphocytes or mature dendritic cells and, among adenocarcinoma type, tumor grade (all p285 mg/L prealbumin levels and high (>96/mm2 CD8+ cell count had a 5-year survival rate of 80% [60.9-91.1] as compared to 18% [7.9-35.6] in patients with an opposite pattern of values. When stages I-II were considered alone, the prognostic significance of these factors was even more pronounced. CONCLUSIONS: Our data show that nutrition, systemic inflammation and tumoral immune contexture are prognostic determinants that, taken together, may predict outcome.

  4. Chemomics-Integrated Proteomics Analysis of Jie-Geng-Tang to Ameliorate Lipopolysaccharide-Induced Acute Lung Injury in Mice

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    Jin Tao

    2016-01-01

    Full Text Available Jie-Geng-Tang (JGT, a classic and famous traditional Chinese medicine (TCM prescription composed of Platycodon grandiflorum (Jacq. A. DC. (PG and Glycyrrhiza uralensis Fisch. (GU, is well known for “clearing heat and relieving toxicity” and its ability to “diffuse the lung and relieve sore throat.” However, the mechanism underlying its action remains unclear. In this study, potential anti-inflammatory ingredients were screened and submitted to PharmMapper and the KEGG bioinformatics website to predict the target proteins and related pathways, respectively. Differentially expressed candidate proteins from acute lung injury (ALI mice treated with JGT were identified by isobaric tags for relative and absolute quantitation (iTRAQ and LC Triple-TOF. Eleven potential anti-inflammatory ingredients were found, including the derivatives of glycyrrhizic acid, licorice-saponin, liquiritin, and platycodigenin. A total of sixty-seven differentially expressed proteins were confirmed after JGT treatment with four therapeutic functions, including immunoregulation, anti-inflammation, ribosome, and muscle contraction. PG and GU comediate PI3K/Akt signal pathway inhibition of NF-κB, VCAM1, and ICAM1 release which primarily act on PI3K, PDK1, AKT, and GSK3β. GU markedly inhibits the ERK/MAPK signaling pathways and primarily acts on LCK, RAS, and MEK. A network was constructed using bioactive ingredients, targets, and pathways to determine the mechanism underlying JGT treatment of ALI.

  5. Acute effects of thoracic irradiation on lung function and structure in awake sheep

    International Nuclear Information System (INIS)

    Loyd, J.E.; Bolds, J.M.; Sheller, J.R.; Duke, S.S.; Gillette, A.W.; Malcolm, A.W.; Meyrick, B.O.; Brigham, K.L.

    1987-01-01

    To investigate the acute physiological and structural changes after lung irradiation, the effects of whole-lung irradiation were investigated in fourteen sheep. Ten sheep were prepared with vascular and chronic lung lymph catheters, then a week later were given 1,500 rad whole-lung radiation and monitored for 2 days. Four sheep were given the same dose of radiation and were killed 4 h later for structural studies. Lung lymph flow increased at 3 h after radiation (14.6 +/- 2.1 ml/h) to twice the base-line flow rate (7.5 +/- 1.3), with a high lymph-to-plasma protein concentration. Pulmonary arterial pressure increased twofold from base line (18 +/- 1.6 cmH2O) at 2 h after radiation (33 +/- 3.8). Cardiac output and systemic pressure in the aorta did not change after lung radiation. Arterial O 2 tension decreased from 85 +/- 3 to 59 +/- 4 Torr at 1 day after radiation. Lymphocyte counts in both blood and lung lymph decreased to a nadir by 4 h and remained low. Thromboxane B2 concentration in lung lymph increased from base line (0.07 +/- 0.03 ng/ml) to peak at 3 h after radiation (8.2 +/- 3.7 ng/ml). The structural studies showed numerous damaged lymphocytes in the peripheral lung and bronchial associated lymphoid tissue. Quantitative analysis of the number of granulocytes in peripheral lung showed no significant change (base line 6.2 +/- 0.8 granulocytes/100 alveoli, 4 h = 10.3 +/- 2.3). The most striking change involved lung airways. The epithelial lining of the majority of airways from intrapulmonary bronchus to respiratory bronchiolus revealed damage with the appearance of intracellular and intercellular cell fragments and granules. This new large animal model of acute radiation lung injury can be used to monitor physiological, biochemical, and morphological changes after lung radiation. It is relevant to the investigation of diffuse oxidant lung injury as well as to radiobiology per se

  6. Risk factors and outcome of transfusion-related acute lung injury in the critically ill: A nested case-control study

    NARCIS (Netherlands)

    Vlaar, Alexander P. J.; Binnekade, Jan M.; Prins, David; van Stein, Danielle; Hofstra, Jorrit J.; Schultz, Marcus J.; Juffermans, Nicole P.

    2010-01-01

    Objectives: To determine the incidence, risk factors, and outcome of transfusion-related acute lung injury in a cohort of critically ill patients. Design: In a retrospective cohort study, patients with transfusion-related acute lung injury were identified using the consensus criteria of acute lung

  7. Risk factors and outcome of transfusion-related acute lung injury in the critically ill : A nested case-control study

    NARCIS (Netherlands)

    Vlaar, Alexander P. J.; Binnekade, Jan M.; Prins, David; van Stein, Danielle; Hofstra, Jorrit J.; Schultz, Marcus J.; Juffermans, Nicole P.

    Objectives: To determine the incidence, risk factors, and outcome of transfusion-related acute lung injury in a cohort of critically ill patients. Design: In a retrospective cohort study, patients with transfusion-related acute lung injury were identified using the consensus criteria of acute lung

  8. Lung-protective mechanical ventilation does not protect against acute kidney injury in patients without lung injury at onset of mechanical ventilation

    NARCIS (Netherlands)

    Cortjens, Bart; Royakkers, Annick A. N. M.; Determann, Rogier M.; van Suijlen, Jeroen D. E.; Kamphuis, Stephan S.; Foppen, Jannetje; de Boer, Anita; Wieland, Cathrien W.; Spronk, Peter E.; Schultz, Marcus J.; Bouman, Catherine S. C.

    2012-01-01

    Introduction: Preclinical and clinical studies suggest that mechanical ventilation contributes to the development of acute kidney injury (AKI), particularly in the setting of lung-injurious ventilator strategies. Objective: To determine whether ventilator settings in critically ill patients without

  9. Tetramethylpyrazine attenuates oleic acid-induced acute lung injury ...

    African Journals Online (AJOL)

    Jane

    2011-09-28

    Sep 28, 2011 ... exerts potent anti-inflammatory effects in this model. After 4, 8 and 12 ... measured by immunohistochemistry and Western blotting. ... endothelial and infiltrating inflammatory cells results in the ... Electrophoresis apparatus and electric switch slot were ... after tying off the right lung at the main stem bronchus.

  10. Adrenal-derived stress hormones modulate ozone-induced lung injury and inflammation

    Data.gov (United States)

    U.S. Environmental Protection Agency — This data set shows high throughput gene expression assessment using RNAseq to examine how ozone-induced transcriptional changes in the lung are influenced by...

  11. Donor dopamine treatment limits pulmonary oedema and inflammation in lung allografts subjected to prolonged hypothermia

    NARCIS (Netherlands)

    Hanusch, Christine; Nowak, Kai; Toerlitz, Patrizia; Gill, Ishar S.; Song, Hui; Rafat, Neysan; Brinkkoetter, Paul T.; Leuvenink, Henri G.; Van Ackern, Klaus C.; Yard, Benito A.; Beck, Grietje C.

    2008-01-01

    Background. Endothelial barrier dysfunction severely compromises organ function after reperfusion. Because dopamine pretreatment improves hypothermia mediated barrier dysfunction, we tested the hypothesis that dopamine treatment of lung allografts positively affects tissue damage associated with

  12. OPTICAL IMAGING OF LIPOPOLYSACCHARIDE-INDUCED OXIDATIVE STRESS IN ACUTE LUNG INJURY FROM HYPEROXIA AND SEPSIS

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    REYHANEH SEPEHR

    2013-07-01

    Full Text Available Reactive oxygen species (ROS have been implicated in the pathogenesis of many acute and chronic pulmonary disorders such as acute lung injury (ALI in adults and bronchopulmonary dysplasia (BPD in premature infants. Bacterial infection and oxygen toxicity, which result in pulmonary vascular endothelial injury, contribute to impaired vascular growth and alveolar simplification seen in the lungs of premature infants with BPD. Hyperoxia induces ALI, reduces cell proliferation, causes DNA damage and promotes cell death by causing mitochondrial dysfunction. The objective of this study was to use an optical imaging technique to evaluate the variations in fluorescence intensities of the auto-fluorescent mitochondrial metabolic coenzymes, NADH and FAD in four different groups of rats. The ratio of these fluorescence signals (NADH/FAD, referred to as NADH redox ratio (NADH RR has been used as an indicator of tissue metabolism in injuries. Here, we investigated whether the changes in metabolic state can be used as a marker of oxidative stress caused by hyperoxia and bacterial lipopolysaccharide (LPS exposure in neonatal rat lungs. We examined the tissue redox states of lungs from four groups of rat pups: normoxic (21% O2 pups, hyperoxic (90% O2 pups, pups treated with LPS (normoxic + LPS, and pups treated with LPS and hyperoxia (hyperoxic + LPS. Our results show that hyperoxia oxidized the respiratory chain as reflected by a ~ 31% decrease in lung tissue NADH RR as compared to that for normoxic lungs. LPS treatment alone or with hyperoxia had no significant effect on lung tissue NADH RR as compared to that for normoxic or hyperoxic lungs, respectively. Thus, NADH RR serves as a quantitative marker of oxidative stress level in lung injury caused by two clinically important conditions: hyperoxia and LPS exposure.

  13. Alcohol Exposure Alters Mouse Lung Inflammation in Response to Inhaled Dust

    Directory of Open Access Journals (Sweden)

    Jill A. Poole

    2012-07-01

    Full Text Available Alcohol exposure is associated with increased lung infections and decreased mucociliary clearance. Occupational workers exposed to dusts from concentrated animal feeding operations (CAFOs are at risk for developing chronic inflammatory lung diseases. Agricultural worker co-exposure to alcohol and organic dust has been established, although little research has been conducted on the combination effects of alcohol and organic dusts on the lung. Previously, we have shown in a mouse model that exposure to hog dust extract (HDE collected from a CAFO results in the activation of protein kinase C (PKC, elevated lavage fluid cytokines/chemokines including interleukin-6 (IL-6, and the development of significant lung pathology. Because alcohol blocks airway epithelial cell release of IL-6 in vitro, we hypothesized that alcohol exposure would alter mouse lung inflammatory responses to HDE. To test this hypothesis, C57BL/6 mice were fed 20% alcohol or water ad libitum for 6 weeks and treated with 12.5% HDE by intranasal inhalation method daily during the final three weeks. Bronchoalveolar lavage fluid (BALF, tracheas and lungs were collected. HDE stimulated a 2–4 fold increase in lung and tracheal PKCε (epsilon activity in mice, but no such increase in PKCε activity was observed in dust-exposed mice fed alcohol. Similarly, alcohol-fed mice demonstrated significantly less IL-6 in lung lavage in response to dust than that observed in control mice instilled with HDE. TNFα levels were also inhibited in the alcohol and HDE-exposed mouse lung tissue as compared to the HDE only exposed group. HDE-induced lung inflammatory aggregates clearly present in the tissue from HDE only exposed animals were not visually detectable in the HDE/alcohol co-exposure group. Statistically significant weight reductions and 20% mortality were also observed in the mice co-exposed to HDE and alcohol. These data suggest that alcohol exposure depresses the ability

  14. Lack of evidence of CD40 ligand involvement in transfusion-related acute lung injury

    NARCIS (Netherlands)

    Tuinman, P. R.; Gerards, M. C.; Jongsma, G.; Vlaar, A. P.; Boon, L.; Juffermans, N. P.

    2011-01-01

    Activated platelets have been implicated in playing a major role in transfusion-related acute lung injury (TRALI), as platelets can trigger neutrophils, resulting in vascular damage. We hypothesized that binding of platelet CD40 ligand (CD40L) to endothelial CD40 is essential in the onset of TRALI.

  15. Acute phase proteins: Biomarkers of infection and inflammation in veterinary medicine.

    Science.gov (United States)

    Eckersall, P D; Bell, R

    2010-07-01

    Acute phase proteins (APPs) have been used as biomarkers of inflammation, infection and trauma for decades in human medicine but have been relatively under-utilised in the context of veterinary medicine. However, significant progress has been made in the detection, measurement and application of APPs as biomarkers in both companion and farm animal medicine over recent years. In the dog, C-reactive protein, haptoglobin and serum amyloid A have been identified as significant diagnostic 'markers' of steroid-responsive meningitis-arteritis, while in cats and cattle haptoglobin and alpha(1) acid glycoprotein and haptoglobin and serum amyloid A have proved valuable biomarkers of disease, respectively. In dairy cattle, haptoglobin and a mammary-associated serum amyloid A3 isoform, produced by the inflamed mammary gland during episodes of mastitis, have great potential as biomarkers of this economically important disease. Understanding the use of APP as biomarkers of inflammatory conditions of domestic animals has expanded significantly over recent years, and, with the insights provided by ongoing research, it is likely that these compounds will be increasingly used in the future in the diagnosis and prognosis of both companion and farm animal disease. Copyright 2010 Elsevier Ltd. All rights reserved.

  16. Cross-sectional detection of acute HIV infection: timing of transmission, inflammation and antiretroviral therapy.

    Directory of Open Access Journals (Sweden)

    Cynthia Gay

    Full Text Available BACKGROUND: Acute HIV infection (AHI is a critical phase of infection when irreparable damage to the immune system occurs and subjects are very infectious. We studied subjects with AHI prospectively to develop better treatment and public health interventions. METHODS: Cross-sectional screening was employed to detect HIV RNA positive, antibody negative subjects. Date of HIV acquisition was estimated from clinical history and correlated with sequence diversity assessed by single genome amplification (SGA. Twenty-two cytokines/chemokines were measured from enrollment through week 24. RESULTS: Thirty-seven AHI subjects were studied. In 7 participants with limited exposure windows, the median exposure to HIV occurred 14 days before symptom onset. Lack of viral sequence diversification confirmed the short duration of infection. Transmission dates estimated by SGA/sequencing using molecular clock models correlated with transmission dates estimated by symptom onset in individuals infected with single HIV variants (mean of 28 versus 33 days. Only 10 of 22 cytokines/chemokines were significantly elevated among AHI participants at enrollment compared to uninfected controls, and only 4 participants remained seronegative at enrollment. DISCUSSION: The results emphasize the difficulty in recruiting subjects early in AHI. Viral sequence diversity proved accurate in estimating time of infection. Regardless of aggressive screening, peak viremia and inflammation occurred before enrollment and potential intervention. Given the personal and public health importance, improved AHI detection is urgently needed.

  17. Drug fever and acute inflammation from hypercytokinemia triggered by dipeptidyl peptidase-4 inhibitor vildagliptin.

    Science.gov (United States)

    Anno, Takatoshi; Kaneto, Hideaki; Kawasaki, Fumiko; Shigemoto, Ryo; Aoyama, Yumi; Kaku, Kohei; Okimoto, Niro

    2018-04-01

    A 69-year-old man started taking the dipeptidyl peptidase-4 inhibitor, vildagliptin. One week later, C-reactive protein and plasma immunoglobulin E levels were markedly elevated, and the vildagliptin was stopped. After the patient's laboratory findings were normalized, we decided to restart vildagliptin with the patient's agreement. The next day, he had a high fever, and C-reactive protein and procalcitonin levels were elevated. Although we failed to find a focus of infection, we started antibiotics therapy. Two days later, the high fever had improved, and the C-reactive protein level had decreased. A drug lymphocyte stimulation test showed a positive result for vildagliptin. We examined various kinds of cytokine and infection markers just before and after the treatment with vildagliptin. Finally, we diagnosed the patient with vildagliptin-induced drug fever, probably based on the increase of various inflammatory cytokine levels and the response to this. Taken together, we should be aware of the possibility of vildagliptin inducing drug fever and/or acute inflammation. © 2018 The Authors. Journal of Diabetes Investigation published by Asian Association for the Study of Diabetes (AASD) and John Wiley & Sons Australia, Ltd.

  18. Microbiota alterations in acute and chronic gastrointestinal inflammation of cats and dogs

    Science.gov (United States)

    Honneffer, Julia B; Minamoto, Yasushi; Suchodolski, Jan S

    2014-01-01

    The intestinal microbiota is the collection of the living microorganisms (bacteria, fungi, protozoa, and viruses) inhabiting the gastrointestinal tract. Novel bacterial identification approaches have revealed that the gastrointestinal microbiota of dogs and cats is, similarly to humans, a highly complex ecosystem. Studies in dogs and cats have demonstrated that acute and chronic gastrointestinal diseases, including inflammatory bowel disease (IBD), are associated with alterations in the small intestinal and fecal microbial communities. Of interest is that these alterations are generally similar to the dysbiosis observed in humans with IBD or animal models of intestinal inflammation, suggesting that microbial responses to inflammatory conditions of the gut are conserved across mammalian host types. Studies have also revealed possible underlying susceptibilities in the innate immune system of dogs and cats with IBD, which further demonstrate the intricate relationship between gut microbiota and host health. Commonly identified microbiome changes in IBD are decreases in bacterial groups within the phyla Firmicutes and Bacteroidetes, and increases within Proteobacteia. Furthermore, a reduction in the diversity of Clostridium clusters XIVa and IV (i.e., Lachnospiraceae and Clostridium coccoides subgroups) are associated with IBD, suggesting that these bacterial groups may play an important role in maintenance of gastrointestinal health. Future studies are warranted to evaluate the functional changes associated with intestinal dysbiosis in dogs and cats. PMID:25469017

  19. Biomarkers for Pulmonary Inflammation and Fibrosis and Lung Ventilation Function in Chinese Occupational Refractory Ceramic Fibers-Exposed Workers.

    Science.gov (United States)

    Zhu, Xiaojun; Gu, Yishuo; Ma, Wenjun; Gao, Panjun; Liu, Mengxuan; Xiao, Pei; Wang, Hongfei; Chen, Juan; Li, Tao

    2017-12-27

    Refractory ceramic fibers (RCFs) can cause adverse health effects on workers' respiratory system, yet no proper biomarkers have been used to detect early pulmonary injury of RCFs-exposed workers. This study assessed the levels of two biomarkers that are related to respiratory injury in RCFs-exposed workers, and explored their relations with lung function. The exposure levels of total dust and respirable fibers were measured simultaneously in RCFs factories. The levels of TGF-β1 and ceruloplasmin (CP) increased with the RCFs exposure level ( p relations were found between the concentrations of CP and FVC (B = -0.423, p = 0.025), or FEV₁ (B = -0.494, p = 0.014). The concentration of TGF-β1 (B = 0.103, p = 0.001) and CP (B = 8.027, p = 0.007) were associated with respirable fiber exposure level. Occupational exposure to RCFs can impair lung ventilation function and may have the potential to cause pulmonary inflammation and fibrosis. TGF-β1 and CP might be used as sensitive and noninvasive biomarkers to detect lung injury in occupational RCFs-exposed workers. Respirable fiber concentration can better reflect occupational RCFs exposure and related respiratory injuries.

  20. Pediatric acute respiratory distress syndrome: definition, incidence, and epidemiology: proceedings from the Pediatric Acute Lung Injury Consensus Conference.

    Science.gov (United States)

    Khemani, Robinder G; Smith, Lincoln S; Zimmerman, Jerry J; Erickson, Simon

    2015-06-01

    Although there are similarities in the pathophysiology of acute respiratory distress syndrome in adults and children, pediatric-specific practice patterns, comorbidities, and differences in outcome necessitate a pediatric-specific definition. We sought to create such a definition. A subgroup of pediatric acute respiratory distress syndrome investigators who drafted a pediatric-specific definition of acute respiratory distress syndrome based on consensus opinion and supported by detailed literature review tested elements of the definition with patient data from previously published investigations. International PICUs. Children enrolled in published investigations of pediatric acute respiratory distress syndrome. None. Several aspects of the proposed pediatric acute respiratory distress syndrome definition align with the Berlin Definition of acute respiratory distress syndrome in adults: timing of acute respiratory distress syndrome after a known risk factor, the potential for acute respiratory distress syndrome to coexist with left ventricular dysfunction, and the importance of identifying a group of patients at risk to develop acute respiratory distress syndrome. There are insufficient data to support any specific age for "adult" acute respiratory distress syndrome compared with "pediatric" acute respiratory distress syndrome. However, children with perinatal-related respiratory failure should be excluded from the definition of pediatric acute respiratory distress syndrome. Larger departures from the Berlin Definition surround 1) simplification of chest imaging criteria to eliminate bilateral infiltrates; 2) use of pulse oximetry-based criteria when PaO2 is unavailable; 3) inclusion of oxygenation index and oxygen saturation index instead of PaO2/FIO2 ratio with a minimum positive end-expiratory pressure level for invasively ventilated patients; 4) and specific inclusion of children with preexisting chronic lung disease or cyanotic congenital heart disease. This

  1. The Epidemiology of Transfusion-related Acute Lung Injury Varies According to the Applied Definition of Lung Injury Onset Time.

    Science.gov (United States)

    Vande Vusse, Lisa K; Caldwell, Ellen; Tran, Edward; Hogl, Laurie; Dinwiddie, Steven; López, José A; Maier, Ronald V; Watkins, Timothy R

    2015-09-01

    Research that applies an unreliable definition for transfusion-related acute lung injury (TRALI) may draw false conclusions about its risk factors and biology. The effectiveness of preventive strategies may decrease as a consequence. However, the reliability of the consensus TRALI definition is unknown. To prospectively study the effect of applying two plausible definitions of acute respiratory distress syndrome onset time on TRALI epidemiology. We studied 316 adults admitted to the intensive care unit and transfused red blood cells within 24 hours of blunt trauma. We identified patients with acute respiratory distress syndrome, and defined acute respiratory distress syndrome onset time two ways: (1) the time at which the first radiographic or oxygenation criterion was met, and (2) the time both criteria were met. We categorized two corresponding groups of TRALI cases transfused in the 6 hours before acute respiratory distress syndrome onset. We used Cohen's kappa to measure agreement between the TRALI cases and implicated blood components identified by the two acute respiratory distress syndrome onset time definitions. In a nested case-control study, we examined potential risk factors for each group of TRALI cases, including demographics, injury severity, and characteristics of blood components transfused in the 6 hours before acute respiratory distress syndrome onset. Forty-two of 113 patients with acute respiratory distress syndrome were TRALI cases per the first acute respiratory distress syndrome onset time definition and 63 per the second definition. There was slight agreement between the two groups of TRALI cases (κ = 0.16; 95% confidence interval, -0.01 to 0.33) and between the implicated blood components (κ = 0.15, 95% confidence interval, 0.11-0.20). Age, Injury Severity Score, high plasma-volume components, and transfused plasma volume were risk factors for TRALI when applying the second acute respiratory distress syndrome onset time definition

  2. The protective effects of sildenafil in acute lung injury in a rat model of severe scald burn: A biochemical and histopathological study.

    Science.gov (United States)

    Gokakin, Ali Kagan; Deveci, Koksal; Kurt, Atilla; Karakus, Boran Cihat; Duger, Cevdet; Tuzcu, Mehmet; Topcu, Omer

    2013-09-01

    Severe burn induces biochemical mediators such as reactive oxygen species that leads to lipid peroxidation which may have a key role in formation of acute lung injury (ALI). Sildenafil is a selective and potent inhibitor of cyclic guanosine monophosphate specific phosphodiesterase-5. Sildenafil preserves alveolar growth, angiogenesis, reduces inflammation and airway reactivity. The purpose of the present study was to evaluate the effects of different dosages of sildenafil in ALI due to severe scald burn in rats. Twenty-four rats were subjected to 30% total body surface area severe scald injury and were randomly divided into three equal groups as follow: control, 10 and 20mg/kg sildenafil groups. Levels of malondialdehyde (MDA), activities of glutathione peroxidase (Gpx), catalase (Cat), total oxidative stress (TOS), and total antioxidative capacity (TAC) were measured in both tissues and serums. Oxidative stress index (OSI) was calculated. A semi-quantitative scoring system was used for the evaluation of histopatological findings. Sildenafil increased Gpx, Cat, TAC and decreased MDA, TOS and OSI. Sildenafil decreased inflammation scores in lungs. Our results reveal that sildenafil is protective against scald burn related ALI by decreasing oxidative stress and inflammation and the dosage of 10mg/kg could be apparently better than 20mg/kg. Copyright © 2013 Elsevier Ltd and ISBI. All rights reserved.

  3. Adaptive Support Ventilation May Deliver Unwanted Respiratory Rate-Tidal Volume Combinations in Patients with Acute Lung Injury Ventilated According to an Open Lung Concept

    NARCIS (Netherlands)

    Dongelmans, Dave A.; Paulus, Frederique; Veelo, Denise P.; Binnekade, Jan M.; Vroom, Margreeth B.; Schultz, Marcus J.

    2011-01-01

    Background: With adaptive support ventilation, respiratory rate and tidal volume (V(T)) are a function of the Otis least work of breathing formula. We hypothesized that adaptive support ventilation in an open lung ventilator strategy would deliver higher V(T)s to patients with acute lung injury.

  4. The cardiopulmonary continuum systemic inflammation as 'common soil' of heart and lung disease

    NARCIS (Netherlands)

    Ukena, Christian; Mahfoud, Felix; Kindermann, Michael; Kindermann, Ingrid; Bals, Robert; Voors, Adriaan A.; van Veldhuisen, Dirk J.; Boehm, Michael

    2010-01-01

    Coronary artery disease (CAD), chronic heart failure (CHF) or chronic obstructive pulmonary disease (COPD) occur commonly in the presence of each other and are associated with similar systemic inflammatory reactions. Inflammation plays a central role in the pathogenesis of these diseases. C-reactive

  5. Protective Effects of the Ethanol Extract of Viola tianshanica Maxim against Acute Lung Injury Induced by Lipopolysaccharides in Mice.

    Science.gov (United States)

    Wang, Xue; Yang, Qiao-Li; Shi, Yu-Zhu; Hou, Bi-Yu; Yang, Sheng-Qian; Huang, Hua; Zhang, Li; Du, Guan-Hua

    2017-09-28

    Viola tianshanica Maxim, belonging to the Violaceae plant family, is traditionally used in Uighur medicine for treating pneumonia, headache, and fever. There is, however, a lack of basic understanding of its pharmacological activities. This study was designed to observe the effects of the ethanol extract (TSM) from Viola tianshanica Maxim on the inflammation response in acute lung injury (ALI) induced by LPS and the possible underlying mechanisms. We found that TSM (200 and 500 mg/kg) significantly decreased inflammatory cytokine production and the number of inflammatory cells, including macrophages and neutrophils, in bronchoalveolar lavage fluid. TSM also markedly inhibited the lung wet-to-dry ratio and alleviated pathological changes in lung tissues. In vitro, after TSM (12.5-100 μg/ml) treatment to RAW 264.7 cells for 1 h, LPS (1 μg/ml) was added and the cells were further incubated for 24 h. TSM dose-dependently inhibited the levels of proinflammatory cytokines, such as NO, PGE2, TNF-α, IL-6, and IL-1β, and remarkably decreased the protein and mRNA expression of TNF-α and IL-6 in LPS-stimulated RAW 264.7 cells. TSM also suppressed protein expression of p-IκBa and p-ERK1/2 and blocked nuclear translocation of NF-κB p65. The results indicate that TSM exerts anti-inflammatory effects related with inhibition on NF-κB and MAPK (p-ERK1/2) signaling pathways. In conclusion, our data demonstrate that TSM might be a potential agent for the treatment of ALI.

  6. Splenectomy exacerbates lung injury after ischemic acute kidney injury in mice

    Science.gov (United States)

    Andrés-Hernando, Ana; Altmann, Christopher; Ahuja, Nilesh; Lanaspa, Miguel A.; Nemenoff, Raphael; He, Zhibin; Ishimoto, Takuji; Simpson, Pete A.; Weiser-Evans, Mary C.; Bacalja, Jasna

    2011-01-01

    Patients with acute kidney injury (AKI) have increased serum proinflammatory cytokines and an increased occurrence of respiratory complications. The aim of the present study was to examine the effect of renal and extrarenal cytokine production on AKI-mediated lung injury in mice. C57Bl/6 mice underwent sham surgery, splenectomy, ischemic AKI, or ischemic AKI with splenectomy and kidney, spleen, and liver cytokine mRNA, serum cytokines, and lung injury were examined. The proinflammatory cytokines IL-6, CXCL1, IL-1β, and TNF-α were increased in the kidney, spleen, and liver within 6 h of ischemic AKI. Since splenic proinflammatory cytokines were increased, we hypothesized that splenectomy would protect against AKI-mediated lung injury. On the contrary, splenectomy with AKI resulted in increased serum IL-6 and worse lung injury as judged by increased lung capillary leak, higher lung myeloperoxidase activity, and higher lung CXCL1 vs. AKI alone. Splenectomy itself was not associated with increased serum IL-6 or lung injury vs. sham. To investigate the mechanism of the increased proinflammatory response, splenic production of the anti-inflammatory cytokine IL-10 was determined and was markedly upregulated. To confirm that splenic IL-10 downregulates the proinflammatory response of AKI, IL-10 was administered to splenectomized mice with AKI, which reduced serum IL-6 and improved lung injury. Our data demonstrate that AKI in the absence of a counter anti-inflammatory response by splenic IL-10 production results in an exuberant proinflammatory response and lung injury. PMID:21677145

  7. Variability in usual care mechanical ventilation for pediatric acute lung injury: the potential benefit of a lung protective computer protocol.

    Science.gov (United States)

    Khemani, Robinder G; Sward, Katherine; Morris, Alan; Dean, J Michael; Newth, Christopher J L

    2011-11-01

    Although pediatric intensivists claim to embrace lung protective ventilation for acute lung injury (ALI), ventilator management is variable. We describe ventilator changes clinicians made for children with hypoxemic respiratory failure, and evaluate the potential acceptability of a pediatric ventilation protocol. This was a retrospective cohort study performed in a tertiary care pediatric intensive care unit (PICU). The study period was from January 2000 to July 2007. We included mechanically ventilated children with PaO(2)/FiO(2) (P/F) ratio less than 300. We assessed variability in ventilator management by evaluating actual changes to ventilator settings after an arterial blood gas (ABG). We evaluated the potential acceptability of a pediatric mechanical ventilation protocol we adapted from National Institutes of Health/National Heart, Lung, and Blood Institute (NIH/NHLBI) Acute Respiratory Distress Syndrome (ARDS) Network protocols by comparing actual practice changes in ventilator settings to changes that would have been recommended by the protocol. A total of 2,719 ABGs from 402 patients were associated with 6,017 ventilator settings. Clinicians infrequently decreased FiO(2), even when the PaO(2) was high (>68 mmHg). The protocol would have recommended more positive end expiratory pressure (PEEP) than was used in actual practice 42% of the time in the mid PaO(2) range (55-68 mmHg) and 67% of the time in the low PaO(2) range (ventilator rate (VR) when the protocol would have recommended a change, even when the pH was greater than 7.45 with PIP at least 35 cmH(2)O. There may be lost opportunities to minimize potentially injurious ventilator settings for children with ALI. A reproducible pediatric mechanical ventilation protocol could prompt clinicians to make ventilator changes that are consistent with lung protective ventilation.

  8. Effect of protective lung ventilation strategy combined with lung recruitment maneuver in patients with acute respiratory distress syndrome (ARDS

    Directory of Open Access Journals (Sweden)

    Sheng Yu

    2017-01-01

    Full Text Available Objective: To evaluate the efficacy and safety of protective lung ventilation strategy combined with lung recruitment maneuver (RM in the treatment patients with acute respiratory distress syndrome (ARDS.Methods: Totally 74 patients with ARDS admitted to the Department of Intensive Care Unit, Changshu Second People's Hospital in Jiangsu Province between September 2010 and June 2013 were selected and randomly divided into lung recruitment group and non-lung recruitment group, and the initial ventilation solution for both groups was synchronized intermittent mandatory ventilation (SIMV. For RM, SIMV mode (pressure control and pressure support was adopted. Positive end expiratory pressure (PEEP was increased by 5 cm H2O every time and maintained for 40-50 s before entering the next increasing period, and the peak airway pressure was kept below 45 cm H2O. After PEEP reached the maximum value, it was gradually reduced by 5 cm H2O every time and finally maintained at 15 cm H2O for 10 min.Results: A total of 74 patients with mean age of (49.0±18.6 years old were enrolled, 36 patients were enrolled in lung recruitment maneuver (RM group and 38 patients were enrolled into non-lung recruitment maneuver (non-RM group. 44 were male and accounted for 59.5% of all the patients. For the indicators such as PEEP, pressure support (PS, plateau airway pressure (Pplat, peak airway pressure (Ppeak, vital capacity (VC and fraction of inspired oxygen (FiO2, no statistical differences in the indicators were found between the RM group and non-RM group on D1, D3 and D7 (P>0.05, except that only FiO2 of RM group on D7 was significantly lower than that of non-RM group (47.2±10.0 vs. (52.2±10.5, P0.05. 28-day mortality, ICU mortality and in-hospital mortality were 25% vs. 28.9%, 25% vs. 26.3% and 36.1% vs. 39.5% respectively between RM group and non-RM group (all P>0.05.Conclusion: Protective lung ventilation strategy combined with lung recruitment maneuver can improve

  9. The expression and activation of the AIM2 inflammasome correlates with inflammation and disease severity in patients with acute pancreatitis.

    Science.gov (United States)

    Algaba-Chueca, Francisco; de-Madaria, Enrique; Lozano-Ruiz, Beatriz; Martínez-Cardona, Claudia; Quesada-Vázquez, Noé; Bachiller, Victoria; Tarín, Fabián; Such, José; Francés, Rubén; Zapater, Pedro; González-Navajas, José M

    Acute pancreatitis is an inflammatory disorder of the pancreas that is responsible for significant morbidity and mortality. The inflammasome pathway has acquired significant relevance in the pathogenesis of many inflammatory disorders, but its role in patients with acute pancreatitis still awaits clarification. We performed a prospective study in which 27 patients with acute pancreatitis and 16 healthy controls were included. We isolated peripheral blood mononuclear cells (PBMCs) and we assessed the expression and activation of different inflammasomes as well as their association with the clinical course of the disease. Our results show that PBMCs from patients with acute pancreatitis have elevated expression of several components of the inflammasome complex, including the inflammasome-forming receptor absent in melanoma 2 (AIM2), early during the onset of the disease. Activation of the AIM2 or NLRP3 inflammasomes in PBMCs from patients with acute pancreatitis results in exacerbated IL-1β and IL-18 production compared with PBMCs from healthy controls. Furthermore, both AIM2 mRNA expression and AIM2-mediated production of IL-1β by PBMCs correlated with increased systemic inflammation in these patients. Last, AIM2 expression was further increased in those patients that developed transient or persistent organ failure (moderate or severe acute pancreatitis). Our data demonstrates that AIM2 inflammasome expression and activation is increased early during the course of acute pancreatitis, and suggests that AIM2 activation may affect systemic inflammation and organ failure in these patients. Copyright © 2017 IAP and EPC. Published by Elsevier B.V. All rights reserved.

  10. Effects of tidal volume on work of breathing during lung-protective ventilation in patients with acute lung injury and acute respiratory distress syndrome.

    Science.gov (United States)

    Kallet, Richard H; Campbell, Andre R; Dicker, Rochelle A; Katz, Jeffrey A; Mackersie, Robert C

    2006-01-01

    To assess the effects of step-changes in tidal volume on work of breathing during lung-protective ventilation in patients with acute lung injury (ALI) or the acute respiratory distress syndrome (ARDS). Prospective, nonconsecutive patients with ALI/ARDS. Adult surgical, trauma, and medical intensive care units at a major inner-city, university-affiliated hospital. Ten patients with ALI/ARDS managed clinically with lung-protective ventilation. Five patients were ventilated at a progressively smaller tidal volume in 1 mL/kg steps between 8 and 5 mL/kg; five other patients were ventilated at a progressively larger tidal volume from 5 to 8 mL/kg. The volume mode was used with a flow rate of 75 L/min. Minute ventilation was maintained constant at each tidal volume setting. Afterward, patients were placed on continuous positive airway pressure for 1-2 mins to measure their spontaneous tidal volume. Work of breathing and other variables were measured with a pulmonary mechanics monitor (Bicore CP-100). Work of breathing progressively increased (0.86 +/- 0.32, 1.05 +/- 0.40, 1.22 +/- 0.36, and 1.57 +/- 0.43 J/L) at a tidal volume of 8, 7, 6, and 5 mL/kg, respectively. In nine of ten patients there was a strong negative correlation between work of breathing and the ventilator-to-patient tidal volume difference (R = -.75 to -.998). : The ventilator-delivered tidal volume exerts an independent influence on work of breathing during lung-protective ventilation in patients with ALI/ARDS. Patient work of breathing is inversely related to the difference between the ventilator-delivered tidal volume and patient-generated tidal volume during a brief trial of unassisted breathing.

  11. Pneumovirus-Induced Lung Disease in Mice Is Independent of Neutrophil-Driven Inflammation

    NARCIS (Netherlands)

    Cortjens, Bart; Lutter, René; Boon, Louis; Bem, Reinout A.; van Woensel, Job B. M.

    2016-01-01

    The human pneumovirus respiratory syncytial virus (RSV) is the most common pathogen causing lower respiratory tract disease in young children worldwide. A hallmark of severe human RSV infection is the strong neutrophil recruitment to the airways and lungs. Massive neutrophil activation has been

  12. Propagation prevention: a complementary mechanism for "lung protective" ventilation in acute respiratory distress syndrome.

    Science.gov (United States)

    Marini, John J; Gattinoni, Luciano

    2008-12-01

    To describe the clinical implications of an often neglected mechanism through which localized acute lung injury may be propagated and intensified. Experimental and clinical evidence from the medical literature relevant to the airway propagation hypothesis and its consequences. The diffuse injury that characterizes acute respiratory distress syndrome is often considered a process that begins synchronously throughout the lung, mediated by inhaled or blood-borne noxious agents. Relatively little attention has been paid to possibility that inflammatory lung injury may also begin focally and propagate sequentially via the airway network, proceeding mouth-ward from distal to proximal. Were this true, modifications of ventilatory pattern and position aimed at geographic containment of the injury process could help prevent its generalization and limit disease severity. The purposes of this communication are to call attention to this seldom considered mechanism for extending lung injury that might further justify implementation of low tidal volume/high positive end-expiratory pressure ventilatory strategies for lung protection and to suggest additional therapeutic measures implied by this broadened conceptual paradigm.

  13. Protective effect of U74500A on phorbol myristate acetate-induced acute lung injury.

    Science.gov (United States)

    Chu, Shi-Jye; Chang, Deh-Ming; Wang, David; Lin, Hen-I; Lin, Shih-Hua; Hsu, Kang

    2004-08-01

    1. The present study was designed to determine whether U74500A could ameliorate acute lung injury (ALI) induced by phorbol myristate acetate (PMA) in our rat isolated lung model compared with any amelioration induced by dimethylthiourea (DMTU), superoxide dismutase (SOD) and catalase. 2. Acute lung injury was induced successfully by PMA during 60 min of observation. At 2 microg/kg, PMA elicited a significant increase in microvascular permeability (measured using the capillary filtration coefficient Kfc), lung weight gain, the lung weight/bodyweight ratio, pulmonary arterial pressure and protein concentration of the bronchoalveolar lavage fluid. 3. Pretreatment with 1.5 mg/kg U74500A significantly attenuated ALI; there was no significant increase in any parameters measured, except for pulmonary arterial pressure. The protective effect of U74500A was approximately the same as that of 600 mg/kg DMTU. However, 6000 U/kg SOD, 50,000 U/kg catalase and 6000 U/kg SOD + 50,000 U/kg catalase had no protective effect. 4. These experimental data suggest that U74500A significantly ameliorates ALI induced by PMA in rats.

  14. Effects of balneotherapy on the reactants of acute inflammation phase in Ankylosing spondylitis

    Directory of Open Access Journals (Sweden)

    Stamenković Bojana

    2009-01-01

    Full Text Available Introduction. Ankylosing spondylitis (AS is a chronic inflammatory disease that affects sacroiliac joints, spinal column and peripheral joints. Beside medication therapy, physical and balneotherapy play an important role in its complex treatment. Objective. The aim of the research was to establish serum concentrations of C-reactive protein (CRP, α 1-acid glycoprotein (α 1-AGP, ceruloplasmine (CP and erythrocyte sedimentation rate (SE before and after the balneotherapy in ankylosing spondylitis. Methods. The research included 50 AS patients according to the revised New York criteria, of mean age 43 years, who were treated for 14 days on the average at the Clinic for Rheumatology of the Institute 'Niška Banja'. All the patients received medications and balneotherapy (radioactive oligomineral baths, peloid, massage, kinesitherapy; the serum concentrations of CRP, α1-AGP, CP and SE were measured before and after balneotherapy. Serum proteins were determined using original Nor Partigen plates Boehringer. Erythrocyte sedimentation rate was measured by Westergreen method. Balneotherapy was applied individually, intensively or mildly, depending on the AS stage and activity phase. Results. After dosed balneotherapy, a significant decrease in the concentrations of CP (p<0.05, α1-AGP (p<0.01 and CRP (p<0.05 was registered in the serums of AS patients. ESR was not significantly reduced. Conclusion. The research proved that α 1-acid glycoprotein, ceruloplasmine and C-reactive protein represent more sensitive inflammation markers as compared to erythrocyte sedimentation rate. The identification of acute phase reactants is important in the evaluation of dosed balneotherapy efficiency in the treatment of ankylosing spondylitis.

  15. Memory and multitasking performance during acute allergic inflammation in seasonal allergic rhinitis.

    Science.gov (United States)

    Trikojat, K; Buske-Kirschbaum, A; Plessow, F; Schmitt, J; Fischer, R

    2017-04-01

    In previous research, patients with seasonal allergic rhinitis (SAR) showed poorer school and work performance during periods of acute allergic inflammation, supporting the idea of an impact of SAR on cognitive functions. However, the specific cognitive domains particularly vulnerable to inflammatory processes are unclear. In this study, the influence of SAR on memory and multitasking performance, as two potentially vulnerable cognitive domains essential in everyday life functioning, was investigated in patients with SAR. Non-medicated patients with SAR (n = 41) and healthy non-allergic controls (n = 42) performed a dual-task paradigm and a verbal learning and memory test during and out of symptomatic allergy periods (pollen vs. non-pollen season). Disease-related factors (e.g. symptom severity, duration of symptoms, duration of disease) and allergy-related quality of life were evaluated as potential influences of cognitive performance. During the symptomatic allergy period, patients showed (1) poorer performance in word list-based learning (P = 0.028) and (2) a general slowing in processing speed (P multitasking. Yet, typical parameters indicating specific multitasking costs were not affected. A significant negative association was found between learning performance and duration of disease (r = -0.451, P = 0.004), whereas symptom severity (r = 0.326; P = 0.037) and quality of life (r = 0.379; P = 0.015) were positively associated with multitasking strategy. Our findings suggest that SAR has a differentiated and complex impact on cognitive functions, which should be considered in the management of SAR symptoms. They also call attention to the importance of selecting sensitive measures and carefully interpreting cognitive outcomes. © 2017 John Wiley & Sons Ltd.

  16. Treatment for Sulfur Mustard Lung Injuries; New Therapeutic Approaches from Acute to Chronic Phase

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    Zohreh Poursaleh

    2012-09-01

    Full Text Available Objective: Sulfur mustard (SM is one of the major potent chemical warfare and attractive weapons for terrorists. It has caused deaths to hundreds of thousands of victims in World War I and more recently during the Iran-Iraq war (1980-1988. It has ability to develop severe acute and chronic damage to the respiratory tract, eyes and skin. Understanding the acute and chronic biologic consequences of SM exposure may be quite essential for developing efficient prophylactic/therapeutic measures. One of the systems majorly affected by SM is the respiratory tract that numerous clinical studies have detailed processes of injury, diagnosis and treatments of lung. The low mortality rate has been contributed to high prevalence of victims and high lifetime morbidity burden. However, there are no curative modalities available in such patients. In this review, we collected and discussed the related articles on the preventive and therapeutic approaches to SM-induced respiratory injury and summarized what is currently known about the management and therapeutic strategies of acute and long-term consequences of SM lung injuries.Method:This review was done by reviewing all papers found by searching following key words sulfur mustard; lung; chronic; acute; COPD; treatment.Results:Mustard lung has an ongoing pathological process and is active disorder even years after exposure to SM. Different drug classes have been studied, nevertheless there are no curative modalities for mustard lung. Conclusion:Complementary studies on one hand regarding pharmacokinetic of drugs and molecular investigations are mandatory to obtain more effective treatments.

  17. Treatment for sulfur mustard lung injuries; new therapeutic approaches from acute to chronic phase

    Directory of Open Access Journals (Sweden)

    Poursaleh Zohreh

    2012-09-01

    Full Text Available Abstract Objective Sulfur mustard (SM is one of the major potent chemical warfare and attractive weapons for terrorists. It has caused deaths to hundreds of thousands of victims in World War I and more recently during the Iran-Iraq war (1980–1988. It has ability to develop severe acute and chronic damage to the respiratory tract, eyes and skin. Understanding the acute and chronic biologic consequences of SM exposure may be quite essential for developing efficient prophylactic/therapeutic measures. One of the systems majorly affected by SM is the respiratory tract that numerous clinical studies have detailed processes of injury, diagnosis and treatments of lung. The low mortality rate has been contributed to high prevalence of victims and high lifetime morbidity burden. However, there are no curative modalities available in such patients. In this review, we collected and discussed the related articles on the preventive and therapeutic approaches to SM-induced respiratory injury and summarized what is currently known about the management and therapeutic strategies of acute and long-term consequences of SM lung injuries. Method This review was done by reviewing all papers found by searching following key words sulfur mustard; lung; chronic; acute; COPD; treatment. Results Mustard lung has an ongoing pathological process and is active disorder even years after exposure to SM. Different drug classes have been studied, nevertheless there are no curative modalities for mustard lung. Conclusion Complementary studies on one hand regarding pharmacokinetic of drugs and molecular investigations are mandatory to obtain more effective treatments.

  18. Acute cardiovascular toxicity of sterilizers, PHMG, and PGH: severe inflammation in human cells and heart failure in zebrafish.

    Science.gov (United States)

    Kim, Jae-Yong; Kim, Hak Hyeon; Cho, Kyung-Hyun

    2013-06-01

    In 2011, dozens of children and pregnant women in Korea died by exposure to sterilizer for household humidifier, such as Oxy(®) and Cefu(®). Until now, however, it remains unknown how the sterilizer affect the human health to cause the acute deaths. To find its toxicity for organ, we investigated the putative toxicity of the sterilizer in the cardiovascular system. The sterilizers, polyhexamethylene guanidine phosphate (PHMG, Cefu(®)), and oligo-[2-(2-ethoxy)-ethoxyethyl)-guanidinium-chloride (PGH, Oxy(®)) were treated to human lipoproteins, macrophages, and dermal fibroblast cells. The PGH and PHMG at normal dosages caused severe atherogenic process in human macrophages, cytotoxic effect, and aging in human dermal cell. Zebrafish embryos, which were exposed to the sterilizer, showed early death with acute inflammation and attenuated developmental speed. All zebrafish exposed to the working concentration of PHMG (final 0.3 %) and PGH (final 10 mM) died within 70 min and displayed acute increases in serum triacylglycerol level and fatty liver induction. The dead zebrafish showed severe accumulation of fibrous collagen in the bulbous artery of the heart with elevation of reactive oxygen species. In conclusion, the sterilizers showed acute toxic effect in blood circulation system, causing by severe inflammation, atherogenesis, and aging, with embryo toxicity.

  19. Effects of an Amifostine analogue on radiation induced lung inflammation and fibrosis

    International Nuclear Information System (INIS)

    Arora, Aastha; Bhuria, Vikas; Soni, Ravi; Singh, Saurabh; Hazari, Puja Panwar; Bhatt, Anant Narayan; Dwarakanath, B.S.; Pathak, Uma; Mathur, Shweta; Sandhir, Rajat

    2014-01-01

    Radiation-induced pulmonary toxicity causes significant morbidity and mortality in patients irradiated for thoracic malignancies as well as in victims of accidental radiation exposure. We have recently established the efficacy of an analogue of Amifostine (DRDE-30) in reducing the mortality of whole body irradiated mice. The widely used radioprotector Amifostine has been found to reduce the incidence of radiation induced pneumonitis during radiation therapy for non small cell lung carcinoma. In the present study, we investigated the potential of DRDE-30 in ameliorating the radiation induced lung damage. Intra-peritoneal administration of DRDE-30 at 220 mg/kg b.wt 30 min. prior to 13.5 Gy thoracic radiation enhanced the 24-month survival of C57BL/6 mice to 80% compared to 0% with radiation alone. Reduced protein content and cell number in the broncheo-alveolar lavage fluid suggested reduction in radiation induced vascular permeability in DRDE-30 treated mice. Higher levels of MnSOD and Catalase observed under these conditions indicated that strengthening of the anti-oxidant defense system by DRDE-30 could also contribute to the protection against radiation induced lung damage. Reduced levels of p-p38 observed under these conditions suggested down-regulation of the p38/MAP kinase pathway as one of the plausible mechanisms underlying anti-inflammatory effects of DRDE-30, while lower levels of Vimentin seen, indicated inhibition of epithelial to mesenchymal transition revealing its anti-fibrotic effect as well. Structural analysis with X-ray CT indicated comparable lung architecture in control and drug treated mice in terms of reduced opacity, which correlated well with the lung morphology (H and E staining) and reduced collagen deposition (trichrome staining). These results demonstrate the potential of DRDE-30 in reducing radiation induced pulmonary toxicity by attenuating the inflammatory and fibrotic responses. (author)

  20. Low tidal volume and high positive end-expiratory pressure mechanical ventilation results in increased inflammation and ventilator-associated lung injury in normal lungs.

    Science.gov (United States)

    Hong, Caron M; Xu, Da-Zhong; Lu, Qi; Cheng, Yunhui; Pisarenko, Vadim; Doucet, Danielle; Brown, Margaret; Aisner, Seena; Zhang, Chunxiang; Deitch, Edwin A; Delphin, Ellise

    2010-06-01

    Protective mechanical ventilation with low tidal volume (Vt) and low plateau pressure reduces mortality and decreases the length of mechanical ventilation in patients with acute respiratory distress syndrome. Mechanical ventilation that will protect normal lungs during major surgical procedures of long duration may improve postoperative outcomes. We performed an animal study comparing 3 ventilation strategies used in the operating room in normal lungs. We compared the effects on pulmonary mechanics, inflammatory mediators, and lung tissue injury. Female pigs were randomized into 3 groups. Group H-Vt/3 (n = 6) was ventilated with a Vt of 15 mL/kg predicted body weight (PBW)/positive end-expiratory pressure (PEEP) of 3 cm H(2)O, group L-Vt/3 (n = 6) with a Vt of 6 mL/kg PBW/PEEP of 3 cm H(2)O, and group L-Vt/10 (n = 6) with a Vt of 6 mL/kg PBW/PEEP of 10 cm H(2)O, for 8 hours. Hemodynamics, airway mechanics, arterial blood gases, and inflammatory markers were monitored. Bronchoalveolar lavage (BAL) was analyzed for inflammatory markers and protein concentration. The right lower lobe was assayed for mRNA of specific cytokines. The right lower lobe and right upper lobe were evaluated histologically. In contrast to groups H-Vt/3 and L-Vt/3, group L-Vt/10 exhibited a 6-fold increase in inflammatory mediators in BAL (P ventilation with high PEEP resulted in increased production of inflammatory markers. Low PEEP resulted in lower levels of inflammatory markers. High Vt/low PEEP resulted in less histologic lung injury.

  1. Design, synthesis, and structure-activity relationships of 2-benzylidene-1-indanone derivatives as anti-inflammatory agents for treatment of acute lung injury.

    Science.gov (United States)

    Xiao, Siyang; Zhang, Wenxin; Chen, Hongjin; Fang, Bo; Qiu, Yinda; Chen, Xianxin; Chen, Lingfeng; Shu, Sheng; Zhang, Yali; Zhao, Yunjie; Liu, Zhiguo; Liang, Guang

    2018-01-01

    The purpose of this study was to design and synthesize novel 2-benzylidene-1-indanone derivatives for treatment of acute lung injury. A series of 39 novel 2-benzylidene-indanone structural derivatives were synthesized and evaluated for anti-inflammatory activity in lipopolysaccharide (LPS)-stimulated murine primary macrophages. Most of the obtained compounds effectively inhibited the LPS-induced expression of IL-6 and TNF-α. The most active compound, 8f , was found to significantly reduce LPS-induced pulmonary inflammation, as reflected by reductions in the concentration of total protein, inflammatory cell count, as well as the lung wet/dry ratio in bronchoalveolar lavage (BAL) fluid. Furthermore, 8f effectively inhibited mRNA expression of several inflammatory cytokines after LPS challenge in vitro and in vivo. Administration of 8f also blocked LPS-induced activation of the proinflammatory NF-κB/MAPK signaling pathway. The simple synthetic preparation and biological properties of these derivatives make these 2-benzylidene-indanone scaffolds promising new entities for the development of anti-inflammatory therapeutics for the treatment of acute lung injury.

  2. Design, synthesis, and structure–activity relationships of 2-benzylidene-1-indanone derivatives as anti-inflammatory agents for treatment of acute lung injury

    Science.gov (United States)

    Chen, Hongjin; Fang, Bo; Qiu, Yinda; Chen, Xianxin; Chen, Lingfeng; Shu, Sheng; Zhang, Yali; Zhao, Yunjie; Liu, Zhiguo; Liang, Guang

    2018-01-01

    Purpose The purpose of this study was to design and synthesize novel 2-benzylidene-1-indanone derivatives for treatment of acute lung injury. Methods A series of 39 novel 2-benzylidene-indanone structural derivatives were synthesized and evaluated for anti-inflammatory activity in lipopolysaccharide (LPS)-stimulated murine primary macrophages. Results Most of the obtained compounds effectively inhibited the LPS-induced expression of IL-6 and TNF-α. The most active compound, 8f, was found to significantly reduce LPS-induced pulmonary inflammation, as reflected by reductions in the concentration of total protein, inflammatory cell count, as well as the lung wet/dry ratio in bronchoalveolar lavage (BAL) fluid. Furthermore, 8f effectively inhibited mRNA expression of several inflammatory cytokines after LPS challenge in vitro and in vivo. Administration of 8f also blocked LPS-induced activation of the proinflammatory NF-κB/MAPK signaling pathway. Conclusion The simple synthetic preparation and biological properties of these derivatives make these 2-benzylidene-indanone scaffolds promising new entities for the development of anti-inflammatory therapeutics for the treatment of acute lung injury. PMID:29719375

  3. Cytokine levels in pleural fluid as markers of acute rejection after lung transplantation

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    Priscila Cilene León Bueno de Camargo

    2014-08-01

    Full Text Available Our objective was to determine the levels of lactate dehydrogenase, IL-6, IL-8, and VEGF, as well as the total and differential cell counts, in the pleural fluid of lung transplant recipients, correlating those levels with the occurrence and severity of rejection. We analyzed pleural fluid samples collected from 18 patients at various time points (up to postoperative day 4. The levels of IL-6, IL-8, and VEGF tended to elevate in parallel with increases in the severity of rejection. Our results suggest that these levels are markers of acute graft rejection in lung transplant recipients.

  4. Urtica dioica attenuates ovalbumin-induced inflammation and lipid peroxidation of lung tissues in rat asthma model.

    Science.gov (United States)

    Zemmouri, Hanene; Sekiou, Omar; Ammar, Sonda; El Feki, Abdelfattah; Bouaziz, Mohamed; Messarah, Mahfoud; Boumendjel, Amel

    2017-12-01

    To find bioactive medicinal herbs exerting anti-asthmatic activity, we investigated the effect of an aqueous extract of Urtica dioica L. (Urticaceae) leaves (UD), the closest extract to the Algerian traditional use. In this study, we investigated the in vivo anti-asthmatic and antioxidant activities of nettle extract. Adult male Wistar rats were divided into four groups: Group I: negative control; group II: Ovalbumin sensitized/challenged rats (positive control); group III: received UD extract (1.5 g/kg/day) orally along the experimental protocol; group IV: received UD extract (1.5 g/kg/day) orally along the experimental protocol and sensitized/challenged with ovalbumin. After 25 days, blood and tissue samples were collected for haematological and histopathological analysis, respectively. The oxidative stress parameters were evaluated in the lungs, liver and erythrocytes. Then, correlations between markers of airway inflammation and markers of oxidative stress were explored. UD extract significantly (p nettle extract was also investigated for the total phenolic content (30.79 ± 0.96 mg gallic acid/g dry extract) and shows DPPH radical scavenging activity with 152.34 ± 0.37 μg/mL IC 50 value. The results confirmed that UD administration might be responsible for the protective effects of this extract against airway inflammation.

  5. Sodium butyrate protects against severe burn-induced remote acute lung injury in rats.

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    Xun Liang

    Full Text Available High-mobility group box 1 protein (HMGB1, a ubiquitous nuclear protein, drives proinflammatory responses when released extracellularly. It plays a key role as a distal mediator in the development of acute lung injury (ALI. Sodium butyrate, an inhibitor of histone deacetylase, has been demonstrated to inhibit HMGB1 expression. This study investigates the effect of sodium butyrate on burn-induced lung injury. Sprague-Dawley rats were divided into three groups: 1 sham group, sham burn treatment; 2 burn group, third-degree burns over 30% total body surface area (TBSA with lactated Ringer's solution for resuscitation; 3 burn plus sodium butyrate group, third-degree burns over 30% TBSA with lactated Ringer's solution containing sodium butyrate for resuscitation. The burned animals were sacrificed at 12, 24, and 48 h after burn injury. Lung injury was assessed in terms of histologic changes and wet weight to dry weight (W/D ratio. Tumor necrosis factor (TNF-α and interleukin (IL-8 protein concentrations in bronchoalveolar lavage fluid (BALF and serum were measured by enzyme-linked immunosorbent assay, and HMGB1 expression in the lung was determined by Western blot analysis. Pulmonary myeloperoxidase (MPO activity and malondialdehyde (MDA concentration were measured to reflect neutrophil infiltration and oxidative stress in the lung, respectively. As a result, sodium butyrate significantly inhibited the HMGB1 expressions in the lungs, reduced the lung W/D ratio, and improved the pulmonary histologic changes induced by burn trauma. Furthermore, sodium butyrate administration decreased the TNF-α and IL-8 concentrations in BALF and serum, suppressed MPO activity, and reduced the MDA content in the lungs after severe burn. These results suggest that sodium butyrate attenuates inflammatory responses, neutrophil infiltration, and oxidative stress in the lungs, and protects against remote ALI induced by severe burn, which is associated with inhibiting HMGB1

  6. Molecular Analysis of a Multistep Lung Cancer Model Induced by Chronic Inflammation Reveals Epigenetic Regulation of p16, Activation of the DNA Damage Response Pathway

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    David Blanco

    2007-10-01

    Full Text Available The molecular hallmarks of inflammation-mediated lung carcinogenesis have not been fully clarified, mainly due to the scarcity of appropriate animal models. We have used a silica-induced multistep lung carcinogenesis model driven by chronic inflammation to study the evolution of molecular markers, genetic alterations. We analyzed markers of DNA damage response (DDR, proliferative stress, telomeric stress: δ-H2AX, p16, p53, TERT. Lung cancer-related epigenetic, genetic alterations, including promoter hypermethylation status of p16(CDKN2A, APC, CDH13, Rassf1, Nore1A, as well as mutations of Tp53, epidermal growth factor receptor, K-ras, N-ras, c-H-ras, have been also studied. Our results showed DDR pathway activation in preneoplastic lesions, in association with inducible nitric oxide synthase, p53 induction. p16 was also induced in early tumorigenic progression, was inactivated in bronchiolar dysplasias, tumors. Remarkably, lack of mutations of Ras, epidermal growth factor receptor, a very low frequency of Tp53 mutations suggest that they are not required for tumorigenesis in this model. In contrast, epigenetic alterations in p16(CDKN2A, CDH13, APC, but not in Rassf1, Nore1A, were clearly observed. These data suggest the existence of a specific molecular signature of inflammation-driven lung carcinogenesis that shares some, but not all, of the molecular landmarks of chemically induced lung cancer.

  7. No mediating effects of glycemic control and inflammation on the association between vitamin D and lung function in the general population.

    Science.gov (United States)

    Kaul, Anne; Gläser, Sven; Hannemann, Anke; Stubbe, Beate; Felix, Stefan B; Nauck, Matthias; Ewert, Ralf; Friedrich, Nele

    2017-04-01

    Vitamin D deficiency is discussed to be associated with lung health. While former studies focused on subjects suffering from pulmonary diseases, we aimed to investigate the association of 25-hydroxy vitamin D [25(OH)D] with lung function in the general population and examined whether mediating effects of inflammation, glycemic control or renal function exist. 1404 participants from the Study of Health in Pomerania with pulmonary function testing assessed by expiratory volume in 1 s (FEV 1 ), forced vital capacity (FVC), total lung capacity and Krogh index were used. Adjusted analysis of variance, linear regression models and mediation analyses were performed. Significant positive associations between 25(OH)D levels and FEV 1 , FVC and Krogh index were found. Mediator analyses revealed no mediating effect of inflammation (fibrinogen), glycemic control (HbA1c) or renal function (eGFR) on associations with FEV 1 or FVC. With respect to Krogh-Index, the association to 25(OH)D was slightly mediated by fibrinogen with a proportion mediated of 9.7%. Significant positive associations of 25(OH)D with lung function were revealed in a general population. The proposed mediating effects of inflammation, glycemic control and renal function on these relations were not confirmed. Further studies examining the causality of the association between 25(OH)D and lung function are necessary. Copyright © 2017 Elsevier Ltd. All rights reserved.

  8. Inhalation exposure to chloramine T induces DNA damage and inflammation in lung of Sprague-Dawley rats.

    Science.gov (United States)

    Shim, Ilseob; Seo, Gyun-Baek; Oh, Eunha; Lee, Mimi; Kwon, Jung-Taek; Sul, Donggeun; Lee, Byung-Woo; Yoon, Byung-Il; Kim, Pilje; Choi, Kyunghee; Kim, Hyun-Mi

    2013-01-01

    Chloramine T has been widely used as a disinfectant in many areas such as kitchens, laboratories and hospitals. It has been also used as a biocide in air fresheners and deodorants which are consumer products; however, little is known about its toxic effects by inhalation route. This study was performed to identify the subacute inhalation toxicity of chloramine T under whole-body inhalation exposure conditions. Male and female groups of rats were exposed to chloramine T at concentrations of 0.2, 0.9 and 4.0 mg/m³ for 6 hr/day, 5 days/week during 4 weeks. After 28-day repeated inhalation of chloramine T, there were dose-dependently significant DNA damage in the rat tissues evaluated and inflammation was histopathologically noted around the terminal airways of the lung in both genders. As a result of the expression of three types of antioxidant enzymes (SOD-2, GPx-1, PRX-1) in rat's lung after exposure, there was no significant change of all antioxidant enzymes in the male and female rats. The results showed that no observed adverse effect level (NOAEL) was 0.2 mg/m³ in male rats and 0.9 mg/m³ in female rats under the present experimental condition.

  9. Restoring Cystic Fibrosis Transmembrane Conductance Regulator Function Reduces Airway Bacteria and Inflammation in People with Cystic Fibrosis and Chronic Lung Infections.

    Science.gov (United States)

    Hisert, Katherine B; Heltshe, Sonya L; Pope, Christopher; Jorth, Peter; Wu, Xia; Edwards, Rachael M; Radey, Matthew; Accurso, Frank J; Wolter, Daniel J; Cooke, Gordon; Adam, Ryan J; Carter, Suzanne; Grogan, Brenda; Launspach, Janice L; Donnelly, Seamas C; Gallagher, Charles G; Bruce, James E; Stoltz, David A; Welsh, Michael J; Hoffman, Lucas R; McKone, Edward F; Singh, Pradeep K

    2017-06-15

    Previous work indicates that ivacaftor improves cystic fibrosis transmembrane conductance regulator (CFTR) activity and lung function in people with cystic fibrosis and G551D-CFTR mutations but does not reduce density of bacteria or markers of inflammation in the airway. These findings raise the possibility that infection and inflammation may progress independently of CFTR activity once cystic fibrosis lung disease is established. To better understand the relationship between CFTR activity, airway microbiology and inflammation, and lung function in subjects with cystic fibrosis and chronic airway infections. We studied 12 subjects with G551D-CFTR mutations and chronic airway infections before and after ivacaftor. We measured lung function, sputum bacterial content, and inflammation, and obtained chest computed tomography scans. Ivacaftor produced rapid decreases in sputum Pseudomonas aeruginosa density that began within 48 hours and continued in the first year of treatment. However, no subject eradicated their infecting P. aeruginosa strain, and after the first year P. aeruginosa densities rebounded. Sputum total bacterial concentrations also decreased, but less than P. aeruginosa. Sputum inflammatory measures decreased significantly in the first week of treatment and continued to decline over 2 years. Computed tomography scans obtained before and 1 year after ivacaftor treatment revealed that ivacaftor decreased airway mucous plugging. Ivacaftor caused marked reductions in sputum P. aeruginosa density and airway inflammation and produced modest improvements in radiographic lung disease in subjects with G551D-CFTR mutations. However, P. aeruginosa airway infection persisted. Thus, measures that control infection may be required to realize the full benefits of CFTR-targeting treatments.

  10. Bioinformatics Methods for Learning Radiation-Induced Lung Inflammation from Heterogeneous Retrospective and Prospective Data

    Science.gov (United States)

    Spencer, Sarah J.; Almiron Bonnin, Damian; Deasy, Joseph O.; Bradley, Jeffrey D.; El Naqa, Issam

    2009-01-01

    Radiotherapy outcomes are determined by complex interactions between physical and biological factors, reflecting both treatment conditions and underlying genetics. Recent advances in radiotherapy and biotechnology provide new opportunities and challenges for predicting radiation-induced toxicities, particularly radiation pneumonitis (RP), in lung cancer patients. In this work, we utilize datamining methods based on machine learning to build a predictive model of lung injury by retrospective analysis of treatment planning archives. In addition, biomarkers for this model are extracted from a prospective clinical trial that collects blood serum samples at multiple time points. We utilize a 3-way proteomics methodology to screen for differentially expressed proteins that are related to RP. Our preliminary results demonstrate that kernel methods can capture nonlinear dose-volume interactions, but fail to address missing biological factors. Our proteomics strategy yielded promising protein candidates, but their role in RP as well as their interactions with dose-volume metrics remain to be determined. PMID:19704920

  11. Critical role of aldehydes in cigarette smoke-induced acute airway inflammation

    NARCIS (Netherlands)

    van der Toorn, Marco; Slebos, Dirk-Jan; de Bruin, Harold G.; Gras, Renee; Rezayat, Delaram; Jorge, Lucie; Sandra, Koen; van Oosterhout, Antoon J. M.

    2013-01-01

    Background: Cigarette smoking (CS) is the most important risk factor for COPD, which is associated with neutrophilic airway inflammation. We hypothesize, that highly reactive aldehydes are critical for CS-induced neutrophilic airway inflammation. Methods: BALB/c mice were exposed to CS, water

  12. Inflammation and vascular responses to acute mental stress : implications for the triggering of myocardial infarction

    NARCIS (Netherlands)

    Paine, N.J.; Bosch, J.A.; Veldhuijzen Van Zanten, J.J.C.S.

    2012-01-01

    There is evidence that mental stress can trigger myocardial infarction. Even though the underlying mechanisms remain to be determined, both inflammation and vascular responses to mental stress have been implicated as contributing factors. This review explores the effects of inflammation on the

  13. The roles of ADAM33, ADAM28, IL-13 and IL-4 in the development of lung injuries in children with lethal non-pandemic acute infectious pneumonia.

    Science.gov (United States)

    Baurakiades, Emanuele; Costa, Victor Horácio; Raboni, Sonia Mara; de Almeida, Vivian Rafaela Telli; Larsen, Kelly Susana Kunze; Kohler, Juliana Nemetz; Gozzo, Priscilla do Carmo; Klassen, Giseli; Manica, Graciele C M; de Noronha, Lucia

    2014-12-01

    ADAM28, ADAM33, IL-13, IL-4 and other cytokines (IL-6 and IL-10) seem to play important roles in the persistence and maintenance of acute inflammatory processes that ultimately lead to lung remodeling and pulmonary fibrosis, which may be responsible for the high morbidity and mortality rates associated with non-pandemic acute viral pneumonias in childhood. The aim of this study was to evaluate the roles of ADAM33, ADAM28, IL4, IL6, IL10 and IL13 in the development of inflammation and alveolar fibrosis due to lethal acute respiratory infections of the lower airway in a pediatric population, especially in those with viral etiology. For this study, 193 cases were selected, and samples from the cases were processed for viral antigen detection by immunohistochemistry and then separated into two groups: virus-positive (n=68) and virus-negative (n=125). Immunohistochemistry was performed to assess the presence of metalloproteinases (ADAM33 and ADAM28) and inflammatory cytokines (IL-4, IL-13, IL-6, IL-10) in the alveolar septa. The virus-positive group showed stronger immunolabeling for ADAM33, ADAM28, IL-4 and IL-13 (pplay important roles in pulmonary inflammatory reactions elicited against etiological viral agents. In addition, these mediators may affect the process of lung remodeling and the development of pulmonary fibrosis. Copyright © 2014 Elsevier B.V. All rights reserved.

  14. Effects of vertical positioning on gas exchange and lung volumes in acute respiratory distress syndrome.

    Science.gov (United States)

    Richard, Jean-Christophe M; Maggiore, Salvatore Maurizio; Mancebo, Jordi; Lemaire, François; Jonson, Bjorn; Brochard, Laurent

    2006-10-01

    Supine position may contribute to the loss of aerated lung volume in patients with acute respiratory distress syndrome (ARDS). We hypothesized that verticalization increases lung volume and improves gas exchange by reducing the pressure surrounding lung bases. Prospective observational physiological study in a medical ICU. In 16 patients with ARDS we measured arterial blood gases, pressure-volume curves of the respiratory system recorded from positive-end expiratory pressure (PEEP), and changes in lung volume in supine and vertical positions (trunk elevated at 45 degrees and legs down at 45 degrees ). Vertical positioning increased PaO(2) significantly from 94+/-33 to 142+/-49 mmHg, with an increase higher than 40% in 11 responders. The volume at 20 cmH(2)O measured on the PV curve from PEEP increased using the vertical position only in responders (233+/-146 vs. -8+/-9 1ml in nonresponders); this change was correlated to oxygenation change (rho=0.55). End-expiratory lung volume variation from supine to vertical and 1 h later back to supine, measured in 12 patients showed a significant increase during the 1-h upright period in responders (n=7) but not in nonresponders (n=5; 215+/-220 vs. 10+/-22 ml), suggesting a time-dependent recruitment. Vertical positioning is a simple technique that may improve oxygenation and lung recruitment in ARDS patients.

  15. Biomarkers for Pulmonary Inflammation and Fibrosis and Lung Ventilation Function in Chinese Occupational Refractory Ceramic Fibers-Exposed Workers

    Directory of Open Access Journals (Sweden)

    Xiaojun Zhu

    2017-12-01

    Full Text Available Refractory ceramic fibers (RCFs can cause adverse health effects on workers’ respiratory system, yet no proper biomarkers have been used to detect early pulmonary injury of RCFs-exposed workers. This study assessed the levels of two biomarkers that are related to respiratory injury in RCFs-exposed workers, and explored their relations with lung function. The exposure levels of total dust and respirable fibers were measured simultaneously in RCFs factories. The levels of TGF-β1 and ceruloplasmin (CP increased with the RCFs exposure level (p < 0.05, and significantly increased in workers with high exposure level (1.21 ± 0.49 ng/mL, 115.25 ± 32.44 U/L when compared with the control group (0.99 ± 0.29 ng/mL, 97.90 ± 35.01 U/L (p < 0.05. The levels of FVC and FEV1 were significantly decreased in RCFs exposure group (p < 0.05. Negative relations were found between the concentrations of CP and FVC (B = −0.423, p = 0.025, or FEV1 (B = −0.494, p = 0.014. The concentration of TGF-β1 (B = 0.103, p = 0.001 and CP (B = 8.027, p = 0.007 were associated with respirable fiber exposure level. Occupational exposure to RCFs can impair lung ventilation function and may have the potential to cause pulmonary inflammation and fibrosis. TGF-β1 and CP might be used as sensitive and noninvasive biomarkers to detect lung injury in occupational RCFs-exposed workers. Respirable fiber concentration can better reflect occupational RCFs exposure and related respiratory injuries.

  16. Dietary intake, lung function and airway inflammation in Mexico City school children exposed to air pollutants

    Directory of Open Access Journals (Sweden)

    Díaz-Sánchez David

    2009-12-01

    Full Text Available Abstract Introduction Air pollutant exposure has been associated with an increase in inflammatory markers and a decline in lung function in asthmatic children. Several studies suggest that dietary intake of fruits and vegetables might modify the adverse effect of air pollutants. Methods A total of 158 asthmatic children recruited at the Children's Hospital of Mexico and 50 non-asthmatic children were followed for 22 weeks. Pulmonary function was measured and nasal lavage collected and analyzed every 2 weeks. Dietary intake was evaluated using a 108-item food frequency questionnaire and a fruit and vegetable index (FVI and a Mediterranean diet index (MDI were constructed. The impact of these indices on lung function and interleukin-8 (IL-8 and their interaction with air pollutants were determined using mixed regression models with random intercept and random slope. Results FVI was inversely related to IL-8 levels in nasal lavage (p 1 (test for trend p 1 and FVC as was with MDI and ozone for FVC. No effect of diet was observed among healthy children. Conclusion Our results suggest that fruit and vegetable intake and close adherence to the Mediterranean diet have a beneficial effect on inflammatory response and lung function in asthmatic children living in Mexico City.

  17. Epigallocatechin-3-gallate Ameliorates Seawater Aspiration-Induced Acute Lung Injury via Regulating Inflammatory Cytokines and Inhibiting JAK/STAT1 Pathway in Rats

    Science.gov (United States)

    Liu, Wei; Dong, Mingqing; Bo, Liyan; Li, Congcong; Liu, Qingqing; Li, Yanyan; Ma, Lijie; Xie, Yonghong; Fu, Enqing; Mu, Deguang; Pan, Lei; Jin, Faguang; Li, Zhichao

    2014-01-01

    Signal transducers and activators of transcriptions 1 (STAT1) play an important role in the inflammation process of acute lung injury (ALI). Epigallocatechin-3-gallate (EGCG) exhibits a specific and strong anti-STAT1 activity. Therefore, our study is to explore whether EGCG pretreatment can ameliorate seawater aspiration-induced ALI and its possible mechanisms. We detected the arterial partial pressure of oxygen, lung wet/dry weight ratios, protein content in bronchoalveolar lavage fluid, and the histopathologic and ultrastructure staining of the lung. The levels of IL-1, TNF-α, and IL-10 and the total and the phosphorylated protein level of STAT1, JAK1, and JAK2 were assessed in vitro and in vivo. The results showed that EGCG pretreatment significantly improved hypoxemia and histopathologic changes, alleviated pulmonary edema and lung vascular leak, reduced the production of TNF-α and IL-1, and increased the production of IL-10 in seawater aspiration-induced ALI rats. EGCG also prevented the seawater aspiration-induced increase of TNF-α and IL-1 and decrease of IL-10 in NR8383 cell line. Moreover, EGCG pretreatment reduced the total and the phosphorylated protein level of STAT1 in vivo and in vitro and reduced the phosphorylated protein level of JAK1 and JAK2. The present study demonstrates that EGCG ameliorates seawater aspiration-induced ALI via regulating inflammatory cytokines and inhibiting JAK/STAT1 pathway in rats. PMID:24692852

  18. Suppression of Th17-polarized airway inflammation by rapamycin.

    Science.gov (United States)

    Joean, Oana; Hueber, Anja; Feller, Felix; Jirmo, Adan Chari; Lochner, Matthias; Dittrich, Anna-Maria; Albrecht, Melanie

    2017-11-10

    Because Th17-polarized airway inflammation correlates with poor control in bronchial asthma and is a feature of numerous other difficult-to-treat inflammatory lung diseases, new therapeutic approaches for this type of airway inflammation are necessary. We assessed different licensed anti-inflammatory agents with known or expected efficacy against Th17-polarization in mouse models of Th17-dependent airway inflammation. Upon intravenous transfer of in vitro derived Th17 cells and intranasal challenge with the corresponding antigen, we established acute and chronic murine models of Th17-polarised airway inflammation. Consecutively, we assessed the efficacy of methylprednisolone, roflumilast, azithromycin, AM80 and rapamycin against acute or chronic Th17-dependent airway inflammation. Quantifiers for Th17-associated inflammation comprised: bronchoalveolar lavage (BAL) differential cell counts, allergen-specific cytokine and immunoglobulin secretion, as well as flow cytometric phenotyping of pulmonary inflammatory cells. Only rapamycin proved effective against acute Th17-dependent airway inflammation, accompanied by increased plasmacytoid dendritic cells (pDCs) and reduced neutrophils as well as reduced CXCL-1 levels in BAL. Chronic Th17-dependent airway inflammation was unaltered by rapamycin treatment. None of the other agents showed efficacy in our models. Our results demonstrate that Th17-dependent airway inflammation is difficult to treat with known agents. However, we identify rapamycin as an agent with inhibitory potential against acute Th17-polarized airway inflammation