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Sample records for lung injury mouse

  1. 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

  2. Cold stress aggravates inflammatory responses in an LPS-induced mouse model of acute lung injury

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    Joo, Su-Yeon; Park, Mi-Ju; Kim, Kyun-Ha; Choi, Hee-Jung; Chung, Tae-Wook; Kim, Yong Jin; Kim, Joung Hee; Kim, Keuk-Jun; Joo, Myungsoo; Ha, Ki-Tae

    2016-08-01

    Although the relationship between environmental cold temperature and susceptibility to respiratory infection is generally accepted, the effect of ambient cold temperature on host reactivity in lung inflammation has not been fully studied. To examine the function of ambient cold temperature on lung inflammation, mice were exposed to 4 °C for 8 h each day for 14 days. In the lungs of mice exposed to cold stress, inflammatory cells in bronchoalveolar lavage (BAL) fluid and lung tissues were slightly increased by about twofold. However, the structures of pulmonary epithelial cells were kept within normal limits. Next, we examined the effect of cold stress on the inflammatory responses in a lipopolysaccharide (LPS)-induced acute lung injury (ALI) mouse model. The infiltration of neutrophils and inflammation of lung tissue determined by histology were significantly increased by exposure to ambient cold temperature. In addition, the production of pro-inflammatory cytokines including interleukin (IL)-12, IL-17, and monokine induced by gamma interferon (MIG) was elevated by exposure to cold stress. Therefore, we suggest that cold stress is a factor that exacerbates lung inflammation including ALI. To our knowledge, this is the first report on the relationship between cold stress and severity of lung inflammation.

  3. ICOS-expressing lymphocytes promote resolution of CD8-mediated lung injury in a mouse model of lung rejection.

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    Qiang Wu

    Full Text Available Acute rejection, a common complication of lung transplantation, may promote obliterative bronchiolitis leading to graft failure in lung transplant recipients. During acute rejection episodes, CD8(+ T cells can contribute to lung epithelial injury but the mechanisms promoting and controlling CD8-mediated injury in the lung are not well understood. To study the mechanisms regulating CD8(+ T cell-mediated lung rejection, we used a transgenic model in which adoptively transferred ovalbumin (OVA-specific cytotoxic T lymphocytes (CTL induce lung injury in mice expressing an ovalbumin transgene in the small airway epithelium of the lungs (CC10-OVA mice. The lung pathology is similar to findings in humans with acute lung transplant. In the presence of an intact immune response the inflammation resolves by day 30. Using CC10-OVA.RAG(-/- mice, we found that CD4(+ T cells and ICOS(+/+ T cells were required for protection against lethal lung injury, while neutrophil depletion was not protective. In addition, CD4(+Foxp3 (+ ICOS(+ T cells were enriched in the lungs of animals surviving lung injury and ICOS(+/+ Tregs promoted survival in animals that received ICOS(-/- T cells. Direct comparison of ICOS(-/- Tregs to ICOS(+/+ Tregs found defects in vitro but no differences in the ability of ICOS(-/- Tregs to protect from lethal lung injury. These data suggest that ICOS affects Treg development but is not necessarily required for Treg effector function.

  4. A genetic mouse model to investigate hyperoxic acute lung injury survival.

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    Prows, Daniel R; Hafertepen, Amanda P; Gibbons, William J; Winterberg, Abby V; Nick, Todd G

    2007-08-20

    Acute lung injury (ALI) is a devastating disease that maintains a high mortality rate, despite decades of research. Hyperoxia, a universal treatment for ALI and other critically ill patients, can itself cause pulmonary damage, which drastically restricts its therapeutic potential. We stipulate that having the ability to use higher levels of supplemental O2 for longer periods would improve recovery rates. Toward this goal, a mouse model was sought to identify genes contributing to hyperoxic ALI (HALI) mortality. Eighteen inbred mouse strains were screened in continuous >95% O2. A significant survival difference was identified between sensitive C57BL/6J and resistant 129X1/SvJ strains. Although resistant, only one-fourth of 129X1/SvJ mice survived longer than any C57BL/6J mouse, demonstrating decreased penetrance of resistance. A survival time difference between reciprocal F1 mice implicated a parent-of-origin (imprinting) effect. To further evaluate imprinting and begin to delineate the genetic components of HALI survival, we generated and phenotyped offspring from all four possible intercrosses. Segregation analysis supported maternal inheritance of one or more genes but paternal inheritance of one or more contributor genes. A significant sex effect was demonstrated, with males more resistant than females for all F2 crosses. Survival time ranges and sensitive-to-resistant ratios of the different F2 crosses also supported imprinting and predicted that increased survival is due to dominant resistance alleles contributed by both the resistant and sensitive parental strains. HALI survival is multigenic with a complex mode of inheritance, which should be amenable to genetic dissection with this mouse model.

  5. Sonic Hedgehog Signaling: Evidence for Its Protective Role in Endotoxin Induced Acute Lung Injury in Mouse Model.

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    Xing Chen

    Full Text Available To investigate the protective role of the sonic hedgehog (SHH signaling associated with a lipopolysaccharide (LPS-induced acute lung injury (ALI in a mouse model.Male BALB/c mice were randomly divided into four groups: control, LPS, LPS-cyclopamine group and cyclopamine group. ALI was induced by LPS ip injection (5 mg/kg. The sonic hedgehog inhibitor cyclopamine (50 mg/kg was given to the LPS-cyclopamine group at 30 min after LPS injection as well as normal mice as control. Lung injury was observed histologically in hematoxylin and eosin (HE stained tissue sections, semi-quantified by lung tissue injury score, and the lung tissue mass alteration was measured by wet to dry weight ratio (W/D. mRNA expression levels of TNF-α, SHH, Patched (PTC and GLI1 in lung tissue were studied with real time quantitative PCR (RT-PCR, while the protein expression of SHH and GLI1 was determined by western blot analysis.Lung tissue injury score, thickness of alveolar septa, W/D, and TNF-α mRNA expression levels were significantly higher in the ALI mice than the normal mice (P<0.05. The mRNA expression levels of SHH, PTC, and GLI1 in the ALI mice were significantly higher at 12h and 24h after LPS injection, but not at the 6h time point. Protein production of SHH and GLI1 at 6h, 12h, and 24h in the lungs of ALI mice significantly increased, in a time-dependent manner, compared with that in normal mice. Cyclopamine alone has no effect on pathological changes in normal mice. Intervention with cyclopamine in ALI mice led to a reduction in mRNA levels of SHH, PTC, and GLI1 as well as SHH and GLI1 protein levels; meanwhile, the pathological injury scores of lung tissues, thickness of alveolar septa, W/D, and mRNA expression levels of TNF-α increased compared with mice receiving LPS only.The SHH signaling pathway was activated in response to LPS-induced ALI, and up-regulation of SHH expression could alleviate lung injury and be involved in the repair of injured lung

  6. [Pulmonary apoptosis and necrosis in hyperoxia-induced acute mouse lung injury].

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    Zhang, Xiang-feng; Foda, Hussein D

    2004-07-01

    To investigate the pathways to cell death in hyperoxia-induced lung injury and the functional significance of apoptosis in vivo in response to hyperoxia. Seventy-two mice were exposed in sealed cages > 98% oxygen (for 24 - 72 h) or room air, and the severity of lung injury and epithelium sloughing was evaluated. The extent and location of apoptosis in injured lung tissues were studied by terminal transferase dUTP end labeling assay (TUNEL), reverse transcript-polymerase chain reaction (RT-PCR) and immunohistochemistry. Hyperoxia caused acute lung injury; the hyperoxic stress resulted in marked epithelium sloughing. TUNEL assay exhibited increased apoptosis index both in alveolar epithelial cells and bronchial epithelial cells in sections from mice after 48 h hyperoxia compared with their control group (0.51 +/- 0.10, 0.46 +/- 0.08 verse 0.04 +/- 0.02, 0.02 +/- 0.01). This was accompanied by increased expression of caspase-3 mRNA in lung tissues after 48 h hyperoxia compared with their control group (0.53 +/- 0.09 verse 0.34 +/- 0.07), the expression was higher at 72 h of hyperoxia (0.60 +/- 0.08). Immunohistochemistry study showed caspase-3 protein was located in cytoplasm and nuclei of airway epithelial cells, alveolar epithelial cells and macrophage in hyperoxia mice. The expression of caspase-3 protein in airway epithelium significantly increased at 24 h of hyperoxia compared with their control group (41.62 +/- 3.46 verse 15.86 +/- 1.84), the expression level was highest at 72 h of hyperoxia (55.24 +/- 6.80). Both apoptosis and necrosis contribute to cell death during hyperoxia. Apoptosis plays an important role in alveolar damage and cell death from hyperoxia.

  7. DIETARY FLAXSEED PREVENTS RADIATION-INDUCED OXIDATIVE LUNG DAMAGE, INFLAMMATION AND FIBROSIS IN A MOUSE MODEL OF THORACIC RADIATION INJURY

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    Lee, James C.; Krochak, Ryan; Blouin, Aaron; Kanterakis, Stathis; Chatterjee, Shampa; Arguiri, Evguenia; Vachani, Anil; Solomides, Charalambos C.; Cengel, Keith A.; Christofidou-Solomidou, Melpo

    2009-01-01

    Flaxseed (FS) has high contents of omega-3 fatty acids and lignans with antioxidant properties. Its use in preventing thoracic X-ray radiation therapy (XRT)-induced pneumonopathy has never been evaluated. We evaluated FS supplementation given to mice given before and post-XRT. FS-derived lignans, known for their direct antioxidant properties, were evaluated in abrogating ROS generation in cultured endothelial cells following gamma radiation exposure. Mice were fed 10% FS or isocaloric control diet for three weeks and given 13.5 Gy thoracic XRT. Lungs were evaluated at 24 hours for markers of radiation-induced injury, three weeks for acute lung damage (lipid peroxidation, lung edema and inflammation), and at four months for late lung damage (inflammation and fibrosis). FS-Lignans blunted ROS generation in vitro, resulting from radiation in a dose-dependent manner. FS-fed mice had reduced expression of lung injury biomarkers (Bax, p21, and TGF-beta1) at 24 hours following XRT and reduced oxidative lung damage as measured by malondialdehyde (MDA) levels at 3 weeks following XRT. In addition, FS-fed mice had decreased lung fibrosis as determined by hydroxyproline content and decreased inflammatory cell influx into lungs at 4 months post XRT. Importantly, when Lewis Lung carcinoma cells were injected systemically in mice, FS dietary supplementation did not appear to protect lung tumors from responding to thoracic XRT. Dietary FS is protective against pulmonary fibrosis, inflammation and oxidative lung damage in a murine model. Moreover, in this model, tumor radioprotection was not observed. FS lignans exhibited potent radiation-induced ROS scavenging action. Taken together, these data suggest that dietary flaxseed may be clinically useful as an agent to increase the therapeutic index of thoracic XRT by increasing the radiation tolerance of lung tissues. PMID:18981722

  8. Understanding Lung Deposition of Alpha-1 Antitrypsin in Acute Experimental Mouse Lung Injury Model Using Fluorescence Microscopy

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    Mengmeng Wang

    2016-01-01

    Full Text Available Human plasma-derived α1-antitrypsin (AAT delivered by intravenous infusion is used as augmentation therapy in patients with emphysema who have a genetic mutation resulting in deficiency of AAT. Inhalation is an alternative route of administration that can potentially increase the efficacy and convenience of treatment. This study was conducted to determine whether delivery to the lungs, initially via the intratracheal (IT route of administration, would deliver efficacious levels of a recombinant AAT (rAAT to the site of action in the lungs in mice. 125I-radiolabeled rAAT, fluorophore-conjugated rAAT (rAAT-Alexa488, and NE680 (neutrophil elastase 680, a silent fluorescent substrate of neutrophil elastase which fluoresces in the near-infrared range upon activation by neutrophil elastase were used to characterize the pharmacokinetics and tissue distribution profile, distribution of rAAT within the lung, and efficacy of rAAT to inhibit neutrophil elastase at the site of action, respectively. The study has demonstrated that rAAT was able to gain access to locations where neutrophil elastase was localized. The histochemical quantification of rAAT activity relative to dose at the site of action provided here will improve confidence in predicting the human dose via the inhalation route.

  9. PATHOGENETIC MECHANISMS OF LUNG INJURY

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    M. I. Marushchak

    2016-05-01

    Results and conclusions. The topical issue of lung pathogenetic injury is to understand the signs and mechanisms responsible for regulation of free radical oxidation and antioxidant defense system, the role of pro- and anti-inflammatory molecules, the influence of active metabolites on the process of restoration and survival of the respiratory tract cells in cases of acute lung injury. The studies of this processes will help to obtain more knowledge on lung pathology.

  10. Biomarkers in acute lung injury.

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    Mokra, Daniela; Kosutova, Petra

    2015-04-01

    Acute respiratory distress syndrome (ARDS) and its milder form acute lung injury (ALI) may result from various diseases and situations including sepsis, pneumonia, trauma, acute pancreatitis, aspiration of gastric contents, near-drowning etc. ALI/ARDS is characterized by diffuse alveolar injury, lung edema formation, neutrophil-derived inflammation, and surfactant dysfunction. Clinically, ALI/ARDS is manifested by decreased lung compliance, severe hypoxemia, and bilateral pulmonary infiltrates. Severity and further characteristics of ALI/ARDS may be detected by biomarkers in the plasma and bronchoalveolar lavage fluid (or tracheal aspirate) of patients. Changed concentrations of individual markers may suggest injury or activation of the specific types of lung cells-epithelial or endothelial cells, neutrophils, macrophages, etc.), and thereby help in diagnostics and in evaluation of the patient's clinical status and the treatment efficacy. This chapter reviews various biomarkers of acute lung injury and evaluates their usefulness in diagnostics and prognostication of ALI/ARDS.

  11. TNFR-Fc减轻LPS所致小鼠ALI炎症反应损伤%Protective role of TNFR-Fc in mouse acute lung injury induced by lipopolysaccharide

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    袁伟锋; 李理; 徐虹; 黄文杰

    2011-01-01

    目的:评价肿瘤坏死因子受体-Fc融合蛋白(TNFR-Fc)能否有效下调炎症反应而减轻急性肺损伤(ALI)小鼠的肺组织破坏.方法:小鼠随机分为脂多糖(LPS)组、TNFR-Fc+LPS组和对照组.气管内滴入LPS复制ALI小鼠模型,TNFR-Fc组在滴入LPS前24 h腹膜腔注射TNFR-Fc (0.4 mg/kg),在滴入LPS后2 h收集标本,检测肺湿/干重、肺泡蛋白含量与肺组织病理评分;ELISA法检测血清TNF-α浓度及检测肺泡灌洗液与血清IL-1β、IL-6、IL-10与IFN-γ浓度.结果:TNFR-Fc显著降低血清TNF-α浓度(P<0.05),轻度降低肺湿/干重比例,显著降低BALF蛋白浓度(P<0.05),显著降低ALI评分数值(P<0.05).TNFR-Fc显著降低致炎症细胞因子IL-6在BALF(P<0.05)与血清(P<0.05)中的浓度,轻度提高BALF中IL-10浓度(P>0.05),但其差异不显著,亦能显著提高血清IL-10浓度(P<0.05).IL-1β与IFN-γ水平处理前后变化不显著.结论:TNFR-Fc中和ALI中过度表达的TNF-α,下调以IL-6为代表的炎症反应,减轻ALI的肺组织破坏.%AIM: Acute lung injury ( ALI ) is associated with excessive inflammation caused by high tumor necrosis factor α( TNF - α ) concentration. We hypothesized that anti - TNF - a therapy would have beneficial effects on mouse ALI model via down - regulating the inflammation. METHODS: Lipopolysaccharide( LPS, 5 mg/kg ) was intratra-cheally administered to BALB/c mice ( 8 ~ 10 weeks old ). Twenty - four hours before LPS treatment, the mice were intrap-eritoneally injected with TNF receptor - Fc fusion protein( TNFR - Fc ) once at a dose of 0.4 mg/kg. Wet to dry ratio of the lung tissues and protein concentration in bronchoalveolar lavage fluid( BALF ) were detected. The histological changes of the lung tissues were also observed to evaluate lung injury. The concentration of TNF - a. In serum as well as interleukin - 1 β( IL - 1 β ), IL - 6, IL - 10 and interferon γ(IFN - γ ) in BALF and serum were measured by ELISA. RESULTS: TNFR - Fc

  12. Expression level and subcellular localization of heme oxygenase-1 modulates its cytoprotective properties in response to lung injury: a mouse model.

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    Fumihiko Namba

    Full Text Available Premature infants exposed to hyperoxia suffer acute and long-term pulmonary consequences. Nevertheless, neonates survive hyperoxia better than adults. The factors contributing to neonatal hyperoxic tolerance are not fully elucidated. In contrast to adults, heme oxygenase (HO-1, an endoplasmic reticulum (ER-anchored protein, is abundant in the neonatal lung but is not inducible in response to hyperoxia. The latter may be important, because very high levels of HO-1 overexpression are associated with significant oxygen cytotoxicity in vitro. Also, in contrast to adults, HO-1 localizes to the nucleus in neonatal mice exposed to hyperoxia. To understand the mechanisms by which HO-1 expression levels and subcellular localization contribute to hyperoxic tolerance in neonates, lung-specific transgenic mice expressing high or low levels of full-length HO-1 (cytoplasmic, HO-1-FL(H or HO-1-FL(L or C-terminally truncated HO-1 (nuclear, Nuc-HO-1-TR were generated. In HO-1-FL(L, the lungs had a normal alveolar appearance and lesser oxidative damage after hyperoxic exposure. In contrast, in HO-1-FL(H, alveolar wall thickness with type II cell hyperproliferation was observed as well worsened pulmonary function and evidence of abnormal lung cell hyperproliferation in recovery from hyperoxia. In Nuc-HO-1-TR, the lungs had increased DNA oxidative damage, increased poly (ADP-ribose polymerase (PARP protein expression, and reduced poly (ADP-ribose (PAR hydrolysis as well as reduced pulmonary function in recovery from hyperoxia. These data indicate that low cytoplasmic HO-1 levels protect against hyperoxia-induced lung injury by attenuating oxidative stress, whereas high cytoplasmic HO-1 levels worsen lung injury by increasing proliferation and decreasing apoptosis of alveolar type II cells. Enhanced lung nuclear HO-1 levels impaired recovery from hyperoxic lung injury by disabling PAR-dependent regulation of DNA repair. Lastly both high cytoplasmic and nuclear

  13. Augmented oxygen-mediated transcriptional activation of cytochrome P450 (CYP)1A expression and increased susceptibilities to hyperoxic lung injury in transgenic mice carrying the human CYP1A1 or mouse 1A2 promoter in vivo.

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    Jiang, Weiwu; Couroucli, Xanthi I; Wang, Lihua; Barrios, Roberto; Moorthy, Bhagavatula

    2011-04-01

    Supplemental oxygen administration is frequently administered to pre-term and term infants having pulmonary insufficiency. However, hyperoxia contributes to the development of bronchopulmonary dysplasia (BPD) in premature infants. Cytochrome P450 (CYP)A enzymes have been implicated in hyperoxic lung injury. In this study, we tested the hypothesis that hyperoxia induces CYP1A1 and 1A2 enzymes by transcriptional activation of the corresponding promoters in vivo, and transgenic mice expressing the human CYP1A1 or the mouse 1A2 promoter would be more susceptible to hyperoxic lung injury than wild type (WT) mice. Adult WT (CD-1) (12week-old) mice, transgenic mice carrying a 10kb human CYP1A1 promoter and the luciferase (luc) reporter gene (CYP1A1-luc), or mice expressing the mouse CYP1A2 promoter (CYP1A2-luc) were maintained in room air or exposed to hyperoxia for 24-72h. Hyperoxia exposure of CYP1A1-luc mice for 24 and 48h resulted in 2.5- and 1.25-fold increases, respectively, in signal intensities, compared to room air controls. By 72h, the induction had declined to control levels. CYP1A2-luc mice also showed enhanced luc expression after 24-48h, albeit to a lesser extent than those expressing the CYP1A1 promoter. Also, these mice showed decreased levels of endogenous CYP1A1 and 1A2 expression after prolonged hyperoxia, and were also more susceptible to lung injury than similarly exposed WT mice, with CYP1A2-luc mice showing the greatest injury. Our results support the hypothesis that hyperoxia induces CYP1A enzymes by transcriptional activation of its corresponding promoters, and that decreased endogenous expression of these enzymes contribute to the increased susceptibilities to hyperoxic lung injury in the transgenic animals. In summary, this is the first report providing direct evidence of hyperoxia-mediated induction of CYP1A1 and CYP1A2 expression in vivo by mechanisms entailing transcriptional activation of the corresponding promoters, a phenomenon that has

  14. RAGE inhibition reduces acute lung injury in mice.

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    Blondonnet, Raiko; Audard, Jules; Belville, Corinne; Clairefond, Gael; Lutz, Jean; Bouvier, Damien; Roszyk, Laurence; Gross, Christelle; Lavergne, Marilyne; Fournet, Marianne; Blanchon, Loic; Vachias, Caroline; Damon-Soubeyrand, Christelle; Sapin, Vincent; Constantin, Jean-Michel; Jabaudon, Matthieu

    2017-08-03

    The receptor for advanced glycation end-products (RAGE) is involved in inflammatory response during acute respiratory distress syndrome (ARDS). Growing body of evidence support strategies of RAGE inhibition in experimental lung injury, but its modalities and effects remain underinvestigated. Anesthetised C57BL/6JRj mice were divided in four groups; three of them underwent orotracheal instillation of acid and were treated with anti-RAGE monoclonal antibody (mAb) or recombinant soluble RAGE (sRAGE), acting as a decoy receptor. The fourth group served as a control. Lung injury was assessed by the analysis of blood gases, alveolar permeability, histology, AFC, and cytokines. Lung expression and distribution epithelial channels ENaC, Na,K-ATPase, and aquaporin (AQP)-5 were assessed. Treatment with either anti-RAGE mAb or sRAGE improved lung injury, arterial oxygenation and decreased alveolar inflammation in acid-injured animals. Anti-RAGE therapies were associated with restored AFC and increased lung expression of AQP-5 in alveolar cell. Blocking RAGE had potential therapeutic effects in a translational mouse model of ARDS, possibly through a decrease in alveolar type 1 epithelial cell injury as shown by restored AFC and lung AQP-5 expression. Further mechanistic studies are warranted to describe intracellular pathways that may control such effects of RAGE on lung epithelial injury and repair.

  15. Mitochondrial biogenesis in the pulmonary vasculature during inhalation lung injury and fibrosis

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    Cell survival and injury repair is facilitated by mitochondrial biogenesis; however, the role of this process in lung repair is unknown. We evaluated mitochondrial biogenesis in the mouse lung in two injuries that cause acute inflammation and in two that cause chronic inflammatio...

  16. Sox9 Activation is Essential for the Recovery of Lung Function after Acute Lung Injury

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    Lei Li

    2015-09-01

    Full Text Available Background/Aims: Acute lung injury (ALI often predisposes acute respiratory distress syndrome (ARDS in humans, and is featured with neutrophilic alveolitis, injury of the alveolar epithelium and endothelium, hyaline membrane formation, and microvascular thrombi. Although the pathogenesis of ALI is relatively well studied, the knowledge on the molecular regulation of the post-ALI lung recovery are poorly understood. Methods: Here, we used a widely applied bleomycin-induced ALI model to study the molecular mechanisms that underlie the post-ALI lung recovery in mice. We analyzed Sox9 expression in mouse lung by RT-qPCR, Western blot and immunohistochemistry. We analyzed miR-101 levels in mouse lung by RT-qPCR. We inhibited Sox9 in mouse lung by expressing either shRNA for Sox9 or miR-101, and analyzed the effects of Sox9 suppression on lung recovery. Results: We detected a significant increase in Sox9 protein but not mRNA, and a signifcant decrease in miR-101 levels in the mouse lung after ALI. MiR-101 was found to target 3'-UTR of Sox9 mRNA to inhibit its expression. Sox9 inhibition by either shRNA for Sox9 or by miR-101 further impaired the functional recovery of the lung after ALI. Conclusion: Our data suggest that Sox9 activation is essential for the recovery of lung function after ALI, which highlights a previously unappreciated mechanism that controls the post-ALI lung recovery.

  17. Do variations in mast cell hyperplasia account for differences in radiation-induced lung injury among different mouse strains, rats and nonhuman primates?

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    Down, Julian D; Medhora, Meetha; Jackson, Isabel L; Cline, J Mark; Vujaskovic, Zeljko

    2013-08-01

    The role of mast cell infiltrates in the pathology of radiation damage to the lung has been a subject of continuing investigation over the past four decades. This has been accompanied by a number of proposals as to how mast cells and the secretory products thereof participate in the generation of acute inflammation (pneumonitis) and the chronic process of collagen deposition (fibrosis). An additional pathophysiology examines the possible connection between mast cell hyperplasia and pulmonary hypertension through the release of vasoactive mediators. The timing and magnitude of pneumonitis and fibrosis are known to vary tremendously among different genetic mouse strains and animal species. Therefore, we have systematically compared mast cell numbers in lung sections from nine mouse strains, two rat strains and nonhuman primates (NHP) after whole thorax irradiation (WTI) at doses ranging from 10-15 Gy and at the time of entering respiratory distress. Mice of the BALB/c strain had a dramatic increase in interstitial mast cell numbers, similar to WAG/Rij and August rats, while relatively low levels of mast cell infiltrate were observed in other mouse strains (CBA, C3H, B6, C57L, WHT and TO mice). Enumeration of mast cell number in five NHPs (rhesus macaque), exhibiting severe pneumonitis at 17 weeks after 10 Gy WTI, also indicated a low response shared by the majority of mouse strains. There appeared to be no relationship between the mast cell response and the strain-dependent susceptibility towards pneumonitis or fibrosis. Further investigations are required to explore the possible participation of mast cells in mediating specific vascular responses and whether a genetically diverse mast cell response occurs in humans.

  18. Mechanisms of enhanced lung injury during sepsis

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    Czermak, B J; Breckwoldt, M; Ravage, Z B;

    1999-01-01

    A major complication in sepsis is progressively impaired lung function and susceptibility to intrapulmonary infection. Why sepsis predisposes the lung to injury is not clear. In the current studies, rats were rendered septic by cecal ligation/puncture and evaluated for increased susceptibility...... to injury after a direct pulmonary insult (deposition of IgG immune complexes or airway instillation of lipopolysaccharide). By itself, cecal ligation/puncture did not produce evidence of lung injury. However, after a direct pulmonary insult, lung injury in septic animals was significantly enhanced...... or treatment with anti-C5a abolished all evidence of enhanced lung injury in septic animals. When stimulated in vitro, bronchoalveolar lavage macrophages from septic animals had greatly enhanced CXC chemokine responses as compared with macrophages from sham-operated animals or from septic animals that had been...

  19. Rabbit lung injury induced by explosive decompression

    Institute of Scientific and Technical Information of China (English)

    2000-01-01

    Objective: To study the mechanism of rabbit lunginjury caused by explosive decompression. Methods: A total of 42 rabbits and 10 rats were served as the experimental animals. A slow recompressiondecompression test and an explosive decompression test were applied to the animals, respectively. And the effects of the given tests on the animals were discussed. Results: The slow recompression-decompression did not cause an obvious lung injury, but the explosive decompression did cause lung injuries in different degrees. The greater the decompression range was, the shorter the decompression duration was, and the heavier the lung injuries were. Conclusions: Explosive decompression can cause a similar lung injury as shock wave does. The primary mechanical causes of the lung injury might be a tensile strain or stress in the alveolar wall and the pulmonary surface's impacts on the inside wall of the chest.

  20. Hydrostatin-SN1, a Sea Snake-Derived Bioactive Peptide, Reduces Inflammation in a Mouse Model of Acute Lung Injury.

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    Wu, Guosheng; Wang, Junjie; Luo, Pengfei; Li, An; Tian, Song; Jiang, Hailong; Zheng, Yongjun; Zhu, Feng; Lu, Yiming; Xia, Zhaofan

    2017-01-01

    Snake venom has been used for centuries as a traditional Chinese medicine. Hydrostatin-SN1 (H-SN1), a bioactive peptide extracted from the Hydrophis cyanocinctus venom gland T7 phage display library, was reported to have the ability to reduce inflammation in a dextran sulfate sodium-induced murine colitis model. In this study, we sought to investigate the inhibitory potential of H-SN1 on inflammation in a murine model of lipopolysaccharide (LPS)-induced acute lung injury (ALI), and elucidate the anti-inflammatory mechanism in LPS-stimulated RAW 264.7 cells. In vivo, C57BL/6 male mice were intratracheally instilled with LPS or physiological saline with concurrent intraperitoneal injection of H-SN1 or saline alone. Lung histopathologic changes, lung wet-to-dry weight ratio, and myeloperoxidase activity in lung tissues were assessed. Total cell number, the protein concentration, and cytokine levels were determined in the bronchial alveolar lavage fluid. In vitro, RAW 264.7 cells were treated with various concentrations of H-SN1 for 2 h followed by incubation with or without 1 μg/ml LPS for 0.5 or 24 h. The mRNA expression of inflammatory cytokines was determined via RT-PCR and protein levels in the supernatants were measured via ELISA. Extracellular-signal related kinase 1/2 (ERK1/2) and nuclear factor-κB (NF-κB) pathways were analyzed via western blot. H-SN1 improved pulmonary edema status, decreased vascular permeability, suppressed pro-inflammatory cytokine production, and lessened lung morphological injury. H-SN1 also dose-dependently inhibited the mRNA expression and release of TNF-α, IL-6, and IL-1β in LPS-stimulated RAW 264.7 cells. Moreover, H-SN1 inhibited the LPS-induced phosphorylation of ERK1/2 and the nuclear translocation of NF-κB. Our results suggest that H-SN1 could attenuate LPS-induced ALI in mice, which is associated with the anti-inflammatory effect of H-SN1. The mechanism might involve inhibiting the production of inflammatory cytokines by

  1. Hydrostatin-SN1, a Sea Snake-Derived Bioactive Peptide, Reduces Inflammation in a Mouse Model of Acute Lung Injury

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    Guosheng Wu

    2017-05-01

    Full Text Available Snake venom has been used for centuries as a traditional Chinese medicine. Hydrostatin-SN1 (H-SN1, a bioactive peptide extracted from the Hydrophis cyanocinctus venom gland T7 phage display library, was reported to have the ability to reduce inflammation in a dextran sulfate sodium-induced murine colitis model. In this study, we sought to investigate the inhibitory potential of H-SN1 on inflammation in a murine model of lipopolysaccharide (LPS-induced acute lung injury (ALI, and elucidate the anti-inflammatory mechanism in LPS-stimulated RAW 264.7 cells. In vivo, C57BL/6 male mice were intratracheally instilled with LPS or physiological saline with concurrent intraperitoneal injection of H-SN1 or saline alone. Lung histopathologic changes, lung wet-to-dry weight ratio, and myeloperoxidase activity in lung tissues were assessed. Total cell number, the protein concentration, and cytokine levels were determined in the bronchial alveolar lavage fluid. In vitro, RAW 264.7 cells were treated with various concentrations of H-SN1 for 2 h followed by incubation with or without 1 μg/ml LPS for 0.5 or 24 h. The mRNA expression of inflammatory cytokines was determined via RT-PCR and protein levels in the supernatants were measured via ELISA. Extracellular-signal related kinase 1/2 (ERK1/2 and nuclear factor-κB (NF-κB pathways were analyzed via western blot. H-SN1 improved pulmonary edema status, decreased vascular permeability, suppressed pro-inflammatory cytokine production, and lessened lung morphological injury. H-SN1 also dose-dependently inhibited the mRNA expression and release of TNF-α, IL-6, and IL-1β in LPS-stimulated RAW 264.7 cells. Moreover, H-SN1 inhibited the LPS-induced phosphorylation of ERK1/2 and the nuclear translocation of NF-κB. Our results suggest that H-SN1 could attenuate LPS-induced ALI in mice, which is associated with the anti-inflammatory effect of H-SN1. The mechanism might involve inhibiting the production of inflammatory

  2. Soluble ICAM-1 activates lung macrophages and enhances lung injury

    DEFF Research Database (Denmark)

    Schmal, H; Czermak, B J; Lentsch, A B

    1998-01-01

    Because of the important role of rat ICAM-1 in the development of lung inflammatory injury, soluble recombinant rat ICAM-1 (sICAM-1) was expressed in bacteria, and its biologic activities were evaluated. Purified sICAM-1 did bind to rat alveolar macrophages in a dose-dependent manner and induced...... of the proteosome inhibitor and by genistein. Alveolar macrophages showed adherence to immobilized sICAM-1 in a CD18-dependent manner. Finally, airway instillation of sICAM-1 intensified lung injury produced by intrapulmonary deposition of IgG immune complexes in a manner associated with enhanced lung production...... of TNF-alpha and MIP-2 and increased neutrophil recruitment. Therefore, through engagement of beta2 integrins, sICAM-1 enhances alveolar macrophage production of MIP-2 and TNF-alpha, the result of which is intensified lung injury after intrapulmonary disposition of immune complexes....

  3. Bleomycin-Induced Lung Injury

    Directory of Open Access Journals (Sweden)

    Tomás Reinert

    2013-01-01

    Full Text Available Bleomycin is a chemotherapeutic agent commonly used to treat curable diseases such as germinative tumors and Hodgkin’s lymphoma. The major limitation of bleomycin therapy is pulmonary toxicity, which can be life threatening in up to 10% of patients receiving the drug. The mechanism of bleomycin-induced pneumonitis (BIP involves oxidative damage, relative deficiency of the deactivating enzyme bleomycin hydrolase, genetic susceptibility, and the elaboration of inflammatory cytokines. Ultimately, BIP can progress to lung fibrosis. The diagnosis of BIP is established by the combination of systemic symptoms, radiological and histological findings, and respiratory function tests abnormalities, while other disorders should be excluded. Although the diagnosis and pathophysiology of this disease have been better characterized over the past few years, there is no effective therapy for the disease. In general, the clinical picture is extremely complex. A greater understanding of the BIP pathogenesis may lead to the development of new agents capable of preventing or even treating the injury already present. Physicians who prescribe bleomycin must be aware of the potential pulmonary toxicity, especially in the presence of risk factors. This review will focus on BIP, mainly regarding recent advances and perspectives in diagnosis and treatment.

  4. Mouse lung adhesion assay for Bordetella pertussis

    Energy Technology Data Exchange (ETDEWEB)

    Burns, K.A.; Freer, J.H. (Department of Microbiology, Alexander Stone Building, Bearsden, Glasgow, Scotland)

    1982-03-01

    The ability of Bordetella pertussis to adhere to cell surfaces has been demonstrated by adhesion to tissue culture cells and adhesion to chicken, hamster or rabbit trachea in organ culture. In this report a mouse lung assay for adhesion is described and the results obtained using two virulent strains of B. pertussis and their avirulent counterparts. These were a C modulation of one of the original virulent strains and a phase IV variant of the other virulent strain. Organisms were radiolabelled by adding 1 ..mu..Ci (37 K Bq) of (/sup 14/C)glutamic acid per 10 ml of culture medium before inoculation and incubation for 5 days. The lungs were washed by perfusion in situ with at least two volumes (1 ml) of sterile 1% (w/v) casamino acids. The percentage of the inoculated organisms retained in the lungs was determined, after removal of the lungs, by one of the following two methods: viable count or radioactive count. Results for both methods were expressed as the percentage of the inoculum retained in the lungs plus or minus one standard deviation.

  5. Transfusion-related acute lung injury.

    Science.gov (United States)

    Jawa, Randeep S; Anillo, Sergio; Kulaylat, Mahmoud N

    2008-01-01

    Transfusion-related acute lung injury (TRALI) refers to a clinical syndrome of acute lung injury that occurs in a temporal relationship with the transfusion of blood products. Because of the difficulty in making its diagnosis, TRALI is often underreported. Three not necessarily mutually exclusive hypotheses have been described to explain its etiogenesis: antibody mediated, non-antibody mediated, and two hit mechanisms. Treatment is primarily supportive and includes supplemental oxygen. Diuretics are generally not indicated, as hypovolemia should be avoided. Compared with many other forms of acute lung injury, including the acute respiratory distress syndrome, TRALI is generally transient, reverses spontaneously, and carries a better prognosis. A variety of prevention strategies have been proposed, ranging from restrictive transfusion strategies to using plasma derived only from males.

  6. 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.

  7. Biomarkers of Lung Injury in Cardiothoracic Surgery

    Science.gov (United States)

    Engels, Gerwin Erik; van Oeveren, Willem

    2015-01-01

    Diagnosis of pulmonary dysfunction is currently almost entirely based on a vast series of physiological changes, but comprehensive research is focused on determining biomarkers for early diagnosis of pulmonary dysfunction. Here we discuss the use of biomarkers of lung injury in cardiothoracic surgery and their ability to detect subtle pulmonary dysfunction in the perioperative period. Degranulation products of neutrophils are often used as biomarker since they have detrimental effects on the pulmonary tissue by themselves. However, these substances are not lung specific. Lung epithelium specific proteins offer more specificity and slowly find their way into clinical studies. PMID:25866435

  8. Stem cells and repair of lung injuries

    Directory of Open Access Journals (Sweden)

    Randell Scott H

    2004-07-01

    Full Text Available Abstract Fueled by the promise of regenerative medicine, currently there is unprecedented interest in stem cells. Furthermore, there have been revolutionary, but somewhat controversial, advances in our understanding of stem cell biology. Stem cells likely play key roles in the repair of diverse lung injuries. However, due to very low rates of cellular proliferation in vivo in the normal steady state, cellular and architectural complexity of the respiratory tract, and the lack of an intensive research effort, lung stem cells remain poorly understood compared to those in other major organ systems. In the present review, we concisely explore the conceptual framework of stem cell biology and recent advances pertinent to the lungs. We illustrate lung diseases in which manipulation of stem cells may be physiologically significant and highlight the challenges facing stem cell-related therapy in the lung.

  9. Interleukin-33 potentiates bleomycin-induced lung injury.

    Science.gov (United States)

    Luzina, Irina G; Kopach, Pavel; Lockatell, Virginia; Kang, Phillip H; Nagarsekar, Ashish; Burke, Allen P; Hasday, Jeffrey D; Todd, Nevins W; Atamas, Sergei P

    2013-12-01

    The mechanisms of interstitial lung disease (ILD) remain incompletely understood, although recent observations have suggested an important contribution by IL-33. Substantial elevations in IL-33 expression were found in the lungs of patients with idiopathic pulmonary fibrosis and scleroderma lung disease, as well as in the bleomycin injury mouse model. Most of the observed IL-33 expression was intracellular and intranuclear, suggesting involvement of the full-length (fl) protein, but not of the proteolytically processed mature IL-33 cytokine. The effects of flIL-33 on mouse lungs were assessed independently and in combination with bleomycin injury, using recombinant adenovirus-mediated gene delivery. Bleomycin-induced changes were not affected by gene deficiency of the IL-33 receptor T1/ST2. Combined flIL-33 expression and bleomycin injury exerted a synergistic effect on pulmonary lymphocyte and collagen accumulation, which could be explained by synergistic regulation of the cytokines transforming growth factor-β, IL-6, monocyte chemotactic protein-1, macrophage inflammatory protein\\x{2013}1α, and tumor necrosis factor-α. By contrast, no increase in the levels of the Th2 cytokines IL-4, IL-5, or IL-13 was evident. Moreover, flIL-33 was found to increase the expression of several heat shock proteins (HSPs) significantly, and in particular HSP70, which is known to be associated with ILD. Thus, flIL-33 is a synergistic proinflammatory and profibrotic regulator that acts by stimulating the expression of several non-Th2 cytokines, and activates the expression of HSP70.

  10. 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...

  11. Potential Biochemical Mechanisms of Lung Injury in Diabetes

    Science.gov (United States)

    Zheng, Hong; Wu, Jinzi; Jin, Zhen; Yan, Liang-Jun

    2017-01-01

    Accumulating evidence has shown that the lung is one of the target organs for microangiopathy in patients with either type 1 or type 2 diabetes mellitus (DM). Diabetes is associated with physiological and structural abnormalities in the diabetic lung concurrent with attenuated lung function. Despite intensive investigations in recent years, the pathogenic mechanisms of diabetic lung injury remain largely elusive. In this review, we summarize currently postulated mechanisms of diabetic lung injury. We mainly focus on the pathogenesis of diabetic lung injury that implicates key pathways, including oxidative stress, non-enzymatic protein glycosylation, polyol pathway, NF-κB pathway, and protein kinase c pathway. We also highlight that while numerous studies have mainly focused on tissue or cell damage in the lung, studies focusing on mitochondrial dysfunction in the diabetic lung have remained sketchy. Hence, further understanding of mitochondrial mechanisms of diabetic lung injury should provide invaluable insights into future therapeutic approaches for diabetic lung injury.

  12. Neurological outcome after experimental lung injury.

    Science.gov (United States)

    Bickenbach, Johannes; Biener, Ingeborg; Czaplik, Michael; Nolte, Kay; Dembinski, Rolf; Marx, Gernot; Rossaint, Rolf; Fries, Michael

    2011-12-15

    We examined the influences of acute lung injury and hypoxia on neurological outcome. Functional performance was assessed using a neurocognitive test and a neurologic deficit score (NDS) five days before. On experimental day, mechanically ventilated pigs were randomized to hypoxia only (HO group, n=5) or to acute lung injury (ALI group, n=5). Hemodynamics, respiratory mechanics, systemic cytokines and further physiologic variables were obtained at baseline, at the time of ALI, 2, 4 and 8h thereafter. Subsequently, injured lungs were recruited and animals weaned from the ventilator. Neurocognitive testing was re-examined for five days. Then, brains were harvested for neurohistopathology. After the experiment, neurocognitive performance was significantly worsened and the NDS increased in the ALI group. Histopathology revealed no significant differences. Oxygenation was comparable between groups although significantly higher inspiratory pressures occured after ALI. Cytokines showed a trend towards higher levels after ALI. Neurocognitive compromise after ALI seems due to a more pronounced inflammatory response and complex mechanical ventilation.

  13. Mechanotransduction via TRPV4 regulates inflammation and differentiation in fetal mouse distal lung epithelial cells.

    Science.gov (United States)

    Nayak, Pritha S; Wang, Yulian; Najrana, Tanbir; Priolo, Lauren M; Rios, Mayra; Shaw, Sunil K; Sanchez-Esteban, Juan

    2015-05-27

    Mechanical ventilation plays a central role in the injury of premature lungs. However, the mechanisms by which mechanical signals trigger an inflammatory cascade to promote lung injury are not well-characterized. Transient receptor potential vanilloid 4 (TRPV4), a calcium-permeable mechanoreceptor channel has been shown to be a major determinant of ventilator-induced acute lung injury in adult models. However, the role of these channels as modulators of inflammation in immature lungs is unknown. In this study, we tested the hypothesis that TRPV4 channels are important mechanotransducers in fetal lung injury. Expression of TRPV4 in the mouse fetal lung was investigated by immunohistochemistry, Western blot and qRT-PCR. Isolated fetal epithelial cells were exposed to mechanical stimulation using the Flexcell Strain Unit and inflammation and differentiation were analyzed by ELISA and SP-C mRNA, respectively. TRPV4 is developmentally regulated in the fetal mouse lung; it is expressed in the lung epithelium and increases with advanced gestation. In contrast, in isolated epithelial cells, TRPV4 expression is maximal at E17-E18 of gestation. Mechanical stretch increases TRPV4 in isolated fetal epithelial cells only during the canalicular stage of lung development. Using the TRPV4 agonist GSK1016790A, the antagonist HC-067047, and the cytokine IL-6 as a marker of inflammation, we observed that TRPV4 regulates release of IL-6 via p38 and ERK pathways. Interestingly, stretch-induced differentiation of fetal epithelial cells was also modulated by TRPV4. These studies demonstrate that TRPV4 may play an important role in the transduction of mechanical signals in the fetal lung epithelium by modulating not only inflammation but also the differentiation of fetal epithelial cells.

  14. Toll-like receptor 4 dependent responses to lung injury in a murine model of pulmonary contusion

    OpenAIRE

    2009-01-01

    Blunt chest trauma resulting in pulmonary contusion with an accompanying acute inflammatory response is a common but poorly understood injury. We previously demonstrated that toll-like receptor 2 participates in the inflammatory response to lung injury. We hypothesized that the toll-like receptor 4, in a MyD88-dependent manner, may also participate in the response to lung injury. To investigate this, we used a model of pulmonary contusion in the mouse that is similar to that observed clinical...

  15. Glutathione reductase targeted to type II cells does not protect mice from hyperoxic lung injury.

    Science.gov (United States)

    Heyob, Kathryn M; Rogers, Lynette K; Welty, Stephen E

    2008-12-01

    Exposure of the lung epithelium to reactive oxygen species without adequate antioxidant defenses leads to airway inflammation, and may contribute to lung injury. Glutathione peroxidase catalyzes the reduction of peroxides by oxidation of glutathione (GSH) to glutathione disulfide (GSSG), which can in turn be reduced by glutathione reductase (GR). Increased levels of GSSG have been shown to correlate negatively with outcome after oxidant exposure, and increased GR activity has been protective against hyperoxia in lung epithelial cells in vitro. We tested the hypothesis that increased GR expression targeted to type II alveolar epithelial cells would improve outcome in hyperoxia-induced lung injury. Human GR with a mitochondrial targeting sequence was targeted to mouse type II cells using the SPC promoter. Two transgenic lines were identified, with Line 2 having higher lung GR activities than Line 1. Both transgenic lines had lower lung GSSG levels and higher GSH/GSSG ratios than wild-type. Six-week-old wild-type and transgenic mice were exposed to greater than 95% O2 or room air (RA) for 84 hours. After exposure, Line 2 mice had higher right lung/body weight ratios and lavage protein concentrations than wild-type mice, and both lines 1 and 2 had lower GSSG levels than wild-type mice. These findings suggest that GSSG accumulation in the lung may not play a significant role in the development of hyperoxic lung injury, or that compensatory responses to unregulated GR expression render animals more susceptible to hyperoxic lung injury.

  16. Acute and subacute chemical-induced lung injuries: HRCT findings

    Energy Technology Data Exchange (ETDEWEB)

    Akira, Masanori, E-mail: Akira@kch.hosp.go.jp [Department of Radiology, National Hospital Organization Kinki-Chuo Chest Medical Center, 1180 Nagasone-cho, Kita-ku, Sakai City, Osaka 591-8555 (Japan); Suganuma, Narufumi [Department of Environmental Medicine, Kochi Medical School (Japan)

    2014-08-15

    Lung injury caused by chemicals includes bronchitis, bronchiolitis, chemical pneumonitis, pulmonary edema, acute respiratory distress syndrome, organizing pneumonia, hypersensitivity pneumonitis, acute eosinophilic pneumonia, and sarcoid-like granulomatous lung disease. Each chemical induces variable pathophysiology and the situation resembles to the drug induced lung disease. The HRCT features are variable and nonspecific, however HRCT may be useful in the evaluation of the lung injuries and so we should know about HRCT features of lung parenchymal abnormalities caused by chemicals.

  17. Systemic complement activation, lung injury, and products of lipid peroxidation.

    OpenAIRE

    Ward, P. A.; Till, G O; Hatherill, J. R.; Annesley, T M; Kunkel, R G

    1985-01-01

    Previously we have demonstrated that systemic activation of the complement system after intravenous injection of cobra venom factor (CVF) results in acute lung injury as reflected by increases in the vascular permeability of the lung as well as by morphologic evidence of damage to lung vascular endothelial cells. In using the vascular permeability of the lung as the reference, the current studies show a quantitative correlation between lung injury and the appearance in plasma of lipid peroxid...

  18. Allograft inflammatory factor-1 in the pathogenesis of bleomycin-induced acute lung injury.

    Science.gov (United States)

    Nagahara, Hidetake; Yamamoto, Aihiro; Seno, Takahiro; Obayashi, Hiroshi; Kida, Takashi; Nakabayashi, Amane; Kukida, Yuji; Fujioka, Kazuki; Fujii, Wataru; Murakami, Ken; Kohno, Masataka; Kawahito, Yutaka

    2016-02-01

    Allograft inflammatory factor-1 (AIF-1) is a protein expressed by macrophages infiltrating the area around the coronary arteries of rats with an ectopic cardiac allograft. Some studies have shown that expression of AIF-1 increased in a mouse model of trinitrobenzene sulfonic acid-induced acute colitis and in acute cellular rejection of human cardiac allografts. These results suggest that AIF-1 is related to acute inflammation. The current study used bleomycin-induced acute lung injury to analyze the expression of AIF-1 and to examine its function in acute lung injury. Results showed that AIF-1 was significantly expressed in lung macrophages and increased in bronchoalveolar lavage fluid from mice with bleomycin-induced acute lung injury in comparison to control mice. Recombinant AIF-1 increased the production of IL-6 and TNF-α from RAW264.7 (a mouse macrophage cell line) and primary lung fibroblasts, and it also increased the production of KC (CXCL1) from lung fibroblasts. These results suggest that AIF-1 plays an important role in the mechanism underlying acute lung injury.

  19. Suppression of lung inflammation in an LPS-induced acute lung injury model by the fruit hull of Gleditsia sinensis.

    Science.gov (United States)

    Kim, Kyun Ha; Kwun, Min Jung; Han, Chang Woo; Ha, Ki-Tae; Choi, Jun-Yong; Joo, Myungsoo

    2014-10-15

    The fruit hull of Gleditsia sinensis (FGS) used in traditional Asian medicine was reported to have a preventive effect on lung inflammation in an acute lung injury (ALI) mouse model. Here, we explored FGS as a possible therapeutics against inflammatory lung diseases including ALI, and examined an underlying mechanism for the effect of FGS. The decoction of FGS in water was prepared and fingerprinted. Mice received an intra-tracheal (i.t.) FGS 2 h after an intra-peritoneal (i.p.) injection of lipopolysaccharide (LPS). The effect of FGS on lung inflammation was determined by chest imaging of NF-κB reporter mice, counting inflammatory cells in bronchoalveolar lavage fluid, analyzing lung histology, and performing semi-quantitative RT-PCR analysis of lung tissue. Impact of Nrf2 on FGS effect was assessed by comparing Nrf2 knockout (KO) and wild type (WT) mice that were treated similarly. Bioluminescence from the chest of the reporter mice was progressively increased to a peak at 16 h after an i.p. LPS treatment. FGS treatment 2 h after LPS reduced the bioluminescence and the expression of pro-inflammatory cytokine genes in the lung. While suppressing the infiltration of inflammatory cells to the lungs of WT mice, FGS post-treatment failed to reduce lung inflammation in Nrf2 KO mice. FGS activated Nrf2 and induced Nrf2-dependent gene expression in mouse lung. FGS post-treatment suppressed lung inflammation in an LPS-induced ALI mouse model, which was mediated at least in part by Nrf2. Our results suggest a therapeutic potential of FGS on inflammatory lung diseases.

  20. Relationship between Ulcerative Colitis and Lung Injuries

    Institute of Scientific and Technical Information of China (English)

    Zhi-peng Tang; Jia-wei Wu; Yan-cheng Dai; Ya-li Zhang; Rong-rong Bi

    2015-01-01

    Objective To explore the relationship between ulcerative colitis (UC) and lung injuries by assessing their clinical manifestations and characteristics. Methods From July 2009 to April 2012, 91 UC patients presenting to Longhua Hospital who met the established inclusion and exclusion criteria were enrolled in this retrospective study. According to the scores of disease activity index, the patients were divided into the mild, moderate, and severe groups. Meanwhile, the records of pulmonary symptoms, chest X-ray image, and pulmonary function were reviewed. Results Sixty-eight (74.7%) patients had at least 1 pulmonary symptom, such as cough (38.5%), shortness of breath (27.5%), and expectoration (17.6%). And 77 (84.6%) had at least 1 ventilation abnormality. Vital capacity value was significantly lower in the severe group than that in the mild group (91.82%±10.38%vs. 98.92%±12.12%, P Conclusions Lung injury is a common extraintestinal complication of UC. According to the theory in Traditional Chinese Medicine that the lung and large intestine are related, both the lungs and large intestine should be treated simultaneously.

  1. Lung Injury After One-Lung Ventilation: A Review of the Pathophysiologic Mechanisms Affecting the Ventilated and the Collapsed Lung.

    Science.gov (United States)

    Lohser, Jens; Slinger, Peter

    2015-08-01

    Lung injury is the leading cause of death after thoracic surgery. Initially recognized after pneumonectomy, it has since been described after any period of 1-lung ventilation (OLV), even in the absence of lung resection. Overhydration and high tidal volumes were thought to be responsible at various points; however, it is now recognized that the pathophysiology is more complex and multifactorial. All causative mechanisms known to trigger ventilator-induced lung injury have been described in the OLV setting. The ventilated lung is exposed to high strain secondary to large, nonphysiologic tidal volumes and loss of the normal functional residual capacity. In addition, the ventilated lung experiences oxidative stress, as well as capillary shear stress because of hyperperfusion. Surgical manipulation and/or resection of the collapsed lung may induce lung injury. Re-expansion of the collapsed lung at the conclusion of OLV invariably induces duration-dependent, ischemia-reperfusion injury. Inflammatory cytokines are released in response to localized injury and may promote local and contralateral lung injury. Protective ventilation and volatile anesthesia lessen the degree of injury; however, increases in biochemical and histologic markers of lung injury appear unavoidable. The endothelial glycocalyx may represent a common pathway for lung injury creation during OLV, because it is damaged by most of the recognized lung injurious mechanisms. Experimental therapies to stabilize the endothelial glycocalyx may afford the ability to reduce lung injury in the future. In the interim, protective ventilation with tidal volumes of 4 to 5 mL/kg predicted body weight, positive end-expiratory pressure of 5 to 10 cm H2O, and routine lung recruitment should be used during OLV in an attempt to minimize harmful lung stress and strain. Additional strategies to reduce lung injury include routine volatile anesthesia and efforts to minimize OLV duration and hyperoxia.

  2. Micro-imaging of the Mouse Lung via MRI

    Science.gov (United States)

    Wang, Wei

    Quantitative measurement of lung microstructure is of great significance in assessment of pulmonary disease, particularly in the earliest stages. Conventional stereological assessment of ex-vivo fixed tissue specimens under the microscope has a long and successful tradition and is regarded as a gold standard, but the invasive nature limits its applications and the practicality of use in longitudinal studies. The technique for diffusion MRI-based 3He lung morphometry was previously developed and validated for human lungs, and was recently extended to ex-vivo mouse lungs. The technique yields accurate, quantitative information about the microstructure and geometry of acinar airways. In this dissertation, the 3He lung morphometry technique is for the first time successfully implemented for in-vivo studies of mice. It can generate spatially-resolved maps of parameters that reveal the microstructure of mouse lung. Results in healthy mice indicate excellent agreement between in-vivo morphometry via 3He MRI and microscopic morphometry after sacrifice. The implementation and validation of 3He morphometry in healthy mice open up new avenues for application of the technique as a precise, noninvasive, in-vivo biomarker of changes in lung microstructure, within various mouse models of lung disease. We have applied 3He morphometry to the Sendai mouse model of lung disease. Specifically, the Sendai-virus model of chronic obstructive lung disease has demonstrated an innate immune response in mouse airways that exhibits similarities to the chronic airway inflammation in human COPD and asthma, but the effect on distal lung parenchyma had not been investigated. We imaged the time course and regional distribution of mouse lung microstructural changes in vivo after Sendai virus (SeV) infection with 1H and 3He diffusion MRI. 1H MR images detected the SeV-induced pulmonary inflammation in vivo and 3He lung morphometry showed modest increase in alveolar duct radius distal to airway

  3. Injury to the Developing Lung: experimental and clinic al aspects

    NARCIS (Netherlands)

    I.K.M. Reiss (Irwin)

    2008-01-01

    textabstractInjury to the developing lung or disturbance of normal lung development may lead to a chronic lung disease, bronchopulmonary dysplasia (BPD), which may have long-term effects. BPD is characterized by an arrest of development of the lung and the pulmonary vascular system and occurs in aro

  4. DNaseI Protects against Paraquat-Induced Acute Lung Injury and Pulmonary Fibrosis Mediated by Mitochondrial DNA

    Directory of Open Access Journals (Sweden)

    Guo Li

    2015-01-01

    Full Text Available Background. Paraquat (PQ poisoning is a lethal toxicological challenge that served as a disease model of acute lung injury and pulmonary fibrosis, but the mechanism is undetermined and no effective treatment has been discovered. Methods and Findings. We demonstrated that PQ injures mitochondria and leads to mtDNA release. The mtDNA mediated PBMC recruitment and stimulated the alveolar epithelial cell production of TGF-β1 in vitro. The levels of mtDNA in circulation and bronchial alveolar lavage fluid (BALF were elevated in a mouse of PQ-induced lung injury. DNaseI could protect PQ-induced lung injury and significantly improved survival. Acute lung injury markers, such as TNFα, IL-1β, and IL-6, and marker of fibrosis, collagen I, were downregulated in parallel with the elimination of mtDNA by DNaseI. These data indicate a possible mechanism for PQ-induced, mtDNA-mediated lung injury, which may be shared by other causes of lung injury, as suggested by the same protective effect of DNaseI in bleomycin-induced lung injury model. Interestingly, increased mtDNA in the BALF of patients with amyopathic dermatomyositis-interstitial lung disease can be appreciated. Conclusions. DNaseI targeting mtDNA may be a promising approach for the treatment of PQ-induced acute lung injury and pulmonary fibrosis that merits fast tracking through clinical trials.

  5. 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.

  6. Quantitative analysis of tumor burden in mouse lung via MRI.

    Science.gov (United States)

    Tidwell, Vanessa K; Garbow, Joel R; Krupnick, Alexander S; Engelbach, John A; Nehorai, Arye

    2012-02-01

    Lung cancer is the leading cause of cancer death in the United States. Despite recent advances in screening protocols, the majority of patients still present with advanced or disseminated disease. Preclinical rodent models provide a unique opportunity to test novel therapeutic drugs for targeting lung cancer. Respiratory-gated MRI is a key tool for quantitatively measuring lung-tumor burden and monitoring the time-course progression of individual tumors in mouse models of primary and metastatic lung cancer. However, quantitative analysis of lung-tumor burden in mice by MRI presents significant challenges. Herein, a method for measuring tumor burden based upon average lung-image intensity is described and validated. The method requires accurate lung segmentation; its efficiency and throughput would be greatly aided by the ability to automatically segment the lungs. A technique for automated lung segmentation in the presence of varying tumor burden levels is presented. The method includes development of a new, two-dimensional parametric model of the mouse lungs and a multi-faceted cost function to optimally fit the model parameters to each image. Results demonstrate a strong correlation (0.93), comparable with that of fully manual expert segmentation, between the automated method's tumor-burden metric and the tumor burden measured by lung weight.

  7. 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.

  8. The role of autophagy in lung ischemia/reperfusion injury after lung transplantation in rats

    Science.gov (United States)

    Liu, Sheng; Zhang, Jun; Yu, Bentong; Huang, Lei; Dai, Bin; Liu, Jichun; Tang, Jian

    2016-01-01

    Background: The aim of this study was to explore the role of autophagy in the cold I/R injury following lung transplantation. Methods: The rat orthotopic lung transplantation model was established to perform the level of autophagy in the cold I/R injury in this study. The pretreatment of inhibitor (3-Methyladenine [3-MA]) and activator (rapamycin [RAPA]) of autophagy were performed to assess the role of autophagy in the cold I/R injury following lung transplantation in rats. Results: After lung transplantation, the autophagy, lung cell apoptosis and lung injury were aggravated and peaked at 6 h following the transplantation. The inhibition of autophagy by 3-MA induced downregulated of autophagy, decreased cell apoptosis. Meanwhile, the lung injury, which was indicated by calculating the peak inspiratory pressure (PIP), pulmonary vein blood gas analysis (PO2) and ratio of wet to dry in lung (W/D), was ameliorated after treatment with 3-MA. The activation of autophagy by RAPA causing the upregulated of autophagy and apoptosis of lung cells, and enhanced the lung injury. Conclusion: All the results suggested that the autophagy was involved in the cold I/R injury in lung transplantation model, and played a potential role on the regulation of I/R injury after lung transplantation. PMID:27648150

  9. Spontaneous breathing during high-frequency oscillatory ventilation improves regional lung characteristics in experimental lung injury

    NARCIS (Netherlands)

    van Heerde, M.; Roubik, K.; Kopelent, V.; Kneyber, M. C. J.; Markhorst, D. G.

    2010-01-01

    Background Maintenance of spontaneous breathing is advocated in mechanical ventilation. This study evaluates the effect of spontaneous breathing on regional lung characteristics during high-frequency oscillatory (HFO) ventilation in an animal model of mild lung injury. Methods Lung injury was

  10. Spontaneous breathing during high-frequency oscillatory ventilation improves regional lung characteristics in experimental lung injury

    NARCIS (Netherlands)

    van Heerde, M.; Roubik, K.; Kopelent, V.; Kneyber, M. C. J.; Markhorst, D. G.

    2010-01-01

    Background Maintenance of spontaneous breathing is advocated in mechanical ventilation. This study evaluates the effect of spontaneous breathing on regional lung characteristics during high-frequency oscillatory (HFO) ventilation in an animal model of mild lung injury. Methods Lung injury was induce

  11. Pathogenesis of acute lung injury in severe acute pancreatitis

    Institute of Scientific and Technical Information of China (English)

    SHI Lei; YUE Yuan; ZHANG Mei; PAN Cheng-en

    2005-01-01

    Objective:To study the pathogenesis of acute lung injury in severe acute pancreatitis (SAP). Methods:Rats were sacrificed at 1, 3, 5, 6, 9 and 12 h after establishment of inducing model. Pancreas and lung tissues were obtained for pathological study, microvascular permeability and MPO examination. Gene expressions of TNF-α and ICAM-1 in pancreas and lung tissues were detected by RT-PCR. Results:After inducing SAP model, the injury degree of the pancreas and the lung increased gradually, accompanied with gradually increased MPO activity and microvascular permeability. Gene expressions of TNF-α and ICAM-1 in pancreas rose at 1 h and reached peak at 7 h. Relatively, their gene expressions in the lungs only rose slightly at 1 h and reached peak at 9-12 h gradually. Conclusion:There is an obvious time window between SAP and lung injury, when earlier protection is beneficial to prevent development of acute lung injury.

  12. Differential responses in the lungs of newborn mouse pups exposed to 85% or >95% oxygen.

    Science.gov (United States)

    Rogers, Lynette K; Tipple, Trent E; Nelin, Leif D; Welty, Stephen E

    2009-01-01

    Premature infants often develop serious clinical complications associated with respiratory failure and hyperoxic lung injury that includes lung inflammation and alterations in lung development. The goal of these studies is to test the hypothesis that there are differences in the course of lung injury in newborn mice exposed to 85% or >95% oxygen that provide models to address the differential effects of oxidation and inflammation. Our results indicate differences between the 85% and >95% O2 exposure groups by day 14 in weight gain and lung alveolarization. Inflammation, assessed by neutrophil counts, was observed in both hyperoxia groups by day 3 but was dramatically greater in the >95% O2-exposed groups by day 14 and associated with greater developmental deficits. Cytoplasmic phospholipase A2, cyclooxygenase-2, and 5-lipoxygenase levels were elevated but no patterns of differences were observed between exposure groups. Prostaglandins D2, E2, and F2alpha were increased in the tissues from mouse pups exposed to >95% O2 at 7 d indicating a differential expression of cyclooxygenase-2 products. Our data indicate that there are differences in the models of 85% or >95% O2 exposure and these differences may provide mechanistic insights into hyperoxic lung injury in an immature system.

  13. Differential Responses in the Lungs of Newborn Mouse Pups Exposed to 85% or >95% Oxygen

    Science.gov (United States)

    Rogers, Lynette K.; Tipple, Trent E.; Nelin, Leif D.; Welty, Stephen E.

    2008-01-01

    Premature infants often develop serious clinical complications associated with respiratory failure and hyperoxic lung injury that include lung inflammation, and alterations in lung development. The goal of these studies is to test the hypothesis that there are differences in the course of lung injury in newborn mice exposed to 85% or >95% oxygen that provide models to address the differential effects of oxidation and inflammation. Our results indicate differences between the 85% and >95% O2 exposure groups by day 14 in weight gain and lung alveolarization. Inflammation, assessed by neutrophil counts, was observed in both hyperoxia groups by day 3 but was dramatically greater in the >95% O2 exposed groups by day 14 and associated with greater developmental deficits. Cytoplasmic phospholipase A2, cyclooxygenase-2, and 5-lipoxygenase levels were elevated but no patterns of differences were observed between exposure groups. Prostaglandins (PG) D2, E2, and F2α were increased in the tissues from mouse pups exposed to >95% O2 at 7 days indicating a differential expression of COX-2 products. Our data indicate that there are differences in the models of 85% or >95% O2 exposure and these differences may provide mechanistic insights into hyperoxic lung injury in an immature system. PMID:18703992

  14. Surfactant for pediatric acute lung injury.

    Science.gov (United States)

    Willson, Douglas F; Chess, Patricia R; Notter, Robert H

    2008-06-01

    This article reviews exogenous surfactant therapy and its use in mitigating acute lung injury (ALI) and the acute respiratory distress syndrome (ARDS) in infants, children, and adults. Biophysical and animal research documenting surfactant dysfunction in ALI/ARDS is described, and the scientific rationale for treatment with exogenous surfactant is discussed. Major emphasis is placed on reviewing clinical studies of surfactant therapy in pediatric and adult patients who have ALI/ARDS. Particular advantages from surfactant therapy in direct pulmonary forms of these syndromes are described. Also discussed are additional factors affecting the efficacy of exogenous surfactants in ALI/ARDS.

  15. Differential Gene Expression in Chemically Induced Mouse Lung Adenomas

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    Ruisheng Yao

    2003-01-01

    Full Text Available Because of similarities in histopathology and tumor progression stages between mouse and human lung adenocarcinomas, the mouse lung tumor model with lung adenomas as the endpoint has been used extensively to evaluate the efficacy of putative lung cancer chemopreventive agents. In this study, a competitive cDNA library screening (CCLS was employed to determine changes in the expression of mRNA in chemically induced lung adenomas compared with paired normal lung tissues. A total of 2555 clones having altered expression in tumors were observed following competitive hybridization between normal lung and lung adenomas after primary screening of over 160,000 clones from a mouse lung cDNA library. Among the 755 clones confirmed by dot blot hybridization, 240 clones were underexpressed, whereas 515 clones were overexpressed in tumors. Sixty-five clones with the most frequently altered expression in six individual tumors were confirmed by semiquantitative RT-PCR. When examining the 58 known genes, 39 clones had increased expression and 19 had decreased expression, whereas the 7 novel genes showed overexpression. A high percentage (>60% of overexpressed or underexpressed genes was observed in at least two or three of the lesions. Reproducibly overexpressed genes included ERK-1, JAK-1, surfactant proteins A, B, and C, NFAT1, α-1 protease inhibitor, helix-loop-helix ubiquitous kinase (CHUK, α-adaptin, α-1 PI2, thioether S-methyltransferase, and CYP2C40. Reproducibly underexpressed genes included paroxanase, ALDH II, CC10, von Ebner salivary gland protein, and α- and β-globin. In addition, CCLS identified several novel genes or genes not previously associated with lung carcinogenesis, including a hypothetical protein (FLJ11240 and a guanine nucleotide exchange factor homologue. This study shows the efficacy of this methodology for identifying genes with altered expression. These genes may prove to be helpful in our understanding of the genetic basis of

  16. TLR2 deficiency aggravates lung injury caused by mechanical ventilation

    NARCIS (Netherlands)

    Kuipers, Maria Theresa; Jongsma, Geartsje; Hegeman, Maria A; Tuip-de Boer, Anita M; Wolthuis, Esther K; Choi, Goda; Bresser, Paul; van der Poll, Tom; Schultz, Marcus J; Wieland, Catharina W

    2014-01-01

    Innate immunity pathways are found to play an important role in ventilator-induced lung injury. We analyzed pulmonary expression of Toll-like receptor 2 (TLR2) in humans and mice and determined the role of TLR2 in the pathogenesis of ventilator-induced lung injury in mice. Toll-like receptor 2 gene

  17. Traumatic Brain Injury in Rats Induces Lung Injury and Systemic Immune Suppression

    NARCIS (Netherlands)

    Vermeij, Jan-Dirk; Aslami, Hamid; Fluiter, Kees; Roelofs, Joris J.; van den Bergh, Walter M.; Juffermans, Nicole P.; Schultz, Marcus J.; Van der Sluijs, Koen; van de Beek, Diederik; van Westerloo, David J.

    2013-01-01

    Traumatic brain injury (TBI) is frequently complicated by acute lung injury, which is predictive for poor outcome. However, it is unclear whether lung injury develops independently or as a result of mechanical ventilation after TBI. Further, TBI is strongly associated with the development of pneumon

  18. Glutamine Attenuates Acute Lung Injury Caused by Acid Aspiration

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    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.

  19. Finite element modeling of blast lung injury in sheep.

    Science.gov (United States)

    Gibbons, Melissa M; Dang, Xinglai; Adkins, Mark; Powell, Brian; Chan, Philemon

    2015-04-01

    A detailed 3D finite element model (FEM) of the sheep thorax was developed to predict heterogeneous and volumetric lung injury due to blast. A shared node mesh of the sheep thorax was constructed from a computed tomography (CT) scan of a sheep cadaver, and while most material properties were taken from literature, an elastic-plastic material model was used for the ribs based on three-point bending experiments performed on sheep rib specimens. Anesthetized sheep were blasted in an enclosure, and blast overpressure data were collected using the blast test device (BTD), while surface lung injury was quantified during necropsy. Matching blasts were simulated using the sheep thorax FEM. Surface lung injury in the FEM was matched to pathology reports by setting a threshold value of the scalar output termed the strain product (maximum value of the dot product of strain and strain-rate vectors over all simulation time) in the surface elements. Volumetric lung injury was quantified by applying the threshold value to all elements in the model lungs, and a correlation was found between predicted volumetric injury and measured postblast lung weights. All predictions are made for the left and right lungs separately. This work represents a significant step toward the prediction of localized and heterogeneous blast lung injury, as well as volumetric injury, which was not recorded during field testing for sheep.

  20. Anti-inflammatory effects of adult stem cells in sustained lung injury: a comparative study.

    Science.gov (United States)

    Moodley, Yuben; Vaghjiani, Vijesh; Chan, James; Baltic, Svetlana; Ryan, Marisa; Tchongue, Jorge; Samuel, Chrishan S; Murthi, Padma; Parolini, Ornella; Manuelpillai, Ursula

    2013-01-01

    Lung diseases are a major cause of global morbidity and mortality that are treated with limited efficacy. Recently stem cell therapies have been shown to effectively treat animal models of lung disease. However, there are limitations to the translation of these cell therapies to clinical disease. Studies have shown that delayed treatment of animal models does not improve outcomes and that the models do not reflect the repeated injury that is present in most lung diseases. We tested the efficacy of amnion mesenchymal stem cells (AM-MSC), bone marrow MSC (BM-MSC) and human amniotic epithelial cells (hAEC) in C57BL/6 mice using a repeat dose bleomycin-induced model of lung injury that better reflects the repeat injury seen in lung diseases. The dual bleomycin dose led to significantly higher levels of inflammation and fibrosis in the mouse lung compared to a single bleomycin dose. Intravenously infused stem cells were present in the lung in similar numbers at days 7 and 21 post cell injection. In addition, stem cell injection resulted in a significant decrease in inflammatory cell infiltrate and a reduction in IL-1 (AM-MSC), IL-6 (AM-MSC, BM-MSC, hAEC) and TNF-α (AM-MSC). The only trophic factor tested that increased following stem cell injection was IL-1RA (AM-MSC). IL-1RA levels may be modulated by GM-CSF produced by AM-MSC. Furthermore, only AM-MSC reduced collagen deposition and increased MMP-9 activity in the lung although there was a reduction of the pro-fibrogenic cytokine TGF-β following BM-MSC, AM-MSC and hAEC treatment. Therefore, AM-MSC may be more effective in reducing injury following delayed injection in the setting of repeated lung injury.

  1. Anti-inflammatory effects of adult stem cells in sustained lung injury: a comparative study.

    Directory of Open Access Journals (Sweden)

    Yuben Moodley

    Full Text Available Lung diseases are a major cause of global morbidity and mortality that are treated with limited efficacy. Recently stem cell therapies have been shown to effectively treat animal models of lung disease. However, there are limitations to the translation of these cell therapies to clinical disease. Studies have shown that delayed treatment of animal models does not improve outcomes and that the models do not reflect the repeated injury that is present in most lung diseases. We tested the efficacy of amnion mesenchymal stem cells (AM-MSC, bone marrow MSC (BM-MSC and human amniotic epithelial cells (hAEC in C57BL/6 mice using a repeat dose bleomycin-induced model of lung injury that better reflects the repeat injury seen in lung diseases. The dual bleomycin dose led to significantly higher levels of inflammation and fibrosis in the mouse lung compared to a single bleomycin dose. Intravenously infused stem cells were present in the lung in similar numbers at days 7 and 21 post cell injection. In addition, stem cell injection resulted in a significant decrease in inflammatory cell infiltrate and a reduction in IL-1 (AM-MSC, IL-6 (AM-MSC, BM-MSC, hAEC and TNF-α (AM-MSC. The only trophic factor tested that increased following stem cell injection was IL-1RA (AM-MSC. IL-1RA levels may be modulated by GM-CSF produced by AM-MSC. Furthermore, only AM-MSC reduced collagen deposition and increased MMP-9 activity in the lung although there was a reduction of the pro-fibrogenic cytokine TGF-β following BM-MSC, AM-MSC and hAEC treatment. Therefore, AM-MSC may be more effective in reducing injury following delayed injection in the setting of repeated lung injury.

  2. Glutathione Reductase Targeted to Type II Cells Does Not Protect Mice from Hyperoxic Lung Injury

    Science.gov (United States)

    Heyob, Kathryn M.; Rogers, Lynette K.; Welty, Stephen E.

    2008-01-01

    Exposure of the lung epithelium to reactive oxygen species without adequate antioxidant defenses leads to airway inflammation, and may contribute to lung injury. Glutathione peroxidase catalyzes the reduction of peroxides by oxidation of glutathione (GSH) to glutathione disulfide (GSSG), which can in turn be reduced by glutathione reductase (GR). Increased levels of GSSG have been shown to correlate negatively with outcome after oxidant exposure, and increased GR activity has been protective against hyperoxia in lung epithelial cells in vitro. We tested the hypothesis that increased GR expression targeted to type II alveolar epithelial cells would improve outcome in hyperoxia-induced lung injury. Human GR with a mitochondrial targeting sequence was targeted to mouse type II cells using the SPC promoter. Two transgenic lines were identified, with Line 2 having higher lung GR activities than Line 1. Both transgenic lines had lower lung GSSG levels and higher GSH/GSSG ratios than wild-type. Six-week-old wild-type and transgenic mice were exposed to greater than 95% O2 or room air (RA) for 84 hours. After exposure, Line 2 mice had higher right lung/body weight ratios and lavage protein concentrations than wild-type mice, and both lines 1 and 2 had lower GSSG levels than wild-type mice. These findings suggest that GSSG accumulation in the lung may not play a significant role in the development of hyperoxic lung injury, or that compensatory responses to unregulated GR expression render animals more susceptible to hyperoxic lung injury. PMID:18566333

  3. Lactobacillus rhamnosus GG and Bifidobacterium longum attenuate lung injury and inflammatory response in experimental sepsis.

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    Ludmila Khailova

    Full Text Available INTRODUCTION: Probiotic use to prevent nosocomial gastrointestinal and potentially respiratory tract infections in critical care has shown great promise in recent clinical trials of adult and pediatric patients. Despite well-documented benefits of probiotic use in intestinal disorders, the potential for probiotic treatment to reduce lung injury following infection and shock has not been well explored. OBJECTIVE: Evaluate if Lactobacillus rhamnosus GG (LGG or Bifidobacterium longum (BL treatment in a weanling mouse model of cecal ligation and puncture (CLP peritonitis will protect against lung injury. METHODS: 3 week-old FVB/N mice were orally gavaged with 200 µl of either LGG, BL or sterile water (vehicle immediately prior to CLP. Mice were euthanized at 24 h. Lung injury was evaluated via histology and lung neutrophil infiltration was evaluated by myeloperoxidase (MPO staining. mRNA levels of IL-6, TNF-α, MyD88, TLR-4, TLR-2, NFΚB (p50/p105 and Cox-2 in the lung analyzed via real-time PCR. TNF-α and IL-6 in lung was analyzed via ELISA. RESULTS: LGG and BL treatment significantly improved lung injury following experimental infection and sepsis and lung neutrophil infiltration was significantly lower than in untreated septic mice. Lung mRNA and protein levels of IL-6 and TNF-α and gene expression of Cox-2 were also significantly reduced in mice receiving LGG or BL treatment. Gene expression of TLR-2, MyD88 and NFΚB (p50/p105 was significantly increased in septic mice compared to shams and decreased in the lung of mice receiving LGG or BL while TLR-4 levels remained unchanged. CONCLUSIONS: Treatment with LGG and BL can reduce lung injury following experimental infection and sepsis and is associated with reduced lung inflammatory cell infiltrate and decreased markers of lung inflammatory response. Probiotic therapy may be a promising intervention to improve clinical lung injury following systemic infection and sepsis.

  4. Transfusion-related acute lung injury.

    Science.gov (United States)

    Federico, Anne

    2009-02-01

    Approximately one person in 5,000 will experience an episode of transfusion-related acute lung injury (TRALI) in conjunction with the transfusion of whole blood or blood components. Its hallmarks include hypoxemia, dyspnea, fever, hypotension, and bilateral pulmonary edema (noncardiogenic). The mortality for reported cases is 16.3%. The incidence and mortality may be even higher than estimated because of under-recognition and under-reporting. Although TRALI was identified as a clinical entity in the 1980s, a lack of consensus regarding a definition was present until 2004. An exact cause has yet to be identified; however, there are two theories regarding the etiology: the "antibody" and the "two-hit" theories. These theories involve both donor and recipient factors. Further education and research are needed to assist in the development of strategies for the prevention and treatment of TRALI.

  5. Surgical technique for lung retransplantation in the mouse

    Science.gov (United States)

    Li, Wenjun; Goldstein, Daniel R.; Bribriesco, Alejandro C.; Nava, Ruben G.; Spahn, Jessica H.; Wang, Xingan; Gelman, Andrew E.; Krupnick, Alexander S.

    2013-01-01

    Microsurgical cuff techniques for orthotopic vascularized murine lung transplantation have allowed for the design of studies that examine mechanisms contributing to the high failure rate of pulmonary grafts. Here, we provide a detailed technical description of orthotopic lung retransplantation in mice, which we have thus far performed in 144 animals. The total time of the retransplantation procedure is approximately 55 minutes, 20 minutes for donor harvest and 35 minutes for the implantation, with a success rate exceeding 95%. The mouse lung retransplantation model represents a novel and powerful tool to examine how cells that reside in or infiltrate pulmonary grafts shape immune responses. PMID:23825768

  6. Acute lung injury, overhydration or both?

    Science.gov (United States)

    Groeneveld, A B Johan; Polderman, Kees H

    2005-04-01

    Acute lung injury or acute respiratory distress syndrome (ALI/ARDS) in the course of sepsis is thought to result from increased pulmonary capillary permeability and resultant edema. However, when the edema is assessed at the bedside by measuring the extravascular thermal volume by transpulmonary dilution, some ALI/ARDS patients with sepsis may have normal extravascular lung water (EVLW). Conversely, a raised EVLW may be present even when criteria for ALI/ARDS are not met, according to GS Martin and colleagues in this issue of Critical Care. This commentary puts the findings into a broader perspective and focuses on the difficulty, at the bedside, in recognizing and separating various types of pulmonary edema. Some of these forms of edema, classically differentiated on the basis of increased permeability and cardiogenic/hydrostatic factors, may overlap, whereas the criteria for ALI/ARDS may be loose, poorly reproducible, relatively insensitive and nonspecific, and highly therapy-dependent. Overhydration is particularly difficult to recognize. Additional diagnostics may be required to improve the delineation of pulmonary edema so as to redirect or redefine treatment and improve patient morbidity and, perhaps, mortality. Monitoring EVLW by single transpulmonary thermal dilution, for instance, might have a future role in this process.

  7. Platelets protect lung from injury induced by systemic inflammatory response

    Science.gov (United States)

    Luo, Shuhua; Wang, Yabo; An, Qi; Chen, Hao; Zhao, Junfei; Zhang, Jie; Meng, Wentong; Du, Lei

    2017-01-01

    Systemic inflammatory responses can severely injure lungs, prompting efforts to explore how to attenuate such injury. Here we explored whether platelets can help attenuate lung injury in mice resulting from extracorporeal circulation (ECC)-induced systemic inflammatory responses. Mice were subjected to ECC for 30 min, then treated with phosphate-buffered saline, platelets, the GPIIb/IIIa inhibitor Tirofiban, or the combination of platelets and Tirofiban. Blood and lung tissues were harvested 60 min later, and lung injury and inflammatory status were assessed. As expected, ECC caused systemic inflammation and pulmonary dysfunction, and platelet transfusion resulted in significantly milder lung injury and higher lung function. It also led to greater numbers of circulating platelet-leukocyte aggregates and greater platelet accumulation in the lung. Platelet transfusion was associated with higher production of transforming growth factor-β and as well as lower levels of tumour necrosis factor-α and neutrophil elastase in plasma and lung. None of these platelet effects was observed in the presence of Tirofiban. Our results suggest that, at least under certain conditions, platelets can protect lung from injury induced by systemic inflammatory responses. PMID:28155889

  8. Inhibition of extracellular HMGB1 attenuates hyperoxia-induced inflammatory acute lung injury

    Directory of Open Access Journals (Sweden)

    Maria Entezari

    2014-01-01

    Full Text Available Prolonged exposure to hyperoxia results in acute lung injury (ALI, accompanied by a significant elevation in the levels of proinflammatory cytokines and leukocyte infiltration in the lungs. However, the mechanisms underlying hyperoxia-induced proinflammatory ALI remain to be elucidated. In this study, we investigated the role of the proinflammatory cytokine high mobility group box protein 1 (HMGB1 in hyperoxic inflammatory lung injury, using an adult mouse model. The exposure of C57BL/6 mice to ≥99% O2 (hyperoxia significantly increased the accumulation of HMGB1 in the bronchoalveolar lavage fluids (BALF prior to the onset of severe inflammatory lung injury. In the airways of hyperoxic mice, HMGB1 was hyperacetylated and existed in various redox forms. Intratracheal administration of recombinant HMGB1 (rHMGB1 caused a significant increase in leukocyte infiltration into the lungs compared to animal treated with a non-specific peptide. Neutralizing anti-HMGB1 antibodies, administrated before hyperoxia significantly attenuated pulmonary edema and inflammatory responses, as indicated by decreased total protein content, wet/dry weight ratio, and numbers of leukocytes in the airways. This protection was also observed when HMGB1 inhibitors were administered after the onset of the hyperoxic exposure. The aliphatic antioxidant, ethyl pyruvate (EP, inhibited HMGB1 secretion from hyperoxic macrophages and attenuated hyperoxic lung injury. Overall, our data suggest that HMGB1 plays a critical role in mediating hyperoxic ALI through the recruitment of leukocytes into the lungs. If these results can be translated to humans, they suggest that HMGB1 inhibitors provide treatment regimens for oxidative inflammatory lung injury in patients receiving hyperoxia through mechanical ventilation.

  9. Acute lung injury probably associated with infusion of propofol emulsion.

    Science.gov (United States)

    Chondrogiannis, K D; Siontis, G C M; Koulouras, V P; Lekka, M E; Nakos, G

    2007-08-01

    We present a case of acute lung injury associated with propofol infusion in a mechanically ventilated patient with intracerebral haemorrhage. Diagnosis was based on the exclusion of other risk factors inducing acute lung injury and on the clinical improvement after discontinuation of the propofol emulsion. Laboratory data such as the increase in total phospholipids, neutral lipids and free fatty acids in the broncho-alveolar lavage fluid, the remarkably high percentage of alveolar macrophages including fat droplets and the similar lipid composition of propofol and broncho-alveolar lavage fluid support the relationship between propofol and acute lung injury.

  10. Oxidative Stress and Lung Ischemia-Reperfusion Injury

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    Renata Salatti Ferrari

    2015-01-01

    Full Text Available Ischemia-reperfusion (IR injury is directly related to the formation of reactive oxygen species (ROS, endothelial cell injury, increased vascular permeability, and the activation of neutrophils and platelets, cytokines, and the complement system. Several studies have confirmed the destructiveness of the toxic oxygen metabolites produced and their role in the pathophysiology of different processes, such as oxygen poisoning, inflammation, and ischemic injury. Due to the different degrees of tissue damage resulting from the process of ischemia and subsequent reperfusion, several studies in animal models have focused on the prevention of IR injury and methods of lung protection. Lung IR injury has clinical relevance in the setting of lung transplantation and cardiopulmonary bypass, for which the consequences of IR injury may be devastating in critically ill patients.

  11. Alcohol Exposure Alters Mouse Lung Inflammation in Response to Inhaled Dust

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    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

  12. Methods of in-vivo mouse lung micro-CT

    Science.gov (United States)

    Recheis, Wolfgang A.; Nixon, Earl; Thiesse, Jacqueline; McLennan, Geoffrey; Ross, Alan; Hoffman, Eric

    2005-04-01

    Micro-CT will have a profound influence on the accumulation of anatomical and physiological phenotypic changes in natural and transgenetic mouse models. Longitudinal studies will be greatly facilitated, allowing for a more complete and accurate description of events if in-vivo studies are accomplished. The purpose of the ongoing project is to establish a feasible and reproducible setup for in-vivo mouse lung micro-computed tomography (μCT). We seek to use in-vivo respiratory-gated μCT to follow mouse models of lung disease with subsequent recovery of the mouse. Methodologies for optimizing scanning parameters and gating for the in-vivo mouse lung are presented. A Scireq flexiVent ventilated the gas-anesthetized mice at 60 breaths/minute, 30 cm H20 PEEP, 30 ml/kg tidal volume and provided a respiratory signal to gate a Skyscan 1076 μCT. Physiologic monitoring allowed the control of vital functions and quality of anesthesia, e.g. via ECG monitoring. In contrary to longer exposure times with ex-vivo scans, scan times for in-vivo were reduced using 35μm pixel size, 158ms exposure time and 18μm pixel size, 316ms exposure time to reduce motion artifacts. Gating via spontaneous breathing was also tested. Optimal contrast resolution was achieved at 50kVp, 200μA, applying an aluminum filter (0.5mm). There were minimal non-cardiac related motion artifacts. Both 35μm and 1μm voxel size images were suitable for evaluation of the airway lumen and parenchymal density. Total scan times were 30 and 65 minutes respectively. The mice recovered following scanning protocols. In-vivo lung scanning with recovery of the mouse delivered reasonable image quality for longitudinal studies, e.g. mouse asthma models. After examining 10 mice, we conclude μCT is a feasible tool evaluating mouse models of lung pathology in longitudinal studies with increasing anatomic detail available for evaluation as one moves from in-vivo to ex-vivo studies. Further developments include automated

  13. [Positive end-expiratory pressure : adjustment in acute lung injury].

    Science.gov (United States)

    Bruells, C S; Dembinski, R

    2012-04-01

    Treatment of patients suffering from acute lung injury is a challenge for the treating physician. In recent years ventilation of patients with acute hypoxic lung injury has changed fundamentally. Besides the use of low tidal volumes, the most beneficial setting of positive end-expiratory pressure (PEEP) has been in the focus of researchers. The findings allow adaption of treatment to milder forms of acute lung injury and severe forms. Additionally computed tomography techniques to assess the pulmonary situation and recruitment potential as well as bed-side techniques to adjust PEEP on the ward have been modified and improved. This review gives an outline of recent developments in PEEP adjustment for patients suffering from acute hypoxic and hypercapnic lung injury and explains the fundamental pathophysiology necessary as a basis for correct treatment.

  14. Obesity, Inflammation, and Lung Injury (OILI): The Good

    OpenAIRE

    Cheryl Wang

    2014-01-01

    Obesity becomes pandemic, predisposing these individuals to great risk for lung injury. In this review, we focused on the anti-inflammatories and addressed the following aspects: adipocytokines and obesity, inflammation and other mechanisms, adipocytokines and lung injury in obesity bridged by inflammation, and potential therapeutic targets. To sum up, the majority of evidence supported that adiponectin, omentin, and secreted frizzled-related protein 5 (SFRP5) were reduced significantly in ob...

  15. Lung Morphological Changes in Closed Chest Injury (an experimental study

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    A. M. Golubev

    2012-01-01

    Full Text Available Objective: to study lung morphological changes in a closed chest injury model in laboratory animals. Material and methods. Experiments were carried out in 30 male albino nonbred rats weighing 350—380 g. Closed chest injury was simulated, by exposing the chest of anesthetized rats to a 300-g metal cylinder falling from a height of 30 cm. The observation periods were 1, 3, 6, and 24 hours. Results. The signs of evident perivenular edema that was uncharas-teristic to acute respiratory distress syndrome induced by other causes are an important peculiarity of lung morphological changes in this experimental model of closed chest injury. Conclusion. The experimental studies clarified the pattern of lung morphological changes in the early period after closed chest injury. Key words: closed chest injury, pulmonary edema.

  16. 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 th

  17. Lung Injury and Repair In Search of New Treatment Modalities

    NARCIS (Netherlands)

    J. Tibboel (Jeroen)

    2013-01-01

    markdownabstract__Abstract__ The lung contains the largest surface of our body that is exposed to the environment. Day in, day out, our lungs are being exposed to many injurious components, ranging from noxious gasses and particles caused by traffic and chemical industries to a multitude of microor

  18. Therapeutic Strategies for Severe Acute Lung Injury

    Science.gov (United States)

    Diaz, Janet. V.; Brower, Roy; Calfee, Carolyn S.; Matthay, Michael A.

    2015-01-01

    Objective In the management of patients with severe Acute Lung Injury and the Acute Respiratory Distress Syndrome (ALI/ARDS), clinicians are sometimes challenged to maintain acceptable gas exchange while avoiding harmful mechanical ventilation practices. In some of these patients, physicians may consider the use of “rescue therapies” to sustain life. Our goal is to provide a practical, evidence-based review to assist critical care physicians’ care for patients with severe ALI/ARDS. Data Sources and Study Selection We searched the Pub Med database for clinical trials examining the use of the following therapies in ALI/ARDS: recruitment maneuvers, high positive end expiratory pressure, prone position, high frequency oscillatory ventilation, glucocorticoids, inhaled nitric oxide, buffer therapy and extracorporeal life support. Study selection All clinical trials that included patients with severe ALI/ARDS were included in the review. Data Synthesis The primary author reviewed the aforementioned trials in depth and then disputed findings and conclusions with other authors until consensus was achieved. Conclusions This article is designed to: a) provide clinicians with a simple, bedside definition for the diagnosis of severe ARDS; b) describe several therapies that can be used in severe ARDS with an emphasis on the potential risks as well as the indications and benefits; and c) to offer practical guidelines for implementation of these therapies. PMID:20562704

  19. Role of caveolin-1 expression in the pathogenesis of pulmonary edema in ventilator-induced lung injury

    Science.gov (United States)

    Maniatis, Nikolaos A.; Kardara, Matina; Hecimovich, Dan; Letsiou, Eleftheria; Castellon, Maricela; Roussos, Charalambos; Shinin, Vasily; Votta-Vellis, E. Gina; Schwartz, David E.; Minshall, Richard D.

    2012-01-01

    Caveolin-1 is a key regulator of pulmonary endothelial barrier function. Here, we tested the hypothesis that caveolin-1 expression is required for ventilator-induced lung injury (VILI). Caveolin-1 gene-disrupted (Cav-1-/-) and age-, sex-, and strain-matched wild-type (WT) control mice were ventilated using two protocols: volume-controlled with protective (8 mL/kg) versus injurious (21 mL/Kg) tidal volume for up to 6 hours; and pressure-controlled with protective (airway pressure = 12 cm H2O) versus injurious (30 cm H2O) ventilation to induce lung injury. Lung microvascular permeability (whole-lung 125I-albumin accumulation, lung capillary filtration coefficient [Kf, c]) and inflammatory markers (bronchoalveolar lavage [BAL] cytokine levels and neutrophil counts) were measured. We also evaluated histologic sections from lungs, and the time course of Src kinase activation and caveolin-1 phosphorylation. VILI induced a 1.7-fold increase in lung 125I-albumin accumulation, fourfold increase in Kf, c, significantly increased levels of cytokines CXCL1 and interleukin-6, and promoted BAL neutrophilia in WT mice. Lung injury by these criteria was significantly reduced in Cav-1-/- mice but fully restored by i.v. injection of liposome/Cav-1 cDNA complexes that rescued expression of Cav-1 in lung microvessels. As thrombin is known to play a significant role in mediating stretch-induced vascular injury, we observed in cultured mouse lung microvascular endothelial cells (MLECs) thrombin-induced albumin hyperpermeability and phosphorylation of p44/42 MAP kinase in WT but not in Cav-1-/- MLECs. Thus, caveolin-1 expression is required for mechanical stretch-induced lung inflammation and endothelial hyperpermeability in vitro and in vivo. PMID:23372929

  20. B-lines quantify the lung water content: a lung ultrasound versus lung gravimetry study in acute lung injury.

    Science.gov (United States)

    Jambrik, Zoltán; Gargani, Luna; Adamicza, Agnes; Kaszaki, József; Varga, Albert; Forster, Tamás; Boros, Mihály; Picano, Eugenio

    2010-12-01

    B-lines (also termed ultrasound lung comets) obtained with lung ultrasound detect experimental acute lung injury (ALI) very early and before hemogasanalytic changes, with a simple, noninvasive, nonionizing and real-time method. Our aim was to estimate the correlation between B-lines number and the wet/dry ratio of the lung tissue, measured by gravimetry, in an experimental model of ALI. Seventeen Na-pentobarbital anesthetized, cannulated (central vein and carotid artery) minipigs were studied: five sham-operated animals served as controls and, in 12 animals, ALI was induced by injection of oleic acid (0.1 mL/kg) via the central venous catheter. B-lines were measured by echographic scanner in four predetermined chest scanning sites in each animal. At the end of each experiment, both lungs were dissected, weighed and dried to determine wet/dry weight ratio by gravimetry. After the injection of oleic acid, B-lines number increased over time. A significant correlation was found between the wet/dry ratio and B-lines number (r = 0.91, p < 0.001). These data suggest that in an experimental pig model of ALI/ARDS, B-lines assessed by lung ultrasound provide a simple, semiquantitative, noninvasive index of lung water accumulation, strongly correlated to invasive gravimetric assessment.

  1. Salidroside Attenuates Ventilation Induced Lung Injury via SIRT1-Dependent Inhibition of NLRP3 Inflammasome

    Directory of Open Access Journals (Sweden)

    Yan Wang

    2017-05-01

    Full Text Available Background: Salidroside (SDS is the main effective ingredient of Rhodiola rosea L with a variety of pharmacologic properties. We aim to investigate the effects of SDS on ventilation induced lung injury (VILI and explore the possible underlying molecular mechanism. Methods: Lung injury was induced in male ICR mice via mechanical ventilation (30 ml/kg for 4h. The mice were divided in four groups:(1 Control group; (2 Ventilation group; (3 SDS group; (4 Ventilation with SDS group. SDS (50 mg/kg was injected intraperitoneally 1h before operation. Mouse lung vascular endothelial cells (MLVECs were subjected to cyclic stretch for 4h. Results: It was found that SDS attenuated VILI as shown in HE staining, cell count and protein content levels in BAL fluid, W/D and Evans blue dye leakage into the lung tissue. SDS treatment inhibited the activation of NLRP3 inflammasome and subsequent caspase-1 cleavage as well as interleukin (IL-1β secretion both in vivo and in vitro. Moreover, SDS administration up-regulated SIRT1 expression. Importantly, knockdown of SIRT1 reversed the inhibitory effect of SDS on NLRP3 inflammasome activation. Conclusions: Taken together, these findings indicate that SDS may confer protection against ventilation induced lung injury via SIRT1-de-pendent inhibition of NLRP3 inflammasome activation.

  2. Obesity, Inflammation, and Lung Injury (OILI: The Good

    Directory of Open Access Journals (Sweden)

    Cheryl Wang

    2014-01-01

    Full Text Available Obesity becomes pandemic, predisposing these individuals to great risk for lung injury. In this review, we focused on the anti-inflammatories and addressed the following aspects: adipocytokines and obesity, inflammation and other mechanisms, adipocytokines and lung injury in obesity bridged by inflammation, and potential therapeutic targets. To sum up, the majority of evidence supported that adiponectin, omentin, and secreted frizzled-related protein 5 (SFRP5 were reduced significantly in obesity, which is associated with increased inflammation, indicated by increase of TNFα and IL-6, through activation of toll-like receptor (TLR4 and nuclear factor light chain κB (NF-κB signaling pathways. Administration of these adipocytokines promotes weight loss and reduces inflammation. Zinc-α2-glycoprotein (ZAG, vaspin, IL-10, interleukin-1 receptor antagonist (IL-1RA, transforming growth factor β (TGF-β1, and growth differentiation factor 15 (GDF15 are also regarded as anti-inflammatories. There were controversial reports. Furthermore, there is a huge lack of studies for obesity related lung injury. The effects of adiponectin on lung transplantation, asthma, chronic obstructive pulmonary diseases (COPD, and pneumonia were anti-inflammatory and protective in lung injury. Administration of IL-10 agonist reduces mortality of acute lung injury in rabbits with acute necrotizing pancreatitis, possibly through inhibiting proinflammation and strengthening host immunity. Very limited information is available for other adipocytokines.

  3. The Field of Tissue Injury in the Lung and Airway

    Science.gov (United States)

    Steiling, Katrina; Ryan, John; Brody, Jerome S.; Spira, Avrum

    2009-01-01

    The concept of field cancerization was first introduced over six decades ago in the setting of oral cancer. Later, field cancerization involving histologic and molecular changes of neoplasms and adjacent tissue began to be characterized in smokers with or without lung cancer. Investigators also described a diffuse, non-neoplastic field of molecular injury throughout the respiratory tract that is attributable to cigarette smoking and susceptibility to smoking-induced lung disease. The potential molecular origins of field cancerization and the field of injury following cigarette smoke exposure in lung and airway epithelia are critical to understanding the impact of the field of injury on clinical diagnostics and therapeutics for smoking-induced lung disease. PMID:19138985

  4. Increased isoprostane levels in oleic acid-induced lung injury

    Energy Technology Data Exchange (ETDEWEB)

    Ono, Koichi [Department of Anesthesiology and Resuscitation, Shinshu University School of Medicine, Matsumoto (Japan); Koizumi, Tomonobu, E-mail: tomonobu@shinshu-u.ac.jp [First Department of Internal Medicine, Shinshu University School of Medicine, Matsumoto (Japan); Tsushima, Kenji; Yoshikawa, Sumiko; Yokoyama, Toshiki [First Department of Internal Medicine, Shinshu University School of Medicine, Matsumoto (Japan); Nakagawa, Rikimaru [Department of Anesthesiology and Resuscitation, Shinshu University School of Medicine, Matsumoto (Japan); Obata, Toru [Department of Molecular Cell Biology, Institute of DNA Medicine, Jikei University School of Medicine, Tokyo (Japan)

    2009-10-16

    The present study was performed to examine a role of oxidative stress in oleic acid-induced lung injury model. Fifteen anesthetized sheep were ventilated and instrumented with a lung lymph fistula and vascular catheters for blood gas analysis and measurement of isoprostanes (8-epi prostaglandin F2{alpha}). Following stable baseline measurements, oleic acid (0.08 ml/kg) was administered and observed 4 h. Isoprostane was measured by gas chromatography mass spectrometry with the isotope dilution method. Isoprostane levels in plasma and lung lymph were significantly increased 2 h after oleic acid administration and then decreased at 4 h. The percent increases in isoprostane levels in plasma and lung lymph at 2 h were significantly correlated with deteriorated oxygenation at the same time point, respectively. These findings suggest that oxidative stress is involved in the pathogenesis of the pulmonary fat embolism-induced acute lung injury model in sheep and that the increase relates with the deteriorated oxygenation.

  5. Mechanism of ethylbenzene-induced mouse-specific lung tumor: metabolism of ethylbenzene by rat, mouse, and human liver and lung microsomes.

    Science.gov (United States)

    Saghir, Shakil A; Rick, David L; McClymont, E L; Zhang, Fagen; Bartels, Michael J; Bus, James S

    2009-02-01

    This study was conducted to determine species differences in the metabolism of ethylbenzene (EB) in liver and lung. EB (0.22-7.0mM) was incubated with mouse, rat and human liver and lung microsomes and the formation of 1-phenylethanol (1PE), acetophenone (AcPh), 2-ethylphenol (2EP), 4-ethylphenol (4EP), 2,5-ethylquinone, and 3,4-ethylquinone were measured. Reactive metabolites (2,5-dihydroxyethylbenzene-GSH [2EP-GSH] and 3,4-dihydroxyethylbenzene-GSH [4EP-GSH]) were monitored via glutathione (GSH) trapping technique. None of the metabolites were formed at detectable levels in incubations with human lung microsomes. Percent conversion of EB to 1PE ranged from 1% (rat lung; 7.0mM EB) to 58% (mouse lung; 0.22 mM EB). More 1PE was formed in mouse lung than in mouse liver microsomes, although formation of 1PE by rat liver and lung microsomes was similar. Metabolism of EB to 1PE was in the order of mouse > rat > human. Formation of AcPh was roughly an order of magnitude lower than 1PE. Conversion of EB to ring-hydroxylated metabolites was much lower (0.0001% [4EP-GSH; rat lung] to 0.6% [2EP-GSH; mouse lung]); 2EP-GSH was typically 10-fold higher than 4EP-GSH. Formation of 2EP-GSH was higher by lung (highest by mouse lung) than liver microsomes and the formation of 2EP-GSH by mouse liver microsomes was higher than rat and human liver microsomes. Increasing concentrations of EB did lead to a decrease in amount of some formed metabolites. This may indicate some level of substrate- or metabolite-mediated inhibition. High concentrations of 2EP and 4EP were incubated with microsomes to further investigate their oxidation to ethylcatechol (ECat) and ethylhydroquinone (EHQ). Conversion of 2EP to EHQ ranged from 6% to 9% by liver (mouse > human > rat) and from 0.1% to 18% by lung microsomes (mouse > rat > human). Conversion of 4EP to ECat ranged from 2% to 4% by liver (mouse > human approximately rat) and from 0.3% to 7% by lung microsomes (mouse > rat > human). Although ring

  6. Isoforskolin pretreatment attenuates lipopolysaccharide-induced acute lung injury in animal models.

    Science.gov (United States)

    Yang, Weimin; Qiang, Dongjin; Zhang, Min; Ma, Limei; Zhang, Yonghui; Qing, Chen; Xu, Yunlong; Zhen, Chunlan; Liu, Jikai; Chen, Yan-Hua

    2011-06-01

    Isoforskolin was isolated from Coleus forskohlii native to Yunnan in China. We hypothesize that isoforskolin pretreatment attenuates acute lung injury induced by lipopolysaccharide (endotoxin). Three acute lung injury models were used: situ perfused rat lung, rat and mouse models of endotoxic shock. Additionally, lipopolysaccharide stimulated proinflammatory cytokine production was evaluated in human mononuclear leukocyte. In situ perfused rat lungs, pre-perfusion with isoforskolin (100, and 200 μM) and dexamethasone (65 μM, positive control) inhibited lipopolysaccharide (10 mg/L) induced increases in lung neutrophil adhesion rate, myeloperoxidase activity, lung weight Wet/Dry ratio, permeability-surface area product value, and tumor necrosis factor (TNF)-α levels. In rats, pretreatments with isoforskolin (5, 10, and 20 mg/kg, i.p.) and dexamethasone (5mg/kg, i.p.) markedly reduced lipopolysaccharide (6 mg/kg i.v.) induced increases of karyocyte, neutrophil counts and protein content in bronchoalveolar lavage fluid, and plasma myeloperoxidase activity. Lung histopathology showed that morphologic changes induced by lipopolysaccharide were less pronounced in the isoforskolin and dexamethasone pretreated rats. In mice, 5 mg/kg isoforskolin and dexamethasone caused 100% and 80% survival, respectively, after administration of lipopolysaccharide (62.5mg/kg, i.v., 40% survival if untreated). In human mononuclear leukocyte, isoforskolin (50, 100, and 200 μM) and dexamethasone (10 μM) pre-incubation lowered lipopolysaccharide (2 μg/mL) induced secretion of the cytokine TNF-α, and interleukins (IL)-1β, IL-6, and IL-8. In conclusion, pretreatment with isoforskolin attenuates lipopolysaccharide-induced acute lung injury in several models, and it is involved in down-regulation of inflammatory responses and proinflammatory cytokines TNF-α, IL-1β, IL-6, and IL-8.

  7. DAP12 expression in lung macrophages mediates ischemia/reperfusion injury by promoting neutrophil extravasation.

    Science.gov (United States)

    Spahn, Jessica H; Li, Wenjun; Bribriesco, Alejandro C; Liu, Jie; Shen, Hua; Ibricevic, Aida; Pan, Jie-Hong; Zinselmeyer, Bernd H; Brody, Steven L; Goldstein, Daniel R; Krupnick, Alexander S; Gelman, Andrew E; Miller, Mark J; Kreisel, Daniel

    2015-04-15

    Neutrophils are critical mediators of innate immune responses and contribute to tissue injury. However, immune pathways that regulate neutrophil recruitment to injured tissues during noninfectious inflammation remain poorly understood. DAP12 is a cell membrane-associated protein that is expressed in myeloid cells and can either augment or dampen innate inflammatory responses during infections. To elucidate the role of DAP12 in pulmonary ischemia/reperfusion injury (IRI), we took advantage of a clinically relevant mouse model of transplant-mediated lung IRI. This technique allowed us to dissect the importance of DAP12 in tissue-resident cells and those that infiltrate injured tissue from the periphery during noninfectious inflammation. Macrophages in both mouse and human lungs that have been subjected to cold ischemic storage express DAP12. We found that donor, but not recipient, deficiency in DAP12 protected against pulmonary IRI. Analysis of the immune response showed that DAP12 promotes the survival of tissue-resident alveolar macrophages and contributes to local production of neutrophil chemoattractants. Intravital imaging demonstrated a transendothelial migration defect into DAP12-deficient lungs, which can be rescued by local administration of the neutrophil chemokine CXCL2. We have uncovered a previously unrecognized role for DAP12 expression in tissue-resident alveolar macrophages in mediating acute noninfectious tissue injury through regulation of neutrophil trafficking.

  8. Therapeutic Effect of Human Umbilical Cord Mesenchymal Stem Cells on Paraquat-Induced Lung Injury in Mouse%人脐带间充质干细胞对百草枯中毒肺损伤小鼠模型的治疗作用

    Institute of Scientific and Technical Information of China (English)

    吕双红; 王慧娜; 杜丽欣; 宋亚昆; 吴东颖; 刘兵; 邱泽武

    2014-01-01

    目的:探讨脐带间充质干细胞(UCMSC)治疗百草枯中毒引起的小鼠肺损伤的可行性。方法:小鼠腹腔一次性注射百草枯制备百草枯中毒小鼠模型,24 h后尾静脉注射UCMSC,分别于治疗后7和21 d取材,观察UCMSC对急性肺损伤和慢性肺纤维化的治疗作用。结果:UCMSC移植对40和50 mg/kg百草枯染毒组急性肺损伤有效,动物死亡率显著降低,但对60 mg/kg百草枯染毒组动物无效。UCMSC治疗对慢性肺纤维化有显著治疗作用,治疗组动物体重恢复早,死亡率降低,肺纤维化评分降低。RT-PCR结果显示,UCMSC移植3 h有人特异性线粒体基因的表达,但24 h后未检测到。结论:UCMSC对百草枯中毒性急慢性肺损伤有一定的治疗作用,这种作用可能是通过旁分泌机制实现的。%Objective: To investigate the possibility if human umbilical cord mesenchymal stem cells(UCMSC) can attenuate paraquat-induced lung injury in mouse. Methods: Mice received one dose of intraperitoneal injec⁃tion of paraquat to prepare animal models of lung injury. UCMSC were injected via tail vein 24 hours later. Then, the animals were executed 7 or 21 days later to evaluate therapeutic effect of cell treatment on the acute lung injury and lung fibrosis. Results: UCMSC decreased the death rates of 40 and 50 mg/kg paraquat intake groups, but had no effect on the animals in 60 mg/kg group. And the cell treatment also ameliorated the score of lung fibrosis and the body weight of the animals recovered earlier than control group. The RT-PCR result of hu⁃man specific chrome B mitochondria showed that human cells existed in the lung after 3 hours of transplantation, but didn't been detected 24 hours later. Conclusion: These results showed that UCMSC have therapeutic effect on acute lung injury and lung fibrosis induced by paraquat poisoning. And this effect may be due to the paracrine characters of mesenchymal stem cells.

  9. ICAM-1 and Acute Pancreatitis Complicated by Acute Lung Injury

    Directory of Open Access Journals (Sweden)

    XiPing Zhang

    2009-01-01

    Full Text Available One of the most common complications of acute pancreatitis is acute lung injury, during which intercellular adhesion molecule-1 (ICAM-1 plays an important role by participating in leukocyte adhesion and activation as well as by inducing the “cascade effect” of inflammatory mediators, pulmonary microcirculation dysfunction and even acute respiratory distress syndrome, multiple organ failure or death. Although it is generally believed that the modulatory mechanism of ICAM-1 during this process is associated with the activation of nuclear transcription factor kappa B which is mediated by IL-1, IL-6, IL-18 and oxygen free radical, etc., further studies are still required to clarify it. Since the upregulation of ICAM-1 expression in the lung during acute lung injury is one of main pathogeneses, the early detection of the ICAM-1 expression level may contribute to the prevention and treatment of acute lung injury. Moreover, reducing pulmonary ICAM-1 expression levels through treatment with anti-ICAM-1 monoclonal antibody (aICAM-1 and antagonists of the neurokinin 1 receptor, etc., should have a positive effect on protecting the lungs during acute pancreatitis. This review aims to further clarify the relationship between ICAM-1 and acute pancreatitis complicated by acute lung injury, and therefore provides a theoretical basis for the formulation of corresponding therapeutic measures in clinical practice for acute pancreatitis.

  10. Extravascular lung water index improves the diagnostic accuracy of lung injury in patients with shock.

    Science.gov (United States)

    Chew, Michelle S; Ihrman, Lilian; During, Joachim; Bergenzaun, Lill; Ersson, Anders; Undén, Johan; Ryden, Jörgen; Åkerman, Eva; Larsson, Marina

    2012-01-03

    The diagnosis of acute lung injury (ALI) may be more robust if more accurate physiological markers can be identified. Extravascular lung water (EVLW) is one possible marker, and it has been shown to correlate with respiratory function and mortality in patients with sepsis. Whether EVLW confers diagnostic value in a general population with shock, as well as which index performs best, is unclear. We investigated the diagnostic accuracy of various EVLW indices in patients with shock. We studied a prospective, observational cohort of 51 patients with shock admitted to a tertiary ICU. EVLW was measured within 6 hours of ICU admission and indexed to actual body weight (EVLW/ABW), predicted body weight (EVLW/PBW) and pulmonary blood volume (EVLW/PBV). The relationship of these indices to the diagnosis and severity of lung injury and ICU mortality were studied. Positive and negative likelihood ratios, pre- and posttest odds for diagnosis of lung injury and mortality were calculated. All EVLW indices were higher among patients with lung injury and significantly correlated with respiratory parameters. Furthermore, all EVLW indices were significantly higher in nonsurvivors. The use of EVLW improves the posttest OR for the diagnosis of ALI, acute respiratory distress syndrome (ARDS) and severe lung injury (sLI) by up to eightfold. Combining increased EVLW and a diagnosis of ALI, ARDS or sLI increases the posttest odds of ICU mortality. EVLW/ABW and EVLW/PBV demonstrated the best diagnostic performance in this population. EVLW was associated with degree of lung injury and mortality, regardless of the index used, confirming that it may be used as a bedside indicator of disease severity. The use of EVLW as a bedside test conferred added diagnostic value for the identification of patients with lung injury.

  11. Rabbit model of radiation-induced lung injury

    Institute of Scientific and Technical Information of China (English)

    Zhen-Zong Du; Hua Ren; Jian-Fei Song; Li-Fei Zhang; Feng Lin; Hai-Yong Wang

    2013-01-01

    Objective:To explore the feasibility of establishing an animal model of chronic radiation-induced lung injury.Methods:Twenty-eightNewZealand white rabbits were randomly divided into3 groups(the right lung irradiation group, the whole lung irradiation group and the control group).Animal model of radiation-induced lung injury was established by high-does radiotherapy in the irradiation groups, then all rabbits underwentCT and pathological examinations at1,2,4,8,12,16 weeks, respectively after radiation.Results:Within4 weeks of irradiation, some rabbits in the right lung irradiation group and whole lung irradiation group died. CT and pathological examinations all showed acute radiation pneumonitis.At8-12 weeks after irradiation,CT scanning showed ground glass samples signs, patchy shadows and fibrotic stripes. Pathological examination showed the fibrosis pulmonary alveolar wall thickened obviously. Conclusions:The clinical animal model of chronic radiation-induced lung injury which corresponds to practical conditions in clinic can be successfully established.

  12. Angiotensin converting enzyme 2 abrogates bleomycin-induced lung injury.

    Science.gov (United States)

    Rey-Parra, G J; Vadivel, A; Coltan, L; Hall, A; Eaton, F; Schuster, M; Loibner, H; Penninger, J M; Kassiri, Z; Oudit, G Y; Thébaud, B

    2012-06-01

    Despite substantial progress, mortality and morbidity of the acute respiratory distress syndrome (ARDS), a severe form of acute lung injury (ALI), remain unacceptably high. There is no effective treatment for ARDS/ALI. The renin-angiotensin system (RAS) through Angiotensin-converting enzyme (ACE)-generated Angiotensin II contributes to lung injury. ACE2, a recently discovered ACE homologue, acts as a negative regulator of the RAS and counterbalances the function of ACE. We hypothesized that ACE2 prevents Bleomycin (BLM)-induced lung injury. Fourteen to 16-week-old ACE2 knockout mice-male (ACE2(-/y)) and female (ACE2(-/-))-and age-matched wild-type (WT) male mice received intratracheal BLM (1.5U/kg). Male ACE2(-/y) BLM injured mice exhibited poorer exercise capacity, worse lung function and exacerbated lung fibrosis and collagen deposition compared with WT. These changes were associated with increased expression of the profibrotic genes α-smooth muscle actin (α-SMA) and Transforming Growth Factor ß1. Compared with ACE2(-/y) exposed to BLM, ACE2(-/-) exhibited better lung function and architecture and decreased collagen deposition. Treatment with intraperitoneal recombinant human (rh) ACE2 (2 mg/kg) for 21 days improved survival, exercise capacity, and lung function and decreased lung inflammation and fibrosis in male BLM-WT mice. Female BLM WT mice had mild fibrosis and displayed a possible compensatory upregulation of the AT2 receptor. We conclude that ACE2 gene deletion worsens BLM-induced lung injury and more so in males than females. Conversely, ACE2 protects against BLM-induced fibrosis. rhACE2 may have therapeutic potential to attenuate respiratory morbidity in ALI/ARDS.

  13. Effects of minimal lipopolysaccharide-instilled lungs on ventilator-induced lung injury in rats

    Institute of Scientific and Technical Information of China (English)

    LI Ke-zhong; WANG Qiu-jun; SUN Tao; YAO Shang-long

    2007-01-01

    @@ Mechanical ventilation (MV) may aggravate lung injury induced by a variety of injuries, including intratracheal hydrochloric acid instillation,1 intratracheal lipopolysaccharide (LPS) instillation with or without concurrent saline lavage,2 intravenous LPS,3 or intravenous oleic acid.4 However, the mechanism for this detrimental effect of MV is unclear.

  14. Smoking water pipe is injurious to lungs

    DEFF Research Database (Denmark)

    Sivapalan, Pradeesh; Ringbæk, Thomas; Lange, Peter

    2014-01-01

    This review describes the pulmonary consequences of water pipe smoking. Smoking water pipe affects the lung function negatively, is significantly associated with chronic obstructive pulmonary disease and increases the risk of lung infections. Case reports suggest that regular smokers of water pipe...

  15. Nitric oxide synthase 3 contributes to ventilator-induced lung injury

    Science.gov (United States)

    Vaporidi, Katerina; Francis, Roland C.; Bloch, Kenneth D.

    2010-01-01

    Nitric oxide synthase (NOS) depletion or inhibition reduces ventilator-induced lung injury (VILI), but the responsible mechanisms remain incompletely defined. The aim of this study was to elucidate the role of endothelial NOS, NOS3, in the pathogenesis of VILI in an in vivo mouse model. Wild-type and NOS3-deficient mice were ventilated with high-tidal volume (HVT; 40 ml/kg) for 4 h, with and without adding NO to the inhaled gas. Additional wild-type mice were pretreated with tetrahydrobiopterin and ascorbic acid, agents that can prevent NOS-generated superoxide production. Arterial blood gas tensions, histology, and lung mechanics were evaluated after 4 h of HVT ventilation. The concentration of protein, IgM, cytokines, malondialdehyde, and 8-isoprostane were measured in bronchoalveolar lavage fluid (BALF). Myeloperoxidase activity, total and oxidized glutathione levels, and NOS-derived superoxide production were measured in lung tissue homogenates. HVT ventilation induced VILI in wild-type mice, as reflected by decreased lung compliance, increased concentrations of protein and cytokines in BALF, and oxidative stress. All indices of VILI were ameliorated in NOS3-deficient mice. Augmenting pulmonary NO levels by breathing NO during mechanical ventilation did not increase lung injury in NOS3-deficient mice. HVT ventilation increased NOS-inhibitable superoxide production in lung extracts from wild-type mice but not in those from NOS3-deficient mice. Administration of tetrahydrobiopterin and ascorbic acid ameliorated VILI in wild-type mice. Our results indicate that NOS3 contributes to ventilator-induced lung injury via increased production of superoxide. PMID:20453164

  16. 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.

  17. Effect of thalidomide in a mouse model of paraquat-induced acute lung injury and the underlying mechanisms%沙利度胺对百草枯诱导小鼠急性肺损伤的干预

    Institute of Scientific and Technical Information of China (English)

    李冬; 徐丽艳; 常子娟; 赵光举; 南超; 卢中秋

    2013-01-01

    Objective To investigate the intervention effect of thalidomide on paraquat-induced acute lung injury in mice and its mechanism.Methods Male ICR mice were randomly allocated to negative control group (n=30),thalidomide control group (n=30),paraquat poisoning group (n=30),50 mg/kg thalidomide treatment group (n=30),100 mg/kg thalidomide treatment group (n=30),and 150 mg/kg thalidomide treatment group (n=30).The negative control group was intraperitoneally injected with the same volume of saline; the thalidomide control group was intraperitoneally injected with thalidomide (150 mg/kg); the paraquat poisoning group was intraperitoneally injected with diluted paraquat solution (22 mg/kg); each thalidomide treatment group was intraperitoneally injected with the same volume of paraquat solution (22 mg/kg) and was injected with thalidomide (50,100,or 150 mg/kg) 1 h later.All mice were anesthetized and sacrificed at 1,3,or 7 d after paraquat poisoning,and their lung tissue was collected.The levels of tumor necrosis factor (TNF)-α,interleukin (IL)-1β,and IL-6 in lung tissue were measured by double-antibody sandwich ELISA; the mRNA expression of nuclear factor-kappa B (NF-κB) was measured by RT-PCR; the protein expression of nuclear NF-κB p65 was measured by Western blot.The pathological changes of lung tissue were observed under light microscope; the wet/dry ratio of the lung was calculated.Results Compared with the negative control group,the paraquat poisoning group had significantly increased levels of TNF-α,IL-1β,IL-6,NF-κB mRNA,and nuclear NF-κB p65and wet/dry ratio of the lung (P<0.05).Compared with the paraquat poisoning group,the thalidomide treatment groups had significantly decreased levels of TNF-α,IL-1β,IL-6,NF-κB mRNA,and nuclear NF-κB p65 and =wet/dry ratios of the lung (P<0.05),and the 150 mg/kg thalidomide treatment group showed the most significant decrease in the levels of TNF-α,IL-1β,IL-6,NF-κB mRNA,and nuclear NF-κB p65.The observation

  18. 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.

  19. Prevention of reperfusion lung injury by lidocaine in isolated rat lung ventilated with higher oxygen levels.

    Directory of Open Access Journals (Sweden)

    Das K

    2003-01-01

    Full Text Available BACKGROUND: Lidocaine, an antiarrhythmic drug has been shown to be effective against post-ischaemic reperfusion injury in heart. However, its effect on pulmonary reperfusion injury has not been investigated. AIMS: We investigated the effects of lidocaine on a postischaemic reperfused rat lung model. MATERIALS AND METHODS: Lungs were isolated and perfused at constant flow with Krebs-Henseilet buffer containing 4% bovine serum albumin, and ventilated with 95% oxygen mixed with 5% CO2. Lungs were subjected to ischaemia by stopping perfusion for 60 minutes followed by reperfusion for 10 minutes. Ischaemia was induced in normothermic conditions. RESULTS: Postischaemic reperfusion caused significant (p < 0.0001 higher wet-to-dry lung weight ratio, pulmonary arterial pressure and peak airway pressure compared to control lungs. Lidocaine, at a dose of 5mg/Kg b.w. was found to significantly (p < 0.0001 attenuate the increase in the wet-to-dry lung weight ratio, pulmonary arterial pressure and peak airway pressure observed in post-ischaemic lungs. CONCLUSION: Lidocaine is effective in preventing post-ischaemic reperfusion injury in isolated, perfused rat lung.

  20. The Field of Tissue Injury in the Lung and Airway

    OpenAIRE

    Steiling, Katrina; Ryan, John; Brody, Jerome S.; Spira, Avrum

    2008-01-01

    The concept of field cancerization was first introduced over six decades ago in the setting of oral cancer. Later, field cancerization involving histologic and molecular changes of neoplasms and adjacent tissue began to be characterized in smokers with or without lung cancer. Investigators also described a diffuse, non-neoplastic field of molecular injury throughout the respiratory tract that is attributable to cigarette smoking and susceptibility to smoking-induced lung disease. The potentia...

  1. Cardiotrophin-1 attenuates endotoxin-induced acute lung injury.

    Science.gov (United States)

    Pulido, E J; Shames, B D; Pennica, D; O'leary, R M; Bensard, D D; Cain, B S; McIntyre, R C

    1999-06-15

    Cardiotrophin-1 (CT-1) is a recently discovered member of the gp130 cytokine family, which includes IL-6, IL-11, leukemia inhibitory factor, ciliary neurotrophic factor, and oncostatin M. Recent evidence suggests that, like other members of this family, CT-1 may possess anti-inflammatory properties. We hypothesized that in vivo CT-1 administration would attenuate endotoxin (ETX)-induced acute lung injury. We studied the effects of CT-1 (100 microgram/kg ip, 10 min prior to ETX) in a rat model of ETX-induced acute lung injury (Salmonella typhimurium lipopolysaccharide, 20 mg/kg ip). Six hours after ETX, lungs were harvested for determination of neutrophil accumulation (myeloperoxidase, MPO, assay) and lung edema (wet-to-dry weight ratio). Mechanisms of pulmonary vasorelaxation were examined in isolated pulmonary artery rings at 6 h by interrogating endothelium-dependent (response to acetylcholine) and endothelium-independent (response to sodium nitroprusside) relaxation following alpha-adrenergic (phenylephrine)-stimulated preconstriction. CT-1 abrogated the endotoxin-induced lung neutrophil accumulation: 2.3 +/- 0.2 units MPO/g wet lung (gwl) vs 6. 3 +/- 0.3 units MPO/gwl in the ETX group (P 0.05 vs control). Similarly, CT-1 prevented ETX-induced lung edema: wet-to-dry-weight ratio, 4.473 +/- 0.039 vs 4.747 +/- 0.039 in the ETX group (P 0.05 vs control). Endotoxin caused significant impairment of both endothelium-dependent and -independent pulmonary vasorelaxation, and CT-1 attenuated this injury. Thus, cardiotrophin-1 possesses significant anti-inflammatory properties in a model of endotoxin-induced acute lung injury. Copyright 1999 Academic Press.

  2. Transfusion-related acute lung injury: report of two cases.

    Science.gov (United States)

    Čermáková, Z; Kořískta, M; Blahutová, Š; Dvořáčková, J; Brát, R; Valkovský, I; Hrdličková, R

    2012-01-01

    Transfusion-related acute lung injury (TRALI) is a severe life-threatening complication of blood transfusion, characterized by acute lung injury developing within 2-6 h of transfusion. However, TRALI is difficult to diagnose, and the initial report or suspicion of TRALI depends on close collaboration between clinical departments and transfusion centres. A total of 17 adverse post-transfusion reactions were reported to the Blood Centre of the University Hospital Ostrava as suspected TRALI between 2005 and 2010. We report two cases of serious TRALI with different pathogenetic mechanisms.

  3. Treatment of intractable interstitial lung injury with alemtuzumab after lung transplantation

    DEFF Research Database (Denmark)

    Kohno, M; Perch, M; Andersen, E;

    2011-01-01

    of transplantation. Routine examination of a lung biopsy, 4 months after transplantation, showed nonspecific, diffuse interstitial inflammation with alveolar septal fibrosis. The patient's clinical status and imaging studies, consistent with nonspecific interstitial pneumonitis, which was considered as signs......, posttransplant antirejection drug regimen. We have since successfully treated with alemtuzumab three additional patients who developed interstitial lung injury after lung transplantation, who are also summarized in this report.......A 44-year-old woman underwent left single-lung transplantation for end-stage emphysema due to α1-antitrypsin deficiency in January 2010. Cyclosporine, azathioprine, and prednisolone were administered for immunosuppression and antithymocyte globulin for induction therapy at the time...

  4. Sports-related lung injury during breath-hold diving

    Directory of Open Access Journals (Sweden)

    Tanja Mijacika

    2016-12-01

    Full Text Available The number of people practising recreational breath-hold diving is constantly growing, thereby increasing the need for knowledge of the acute and chronic effects such a sport could have on the health of participants. Breath-hold diving is potentially dangerous, mainly because of associated extreme environmental factors such as increased hydrostatic pressure, hypoxia, hypercapnia, hypothermia and strenuous exercise. In this article we focus on the effects of breath-hold diving on pulmonary function. Respiratory symptoms have been reported in almost 25% of breath-hold divers after repetitive diving sessions. Acutely, repetitive breath-hold diving may result in increased transpulmonary capillary pressure, leading to noncardiogenic oedema and/or alveolar haemorrhage. Furthermore, during a breath-hold dive, the chest and lungs are compressed by the increasing pressure of water. Rapid changes in lung air volume during descent or ascent can result in a lung injury known as pulmonary barotrauma. Factors that may influence individual susceptibility to breath-hold diving-induced lung injury range from underlying pulmonary or cardiac dysfunction to genetic predisposition. According to the available data, breath-holding does not result in chronic lung injury. However, studies of large populations of breath-hold divers are necessary to firmly exclude long-term lung damage.

  5. Sports-related lung injury during breath-hold diving.

    Science.gov (United States)

    Mijacika, Tanja; Dujic, Zeljko

    2016-12-01

    The number of people practising recreational breath-hold diving is constantly growing, thereby increasing the need for knowledge of the acute and chronic effects such a sport could have on the health of participants. Breath-hold diving is potentially dangerous, mainly because of associated extreme environmental factors such as increased hydrostatic pressure, hypoxia, hypercapnia, hypothermia and strenuous exercise.In this article we focus on the effects of breath-hold diving on pulmonary function. Respiratory symptoms have been reported in almost 25% of breath-hold divers after repetitive diving sessions. Acutely, repetitive breath-hold diving may result in increased transpulmonary capillary pressure, leading to noncardiogenic oedema and/or alveolar haemorrhage. Furthermore, during a breath-hold dive, the chest and lungs are compressed by the increasing pressure of water. Rapid changes in lung air volume during descent or ascent can result in a lung injury known as pulmonary barotrauma. Factors that may influence individual susceptibility to breath-hold diving-induced lung injury range from underlying pulmonary or cardiac dysfunction to genetic predisposition.According to the available data, breath-holding does not result in chronic lung injury. However, studies of large populations of breath-hold divers are necessary to firmly exclude long-term lung damage.

  6. Neutrophils contain cholesterol crystals in transfusion-related acute lung injury (TRALI)

    DEFF Research Database (Denmark)

    Van Ness, Michael; Jensen, Hanne; Adamson, Grete N

    2013-01-01

    Intracellular components of transfusion-related acute lung injury (TRALI) were investigated by transmission electron microscopy.......Intracellular components of transfusion-related acute lung injury (TRALI) were investigated by transmission electron microscopy....

  7. A role for mesenchyme dynamics in mouse lung branching morphogenesis.

    Directory of Open Access Journals (Sweden)

    Pierre Blanc

    Full Text Available Mammalian airways are highly ramified tree-like structures that develop by the repetitive branching of the lung epithelium into the surrounding mesenchyme through reciprocal interactions. Based on a morphometric analysis of the epithelial tree, it has been recently proposed that the complete branching scheme is specified early in each lineage by a programme using elementary patterning routines at specific sites and times in the developing lung. However, the coupled dynamics of both the epithelium and mesenchyme have been overlooked in this process. Using a qualitative and quantitative in vivo morphometric analysis of the E11.25 to E13.5 mouse whole right cranial lobe structure, we show that beyond the first generations, the branching stereotypy relaxes and both spatial and temporal variations are common. The branching pattern and branching rate are sensitive to the dynamic changes of the mesoderm shape that is in turn mainly dependent upon the volume and shape of the surrounding intrathoracic organs. Spatial and temporal variations of the tree architecture are related to local and subtle modifications of the mesoderm growth. Remarkably, buds never meet after suffering branching variations and continue to homogenously fill the opening spaces in the mesenchyme. Moreover despite inter-specimen variations, the growth of the epithelial tree and the mesenchyme remains highly correlated over time at the whole lobe level, implying a long-range regulation of the lung lobe morphogenesis. Together, these findings indicate that the lung epithelial tree is likely to adapt in real time to fill the available space in the mesenchyme, rather than being rigidly specified and predefined by a global programme. Our results strongly support the idea that a comprehensive understanding of lung branching mechanisms cannot be inferred from the branching pattern or behavior alone. Rather it needs to be elaborated upon with the reconsideration of mesenchyme

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

    Directory of Open Access Journals (Sweden)

    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.

  9. Mitogen-Activated Protein Kinases Regulate Susceptibility to Ventilator-Induced Lung Injury

    OpenAIRE

    2008-01-01

    BACKGROUND: Mechanical ventilation causes ventilator-induced lung injury in animals and humans. Mitogen-activated protein kinases have been implicated in ventilator-induced lung injury though their functional significance remains incomplete. We characterize the role of p38 mitogen-activated protein kinase/mitogen activated protein kinase kinase-3 and c-Jun-NH(2)-terminal kinase-1 in ventilator-induced lung injury and investigate novel independent mechanisms contributing to lung injury during ...

  10. First-pass studies of acute lung injury.

    Science.gov (United States)

    Chu, R Y; Sidhu, N; Basmadjian, G; Burow, R; Allen, E W

    1993-10-01

    Mild hydrochloric acid was introduced to a caudal lung section in each of eight dogs to induce injury. Transits of 99mTc-labeled red blood cells (RBC) and [123I]iodoantipyrine (IAP) injected intravenously were recorded by a scintillation camera. Lungs and blood samples were analyzed post-mortem. Peak-to-equilibrium ratios (P/E) of RBC time-activity curves were computed to be 3.83 +/- 0.54 for the control lung, 2.58 +/- 0.55 for the injured lung and 2.23 +/- 0.58 for the injured caudal section. For IAP, the respective results were 3.78 +/- 0.29, 2.02 +/- 0.18 and 1.77 +/- 0.17. The decrease of P/E in injured areas was attributed to reduced blood flow. Using mean transit times of the tracers, we computed extravascular lung water per unit blood volume to be 0.35 +/- 0.18 for the control lungs and an increased value of 0.68 +/- 0.24 for the injured lungs. These results displayed sensitivity to injury, but were gross underestimates relative to the corresponding values of 2.04 +/- 0.54 and 4.56 +/- 1.85 in post-mortem analyses.

  11. First-pass studies of acute lung injury

    Energy Technology Data Exchange (ETDEWEB)

    Chu, R.Y.L.; Sidhu, N.; Basmadjian, G.; Burow, R.; Allen, E.W. (Oklahoma Univ. and Dept. of Veterans Affairs Medical Centre, Oklahoma City, OK (United States))

    1993-10-01

    Mild hydrochloric acid was introduced to a caudal lung section in each of eight dogs to induce injury. Transits of [sup 99m]Tc-labeled red blood cells (RBC) and [[sup 123]I]iodoantipyrine (IAP) injected intravenously were recorded by a scintillation camera. Lungs and blood samples were analyzed post-mortem. Peak-to-equilibrium ratios (P/E) of RBC time-activity curves were computed to be 3.83 [+-] 0.54 for the control lung, 2.58 [+-] 0.55 for the injured lung and 2.23 [+-] 0.58 for the injured caudal section. For IAP, the respective results were 3.78 [+-] 0.29, 2.02 [+-] 0.18 and 1.77 [+-] 0.17. The decrease of P/E in injured areas was attributed to reduced blood flow. Using mean transit times of the tracers, we computed extravascular lung water per unit blood volume to be 0.35 [+-] 0.18 for the control lungs and an increased value of 0.68 [+-] 0.24 for the injured lungs. These results displayed sensitivity to injury, but were gross underestimates relative to the corresponding values of 2.04 [+-] 0.54 and 4.56 [+-] 1.85 in post-mortem analyses. (Author).

  12. Crocin attenuates lipopolysacchride-induced acute lung injury in mice

    Science.gov (United States)

    Wang, Jian; Kuai, Jianke; Luo, Zhonghua; Wang, Wuping; Wang, Lei; Ke, Changkang; Li, Xiaofei; Ni, Yunfeng

    2015-01-01

    Crocin, a representative of carotenoid compounds, exerts a spectrum of activities including radical scavenger, anti-microbial and anti-inflammatory properties. To investigate the protective effect of crocin on lipopolysaccharide (LPS)-induced acute lung injury (ALI) in mice. ALI was induced in mice by intratracheal instillation of LPS (1 mg/kg). The mice received intragastric injection of crocin (50 mg/kg) 1 h before LPS administration. Pulmonary histological changes were evaluated by hematoxylineosin stain and lung wet/dry weight ratios were observed. Concentrations of tumor necrosis factor (TNF)-α, interleukin (IL)-1β and nitric oxide (NO), and myeloperoxidase (MPO) activity were measured by enzymelinked immunosorbent assay. Expression of inducible nitric oxide synthase (iNOS) in lung tissues was determined by Western blot analysis. Crocin pretreatment significantly alleviated the severity of lung injury and inhibited the production of TNF-α and IL-1β in mice with ALI. After LPS administration, the lung wet/dry weight ratios, as an index of lung edema, and MPO activity were also markedly reduced by crocin pretreatment. Crocin pretreatment also reduced the concentrations of NO in lung tissues. Furthermore, the expression of iNOS was significantly suppressed by crocin pretreatment. Croncin potently protected against LPS-induced ALI and the protective effects of crocin may attribute partly to the suppression of iNOS expression. PMID:26191176

  13. Influenza Virus Infection Induces Platelet-Endothelial Adhesion Which Contributes to Lung Injury.

    Science.gov (United States)

    Sugiyama, Michael G; Gamage, Asela; Zyla, Roman; Armstrong, Susan M; Advani, Suzanne; Advani, Andrew; Wang, Changsen; Lee, Warren L

    2015-12-04

    Lung injury after influenza infection is characterized by increased permeability of the lung microvasculature, culminating in acute respiratory failure. Platelets interact with activated endothelial cells and have been implicated in the pathogenesis of some forms of acute lung injury. Autopsy studies have revealed pulmonary microthrombi after influenza infection, and epidemiological studies suggest that influenza vaccination is protective against pulmonary thromboembolism; however, the effect of influenza infection on platelet-endothelial interactions is unclear. We demonstrate that endothelial infection with both laboratory and clinical strains of influenza virus increased the adhesion of human platelets to primary human lung microvascular endothelial cells. Platelets adhered to infected cells as well as to neighboring cells, suggesting a paracrine effect. Influenza infection caused the upregulation of von Willebrand factor and ICAM-1, but blocking these receptors did not prevent platelet-endothelial adhesion. Instead, platelet adhesion was inhibited by both RGDS peptide and a blocking antibody to platelet integrin α5β1, implicating endothelial fibronectin. Concordantly, lung histology from infected mice revealed viral dose-dependent colocalization of viral nucleoprotein and the endothelial marker PECAM-1, while platelet adhesion and fibronectin deposition also were observed in the lungs of influenza-infected mice. Inhibition of platelets using acetylsalicylic acid significantly improved survival, a finding confirmed using a second antiplatelet agent. Thus, influenza infection induces platelet-lung endothelial adhesion via fibronectin, contributing to mortality from acute lung injury. The inhibition of platelets may constitute a practical adjunctive strategy to the treatment of severe infections with influenza.IMPORTANCE There is growing appreciation of the involvement of the lung endothelium in the pathogenesis of severe infections with influenza virus. We have

  14. NLRP3 inflammasome activation is essential for paraquat-induced acute lung injury.

    Science.gov (United States)

    Liu, Zhenning; Zhao, Hongyu; Liu, Wei; Li, Tiegang; Wang, Yu; Zhao, Min

    2015-02-01

    The innate immune response is important in paraquat-induced acute lung injury, but the exact pathways involved are not elucidated. The objectives of this study were to determine the specific role of the NLRP3 inflammasome in the process. Acute lung injury was induced by administering paraquat (PQ) intraperitoneally. NLRP3 inflammasome including NLRP3, ASC, and caspase-1 mRNA and protein expression in lung tissue and IL-1β and IL-18 levels in BALF were detected at 4, 8, 24, and 72 h after PQ administration in rats. Moreover, rats were pretreated with 10, 30, and 50 mg/kg NLRP3 inflammasome blocker glybenclamide, respectively, 1 h before PQ exposure. At 72 h after PQ administration, lung histopathology changes, NLRP3, ASC, and caspase-1 protein expression, as well as secretion of cytokines including IL-1β and IL-18 in BALF were investigated. The NLRP3 inflammasome including NLRP3, ASC, caspase-1 expression, and cytokines IL-1β and IL-18 levels in PQ poisoning rats were significantly higher than that in the control group. NLRP3 inflammasome blocker glybenclamide pretreatment attenuated lung edema, inhibited the NLRP3, ASC, and caspase-1 activation, and reduced IL-1β and IL-18 levels in BALF. In the in vitro experiments, IL-1β and IL-18 secreted from RAW264.7 mouse macrophages treated with paraquat were attenuated by glybenclamide. In conclusion, paraquat can induce IL-1β/IL-18 secretion via NLRP3-ASC-caspase-1 pathway, and the NLRP3 inflammasome is essential for paraquat-induced acute lung injury.

  15. Ventilator-induced Lung Injury : Similarity and Differences between Children and Adults

    NARCIS (Netherlands)

    Kneyber, Martin C.J.; Zhang, Haibo; Slutsky, Arthur S.

    2014-01-01

    It is well established that mechanical ventilation can injure the lung, producing an entity known as ventilator-induced lung injury (VILI). There are various forms of VILI, including volutrauma (i.e., injury caused by overdistending the lung), atelectrauma (injury due to repeated opening/closing of

  16. Proteome Profiling in Lung Injury after Hematopoietic Stem Cell Transplantation.

    Science.gov (United States)

    Bhargava, Maneesh; Viken, Kevin J; Dey, Sanjoy; Steinbach, Michael S; Wu, Baolin; Jagtap, Pratik D; Higgins, LeeAnn; Panoskaltsis-Mortari, Angela; Weisdorf, Daniel J; Kumar, Vipin; Arora, Mukta; Bitterman, Peter B; Ingbar, David H; Wendt, Chris H

    2016-08-01

    Pulmonary complications due to infection and idiopathic pneumonia syndrome (IPS), a noninfectious lung injury in hematopoietic stem cell transplant (HSCT) recipients, are frequent causes of transplantation-related mortality and morbidity. Our objective was to characterize the global bronchoalveolar lavage fluid (BALF) protein expression of IPS to identify proteins and pathways that differentiate IPS from infectious lung injury after HSCT. We studied 30 BALF samples from patients who developed lung injury within 180 days of HSCT or cellular therapy transfusion (natural killer cell transfusion). Adult subjects were classified as having IPS or infectious lung injury by the criteria outlined in the 2011 American Thoracic Society statement. BALF was depleted of hemoglobin and 14 high-abundance proteins, treated with trypsin, and labeled with isobaric tagging for relative and absolute quantification (iTRAQ) 8-plex reagent for two-dimensional capillary liquid chromatography (LC) and data dependent peptide tandem mass spectrometry (MS) on an Orbitrap Velos system in higher-energy collision-induced dissociation activation mode. Protein identification employed a target-decoy strategy using ProteinPilot within Galaxy P. The relative protein abundance was determined with reference to a global internal standard consisting of pooled BALF from patients with respiratory failure and no history of HSCT. A variance weighted t-test controlling for a false discovery rate of ≤5% was used to identify proteins that showed differential expression between IPS and infectious lung injury. The biological relevance of these proteins was determined by using gene ontology enrichment analysis and Ingenuity Pathway Analysis. We characterized 12 IPS and 18 infectious lung injury BALF samples. In the 5 iTRAQ LC-MS/MS experiments 845, 735, 532, 615, and 594 proteins were identified for a total of 1125 unique proteins and 368 common proteins across all 5 LC-MS/MS experiments. When comparing IPS to

  17. The role of alveolar epithelium in radiation-induced lung injury.

    Science.gov (United States)

    Almeida, Celine; Nagarajan, Devipriya; Tian, Jian; Leal, Sofia Walder; Wheeler, Kenneth; Munley, Michael; Blackstock, William; Zhao, Weiling

    2013-01-01

    Pneumonitis and fibrosis are major lung complications of irradiating thoracic malignancies. In the current study, we determined the effect of thoracic irradiation on the lungs of FVB/N mice. Survival data showed a dose-dependent increase in morbidity following thoracic irradiation with single (11-13 Gy) and fractionated doses (24-36 Gy) of (137)Cs γ-rays. Histological examination showed a thickening of vessel walls, accumulation of inflammatory cells, collagen deposition, and regional fibrosis in the lungs 14 weeks after a single 12 Gy dose and a fractionated 30 Gy dose; this damage was also seen 5 months after a fractionated 24 Gy dose. After both single and fractionated doses, i] aquaporin-5 was markedly decreased, ii] E-cadherin was reduced and iii] prosurfactant Protein C (pro-SP-c), the number of pro-SP-c(+) cells and vimentin expression were increased in the lungs. Immunofluorescence analysis revealed co-localization of pro-SP-c and α-smooth muscle actin in the alveoli after a single dose of 12 Gy. These data suggest that, i] the FVB/N mouse strain is sensitive to thoracic radiation ii] aquaporin-5, E-cadherin, and pro-SP-c may serve as sensitive indicators of radiation-induced lung injury; and iii] the epithelial-to-mesenchymal transition may play an important role in the development of radiation-induced lung fibrosis.

  18. The role of alveolar epithelium in radiation-induced lung injury.

    Directory of Open Access Journals (Sweden)

    Celine Almeida

    Full Text Available Pneumonitis and fibrosis are major lung complications of irradiating thoracic malignancies. In the current study, we determined the effect of thoracic irradiation on the lungs of FVB/N mice. Survival data showed a dose-dependent increase in morbidity following thoracic irradiation with single (11-13 Gy and fractionated doses (24-36 Gy of (137Cs γ-rays. Histological examination showed a thickening of vessel walls, accumulation of inflammatory cells, collagen deposition, and regional fibrosis in the lungs 14 weeks after a single 12 Gy dose and a fractionated 30 Gy dose; this damage was also seen 5 months after a fractionated 24 Gy dose. After both single and fractionated doses, i] aquaporin-5 was markedly decreased, ii] E-cadherin was reduced and iii] prosurfactant Protein C (pro-SP-c, the number of pro-SP-c(+ cells and vimentin expression were increased in the lungs. Immunofluorescence analysis revealed co-localization of pro-SP-c and α-smooth muscle actin in the alveoli after a single dose of 12 Gy. These data suggest that, i] the FVB/N mouse strain is sensitive to thoracic radiation ii] aquaporin-5, E-cadherin, and pro-SP-c may serve as sensitive indicators of radiation-induced lung injury; and iii] the epithelial-to-mesenchymal transition may play an important role in the development of radiation-induced lung fibrosis.

  19. Influence of glutathione-S-transferase (GST) inhibition on lung epithelial cell injury: role of oxidative stress and metabolism.

    Science.gov (United States)

    Fletcher, Marianne E; Boshier, Piers R; Wakabayashi, Kenji; Keun, Hector C; Smolenski, Ryszard T; Kirkham, Paul A; Adcock, Ian M; Barton, Paul J; Takata, Masao; Marczin, Nandor

    2015-06-15

    Oxidant-mediated tissue injury is key to the pathogenesis of acute lung injury. Glutathione-S-transferases (GSTs) are important detoxifying enzymes that catalyze the conjugation of glutathione with toxic oxidant compounds and are associated with acute and chronic inflammatory lung diseases. We hypothesized that attenuation of cellular GST enzymes would augment intracellular oxidative and metabolic stress and induce lung cell injury. Treatment of murine lung epithelial cells with GST inhibitors, ethacrynic acid (EA), and caffeic acid compromised lung epithelial cell viability in a concentration-dependent manner. These inhibitors also potentiated cell injury induced by hydrogen peroxide (H2O2), tert-butyl-hydroperoxide, and hypoxia and reoxygenation (HR). SiRNA-mediated attenuation of GST-π but not GST-μ expression reduced cell viability and significantly enhanced stress (H2O2/HR)-induced injury. GST inhibitors also induced intracellular oxidative stress (measured by dihydrorhodamine 123 and dichlorofluorescein fluorescence), caused alterations in overall intracellular redox status (as evidenced by NAD(+)/NADH ratios), and increased protein carbonyl formation. Furthermore, the antioxidant N-acetylcysteine completely prevented EA-induced oxidative stress and cytotoxicity. Whereas EA had no effect on mitochondrial energetics, it significantly altered cellular metabolic profile. To explore the physiological impact of these cellular events, we used an ex vivo mouse-isolated perfused lung model. Supplementation of perfusate with EA markedly affected lung mechanics and significantly increased lung permeability. The results of our combined genetic, pharmacological, and metabolic studies on multiple platforms suggest the importance of GST enzymes, specifically GST-π, in the cellular and whole lung response to acute oxidative and metabolic stress. These may have important clinical implications.

  20. Life-threatening acute lung injury after gamma butyrolactone ingestion

    NARCIS (Netherlands)

    van Gerwen, M.; Scheper, H.; Touw, D. J.; van Nieuwkoop, C.

    2015-01-01

    We describe a case of a 44-year-old woman with a borderline personality disorder and chronic gamma-butyrolactone (GBL) use who presented with progressive dyspnoea and an altered mental status. A high anion gap metabolic acidosis and acute lung injury was diagnosed. We hypothesise this was caused by

  1. Reducing ventilator-induced lung injury and other organ injury by the prone position

    Science.gov (United States)

    Suter, Peter M

    2006-01-01

    Mechanical ventilation can cause structural and functional disturbances in the lung, as well as other vital organ dysfunctions. Apoptosis is thought to be a histological sign of distant organ damage in ventilator-induced lung injury (VILI). Nakos and colleagues observed a protective effect of prone positioning against VILI in normal sheep. Less alteration in the lung architecture and function and in liver transaminases, and lower indices for apoptosis in the liver, the diaphragm and the lung were noted in the prone position compared with the supine position. If confirmed, these data open a new hypothesis for pathogenesis and prevention of VILI and its extrapulmonary complications. PMID:16677405

  2. IL-17 response mediates acute lung injury induced by the 2009 Pandemic Influenza A(H1N1)Virus

    Institute of Scientific and Technical Information of China (English)

    Chenggang Li; Chen Wang; Zhongwei Chen; Li Xing; Chong Tang; Xiangwu Ju; Feng Guo; Jiejie Deng; Yan Zhao; Peng Yang; Jun Tang; Penghui Yang; Huanling Wang; Zhongpeng Zhao; Zhinan Yin; Bin Cao; Xiliang Wang; Chengyu Jiang; Yang Sun; Taisheng Li; Chen Wang; Zhong Wang; Zhen Zou; Yiwu Yan; Wei Wang

    2012-01-01

    The 2009 flu pandemic involved the emergence of a new strain of a swine-origin H1N1 influenza virus(S-OIV H1N1)that infected almost every country in the world.Most infections resulted in respiratory illness and some severe cases resulted in acute lung injury.In this report,we are the first to describe a mouse model of S-OIV virus infection with acute lung injury and immune responses that reflect human clinical disease.The clinical efficacy of the antiviral oseltamivir(Tamiflu)administered in the early stages of S-OIV H1N1 infection was confirmed in the mouse model.Moreover,elevated levels of IL-17,Th-17 mediators and IL-17-responsive cytokines were found in serum samples of S-OIV-infected patients in Beijing.IL-17 deficiency or treatment with monoclonal antibodies against IL-17-ameliorated acute lung injury induced by the S-OIV H1N1 virus in mice.These results suggest that IL-17 plays an important role in S-OIV-induced acute lung injury and that monoclonal antibodies against IL-17 could be useful as a potential therapeutic remedy for future S-OIV H1N1 pandemics.

  3. Phosphatidic acid signaling mediates lung cytokine expression and lung inflammatory injury after hemorrhage in mice.

    Science.gov (United States)

    Abraham, E; Bursten, S; Shenkar, R; Allbee, J; Tuder, R; Woodson, P; Guidot, D M; Rice, G; Singer, J W; Repine, J E

    1995-02-01

    Because phosphatidic acid (PA) pathway signaling may mediate many basic reactions involving cytokine-dependent responses, we investigated the effects of CT1501R, a functional inhibitor of the enzyme lysophosphatidic acid acyltransferase (LPAAT) which converts lysophosphatidic acid (Lyso-PA) to PA. We found that CT1501R treatment not only prevented hypoxia-induced PA increases and lyso-PA consumption in human neutrophils, but also prevented neutrophil chemotaxis and adherence in vitro, and lung injury and lung neutrophil accumulation in mice subjected to hemorrhage and resuscitation. In addition, CT1501R treatment prevented increases in mRNA levels and protein production of a variety of proinflammatory cytokines in multiple lung cell populations after blood loss and resuscitation. Our results indicate the fundamental role of PA metabolism in the development of acute inflammatory lung injury after blood loss.

  4. Overview of KRAS-Driven Genetically Engineered Mouse Models of Non-Small Cell Lung Cancer.

    Science.gov (United States)

    Sheridan, Clare; Downward, Julian

    2015-01-01

    KRAS, the most frequently mutated oncogene in non-small cell lung cancer, has been utilized extensively to model human lung adenocarcinomas. The results from such studies have enhanced considerably an understanding of the relationship between KRAS and the development of lung cancer. Detailed in this overview are the features of various KRAS-driven genetically engineered mouse models (GEMMs) of non-small cell lung cancer, their utilization, and the potential of these models for the study of lung cancer biology.

  5. The Role of Neutrophil Collagenase in Endotoxic Acute Lung Injury

    Institute of Scientific and Technical Information of China (English)

    徐涛; 曾邦雄; 李兴旺

    2004-01-01

    The aim of this study was to determine the role of neutrophil collagenase in the pathogenesis of acute lung injury induced by endotoxin. 28 Sprague-Dawley were randomized into control group and LPS-enduced groups. Samples of left lung were obtained in 2 h (group L1 ), 6 h (group L2), 12 h (group L3 ) after intravenous LPS. Immunohistochemsitry was employed for detection of expression of neutrophil collagenase. Pathological scores, lung wet/dry weight ratio and the number of neutrophils were measured. The results showed that the concentration of neutrophil collagenase in LPS-enduced groups (group L1, L2, L3 ) were significantly higher than that of control group (P<0.01). Pathological scores, lung wet/dry weight ratio and the number of neutrophils in LPS-enduced groups (group L1, L2, L3 ) were also significantly higher than that of control group (P<0.01).Moreover, among group L1, L2 and L3, there were significant correlations in concentration of neutrophil collagenase and pathological scores, lung wet/dry weight ratio, the number of neutrophils (P<0.05). The present study showed that neutrophil collagenase play an important role in the pathogenesis and progress of endotoxic acute lung injury.

  6. Treatment of intractable interstitial lung injury with alemtuzumab after lung transplantation

    DEFF Research Database (Denmark)

    Kohno, M; Perch, M; Andersen, E;

    2011-01-01

    of acute rejection, worsened within 2 weeks, despite high-dose steroids, change of calcineurin inhibitor, and plasmapheresis. Within a few days after a single, 10-mg, intravenous dose of alemtuzumab, the patient's health improved markedly. She has remained stable for 4 months on a standard, ambulatory......, posttransplant antirejection drug regimen. We have since successfully treated with alemtuzumab three additional patients who developed interstitial lung injury after lung transplantation, who are also summarized in this report....

  7. A novel SCID mouse model for studying spontaneous metastasis of human lung cancer to human tissue.

    Science.gov (United States)

    Teraoka, S; Kyoizumi, S; Seyama, T; Yamakido, M; Akiyama, M

    1995-05-01

    We established a novel severe combined immunodeficient (SCID) mouse model for the study of human lung cancer metastasis to human lung. Implantation of both human fetal and adult lung tissue into mammary fat pads of SCID mice showed a 100% rate of engraftment, but only fetal lung implants revealed normal morphology of human lung tissue. Using these chimeric mice, we analyzed human lung cancer metastasis to both mouse and human lungs by subcutaneous inoculation of human squamous cell carcinoma and adenocarcinoma cell lines into the mice. In 60 to 70% of SCID mice injected with human-lung squamous-cell carcinoma, RERF-LC-AI, cancer cells were found to have metastasized to both mouse lungs and human fetal lung implants but not to human adult lung implants 80 days after cancer inoculation. Furthermore, human-lung adenocarcinoma cells, RERF-LC-KJ, metastasized to the human lung implants within 90 days in about 40% of SCID mice, whereas there were no metastases to the lungs of the mice. These results demonstrate the potential of this model for the in vivo study of human lung cancer metastasis.

  8. Mouse allergen, lung function, and atopy in Puerto Rican children.

    Directory of Open Access Journals (Sweden)

    Erick Forno

    Full Text Available To examine the relation between mouse allergen exposure and asthma in Puerto Rican children.Mus m 1, Der p 1, Bla g 2, and Fel d 1 allergens were measured in dust samples from homes of Puerto Rican children with (cases and without (controls asthma in Hartford, CT (n = 449 and San Juan (SJ, Puerto Rico (n = 678. Linear or logistic regression was used for the multivariate analysis of mouse allergen (Mus m 1 and lung function (FEV(1 and FEV(1/FVC and allergy (total IgE and skin test reactivity (STR to ≥1 allergen measures.Homes in SJ had lower mouse allergen levels than those in Hartford. In multivariate analyses, mouse allergen was associated with higher FEV(1 in cases in Hartford (+70.6 ml, 95% confidence interval (CI = 8.6-132.7 ml, P = 0.03 and SJ (+45.1 ml, 95% CI =  -0.5 to 90.6 ml, P = 0.05. In multivariate analyses of controls, mouse allergen was inversely associated with STR to ≥1 allergen in non-sensitized children (odds ratio [OR] for each log-unit increment in Mus m 1 = 0.7, 95% CI = 0.5-0.9, P<0.01. In a multivariate analysis including all children at both study sites, each log-increment in mouse allergen was positively associated with FEV(1 (+28.3 ml, 95% CI = 1.4-55.2 ml, P = 0.04 and inversely associated with STR to ≥1 allergen (OR for each log-unit increment in Mus m 1 = 0.8, 95% CI = 0.6-0.9, P<0.01.Mouse allergen is associated with a higher FEV(1 and lower odds of STR to ≥1 allergen in Puerto Rican children. This may be explained by the allergen itself or correlated microbial exposures.

  9. A human lung xenograft mouse model of Nipah virus infection.

    Directory of Open Access Journals (Sweden)

    Gustavo Valbuena

    2014-04-01

    Full Text Available Nipah virus (NiV is a member of the genus Henipavirus (family Paramyxoviridae that causes severe and often lethal respiratory illness and encephalitis in humans with high mortality rates (up to 92%. NiV can cause Acute Lung Injury (ALI in humans, and human-to-human transmission has been observed in recent outbreaks of NiV. While the exact route of transmission to humans is not known, we have previously shown that NiV can efficiently infect human respiratory epithelial cells. The molecular mechanisms of NiV-associated ALI in the human respiratory tract are unknown. Thus, there is an urgent need for models of henipavirus infection of the human respiratory tract to study the pathogenesis and understand the host responses. Here, we describe a novel human lung xenograft model in mice to study the pathogenesis of NiV. Following transplantation, human fetal lung xenografts rapidly graft and develop mature structures of adult lungs including cartilage, vascular vessels, ciliated pseudostratified columnar epithelium, and primitive "air" spaces filled with mucus and lined by cuboidal to flat epithelium. Following infection, NiV grows to high titers (10(7 TCID50/gram lung tissue as early as 3 days post infection (pi. NiV targets both the endothelium as well as respiratory epithelium in the human lung tissues, and results in syncytia formation. NiV infection in the human lung results in the production of several cytokines and chemokines including IL-6, IP-10, eotaxin, G-CSF and GM-CSF on days 5 and 7 pi. In conclusion, this study demonstrates that NiV can replicate to high titers in a novel in vivo model of the human respiratory tract, resulting in a robust inflammatory response, which is known to be associated with ALI. This model will facilitate progress in the fundamental understanding of henipavirus pathogenesis and virus-host interactions; it will also provide biologically relevant models for other respiratory viruses.

  10. Lung injury in dimethyl sulfate poisoning

    Energy Technology Data Exchange (ETDEWEB)

    Ip, M.; Wong, K.L.; Wong, K.F.; So, S.Y.

    1989-02-01

    Two manual laborers were exposed to dimethyl sulfate during work and sustained mucosal injury to the eyes and respiratory tract. In one of them, noncardiogenic pulmonary edema occurred and improved with high-dose methylprednisolone. On follow-up for 10 months, this patient developed persistent productive cough with no evidence of bronchiectasis or bronchial hyperreactivity.

  11. Strategies to prevent intraoperative lung injury during cardiopulmonary bypass

    Directory of Open Access Journals (Sweden)

    Siminelakis Stavros N

    2010-01-01

    Full Text Available Abstract During open heart surgery the influence of a series of factors such as cardiopulmonary bypass (CPB, hypothermia, operation and anaesthesia, as well as medication and transfusion can cause a diffuse trauma in the lungs. This injury leads mostly to a postoperative interstitial pulmonary oedema and abnormal gas exchange. Substantial improvements in all of the above mentioned factors may lead to a better lung function postoperatively. By avoiding CPB, reducing its time, or by minimizing the extracorporeal surface area with the use of miniaturized circuits of CPB, beneficial effects on lung function are reported. In addition, replacement of circuit surface with biocompatible surfaces like heparin-coated, and material-independent sources of blood activation, a better postoperative lung function is observed. Meticulous myocardial protection by using hypothermia and cardioplegia methods during ischemia and reperfusion remain one of the cornerstones of postoperative lung function. The partial restoration of pulmonary artery perfusion during CPB possibly contributes to prevent pulmonary ischemia and lung dysfunction. Using medication such as corticosteroids and aprotinin, which protect the lungs during CPB, and leukocyte depletion filters for operations expected to exceed 90 minutes in CPB-time appear to be protective against the toxic impact of CPB in the lungs. The newer methods of ultrafiltration used to scavenge pro-inflammatory factors seem to be protective for the lung function. In a similar way, reducing the use of cardiotomy suction device, as well as the contact-time between free blood and pericardium, it is expected that the postoperative lung function will be improved.

  12. Ozone therapy ameliorates paraquat-induced lung injury in rats.

    Science.gov (United States)

    Kaldirim, Umit; Uysal, Bulent; Yuksel, Ramazan; Macit, Enis; Eyi, Yusuf E; Toygar, Mehmet; Tuncer, Salim K; Ardic, Sukru; Arziman, Ibrahim; Aydin, Ibrahim; Oztas, Yesim; Karslioglu, Yildirim; Topal, Turgut

    2014-12-01

    Paraquat (PQ) overdose can cause acute lung injury and death. Ozone therapy (OT) was previously demonstrated to alleviate inflammation and necrosis in various pathologies. We therefore hypothesized that OT has ameliorative and preventive effects on PQ-induced lung damage due to anti-inflammatory and antioxidants properties. Sprague-Dawley rats (n = 24) were separated into three groups: sham, PQ, and PQ+OT groups. 15 mg/kg PQ was administered intraperitoneally in PQ and PQ+OT groups to induce experimental lung injury. One hour after PQ treatment, PQ+OT group was administered a single dose of ozone-oxygen mixture (1 mg/kg/day) by intraperitoneal route for four consecutive days. The animals were sacrificed on fifth day after PQ administration. Blood samples and lung tissues were collected to evaluate the inflammatory processes, antioxidant defense and pulmonary damage. Serum lactate dehydrogenase (LDH) and neopterin levels, tissue oxidative stress parameters, total TGF-β1 levels, and histological injury scores in PQ+OT group were significantly lower than PQ group (Ptherapy.

  13. 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

  14. Role of Nitric Oxide Isoforms in Vascular and Alveolar Development and Lung Injury in Vascular Endothelial Growth Factor Overexpressing Neonatal Mice Lungs.

    Directory of Open Access Journals (Sweden)

    Mansoor A Syed

    Full Text Available The role of vascular endothelial growth factor (VEGF-induced 3 different nitric oxide synthase (NOS isoforms in lung development and injury in the newborn (NB lung are not known. We hypothesized that VEGF-induced specific NOS pathways are critical regulators of lung development and injury.We studied NB wild type (WT, lung epithelial cell-targeted VEGF165 doxycycline-inducible overexpressing transgenic (VEGFTG, VEGFTG treated with a NOS1 inhibitor (L-NIO, VEGFTG x NOS2-/- and VEGFTG x NOS3+/- mice in room air (RA for 7 postnatal (PN days. Lung morphometry (chord length, vascular markers (Ang1, Ang2, Notch2, vWF, CD31 and VE-cadherin, cell proliferation (Ki67, vascular permeability, injury and oxidative stress markers (hemosiderin, nitrotyrosine and 8-OHdG were evaluated.VEGF overexpression in RA led to increased chord length and vascular markers at PN7, which were significantly decreased to control values in VEGFTG x NOS2-/- and VEGFTG x NOS3+/- lungs. However, we found no noticeable effect on chord length and vascular markers in the VEGFTG / NOS1 inhibited group. In the NB VEGFTG mouse model, we found VEGF-induced vascular permeability in the NB murine lung was partially dependent on NOS2 and NOS3-signaling pathways. In addition, the inhibition of NOS2 and NOS3 resulted in a significant decrease in VEGF-induced hemosiderin, nitrotyrosine- and 8-OHdG positive cells at PN7. NOS1 inhibition had no significant effect.Our data showed that the complete absence of NOS2 and partial deficiency of NOS3 confers protection against VEGF-induced pathologic lung vascular and alveolar developmental changes, as well as injury markers. Inhibition of NOS1 does not have any modulating role on VEGF-induced changes in the NB lung. Overall, our data suggests that there is a significant differential regulation in the NOS-mediated effects of VEGF overexpression in the developing mouse lung.

  15. 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

  16. 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

  17. Synergistic protection against hyperoxia-induced lung injury by neutrophils blockade and EC-SOD overexpression

    Directory of Open Access Journals (Sweden)

    Min Jae H

    2012-07-01

    Full Text Available Abstract Background Oxygen may damage the lung directly via generation of reactive oxygen species (ROS or indirectly via the recruitment of inflammatory cells, especially neutrophils. Overexpression of extracellular superoxide dismutase (EC-SOD has been shown to protect the lung against hyperoxia in the newborn mouse model. The CXC-chemokine receptor antagonist (Antileukinate successfully inhibits neutrophil influx into the lung following a variety of pulmonary insults. In this study, we tested the hypothesis that the combined strategy of overexpression of EC-SOD and inhibiting neutrophil influx would reduce the inflammatory response and oxidative stress in the lung after acute hyperoxic exposure more efficiently than either single intervention. Methods Neonate transgenic (Tg (with an extra copy of hEC-SOD and wild type (WT were exposed to acute hyperoxia (95% FiO2 for 7 days and compared to matched room air groups. Inflammatory markers (myeloperoxidase, albumin, number of inflammatory cells, oxidative markers (8-isoprostane, ratio of reduced/oxidized glutathione, and histopathology were examined in groups exposed to room air or hyperoxia. During the exposure, some mice received a daily intraperitoneal injection of Antileukinate. Results Antileukinate-treated Tg mice had significantly decreased pulmonary inflammation and oxidative stress compared to Antileukinate-treated WT mice (p p  Conclusion Combined strategy of EC-SOD and neutrophil influx blockade may have a therapeutic benefit in protecting the lung against acute hyperoxic injury.

  18. Protective effects of asiaticoside on septic lung injury in mice.

    Science.gov (United States)

    Zhang, Li-na; Zheng, Jia-jia; Zhang, Li; Gong, Xia; Huang, Hai; Wang, Chang-dong; Wang, Bin; Wu, Meng-jiao; Li, Xiao-hui; Sun, Wen-juan; Liu, Ying-ju; Wan, Jing-yuan

    2011-09-01

    Asiaticoside (AS), a major triterpenoid saponin component isolated from Centella asiatica, has been described to exhibit antioxidant and anti-inflammatory activities. The present study aimed to determine the protective effects and the underlying mechanisms of AS on septic lung injury induced by cecal ligation and puncture (CLP). Mice were pretreated with the AS (45 mg/kg) or AS as well as GW9662 at 1h before CLP, the survival, lung injury, inflammatory mediators and signaling molecules, and Peroxisome proliferator-activated receptor-γ (PPAR-γ) were determined 24 h after CLP. The results showed that AS significantly decreased CLP-induced the mortality, lung pathological damage, the infiltration of mononuclear, polymorphonuclear (PMN) leucocytes and total proteins. Moreover, AS inhibited CLP-induced the activation of mitogen-activated protein kinases (MAPKs) and nuclear factor-κB (NF-κB), the expression of cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) protein in lung tissues, and the production of serum tumor necrosis factor (TNF-α) and interleukin-6 (IL-6). Interestingly, the expression of PPAR-γ protein in lung tissue was up-regulated by AS. Furthermore, GW9662 (the inhibitor of PPAR-γ) significantly reversed these beneficial effects of AS in septic mice. These findings suggest that AS could effectively protect from septic lung injury induced by CLP and the underlying mechanisms might be related to up-regulation of PPAR-γ expression to some extent, which inhibits MAPKs and NF-κB pathway.

  19. Fibrogenic Lung Injury Induces Non-Cell-Autonomous Fibroblast Invasion.

    Science.gov (United States)

    Ahluwalia, Neil; Grasberger, Paula E; Mugo, Brian M; Feghali-Bostwick, Carol; Pardo, Annie; Selman, Moisés; Lagares, David; Tager, Andrew M

    2016-06-01

    Pathologic accumulation of fibroblasts in pulmonary fibrosis appears to depend on their invasion through basement membranes and extracellular matrices. Fibroblasts from the fibrotic lungs of patients with idiopathic pulmonary fibrosis (IPF) have been demonstrated to acquire a phenotype characterized by increased cell-autonomous invasion. Here, we investigated whether fibroblast invasion is further stimulated by soluble mediators induced by lung injury. We found that bronchoalveolar lavage fluids from bleomycin-challenged mice or patients with IPF contain mediators that dramatically increase the matrix invasion of primary lung fibroblasts. Further characterization of this non-cell-autonomous fibroblast invasion suggested that the mediators driving this process are produced locally after lung injury and are preferentially produced by fibrogenic (e.g., bleomycin-induced) rather than nonfibrogenic (e.g., LPS-induced) lung injury. Comparison of invasion and migration induced by a series of fibroblast-active mediators indicated that these two forms of fibroblast movement are directed by distinct sets of stimuli. Finally, knockdown of multiple different membrane receptors, including platelet-derived growth factor receptor-β, lysophosphatidic acid 1, epidermal growth factor receptor, and fibroblast growth factor receptor 2, mitigated the non-cell-autonomous fibroblast invasion induced by bronchoalveolar lavage from bleomycin-injured mice, suggesting that multiple different mediators drive fibroblast invasion in pulmonary fibrosis. The magnitude of this mediator-driven fibroblast invasion suggests that its inhibition could be a novel therapeutic strategy for pulmonary fibrosis. Further elaboration of the molecular mechanisms that drive non-cell-autonomous fibroblast invasion consequently may provide a rich set of novel drug targets for the treatment of IPF and other fibrotic lung diseases.

  20. Toll-like receptor 4-dependent responses to lung injury in a murine model of pulmonary contusion.

    Science.gov (United States)

    Hoth, J Jason; Wells, Jonathan D; Brownlee, Noel A; Hiltbold, Elizabeth M; Meredith, J Wayne; McCall, Charles E; Yoza, Barbara K

    2009-04-01

    Blunt chest trauma resulting in pulmonary contusion with an accompanying acute inflammatory response is a common but poorly understood injury. We previously demonstrated that toll-like receptor 2 (TLR-2) participates in the inflammatory response to lung injury. We hypothesized that the TLR-4, in an MyD88-dependent manner, may also participate in the response to lung injury. To investigate this, we used a model of pulmonary contusion in the mouse that is similar to that observed clinically in humans and evaluated postinjury lung function, pulmonary neutrophil recruitment, and the systemic innate immune response. Comparisons were made between wild-type mice and mice deficient in TLR-4 or MyD88. We found TLR-4-dependent responses to pulmonary contusion that include hypoxemia, edema, and neutrophil infiltration. Increased expression of IL-6 and chemokine (C-X-C motif) ligand 1 in the bronchoalveolar lavage and serum was also dependent on TLR-4 activation. We further demonstrated that these responses to pulmonary contusion were dependent on MyD88, an adapter protein in the signal transduction pathway mediated by TLRs. These results show that TLRs have a primary role in the response to acute lung injury. Lung inflammation and systemic innate immune responses are dependent on TLR activation by pulmonary contusion.

  1. Cotton dust-mediated lung epithelial injury.

    OpenAIRE

    Ayars, G H; Altman, L C; O'Neil, C E; Butcher, B T; Chi, E Y

    1986-01-01

    To determine if constituents of cotton plants might play a role in byssinosis by injuring pulmonary epithelium, we added extracts of cotton dust, green bract, and field-dried bract to human A549 and rat type II pneumocytes. Injury was measured as pneumocyte lysis and detachment, and inhibition of protein synthesis. Extracts of cotton dust and field-dried bract produced significant dose- and time-dependent lysis and detachment of both target cells, while green bract extract was less damaging. ...

  2. Chorioamnionitis and Lung Injury in Preterm Newborns

    Directory of Open Access Journals (Sweden)

    Gustavo Rocha

    2013-01-01

    Full Text Available There is a strong evidence that histologic chorioamnionitis is associated with a reduction of incidence and severity of respiratory distress syndrome (RDS. Short-term maturational effects on the lungs of extremely premature infants seem to be, however, accompanied by a greater susceptibility of the lung, eventually contributing to an increased risk of bronchopulmonary dysplasia (BPD. Genetic susceptibility to BPD is an evolving area of research and several studies have directly related the risk of BPD to genomic variants. There is a substantial heterogeneity across the studies in the magnitude of the association between chorioamnionitis and BPD, and whether or not the association is statistically significant. Considerable variation is largely dependent on differences of inclusion and exclusion criteria, as well as on clinical and histopathological definitions. The presence of significant publication bias may exaggerate the magnitude of the association. Controlling for publication bias may conduct to adjusted results that are no longer significant. Recent studies generally seem to confirm the effect of chorioamnionitis on RDS incidence, while no effect on BPD is seen. Recent data suggest susceptibility for subsequent asthma to be increased on long-term followup. Additional research on this field is needed.

  3. Toll-like receptor 2 participates in the response to lung injury in a murine model of pulmonary contusion.

    Science.gov (United States)

    Hoth, J Jason; Hudson, William P; Brownlee, Noel A; Yoza, Barbara K; Hiltbold, Elizabeth M; Meredith, J Wayne; McCall, Charles E

    2007-10-01

    Blunt chest trauma resulting in pulmonary contusion with an accompanying acute inflammatory response is a common but poorly understood injury. We report that Toll-like receptor (TLR) 2 participates in the inflammatory response to lung injury. To show this, we use a model of pulmonary contusion in the mouse that is similar to that observed clinically in humans based on histologic, morphologic, and biochemical criteria of acute lung injury. The inflammatory response to pulmonary contusion in our mouse model is characterized by pulmonary edema, neutrophil transepithelial migration, and increased expression of the innate immunity proinflammatory cytokines IL 1beta and IL 6, the adhesion intracellular adhesion molecule 1, and chemokine (CXC motif) ligand 1. Compared with wild-type animals, contused Tlr2(-/-) mice have significantly reduced pulmonary edema and neutrophilia. These findings are associated with decreased levels of circulating chemokine (CXC motif) ligand 1. In contrast, systemic IL 6 levels remain elevated in the TLR2-deficient phenotype. These results show that TLR2 has a primary role in the neutrophil response to acute lung injury. We suggest that an unidentified noninfectious ligand generated by pulmonary contusion acts via TLR2 to generate inflammatory responses.

  4. Regulatory effects of intrinsic IL-10 in IgG immune complex-induced lung injury

    DEFF Research Database (Denmark)

    Shanley, T P; Schmal, H; Friedl, H P;

    1995-01-01

    injury. In the current study, we sought to determine whether endogenous IL-10 is playing a regulatory role in the lung inflammatory response. On the basis of lung mRNA and ELISA measurements, IL-10 induction was found during development of inflammation in the IgG immune complex model of lung injury...

  5. Melatonin alleviates acute lung injury through inhibiting the NLRP3 inflammasome.

    Science.gov (United States)

    Zhang, Yong; Li, Xiru; Grailer, Jamison J; Wang, Na; Wang, Mingming; Yao, Jianfei; Zhong, Rui; Gao, George F; Ward, Peter A; Tan, Dun-Xian; Li, Xiangdong

    2016-05-01

    Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are clinically severe respiratory disorders, and there are currently no Food and Drug Administration-approved drug therapies. Melatonin is a well-known anti-inflammatory molecule, which has proven to be effective in ALI induced by many conditions. Emerging studies suggest that the NLRP3 inflammasome plays a critical role during ALI. How melatonin directly blocks activation of the NLRP3 inflammasome in ALI remains unclear. In this study, using an LPS-induced ALI mouse model, we found intratracheal (i.t.) administration of melatonin markedly reduced the pulmonary injury and decreased the infiltration of macrophages and neutrophils into lung. During ALI, the NLRP3 inflammasome is significantly activated with a large amount of IL-1β and the activated caspase-1 occurring in the lung. Melatonin inhibits the activation of the NLRP3 inflammasome by both suppressing the release of extracellular histones and directly blocking histone-induced NLRP3 inflammasome activation. Notably, i.t. route of melatonin administration opens a more efficient therapeutic approach for treating ALI.

  6. Galangin dampens mice lipopolysaccharide-induced acute lung injury.

    Science.gov (United States)

    Shu, Yu-Sheng; Tao, Wei; Miao, Qian-Bing; Lu, Shi-Chun; Zhu, Ya-Bing

    2014-10-01

    Galangin, an active ingredient of Alpinia galangal, has been shown to possess anti-inflammatory and antioxidant activities. Inflammation and oxidative stress are known to play vital effect in the pathogenesis of acute lung injury (ALI). In this study, we determined whether galangin exerts lung protection in lipopolysaccharide (LPS)-induced ALI. Male BALB/c mice were randomized to receive galangin or vehicle intraperitoneal injection 3 h after LPS challenge. Samples were harvested 24 h post LPS administration. Galangin administration decreased biochemical parameters of oxidative stress and inflammation, and improved oxygenation and lung edema in a dose-dependent manner. These protective effects of galangin were associated with inhibition of nuclear factor (NF)-κB and upregulation of heme oxygenase (HO)-1. Galangin reduces LPS-induced ALI by inhibition of inflammation and oxidative stress.

  7. Desferrioxamine attenuates minor lung injury following surgical acute liver failure.

    Science.gov (United States)

    Kostopanagiotou, G G; Kalimeris, K A; Arkadopoulos, N P; Pafiti, A; Panagopoulos, D; Smyrniotis, V; Vlahakos, D; Routsi, C; Lekka, M E; Nakos, G

    2009-06-01

    Acute liver failure (ALF) can be complicated by lung dysfunction. The aim of this study was to test the hypothesis that inhibition of oxidative stress through iron chelation with desferrioxamine (DFX) attenuates pulmonary injury caused by ALF. 14 adult female domestic pigs were subjected to surgical devascularisation of the liver and were randomised to a study group (DFX group, n = 7), which received post-operative intravenous infusion of DFX (14.5 mg x kg(-1) x h(-1) for the first 6 h post-operatively and 2.4 mg x kg(-1) x h(-1) until completion of 24 h), and a control group (n = 7). Post-operative lung damage was evaluated by histological and bronchoalveolar lavage fluid (BALF) analysis. DFX resulted in reduced BALF protein levels and tissue phospholipase (PL)A(2) activity. Plasma malondialdehyde and BALF nitrate and nitrite concentrations were lower, while catalase activity in the lung was higher after DFX treatment. PLA(2), platelet-activating factor acetylhydrolase and total cell counts in BALF did not differ between groups. Histological examination revealed reduced alveolar collapse, pneumonocyte necrosis and total lung injury in the DFX-treated animals. DFX reduced systemic and pulmonary oxidative stress during ALF. The limited activity of PLA(2) and the attenuation of pneumonocyte necrosis could represent beneficial mechanisms by which DFX improves alveolar-capillary membrane permeability and prevents alveolar space collapse.

  8. Sex-specific differences in hyperoxic lung injury in mice: Implications for acute and chronic lung disease in humans

    Energy Technology Data Exchange (ETDEWEB)

    Lingappan, Krithika, E-mail: lingappa@bcm.edu [Department of Pediatrics, Section of Neonatology, Texas Children' s Hospital, Baylor College of Medicine, 1102 Bates Avenue, MC: FC530.01, Houston, TX 77030 (United States); Jiang, Weiwu; Wang, Lihua; Couroucli, Xanthi I. [Department of Pediatrics, Section of Neonatology, Texas Children' s Hospital, Baylor College of Medicine, 1102 Bates Avenue, MC: FC530.01, Houston, TX 77030 (United States); Barrios, Roberto [Department of Pathology and Genomic Medicine, The Methodist Hospital Physician Organization, 6565 Fannin Street, Suite M227, Houston, TX 77030 (United States); Moorthy, Bhagavatula [Department of Pediatrics, Section of Neonatology, Texas Children' s Hospital, Baylor College of Medicine, 1102 Bates Avenue, MC: FC530.01, Houston, TX 77030 (United States)

    2013-10-15

    Sex-specific differences in pulmonary morbidity in humans are well documented. Hyperoxia contributes to lung injury in experimental animals and humans. The mechanisms responsible for sex differences in the susceptibility towards hyperoxic lung injury remain largely unknown. In this investigation, we tested the hypothesis that mice will display sex-specific differences in hyperoxic lung injury. Eight week-old male and female mice (C57BL/6J) were exposed to 72 h of hyperoxia (FiO{sub 2} > 0.95). After exposure to hyperoxia, lung injury, levels of 8-iso-prostaglandin F{sub 2} alpha (8-iso-PGF 2α) (LC–MS/MS), apoptosis (TUNEL) and inflammatory markers (suspension bead array) were determined. Cytochrome P450 (CYP)1A expression in the lung was assessed using immunohistochemistry and western blotting. After exposure to hyperoxia, males showed greater lung injury, neutrophil infiltration and apoptosis, compared to air-breathing controls than females. Pulmonary 8-iso-PGF 2α levels were higher in males than females after hyperoxia exposure. Sexually dimorphic increases in levels of IL-6 (F > M) and VEGF (M > F) in the lungs were also observed. CYP1A1 expression in the lung was higher in female mice compared to males under hyperoxic conditions. Overall, our results support the hypothesis that male mice are more susceptible than females to hyperoxic lung injury and that differences in inflammatory and oxidative stress markers contribute to these sex-specific dimorphic effects. In conclusion, this paper describes the establishment of an animal model that shows sex differences in hyperoxic lung injury in a temporal manner and thus has important implications for lung diseases mediated by hyperoxia in humans. - Highlights: • Male mice were more susceptible to hyperoxic lung injury than females. • Sex differences in inflammatory markers were observed. • CYP1A expression was higher in females after hyperoxia exposure.

  9. Cannabidiol improves lung function and inflammation in mice submitted to LPS-induced acute lung injury.

    Science.gov (United States)

    Ribeiro, A; Almeida, V I; Costola-de-Souza, C; Ferraz-de-Paula, V; Pinheiro, M L; Vitoretti, L B; Gimenes-Junior, J A; Akamine, A T; Crippa, J A; Tavares-de-Lima, W; Palermo-Neto, J

    2015-02-01

    We have previously shown that the prophylactic treatment with cannabidiol (CBD) reduces inflammation in a model of acute lung injury (ALI). In this work we analyzed the effects of the therapeutic treatment with CBD in mice subjected to the model of lipopolysaccharide (LPS)-induced ALI on pulmonary mechanics and inflammation. CBD (20 and 80 mg/kg) was administered (i.p.) to mice 6 h after LPS-induced lung inflammation. One day (24 h) after the induction of inflammation the assessment of pulmonary mechanics and inflammation were analyzed. The results show that CBD decreased total lung resistance and elastance, leukocyte migration into the lungs, myeloperoxidase activity in the lung tissue, protein concentration and production of pro-inflammatory cytokines (TNF and IL-6) and chemokines (MCP-1 and MIP-2) in the bronchoalveolar lavage supernatant. Thus, we conclude that CBD administered therapeutically, i.e. during an ongoing inflammatory process, has a potent anti-inflammatory effect and also improves the lung function in mice submitted to LPS-induced ALI. Therefore the present and previous data suggest that in the future cannabidiol might become a useful therapeutic tool for the attenuation and treatment of inflammatory lung diseases.

  10. Establishment of the critical period of severe acute pancreatitis-associated lung injury

    Institute of Scientific and Technical Information of China (English)

    Yi-Peng Chen; Jian-Wen Ning; Feng Ji

    2009-01-01

    BACKGROUND: Since respiratory dysfunction is the main cause of death in patients with severe acute pancreatitis (SAP), elucidating the critical period of acute pancreatitis-associated lung injury (APALI) is of important clinical value. This study aimed to define the risk period of APALI by a series of studies including a dynamic analysis of total water content, ultrastructure and number of type Ⅱ alveolar epithelial cells, and reactive oxygen metabolites (ROMs) of lung tissue in a mouse model of SAP, and a clinical analysis of APALI patients. METHODS: ICR mice were selected to establish a SAP model. They were given 7 intraperitoneal injections of cerulein (50 μg/kg body weight) at hourly intervals, followed by an intraperitoneal injection of lipopolysaccharide (15 mg/kg body weight). The total water content, ultrastructure, and number of type Ⅱ alveolar epithelial cells, and ROMs of lung tissue were assessed before (0 hour) and after the establishment of SAP model (6 hours, 12 hours, 1 day, 4 days, and 7 days). In addition, we analyzed the data from 215 patients with APALI (PaO2 RESULTS: The total water content and ultrastructure of type Ⅱ alveolar epithelial cells (mitochondria and lamellar bodies) of the lung in the SAP mice were significantly altered at 12 hours after the establishment of SAP model, and reached a maximum at 1 to 4 days. The number of type Ⅱ alveolar epithelial cells and ROMs increased maximally at 1 day after the establishment of the model. Furthermore, clinical results showed that lung injury occurred at a mean of 3.1435±1.0199 days in patients with SAP. These clinical data were almost consistent with the results of the SAP model. CONCLUSION: The risk period for APALI is between the first and fourth day during the course of SAP.

  11. Lung contusion: inflammatory mechanisms and interaction with other injuries.

    Science.gov (United States)

    Raghavendran, Krishnan; Notter, Robert H; Davidson, Bruce A; Helinski, Jadwiga D; Kunkel, Steven L; Knight, Paul R

    2009-08-01

    This article reviews current animal models and laboratory studies investigating the pathophysiology of lung contusion (LC), a common and severe condition in patients with blunt thoracic trauma. Emphasis is on studies elucidating cells, mediators, receptors, and processes important in the innate pulmonary inflammatory response that contribute to LC injury. Surfactant dysfunction in the pathogenesis of LC is also discussed, as is the potential role of epithelial cell or neutrophil apoptosis. Studies examining combination injuries where LC is exacerbated by secondary insults such as gastric aspiration in trauma patients are also noted. The need for continuing mechanism-based research to further clarify the pathophysiology of LC injury, and to define and test potential therapeutic interventions targeting specific aspects of inflammation or surfactant dysfunction to improve clinical outcomes in patients with LC, is also emphasized.

  12. Matrine Attenuates COX-2 and ICAM-1 Expressions in Human Lung Epithelial Cells and Prevents Acute Lung Injury in LPS-Induced Mice

    Directory of Open Access Journals (Sweden)

    Chian-Jiun Liou

    2016-01-01

    Full Text Available Matrine is isolated from Sophora flavescens and shows anti-inflammatory effects in macrophages. Here we evaluated matrine’s suppressive effects on cyclooxygenase 2 (COX-2 and intercellular adhesion molecule-1 (ICAM-1 expressions in lipopolysaccharide- (LPS- stimulated human lung epithelial A549 cells. Additionally, BALB/c mice were given various matrine doses by intraperitoneal injection, and then lung injury was induced via intratracheal instillation of LPS. In LPS-stimulated A549 cells, matrine inhibited the productions of interleukin-8 (IL-8, monocyte chemotactic protein-1, and IL-6 and decreased COX-2 expression. Matrine treatment also decreased ICAM-1 protein expression and suppressed the adhesion of neutrophil-like cells to inflammatory A549 cells. In vitro results demonstrated that matrine significantly inhibited mitogen-activated protein kinase phosphorylation and decreased nuclear transcription factor kappa-B subunit p65 protein translocation into the nucleus. In vivo data indicated that matrine significantly inhibited neutrophil infiltration and suppressed productions of tumor necrosis factor-α and IL-6 in mouse bronchoalveolar lavage fluid and serum. Analysis of lung tissue showed that matrine decreased the gene expression of proinflammatory cytokines, chemokines, COX-2, and ICAM-1. Our findings suggest that matrine improved lung injury in mice and decreased the inflammatory response in human lung epithelial cells.

  13. Matrine Attenuates COX-2 and ICAM-1 Expressions in Human Lung Epithelial Cells and Prevents Acute Lung Injury in LPS-Induced Mice.

    Science.gov (United States)

    Liou, Chian-Jiun; Lai, You-Rong; Chen, Ya-Ling; Chang, Yi-Hsien; Li, Zih-Ying; Huang, Wen-Chung

    2016-01-01

    Matrine is isolated from Sophora flavescens and shows anti-inflammatory effects in macrophages. Here we evaluated matrine's suppressive effects on cyclooxygenase 2 (COX-2) and intercellular adhesion molecule-1 (ICAM-1) expressions in lipopolysaccharide- (LPS-) stimulated human lung epithelial A549 cells. Additionally, BALB/c mice were given various matrine doses by intraperitoneal injection, and then lung injury was induced via intratracheal instillation of LPS. In LPS-stimulated A549 cells, matrine inhibited the productions of interleukin-8 (IL-8), monocyte chemotactic protein-1, and IL-6 and decreased COX-2 expression. Matrine treatment also decreased ICAM-1 protein expression and suppressed the adhesion of neutrophil-like cells to inflammatory A549 cells. In vitro results demonstrated that matrine significantly inhibited mitogen-activated protein kinase phosphorylation and decreased nuclear transcription factor kappa-B subunit p65 protein translocation into the nucleus. In vivo data indicated that matrine significantly inhibited neutrophil infiltration and suppressed productions of tumor necrosis factor-α and IL-6 in mouse bronchoalveolar lavage fluid and serum. Analysis of lung tissue showed that matrine decreased the gene expression of proinflammatory cytokines, chemokines, COX-2, and ICAM-1. Our findings suggest that matrine improved lung injury in mice and decreased the inflammatory response in human lung epithelial cells.

  14. Effects of resolvin D1 on inflammatory responses and oxidative stress of lipopolysaccharide-induced acute lung injury in mice

    Institute of Scientific and Technical Information of China (English)

    Wang Lei; Yuan Ruixia; Yao Chengyue; Wu Qingping; Marie Christelle; Xie Wanli; Zhang Xingcai

    2014-01-01

    Background A variety of inflammatory mediators and effector cells participate together in acute lung injury,and lead to secondary injury that is due to an inflammatory cascade and secondary diffuse lung parenchyma injury.Inflammation is associated with an oxidative stress reaction,which is produced in the development of airway inflammation,and which has positive feedback on inflammation itself.Resolvin D1 can reduce the infiltration of neutrophils,regulate cytokine levels and reduce the inflammation reaction,and thereby promote the resolution of inflammation.The purpose of this study is to investigate the effects of resolvin D1 on an inflammatory response and oxidative stress during lipopolysaccharide (LPS)-induced acute lung injury.Methods LPS (3 mg/kg) was used to induce the acute lung injury model.Pretreatment resolvin D1 (100 ng/mouse) was given to mice 30 minutes before inducing acute lung injury.Mice were observed at 6 hours,12 hours,1 day,2 days,3 days,4 days and 7 days after LPS was administrated,then they were humanely sacrificed.We collected bronchoalveolar lavage fluid (BALF) and the lung tissues for further analysis.Paraffin section and HE staining of the lung tissues were made for histopathology observations.Parts of the lung tissues were evaluated for wet-to-dry (W/D) weight ratio.tumor necrosis factor (TNF)-α,inter leukin (IL)-1β,IL-10 and myeloperoxidase (MPO) were detected by enzyme-linked immunosorbent assay (ELISA).A lipid peroxidation malondialdehyde (MDA) assay kit was used to detect MDA.A total superoxide dismutase assay kit with WST-1 was used to analyze superoxide dismutase (SOD).We determined the apoptosis of neutrophils by Flow Cytometry.A real-time quantitative PCR Detecting System detected the expression of mRNA for heme oxygenase (HO)-1.Results Pretreatment with resolvin D1 reduced the pathological damage in the lung,decreased the recruitment of neutrophils and stimulated their apoptosis.It markedly decreased the expressions of TNF

  15. [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.

  16. Acute lung injury after instillation of human breast milk or infant formula into rabbits' lungs.

    Science.gov (United States)

    O'Hare, B; Lerman, J; Endo, J; Cutz, E

    1996-06-01

    Recent interest in shortening the fasting interval after ingestion of milk products demonstrated large volumes of breast milk in the stomach 2 h after breastfeeding. Although aspiration is a rare event, if it were to occur with human breast milk, it is important to understand the extent of the lung injury that might occur. Therefore, the response to instillation of acidified breast milk and infant formula in the lungs of adult rabbits was studied. In 18 anesthetized adult rabbits, 1 of 3 fluids (in a volume of 0.8 ml.kg-1 and pH level of 1.8, acidified with hydrochloric acid); saline, breast milk, or infant formula (SMA, Wyeth, Windsor, Ontario), was instilled into the lungs via a tracheotomy. The lungs were ventilated for 4 h after instillation. Alveolar-to-arterial oxygen gradient and dynamic compliance were measured before and at hourly intervals after instillation. After 4 h, the rabbits were killed and the lungs were excised. Neutrophil infiltration was quantitated by a pathologist blinded to the instilled fluid. A histologic control group of four rabbits was ventilated under study conditions without any intratracheal fluid instillation. Alveolar-to-arterial oxygen gradient increased and dynamic compliance decreased significantly during the 4 h after instillation of both breast milk and infant formula compared with baseline measurements and with saline controls (P formula rabbits were significantly greater than those in the control group. Instillation of acidified breast milk or infant formula (in a volume of 0.8 ml.kg-1 and pH level of 1.8) into rabbits' lungs induces acute lung injury of similar intensity that lasts at least 4 h.

  17. A new therapeutic strategy for lung tissue injury induced by influenza with CR2 targeting complement inhibitior

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    Tomlinson Stephen

    2010-02-01

    Full Text Available Abstract Background Influenza is a respiratory disease that seriously threatens human health. In fact, influenza virus itself does not make critical contribution to mortality induced by influenza, but "cytokine storm" produced by the excessive immune response triggered by the virus can result in inflammatory reaction of lung tissues and fatal lung tissue injury, and thus increase influenza mortality. Therefore, besides antiviral drugs, immunosuppression drugs should also be included in infection treatment. Presentation of the hypothesis Complement is the center of inflammatory reaction. If complement system is over activated, the body will have strong inflammatory reaction or tissue injury, resulting in pathological process. Many studies have proved that, inflammatory injury of lung tissues caused by influenza virus is closely related to complement activation. Therefore, inhibiting complement activation can significantly reduce inflammatory injury in lung tissues. As complement is both a physiological defense and pathological damage medium, systematic inhibition may result in side effects including infection. Therefore, we design targeting complement inhibitors for complement activation sites, i.e. with CR2 as targeting vector, complement inhibitors like CD59 and Crry are targeted to inflammatory sites to specially inhibit the complement activation in local injury, thus local inflammatory reaction is inhibited. Testing the hypothesis CR2-CD59 and CR2-Crry targeting complement inhibitors are fusion-expressed, and their biological activity is examined via in vivo and in vitro tests. CR2 targeting complement inhibitors are used to treat mouse influenza viral pneumonia model, with PBS treatment group as the control. The survival and lung tissue injury of the mice is observed and the effect of CR2 targeting complement inhibitors on pneumonia induced by influenza virus is evaluated. Implications of the hypothesis CR2 targeting complement inhibitors

  18. Nicotinamide exacerbates hypoxemia in ventilator-induced lung injury independent of neutrophil infiltration.

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    Heather D Jones

    Full Text Available Ventilator-induced lung injury is a form of acute lung injury that develops in critically ill patients on mechanical ventilation and has a high degree of mortality. Nicotinamide phosphoribosyltransferase is an enzyme that is highly upregulated in ventilator-induced lung injury and exacerbates the injury when given exogenously. Nicotinamide (vitamin B3 directly inhibits downstream pathways activated by Nicotinamide phosphoribosyltransferase and is protective in other models of acute lung injury.We administered nicotinamide i.p. to mice undergoing mechanical ventilation with high tidal volumes to study the effects of nicotinamide on ventilator-induced lung injury. Measures of injury included oxygen saturations and bronchoalveolar lavage neutrophil counts, protein, and cytokine levels. We also measured expression of nicotinamide phosophoribosyltransferase, and its downstream effectors Sirt1 and Cebpa, Cebpb, Cebpe. We assessed the effect of nicotinamide on the production of nitric oxide during ventilator-induced lung injury. We also studied the effects of ventilator-induced lung injury in mice deficient in C/EBPε.Nicotinamide treatment significantly inhibited neutrophil infiltration into the lungs during ventilator-induced lung injury, but did not affect protein leakage or cytokine production. Surprisingly, mice treated with nicotinamide developed significantly worse hypoxemia during mechanical ventilation. This effect was not linked to increases in nitric oxide production or alterations in expression of Nicotinamide phosphoribosyl transferase, Sirt1, or Cebpa and Cebpb. Cebpe mRNA levels were decreased with either nicotinamide treatment or mechanical ventilation, but mice lacking C/EBPε developed the same degree of hypoxemia and ventilator-induced lung injury as wild-type mice.Nicotinamide treatment during VILI inhibits neutrophil infiltration of the lungs consistent with a strong anti-inflammatory effect, but paradoxically also leads to the

  19. Nicotinamide Exacerbates Hypoxemia in Ventilator-Induced Lung Injury Independent of Neutrophil Infiltration

    Science.gov (United States)

    Jones, Heather D.; Yoo, Jeena; Crother, Timothy R.; Kyme, Pierre; Ben-Shlomo, Anat; Khalafi, Ramtin; Tseng, Ching W.; Parks, William C.; Arditi, Moshe

    2015-01-01

    Background Ventilator-induced lung injury is a form of acute lung injury that develops in critically ill patients on mechanical ventilation and has a high degree of mortality. Nicotinamide phosphoribosyltransferase is an enzyme that is highly upregulated in ventilator-induced lung injury and exacerbates the injury when given exogenously. Nicotinamide (vitamin B3) directly inhibits downstream pathways activated by Nicotinamide phosphoribosyltransferase and is protective in other models of acute lung injury. Methods We administered nicotinamide i.p. to mice undergoing mechanical ventilation with high tidal volumes to study the effects of nicotinamide on ventilator-induced lung injury. Measures of injury included oxygen saturations and bronchoalveolar lavage neutrophil counts, protein, and cytokine levels. We also measured expression of nicotinamide phosophoribosyltransferase, and its downstream effectors Sirt1 and Cebpa, Cebpb, Cebpe. We assessed the effect of nicotinamide on the production of nitric oxide during ventilator-induced lung injury. We also studied the effects of ventilator-induced lung injury in mice deficient in C/EBPε. Results Nicotinamide treatment significantly inhibited neutrophil infiltration into the lungs during ventilator-induced lung injury, but did not affect protein leakage or cytokine production. Surprisingly, mice treated with nicotinamide developed significantly worse hypoxemia during mechanical ventilation. This effect was not linked to increases in nitric oxide production or alterations in expression of Nicotinamide phosphoribosyl transferase, Sirt1, or Cebpa and Cebpb. Cebpe mRNA levels were decreased with either nicotinamide treatment or mechanical ventilation, but mice lacking C/EBPε developed the same degree of hypoxemia and ventilator-induced lung injury as wild-type mice. Conclusions Nicotinamide treatment during VILI inhibits neutrophil infiltration of the lungs consistent with a strong anti-inflammatory effect, but

  20. C-peptide attenuates acute lung inflammation in a murine model of hemorrhagic shock and resuscitation by reducing gut injury.

    Science.gov (United States)

    Kao, Raymond L C; Xu, Xuemei; Xenocostas, Anargyros; Parry, Neil; Mele, Tina; Martin, Claudio M; Rui, Tao

    2017-08-01

    The study aims to evaluate whether C-peptide can reduce gut injury during hemorrhagic shock (HS) and resuscitation (R) therefore attenuate shock-induced inflammation and subsequent acute lung injury. Twelve-week-old male mice (C57/BL6) were hemorrhaged (mean arterial blood pressure maintained at 35 mm Hg for 60 minutes) and then resuscitated with Ringer's lactate, followed by red blood cell transfusion with (HS/R) or without C-peptide (HS/R + C-peptide). Mouse gut permeability, bacterial translocation into the circulatory system and intestinal pathology, circulating HMGB1, and acute lung injury were assessed at different times after R. The mice in the control group underwent sham procedures without HS. Compared to the sham group, the mice in the HS/R group showed increased gut permeability (6.07 ± 3.41 μg of FD4/mL) and bacterial translocation into the circulatory system (10.05 ± 4.92, lipopolysaccharide [LPS] of pg/mL), and increased gut damage; conversely, mice in the HS/R + C-peptide group showed significantly reduced gut permeability (1.59 ± 1.39 μg of FD4/mL; p C-peptide group showed decreased HMGB1 (7.27 ± 1.93 ng/mL; p C-peptide exerts beneficial effects to attenuate gut injury and dysfunction, therefore diminishing lung inflammation and subsequent injury in mice with HS and R.

  1. [Role of autophagy in ameliorating sepsis-induced acute lung injury by allicinin in mice].

    Science.gov (United States)

    Peng, Yue; Jiang, Yu; Ou, Hao; Xing, Wei; Yang, Mingshi; Gao, Min

    2017-08-28

    To investigate roles of autophagy in ameliorating sepsis-induced acute lung injury by allicinin in mice.
 Methods: A total of 152 male Balb/c mice (8-week old) were randomly divided into a sham group, a septic model group, an allicin treatment group, and an autophagy inhibition group. Septic mouse model was established by cecal ligation and puncture (CLP). Mice in the allicin treatment group were given allicin (30 mg/kg, intra-peritoneal injection) at 6 and 12 h, while those in the autophagy inhibition group were given autophagy inhibitor 3-MA (15 mg/kg, intra-peritoneal injection) at half an hour after allicin administration. Mice in the model and sham group were administered with the same amount of saline. Twenty mice in each group were randomly chosen to observe the 7 d survival rate. The other 12 mice were killed at 24 h, and the bronchoalveolar lavage fluid (BALF) (n=6) and lung tissues (n=6) were collected. ELISA was used to detect the tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) in the BALF. Hematoxylin-eosin staining was preformed to show the morphological changes in the lung tissues. Malondialdehyde (MDA) content and the activity of superoxide dismutase (SOD) in the lung tissues were examined. The expression of LC3B and Beclin-1 was determined by immunohistochemical analysis.
 Results: Compared with the sham group, the 7 d survival rate and lung SOD activity were decreased in the CLP group (P<0.05); the lung morphological damage score, the levels of TNF-α and IL-6 in the BALF, MDA content in the lung, and expression of LC3B and Beclin-1 were increased greatly in the CLP group (P<0.05). Compared with the CLP group, the 7 d survival rate, lung SOD activity and the expressions of LC3B and Beclin-1 were increased significantly in the allicin treatment group (P<0.05); the lung morphological damage scores, the levels of TNF-α and IL-6 in the BALF and MDA content in the lung were decreased obviously in the allicin treatment group (P<0

  2. KGFR promotes Na+ channel expression in a rat acute lung injury ...

    African Journals Online (AJOL)

    KGFR promotes Na+ channel expression in a rat acute lung injury model. ... Recombinant adenovirus (AdEasy-KGFR) was injected via the tail vein. ... the three other groups; expression of these two genes in the injury adenovirus transduced ...

  3. Traumatic Brain Injury Severity Affects Neurogenesis in Adult Mouse Hippocampus.

    Science.gov (United States)

    Wang, Xiaoting; Gao, Xiang; Michalski, Stephanie; Zhao, Shu; Chen, Jinhui

    2016-04-15

    Traumatic brain injury (TBI) has been proven to enhance neural stem cell (NSC) proliferation in the hippocampal dentate gyrus. However, various groups have reported contradictory results on whether TBI increases neurogenesis, partially due to a wide range in the severities of injuries seen with different TBI models. To address whether the severity of TBI affects neurogenesis in the injured brain, we assessed neurogenesis in mouse brains receiving different severities of controlled cortical impact (CCI) with the same injury device. The mice were subjected to mild, moderate, or severe TBI by a CCI device. The effects of TBI severity on neurogenesis were evaluated at three stages: NSC proliferation, immature neurons, and newly-generated mature neurons. The results showed that mild TBI did not affect neurogenesis at any of the three stages. Moderate TBI promoted NSC proliferation without increasing neurogenesis. Severe TBI increased neurogenesis at all three stages. Our data suggest that the severity of injury affects adult neurogenesis in the hippocampus, and thus it may partially explain the inconsistent results of different groups regarding neurogenesis following TBI. Further understanding the mechanism of TBI-induced neurogenesis may provide a potential approach for using endogenous NSCs to protect against neuronal loss after trauma.

  4. Mitogen-activated protein kinases regulate susceptibility to ventilator-induced lung injury.

    Directory of Open Access Journals (Sweden)

    Tamás Dolinay

    Full Text Available BACKGROUND: Mechanical ventilation causes ventilator-induced lung injury in animals and humans. Mitogen-activated protein kinases have been implicated in ventilator-induced lung injury though their functional significance remains incomplete. We characterize the role of p38 mitogen-activated protein kinase/mitogen activated protein kinase kinase-3 and c-Jun-NH(2-terminal kinase-1 in ventilator-induced lung injury and investigate novel independent mechanisms contributing to lung injury during mechanical ventilation. METHODOLOGY AND PRINCIPLE FINDINGS: C57/BL6 wild-type mice and mice genetically deleted for mitogen-activated protein kinase kinase-3 (mkk-3(-/- or c-Jun-NH(2-terminal kinase-1 (jnk1(-/- were ventilated, and lung injury parameters were assessed. We demonstrate that mkk3(-/- or jnk1(-/- mice displayed significantly reduced inflammatory lung injury and apoptosis relative to wild-type mice. Since jnk1(-/- mice were highly resistant to ventilator-induced lung injury, we performed comprehensive gene expression profiling of ventilated wild-type or jnk1(-/- mice to identify novel candidate genes which may play critical roles in the pathogenesis of ventilator-induced lung injury. Microarray analysis revealed many novel genes differentially expressed by ventilation including matrix metalloproteinase-8 (MMP8 and GADD45alpha. Functional characterization of MMP8 revealed that mmp8(-/- mice were sensitized to ventilator-induced lung injury with increased lung vascular permeability. CONCLUSIONS: We demonstrate that mitogen-activated protein kinase pathways mediate inflammatory lung injury during ventilator-induced lung injury. C-Jun-NH(2-terminal kinase was also involved in alveolo-capillary leakage and edema formation, whereas MMP8 inhibited alveolo-capillary protein leakage.

  5. Developing Novel Therapeutic Approaches in Small Cell Lung Carcinoma Using Genetically Engineered Mouse Models and Human Circulating Tumor Cells

    Science.gov (United States)

    2015-10-01

    Using Genetically Engineered Mouse Models and Human Circulating Tumor Cells PRINCIPAL INVESTIGATOR: Jeffrey Engelman MD PhD CONTRACTING...SUBTITLE Developiing Novel Therapeutic Approaches in Small Cell Lung 5a. CONTRACT NUMBER Carcinoma Using Genetically Engineered Mouse Models and 5b...biomarkers. 15. SUBJECT TERMS Small cell lung cancer (SCLC), Genetically engineered mouse model (GEMM), BH3 mimetic, TORC inhibitor, Apoptosis

  6. Role of Nrf2 and Autophagy in Acute Lung Injury

    Science.gov (United States)

    de la Vega, Montserrat Rojo; Dodson, Matthew; Gross, Christine; Manzour, Heidi; Lantz, R. Clark; Chapman, Eli; Wang, Ting; Black, Stephen M.; Garcia, Joe G.N.; Zhang, Donna D.

    2016-01-01

    Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are the clinical manifestations of severe lung damage and respiratory failure. Characterized by severe inflammation and compromised lung function, ALI/ARDS result in very high mortality of affected individuals. Currently, there are no effective treatments for ALI/ARDS, and ironically, therapies intended to aid patients (specifically mechanical ventilation, MV) may aggravate the symptoms. Key events contributing to the development of ALI/ARDS are: increased oxidative and proteotoxic stresses, unresolved inflammation, and compromised alveolar-capillary barrier function. Since the airways and lung tissues are constantly exposed to gaseous oxygen and airborne toxicants, the bronchial and alveolar epithelial cells are under higher oxidative stress than other tissues. Cellular protection against oxidative stress and xenobiotics is mainly conferred by Nrf2, a transcription factor that promotes the expression of genes that regulate oxidative stress, xenobiotic metabolism and excretion, inflammation, apoptosis, autophagy, and cellular bioenergetics. Numerous studies have demonstrated the importance of Nrf2 activation in the protection against ALI/ARDS, as pharmacological activation of Nrf2 prevents the occurrence or mitigates the severity of ALI/ARDS. Another promising new therapeutic strategy in the prevention and treatment of ALI/ARDS is the activation of autophagy, a bulk protein and organelle degradation pathway. In this review, we will discuss the strategy of concerted activation of Nrf2 and autophagy as a preventive and therapeutic intervention to ameliorate ALI/ARDS. PMID:27313980

  7. Peptide nanomedicines for treatment of acute lung injury.

    Science.gov (United States)

    Sadikot, Ruxana T

    2012-01-01

    Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) represent a heterogenous group of lung disease in critically ill patients. Despite the increased understanding of the molecular pathogenesis of ARDS, the mortality remains unacceptably high, ranging from 34% to 64%. Hence, ARDS represents an unmet medical need with an urgency to develop effective pharmacotherapies. Several promising targets that have been identified as potential therapies for ARDS have been limited because of difficulty with delivery. In particular, delivery of peptides and proteins to the lung is an ongoing challenge. Nanobiotechnology and nanoscience are the basis of innovative techniques to deliver drugs targeted to the site of inflamed organs, such as the lungs. Nanoscale drug delivery systems have the ability to improve the pharmacokinetics and pharmakodynamics of agents allowing an increase in the biodistribution of therapeutic agents to target organs, resulting in improved efficacy with reduction in drug toxicity. These systems are exploited for therapeutic purpose to carry the drug in the body in a controlled manner from the site of administration to the therapeutic target. Hence, it is an attractive strategy to test potential targets for ALI/ARDS using nanotechnology. To this end, we have identified several potential targets and proposed the delivery of these agents using nanomicelles to improve the drug delivery. Copyright © 2012 Elsevier Inc. All rights reserved.

  8. Pleiotropic Effects of Levofloxacin, Fluoroquinolone Antibiotics, against Influenza Virus-Induced Lung Injury.

    Directory of Open Access Journals (Sweden)

    Yuki Enoki

    Full Text Available Reactive oxygen species (ROS and nitric oxide (NO are major pathogenic molecules produced during viral lung infections, including influenza. While fluoroquinolones are widely used as antimicrobial agents for treating a variety of bacterial infections, including secondary infections associated with the influenza virus, it has been reported that they also function as anti-oxidants against ROS and as a NO regulator. Therefore, we hypothesized that levofloxacin (LVFX, one of the most frequently used fluoroquinolone derivatives, may attenuate pulmonary injuries associated with influenza virus infections by inhibiting the production of ROS species such as hydroxyl radicals and neutrophil-derived NO that is produced during an influenza viral infection. The therapeutic impact of LVFX was examined in a PR8 (H1N1 influenza virus-induced lung injury mouse model. ESR spin-trapping experiments indicated that LVFX showed scavenging activity against neutrophil-derived hydroxyl radicals. LVFX markedly improved the survival rate of mice that were infected with the influenza virus in a dose-dependent manner. In addition, the LVFX treatment resulted in a dose-dependent decrease in the level of 8-hydroxy-2'-deoxyguanosine (a marker of oxidative stress and nitrotyrosine (a nitrative marker in the lungs of virus-infected mice, and the nitrite/nitrate ratio (NO metabolites and IFN-γ in BALF. These results indicate that LVFX may be of substantial benefit in the treatment of various acute inflammatory disorders such as influenza virus-induced pneumonia, by inhibiting inflammatory cell responses and suppressing the overproduction of NO in the lungs.

  9. Pleiotropic Effects of Levofloxacin, Fluoroquinolone Antibiotics, against Influenza Virus-Induced Lung Injury.

    Science.gov (United States)

    Enoki, Yuki; Ishima, Yu; Tanaka, Ryota; Sato, Keizo; Kimachi, Kazuhiko; Shirai, Tatsuya; Watanabe, Hiroshi; Chuang, Victor T G; Fujiwara, Yukio; Takeya, Motohiro; Otagiri, Masaki; Maruyama, Toru

    2015-01-01

    Reactive oxygen species (ROS) and nitric oxide (NO) are major pathogenic molecules produced during viral lung infections, including influenza. While fluoroquinolones are widely used as antimicrobial agents for treating a variety of bacterial infections, including secondary infections associated with the influenza virus, it has been reported that they also function as anti-oxidants against ROS and as a NO regulator. Therefore, we hypothesized that levofloxacin (LVFX), one of the most frequently used fluoroquinolone derivatives, may attenuate pulmonary injuries associated with influenza virus infections by inhibiting the production of ROS species such as hydroxyl radicals and neutrophil-derived NO that is produced during an influenza viral infection. The therapeutic impact of LVFX was examined in a PR8 (H1N1) influenza virus-induced lung injury mouse model. ESR spin-trapping experiments indicated that LVFX showed scavenging activity against neutrophil-derived hydroxyl radicals. LVFX markedly improved the survival rate of mice that were infected with the influenza virus in a dose-dependent manner. In addition, the LVFX treatment resulted in a dose-dependent decrease in the level of 8-hydroxy-2'-deoxyguanosine (a marker of oxidative stress) and nitrotyrosine (a nitrative marker) in the lungs of virus-infected mice, and the nitrite/nitrate ratio (NO metabolites) and IFN-γ in BALF. These results indicate that LVFX may be of substantial benefit in the treatment of various acute inflammatory disorders such as influenza virus-induced pneumonia, by inhibiting inflammatory cell responses and suppressing the overproduction of NO in the lungs.

  10. Melatonin reduces acute lung injury in endotoxemic rats

    Institute of Scientific and Technical Information of China (English)

    SHANG You; XU San-peng; WU Yan; JIANG Yuan-xu; WU Zhou-yang; YUAN Shi-ying; YAO Shang-long

    2009-01-01

    Background Treatment with melatonin significantly reduces lung injury induced by bleomycin, paraquat and ischemia reperfusion. In the present study, we investigated the possible protective roles of melatonin in pulmonary inflammation and lung injury during acute endotoxemia.Methods Thirty-two male Sprague-Dawley rats were randomly assigned to four groups: vehicle + saline group, melatonin + saline group, vehicle + lipopolysaccharide group, melatonin + lipopolysaccharide group. The rats were treated with melatonin (10 mg/kg, intraperitoneal injection (I.p.)) or vehicle (1% ethanol saline), 30 minutes prior to lipopolysaccharide administration (6 mg/kg, intravenous injection). Four hours after lipopolysaccharide injection, samples of pulmonary tissue were collected. Blood gas analysis was carried out. Optical microscopy was performed to examine pathological changes in lungs and lung injury score was assessed. Wet/dry ratios (W/D), myeloperoxidase activity, malondialdehyde concentrations and tumor necrosis factor-alpha (TNF-a) and interleukin-10 (IL-10) levels in lungs were measured. The pulmonary expression of nuclear factor-kappa B (NF-KB) p65 was evaluated by Western blotting. Results PaO2 in the vehicle + lipopolysaccharide group decreased compared with that in the vehicle + saline group. This decrease was significantly reduced in the melatonin + lipopolysaccharide group. The lung tissues from the saline + lipopolysaccharide group were significantly damaged, which were less pronounced in the melatonin + lipopolysaccharide group. The W/D ratio increased significantly in the vehicle + lipopolysaccharide group (6.1±0.18) as compared with that in the vehicle + saline group (3.611±0.3) (P <0.01), which was significantly reduced in the melatonin + lipopolysaccharide group (4.8±0.25) (P <0.01). Myeloperoxidase activity and malondialdehyde levels increased significantly in the vehicle + lipopolysaccharide group compared with that in the vehicle + saline group, which

  11. Stressed lungs: unveiling the role of circulating stress hormones in ozone-induced lung injury and inflammation.

    Science.gov (United States)

    Ozone, a major component of smog generated through the interaction of light and anthropogenic emissions, induces adverse pulmonary, cardiovascular, and systemic health effects upon inhalation. It is generally accepted that ozone-induced lung injury is mediated by its interaction ...

  12. Histomorphologic change of radiation pneumonitis in rat lungs: captopril reduces rat lung injury induced by irradiation

    Energy Technology Data Exchange (ETDEWEB)

    Kim, Jin Hee [College of Medicine, Keimhyung Univ., Taegu (Korea, Republic of)

    1999-09-01

    To assess the histomorphologic changes in the rat lung injury induced by radiation, to determine whether captopril reduces the rat lung injury and to evaluate change in TNF-{alpha} and TGF {beta} and rat lung damage by radiation and captopril. Right lungs in male Sprague-Dawley rats were divided irradiation alone (10, 20, 30 Gy) or radiation (same dose with radiation alone group) with captopril (500 mg/L). Radiation alone group were sacrificed at twelve hours and eleven weeks after radiation and radiation with captopril group (captopril group) were sacrificed at eleven weeks after radiation with captopril. We examined the light microscope and electron microscopic features in the groups. In radiation alone group, there were patch parenchymal collapse and consolidation at twelve hours after radiation. The increase of radiation dose shows more prominent the severity and broader the affected areas. Eleven weeks after radiation, the severity and areas of fibrosis had increased in proportion to radiation dose given in the radiation alone group. There was notable decrease of lung fibrosis in captopril group than in radiation alone group. The number of mast cells rapidly increased with increase of radiation dose in radiation alone group and the degree of increase of mast cell number and severity of collagen accumulation more decreased in captopril group than in radiation alone group. In radiation alone group expression of TNF-{alpha} and TGF-{beta}] increased according to increase of radiation dose at twelve hours after radiation in both group. At eleven weeks after radiation, expression of TGF- P increased according to increase of radiation dose in radiation group but somewhat decreased in captopril group. In the captopril group the collagen deposition increased but less dense than those of radiation alone group. The severity of perivascular thickening, capillary change, the number and degranulation of mast cells more decreased in the captopril group than in the radiation

  13. Inhaled aerosolized insulin ameliorates hyperglycemia-induced inflammatory responses in the lungs in an experimental model of acute lung injury

    OpenAIRE

    Fan, Wei; Nakazawa, Koichi; Abe, Shinya; Inoue, Miori; Kitagawa, Masanobu; Nagahara, Noriyuki; Makita, Koshi

    2013-01-01

    Introduction Previous studies have shown that patients with diabetes mellitus appear to have a lower prevalence of acute lung injury. We assumed that insulin prescribed to patients with diabetes has an anti-inflammatory property and pulmonary administration of insulin might exert beneficial effects much more than intravenous administration. Methods Twenty-eight mechanically ventilated rabbits underwent lung injury by saline lavage, and then the animals were allocated into a normoglycemia grou...

  14. Parasite burden and CD36-mediated sequestration are determinants of acute lung injury in an experimental malaria model.

    Directory of Open Access Journals (Sweden)

    Fiona E Lovegrove

    2008-05-01

    Full Text Available Although acute lung injury (ALI is a common complication of severe malaria, little is known about the underlying molecular basis of lung dysfunction. Animal models have provided powerful insights into the pathogenesis of severe malaria syndromes such as cerebral malaria (CM; however, no model of malaria-induced lung injury has been definitively established. This study used bronchoalveolar lavage (BAL, histopathology and gene expression analysis to examine the development of ALI in mice infected with Plasmodium berghei ANKA (PbA. BAL fluid of PbA-infected C57BL/6 mice revealed a significant increase in IgM and total protein prior to the development of CM, indicating disruption of the alveolar-capillary membrane barrier-the physiological hallmark of ALI. In contrast to sepsis-induced ALI, BAL fluid cell counts remained constant with no infiltration of neutrophils. Histopathology showed septal inflammation without cellular transmigration into the alveolar spaces. Microarray analysis of lung tissue from PbA-infected mice identified a significant up-regulation of expressed genes associated with the gene ontology categories of defense and immune response. Severity of malaria-induced ALI varied in a panel of inbred mouse strains, and development of ALI correlated with peripheral parasite burden but not CM susceptibility. Cd36(-/- mice, which have decreased parasite lung sequestration, were relatively protected from ALI. In summary, parasite burden and CD36-mediated sequestration in the lung are primary determinants of ALI in experimental murine malaria. Furthermore, differential susceptibility of mouse strains to malaria-induced ALI and CM suggests that distinct genetic determinants may regulate susceptibility to these two important causes of malaria-associated morbidity and mortality.

  15. Characterization of mouse pulmonary mesenchymal stem cells isolated in vitro and the intervention effects on lung injury%体外分离培养小鼠肺间充质干细胞的生物学特性及其对肺损伤干预效果

    Institute of Scientific and Technical Information of China (English)

    王莉; 张伟京; 刘兵; 李秀森

    2008-01-01

    BACKGROUND: There are several types of endogenons stem/progenitor cells in lung that develop from either endoderm or mesoderm precursors.To elucidate the characteristics of the intrapulmonary stem ceils wig help to understand their biological behavior in lung injury.OBJECTIVE: To isolate the mesenchymal stem cells (MSCs) from mouse lung tissues,and identify their morphology and growth characteristics,cell surface antigens,differentiation potential in vitro,stem cell properties,and to investigate the protective role in bleomycin challenged lung.DESIGN,TIME AND SETTING: The present randomized controlled in vivo animal experiment based on in vitro observation of cytology was performed at the Laboratory of Cell Biology,Institute of Basic Medical Science,the Academy of Military Medical Science between October 2005 and August 2007.MATERIALS: Male(3-4 weeks) and female C57BL/6 (6-8 weeks) mice were used.Twenty female C57BL/6 mice were randomly and evenly divided into a pulmonary MSCs (PMSCs)-treated group and a myelosuppression group.METHODS: The lungs from male C57BL/6 mice were digested with collagenase Ⅱ,followed by centrifugation over a Ficoll step.The interface fraction was collected and cultured by adherent method.When the monolayer of adherent cells reached 70%-80%confluence,the adherent cells were detected and expanded in culture medium.The mice in the PMSCs-treated and myelosuppression groups were intraperitoneally administered busulfan to inhibit the immigration of bone marrow stem cells.In addition,pulmonary fibrosis injury was induced in these mice with bleomycin.The PMSCs-treated group was intravenously administered 5×105 PMSCs.At the same time,the myelosuppression group received 100 μ L of phosphate buffered saline.After 14 days,the lungs were taken to prepare paraffin-embedded section.MAIN OUTCOME MEASURES: Cell morphology,immunophenotype,specific markers of the induced cells,expression of gene peroxisome proliferator activated receptor

  16. Riboflavin supplementation does not attenuate hyperoxic lung injury in transgenic (spc-mt)hGR mice.

    Science.gov (United States)

    Heyob, Kathryn M; Rogers, Lynette K; Tipple, Trent E; Welty, Stephen E

    2011-04-01

    The aims of this study were to test the hypothesis that mice expressing mitochondrially targeted human glutathione reductase (GR) driven by a surfactant protein C promoter ((spc-mt)hGR) are functionally riboflavin deficient and that this deficiency exacerbates hyperoxic lung injury. The authors further hypothesized that dietary supplementation with riboflavin (FADH) will improve the bioactivity of GR, thus enhancing resistance to hyperoxic lung injury. Transgenic (mt-spc)hGR mice and their nontransgenic littermates were fed control or riboflavin-supplemented diets upon weaning. At 6 weeks of age the mice were exposed to either room air (RA) or >95% O(2) for up to 84 hours. GR activities (with and without exogenous FADH) and GR protein levels were measured in lung tissue homogenates. Glutathione (GSH) and glutathione disulfide (GSSG) concentrations were assayed to identify changes in GR activity in vivo. Lung injury was assessed by right lung to body weight ratios and bronchoalveolar lavage protein concentrations. The data showed that enhanced GR activity in the mitochondria of lung type II cells does not protect adult mice from hyperoxic lung injury. Furthermore, the addition of riboflavin to the diets of (spc-mt)hGR mice neither enhances GR activities nor offers protection from hyperoxic lung injury. The results indicated that modulation of mitochondrial GR activity in lung type II cells is not an effective therapy to minimize hyperoxic lung injury.

  17. Riboflavin supplementation does not attenuate hyperoxic lung injury in transgenic spc–mthGR mice

    Science.gov (United States)

    Heyob, Kathryn M.; Rogers, Lynette K.; Tipple, Trent E.; Welty, Stephen E.

    2017-01-01

    The aims of this study were to test the hypothesis that mice expressing mitochondrially targeted human glutathione reductase (GR) driven by a surfactant protein C promoter (spc–mthGR) are functionally riboflavin deficient and that this deficiency exacerbates hyperoxic lung injury. The authors further hypothesized that dietary supplementation with riboflavin (FADH) will improve the bioactivity of GR, thus enhancing resistance to hyperoxic lung injury. Transgenic mt–spchGR mice and their nontransgenic littermates were fed control or riboflavin-supplemented diets upon weaning. At 6 weeks of age the mice were exposed to either room air (RA) or >95% O2 for up to 84 hours. GR activities (with and without exogenous FADH) and GR protein levels were measured in lung tissue homogenates. Glutathione (GSH) and glutathione disulfide (GSSG) concentrations were assayed to identify changes in GR activity in vivo. Lung injury was assessed by right lung to body weight ratios and bronchoalveolar lavage protein concentrations. The data showed that enhanced GR activity in the mitochondria of lung type II cells does not protect adult mice from hyperoxic lung injury. Furthermore, the addition of riboflavin to the diets of spc–mthGR mice neither enhances GR activities nor offers protection from hyperoxic lung injury. The results indicated that modulation of mitochondrial GR activity in lung type II cells is not an effective therapy to minimize hyperoxic lung injury. PMID:21128861

  18. Acute lung injury | EU Clinical Trials Register [EU Clinical Trials Register

    Lifescience Database Archive (English)

    Full Text Available reductase inhibition with simvastatin in Acute lung injury to Reduce Pulmonary dysfunction(HARP 2) A.3.1Tit...ical condition(s) being investigated Acute lung injury E.1.1.1Medical condition in easily understood languag...eclined to onset is defined as follows: th

  19. Total liquid ventilation reduces oleic acid-induced lung injury in piglets

    Institute of Scientific and Technical Information of China (English)

    ZHU Yao-bin; LIU Dong-hai; ZHANG Yan-bo; LIU Ai-jun; FAN Xiang-ming; QIAO Chen-hui; WANG Qiang

    2013-01-01

    Background Pediatric patients are susceptible to lung injury that does not respond to traditional therapies.Total liquid ventilation has been developed as an alternative ventilatory strategy for severe lung injury.The aim of this study is to investigate the effect of total liquid ventilation on oleic acid (OA)-induced lung injury in piglets.Methods Twelve Chinese immature piglets were induced acute lung injury by OA.Twelve piglets were randomly treated with conventional gas ventilation (control group) or total liquid ventilation (study group) for 240 minutes.Samples for blood gas analysis were collected before,and at 60-minute intervals after OA-induced lung injury.The degree of lung injury was quantified by histologic examination.The inflammatory cells and the levels of IL-1β,IL-6,IL-10 and TNF-α in plasma,tissue and bronchoalveolar lavage were analyzed.Results Neutrophil and macrophage counts in bronchoalveolar lavage were significantly decreased in the study group (P<0.05).The total lung injury score was also reduced in the study group (P<0.05).The cconcentrations of IL-1β,IL-6,IL-10and TNF-α in plasma,tissue and bronchoalveolar lavage were significantly reduced in the study group (P<0.05).Conclusions Total liquid ventilation reduces biochemical and histologic OA-induced lung injury in piglets.

  20. Cytokines and biotrauma in ventilator-induced lung injury: a critical review of the literature.

    NARCIS (Netherlands)

    Halbertsma, F.J.; Vaneker, M.; Scheffer, G.J.; Hoeven, J.G. van der

    2005-01-01

    BACKGROUND: Mechanical ventilation is known to induce and aggravate lung injury. One of the underlying mechanisms is biotrauma, an inflammatory response in which cytokines play a crucial role. OBJECTIVE: To review the literature on the role of cytokines in ventilator-induced lung injury (VILI) and

  1. A metabolomic approach to the pathogenesis of ventilator-induced lung injury

    OpenAIRE

    Izquierdo García, José L.; Naz, Shama; Nin, Nicolás; Rojas, Yeny; Erazo, Marcela; Martínez Caro, Leticia; García, Antonia; De Paula, Marta; Fernández Segoviano, P.; Casals, Cristina; Esteban, Andrés; Ruíz Cabello, Jesús; Barbas, Coral; Lorente Balanza, José Ángel

    2014-01-01

    Global metabolic profiling using quantitative nuclear magnetic resonance spectroscopy (MRS) and mass spectrometry (MS) is useful for biomarker discovery. The objective of this study was to discover biomarkers of acute lung injury induced by mechanical ventilation (ventilator-induced lung injury [VILI]), by using MRS and MS. 5.879 JCR (2014) Q1, 1/30 Anesthesiology UEM

  2. Arctigenin attenuates lipopolysaccharide-induced acute lung injury in rats.

    Science.gov (United States)

    Shi, Xianbao; Sun, Hongzhi; Zhou, Dun; Xi, Huanjiu; Shan, Lina

    2015-04-01

    Arctigenin (ATG) has been reported to possess anti-inflammatory properties. However, the effects of ATG on lipopolysaccharide (LPS)-induced acute lung injury (ALI) remains not well understood. In the present study, our investigation was designed to reveal the effect of ATG on LPS-induced ALI in rats. We found that ATG pretreatment attenuated the LPS-induced ALI, as evidenced by the reduced histological scores, myeloperoxidase activity, and wet-to-dry weight ratio in the lung tissues. This was accompanied by the decreased levels of tumor necrosis factor alpha (TNF-α), interleukin-1β (IL-1β), and interleukin-1 (IL-6) in the bronchoalveolar lavage fluid. Furthermore, ATG downregulated the expression of nuclear factor kappa B (NF-κB) p65, promoted the phosphorylation of inhibitor of nuclear factor-κB-α (IκBα) and activated the adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPKα) in the lung tissues. Our results suggested that ATG attenuates the LPS-induced ALI via activation of AMPK and suppression of NF-κB signaling pathway.

  3. Smoked marijuana as a cause of lung injury.

    Science.gov (United States)

    Tashkin, D P

    2005-06-01

    In many societies, marijuana is the second most commonly smoked substance after tobacco. While delta9-tetrahydrocannabinol (THC) is unique to marijuana and nicotine to tobacco, the smoke of marijuana, like that of tobacco, consists of a toxic mixture of gases and particulates, many of which are known to be harmful to the lung. Although far fewer marijuana than tobacco cigarettes are generally smoked on a daily basis, the pulmonary consequences of marijuana smoking may be magnified by the greater deposition of smoke particulates in the lung due to the differing manner in which marijuana is smoked. Whereas THC causes modest short-term bronchodilation, regular marijuana smoking produces a number of long-term pulmonary consequences, including chronic cough and sputum, histopathologic evidence of widespread airway inflammation and injury and immunohistochemical evidence of dysregulated growth of respiratory epithelial cells, that may be precursors to lung cancer. The THC in marijuana could contribute to some of these injurious changes through its ability to augment oxidative stress, cause mitochondrial dysfunction, and inhibit apoptosis. On the other hand, physiologic, clinical or epidemiologic evidence that marijuana smoking may lead to chronic obstructive pulmonary disease or respiratory cancer is limited and inconsistent. Habitual use of marijuana is also associated with abnormalities in the structure and function of alveolar macrophages, including impairment in microbial phagocytosis and killing that is associated with defective production of immunostimulatory cytokines and nitric oxide, thereby potentially predisposing to pulmonary infection. In view of the growing interest in medicinal marijuana, further epidemiologic studies are needed to clarify the true risks of regular marijuana smoking on respiratory health.

  4. Protective effects of imipramine in murine endotoxin-induced acute lung injury.

    Science.gov (United States)

    Yang, Jin; Qu, Jie-ming; Summah, Hanssa; Zhang, Jin; Zhu, Ying-gang; Jiang, Hong-ni

    2010-07-25

    The tricyclic antidepressant imipramine has recently emerged as a cytoprotective agent, exerting beneficial effects in inflammatory tissue injury. The present study aimed to investigate therapeutic effects of imipramine in murine model of endotoxin-induced acute lung injury. Mice were administrated intraperitoneally with LPS (lipopolysaccharide) from Escherichia coli or vehicle. Imipramine was administrated intraperitoneally 30 min before LPS challenge. Pretreatment of mice with imipramine reduced lethality. Impramine also significantly attenuated lung inflammation, lung edema, MPO (myeloperoxidase) activity, lung tissue pathological changes and nuclear factor-kappaB DNA binding activity. The results of this study suggest that imipramine can exert protective effects in endotoxin-induced acute lung injury by suppressing nuclear factor-kappaB-mediated expression of inflammatory genes. Thus, imipramine could be a potential novel therapeutic agent for the treatment for acute lung injury.

  5. Protective effect of salvianolate on lung injury induced by ischemia reperfusion injury of liver in mice

    Directory of Open Access Journals (Sweden)

    Zheng-xin WANG

    2011-11-01

    Full Text Available Objective To evaluate the protective effect of salvianolate on lung injury induced by hepatic ischemia reperfusion(IR injury in mice and its underlying mechanisms.Methods A hepatic IR model of mice was reproduced,and 24 animals were assigned into 3 groups(8 each: sham operation(SO group,control group and salvianolate(SV group.Just before ischemia induction,animals in SV group received salvianolate injection at a dose of 60 mg/kg via tail vein,while in control group the mice received normal saline with an equal volume,and in SO group the mice received the same operation as in SV group but without producing liver ischemia.Four hours after reperfusion,the serum,liver and lung tissue were collected.The alanine aminotransferase(ALT and aspartate aminotransferase(AST levels in serum were detected and the histological changes in liver and lung were examined.The wet-to-dry weight ratio of pulmonary tissue was measured.The contents of tumor necrosis factor α(TNF-α,interleukin(IL-6,IL-1β and IL-10 in bronchoalveolar lavage fluid(BALF were detected by enzyme linked immunosorbent assay(ELISA,and the relative mRNA levels of TNF-α,IL-6,IL-1β and IL-10 in pulmonary tissue were analyzed by real-time reverse transcription PCR(RT-PCR.The activaty of transcription factor NF-κB was measured with Western blotting analysis.Results No significant pathologic change was found in mice of SO group.Compared with the mice in control group,those in SV group exhibited lower levels of ALT and AST(P < 0.01,lighter histological changes in liver and lung(P < 0.05,lower levels of wet-to-dry weight ratio of lung tissue(P < 0.05,lower expression levels of TNF-α,IL-6,IL-1β and IL-10 in BALF and lung tissue(P < 0.05 or P < 0.01.Further examination demonstrated that the activity of NF-κB in SV group was significantly down-regulated as compared with that in control group.Conclusion Salvianolate can attenuate lung injury induced by hepatic IR in mice,the mechanism may inclade

  6. Stem cell factor improves lung recovery in rats following neonatal hyperoxia-induced lung injury

    Science.gov (United States)

    Miranda, Luis F.; Rodrigues, Claudia O.; Ramachandran, Shalini; Torres, Eneida; Huang, Jian; Klim, Jammie; Hehre, Dorothy; McNiece, Ian; Hare, Joshua M.; Suguihara, Cleide Y.; Young, Karen C.

    2016-01-01

    BACKGROUND Stem cell factor (SCF) and its receptor, c-kit, are modulators of angiogenesis. Neonatal hyperoxia-induced lung injury (HILI) is characterized by disordered angiogenesis. The objective of this study was to determine whether exogenous SCF improves recovery from neonatal HILI by improving angiogenesis. METHODS Newborn rats assigned to normoxia (RA: 20.9% O2) or hyperoxia (90% O2) from postnatal day (P) 2 to 15, received daily injections of SCF 100 µg/kg or placebo (PL) from P15 to P21. Lung morphometry was performed at P28. Capillary tube formation in SCF-treated hyperoxia-exposed pulmonary microvascular endothelial cells (HPMECs) was determined by Matrigel assay. RESULTS As compared with RA, hyperoxic-PL pups had decrease in alveolarization and in lung vascular density, and this was associated with increased right ventricular systolic pressure (RVSP), right ventricular hypertrophy, and vascular remodeling. In contrast, SCF-treated hyperoxic pups had increased angiogenesis, improved alveolarization, and attenuation of pulmonary hypertension as evidenced by decreased RVSP, right ventricular hypertrophy, and vascular remodeling. Moreover, in an in vitro model, SCF increased capillary tube formation in hyperoxia-exposed HPMECs. CONCLUSION Exogenous SCF restores alveolar and vascular structure in neonatal rats with HILI by promoting neoangiogenesis. These findings suggest a new strategy to treat lung diseases characterized by dysangiogenesis. PMID:24153399

  7. Hydrogen gas reduces hyperoxic lung injury via the Nrf2 pathway in vivo

    Science.gov (United States)

    Kawamura, Tomohiro; Wakabayashi, Nobunao; Shigemura, Norihisa; Huang, Chien-Sheng; Masutani, Kosuke; Tanaka, Yugo; Noda, Kentaro; Peng, Ximei; Takahashi, Toru; Billiar, Timothy R.; Okumura, Meinoshin; Toyoda, Yoshiya; Kensler, Thomas W.

    2013-01-01

    Hyperoxic lung injury is a major concern in critically ill patients who receive high concentrations of oxygen to treat lung diseases. Successful abrogation of hyperoxic lung injury would have a huge impact on respiratory and critical care medicine. Hydrogen can be administered as a therapeutic medical gas. We recently demonstrated that inhaled hydrogen reduced transplant-induced lung injury and induced heme oxygenase (HO)-1. To determine whether hydrogen could reduce hyperoxic lung injury and investigate the underlying mechanisms, we randomly assigned rats to four experimental groups and administered the following gas mixtures for 60 h: 98% oxygen (hyperoxia), 2% nitrogen; 98% oxygen (hyperoxia), 2% hydrogen; 98% balanced air (normoxia), 2% nitrogen; and 98% balanced air (normoxia), 2% hydrogen. We examined lung function by blood gas analysis, extent of lung injury, and expression of HO-1. We also investigated the role of NF-E2-related factor (Nrf) 2, which regulates HO-1 expression, by examining the expression of Nrf2-dependent genes and the ability of hydrogen to reduce hyperoxic lung injury in Nrf2-deficient mice. Hydrogen treatment during exposure to hyperoxia significantly improved blood oxygenation, reduced inflammatory events, and induced HO-1 expression. Hydrogen did not mitigate hyperoxic lung injury or induce HO-1 in Nrf2-deficient mice. These findings indicate that hydrogen gas can ameliorate hyperoxic lung injury through induction of Nrf2-dependent genes, such as HO-1. The findings suggest a potentially novel and applicable solution to hyperoxic lung injury and provide new insight into the molecular mechanisms and actions of hydrogen. PMID:23475767

  8. Gremlin-1 Overexpression in Mouse Lung Reduces Silica-Induced Lymphocyte Recruitment - A Link to Idiopathic Pulmonary Fibrosis through Negative Correlation with CXCL10 Chemokine.

    Science.gov (United States)

    Koli, Katri; Sutinen, Eva; Rönty, Mikko; Rantakari, Pia; Fortino, Vittorio; Pulkkinen, Ville; Greco, Dario; Sipilä, Petra; Myllärniemi, Marjukka

    2016-01-01

    Idiopathic pulmonary fibrosis (IPF) is characterized by activation and injury of epithelial cells, the accumulation of connective tissue and changes in the inflammatory microenvironment. The bone morphogenetic protein (BMP) inhibitor protein gremlin-1 is associated with the progression of fibrosis both in human and mouse lung. We generated a transgenic mouse model expressing gremlin-1 in type II lung epithelial cells using the surfactant protein C (SPC) promoter and the Cre-LoxP system. Gremlin-1 protein expression was detected specifically in the lung after birth and did not result in any signs of respiratory insufficiency. Exposure to silicon dioxide resulted in reduced amounts of lymphocyte aggregates in transgenic lungs while no alteration in the fibrotic response was observed. Microarray gene expression profiling and analyses of bronchoalveolar lavage fluid cytokines indicated a reduced lymphocytic response and a downregulation of interferon-induced gene program. Consistent with reduced Th1 response, there was a downregulation of the mRNA and protein expression of the anti-fibrotic chemokine CXCL10, which has been linked to IPF. In human IPF patient samples we also established a strong negative correlation in the mRNA expression levels of gremlin-1 and CXCL10. Our results suggest that in addition to regulation of epithelial-mesenchymal crosstalk during tissue injury, gremlin-1 modulates inflammatory cell recruitment and anti-fibrotic chemokine production in the lung.

  9. Gremlin-1 Overexpression in Mouse Lung Reduces Silica-Induced Lymphocyte Recruitment - A Link to Idiopathic Pulmonary Fibrosis through Negative Correlation with CXCL10 Chemokine.

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    Katri Koli

    Full Text Available Idiopathic pulmonary fibrosis (IPF is characterized by activation and injury of epithelial cells, the accumulation of connective tissue and changes in the inflammatory microenvironment. The bone morphogenetic protein (BMP inhibitor protein gremlin-1 is associated with the progression of fibrosis both in human and mouse lung. We generated a transgenic mouse model expressing gremlin-1 in type II lung epithelial cells using the surfactant protein C (SPC promoter and the Cre-LoxP system. Gremlin-1 protein expression was detected specifically in the lung after birth and did not result in any signs of respiratory insufficiency. Exposure to silicon dioxide resulted in reduced amounts of lymphocyte aggregates in transgenic lungs while no alteration in the fibrotic response was observed. Microarray gene expression profiling and analyses of bronchoalveolar lavage fluid cytokines indicated a reduced lymphocytic response and a downregulation of interferon-induced gene program. Consistent with reduced Th1 response, there was a downregulation of the mRNA and protein expression of the anti-fibrotic chemokine CXCL10, which has been linked to IPF. In human IPF patient samples we also established a strong negative correlation in the mRNA expression levels of gremlin-1 and CXCL10. Our results suggest that in addition to regulation of epithelial-mesenchymal crosstalk during tissue injury, gremlin-1 modulates inflammatory cell recruitment and anti-fibrotic chemokine production in the lung.

  10. Extent and computed tomography appearance of early radiation induced lung injury for non-small cell lung cancer

    DEFF Research Database (Denmark)

    Bernchou, Uffe; Christiansen, Rasmus Lübeck; Asmussen, Jon Thor

    2017-01-01

    scans acquired up to six months after radiotherapy were evaluated for radiologic injuries in 220 NSCLC patients. Radiologic injuries were divided into three categories: (1) interstitial changes, (2) ground-glass opacity, or (3) consolidation. The relationship between the fraction of injured lung of each...

  11. Mechanical ventilation injury and repair in extremely and very preterm lungs.

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    Nadine Brew

    Full Text Available BACKGROUND: Extremely preterm infants often receive mechanical ventilation (MV, which can contribute to bronchopulmonary dysplasia (BPD. However, the effects of MV alone on the extremely preterm lung and the lung's capacity for repair are poorly understood. AIM: To characterise lung injury induced by MV alone, and mechanisms of injury and repair, in extremely preterm lungs and to compare them with very preterm lungs. METHODS: Extremely preterm lambs (0.75 of term were transiently exposed by hysterotomy and underwent 2 h of injurious MV. Lungs were collected 24 h and at 15 d after MV. Immunohistochemistry and morphometry were used to characterise injury and repair processes. qRT-PCR was performed on extremely and very preterm (0.85 of term lungs 24 h after MV to assess molecular injury and repair responses. RESULTS: 24 h after MV at 0.75 of term, lung parenchyma and bronchioles were severely injured; tissue space and myofibroblast density were increased, collagen and elastin fibres were deformed and secondary crest density was reduced. Bronchioles contained debris and their epithelium was injured and thickened. 24 h after MV at 0.75 and 0.85 of term, mRNA expression of potential mediators of lung repair were significantly increased. By 15 days after MV, most lung injury had resolved without treatment. CONCLUSIONS: Extremely immature lungs, particularly bronchioles, are severely injured by 2 h of MV. In the absence of continued ventilation these injured lungs are capable of repair. At 24 h after MV, genes associated with injurious MV are unaltered, while potential repair genes are activated in both extremely and very preterm lungs.

  12. Suspended animation inducer hydrogen sulfide is protective in an in vivo model of ventilator-induced lung injury

    NARCIS (Netherlands)

    Aslami, H.; Heinen, A.; Roelofs, J.J.T.H.; Zuurbier, C.J.; Schultz, M.J.; Juffermans, N.P.

    2010-01-01

    Acute lung injury is characterized by an exaggerated inflammatory response and a high metabolic demand. Mechanical ventilation can contribute to lung injury, resulting in ventilator-induced lung injury (VILI). A suspended-animation-like state induced by hydrogen sulfide (H2S) protects against hypoxi

  13. Suspended animation inducer hydrogen sulfide is protective in an in vivo model of ventilator-induced lung injury

    NARCIS (Netherlands)

    Aslami, H.; Heinen, A.; Roelofs, J.J.T.H.; Zuurbier, C.J.; Schultz, M.J.; Juffermans, N.P.

    2010-01-01

    Acute lung injury is characterized by an exaggerated inflammatory response and a high metabolic demand. Mechanical ventilation can contribute to lung injury, resulting in ventilator-induced lung injury (VILI). A suspended-animation-like state induced by hydrogen sulfide (H2S) protects against

  14. Amniotic fluid stem cells from EGFP transgenic mice attenuate hyperoxia-induced acute lung injury.

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    Shih-Tao Wen

    Full Text Available High concentrations of oxygen aggravate the severity of lung injury in patients requiring mechanical ventilation. Although mesenchymal stem cells have been shown to effectively attenuate various injured tissues, there is limited information regarding a role for amniotic fluid stem cells (AFSCs in treating acute lung injury. We hypothesized that intravenous delivery of AFSCs would attenuate lung injury in an experimental model of hyperoxia-induced lung injury. AFSCs were isolated from EGFP transgenic mice. The in vitro differentiation, surface markers, and migration of the AFSCs were assessed by specific staining, flow cytometry, and a co-culture system, respectively. The in vivo therapeutic potential of AFSCs was evaluated in a model of acute hyperoxia-induced lung injury in mice. The administration of AFSCs significantly reduced the hyperoxia-induced pulmonary inflammation, as reflected by significant reductions in lung wet/dry ratio, neutrophil counts, and the level of apoptosis, as well as reducing the levels of inflammatory cytokine (IL-1β, IL-6, and TNF-α and early-stage fibrosis in lung tissues. Moreover, EGFP-expressing AFSCs were detected and engrafted into a peripheral lung epithelial cell lineage by fluorescence microscopy and DAPI stain. Intravenous administration of AFSCs may offer a new therapeutic strategy for acute lung injury (ALI, for which efficient treatments are currently unavailable.

  15. Bronchoscopy-derived correlates of lung injury following inhalational injuries: a prospective observational study.

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    Samuel W Jones

    Full Text Available BACKGROUND: Acute lung injury (ALI is a major factor determining morbidity following burns and inhalational injury. In experimental models, factors potentially contributing to ALI risk include inhalation of toxins directly causing cell damage; inflammation; and infection. However, few studies have been done in humans. METHODS: We carried out a prospective observational study of patients admitted to the NC Jaycees Burn Center who were intubated and on mechanical ventilation for burns and suspected inhalational injury. Subjects were enrolled over an 8-month period and followed till discharge or death. Serial bronchial washings from clinically-indicated bronchoscopies were collected and analyzed for markers of cell injury and inflammation. These markers were compared with clinical markers of ALI. RESULTS: Forty-three consecutive patients were studied, with a spectrum of burn and inhalation injury severity. Visible soot at initial bronchoscopy and gram negative bacteria in the lower respiratory tract were associated with ALI in univariate analyses. Subsequent multivariate analysis also controlled for % body surface area burns, infection, and inhalation severity. Elevated IL-10 and reduced IL-12p70 in bronchial washings were statistically significantly associated with ALI. CONCLUSIONS: Independently of several factors including initial inhalational injury severity, infection, and extent of surface burns, high early levels of IL-10 and low levels of IL-12p70 in the central airways are associated with ALI in patients intubated after acute burn/inhalation injury. Lower airway secretions can be collected serially in critically ill burn/inhalation injury patients and may yield important clues to specific pathophysiologic pathways.

  16. AKT1E¹⁷K Is Oncogenic in Mouse Lung and Cooperates with Chemical Carcinogens in Inducing Lung Cancer.

    Science.gov (United States)

    Malanga, Donatella; Belmonte, Stefania; Colelli, Fabiana; Scarfò, Marzia; De Marco, Carmela; Oliveira, Duarte Mendes; Mirante, Teresa; Camastra, Caterina; Gagliardi, Monica; Rizzuto, Antonia; Mignogna, Chiara; Paciello, Orlando; Papparella, Serenella; Fagman, Henrik; Viglietto, Giuseppe

    2016-01-01

    The hotspot AKT1E17K mutation in the pleckstrin homology domain of AKT1 occurs in approximately 0.6-2% of human lung cancers. Recently, we have demonstrated that AKT1E17K transforms immortalized human bronchial cells. Here by use of a transgenic Cre-inducible murine strain in the wild type Rosa26 (R26) locus (R26-AKT1E17K mice) we demonstrate that AKT1E17K is a bona-fide oncogene and plays a role in the development of lung cancer in vivo. In fact, we report that mutant AKT1E17K induces bronchial and/or bronchiolar hyperplastic lesions in murine lung epithelium, which progress to frank carcinoma at very low frequency, and accelerates tumor formation induced by chemical carcinogens. In conclusion, AKT1E17K induces hyperplasia of mouse lung epithelium in vivo and cooperates with urethane to induce the fully malignant phenotype.

  17. Genetic ablation of CXCR2 protects against cigarette smoke-induced lung inflammation and injury

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    Chad A Lerner

    2016-10-01

    Full Text Available Antagonism of CXCR2 receptors, predominately located on neutrophils and critical for their immunomodulatory activity, is an attractive pharmacological therapeutic approach aimed at reducing the potentially damaging effects of heightened neutrophil influx into the lung caused by environmental agents including tobacco smoke. The role CXCR2 in lung inflammation in response to cigarette smoke (CS inhalation using the mutant mouse approach is not known. We hypothesized that genetic ablation of CXCR2 would protect mice against CS-induced inflammation and DNA damaging response. We used CXCR2 -/- deficient/mutant (knock-out, KO mice, and assessed the changes in critical lung inflammatory NF-B-driven chemokines released from the parenchyma of CS-exposed mice, and indications of the extent of tissue damage assessed by the number of DNA damaging γH2AX positive cells. CXCR2 KO mice exhibited protection from heightened levels of neutrophils measured in BALF taken from mice exposed to CS. IL-8 (KC mouse levels in the BALF from CS-exposed CXCR2 KO were elevated compared to WT. IL-6 levels in BALF were refractory to increase by CS in CXCR2 KO mice. There were no significant changes to MIP-2, MCP-1, or IL-1β. Total levels of NF-κB were maintained at lower levels in CS-exposed CXCR2 KO mice compared to WT mice exposed to CS. Finally CXCR2 KO mice were protected from increased number of lung cells positive for DNA damage response and senescence marker γH2AX, CXCR2 KO mice are protected from heightened inflammatory response mediated by increased neutrophil response as a result of acute 3 day CS exposure. This is also associated with changes in pro-inflammatory chemokines and reduced incursion of γH2AX indicating CXCR2 deficient mice are protected from lung injury. Thus CXCR2 may be a pharmacological target in setting of inflammation and DNA damage in the pathogenesis of COPD.

  18. Activation of MTOR in pulmonary epithelium promotes LPS-induced acute lung injury.

    Science.gov (United States)

    Hu, Yue; Lou, Jian; Mao, Yuan-Yuan; Lai, Tian-Wen; Liu, Li-Yao; Zhu, Chen; Zhang, Chao; Liu, Juan; Li, Yu-Yan; Zhang, Fan; Li, Wen; Ying, Song-Min; Chen, Zhi-Hua; Shen, Hua-Hao

    2016-12-01

    MTOR (mechanistic target of rapamycin [serine/threonine kinase]) plays a crucial role in many major cellular processes including metabolism, proliferation and macroautophagy/autophagy induction, and is also implicated in a growing number of proliferative and metabolic diseases. Both MTOR and autophagy have been suggested to be involved in lung disorders, however, little is known about the role of MTOR and autophagy in pulmonary epithelium in the context of acute lung injury (ALI). In the present study, we observed that lipopolysaccharide (LPS) stimulation induced MTOR phosphorylation and decreased the expression of MAP1LC3B/LC3B (microtubule-associated protein 1 light chain 3 β)-II, a hallmark of autophagy, in mouse lung epithelium and in human bronchial epithelial (HBE) cells. The activation of MTOR in HBE cells was mediated by TLR4 (toll-like receptor 4) signaling. Genetic knockdown of MTOR or overexpression of autophagy-related proteins significantly attenuated, whereas inhibition of autophagy further augmented, LPS-induced expression of IL6 (interleukin 6) and IL8, through NFKB signaling in HBE cells. Mice with specific knockdown of Mtor in bronchial or alveolar epithelial cells exhibited significantly attenuated airway inflammation, barrier disruption, and lung edema, and displayed prolonged survival in response to LPS exposure. Taken together, our results demonstrate that activation of MTOR in the epithelium promotes LPS-induced ALI, likely through downregulation of autophagy and the subsequent activation of NFKB. Thus, inhibition of MTOR in pulmonary epithelial cells may represent a novel therapeutic strategy for preventing ALI induced by certain bacteria.

  19. TGFβ signaling in lung epithelium regulates bleomycin-induced alveolar injury and fibroblast recruitment

    OpenAIRE

    Degryse, Amber L.; Tanjore, Harikrishna; Xu, Xiaochuan C.; Polosukhin, Vasiliy V.; Jones, Brittany R.; Chad S Boomershine; Ortiz, Camila; Sherrill, Taylor P.; McMahon, Frank B.; Gleaves, Linda A.; Blackwell, Timothy S.; Lawson, William E.

    2011-01-01

    The response of alveolar epithelial cells (AECs) to lung injury plays a central role in the pathogenesis of pulmonary fibrosis, but the mechanisms by which AECs regulate fibrotic processes are not well defined. We aimed to elucidate how transforming growth factor-β (TGFβ) signaling in lung epithelium impacts lung fibrosis in the intratracheal bleomycin model. Mice with selective deficiency of TGFβ receptor 2 (TGFβR2) in lung epithelium were generated and crossed to cell fate reporter mice tha...

  20. 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.

  1. Mesenchymal Stem Cell Attenuates Neutrophil-predominant Inflammation and Acute Lung Injury in an In Vivo Rat Model of Ventilator-induced Lung Injury

    Institute of Scientific and Technical Information of China (English)

    Tian-Shun Lai; Zhi-Hong Wang; Shao-Xi Cai

    2015-01-01

    Background:Subsequent neutrophil (polymorphonuclear neutrophil [PMN])-predominant inflammatory response is a predominant feature of ventilator-induced lung injury (VILI),and mesenchymal stem cell (MSC) can improve mice survival model of endotoxin-induced acute lung injury,reduce lung impairs,and enhance the repair of VILI.However,whether MSC could attenuate PMN-predominant inflammatory in the VILI is still unknown.This study aimed to test whether MSC intervention could attenuate the PMN-predominate inflammatory in the mechanical VILI.Methods:Sprague-Dawley rats were ventilated for 2 hours with large tidal volume (20 mL/kg).MSCs were given before or after ventilation.The inflammatory chemokines and gas exchange were observed and compared dynamically until 4 hours after ventilation,and pulmonary pathological change and activation of PMN were observed and compared 4 hours after ventilation.Results:Mechanical ventilation (MV) caused significant lung injury reflected by increasing in PMN pulmonary sequestration,inflammatory chemokines (tumor necrosis factor-alpha,interleukin-6 and macrophage inflammatory protein 2) in the bronchoalveolar lavage fluid,and injury score of the lung tissue.These changes were accompanied with excessive PMN activation which reflected by increases in PMN elastase activity,production of radical oxygen series.MSC intervention especially pretreatment attenuated subsequent lung injury,systemic inflammation response and PMN pulmonary sequestration and excessive PMN activation initiated by injurious ventilation.Conclusions:MV causes profound lung injury and PMN-predominate inflammatory responses.The protection effect of MSC in the VILI rat model is related to the suppression of the PMN activation.

  2. Modulation of epithelial sodium channel (ENaC expression in mouse lung infected with Pseudomonas aeruginosa

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    Radzioch Danuta

    2005-01-01

    Full Text Available Abstract Background The intratracheal instillation of Pseudomonas aeruginosa entrapped in agar beads in the mouse lung leads to chronic lung infection in susceptible mouse strains. As the infection generates a strong inflammatory response with some lung edema, we tested if it could modulate the expression of genes involved in lung liquid clearance, such as the α, β and γ subunits of the epithelial sodium channel (ENaC and the catalytic subunit of Na+-K+-ATPase. Methods Pseudomonas aeruginosa entrapped in agar beads were instilled in the lung of resistant (BalB/c and susceptible (DBA/2, C57BL/6 and A/J mouse strains. The mRNA expression of ENaC and Na+-K+-ATPase subunits was tested in the lung by Northern blot following a 3 hours to 14 days infection. Results The infection of the different mouse strains evoked regulation of α and β ENaC mRNA. Following Pseudomonas instillation, the expression of αENaC mRNA decreased to a median of 43% on days 3 and 7 after infection and was still decreased to a median of 45% 14 days after infection (p 1Na+-K+-ATPase mRNA, the catalytic subunit of the sodium pump, was recorded. The distinctive expression profiles of the three subunits were not different, between the susceptible and resistant mouse strains. Conclusions These results show that Pseudomonas infection, by modulating ENaC subunit expression, could influence edema formation and clearance in infected lungs.

  3. 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

  4. High bias gas flows increase lung injury in the ventilated preterm lamb.

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    Katinka P Bach

    Full Text Available BACKGROUND: Mechanical ventilation of preterm babies increases survival but can also cause ventilator-induced lung injury (VILI, leading to the development of bronchopulmonary dysplasia (BPD. It is not known whether shear stress injury from gases flowing into the preterm lung during ventilation contributes to VILI. METHODS: Preterm lambs of 131 days' gestation (term = 147 d were ventilated for 2 hours with a bias gas flow of 8 L/min (n = 13, 18 L/min (n = 12 or 28 L/min (n = 14. Physiological parameters were measured continuously and lung injury was assessed by measuring mRNA expression of early injury response genes and by histological analysis. Control lung tissue was collected from unventilated age-matched fetuses. Data were analysed by ANOVA with a Tukey post-hoc test when appropriate. RESULTS: High bias gas flows resulted in higher ventilator pressures, shorter inflation times and decreased ventilator efficiency. The rate of rise of inspiratory gas flow was greatest, and pulmonary mRNA levels of the injury markers, EGR1 and CTGF, were highest in lambs ventilated with bias gas flows of 18 L/min. High bias gas flows resulted in increased cellular proliferation and abnormal deposition of elastin, collagen and myofibroblasts in the lung. CONCLUSIONS: High ventilator bias gas flows resulted in increased lung injury, with up-regulation of acute early response genes and increased histological lung injury. Bias gas flows may, therefore, contribute to VILI and BPD.

  5. Protective effect of albumin on lung injury in traumatic/hemorrhagic shock in rats

    Institute of Scientific and Technical Information of China (English)

    DING Chen-yan; CHEN Zuo-bing; ZHENG Shu-sen; GAO Yuan; ZHANG Yun; ZHAO Xue-hong; NI Ling-mei

    2005-01-01

    Objective: To determine the effect of albumin administration on lung injury in traumatic/hemorrhagic shock (T/HS) in rats. Methods: Forty-eight adult Sprague-Dawley rats were divided into three groups randomly (n=16 in each group): Group A, Group B, Group C. In Group A, rats underwent laparotomy without shock. In Group B, rats undergoing T/HS were resuscitated with their blood plus lactated Ringer's (twice the volume of shed blood). In Group C, rats undergoing T/HS were resuscitated with their shed blood plus additional 3 ml of 5% human albumin. The expression of polymorphonuclear neutrophils CD18/CD11b in jugular vein blood was evaluated. The main lung injury indexes (the activity of myeloperoxidase and lung injury score) were measured. Results: Significant differences of the expression of CD18/11b and the severity degree of lung injury were found between the three groups.(P<0.05). The expression of CD18/CD11b and the main lung injury indexes in Group B and Goup C incresed significantly compared with those in Group A(P<0.05).At the same time, the expression of CD18/CD11b and the main lung injury indexes in Group C decreased dramatically, compared with those in Group B (P<0.05). Conclusions: The infusion of albumin during resuscitation period can protect lungs from injury and decrease the expression of CD18/CD11b in T/HS rats.

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

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    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.

  7. High Bias Gas Flows Increase Lung Injury in the Ventilated Preterm Lamb

    Science.gov (United States)

    Bach, Katinka P.; Kuschel, Carl A.; Hooper, Stuart B.; Bertram, Jean; McKnight, Sue; Peachey, Shirley E.; Zahra, Valerie A.; Flecknoe, Sharon J.; Oliver, Mark H.; Wallace, Megan J.; Bloomfield, Frank H.

    2012-01-01

    Background Mechanical ventilation of preterm babies increases survival but can also cause ventilator-induced lung injury (VILI), leading to the development of bronchopulmonary dysplasia (BPD). It is not known whether shear stress injury from gases flowing into the preterm lung during ventilation contributes to VILI. Methods Preterm lambs of 131 days’ gestation (term = 147 d) were ventilated for 2 hours with a bias gas flow of 8 L/min (n = 13), 18 L/min (n = 12) or 28 L/min (n = 14). Physiological parameters were measured continuously and lung injury was assessed by measuring mRNA expression of early injury response genes and by histological analysis. Control lung tissue was collected from unventilated age-matched fetuses. Data were analysed by ANOVA with a Tukey post-hoc test when appropriate. Results High bias gas flows resulted in higher ventilator pressures, shorter inflation times and decreased ventilator efficiency. The rate of rise of inspiratory gas flow was greatest, and pulmonary mRNA levels of the injury markers, EGR1 and CTGF, were highest in lambs ventilated with bias gas flows of 18 L/min. High bias gas flows resulted in increased cellular proliferation and abnormal deposition of elastin, collagen and myofibroblasts in the lung. Conclusions High ventilator bias gas flows resulted in increased lung injury, with up-regulation of acute early response genes and increased histological lung injury. Bias gas flows may, therefore, contribute to VILI and BPD. PMID:23056572

  8. Salidroside ameliorates sepsis-induced acute lung injury and mortality via downregulating NF-κB and HMGB1 pathways through the upregulation of SIRT1.

    Science.gov (United States)

    Lan, Kuo-Cheng; Chao, Sung-Chuan; Wu, Hsiao-Yi; Chiang, Chia-Lien; Wang, Ching-Chia; Liu, Shing-Hwa; Weng, Te-I

    2017-09-20

    Sepsis is a life-threatening medical condition. Salidroside, a substance isolated from Rhodiola rosea, possesses antioxidant and anti-inflammatory properties. The effect and mechanism of salidroside on sepsis-induced acute lung injury still remains to be well clarified. Here, we investigated the effect and mechanism of salidroside on septic mouse models and explored the role of salidroside-upregulated SIRT1. Salidroside inhibited the inflammatory responses and HMGB1 productions in bacterial lipopolysaccharide (LPS)-treated macrophages and mice. Salidroside could also reverse the decreased SIRT1 protein expression in LPS-treated macrophages and mice. Salidroside also alleviated the sepsis-induced lung edema, lipid peroxidation, and histopathological changes and the mortality, and improved the lung PaO2/FiO2 ratio in cecal ligation and puncture (CLP)-induced septic mice. Salidroside significantly decreased the serum TNF-α, IL-6, NO, and HMGB1 productions, pulmonary inducible NO synthase (iNOS) and phosphorylated NF-κB-p65 protein expressions, and pulmonary HMGB1 nuclear translocation in CLP septic mice. Moreover, sepsis decreased the SIRT1 protein expression in the lungs of CLP septic mice. Salidroside significantly upregulated the SIRT1 expression and inhibited the inflammatory responses in CLP septic mouse lungs. These results suggest that salidroside protects against sepsis-induced acute lung injury and mortality, which might be through the SIRT1-mediated repression of NF-κB activation and HMGB1 nucleocytoplasmic translocation.

  9. EXPRESSION OF INTERCELLULAR ADHESION MOLECULE IN LUNG TISSUES OF EXPERIMENTAL ACUTE LUNG INJURY AND THE AFFECT OF RHUBARB ON IT

    Institute of Scientific and Technical Information of China (English)

    李春盛; 桂培春; 何新华

    2000-01-01

    Objeaive. To approach the relation and the possible mechanism between the expression of intercellular adhesion molecule (ICAM-1) mRNA and acute lung injury (ALI) and the mechanisms of rhubarb in the prevention and treatment of the lung injury. Methods. Lipopolysaeeharide (LPS) was injected into the sublingual vein of male Wistar rats to perform ALI animal model. The rats were divided into 4 groups: LPS group, control group, rhubarb group and dexamethasoue group.Macroscopic and histopathological e~aminatiom were performed and biological markers were measured for the lung specimem. The markers included lung wet/dry weight, the rate of neutrophils and protein content in the pulmonary alveolar lavage fluid, pulmonary vascular permeability and pulmonary alveolar permeability index. Molecular hybridization method was used to determine the expression of ICAM-1 mRNA. Results. In the lung tissues, the ICAM-1 mRNA expression was increased in the endothelial cells of pulmonary veins and capillaries, rhubarb and dexamethasone had the action of decreasing the expression. The light reflex value in the gray scale scanning showed that in the comparison between the LPS and the control group, the gray scale value of the lung tissues in ALI was significantly increased, thus the light reflex value was markedly decreased (P < 0.01),demonstrating the expression of ICAM-1 mRNA was increased. In comparison with the LPS group, dexamethasoue and rhubarb emfld decrease the gray scale value of the lung tissue significantly, thus the light reflex value was elevated (P< 0.01, P < 0.05) ; the correslxmding pathologic changes of lung tissues and the biological markers of the lung injury were simifieantlv decreased or ameliorated. Conclusions. The increase of the expression d ICAM-1 mRNA in the lung tissues of ALI plays the roles in ALI.The application of rhubarb and dexamethasone can decrease the expression and ameliorate the lung damage; its mechanism is possibly via the inhibition of ICAM-1 m

  10. EXPRESSION OF INTERCELLULAR ADHESION MOLECULE IN LUNG TISSUES OF EXPERIMENTAL ACUTE LUNG INJURY AND THE AFFECT OF RHUBARB ON IT

    Institute of Scientific and Technical Information of China (English)

    2000-01-01

    Objective. To approach the relation and the possible mechanism between the expression of intercellular adhesion molecule (ICAM-1) mRNA and acute lung injury (ALI) and the mechanisms of rhubarb in the prevention and treatment of the lung injury.Methods. Lipopolysaccharide (LPS) was injected into the sublingual vein of male Wistar rats to perform ALI animal model. The rats were divided into 4 groups: LPS group, control group, rhubarb group and dexamethasone group. Macroscopic and histopathological examinations were performed and biological markers were measured for the lung specimens. The markers included lung wet/dry weight, the rate of neutrophils and protein content in the pulmonary alveolar lavage fluid, pulmonary vascular permeability and pulmonary alveolar permeability index. Molecular hybridization method was used to determine the expression of ICAM-1 mRNA.Results. In the lung tissues, the ICAM-1 mRNA expression was increased in the endothelial cells of pulmonary veins and capillaries, rhubarb and dexamethasone had the action of decreasing the expression. The light reflex value in the gray scale scanning showed that in the comparison between the LPS and the control group, the gray scale value of the lung tissues in ALI was significantly increased, thus the light reflex value was markedly decreased (P<0.01), demonstrating the expression of ICAM-1 mRNA was increased. In comparison with the LPS group, dexamethasone and rhubarb could decrease the gray scale value of the lung tissue significantly, thus the light reflex value was elevated (P<0.01, P<0.05); the corresponding pathologic changes of lung tissues and the biological markers of the lung injury were significantly decreased or ameliorated.Conclusions. The increase of the expression of ICAM-1 mRNA in the lung tissues of ALI plays the roles in ALI. The application of rhubarb and dexamethasone can decrease the expression and ameliorate the lung damage; its mechanism is possibly via the inhibition of ICAM

  11. Lung surfactant protein D (SP-D) response and regulation during acute and chronic lung injury.

    Science.gov (United States)

    Gaunsbaek, Maria Quisgaard; Rasmussen, Karina Juhl; Beers, Michael F; Atochina-Vasserman, Elena N; Hansen, Soren

    2013-06-01

    Surfactant protein D (SP-D) is a collection that plays important roles in modulating host defense functions and maintaining phospholipid homeostasis in the lung. The aim of current study was to characterize comparatively the SP-D response in bronchoalveolar lavage (BAL) and serum in three murine models of lung injury, using a validated ELISA technology for estimation of SP-D levels. Mice were exposed to lipopolysaccharide, bleomycin, or Pneumocystis carinii (Pc) and sacrificed at different time points. In lipopolysaccharide-challenged mice, the level of SP-D in BAL increased within 6 h, peaked at 51 h (4,518 ng/ml), and returned to base level at 99 h (612 ng/ml). Serum levels of SP-D increased immediately (8.6 ng/ml), peaked at 51 h (16 ng/ml), and returned to base levels at 99 h (3.8 ng/ml). In a subacute bleomycin inflammation model, SP-D levels were 4,625 and 367 ng/ml in BAL and serum, respectively, 8 days after exposure. In a chronic Pc inflammation model, the highest level of SP-D was observed 6 weeks after inoculation, with BAL and serum levels of 1,868 and 335 ng/ml, respectively. We conclude that serum levels of SP-D increase during lung 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.

  12. Lessons learned using different mouse models during space radiation-induced lung tumorigenesis experiments

    Science.gov (United States)

    Wang, Jian; Zhang, Xiangming; Wang, Ping; Wang, Xiang; Farris, Alton B.; Wang, Ya

    2016-06-01

    Unlike terrestrial ionizing radiation, space radiation, especially galactic cosmic rays (GCR), contains high energy charged (HZE) particles with high linear energy transfer (LET). Due to a lack of epidemiologic data for high-LET radiation exposure, it is highly uncertain how high the carcinogenesis risk is for astronauts following exposure to space radiation during space missions. Therefore, using mouse models is necessary to evaluate the risk of space radiation-induced tumorigenesis; however, which mouse model is better for these studies remains uncertain. Since lung tumorigenesis is the leading cause of cancer death among both men and women, and low-LET radiation exposure increases human lung carcinogenesis, evaluating space radiation-induced lung tumorigenesis is critical to enable safe Mars missions. Here, by comparing lung tumorigenesis obtained from different mouse strains, as well as miR-21 in lung tissue/tumors and serum, we believe that wild type mice with a low spontaneous tumorigenesis background are ideal for evaluating the risk of space radiation-induced lung tumorigenesis, and circulating miR-21 from such mice model might be used as a biomarker for predicting the risk.

  13. Lessons learned using different mouse models during space radiation-induced lung tumorigenesis experiments.

    Science.gov (United States)

    Wang, Jian; Zhang, Xiangming; Wang, Ping; Wang, Xiang; Farris, Alton B; Wang, Ya

    2016-06-01

    Unlike terrestrial ionizing radiation, space radiation, especially galactic cosmic rays (GCR), contains high energy charged (HZE) particles with high linear energy transfer (LET). Due to a lack of epidemiologic data for high-LET radiation exposure, it is highly uncertain how high the carcinogenesis risk is for astronauts following exposure to space radiation during space missions. Therefore, using mouse models is necessary to evaluate the risk of space radiation-induced tumorigenesis; however, which mouse model is better for these studies remains uncertain. Since lung tumorigenesis is the leading cause of cancer death among both men and women, and low-LET radiation exposure increases human lung carcinogenesis, evaluating space radiation-induced lung tumorigenesis is critical to enable safe Mars missions. Here, by comparing lung tumorigenesis obtained from different mouse strains, as well as miR-21 in lung tissue/tumors and serum, we believe that wild type mice with a low spontaneous tumorigenesis background are ideal for evaluating the risk of space radiation-induced lung tumorigenesis, and circulating miR-21 from such mice model might be used as a biomarker for predicting the risk.

  14. Evaluation of Angiogenesis Using Micro-Computed Tomography in a Xenograft Mouse Model of Lung Cancer

    Directory of Open Access Journals (Sweden)

    Rajkumar Savai

    2009-01-01

    Full Text Available Quantitative evaluation of lung tumor angiogenesis using immunohistochemical techniques has been limited by difficulties in generating reproducible data. To analyze intrapulmonary tumor angiogenesis, we used high-resolution micro-computed tomography (micro-CT of lung tumors of mice inoculated with mouse Lewis lung carcinoma (LLC1 or human adenocarcinoma (A549 cell lines. The lung vasculature was filled with the radiopaque silicone rubber, Microfil, through the jugular vein (in vivo application or pulmonary artery (ex vivo application. In addition, human adenocarcinoma lung tumor-bearing mice treated site-specifically with humanized monoclonal antibody (bevacizumab against vascular endothelial growth factor. Quantitative analysis of lung tumor microvessels imaged with micro-CT showed that more vessels (mainly small, <0.02 mm2 were filled using the in vivo (5.4% compared with the ex vivo (2.1% method. Furthermore, bevacizumab-treated lung tumor-bearing mice showed significantly reduced lung tumor volume and lung tumor angiogenesis compared with untreated mice as assessed by micro-CT. Interestingly, microvascularization of mainly the smaller vessels (<0.02 mm2 was reduced after bevacizumab treatment. This observation with micro-CT was nicely correlated with immunohistochemical measurement of microvessels. Therefore, micro-CT is a novel method for investigating lung tumor angiogenesis, and this might be considered as an additional complementary tool for precise quantification of angiogenesis.

  15. Aberrant lung remodeling in a mouse model of surfactant dysregulation induced by modulation of the Abca3 gene.

    Science.gov (United States)

    Beers, Michael F; Knudsen, Lars; Tomer, Yaniv; Maronn, Julian; Zhao, Ming; Ochs, Matthias; Mulugeta, Surafel

    2017-03-01

    The lipid transporter, ATP binding cassette class A3 (ABCA3), plays a critical role in the biogenesis of alveolar type 2 (AT2) cell lamellar bodies (LBs). A relatively large number of mutations in the ABCA3 gene have been identified in association with diffuse parenchymal lung disease (DPLD), the most common of which is a missense mutation (valine substitution for lysine at residue 292 (ABCA3(E292V))) that leads to functional impairment of the transporter in vitro. The consequences of ABCA3(E292)(V) gene expression in vivo are unknown. To address this question, we developed mouse models expressing ABCA3(E292V) knocked-in to the endogenous mouse locus. The parental (F1) mouse line (mAbca3(E292)(V)) that retained an intronic pgk-Neo selection cassette (inserted in reverse orientation) (mAbca3(E292)(V)-rNeo) demonstrated an allele dependent extracellular surfactant phospholipid (PL) deficiency. We hypothesize that this PL deficiency leads to aberrant parenchymal remodeling contributing to the pathophysiology of the DPLD phenotype. Compared to wild type littermates, baseline studies of mice homozygous for the pgk-Neo insert (mAbca3(E292)(V)-rNeo(+/)(+)) revealed nearly 50% reduction in bronchoalveolar lavage (BAL) PL content that was accompanied by quantitative reduction in AT2 LB size with a compensatory increase in LB number. The phenotypic alteration in surfactant lipid homeostasis resulted in an early macrophage predominant alveolitis which peaked at 8 weeks of age. This was followed by age-dependent development of histological DPLD characterized initially by peribronchial inflammatory cell infiltration and culminating in both an emphysema-like phenotype (which included stereologically quantifiable reductions in both alveolar septal surface area and volume of septal wall tissue) plus foci of trichrome-positive collagen deposition together with substantial proliferation of hyperplastic AT2 cells. In addition to spontaneous lung remodeling, mABCA3(E292V)-rNeo mice

  16. Klebsiella pneumoniae alleviates influenza-induced acute lung injury via limiting NK cell expansion.

    Science.gov (United States)

    Wang, Jian; Li, Fengqi; Sun, Rui; Gao, Xiang; Wei, Haiming; Tian, Zhigang

    2014-08-01

    A protective effect induced by bacterial preinfection upon a subsequent lethal influenza virus infection has been observed, but the underlying immune mechanisms have not yet been fully elucidated. In this study, we used a mouse model of Klebsiella pneumoniae preinfection to gain insight into how bacterial preinfection influences the subsequent lethal influenza virus infection. We found that K. pneumoniae preinfection significantly attenuated lung immune injury and decreased mortality during influenza virus infection, but K. pneumoniae-specific immunity was not involved in this cross-protection against influenza virus. K. pneumoniae preinfection limited NK cell expansion, which was involved in influenza-induced immune injury and death. Furthermore, K. pneumoniae preinfection could not control NK cell expansion and death during influenza virus infection in Rag1(-/-) mice, but adoptive transfer of T cells from wild-type mice was able to restore this protective effect. Our data suggest that the adaptive immune response activated by bacterial infection limits the excessive innate immune response induced by a subsequent influenza infection, ultimately protecting mice from death.

  17. Development of a metastatic fluorescent Lewis Lung carcinoma mouse model

    DEFF Research Database (Denmark)

    Rask, Lene; Fregil, Marianne; Høgdall, Estrid;

    2013-01-01

    models. To examine the mechanisms involved in tumor metastasis, we first generated a stably transfected Lewis Lung carcinoma cell line expressing a far-red fluorescent protein, called Katushka. After in vivo growth in syngeneic mice, two fluorescent Lewis Lung cancer subpopulations were isolated from...... primary tumors and lung metastases. The metastasis-derived cells exhibited a significant improvement in in vitro invasive activity compared to the primary tumor-derived cells, using a quantitative invasion chamber assay. Moreover, expression levels of 84 tumor metastasis-related mRNAs, 88 cancer......-related microRNAs as well as Dicer and Drosha were determined using RT-qPCR. Compared to the primary Lewis Lung carcinoma subculture, the metastasis-derived cells exhibited statistically significantly increased mRNA levels for several matrix metalloproteinases as well as hepatocyte growth factor (HGF...

  18. CXCR4 Blockade Attenuates Hyperoxia Induced Lung Injury in Neonatal Rats

    Science.gov (United States)

    Drummond, Shelley; Ramachandran, Shalini; Torres, Eneida; Huang, Jian; Hehre, Dorothy; Suguihara, Cleide; Young, Karen C.

    2015-01-01

    Background Lung inflammation is a key factor in the pathogenesis of bronchopulmonary dysplasia (BPD). Stromal derived factor-1 (SDF-1) and its receptor chemokine receptor 4 (CXCR4) modulate the inflammatory response. Whether antagonism of CXCR4 will alleviate lung inflammation in neonatal hyperoxia-induced lung injury is unknown. Objective To determine whether CXCR4 antagonism would attenuate lung injury in rodents with experimental BPD by decreasing pulmonary inflammation. Methods Newborn rats exposed to normoxia (RA) or hyperoxia (FiO2=0.9) from postnatal day 2 (P2)-P16 were randomized to receive the CXCR4 antagonist, AMD3100 or placebo (PL) from P5 to P15. Lung alveolarization, angiogenesis, and inflammation were evaluated at P16. Results As compared to RA, hyperoxic-PL pups had a decrease in alveolarization, reduced lung vascular density and increased lung inflammation. In contrast, AMD3100-treated hyperoxic pups had improved alveolarization and increased angiogenesis. This improvement in lung structure was accompanied by a decrease in bronchoalveolar lavage fluid macrophage and neutrophil count and reduced lung myeloperoxidase activity. Conclusion CXCR4 antagonism decreases lung inflammation and improves alveolar as well as vascular structure in neonatal rats with experimental BPD. These findings suggest a novel therapeutic strategy to alleviate lung injury in preterm infants with BPD. PMID:25825119

  19. Surgical technique for lung retransplantation in the mouse

    OpenAIRE

    Li, Wenjun; Goldstein, Daniel R.; Bribriesco, Alejandro C.; Nava, Ruben G.; Spahn, Jessica H.; Wang, Xingan; Gelman, Andrew E.; Krupnick, Alexander S.; Kreisel, Daniel

    2013-01-01

    Microsurgical cuff techniques for orthotopic vascularized murine lung transplantation have allowed for the design of studies that examine mechanisms contributing to the high failure rate of pulmonary grafts. Here, we provide a detailed technical description of orthotopic lung retransplantation in mice, which we have thus far performed in 144 animals. The total time of the retransplantation procedure is approximately 55 minutes, 20 minutes for donor harvest and 35 minutes for the implantation,...

  20. Molecular signatures of trauma-hemorrhagic shock-induced lung injury: hemorrhage- and injury-associated genes.

    Science.gov (United States)

    Feinman, Rena; Deitch, Edwin A; Aris, Virginie; Chu, Hung B; Abungu, Billy; Caputo, Francis J; Galante, Anthony; Xu, DaZhong; Lu, Qi; Colorado, Iriana; Streck, Deanna; Dermody, James; Soteropoulos, Patricia

    2007-09-01

    The etiology of trauma-hemorrhagic shock (T/HS)-induced acute lung injury has been difficult to elucidate because of, at least in part, the inability of in vivo studies to separate the noninjurious pulmonary effects of trauma-hemorrhage from the tissue-injurious ones. To circumvent this in vivo limitation, we used a model of T/HS in which T/HS lung injury was abrogated by dividing the mesenteric lymph duct. In this way, it was possible to separate the pulmonary injurious response from the noninjurious systemic response to T/HS by comparing the pulmonary molecular responses of rats subjected to T/HS, which did and did not develop lung injury, with those of nonshocked rats. Using high-density oligonucleotide arrays and treatment group comparisons of whole lung tissue collected at 3 h after the end of the shock or sham-shock period, 139 of 8,799 assessed genes were identified by significant analysis of microarrays. Hemorrhage without the secondary effects of lung injury modulated the expression of 21 genes such as interleukin 1beta, metallothionein-2, and myeloctomatosis oncogene (c-myc). In response to injury, 42 genes were identified to be differentially expressed. Upregulated genes included the L1 retroposon and guanine deaminase, whereas downregulated genes included catalase and superoxide dismutase 1. Real-time polymerase chain reaction confirmed the differential expression for selected genes. PathwayAssist analysis identified interleukin 1beta as a central regulator of two subpathways of stress response-related genes (c-myc and superoxide dismutase 1/catalase) as well as several unrelated genes such as lipoprotein lipase. Our model system provided a unique opportunity to distinguish the molecular changes associated with T/HS-induced acute lung injury from the systemic molecular response to T/HS.

  1. Preemptive hemodynamic intervention restricting the administration of fluids attenuates lung edema progression in oleic acid-induced lung injury.

    Science.gov (United States)

    Gil Cano, A; Gracia Romero, M; Monge García, M I; Guijo González, P; Ruiz Campos, J

    2017-04-01

    A study is made of the influence of preemptive hemodynamic intervention restricting fluid administration upon the development of oleic acid-induced lung injury. A randomized in vivo study in rabbits was carried out. University research laboratory. Sixteen anesthetized, mechanically ventilated rabbits. Hemodynamic measurements obtained by transesophageal Doppler signal. Respiratory mechanics computed by a least square fitting method. Lung edema assessed by the ratio of wet weight to dry weight of the right lung. Histological examination of the left lung. Animals were randomly assigned to either the early protective lung strategy (EPLS) (n=8) or the early protective hemodynamic strategy (EPHS) (n=8). In both groups, lung injury was induced by the intravenous infusion of oleic acid (OA) (0.133mlkg(-1)h(-1) for 2h). At the same time, the EPLS group received 15mlkg(-1)h(-1) of Ringer lactate solution, while the EPHS group received 30mlkg(-1)h(-1). Measurements were obtained at baseline and 1 and 2h after starting OA infusion. After 2h, the cardiac index decreased in the EPLS group (p<0.05), whereas in the EPHS group it remained unchanged. Lung compliance decreased significantly only in the EPHS group (p<0.05). Lung edema was greater in the EPHS group (p<0.05). Histological damage proved similar in both groups (p=0.4). In this experimental model of early lung injury, lung edema progression was attenuated by preemptively restricting the administration of fluids. Copyright © 2016 Elsevier España, S.L.U. y SEMICYUC. All rights reserved.

  2. Wnt/β-catenin signaling accelerates mouse lung tumorigenesis by imposing an embryonic distal progenitor phenotype on lung epithelium.

    Science.gov (United States)

    Pacheco-Pinedo, Eugenia C; Durham, Amy C; Stewart, Kathleen M; Goss, Ashley M; Lu, Min Min; Demayo, Francesco J; Morrisey, Edward E

    2011-05-01

    Although mutations in Kras are present in 21% of lung tumors, there is a high level of heterogeneity in phenotype and outcome among patients with lung cancer bearing similar mutations, suggesting that other pathways are important. Wnt/β-catenin signaling is a known oncogenic pathway that plays a well-defined role in colon and skin cancer; however, its role in lung cancer is unclear. We have shown here that activation of Wnt/β-catenin in the bronchiolar epithelium of the adult mouse lung does not itself promote tumor development. However, concurrent activation of Wnt/β-catenin signaling and expression of a constitutively active Kras mutant (KrasG12D) led to a dramatic increase in both overall tumor number and size compared with KrasG12D alone. Activation of Wnt/β-catenin signaling altered the KrasG12D tumor phenotype, resulting in a phenotypic switch from bronchiolar epithelium to the highly proliferative distal progenitors found in the embryonic lung. This was associated with decreased E-cadherin expression at the cell surface, which may underlie the increased metastasis of tumors with active Wnt/β-catenin signaling. Together, these data suggest that activation of Wnt/β-catenin signaling can combine with other oncogenic pathways in lung epithelium to produce a more aggressive tumor phenotype by imposing an embryonic distal progenitor phenotype and by decreasing E-cadherin expression.

  3. Mouse lung contains endothelial progenitors with high capacity to form blood and lymphatic vessels

    Directory of Open Access Journals (Sweden)

    Barleon Bernhard

    2010-07-01

    Full Text Available Abstract Background Postnatal endothelial progenitor cells (EPCs have been successfully isolated from whole bone marrow, blood and the walls of conduit vessels. They can, therefore, be classified into circulating and resident progenitor cells. The differentiation capacity of resident lung endothelial progenitor cells from mouse has not been evaluated. Results In an attempt to isolate differentiated mature endothelial cells from mouse lung we found that the lung contains EPCs with a high vasculogenic capacity and capability of de novo vasculogenesis for blood and lymph vessels. Mouse lung microvascular endothelial cells (MLMVECs were isolated by selection of CD31+ cells. Whereas the majority of the CD31+ cells did not divide, some scattered cells started to proliferate giving rise to large colonies (> 3000 cells/colony. These highly dividing cells possess the capacity to integrate into various types of vessels including blood and lymph vessels unveiling the existence of local microvascular endothelial progenitor cells (LMEPCs in adult mouse lung. EPCs could be amplified > passage 30 and still expressed panendothelial markers as well as the progenitor cell antigens, but not antigens for immune cells and hematopoietic stem cells. A high percentage of these cells are also positive for Lyve1, Prox1, podoplanin and VEGFR-3 indicating that a considerabe fraction of the cells are committed to develop lymphatic endothelium. Clonogenic highly proliferating cells from limiting dilution assays were also bipotent. Combined in vitro and in vivo spheroid and matrigel assays revealed that these EPCs exhibit vasculogenic capacity by forming functional blood and lymph vessels. Conclusion The lung contains large numbers of EPCs that display commitment for both types of vessels, suggesting that lung blood and lymphatic endothelial cells are derived from a single progenitor cell.

  4. Fibroblast Growth Factor-10 (FGF-10) Mobilizes Lung-resident Mesenchymal Stem Cells and Protects Against Acute Lung Injury.

    Science.gov (United States)

    Tong, Lin; Zhou, Jian; Rong, Linyi; Seeley, Eric J; Pan, Jue; Zhu, Xiaodan; Liu, Jie; Wang, Qin; Tang, Xinjun; Qu, Jieming; Bai, Chunxue; Song, Yuanlin

    2016-02-12

    FGF-10 can prevent or reduce lung specific inflammation due to traumatic or infectious lung injury. However, the exact mechanisms are poorly characterized. Additionally, the effect of FGF-10 on lung-resident mesenchymal stem cells (LR-MSCs) has not been studied. To better characterize the effect of FGF-10 on LR-MSCs, FGF-10 was intratracheally delivered into the lungs of rats. Three days after instillation, bronchoalveolar lavage was performed and plastic-adherent cells were cultured, characterized and then delivered therapeutically to rats after LPS intratracheal instillation. Immunophenotyping analysis of FGF-10 mobilized and cultured cells revealed expression of the MSC markers CD29, CD73, CD90, and CD105, and the absence of the hematopoietic lineage markers CD34 and CD45. Multipotency of these cells was demonstrated by their capacity to differentiate into osteocytes, adipocytes, and chondrocytes. Delivery of LR-MSCs into the lungs after LPS injury reduced the inflammatory response as evidenced by decreased wet-to-dry ratio, reduced neutrophil and leukocyte recruitment and decreased inflammatory cytokines compared to control rats. Lastly, direct delivery of FGF-10 in the lungs of rats led to an increase of LR-MSCs in the treated lungs, suggesting that the protective effect of FGF-10 might be mediated, in part, by the mobilization of LR-MSCs in lungs.

  5. THE 5-LIPOXYGENASE PATHWAY IS REQUIRED FOR ACUTE LUNG INJURY FOLLOWING HEMORRHAGIC SHOCK

    Science.gov (United States)

    Eun, John C.; Moore, Ernest E.; Mauchley, David C.; Johnson, Chris A.; Meng, Xianzhong; Banerjee, Anirban; Wohlauer, Max V.; Zarini, Simona; Gijón, Miguel A.; Murphy, Robert C.

    2012-01-01

    The cellular and biochemical mechanisms leading to acute lung injury and subsequent multiple organ failure are only partially understood. In order to study the potential role of eicosanoids, particularly leukotrienes, as possible mediators of acute lung injury, we used a murine experimental model of acute lung injury induced by hemorrhagic shock after blood removal via cardiac puncture. Neutrophil sequestration as shown by immunofluorescence, and protein leakage into the alveolar space, were measured as markers of injury. We used liquid chromatography coupled to tandem mass spectrometry to unequivocally identify several eicosanoids in the bronchoalveolar lavage fluid of experimental animals. MK886, a specific inhibitor of the 5-lipoxygenase pathway, as well as transgenic mice deficient in 5-lipoxygenase, were used to determine the role of this enzymatic pathway in this model. Leukotriene B4 and leukotriene C4 were consistently elevated in shock-treated mice compared to sham-treated mice. MK886 attenuated neutrophil infiltration and protein extravasation induced by hemorrhagic shock. 5-lipoxygenase-deficient mice showed reduced neutrophil infiltration and protein extravasation after shock treatment, indicating greatly reduced lung injury. These results support the hypothesis that 5-lipoxygenase, most likely through the generation of leukotrienes, plays an important role in the pathogenesis of acute lung injury induced by hemorrhagic shock in mice. This pathway could represent a new target for pharmacological intervention to reduce lung damage following severe primary injury. PMID:22392149

  6. Effect of ozone oxidative preconditioning in preventing early radiation-induced lung injury in rats

    Directory of Open Access Journals (Sweden)

    B.H. Bakkal

    2013-09-01

    Full Text Available Ionizing radiation causes its biological effects mainly through oxidative damage induced by reactive oxygen species. Previous studies showed that ozone oxidative preconditioning attenuated pathophysiological events mediated by reactive oxygen species. As inhalation of ozone induces lung injury, the aim of this study was to examine whether ozone oxidative preconditioning potentiates or attenuates the effects of irradiation on the lung. Rats were subjected to total body irradiation, with or without treatment with ozone oxidative preconditioning (0.72 mg/kg. Serum proinflammatory cytokine levels, oxidative damage markers, and histopathological analysis were compared at 6 and 72 h after total body irradiation. Irradiation significantly increased lung malondialdehyde levels as an end-product of lipoperoxidation. Irradiation also significantly decreased lung superoxide dismutase activity, which is an indicator of the generation of oxidative stress and an early protective response to oxidative damage. Ozone oxidative preconditioning plus irradiation significantly decreased malondialdehyde levels and increased the activity of superoxide dismutase, which might indicate protection of the lung from radiation-induced lung injury. Serum tumor necrosis factor alpha and interleukin-1 beta levels, which increased significantly following total body irradiation, were decreased with ozone oxidative preconditioning. Moreover, ozone oxidative preconditioning was able to ameliorate radiation-induced lung injury assessed by histopathological evaluation. In conclusion, ozone oxidative preconditioning, repeated low-dose intraperitoneal administration of ozone, did not exacerbate radiation-induced lung injury, and, on the contrary, it provided protection against radiation-induced lung damage.

  7. Effect of ozone oxidative preconditioning in preventing early radiation-induced lung injury in rats

    Energy Technology Data Exchange (ETDEWEB)

    Bakkal, B.H. [Department of Radiation Oncology, School of Medicine, Bulent Ecevit University, Kozlu, Zonguldak (Turkey); Gultekin, F.A. [Department of General Surgery, School of Medicine, Bulent Ecevit University, Kozlu, Zonguldak (Turkey); Guven, B. [Department of Biochemistry, School of Medicine, Bulent Ecevit University, Kozlu, Zonguldak (Turkey); Turkcu, U.O. [Mugla School of Health Sciences, Mugla Sitki Kocman University, Mugla (Turkey); Bektas, S. [Department of Pathology, School of Medicine, Bulent Ecevit University, Kozlu, Zonguldak (Turkey); Can, M. [Department of Biochemistry, School of Medicine, Bulent Ecevit University, Kozlu, Zonguldak (Turkey)

    2013-09-27

    Ionizing radiation causes its biological effects mainly through oxidative damage induced by reactive oxygen species. Previous studies showed that ozone oxidative preconditioning attenuated pathophysiological events mediated by reactive oxygen species. As inhalation of ozone induces lung injury, the aim of this study was to examine whether ozone oxidative preconditioning potentiates or attenuates the effects of irradiation on the lung. Rats were subjected to total body irradiation, with or without treatment with ozone oxidative preconditioning (0.72 mg/kg). Serum proinflammatory cytokine levels, oxidative damage markers, and histopathological analysis were compared at 6 and 72 h after total body irradiation. Irradiation significantly increased lung malondialdehyde levels as an end-product of lipoperoxidation. Irradiation also significantly decreased lung superoxide dismutase activity, which is an indicator of the generation of oxidative stress and an early protective response to oxidative damage. Ozone oxidative preconditioning plus irradiation significantly decreased malondialdehyde levels and increased the activity of superoxide dismutase, which might indicate protection of the lung from radiation-induced lung injury. Serum tumor necrosis factor alpha and interleukin-1 beta levels, which increased significantly following total body irradiation, were decreased with ozone oxidative preconditioning. Moreover, ozone oxidative preconditioning was able to ameliorate radiation-induced lung injury assessed by histopathological evaluation. In conclusion, ozone oxidative preconditioning, repeated low-dose intraperitoneal administration of ozone, did not exacerbate radiation-induced lung injury, and, on the contrary, it provided protection against radiation-induced lung damage.

  8. Nod样受体蛋白3炎性体抑制剂格列苯脲对机械通气致小鼠急性肺损伤的保护作用%Protective effects of Nod-like receptor protein-3 inflammasome inhibitor glyburide for mouse acute lung injury induced by mechanical ventilation

    Institute of Scientific and Technical Information of China (English)

    吕洲; 董文文; 江来

    2016-01-01

    Objective To investigate whether Nod-like receptor protein-3 (NLRP3) inflammasome inhibitor glyburide exerts protective effects for mouse acute lung injury induced by mechanical ventilation.Methods Twenty-eight male ICR mice were randomly divided into 4 groups:control group (group CON,n=6),glyburide group (group GLY,n=6),mechanical ventilation group (group VEN,n=8),and glyburide+mechanical ventilation group (group GLY+VEN,n=8).The content of protein and inflammatory cell counts in bronchoalveolar lavage fluid were measured after 4 h ventilation,the wet/dry(W/D) and morphopathogical changes of lung tissue were examined.Lung tissues were homogenated to detect the IL-1β,IL-6 and TNF-α levels by ELISA.Results The concentration of protein and cell counts in group VEN [(0.534±±0.104) g/L and (3.4±0.7) ×105/ml] were higher than group CON [(0.167±0.021) g/L and (1.86±0.46) ×105/ml](P<0.01),and those in group GLY+VEN[(0.425±0.083) g/L and (2.4±±0.6) ×105/ml] were lower than group VEN (P<0.05).W/D was higher in group VEN(5.1±0.5) than group CON(4.4±0.4)(P<0.01) and group GLY+VEN(4.7±0.4)(P<0.05).The IL-1β,IL-6 and TNF-α levels in lung tissue were increased in group VEN and group GLY+VEN (P<0.05).The IL-1β and IL-6 levels had significant statistical differences between group GLY+VEN and group VEN (P<0.05).Conclusions Our results indicate that pre-treated with glyburide could significantly attenuate mechanical ventilation-induced recruitment of inflammatory cells and lung edema,which might be attributed to the deactivation of NLRP3 inflammasome.%目的 探究Nod样受体蛋白3(Nod-like receptor protein-3,NLRP3)炎性体抑制剂格列苯脲对机械通气导致的小鼠急性肺损伤是否具有保护作用. 方法 28只7~9周的清洁级ICR雄性小鼠,按完全随机分组法分为4组:对照组(CON组,6只)、格列苯脲组(GLY组,6只)、机械通气组(VEN组,8只)和格列苯脲+机械通气组(GLY+VEN组,8

  9. Lipopolysaccharide-induced Lung Injury Involves the Nitration-mediated Activation of RhoA*

    Science.gov (United States)

    Rafikov, Ruslan; Dimitropoulou, Christiana; Aggarwal, Saurabh; Kangath, Archana; Gross, Christine; Pardo, Daniel; Sharma, Shruti; Jezierska-Drutel, Agnieszka; Patel, Vijay; Snead, Connie; Lucas, Rudolf; Verin, Alexander; Fulton, David; Catravas, John D.; Black, Stephen M.

    2014-01-01

    Acute lung injury (ALI) is characterized by increased endothelial hyperpermeability. Protein nitration is involved in the endothelial barrier dysfunction in LPS-exposed mice. However, the nitrated proteins involved in this process have not been identified. The activation of the small GTPase RhoA is a critical event in the barrier disruption associated with LPS. Thus, in this study we evaluated the possible role of RhoA nitration in this process. Mass spectroscopy identified a single nitration site, located at Tyr34 in RhoA. Tyr34 is located within the switch I region adjacent to the nucleotide-binding site. Utilizing this structure, we developed a peptide designated NipR1 (nitration inhibitory peptide for RhoA 1) to shield Tyr34 against nitration. TAT-fused NipR1 attenuated RhoA nitration and barrier disruption in LPS-challenged human lung microvascular endothelial cells. Further, treatment of mice with NipR1 attenuated vessel leakage and inflammatory cell infiltration and preserved lung function in a mouse model of ALI. Molecular dynamics simulations suggested that the mechanism by which Tyr34 nitration stimulates RhoA activity was through a decrease in GDP binding to the protein caused by a conformational change within a region of Switch I, mimicking the conformational shift observed when RhoA is bound to a guanine nucleotide exchange factor. Stopped flow kinetic analysis was used to confirm this prediction. Thus, we have identified a new mechanism of nitration-mediated RhoA activation involved in LPS-mediated endothelial barrier dysfunction and show the potential utility of “shielding” peptides to prevent RhoA nitration in the management of ALI. PMID:24398689

  10. Lipopolysaccharide-induced lung injury involves the nitration-mediated activation of RhoA.

    Science.gov (United States)

    Rafikov, Ruslan; Dimitropoulou, Christiana; Aggarwal, Saurabh; Kangath, Archana; Gross, Christine; Pardo, Daniel; Sharma, Shruti; Jezierska-Drutel, Agnieszka; Patel, Vijay; Snead, Connie; Lucas, Rudolf; Verin, Alexander; Fulton, David; Catravas, John D; Black, Stephen M

    2014-02-21

    Acute lung injury (ALI) is characterized by increased endothelial hyperpermeability. Protein nitration is involved in the endothelial barrier dysfunction in LPS-exposed mice. However, the nitrated proteins involved in this process have not been identified. The activation of the small GTPase RhoA is a critical event in the barrier disruption associated with LPS. Thus, in this study we evaluated the possible role of RhoA nitration in this process. Mass spectroscopy identified a single nitration site, located at Tyr(34) in RhoA. Tyr(34) is located within the switch I region adjacent to the nucleotide-binding site. Utilizing this structure, we developed a peptide designated NipR1 (nitration inhibitory peptide for RhoA 1) to shield Tyr(34) against nitration. TAT-fused NipR1 attenuated RhoA nitration and barrier disruption in LPS-challenged human lung microvascular endothelial cells. Further, treatment of mice with NipR1 attenuated vessel leakage and inflammatory cell infiltration and preserved lung function in a mouse model of ALI. Molecular dynamics simulations suggested that the mechanism by which Tyr(34) nitration stimulates RhoA activity was through a decrease in GDP binding to the protein caused by a conformational change within a region of Switch I, mimicking the conformational shift observed when RhoA is bound to a guanine nucleotide exchange factor. Stopped flow kinetic analysis was used to confirm this prediction. Thus, we have identified a new mechanism of nitration-mediated RhoA activation involved in LPS-mediated endothelial barrier dysfunction and show the potential utility of "shielding" peptides to prevent RhoA nitration in the management of ALI.

  11. Acute fibrinous and organising pneumonia: a rare histopathological variant of chemotherapy-induced lung injury.

    Science.gov (United States)

    Gupta, Arjun; Sen, Shiraj; Naina, Harris

    2016-04-06

    Bleomycin-induced lung injury is the most common chemotherapy-associated lung disease, and is linked with several histopathological patterns. Acute fibrinous and organising pneumonia (AFOP) is a relatively new and rare histological pattern of diffuse lung injury. We report the first known case of bleomycin-induced AFOP. A 36-year-old man with metastatic testicular cancer received three cycles of bleomycin, etoposide and cisplatin, before being transitioned to paclitaxel, ifosfamide and cisplatin. He subsequently presented with exertional dyspnoea, cough and pleuritic chest pain. CT of the chest demonstrated bilateral ground glass opacities with peribronchovascular distribution and pulmonary function tests demonstrated a restrictive pattern of lung disease with impaired diffusion. Transbronchial biopsy revealed intra-alveolar fibrin deposits with organising pneumonia, consisting of intraluminal loose connective tissue consistent with AFOP. The patient received high-dose corticosteroids with symptomatic and radiographic improvement. AFOP should be recognised as a histopathological variant of bleomycin-induced lung injury.

  12. [Analysis of risk factors of drug-induced lung injury in patients receiving gemcitabine treatment].

    Science.gov (United States)

    Nakamichi, Hidenori; Fujita, Tetsuo; Tsuji, Daiki; Atsumi, Ichiko; Totsuka, Kasumi; Suzuki, Rina; Miki, Yoshihiro; Tomita, Kazuhiro; Nakamura, Hidenori; Shiokawa, Mitsuru

    2012-05-01

    Gemcitabine hydrochloride is a very safe medicine that even outpatients can be administered, and the bone marrow depression that is the dose limiting factor remains moderate and does not need special treatment, although it is confirmed in most cases. Meanwhile, caution is required because there is a possibility of drug-induced lung injury and death due to high frequency, compared with the appearance rate described in the packaging insertion. We investigated the clinical background of a patient in whom drug-induced lung injury appeared, and clarified the risk factor by administering gemcitabine hydrochloride. Males, people aged 65 or over, those with a smoking history and those undergoing first-line chemotherapy treatment are at risk of drug-induced lung injury. Attention must be paid to the occurrence of drug-induced lung injury, to examining the clinical course, the chest image, and the blood test, and to do earlier detection, the offending medicine discontinuance, and beginning of the treatment.

  13. KGFR promotes Na+ channel expression in a rat acute lung injury ...

    African Journals Online (AJOL)

    KGFR promotes Na+ channel expression in a rat acute lung injury model. Binjian Liu1※ ... Recombinant adenovirus (AdEasy-KGFR) was injected via the tail vein. Expression of the ..... alternative for many protein replacement therapies, and.

  14. VEGF Production by Ly6C+high Monocytes Contributes to Ventilator-Induced Lung Injury

    National Research Council Canada - National Science Library

    Shi, Chung-Sheng; Huang, Tzu-Hsiung; Lin, Chin-Kuo; Li, Jhy-Ming; Chen, Mei-Hsin; Tsai, Mei-Ling; Chang, Chih-Ching

    2016-01-01

      Background Mechanical ventilation is a life-saving procedure for patients with acute respiratory failure, although it may cause pulmonary vascular inflammation and leakage, leading to ventilator-induced lung injury (VILI). Ly6C...

  15. The receptor for advanced glycation end products in ventilator-induced lung injury

    NARCIS (Netherlands)

    Kuipers, Maria T; Aslami, Hamid; Tuinman, Pieter Roel; Tuip-de Boer, Anita M; Jongsma, Geartsje; van der Sluijs, Koenraad F; Choi, Goda; Wolthuis, Esther K; Roelofs, Joris Jth; Bresser, Paul; Schultz, Marcus J; van der Poll, Tom; Wieland, Catharina W

    2014-01-01

    BACKGROUND: Mechanical ventilation (MV) can cause ventilator-induced lung injury (VILI). The innate immune response mediates this iatrogenic inflammatory condition. The receptor for advanced glycation end products (RAGE) is a multiligand receptor that can amplify immune and inflammatory responses.

  16. Monoacylglycerol lipase (MAGL inhibition attenuates acute lung injury in mice.

    Directory of Open Access Journals (Sweden)

    Carolina Costola-de-Souza

    Full Text Available Endocannabinoid signaling is terminated by enzymatic hydrolysis, a process that, for 2-Arachidonoylglycerol (2-AG, is mediated by monoacylglycerol lipase (MAGL. The piperidine carbamate, 4-nitrophenyl- 4-(dibenzo[d] [1,3]dioxol-5-yl (hydroxy methyl piperidine- 1-carboxylate (JZL184, is a drug that inhibits MAGL and presents high potency and selectivity. Thus, JZL184 increases the levels of 2-AG, an endocannabinoid that acts on the CB1 and CB2 cannabinoid receptors. Here, we investigated the effects of MAGL inhibition, with a single dose (16 mg/kg, intraperitoneally (i.p. of JZL184, in a murine model of lipopolysaccharide (LPS -induced acute lung injury (ALI 6, 24 and 48 hours after the inflammatory insult. Treatment with JZL184 decreased the leukocyte migration into the lungs as well as the vascular permeability measured through the bronchoalveolar lavage fluid (BAL and histological analysis. JZL184 also reduced the cytokine and chemokine levels in the BAL and adhesion molecule expression in the blood and BAL. The CB1 and CB2 receptors were considered involved in the anti-inflammatory effects of JZL184 because the AM281 selective CB1 receptor antagonist (1-(2,4-dichlorophenyl-5-(4-iodophenyl-4-methyl-N-4-morpholinyl-1H-pyrazole-3-carboxamide and the AM630 selective CB2 receptor antagonist ([6-iodo-2-methyl-1-[2-(4-morpholinylethyl]-1H-indol-3-yl](4-methoxyphenyl-methanone blocked the anti-inflammatory effects previously described for JZL184. It was concluded that MAGL inhibition, and consequently the increase in 2-AG levels, produced anti-inflammatory effects in a murine model of LPS-induced ALI, a finding that was considered a consequence of the activation of the CB1 and CB2 receptors.

  17. 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....

  18. β2 adrenergic agonists in acute lung injury? The heart of the matter

    OpenAIRE

    Lee, Jae W

    2009-01-01

    Despite extensive research into its pathophysiology, acute lung injury/acute respiratory distress syndrome (ALI/ARDS) remains a devastating syndrome with mortality approaching 40%. Pharmacologic therapies that reduce the severity of lung injury in vivo and in vitro have not yet been translated to effective clinical treatment options, and innovative therapies are needed. Recently, the use of β2 adrenergic agonists as potential therapy has gained considerable interest due to their ability to in...

  19. Metabotyping Patients’ Journeys Reveals Early Predisposition to Lung Injury after Cardiac Surgery

    DEFF Research Database (Denmark)

    Maltesen, Raluca; Rasmussen, Bodil Steen; Pedersen, Shona

    2017-01-01

    Cardiovascular disease is the leading cause of death worldwide and patients with severe symptoms undergo cardiac surgery. Even after uncomplicated surgeries, some patients experience postoperative complications such as lung injury. We hypothesized that the procedure elicits metabolic activity...... early, during or just after the end of surgery, may have potential impact in hospitals for the early diagnosis of postoperative lung injury, and for the monitoring of therapeutics targeting disease progression....

  20. APRV Mode in Ventilator Induced Lung Injury (VILI

    Directory of Open Access Journals (Sweden)

    Ata Mahmoodpoor

    2014-01-01

    Full Text Available Ventilator-Induced Lung Injury (VILI, being a significant iatrogenic complication in the ICU patients, is associated with high morbidity and mortality. Numerous approaches, protocols and ventilation modes have been introduced and examined to decrease the incidence of VILI in the ICU patients. Airway pressure release ventilation (APRV, firstly introduced by Stock and Downs in 1987, applies higher Continuous Positive Airway Pressure (CPAP levels in prolonged periods (P and T high in order to preserve satisfactory lung volume and consequently alveolar recruitment. This mode benefits a time-cycled release phase to a lower set of pressure for a short period of time (P and T low i.e. release time (1,2. While some advantages have been introduced for APRV such as efficiently recruited alveoli over time, more homogeneous ventilation, less volutrauma, probable stabilization of patent alveoli and reduction in atelectrauma, protective effects of APRV on lung damage only seem to be substantial if spontaneous breathing responds to more than 30% of total minute ventilation (3. APRV in ARDS patients should be administered cautiously; T low<0.6 seconds, for recruiting collapsed alveoli; however overstretching of alveoli especially during P high should not be neglected and appropriate sedation considered. The proposed advantages for APRV give the impression of being outstanding; however, APRV, as a non-physiologic inverse ratio mode of ventilation, might result in inflammation mainly due to impaired patient-ventilator interaction explaining the negative or minimally desirable effects of APRV on inflammation (4. Consequently, continuous infusion of neuromuscular blocking drugs during ARDS has been reported to reduce mortality (5. There are insufficient confirming data on the superiority of APRV above other ventilatory methods in regard to oxygenation, hemodynamics, regional blood flow, patient comfort and length of mechanical ventilation. Based on current findings

  1. Targeting Neutrophils to Prevent Malaria-Associated Acute Lung Injury/Acute Respiratory Distress Syndrome in Mice

    Science.gov (United States)

    Soeiro-Pereira, Paulo V.; Gomes, Eliane; Neto, Antonio Condino; D' Império Lima, Maria R.; Alvarez, José M.; Portugal, Silvia; Epiphanio, Sabrina

    2016-01-01

    Malaria remains one of the greatest burdens to global health, causing nearly 500,000 deaths in 2014. When manifesting in the lungs, severe malaria causes acute lung injury/acute respiratory distress syndrome (ALI/ARDS). We have previously shown that a proportion of DBA/2 mice infected with Plasmodium berghei ANKA (PbA) develop ALI/ARDS and that these mice recapitulate various aspects of the human syndrome, such as pulmonary edema, hemorrhaging, pleural effusion and hypoxemia. Herein, we investigated the role of neutrophils in the pathogenesis of malaria-associated ALI/ARDS. Mice developing ALI/ARDS showed greater neutrophil accumulation in the lungs compared with mice that did not develop pulmonary complications. In addition, mice with ALI/ARDS produced more neutrophil-attracting chemokines, myeloperoxidase and reactive oxygen species. We also observed that the parasites Plasmodium falciparum and PbA induced the formation of neutrophil extracellular traps (NETs) ex vivo, which were associated with inflammation and tissue injury. The depletion of neutrophils, treatment with AMD3100 (a CXCR4 antagonist), Pulmozyme (human recombinant DNase) or Sivelestat (inhibitor of neutrophil elastase) decreased the development of malaria-associated ALI/ARDS and significantly increased mouse survival. This study implicates neutrophils and NETs in the genesis of experimentally induced malaria-associated ALI/ARDS and proposes a new therapeutic approach to improve the prognosis of severe malaria. PMID:27926944

  2. Lung injury induced by lipopolysaccharides and the dynamic observation on the expression of CD26/CD30

    Institute of Scientific and Technical Information of China (English)

    QING LING YANG; YONG XING DING; CHEN HUA LI; QIAO LING DUAN

    2007-01-01

    To observe the dynamic changes on the bias of.Th1/Th2 responses, the mouse lung injury model was established by injection with lipopolysaccharides (LPS) via tail vein into mice and the levels of CD26+ and CD30+ cells were assayed by flow cytometry in order to determine the differentiation of Th1and Th2 cells as well as the bias of Th1/Th2 responses. It was demonstrated that there was marked increase in the number of CD26+ T cells in the group of mice injected with LPS 7 h after injection in comparison with that of the control mice. The highest and lowest levels of differentiation of the CD26+ T cells occurred at 14 h and 38 h after injection with LPS respectively, and then remained at a lower level. Similarly, the CD30+ T cell differentiation was also increased at 7 h after injection and its peak was observed at 38 h after injection. In addition, all the mice injected with LPS showed definite damage of lung tissues 38 h after injection as revealed from the pathological section examinations. It is concluded from above observations that the bias from the Th1 to Th2 responses and the subsequent suppression of the cell-mediated immunity may be the important cause of the LPS-induced lung injury.

  3. Blockage of P2X7 attenuates acute lung injury in mice by inhibiting NLRP3 inflammasome.

    Science.gov (United States)

    Wang, Shuang; Zhao, Jijun; Wang, Hongyue; Liang, Yingjie; Yang, Niansheng; Huang, Yuefang

    2015-07-01

    NLRP3 inflammasome is engaged in the inflammatory response during acute lung injury (ALI). Purinergic receptor P2X7 has been reported to be upstream of NLRP3 activation. However, the therapeutic implication of P2X7 in ALI remains to be explored. The present study used lipopolysaccharide (LPS)-induced mouse model to investigate the therapeutic potential of P2X7 blockage in ALI. Our results showed that P2X7/NLRP3 inflammasome pathway was significantly upregulated in the lungs of ALI mice as compared with control mice. P2X7 antagonist A438079 suppressed NLRP3/ASC/caspase 1 activation, production of IL-1β, IL-17A and IFN-γ and neutrophil infiltration but not the production of IL-10, resulting in a significant amelioration of lung injury. Moreover, blockage of P2X7 significantly inhibited NLRP3 inflammasome activation and IL-1β production in bone marrow derived macrophages. Similar results were obtained using another P2X7 inhibitor brilliant blue G (BBG) in vivo. Thus, pharmacological blockage of P2X7/NLRP3 pathway can be considered as a potential therapeutic strategy in patients with ALI.

  4. Slit and robo expression in the developing mouse lung.

    Science.gov (United States)

    Greenberg, James M; Thompson, Felisa Y; Brooks, Sherry K; Shannon, John M; Akeson, Ann L

    2004-06-01

    Mammalian lung development is mediated through complex interactions between foregut endoderm and surrounding mesenchyme. As airway branching progresses, the mesenchyme undergoes dramatic remodeling and differentiation. Little is understood about the mechanisms that direct mesenchymal organization during lung development. A screen for candidate genes mediating this process identified Slit, a ligand for the Roundabout (Robo) receptor previously associated with guidance of axonal projections during central nervous system development. Here, we demonstrate by in situ hybridization that two Slit genes (Slit-2 and Slit-3) and two Robo genes (Robo-1 and Robo-2) are expressed in fetal lung mesenchyme. Slit-2 and Robo-1 expression is present throughout mesenchyme at midgestation and is not detectable by newborn day 1. Slit-3 and Robo-2 expression is restricted to specific, complementary subsets of mesenchyme. Robo-2 is expressed in mesenchymal cells immediately adjacent to large airways, whereas Slit-3 expression predominates in mesenchyme remote from airway epithelium. The temporal and spatial distribution of Slit and Robo mRNAs indicate that these genes may direct the functional organization and differentiation of fetal lung mesenchyme.

  5. Corticosteroid treatment ameliorates acute lung injury induced by 2009 swine origin influenza A (H1N1 virus in mice.

    Directory of Open Access Journals (Sweden)

    Chenggang Li

    Full Text Available BACKGROUND: The 2009 influenza pandemic affected people in almost all countries in the world, especially in younger age groups. During this time, the debate over whether to use corticosteroid treatment in severe influenza H1N1 infections patients resurfaced and was disputed by clinicians. There is an urgent need for a susceptible animal model of 2009 H1N1 infection that can be used to evaluate the pathogenesis and the therapeutic effect of corticosteroid treatment during infection. METHODOLOGY/PRINCIPAL FINDINGS: We intranasally inoculated two groups of C57BL/6 and BALB/c mice (using 4- or 6-to 8-week-old mice to compare the pathogenesis of several different H1N1 strains in mice of different ages. Based on the results, a very susceptible 4-week-old C57BL/6 mouse model of Beijing 501 strain of 2009 H1N1 virus infection was established, showing significantly elevated lung edema and cytokine levels compared to controls. Using our established animal model, the cytokine production profile and lung histology were assessed at different times post-infection, revealing increased lung lesions in a time-dependent manner. In additional,the mice were also treated with dexamethasone, which significantly improved survival rate and lung lesions in infected mice compared to those in control mice. Our data showed that corticosteroid treatment ameliorated acute lung injury induced by the 2009 A/H1N1 virus in mice and suggested that corticosteroids are valid drugs for treating 2009 A/H1N1 infection. CONCLUSIONS/SIGNIFICANCE: Using the established, very susceptible 2009 Pandemic Influenza A (H1N1 mouse model, our studies indicate that corticosteroids are a potential therapeutic remedy that may address the increasing concerns over future 2009 A/H1N1 pandemics.

  6. Radiological and functional assessment of radiation-induced lung injury in the rat

    NARCIS (Netherlands)

    Vujaskovic, Z; Down, JD; van t'Veld, AA; Mooyaart, EL; Meertens, H; Piers, DA; Szabo, BG; Konings, AWT

    1998-01-01

    The purpose of this study is to develop an experimental model to measure localized radiation-induced lung injury using multiple end-points including breathing frequency, high-resolution computed tomography (CT), and radionuclide perfusion. The rats were anaesthetized and the right lung irradiated wi

  7. 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 fr

  8. Protective effect of hydrogen sulfide on hyperbaric hyperoxia-induced lung injury in a rat model.

    Science.gov (United States)

    Liu, Wenwu; Liu, Kehuan; Ma, Chunqing; Yu, Jiangang; Peng, Zhaoyun; Huang, Guoyang; Cai, Zhiyu; Li, Runping; Xu, Weigang; Sun, Xuejun; Liu, Kan; Zheng, Juan

    2014-01-01

    Hyperbaric oxygen therapy is one of the most widely used clinical interventions to counteract insufficient pulmonary oxygen delivery in patients with severe lung injury. However, prolonged exposure to hyperoxia leads to inflammation and acute lung injury. This study aimed to investigate the protective effect of hydrogen sulfide on hyperbaric hyperoxia-induced lung injury. Rats were intraperitoneally treated with sodium hydrosulphide (NaHS) at 28 μmol/kg immediately before hyperoxia exposure and then exposed to pure oxygen at 2.5 atmospheres absolute (atm abs) with continuous ventilation for six hours, Immediately after hyperoxia exposure, rats were sacrificed via anesthesia. The bronchoalveolar lavage fluid (BALF) was harvested for the detection of protein concentration and IL-1 content, and the lungs were collected for HE staining, TUNEL staining and detection of wet/dry weight ratio. Our results showed hyperbaric hyperoixa exposure could significantly damage the lung (HE staining), increase the protein and IL-13 in the BALF, elevate the wet/dry Weight ratio and raise the TUNEL positive cells. However, pre-treatment with hydrogen sulfide improved the lung morphology, reduced the TUNEL positive cells and attenuated the lung inflammation (reduction in IL-13 of BALF and HE staining). Taken together, our findings indicate that hydrogen sulfide pretreatment may exert protective effects on hyperbaric hyperoxia-induced lung injury.

  9. Radiological and functional assessment of radiation-induced lung injury in the rat

    NARCIS (Netherlands)

    Vujaskovic, Z; Down, JD; van t'Veld, AA; Mooyaart, EL; Meertens, H; Piers, DA; Szabo, BG; Konings, AWT

    1998-01-01

    The purpose of this study is to develop an experimental model to measure localized radiation-induced lung injury using multiple end-points including breathing frequency, high-resolution computed tomography (CT), and radionuclide perfusion. The rats were anaesthetized and the right lung irradiated

  10. Ischemia of the lung causes extensive long-term pulmonary injury: An experimental study

    NARCIS (Netherlands)

    N.P. van der Kaaij (Niels); J. Kluin (Jolanda); J.J. Haitsma (Jack); M.A. den Bakker (Michael); B.N.M. Lambrecht (Bart); B.F. Lachmann (Burkhard); R.W.F. de Bruin (Ron); A.J.J.C. Bogers (Ad)

    2008-01-01

    textabstractBackground: Lung ischemia-reperfusion injury (LIRI) is suggested to be a major risk factor for development of primary acute graft failure (PAGF) following lung transplantation, although other factors have been found to interplay with LIRI. The question whether LIRI exclusively results in

  11. A review of pulmonary coagulopathy in acute lung injury, acute respiratory distress syndrome and pneumonia

    NARCIS (Netherlands)

    Nieuwenhuizen, Laurens; de Groot, Philip G.; Grutters, Jan C.; Biesma, Douwe H.

    2009-01-01

    Enhanced bronchoalveolar coagulation is a hallmark of many acute inflammatory lung diseases such as acute lung injury, acute respiratory distress syndrome and pneumonia. Intervention with natural anticoagulants in these diseases has therefore become a topic of interest. Recently, new data on the rol

  12. Addition of ulinastatin to preservation solution promotes protection against ischemia-reperfusion injury in rabbit lung

    Institute of Scientific and Technical Information of China (English)

    XU Ming; WEN Xiao-hong; CHEN Shu-ping; AN Xiao-xia; XU He-yun

    2011-01-01

    Background The composition of the lung preservation solution used in lung graft procurement has been considered the key to minimize lung injury during the period of ischemia. Low-potassium dextran glucose (LPDG), an extracellular-type solution, has been adopted by most lung transplantation centers, due to the experimental and clinical evidences that LPDG is superior to intracellular-type solutions. Ulinastatin has been shown to attenuate ischemia-reperfusion (I/R) injury in various organs in animals. We supposed that the addition of ulinastatin to LPDG as a flushing solution, would further ameliorate I/R lung injury than LPDG solution alone.Methods Twelve male New Zealand white rabbits were randomly divided into 2 groups. Using an alternative in situ lung I/R model, the left lung in the control group was supplied and preserved with LPDG solution for 120 minutes. In the study group 50 000 U/kg of ulinastatin was added to the LPDG solution for lung preservation. Then re-ventilation and reperfusion of the left lung were performed for 90 minutes. Blood gas analysis (PaO2, PaCO2), mean pulmonary artery pressure (MPAP) and serum TNF-α level were measured intermittently. The pulmonary water index (D/W), tissue myeloperoxidase (MPO) activity, tissue malondialdehyde (MDA) content and morphologic changes were analyzed.Results The study group showed significantly higher PaO2 and lower MPAP at the end of reperfusion. Serum TNF-α level, left lung tissue MPO and MDA in the study group were significantly lower than those in the control group. D/W and pathologic evaluation were also remarkably different between the two groups.Conclusions This study indicated that better lung preservation could be achieved with the use of an ulinastatin modified LPDG solution. Ulinastatin further attenuated lung I/R injury, at least partly by reducing oxidative reactions,inhibiting the release of inflammatory factors and neutrophils immigration.

  13. Genotoxicity of 3-nitrobenzanthrone and 3-aminobenzanthrone in MutaMouse and lung epithelial cells derived from MutaMouse.

    Science.gov (United States)

    Arlt, Volker M; Gingerich, John; Schmeiser, Heinz H; Phillips, David H; Douglas, George R; White, Paul A

    2008-11-01

    FE1 lung epithelial cells derived from MutaMouse are a new model system to provide in vitro mutagenicity data with the potential to predict the outcome of an in vivo MutaMouse test. 3-Nitrobenzanthrone (3-NBA) is a potent mutagen and suspected human carcinogen identified in diesel exhaust and urban air pollution. We investigated the mutagenicity and DNA binding of 3-NBA and its main metabolite 3-aminobenzanthrone (3-ABA) in vitro and in vivo in the MutaMouse assay. Mice were treated with 3-NBA or 3-ABA (0, 2 or 5 mg/kg body weight/day) by gavage for 28 days and 28 days later lacZ mutant frequency (MF) was determined in liver, lung and bone marrow. For both compounds, dose-related increases in MF were seen in liver and bone marrow, but not in lung; mutagenic activity was approximately 2-fold lower for 3-ABA than for 3-NBA. With 3-NBA, highest DNA adduct levels (measured by (32)P-post-labelling) were found in liver (approximately 230 adducts per 10(8) nucleotides) with levels 20- to 40-fold lower in bone marrow and lung. With 3-ABA, DNA adduct levels were again highest in the liver, but approximately 4-fold lower than for 3-NBA. FE1 cells were exposed to up to 10 microg/ml 3-NBA or 3-ABA for 6 h with or without exogenous activation (S9) and harvested after 3 days. For 3-NBA, there was a dose-related increase in MF both with and without S9 mix, which was >10 times higher than observed in vivo. At the highest concentration of 3-ABA (10 microg/ml), we found only around a 2-fold increase in MF relative to controls. DNA adduct formation in FE1 cells was dose-dependent for both compounds, but 10- to 20-fold higher for 3-NBA compared to 3-ABA. Collectively, our data indicate that MutaMouse FE1 cells are well suited for cost-effective testing of suspected mutagens with different metabolic activation pathways as a guide for subsequent in vivo MutaMouse testing.

  14. Nitric Oxide as a Mediator of Oxidant Lung Injury Due to Paraquat

    Science.gov (United States)

    Berisha, Hasan I.; Pakbaz, Hedayatollah; Absood, Afaf; Said, Sami I.

    1994-08-01

    At low concentrations, nitric oxide is a physiological transmitter, but in excessive concentrations it may cause cell and tissue injury. We report that in acute oxidant injury induced by the herbicide paraquat in isolated guinea pig lungs, nitric oxide synthesis was markedly stimulated, as evidenced by increased levels of cyclic GMP in lung perfusate and of nitrite and L-citrulline production in lung tissue. All signs of injury, including increased airway and perfusion pressures, pulmonary edema, and protein leakage into the airspaces, were dose-dependently attenuated or totally prevented by either N^G-nitro-L-arginine methyl ester or N^ω-nitro-L-arginine, selective and competitive inhibitors of nitric oxide synthase. Protection was reversed by excess L-arginine but not by its enantiomer D-arginine. When blood was added to the lung perfusate, the paraquat injury was moderated or delayed as it was when paraquat was given to anesthetized guinea pigs. The rapid onset of injury and its failure to occur in the absence of Ca2+ suggest that constitutive rather than inducible nitric oxide synthase was responsible for the stimulated nitric oxide synthesis. The findings indicate that nitric oxide plays a critical role in the production of lung tissue injury due to paraquat, and it may be a pathogenetic factor in other forms of oxidant tissue injury.

  15. BIIL 284 reduces neutrophils numbers but increases P. aeruginosa bacteraemia and inflammation in mouse lungs

    Science.gov (United States)

    Döring, Gerd; Bragonzi, Alessandra; Paroni, Moira; Aktürk, Firdevs-Fatma; Cigana, Cristina; Schmidt, Annika; Gilpin, Deirdre; Heyder, Susanne; Born, Torsten; Smaczny, Christina; Kohlhäufl, Martin; Wagner, Thomas O. F.; Loebinger, Michael R.; Bilton, Diana; Tunney, Michael M.; Elborn, J. Stuart; Pier, Gerald B.; Konstan, Michael W.; Ulrich, Martina

    2014-01-01

    Background A clinical study to investigate the leukotriene B4 (LTB4)-receptor antagonist BIIL 284 in cystic fibrosis (CF) patients was prematurely terminated due to a significantly increased risk of adverse pulmonary events. We aimed to establish the effect of BIIL284 in models of Pseudomonas aeruginosa lung infection, thereby contributing to a better understanding of what could have led to adverse pulmonary events in CF patients. Methods P. aeruginosa DNA in the blood of CF patients during and after acute pulmonary exacerbations and in stable patients with non-CF bronchiectasis (NCFB) and healthy individuals was assessed by PCR. The effect of BIIL 284 treatment was tested in an agar beads murine model of Pseudomonas aeruginosa lung infection. Bacterial count and inflammation were evaluated in lung and other organs. Result Most CF patients (98%) and all patients with NCFB and healthy individuals had negative P. aeruginosa DNA in their blood. Similarly, the P. aeruginosa-infected mice showed bacterial counts in the lung but not blood or spleen. BIIL 284 treatment decreased pulmonary neutrophils and increased P. aeruginosa numbers in mouse lungs leading to significantly higher bacteremia rates and lung inflammation compared to placebo treated animals. Conclusions Decreased airway neutrophils induced lung proliferation and severe bacteraemia in a murine model of P. aeruginosa lung infection. These data suggest that caution should be taken when administering anti-inflammatory compounds to patients with bacterial infections. PMID:24183915

  16. Transfusion-related acute lung injury risk mitigation: an update.

    Science.gov (United States)

    Otrock, Z K; Liu, C; Grossman, B J

    2017-09-25

    Transfusion-related acute lung injury (TRALI) is a life-threatening complication of transfusion. Greater understanding of the pathophysiology of this syndrome has much improved during the last two decades. Plasma-containing components from female donors with leucocyte antibodies were responsible for the majority of TRALI fatalities before mitigation strategies were implemented. Over the past 15 years, measures to mitigate risk for TRALI have been implemented worldwide and they continued to evolve with time. The AABB requires that all plasma containing components and whole blood for transfusion must be collected from men, women who have not been pregnant, or women who have tested negative for human leucocyte antigen antibodies. Although the incidence of TRALI has decreased following the institution of TRALI mitigation strategies, TRALI is still the most common cause of transfusion-associated death in the United States. In this review, we focus on TRALI risk mitigation strategies. We describe the measures taken by blood collection facilities to reduce the risk of TRALI in the United States, Canada and European countries. We also review the literature for the effectiveness of these measures. © 2017 International Society of Blood Transfusion.

  17. Ameliorative effect of Leflunomide on lung injury following an aspiration.

    Science.gov (United States)

    Yilmaz, M Z; Torun, A C; Guzel, A; Murat, N; Okuyucu, A; Yilmaz, N; Gacar, A; Guvenc, T; Guzel, A

    2015-01-01

    We aimed to investigate the therapeutic effectiveness of leflunomide (LEF) in lung injury after an aspiration of unknown pathophysiology. Forty-two healthy Sprague Dawley rats were anesthetized and allocated to six experimental groups: saline (S) aspirated, S+LEF, hydrochloric acid (HCl) aspirated, HCl+LEF, formula aspirated (FOR), and FOR+LEF. The treatment groups (S+LEF, HCl+LEF, and FOR+LEF) received 20 mg/kg/day intraperitoneal (i.p.) injection of LEF for seven days. At the end of the seven days, blood and tissue samples were taken from the rats for histopathological, biochemical, and immunohistochemical examination. There was a significant increase in serum levels of YKL-40, a chitinase-like protein, in the HCl group after the aspiration (pacid-reactive species (TBARS) values in the HCl and FOR groups compared to the control group (p=0.001 and p<0.01, respectively). In both treatment groups, the serum TBARS values significantly decreased after treatment with LEF (p=0.001 and p<0.05, respectively). There was a significant improvement in the histopathological scores, which deteriorated after the aspiration, and in the number of inducible nitric oxide synthase (iNOS)-positive cells after treatment with LEF.

  18. Stable Somatic Gene Expression in Mouse Lungs Following Electroporation-mediated Tol2 Transposon Delivery.

    Science.gov (United States)

    Muliawan, Hary Sakti; Nakayama, Kazuhiko; Yagi, Keiko; Ikeda, Koji; Yagita, Kazuhiro; Hirata, Ken-ichi; Emoto, Noriaki

    2015-10-07

    Gene delivery to the lung has rapidly progressed as an important method for studying various chronic lung diseases. Viral vectors, albeit highly efficient, are limited by the host immune response. Electroporation, a well-known non-viral method, can efficiently deliver genes to the lung, but is unable to induce stable gene expression. The Tol2 transposon is another non-viral method that can induce stable gene expression by reinserting its genes into the host genome. In this study, we combined electroporation and Tol2 transposons to obtain stable, high-level gene expression in the mouse lung. Tol2 transposon plasmids (pT2A-EGFP; Tol2, pCAGGS-TP; transposase) were optimized in vitro, and the electroporation procedure (pCAG-EGFP) was optimized in mouse lungs. After optimization, a combination of electroporation plus the Tol2 transposon was used in a comparative analysis with electroporation plus pCAG-EGFP. GFP expression levels were quantified and visualized on days 4 and 7 post-electroporation. We successfully reproduced the Tol2 transposon system in vitro and the electroporation procedure in vivo. We observed sustainable GFP expression using electroporation plus the Tol2 transposon on days 4 and 7, while electroporation plus pCAG-EGFP resulted in decreased GFP expression on day 7. We were able to induce high-level, stable gene expression in mouse lungs using a combination of electroporation and the Tol2 transposon. This represents a safer method for lung gene delivery that can be used as an alternative to viral vectors.

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

    Directory of Open Access Journals (Sweden)

    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

  20. Penetrating injury of the lungs and multiple injuries of lower extremities caused by aircraft bombs splinters

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    Golubović Zoran

    2010-01-01

    Full Text Available Introduction. Injuries caused by aircraft bombs cause severe damages to the human body. They are characterized by massive destruction of injured tissues and organs, primary contamination by polymorph bacterial flora and modified reactivity of the body. Upon being wounded by aircraft bombs projectiles a victim simultaneously sustains severe damages of many organs and organ systems due to the fact that a large number of projectiles at the same time injure the chest, stomach, head and extremities. Case report. We presented a patient, 41 years of age, injured by aircraft bomb with hemo-pneumothorax and destruction of the bone and soft tissue structures of the foot, as well as the treatment result of such heavy injuries. After receiving thoracocentesis and short reanimation, the patient underwent surgical procedure. The team performed thoracotomy, primary treatment of the wound and atypical resection of the left lung. Thoracic drains were placed. The wounds on the lower leg and feet were treated primarily. Due to massive destruction of bone tissue of the right foot by cluster bomb splinters, and impossibility of reconstruction of the foot, guillotine amputation of the right lower leg was performed. Twelve days after the wounding caused by cluster bomb splinters, soft tissue of the left lower leg was covered by Tirsch free transplantant and the defect in the area of the left foot was covered by dorsalis pedis flap. The transplant and flap were accepted and the donor sites were epithelized. Twenty-six days following the wounding reamputation was performed and amputation stump of the right lower leg was closed. The patient was given a lower leg prosthesis with which he could move. Conclusion. Upon being wounded by aircraft bomb splinters, the injured person sustains severe wounds of multiple organs and organ systems due to simultaneous injuries caused by a large number of projectiles. It is necessary to take care of the vital organs first because they

  1. Mechanical ventilation enhances lung inflammation and caspase activity in a model of mouse pneumovirus infection

    NARCIS (Netherlands)

    R.A. Bem; J.B.M. van Woensel; A.P. Bos; A. Koski; A.W. Farnand; J.B. Domachowske; H.F. Rosenberg; T.R. Martin; G. Matute-Bello

    2009-01-01

    Severe infection with respiratory syncytial virus (RSV) in children can progress to respiratory distress and acute lung injury (ALI). Accumulating evidence suggests that mechanical ventilation (MV) is an important cofactor in the development of ALI by modulating the host immune responses to bacteria

  2. [Diagnostics of lung contusion in patients with thoracic closed injury and prophylaxis of complications].

    Science.gov (United States)

    Rachko, Iu V

    2007-01-01

    Among 304 patients hospitalised with thorax closed injury 205 patients had lung contusion. The use of a complex diagnostics allowed to discharge 176 patients without any complications. The development of complections was observed in 128 patients, which occurred after the patients had had their injuries. Application of endoscopic sanation and treatment allowed to discharge patients in early terms.

  3. DEPLETION OF IRON AND ASCORBATE IN RODENTS DIMINISHES LUNG INJURY AFTER SILICA

    Science.gov (United States)

    Exposures of the lung to iron chelates can be associated with an injury. The catalysis of oxygen-based free radicals is postulated to participate in this injury. Such oxidant generation by mineral oxide particles can be dependent on availability of both iron and a reductant. We t...

  4. Molecular pathogenesis of transplacentally induced mouse lung tumors.

    Science.gov (United States)

    Miller, M S; Leone-Kabler, S; Rollins, L A; Wessner, L L; Fan, M; Schaeffer, D O; McEntee, M F; O'Sullivan, M G

    1998-01-01

    Previous studies from this and other laboratories have shown that treatment of pregnant mice with 3-methylcholanthrene (MC) caused lung tumors in the offspring, the incidence of which correlated with fetal inducibility of Cyp1a1. Analysis of paraffin-embedded lung tissue for Ki-ras-2 mutations indicated that 79% of the lesions examined contained point mutations in codons 12 and 13 of the Ki-ras-2 gene locus, the majority of which (84%) were G-->T transversions. The mutational spectrum was dependent on the tumor stage, as both the incidence of mutation and type of mutation produced correlated with malignant progression of the tumor. Mutations occurred in 60% of the hyperplasias, 80% of the adenomas, and 100% of the adenocarcinomas. In the tumors with mutations, GLY12-->CYS12 transversions occurred in 100% of the hyperplasias, 42% of the adenomas, and 14% of the adenocarcinomas. GLY12-->VAL12 transversions were not observed in hyperplasias and occurred in 42% of the adenomas and 57% of the adenocarcinomas. The remaining ASP12 and ARG13 mutations occurred only in adenomas (17%) and adenocarcinomas (29%). The tumors were also analyzed for alterations in the structure or function of the tumor suppressor genes Rb, p53, and Cdkn2a. No mutations were observed in exons 5-8 of the p53 gene. SSCP analysis demonstrated that 2 of 15 lung tumors contained shifted bands at the Cdkn2a gene locus. Sequence analysis had identified these as mutations in exon 2, with a CAC-->TAC transition at base 301 (HIS74-->TYR74) in tumor 23-1 and GGG-->GAG transition at base 350 (GLY90-->GLU90) in tumor 36-1. Northern blot analysis of the larger tumors revealed that 14 of 14 of these large lung tumors exhibited markedly decreased expression of Rb gene transcripts. These results were confirmed by immunohistochemistry. The larger tumors, which exhibited features of adenocarcinomas, showed a marked reduction or almost complete absence of nuclear pRb staining compared with smaller adenomas and normal

  5. Effects of Glycyrrhizin in a Mouse Model of Lung Adenocarcinoma

    Directory of Open Access Journals (Sweden)

    Qing-Ping Deng

    2017-03-01

    Full Text Available Background: Currently, there is a global attempt to identify potential anti-cancer agents with low toxicity. Previous studies have found that glycyrrhizin exerts anti-cancer action with low toxicity through suppressing thromboxane A2 (TxA2 in lung cancer cell lines. However, these effects have not yet been determined in animal models of lung cancer. Methods: Human lung adenocarcinoma xenografts were established in nude mice by the introduction of A549 cells with stable transfection of the TxA2 receptor (TPα. The animal model was confirmed by the hematoxylin and eosin (H&E method. Tumor-bearing mice were then administered graded concentrations of glycyrrhizin, cisplatin or both. After the treatments, body weights of all animals were recorded, and immunohistochemistry staining of lung tissues and serum biochemistry detection of aspartate amino transferase (AST, alanine amino transferase (ALT, urea and creatinine were carried out. Results: Treatment with glycyrrhizin alone or the combination of cisplatin and glycyrrhizin profoundly reduced expression of thromboxane synthase (TxAS as well as proliferating cell nuclear antigen (PCNA, recovered the body weight, and rescued damage of liver and kidney in tumor-bearing mice. Although it inhibited PCNA expression, cisplatin could not significantly suppress TxAS expression. Because of a positive feedback loop between TPα and TxAS, the effects of glycyrrhizin are possibly attributable to the suppression of the TxA2 pathway. Conclusions: This study provides in vivo evidence to support glycyrrhizin as a potential candidate for developing new regimens to overcome tumor progression and the resistance and toxicity of cisplatin.

  6. Retention of human bone marrow-derived cells in murine lungs following bleomycin-induced lung injury.

    Science.gov (United States)

    Liebler, Janice M; Lutzko, Carolyn; Banfalvi, Agnes; Senadheera, Dinithi; Aghamohammadi, Neema; Crandall, Edward D; Borok, Zea

    2008-08-01

    We studied the capacity of adult human bone marrow-derived cells (BMDC) to incorporate into distal lung of immunodeficient mice following lung injury. Immunodeficient NOD/SCID and NOD/SCID/beta(2) microglobulin (beta(2)M)(null) mice were administered bleomycin (bleo) or saline intranasally. One, 2, 3 and 4 days after bleo or saline, human BMDC labeled with CellTracker Green CMFDA (5-chloromethylfluorescein diacetate) were infused intravenously. Retention of CMFDA(+) cells was maximal when delivered 4 days after bleo treatment. Seven days after bleo, cells from NOD/SCID mice were CMFDA(+), which increased 10- to 100-fold in NOD/SCID/beta(2)M(null) mice. Preincubation of BMDC with Diprotin A, a reversible inhibitor of CD26 peptidase activity that enhances the stromal-derived factor-1 (SDF-1/CXCL12)/CXCR4 axis, resulted in a 30% increase in the percentage of CMFDA(+) cells retained in the lung. These data indicate that human BMDC can be identified in lungs of mice following injury, albeit at low levels, and this may be modestly enhanced by manipulation of the SDF-1/CXCR4 axis. Given the overall low number of human cells detected, methods to increase homing and retention of adult BMDC, and consideration of other stem cell populations, will likely be required to facilitate engraftment in the treatment of lung injury.

  7. Experimental study of acute lung injury induced by different tidal volume ventilation in rats

    Institute of Scientific and Technical Information of China (English)

    ZHANG Xin-ri; DU Yong-cheng; JIANG Hong-ying; XU Jian-ying; XU Yong-jian

    2005-01-01

    @@ Mechanical ventilation (MV) is a dual blade sward which if misused could lead to lung injury, called ventilator induced lung injury (VILI). Pathogenesis of VILI is very complex with various manifestations, which is the focus in MV field in recent years.1 In our research, the rats were ventilated with different tidal volume, then the pathological changes of the lungs were observed under macroscopy, light and electronic microscope, and various laboratory tests in blood and bronchoalveolar lavage fluid (BALF) were also carried out in order to probe further the pathologic characteristics and the pathogenesis of VILI.

  8. microRNA expression in the aging mouse lung

    Directory of Open Access Journals (Sweden)

    Moschos Sterghios A

    2007-06-01

    Full Text Available Abstract Background MicroRNAs (miRNAs are a novel class of short double stranded RNA that mediate the post-transcriptional regulation of gene expression. Previous studies have implicated changes in miRNA expression in the regulation of development and the induction of diseases such as cancer. However, although miRNAs have been implicated in the process of aging in C. elegans, nothing is known of their role in mammalian tissues. Results To address this question, we have used a highly-sensitive, semi-quantitative RT-PCR based approach to measure the expression profile of 256 of the 493 currently identified miRNAs in the lungs from 6 month (adult and 18 month (aged old female BALB/c mice. We show that, despite the characteristic changes in anatomy and gene expression associated with lung aging, there were no significant changes in the expression of 256 miRNAs. Conclusion Overall, these results show that miRNA transcription is unchanged during lung aging and suggests that stable expression of miRNAs might instead buffer age related changes in the expression of protein-encoding genes.

  9. Upregulation of Shh and Ptc1 in hyperoxia‑induced acute lung injury in neonatal rats.

    Science.gov (United States)

    Dang, Hongxing; Wang, Shaohua; Yang, Lin; Fang, Fang; Xu, Feng

    2012-08-01

    The aim of the present study was to observe the expression of sonic hedgehog (Shh) and Ptc signaling molecules in the lungs of newborn rats exposed to prolonged hyperoxia, and to explore the role of the SHH signaling pathway in hyperoxia‑induced lung injury. Newborn Sprague-Dawley rat pups were placed in chambers containing room air or oxygen above 95% for 14 days following birth. The rats were sacrificed after 3, 7 or 14 days and their lungs were removed. Sections were fixed and subjected to hematoxylin and eosin (H&E) staining. Shh and Ptc1 were quantitated by immunohistochemistry. The total RNA and protein were also extracted from lung tissue; real-time PCR (RT-PCR) and western blot analysis were utilized to assess the mRNA and protein expression of Shh and Ptc1. H&E staining demonstrated significant histomorphological changes in the hyperoxia‑exposed lungs at 3, 7 and 14 days of age. The results of the immunohistochemistry, RT-PCR and western blot analysis demonstrated that the expression of Shh was significantly higher in the hyperoxia-exposed lungs at 3, 7 and 14 days, while Ptc1 was significantly elevated at 7 and 14 days. Exposure of the neonatal rat lung to prolonged hyperoxia resulted in acute lung injury and histomorphological changes. Shh and Ptc1 were upregulated in a time-dependent manner in the course of hyperoxia-induced lung injury. The SHH signal pathway may be involved in the pathogenesis of hyperoxia-induced lung injury. This is the first evidence that in vivo hyperoxia induces activation of the SHH signal transduction pathway in newborn lung.

  10. Protective Effect of Genistein on Lipopolysaccharide-induced Acute Lung Injury in Rats

    Institute of Scientific and Technical Information of China (English)

    LI Xingwang; XU Tao; LIAN Qingquan; ZENG Bangxiong; ZHANG Bing; XIE Yubo

    2005-01-01

    To investigate the protective effect of genistein on endotoxin-induced acute lung injury in rats, and explore the underlying mechanisms, 32 male Sprague-Dawley rats were randomly divided into 4 experimental groups: saline control, genistein alone, lipopolysaccaride alone, and genistein pretreatment. Each treatment group consisted of eight animals. Animals were observed for 6 h after LPS challenge, and the wet/dry (W/D) weight ratio of the lung and bronchoalveolar lavage fluid(BALF) protein content were used as a measure of lung injury. Neutrophil recruitment and activation were evaluated by BALF cellularity and myeloperoxidase (MPO) activity. RT-PCR analysis was performed in lung tissue to assess gene expression of ICAM-1. The histopathological changes were also observed using the HE staining of lung tissue. Our results showed that lung injury parameters, including the wet/dry weight ratio and protein content in BALF, were significantly higher in the LPS alone group than in the saline control group (P<0.01). In the LPS alone group, a larger number of neutrophils and greater MPO activity in cell-free BAL and lung homogenates were observed when compared with the saline control group (P<0.01). There was a significant increase in lung ICAM-1 mRNA in response to LPS challenge (P< 0. 01, group L versus group S).Genistein pretreatment significantly attenuated LPS-induced changes in these indices. LPS caused extensive lung damage, which was also lessened after genistein pretreatment. All above-mentioned parameters in the genistein alone group were not significantly different from those of the saline control group. It is concluded that genistein pretreatment attenuated LPS-induced lung injury in rats.This beneficial effect of genistein may involves, in part, an inhibition of neutrophilic recruitment and activity, possibly through an inhibition of lung ICAM-1 expression.

  11. Study on the inflammatory injury of lung tissue and influence on inflammatory cytokines in mouse induced by recombinant protein CPAF from Chlamydophila pneumoniae%肺炎嗜衣原体CPAF重组蛋白致小鼠肺组织炎症及对炎症细胞因子的影响

    Institute of Scientific and Technical Information of China (English)

    王华丽; 吴移谋; 郑江花; 朱翠明; 李忠玉; 周洲; 余敏君

    2011-01-01

    Escherichia coli . The punfied recombinant GST-CPAFm protein was instilled into anterior nose or injected into the caudal vein of BALB /c mice 3 times on the day 1 ,3 and 6 .On the day 7 ,the mice were killed. Pathological alteration was observed by hematoxylin and eosin staining .The total white blood cells of peripheral blood and bronchoalveolar lavage fluid (BALF ) was counted with blood cell counting plate ,and the concentration of TNF-α and IL-6 in both plasma and BALF was detected by Enzyme-linked immunoadsordent assay technique .Results : (1 ) Histological examination showed a marked inflammatory immune responses in the mouse lung tissues after intranasal application or intravenous injection of 100μg GST-CPAFm and there were obvious leukocyte infiltration ,such as neutrophils ,lymphocytes and macrophages in bronchiole and perivascular .There were no obvious pathological changes in the control and normal group BALB /c. mice . (2 ) The percentage of peripheral blood neutrophils in GST-CPAFm intravenously group was significantly higher than that of the GST group ( P< 0 .05 ) , PBS group ( P< 0 .05 ) and normal group ( P<0 .01) .(3) The level of inflammatory cytokines IL-6 of the peripheral blood in GST-CPAFm intranasally group was significantly higher than that of the GST group ( P<0 .01 ) ,PBS group ( P<0 .01 ) and normal group ( P<0 .01 ) ,and the level of imflammatory cytokines TNF-∝ were significantly higher than in the GST group ( P<0 .05 ) ,PBS group ( P<0 .01) and normal group ( P<0 .01) ;and the level of inflammatory cytokines IL-6 in GST-CPAFm intravenously group was significantly higher than that of the GST group ( P<0 .01) , PBS group ( P< 0 .01) and normal group P< 0 .01 ) .(4 ) The level of inflammatory cytokines IL-6 and TNF-α of BALF in GST-CPAFm intranasally group were significantly higher than that of the GST ,PBS and normal group ( P< 0.01 ) ;and the level of inflammatory cytokines IL-6 and TNF-α of BALF in GST

  12. Leptin attenuates lipopolysaccharide or oleic acid-induced acute lung injury in mice.

    Science.gov (United States)

    Dong, Hai-Ying; Xu, Min; Ji, Zhen-Yu; Wang, Yan-Xia; Dong, Ming-Qing; Liu, Man-Ling; Xu, Dun-Quan; Zhao, Peng-Tao; Liu, Yi; Luo, Ying; Niu, Wen; Zhang, Bo; Ye, Jing; Li, Zhi-Chao

    2013-12-01

    Leptin is reported to be involved in acute lung injury (ALI). However, the role and underlying mechanisms of leptin in ALI remain unclear. The aim of this study was to determine whether leptin deficiency promoted the development of ALI. LPS or oleic acid (OA) were administered to wild-type and leptin deficient (ob/ob) mice to induce ALI. Leptin level, survival rate, and lung injury were examined. Results showed that leptin levels were predominantly increased in the lung, but also in the heart, liver, kidney, and adipose tissue after LPS adminiatration. Compared with wild-type mice, LPS- or OA-induced lung injury was worse and the survival rate was lower in ob/ob mice. Moreover, leptin deficiency promoted the release of proinflammatory cytokines. Exogenous administration of leptin reduced lethality in ob/ob mice and ameliorated lung injury partly through inhibiting the activation of NF-κB, p38, and ERK pathways. These results indicated that leptin deficiency contributed to the development of lung injury by enhancing inflammatory response, and a high level of leptin improved survival and protected against ALI.

  13. beta2 adrenergic agonists in acute lung injury? The heart of the matter.

    Science.gov (United States)

    Lee, Jae W

    2009-01-01

    Despite extensive research into its pathophysiology, acute lung injury/acute respiratory distress syndrome (ALI/ARDS) remains a devastating syndrome with mortality approaching 40%. Pharmacologic therapies that reduce the severity of lung injury in vivo and in vitro have not yet been translated to effective clinical treatment options, and innovative therapies are needed. Recently, the use of beta2 adrenergic agonists as potential therapy has gained considerable interest due to their ability to increase the resolution of pulmonary edema. However, the results of clinical trials of beta agonist therapy for ALI/ARDS have been conflicting in terms of benefit. In the previous issue of Critical Care, Briot and colleagues present evidence that may help clarify the inconsistent results. The authors demonstrate that, in oleic acid lung injury in dogs, the inotropic effect of beta agonists may recruit damaged pulmonary capillaries, leading to increased lung endothelial permeability.

  14. Piperine Ameliorates Lipopolysaccharide-Induced Acute Lung Injury via Modulating NF-κB Signaling Pathways.

    Science.gov (United States)

    Lu, Ying; Liu, Jingyao; Li, Hongyan; Gu, Lina

    2016-02-01

    Piperine, one of the active components of black pepper, has been reported to have antioxidant and anti-inflammatory activities. However, the effects of piperine on lipolysaccharide (LPS)-induced acute lung injury (ALI) have not been reported. Thus, the protective effects of piperine against LPS-induced ALI were investigated in this study. LPS-induced lung injury was assessed by histological study, myeloperoxidase (MPO) activity, and inflammatory cytokine production. Our results demonstrated that piperine attenuated LPS-induced MPO activity, lung edema, and inflammatory cytokines TNF-α, IL-6, and IL-1β production. Histological studies showed that piperine obviously attenuated LPS-induced lung injury. In addition, piperine significantly inhibited LPS-induced NF-κB activation. In conclusion, our results demonstrated that piperine had a protective effect on LPS-induced ALI. The anti-inflammatory mechanism of piperine is through inhibition of NF-κB activation. Piperine may be a potential therapeutic agent for ALI.

  15. The value of nitrogen washout/washin method in assessing alveolar recruitment volume in acute lung injury patients

    Institute of Scientific and Technical Information of China (English)

    李洋

    2013-01-01

    Objective To evaluate the precision and feasibility of nitrogen washout/washin method in assessing lung recruitment of acute lung injury(ALI)patients.Methods Fifteen ALI patients underwent mechanical ventilation

  16. Role of NLRP3 inflammasomes in lung injury induced by gut hypoxic stress and its mechanism

    Directory of Open Access Journals (Sweden)

    Shi-qiang XIONG

    2015-01-01

    Full Text Available Hypoxic stress of the gut may induce impairment of gut barrier function, ensuing translocation of gutderived factors which can damage the function of remote organs, especially the development of acute lung injury (ALI. High altitude pulmonary edema (HAPE is a non-cardiogenic pulmonary injury caused by hypoxia, while inflammation involved in the pathogenesis of HAPE has been gradually recognized. It has been also recognized that the cleavage and maturation of proinflammatory cytokines mediated by NLRP3 inflammasome play a crucial role in the pathogenesis of lung injury. Further investigation on the role of NLRP3 inflammasome in lung injury induced by gut hypoxic stress is of an important clinical significance for further improvement in the treatment of hypoxic inflammatory diseases. DOI: 10.11855/j.issn.0577-7402.2014.11.14

  17. Antenatal and postnatal corticosteroid and resuscitation induced lung injury in preterm sheep

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    Kallapur Suhas G

    2009-12-01

    Full Text Available Abstract Background Initiation of ventilation using high tidal volumes in preterm lambs causes lung injury and inflammation. Antenatal corticosteroids mature the lungs of preterm infants and postnatal corticosteroids are used to treat bronchopulmonary dysplasia. Objective To test if antenatal or postnatal corticosteroids would decrease resuscitation induced lung injury. Methods 129 d gestational age lambs (n = 5-8/gp; term = 150 d were operatively delivered and ventilated after exposure to either 1 no medication, 2 antenatal maternal IM Betamethasone 0.5 mg/kg 24 h prior to delivery, 3 0.5 mg/kg Dexamethasone IV at delivery or 4 Cortisol 2 mg/kg IV at delivery. Lambs then were ventilated with no PEEP and escalating tidal volumes (VT to 15 mL/kg for 15 min and then given surfactant. The lambs were ventilated with VT 8 mL/kg and PEEP 5 cmH20 for 2 h 45 min. Results High VT ventilation caused a deterioration of lung physiology, lung inflammation and injury. Antenatal betamethasone improved ventilation, decreased inflammatory cytokine mRNA expression and alveolar protein leak, but did not prevent neutrophil influx. Postnatal dexamethasone decreased pro-inflammatory cytokine expression, but had no beneficial effect on ventilation, and postnatal cortisol had no effect. Ventilation increased liver serum amyloid mRNA expression, which was unaffected by corticosteroids. Conclusions Antenatal betamethasone decreased lung injury without decreasing lung inflammatory cells or systemic acute phase responses. Postnatal dexamethasone or cortisol, at the doses tested, did not have important effects on lung function or injury, suggesting that corticosteroids given at birth will not decrease resuscitation mediated injury.

  18. Reproduction and evaluation of a rat model of inhalation lung injury caused by black gunpowder smog

    Directory of Open Access Journals (Sweden)

    Yi-fan LIU

    2013-09-01

    Full Text Available Objective To reproduce and evaluate a rat model of inhalation lung injury caused by black gunpowder smog. Methods The smog composition was analyzed and a rat model of inhalation lung injury was reproduced. Forty two healthy male Wistar rats were randomly divided into normal control (NC group and 1h, 2h, 6h, 24h, 48h and 96h after inhalation group (n=6. The arterial blood gas, wet to dry weight ratio (W/D of lung, leukocyte count, and protein concentration in broncho-alveolar lavage fluid (BALF were determined. Macroscopic and microscopic changes in lung tissue were observed. Results The composition of black gunpowder smog was composed mainly of CO2 and CO, and their concentrations remained stable within 12 minutes. Smog inhalation caused a significant hypoxemia, the concentration of blood COHb reached a peak value 1h, and the W/D of lung reached peak value 2h after inhalation (P<0.05. The amount of leukocytes and content of protein in BALF increased significantly within 24h after inhalation (P<0.05. Histopathological observation showed diffuse hemorrhage, edema and inflammatory cell infiltration in lung tissue as manifestations of acute lung injury, and the injury did not recover at 96h after inhalation. Conclusion The rat model of inhalation lung injury can be reproduced using black gunpowder smog, and it has the advantages of its readiness for reproduction, reliability and stability, and it could be used for the experiment of inhalation injury in a battlefield environment.

  19. Neutrophils as early immunologic effectors in hemorrhage- or endotoxemia-induced acute lung injury.

    Science.gov (United States)

    Abraham, E; Carmody, A; Shenkar, R; Arcaroli, J

    2000-12-01

    Acute lung injury is characterized by accumulation of neutrophils in the lungs, accompanied by the development of interstitial edema and an intense inflammatory response. To assess the role of neutrophils as early immune effectors in hemorrhage- or endotoxemia-induced lung injury, mice were made neutropenic with cyclophosphamide or anti-neutrophil antibodies. Endotoxemia- or hemorrhage-induced lung edema was significantly reduced in neutropenic animals. Activation of the transcriptional regulatory factor nuclear factor-kappaB after hemorrhage or endotoxemia was diminished in the lungs of neutropenic mice compared with nonneutropenic controls. Hemorrhage or endotoxemia was followed by increases in pulmonary mRNA and protein levels for interleukin-1beta (IL-1beta), macrophage inflammatory protein-2 (MIP-2), and tumor necrosis factor-alpha (TNF-alpha). Endotoxin-induced increases in proinflammatory cytokine expression were greater than those found after hemorrhage. The amounts of mRNA or protein for IL-1beta, MIP-2, and TNF-alpha were significantly lower after hemorrhage in the lungs of neutropenic versus nonneutropenic mice. Neutropenia was associated with significant reductions in IL-1beta and MIP-2 but not in TNF-alpha expression in the lungs after endotoxemia. These experiments show that neutrophils play a central role in initiating acute inflammatory responses and causing injury in the lungs after hemorrhage or endotoxemia.

  20. Quantification of Lung Metastases from In Vivo Mouse Models.

    Science.gov (United States)

    Chang, Joan; Erler, Janine T

    2016-01-01

    Cancer research has made significant progress in terms of understanding and targeting primary tumors; however, the challenge remains for the successful treatment of metastatic cancers. This highlights the importance to use in vivo models to study the metastatic process, as well as for preclinical testing of compounds that could inhibit metastasis. As a result, proper quantification of metastases from in vivo models is of the utmost significance. Here, we provide a detailed protocol for collecting and handling lung tissues from mice, and guidance for subsequent analysis of metastases, as well as interpretation of data.

  1. Quantification of Lung Metastases from In Vivo Mouse Models

    DEFF Research Database (Denmark)

    Chang, Joan; Erler, Janine T

    2016-01-01

    Cancer research has made significant progress in terms of understanding and targeting primary tumors; however, the challenge remains for the successful treatment of metastatic cancers. This highlights the importance to use in vivo models to study the metastatic process, as well as for preclinical...... testing of compounds that could inhibit metastasis. As a result, proper quantification of metastases from in vivo models is of the utmost significance. Here, we provide a detailed protocol for collecting and handling lung tissues from mice, and guidance for subsequent analysis of metastases, as well...

  2. Pivotal role of the 5-lipoxygenase pathway in lung injury after experimental sepsis.

    Science.gov (United States)

    Monteiro, Ana Paula T; Soledade, Erico; Pinheiro, Carla S; Dellatorre-Teixeira, Ludmilla; Oliveira, Gisele P; Oliveira, Mariana G; Peters-Golden, Marc; Rocco, Patricia R M; Benjamim, Claudia F; Canetti, Claudio

    2014-01-01

    Postsepsis lung injury is a common clinical problem associated with significant morbidity and mortality. Leukotrienes (LTs) are important lipid mediators of infection and inflammation derived from the 5-lipoxygenase (5-LO) metabolism of arachidonate with the potential to contribute to lung damage after sepsis. To test the hypothesis that LTs are mediators of lung injury after sepsis, we assessed lung structure, inflammatory mediators, and mechanical changes after cecal ligation and puncture surgery in wild-type (WT) and 5-LO knockout (5-LO(-/-)) mice and in WT mice treated with a pharmacologic LT synthesis inhibitor (MK886) and LT receptor antagonists (CP105,696 and montelukast). Sixteen hours after surgery, WT animals exhibited severe lung injury (by histological analysis), substantial mechanical impairment (i.e., an increase in static lung elastance), an increase in neutrophil infiltration, and high levels of LTB4, cysteinyl-LTs (cys-LTs), prostaglandin E2, IL-1β, IL-6, IL-10, IL-17, KC (CXCL1), and monocyte chemotactic protein-1 (CCL2) in lung tissue and plasma. 5-LO(-/-) mice and WT mice treated with a pharmacologic 5-LO inhibitor were significantly protected from lung inflammation and injury. Selective antagonists for BLT1 or cys-LT1, the high-affinity receptors for LTB4 and cys-LTs, respectively, were insufficient to provide protection when used alone. These results point to an important role for 5-LO products in sepsis-induced lung injury and suggest that the use of 5-LO inhibitors may be of therapeutic benefit clinically.

  3. AKT1E17K Is Oncogenic in Mouse Lung and Cooperates with Chemical Carcinogens in Inducing Lung Cancer

    Science.gov (United States)

    Malanga, Donatella; Belmonte, Stefania; Colelli, Fabiana; Scarfò, Marzia; De Marco, Carmela; Oliveira, Duarte Mendes; Mirante, Teresa; Camastra, Caterina; Gagliardi, Monica; Rizzuto, Antonia; Mignogna, Chiara; Paciello, Orlando; Papparella, Serenella; Fagman, Henrik; Viglietto, Giuseppe

    2016-01-01

    The hotspot AKT1E17K mutation in the pleckstrin homology domain of AKT1 occurs in approximately 0.6–2% of human lung cancers. Recently, we have demonstrated that AKT1E17K transforms immortalized human bronchial cells. Here by use of a transgenic Cre-inducible murine strain in the wild type Rosa26 (R26) locus (R26-AKT1E17K mice) we demonstrate that AKT1E17K is a bona-fide oncogene and plays a role in the development of lung cancer in vivo. In fact, we report that mutant AKT1E17K induces bronchial and/or bronchiolar hyperplastic lesions in murine lung epithelium, which progress to frank carcinoma at very low frequency, and accelerates tumor formation induced by chemical carcinogens. In conclusion, AKT1E17K induces hyperplasia of mouse lung epithelium in vivo and cooperates with urethane to induce the fully malignant phenotype. PMID:26859676

  4. AKT1E¹⁷K Is Oncogenic in Mouse Lung and Cooperates with Chemical Carcinogens in Inducing Lung Cancer.

    Directory of Open Access Journals (Sweden)

    Donatella Malanga

    Full Text Available The hotspot AKT1E17K mutation in the pleckstrin homology domain of AKT1 occurs in approximately 0.6-2% of human lung cancers. Recently, we have demonstrated that AKT1E17K transforms immortalized human bronchial cells. Here by use of a transgenic Cre-inducible murine strain in the wild type Rosa26 (R26 locus (R26-AKT1E17K mice we demonstrate that AKT1E17K is a bona-fide oncogene and plays a role in the development of lung cancer in vivo. In fact, we report that mutant AKT1E17K induces bronchial and/or bronchiolar hyperplastic lesions in murine lung epithelium, which progress to frank carcinoma at very low frequency, and accelerates tumor formation induced by chemical carcinogens. In conclusion, AKT1E17K induces hyperplasia of mouse lung epithelium in vivo and cooperates with urethane to induce the fully malignant phenotype.

  5. Membrane translocation of IL-33 receptor in ventilator induced lung injury.

    Directory of Open Access Journals (Sweden)

    Shih-Hsing Yang

    Full Text Available Ventilator-induced lung injury is associated with inflammatory mechanism and causes high mortality. The objective of this study was to discover the role of IL-33 and its ST2 receptor in acute lung injury induced by mechanical ventilator (ventilator-induced lung injury; VILI. Male Wistar rats were intubated after tracheostomy and received ventilation at 10 cm H2O of inspiratory pressure (PC10 by a G5 ventilator for 4 hours. The hemodynamic and respiratory parameters were collected and analyzed. The morphological changes of lung injury were also assessed by histological H&E stain. The dynamic changes of lung injury markers such as TNF-α and IL-1β were measured in serum, bronchoalveolar lavage fluid (BALF, and lung tissue homogenization by ELISA assay. During VILI, the IL-33 profile change was detected in BALF, peripheral serum, and lung tissue by ELISA analysis. The Il-33 and ST2 expression were analyzed by immunohistochemistry staining and western blot analysis. The consequence of VILI by H&E stain showed inducing lung congestion and increasing the expression of pro-inflammatory cytokines such as TNF-α and IL-1β in the lung tissue homogenization, serum, and BALF, respectively. In addition, rats with VILI also exhibited high expression of IL-33 in lung tissues. Interestingly, the data showed that ST2L (membrane form was highly accumulated in the membrane fraction of lung tissue in the PC10 group, but the ST2L in cytosol was dramatically decreased in the PC10 group. Conversely, the sST2 (soluble form was slightly decreased both in the membrane and cytosol fractions in the PC10 group compared to the control group. In conclusion, these results demonstrated that ST2L translocation from the cytosol to the cell membranes of lung tissue and the down-expression of sST2 in both fractions can function as new biomarkers of VILI. Moreover, IL-33/ST2 signaling activated by mechanically responsive lung injury may potentially serve as a new therapy target.

  6. Apneic oxygenation combined with extracorporeal arteriovenous carbon dioxide removal provides sufficient gas exchange in experimental lung injury

    DEFF Research Database (Denmark)

    Nielsen, Niels Dalsgaard; Kjærgaard, Benedict; Nielsen, Jakob Koefoed

    injury was induced by repeated lung lavage. Thereafter the tracheal tube was, after a lung recruitment maneuver, connected to 20 cmH2O continuous positive airway pressure (FiO2 = 1.0) for oxygenation of the blood. A pumpless membrane lung (Interventional Lung Assist, NovaLung, Germany) was connected......Background and aim of study We hypothesized that continuous high airway pressure without ventilatory movements (apneic oxygenation), using an open lung approach, combined with extracorporeal, pumpless, arterio-venous, carbon dioxide (CO2) removal would provide adequate gas exchange in acute lung...... injury. The aim of this study was to test this hypothesis in a lung injury model using pigs of human adult size, to mimic the O2 consumption and the CO2 production of adult patients.   Materials and methods In eight anesthetized, tracheally intubated and mechanically ventilated pigs (85-95 kg), lung...

  7. Effects of acute hypercapnia with and without acidosis on lung inflammation and apoptosis in experimental acute lung injury.

    Science.gov (United States)

    Nardelli, L M; Rzezinski, A; Silva, J D; Maron-Gutierrez, T; Ornellas, D S; Henriques, I; Capelozzi, V L; Teodoro, W; Morales, M M; Silva, P L; Pelosi, P; Garcia, C S N B; Rocco, P R M

    2015-01-01

    We investigated the effects of acute hypercapnic acidosis and buffered hypercapnia on lung inflammation and apoptosis in experimental acute lung injury (ALI). Twenty-four hours after paraquat injection, 28 Wistar rats were randomized into four groups (n=7/group): (1) normocapnia (NC, PaCO2=35-45 mmHg), ventilated with 0.03%CO2+21%O2+balancedN2; (2) hypercapnic acidosis (HC, PaCO2=60-70 mmHg), ventilated with 5%CO2+21%O2+balancedN2; and (3) buffered hypercapnic acidosis (BHC), ventilated with 5%CO2+21%O2+balancedN2 and treated with sodium bicarbonate (8.4%). The remaining seven animals were not mechanically ventilated (NV). The mRNA expression of interleukin (IL)-6 (p=0.003), IL-1β (pacidosis, reduced lung inflammation and lung and kidney cell apoptosis.

  8. Spatiotemporal Aeration and Lung Injury Patterns Are Influenced by the First Inflation Strategy at Birth.

    Science.gov (United States)

    Tingay, David G; Rajapaksa, Anushi; Zonneveld, C Elroy; Black, Don; Perkins, Elizabeth J; Adler, Andy; Grychtol, Bartłomiej; Lavizzari, Anna; Frerichs, Inéz; Zahra, Valerie A; Davis, Peter G

    2016-02-01

    Ineffective aeration during the first inflations at birth creates regional aeration and ventilation defects, initiating injurious pathways. This study aimed to compare a sustained first inflation at birth or dynamic end-expiratory supported recruitment during tidal inflations against ventilation without intentional recruitment on gas exchange, lung mechanics, spatiotemporal regional aeration and tidal ventilation, and regional lung injury in preterm lambs. Lambs (127 ± 2 d gestation), instrumented at birth, were ventilated for 60 minutes from birth with either lung-protective positive pressure ventilation (control) or as per control after either an initial 30 seconds of 40 cm H2O sustained inflation (SI) or an initial stepwise end-expiratory pressure recruitment maneuver during tidal inflations (duration 180 s; open lung ventilation [OLV]). At study completion, molecular markers of lung injury were analyzed. The initial use of an OLV maneuver, but not SI, at birth resulted in improved lung compliance, oxygenation, end-expiratory lung volume, and reduced ventilatory needs compared with control, persisting throughout the study. These changes were due to more uniform inter- and intrasubject gravity-dependent spatiotemporal patterns of aeration (measured using electrical impedance tomography). Spatial distribution of tidal ventilation was more stable after either recruitment maneuver. All strategies caused regional lung injury patterns that mirrored associated regional volume states. Irrespective of strategy, spatiotemporal volume loss was consistently associated with up-regulation of early growth response-1 expression. Our results show that mechanical and molecular consequences of lung aeration at birth are not simply related to rapidity of fluid clearance; they are also related to spatiotemporal pressure-volume interactions within the lung during inflation and deflation.

  9. Pathogenesis pathways of idiopathic pulmonary fibrosis in bleomycin-induced lung injury model in mice.

    Science.gov (United States)

    Shi, Keyun; Jiang, Jianzhong; Ma, Tieliang; Xie, Jing; Duan, Lirong; Chen, Ruhua; Song, Ping; Yu, Zhixin; Liu, Chao; Zhu, Qin; Zheng, Jinxu

    2014-01-01

    Our objective was to investigate the pathogenesis pathways of idiopathic pulmonary fibrosis (IPF). Bleomycin (BLM) induced animal models of experimental lung fibrosis were used. CHIP assay was executed to find the link between Smad3 and IL-31, and the expressions of TGF-β1, Smad3, IL-31 and STAT1 were detected to find whether they were similar with each other. We found that in the early injury or inflammation of the animal model, BLM promoted the development of inflammation, leading to severe pulmonary fibrosis. Then the expression of TGF-β1 and Smad3 increased. Activated Smad3 bound to the IL-31 promoter region, followed by the activation of JAK-STAT pathways. The inhibitor of TGF-β1 receptor decreased the IL-31 expression and knocking-down of IL-31 also decreased the STAT1 expression. We conclude that there is a pathway of pathogenesis in BLM-induced mouse model that involves the TGF-β, IL-31 and JAKs/STATs pathway.

  10. Aerosolized alpha-tocopherol ameliorates acute lung injury following combined burn and smoke inhalation injury in sheep.

    Science.gov (United States)

    Morita, Naoki; Traber, Maret G; Enkhbaatar, Perenlei; Westphal, Martin; Murakami, Kazunori; Leonard, Scott W; Cox, Robert A; Hawkins, Hal K; Herndon, David; Traber, Lillian D; Traber, Daniel L

    2006-03-01

    Victims of fire accidents who sustain both thermal injury to the skin and smoke inhalation have gross evidence of oxidant injury. Therefore, we hypothesized that delivery of vitamin E, an oxygen superoxide scavenger, directly into the airway would attenuate acute lung injury postburn and smoke inhalation. Sheep (N = 17 female, 35 +/- 5 kg) were divided into 3 groups: (1) injured, then nebulized with vitamin E (B&S, Vitamin E, n = 6); (2) injured, nebulized with saline (B&S, Saline, n = 6); and (3) not injured, not treated (Sham, n = 5). While under deep anesthesia with isoflurane, the sheep were subjected to a flame burn (40% total body surface area, 3rd degree) and inhalation injury (48 breaths of cotton smoke, Ringer lactate solution (4 mL/kg/%burn/24 h) and placed on a ventilator [positive end-expiratory pressure (PEEP) = 5 cm H2O, tidal volume = 15 mL/kg] for 48 h. B&S injury halved the lung alpha-tocopherol concentrations (0.9 +/- 0.1 nmol/g) compared with sham-injured animals (1.5 +/- 0.3), whereas vitamin E treatment elevated the lung alpha-tocopherol concentrations (7.40 +/- 2.61) in the injured animals. B&S injury decreased pulmonary gas exchange (PaO2/FiO2 ratios) from 517 +/- 15 at baseline to 329 +/- 49 at 24 h and to 149 +/- 32 at 48 h compared with sham ratios of 477 +/- 14, 536 +/- 48, and 609 +/- 49, respectively. Vitamin E treatment resulted in a significant improvement of pulmonary gas exchange; ratios were 415 +/- 34 and 283 +/- 42 at 24 and 48 h, respectively. Vitamin E nebulization therapy improved the clinical responses to burn and smoke inhalation-induced acute lung injury.

  11. The Effects of Lung Protective Ventilation or Hypercapnic Acidosis on Gas Exchange and Lung Injury in Surfactant Deficient Rabbits.

    Directory of Open Access Journals (Sweden)

    Helmut D Hummler

    Full Text Available Permissive hypercapnia has been shown to reduce lung injury in subjects with surfactant deficiency. Experimental studies suggest that hypercapnic acidosis by itself rather than decreased tidal volume may be a key protective factor.To study the differential effects of a lung protective ventilatory strategy or hypercapnic acidosis on gas exchange, hemodynamics and lung injury in an animal model of surfactant deficiency.30 anesthetized, surfactant-depleted rabbits were mechanically ventilated (FiO2 = 0.8, PEEP = 7cmH2O and randomized into three groups: Normoventilation-Normocapnia (NN-group: tidal volume (Vt = 7.5 ml/kg, target PaCO2 = 40 mmHg; Normoventilation-Hypercapnia (NH-group: Vt = 7.5 ml/kg, target PaCO2 = 80 mmHg by increasing FiCO2; and a Hypoventilation-Hypercapnia (HH-group: Vt = 4.5 ml/kg, target PaCO2 = 80 mmHg. Plasma lactate and interleukin (IL-8 were measured every 2 h. Animals were sacrificed after 6 h to perform bronchoalveolar lavage (BAL, to measure lung wet-to-dry weight, lung tissue IL-8, and to obtain lung histology.PaO2 was significantly higher in the HH-group compared to the NN-group (p<0.05, with values of the NH-group between the HH- and NN-groups. Other markers of lung injury (wet-dry-weight, BAL-Protein, histology-score, plasma-IL-8 and lung tissue IL-8 resulted in significantly lower values for the HH-group compared to the NN-group and trends for the NH-group towards lower values compared to the NN-group. Lactate was significantly lower in both hypercapnia groups compared to the NN-group.Whereas hypercapnic acidosis may have some beneficial effects, a significant effect on lung injury and systemic inflammatory response is dependent upon a lower tidal volume rather than resultant arterial CO2 tensions and pH alone.

  12. Effects of budesonide and N-acetylcysteine on acute lung hyperinflation, inflammation and injury in rats.

    Science.gov (United States)

    Jansson, Anne-Helene; Eriksson, Christina; Wang, Xiangdong

    2005-08-01

    Leukocyte activation and production of inflammatory mediators and reactive oxygen species are important in the pathogenesis of lipopolysaccharide (LPS)-induced acute lung injury. The present study investigated acute lung hyperinflation, edema, and lung inflammation 4 h after an intratracheal instillation of LPS (0.5, 2.5, 5, 10, 50, 100, 500, 1000, and 5000 microg/ml/kg). Effects of budesonide, an inhaled anti-inflammatory corticosteroids, and N-acetylcysteine (NAC), an antioxidant, were evaluated in Wistar rats receiving either low (2.5 microg/ml/kg) or high (50 microg/ml/kg) concentrations of LPS. This study demonstrates that LPS in a concentration-dependent pattern induces acute lung hyperinflation measured by excised lung gas volume (25-45% above control), lung injury indicated by increased lung weight (10-60%), and lung inflammation characterized by the infiltration of leukocytes (40-14000%) and neutrophils (80-17000%) and the production of cytokines (up to 2700%) and chemokines (up to 350%) in bronchoalveolar lavage fluid (BALF). Pretreatment with NAC partially prevented tumor necrosis factor alpha (TNFalpha) production induced by the low concentration of LPS, while pretreatment with budesonide totally prevented the increased production of TNFalpha, interleukin (IL)-1beta, IL-6, and monocyte chemoattractive protein (MCP)-1 after LPS challenge at both low and high concentrations. Budesonide failed to prevent BALF levels of macrophage inflammatory protein (MIP)-2 and cytokine-induced neutrophil chemoattractant 1 (GRO/CINC-1) as well as lung hyperinflation induced by both low and high concentrations of LPS. Pretreatment with budesonide totally prevented the formation of lung edema at the low concentration of LPS and had partial effects on acute lung injury and leukocyte influx at the high concentrations. Thus, our data indicate that therapeutic effects of budesonide and NAC are dependent upon the severity of the disease.

  13. Effect of corticosteroid treatment on cell recovery by lung lavage in acute radiation-induced lung injury

    Energy Technology Data Exchange (ETDEWEB)

    Wesselius, L.J.; Floreani, A.A.; Kimler, B.F.; Papasian, C.J.; Dixon, A.Y. (Kansas City Veterans Administration Medical Center, MO (USA))

    1989-11-01

    The purpose of this study was to quantitate cell populations recovered by lung lavage up to 6 weeks following thoracic irradiation (24 Gy) as an index of the acute inflammatory response within lung structures. Additionally, rats were treated five times weekly with intraperitoneal saline (0.3 cc) or methylprednisolone (7.5 mg/kg/week). Lung lavage of irradiated rats recovered increased numbers of total cells compared to controls beginning 3 weeks after irradiation (P less than 0.05). The initial increase in number of cells recovered was attributable to an influx of neutrophils (P less than 0.05), and further increases at 4 and 6 weeks were associated with increased numbers of recovered macrophages (P less than 0.05). Lung lavage of steroid-treated rats at 6 weeks after irradiation recovered increased numbers of all cell populations compared to controls (P less than 0.05); however, numbers of recovered total cells, macrophages, neutrophils, and lymphocytes were all significantly decreased compared to saline-treated rats (P less than 0.05). The number of inflammatory cells recovered by lung lavage during acute radiation-induced lung injury is significantly diminished by corticosteroid treatment. Changes in cells recovered by lung lavage can also be correlated with alteration in body weight and respiration rate subsequent to treatment with thoracic irradiation and/or corticosteroids.

  14. Autotaxin activity increases locally following lung injury, but is not required for pulmonary lysophosphatidic acid production or fibrosis.

    Science.gov (United States)

    Black, Katharine E; Berdyshev, Evgeny; Bain, Gretchen; Castelino, Flavia V; Shea, Barry S; Probst, Clemens K; Fontaine, Benjamin A; Bronova, Irina; Goulet, Lance; Lagares, David; Ahluwalia, Neil; Knipe, Rachel S; Natarajan, Viswanathan; Tager, Andrew M

    2016-06-01

    Lysophosphatidic acid (LPA) is an important mediator of pulmonary fibrosis. In blood and multiple tumor types, autotaxin produces LPA from lysophosphatidylcholine (LPC) via lysophospholipase D activity, but alternative enzymatic pathways also exist for LPA production. We examined the role of autotaxin (ATX) in pulmonary LPA production during fibrogenesis in a bleomycin mouse model. We found that bleomycin injury increases the bronchoalveolar lavage (BAL) fluid levels of ATX protein 17-fold. However, the LPA and LPC species that increase in BAL of bleomycin-injured mice were discordant, inconsistent with a substrate-product relationship between LPC and LPA in pulmonary fibrosis. LPA species with longer chain polyunsaturated acyl groups predominated in BAL fluid after bleomycin injury, with 22:5 and 22:6 species accounting for 55 and 16% of the total, whereas the predominant BAL LPC species contained shorter chain, saturated acyl groups, with 16:0 and 18:0 species accounting for 56 and 14% of the total. Further, administration of the potent ATX inhibitor PAT-048 to bleomycin-challenged mice markedly decreased ATX activity systemically and in the lung, without effect on pulmonary LPA or fibrosis. Therefore, alternative ATX-independent pathways are likely responsible for local generation of LPA in the injured lung. These pathways will require identification to therapeutically target LPA production in pulmonary fibrosis.-Black, K. E., Berdyshev, E., Bain, G., Castelino, F. V., Shea, B. S., Probst, C. K., Fontaine, B. A., Bronova, I., Goulet, L., Lagares, D., Ahluwalia, N., Knipe, R. S., Natarajan, V., Tager, A. M. Autotaxin activity increases locally following lung injury, but is not required for pulmonary lysophosphatidic acid production or fibrosis.

  15. Protective effect of ulinastatin on acute lung injury after radiotherapy in patients with lung cancer and the related molecular mechanism

    Institute of Scientific and Technical Information of China (English)

    Guang-Ping Fan

    2016-01-01

    Objective:To analyze the protective effect of ulinastatin on acute lung injury after radiotherapy in patients with lung cancer and the related molecular mechanism.Methods:A total of 78 patients who received radiotherapy and developed acute lung injury in our hospital between December 2013 and December 2015 were randomly divided into observation group and control group, control group received symptomatic treatment, observation group received symptomatic + ulinastatin treatment, and the content of growth factors, inflammatory factors, disease-related proteins in serum as well as the expression of P38MAPK signaling pathway molecules in alveolar lavage fluid were compared between two groups of patients after treatment.Results:Ten days after treatment, HGF, KGF, VEGF, IL-1β, IL-8, IL-10, IL-18, IL-13, PCT, S100A8, S100A9 and SP-D content in serum of observation group were significantly lower than those of control group while Clara cell protein content was significantly higher than that of control group; phosphorylated p38MAPK, MAPK, MKK3/6 and ATF-2 protein expression levels in alveolar lavage fluid were significantly lower than those of control group.Conclusions:Ulinastatin can alleviate the overall condition in patients with acute lung injury after radiotherapy, and the specific mechanism is associated with P38MAPK signaling pathway.

  16. Inhibition of β-catenin/p300 interaction proximalizes mouse embryonic lung epithelium

    OpenAIRE

    Sasaki, Tomoyo; Kahn, Michael

    2014-01-01

    Background Wnt/β-catenin signaling has been suggested to regulate proximal-distal determination of embryonic lung epithelium based upon genetically modified mouse models. The previously identified and characterized small molecule inhibitor IQ1 can pharmacologically decrease the interaction between β-catenin and its transcriptional coactivator p300, thereby enhancing the β-catenin/CBP interaction. Inhibition of the β-catenin/p300 interaction by IQ1 blocks the differentiation of embryonic stem ...

  17. Metabolism of styrene to styrene oxide and vinylphenols in cytochrome P450 2F2- and P450 2E1-knockout mouse liver and lung microsomes.

    Science.gov (United States)

    Shen, Shuijie; Li, Lei; Ding, Xinxin; Zheng, Jiang

    2014-01-21

    Pulmonary toxicity of styrene is initiated by cytochromes P450-dependent metabolic activation. P450 2E1 and P450 2F2 are considered to be two main cytochrome P450 enzymes responsible for styrene metabolism in mice. The objective of the current study was to determine the correlation between the formation of styrene metabolites (i.e., styrene oxide and 4-vinylphenol) and pulmonary toxicity of styrene, using Cyp2e1- and Cyp2f2-null mouse models. A dramatic decrease in the formation of styrene glycol and 4-vinylphenol was found in Cyp2f2-null mouse lung microsomes relative to that in the wild-type mouse lung microsomes; however, no significant difference in the production of the styrene metabolites was observed between lung microsomes obtained from Cyp2e1-null and the wild-type mice. The knockout and wild-type mice were treated with styrene (6.0 mmol/kg, ip), and cell counts and LDH activity in bronchoalveolar lavage fluids were monitored to evaluate the pulmonary toxicity induced by styrene. Cyp2e1-null mice displayed a susceptibility to lung toxicity of styrene similar to that of the wild-type animals; however, Cyp2f2-null mice were resistant to styrene-induced pulmonary toxicity. In conclusion, both P450 2E1 and P450 2F2 are responsible for the metabolic activation of styrene. The latter enzyme plays an important role in styrene-induced pulmonary toxicity. Both styrene oxide and 4-vinylphenol are suggested to participate in the development of lung injury induced by styrene.

  18. Supplementation of parenteral nutrition with fish oil attenuates acute lung injury in a rat model

    Science.gov (United States)

    Kohama, Keisuke; Nakao, Atsunori; Terashima, Mariko; Aoyama-Ishikawa, Michiko; Shimizu, Takayuki; Harada, Daisuke; Nakayama, Mitsuo; Yamashita, Hayato; Fujiwara, Mayu; Kotani, Joji

    2014-01-01

    Fish oil rich in n-3 polyunsaturated fatty acids has diverse immunomodulatory properties and attenuates acute lung injury when administered in enternal nutrition. However, enteral nutrition is not always feasible. Therefore, we investigated the ability of parenteral nutrition supplemented with fish oil to ameliorate acute lung injury. Rats were infused with parenteral nutrition solutions (without lipids, with soybean oil, or with soybean oil and fish oil) for three days. Lipopolysaccharide (15 mg/kg) was then administered intratracheally to induce acute lung injury, characterized by impaired lung function, polymorphonuclear leukocyte recruitment, parenchymal tissue damage, and upregulation of mRNAs for inflammatory mediators. Administration of parenteral nutrition supplemented with fish oil prior to lung insult improved gas exchange and inhibited neutrophil recruitment and upregulation of mRNAs for inflammatory mediators. Parenteral nutrition supplemented with fish oil also prolonged survival. To investigate the underlying mechanisms, leukotriene B4 and leukotriene B5 secretion was measured in neutrophils from the peritoneal cavity. The neutrophils from rats treated with fish oil-rich parenteral nutrition released significantly more leukotriene B5, an anti-inflammatory eicosanoid, than neutrophils isolated from rats given standard parenteral nutrition. Parenteral nutrition with fish oil significantly reduced lipopolysaccharide-induced lung injury in rats in part by promoting the synthesis of anti-inflammatory eicosanoids. PMID:24688221

  19. Effect of terbutaline on alveolar liquid clearance after oleic acid-induced lung injury in rats

    Institute of Scientific and Technical Information of China (English)

    TAO Jun; YANG Tian-de; LI Hong; DU Zhi-yong

    2006-01-01

    Objective: To investigate whether terbutaline affects alveolar liquid clearance after oleic acid-induced lung injury in rats.Methods: Forty healthy Wistar rats ( weighing 250-280 g) were randomly divided into five groups ( n = 8 in each group): the normal control group ( control group),oleic acid injury group ( injury group), terbutaline-treated group (terbutaline group ), terbutaline plus amiloridetreated group (terbutaline + amiloride group ) and terbutaline plus ouabain-treated group (terbutaline + ouabain group). Acute lung injury model was induced by intravenous oleic acid (0. 25 mi/kg body weight). 24 hours later, 1.5 μCi 125I-labeled 5% albumin solution (5 ml/kg body weight) was dripped into the lungs through trachea.The alveolar liquid clearance rate, extravascular lung water content, and arterial blood gas were measured 1 hour thereafter.Results: At 24 hours after infusion of oleic acid, the rats developed pulmonary edema and severe hypoxemia,with the alveolar liquid clearance rate decreased by 49.2 % and the extravascular lung water content elevated by 47.9%. Compared with the rats in the injury group,terbutaline (10-4 mol/L ) significantly increased the alveolar liquid clearance rate, decreased the extravascular lung water content and improved hypoxemia. The effect of terbutaline was partly blocked by amiloride and ouabain,which were inhibitors of sodium transport. Terbutaline increased the alveolar liquid clearance rate by 63.7 %, and amiloride and ouabain reduced the alveolar liquid clearance rate by 54.7% and 56.8%, respectively.Conclusions: Terbutaline can accelerate alveolar liquid clearance through increasing sodium transport to attenuate pulmonary edema, thus improving gas exchange,which may have therapeutical effect on pulmonary edema after acute lung injury.

  20. Effects of biliverdin administration on acute lung injury induced by hemorrhagic shock and resuscitation in rats.

    Directory of Open Access Journals (Sweden)

    Junko Kosaka

    Full Text Available Hemorrhagic shock and resuscitation induces pulmonary inflammation that leads to acute lung injury. Biliverdin, a metabolite of heme catabolism, has been shown to have potent cytoprotective, anti-inflammatory, and anti-oxidant effects. This study aimed to examine the effects of intravenous biliverdin administration on lung injury induced by hemorrhagic shock and resuscitation in rats. Biliverdin or vehicle was administered to the rats 1 h before sham or hemorrhagic shock-inducing surgery. The sham-operated rats underwent all surgical procedures except bleeding. To induce hemorrhagic shock, rats were bled to achieve a mean arterial pressure of 30 mmHg that was maintained for 60 min, followed by resuscitation with shed blood. Histopathological changes in the lungs were evaluated by histopathological scoring analysis. Inflammatory gene expression was determined by Northern blot analysis, and oxidative DNA damage was assessed by measuring 8-hydroxy-2' deoxyguanosine levels in the lungs. Hemorrhagic shock and resuscitation resulted in prominent histopathological damage, including congestion, edema, cellular infiltration, and hemorrhage. Biliverdin administration prior to hemorrhagic shock and resuscitation significantly ameliorated these lung injuries as judged by histopathological improvement. After hemorrhagic shock and resuscitation, inflammatory gene expression of tumor necrosis factor-α and inducible nitric oxide synthase were increased by 18- and 8-fold, respectively. Inflammatory gene expression significantly decreased when biliverdin was administered prior to hemorrhagic shock and resuscitation. Moreover, after hemorrhagic shock and resuscitation, lung 8-hydroxy-2' deoxyguanosine levels in mitochondrial DNA expressed in the pulmonary interstitium increased by 1.5-fold. Biliverdin administration prior to hemorrhagic shock and resuscitation decreased mitochondrial 8-hydroxy-2' deoxyguanosine levels to almost the same level as that in the

  1. Susceptibility to quantum dot induced lung inflammation differs widely among the Collaborative Cross founder mouse strains

    Science.gov (United States)

    Scoville, David K.; White, Collin C.; Botta, Dianne; McConnachie, Lisa A.; Zadworny, Megan E.; Schmuck, Stefanie C.; Hu, Xiaoge; Gao, Xiaohu; Yu, Jianbo; Dills, Russell L.; Sheppard, Lianne; Delaney, Martha A.; Griffith, William C.; Beyer, Richard P.; Zangar, Richard C.; Pounds, Joel G.; Faustman, Elaine M.; Kavanagh, Terrance J.

    2015-01-01

    Quantum dots (QDs) are engineered semiconductor nanoparticles with unique physicochemical properties that make them potentially useful in clinical, research and industrial settings. However, a growing body of evidence indicates that like other engineered nanomaterials, QDs have the potential to be respiratory hazards, especially in the context of the manufacture of QDs and products containing them, as well as exposures to consumers using these products. The overall goal of this study was to investigate the role of mouse strain in determining susceptibility to QD-induced pulmonary inflammation and toxicity. Male mice from 8 genetically diverse inbred strains (the Collaborative Cross founder strains) were exposed to CdSe–ZnS core–shell QDs stabilized with an amphiphilic polymer. QD treatment resulted in significant increases in the percentage of neutrophils and levels of cytokines present in bronchoalveolar lavage fluid (BALF) obtained from NOD/ShiLtJ and NZO/HlLtJ mice relative to their saline (Sal) treated controls. Cadmium measurements in lung tissue indicated strain-dependent differences in disposition of QDs in the lung. Total glutathione levels in lung tissue were significantly correlated with percent neutrophils in BALF as well as with lung tissue Cd levels. Our findings indicate that QD-induced acute lung inflammation is mouse strain dependent, that it is heritable, and that the choice of mouse strain is an important consideration in planning QD toxicity studies. These data also suggest that formal genetic analyses using additional strains or recombinant inbred strains from these mice could be useful for discovering potential QD-induced inflammation susceptibility loci. PMID:26476918

  2. [Distribution of compact bone mesenchymal stem cells in lung tissue and bone marrow of mouse].

    Science.gov (United States)

    Wang, Rui-Ping; Wu, Ren-Na; Guo, Yu-Qing; Zhang, Bin; Chen, Hu

    2014-02-01

    This study was aimed to investigate the distribution of compact bone mesenchymal stem cells(MSC) marked with lentiviral plasmid pGC FU-RFP-LV in lung tissue and bone marrow of mouse. The MSC were infected by lentivirus with infection efficiency 78%, the infected MSC were injected into BALB/c mice via tail veins in concentration of 1×10(6) /mouse. The mice were randomly divided into 4 group according to 4 time points as 1, 2, 5 and 7 days. The lung tissue and bone marrow were taken and made of frozen sections and smears respectively in order to observed the distributions of MSC. The results indicated that the lentiviral infected MSC displayed phenotypes and biological characteristics which conformed to MSC by immunophenotyping analysis and induction differentiation detection. After the MSC were infected with optimal viral titer MOI = 50, the cell growth no significantly changed; the fluorescent microscopy revealed that the distributions of MSC in bone marrow on day 1, 2, 5 and 7 were 0.50 ± 0.20, 0.67 ± 0.23, 0.53 ± 0.14, 0.33 ± 0.16; those in lung tissue were 0.55 ± 0.15, 0.47 ± 0.13, 0.29 ± 0.13, 0.26 ± 0.08. It is concluded that the distribution of MSC in lung tissue reaches a peak on day 1, while distribution of MSC in bone marrow reaches a peak on day 2. The distribution of mouse MSC relates with RFP gene expression and implantation of MSC in lung tissue and bone marrow.

  3. Mast Cell Protease 5 Mediates Ischemia-Reperfusion Injury of Mouse Skeletal Muscle1

    Science.gov (United States)

    Abonia, J. Pablo; Friend, Daniel S.; Austen, William G.; Moore, Francis D.; Carroll, Michael C.; Chan, Rodney; Afnan, Jalil; Humbles, Alison; Gerard, Craig; Knight, Pamela; Kanaoka, Yoshihide; Yasuda, Shinsuke; Morokawa, Nasa; Austen, K. Frank; Stevens, Richard L.; Gurish, Michael F.

    2010-01-01

    Ischemia with subsequent reperfusion (IR) injury is a significant clinical problem that occurs after physical and surgical trauma, myocardial infarction, and organ transplantation. IR injury of mouse skeletal muscle depends on the presence of both natural IgM and an intact C pathway. Disruption of the skeletal muscle architecture and permeability also requires mast cell (MC) participation, as revealed by the fact that IR injury is markedly reduced in c-kit defective, MC-deficient mouse strains. In this study, we sought to identify the pathobiologic MC products expressed in IR injury using transgenic mouse strains with normal MC development, except for the lack of a particular MC-derived mediator. Histologic analysis of skeletal muscle from BALB/c and C57BL/6 mice revealed a strong positive correlation (R2 = 0.85) between the extent of IR injury and the level of MC degranulation. Linkage between C activation and MC degranulation was demonstrated in mice lacking C4, in which only limited MC degranulation and muscle injury were apparent. No reduction in injury was observed in transgenic mice lacking leukotriene C4 synthase, hemopoietic PGD2 synthase, N-deacetylase/N-sulfotransferase-2 (enzyme involved in heparin biosynthesis), or mouse MC protease (mMCP) 1. In contrast, muscle injury was significantly attenuated in mMCP-5-null mice. The MCs that reside in skeletal muscle contain abundant amounts of mMCP-5 which is the serine protease that is most similar in sequence to human MC chymase. We now report a cytotoxic activity associated with a MC-specific protease and demonstrate that mMCP-5 is critical for irreversible IR injury of skeletal muscle. PMID:15905575

  4. Mast cell protease 5 mediates ischemia-reperfusion injury of mouse skeletal muscle.

    Science.gov (United States)

    Abonia, J Pablo; Friend, Daniel S; Austen, William G; Moore, Francis D; Carroll, Michael C; Chan, Rodney; Afnan, Jalil; Humbles, Alison; Gerard, Craig; Knight, Pamela; Kanaoka, Yoshihide; Yasuda, Shinsuke; Morokawa, Nasa; Austen, K Frank; Stevens, Richard L; Gurish, Michael F

    2005-06-01

    Ischemia with subsequent reperfusion (IR) injury is a significant clinical problem that occurs after physical and surgical trauma, myocardial infarction, and organ transplantation. IR injury of mouse skeletal muscle depends on the presence of both natural IgM and an intact C pathway. Disruption of the skeletal muscle architecture and permeability also requires mast cell (MC) participation, as revealed by the fact that IR injury is markedly reduced in c-kit defective, MC-deficient mouse strains. In this study, we sought to identify the pathobiologic MC products expressed in IR injury using transgenic mouse strains with normal MC development, except for the lack of a particular MC-derived mediator. Histologic analysis of skeletal muscle from BALB/c and C57BL/6 mice revealed a strong positive correlation (R(2) = 0.85) between the extent of IR injury and the level of MC degranulation. Linkage between C activation and MC degranulation was demonstrated in mice lacking C4, in which only limited MC degranulation and muscle injury were apparent. No reduction in injury was observed in transgenic mice lacking leukotriene C(4) synthase, hemopoietic PGD(2) synthase, N-deacetylase/N-sulfotransferase-2 (enzyme involved in heparin biosynthesis), or mouse MC protease (mMCP) 1. In contrast, muscle injury was significantly attenuated in mMCP-5-null mice. The MCs that reside in skeletal muscle contain abundant amounts of mMCP-5 which is the serine protease that is most similar in sequence to human MC chymase. We now report a cytotoxic activity associated with a MC-specific protease and demonstrate that mMCP-5 is critical for irreversible IR injury of skeletal muscle.

  5. Lung mechanics in the TIMP3 null mouse and its response to mechanical ventilation.

    Science.gov (United States)

    Martin, Erica L; Truscott, Emily A; Bailey, Timothy C; Leco, Kevin J; McCaig, Lynda A; Lewis, James F; Veldhuizen, Ruud A W

    2007-03-01

    Tissue inhibitor of metalloproteinase-3 (TIMP3) null mice develop emphysema-like airspace enlargement due to an enzymatic imbalance. This study investigates how these abnormalities alter lung mechanics and the response to 2 different mechanical ventilation strategies. Phenotypically, TIMP3 null mice had increased compliance, and decreased resistance, tissue damping, and tissue elastance over wild-type controls. Decreased compliance and increased resistance were observed following the injurious ventilation strategy; however, the TIMP3 null response to both ventilation strategies was similar to wild-type mice. In conclusion, TIMP3 null mice have significant alterations in lung mechanics; however, this does not affect their response to ventilation.

  6. Early administration of IL-6RA does not prevent radiation-induced lung injury in mice

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    Inoue Takehiro

    2010-04-01

    Full Text Available Abstract Background Radiation pneumonia and subsequent radiation lung fibrosis are major dose-limiting complications for patients undergoing thoracic radiotherapy. Interleukin-6 (IL-6 is a pleiotropic cytokine and plays important roles in the regulation of immune response and inflammation. The purpose of this study was to investigate whether anti-IL-6 monoclonal receptor antibody (IL-6RA could ameliorate radiation-induced lung injury in mice. Methods BALB/cAnNCrj mice having received thoracic irradiation of 21 Gy were injected intraperitoneally with IL-6RA (MR16-1 or control rat IgG twice, immediately and seven days after irradiation. Enzyme-linked immunosorbent assay was used to examine the plasma level of IL-6 and serum amyloid A (SAA. Lung injury was assessed by histological staining with haematoxylin and eosin or Azan, measuring lung weight, and hydroxyproline. Results The mice treated with IL-6RA did not survive significantly longer than the rat IgG control. We observed marked up-regulation of IL-6 in mice treated with IL-6RA 150 days after irradiation, whereas IL-6RA temporarily suppressed early radiation-induced increase in the IL-6 release level. Histopathologic assessment showed no differences in lung section or lung weight between mice treated with IL-6RA and control. Conclusions Our findings suggest that early treatment with IL-6RA after irradiation alone does not protect against radiation-induced lung injury.

  7. Early administration of IL-6RA does not prevent radiation-induced lung injury in mice.

    Science.gov (United States)

    Ogata, Toshiyuki; Yamazaki, Hideya; Teshima, Teruki; Kihara, Ayaka; Suzumoto, Yuko; Inoue, Takehiro; Nishimoto, Norihiro; Matsuura, Nariaki

    2010-04-07

    Radiation pneumonia and subsequent radiation lung fibrosis are major dose-limiting complications for patients undergoing thoracic radiotherapy. Interleukin-6 (IL-6) is a pleiotropic cytokine and plays important roles in the regulation of immune response and inflammation. The purpose of this study was to investigate whether anti-IL-6 monoclonal receptor antibody (IL-6RA) could ameliorate radiation-induced lung injury in mice. BALB/cAnNCrj mice having received thoracic irradiation of 21 Gy were injected intraperitoneally with IL-6RA (MR16-1) or control rat IgG twice, immediately and seven days after irradiation. Enzyme-linked immunosorbent assay was used to examine the plasma level of IL-6 and serum amyloid A (SAA). Lung injury was assessed by histological staining with haematoxylin and eosin or Azan, measuring lung weight, and hydroxyproline. The mice treated with IL-6RA did not survive significantly longer than the rat IgG control. We observed marked up-regulation of IL-6 in mice treated with IL-6RA 150 days after irradiation, whereas IL-6RA temporarily suppressed early radiation-induced increase in the IL-6 release level. Histopathologic assessment showed no differences in lung section or lung weight between mice treated with IL-6RA and control. Our findings suggest that early treatment with IL-6RA after irradiation alone does not protect against radiation-induced lung injury.

  8. 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

  9. OPTICAL IMAGING OF LIPOPOLYSACCHARIDE-INDUCED OXIDATIVE STRESS IN ACUTE LUNG INJURY FROM HYPEROXIA AND SEPSIS

    Directory of Open Access Journals (Sweden)

    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.

  10. OPTICAL IMAGING OF LIPOPOLYSACCHARIDE-INDUCED OXIDATIVE STRESS IN ACUTE LUNG INJURY FROM HYPEROXIA AND SEPSIS.

    Science.gov (United States)

    Sepehr, Reyhaneh; Audi, Said H; Maleki, Sepideh; Staniszewski, Kevin; Eis, Annie L; Konduri, Girija G; Ranji, Mahsa

    2013-07-01

    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.

  11. Sodium butyrate protects against severe burn-induced remote acute lung injury in rats.

    Directory of Open Access Journals (Sweden)

    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

  12. Infliximab attenuates activated charcoal and polyethylene glycol aspiration-induced lung injury in rats.

    Science.gov (United States)

    Güzel, Aygül; Günaydin, Mithat; Güzel, Ahmet; Alaçam, Hasan; Murat, Naci; Gacar, Ayhan; Güvenç, Tolga

    2012-04-01

    Aspiration is a serious complication of gastrointestinal (GI) decontamination procedure. Studies have shown that tumor necrosis factor-α (TNF-α) blockers have beneficial effects on lung injury. Therefore, the authors investigated the attenuation by infliximab (INF) on activated charcoal (AC)- and polyethylene glycol (PEG)-induced lung injury in rat model. Forty-two male Sprague-Dawley rats were allotted into 1 of 6 groups: saline (NS), activated charcoal (AC), polyethylene glycol (PEG), NS+INF treated, AC+INF treated, and PEG+INF treated. All materials were aspirated into the lungs at a volume of 1 mL/kg. Before aspiration, the rats were injected subcutaneously with INF. Seven days later, both lungs and serum specimens in all groups were evaluated histopathologically, immunohistochemically, and biochemically. Following aspiration of AC and PEG, evident histopathological changes were assigned in the lung tissue that were associated with increased expression of inducible nitric oxide synthase (iNOS), increased serum levels of oxidative stress markers (malondialdehyde [MDA], surfactant protein-D [SP-D], TNF-α), and decreased antioxidant enzyme (glutathione peroxidase [GSH-Px]) activities. INF treatment significantly decreased the elevated serum MDA and TNF-α levels and increased serum GSH-Px levels. Furthermore, the current results show that there is a significant reduction in the activity of iNOS in lung tissue and increased serum SP-D levels of AC and PEG aspiration-induced lung injury with INF treatment. These findings suggest that INF attenuates lung inflammation and prevents GI decontamination agent-induced lung injury in rats.

  13. Computational multiscale toxicodynamic modeling of silver and carbon nanoparticle effects on mouse lung function.

    Directory of Open Access Journals (Sweden)

    Dwaipayan Mukherjee

    Full Text Available A computational, multiscale toxicodynamic model has been developed to quantify and predict pulmonary effects due to uptake of engineered nanomaterials (ENMs in mice. The model consists of a collection of coupled toxicodynamic modules, that were independently developed and tested using information obtained from the literature. The modules were developed to describe the dynamics of tissue with explicit focus on the cells and the surfactant chemicals that regulate the process of breathing, as well as the response of the pulmonary system to xenobiotics. Alveolar type I and type II cells, and alveolar macrophages were included in the model, along with surfactant phospholipids and surfactant proteins, to account for processes occurring at multiple biological scales, coupling cellular and surfactant dynamics affected by nanoparticle exposure, and linking the effects to tissue-level lung function changes. Nanoparticle properties such as size, surface chemistry, and zeta potential were explicitly considered in modeling the interactions of these particles with biological media. The model predictions were compared with in vivo lung function response measurements in mice and analysis of mice lung lavage fluid following exposures to silver and carbon nanoparticles. The predictions were found to follow the trends of observed changes in mouse surfactant composition over 7 days post dosing, and are in good agreement with the observed changes in mouse lung function over the same period of time.

  14. Failure of the cultivated mushroom (Agaricus bisporus) to induce tumors in the A/J mouse lung tumor model

    DEFF Research Database (Denmark)

    Pilegaard, Kirsten; Kristiansen, E.; Meyer, Otto A.

    1997-01-01

    We studied whether the cultivated mushroom (Agaricus bisporus) or 4-(carboxy)phenylhydrazine (CP) induce lung adenomas in the A/J mouse lung tumor model. For 26 weeks female mice were fed a semisynthetic diet where 11 or 22% of the diet was replaced by freeze-dried mushrooms. The intake...

  15. Establishment of Orthotopic Xuanwei Lung Cancer SCID Mouse Model 
and Analysis of Biological Properties

    Directory of Open Access Journals (Sweden)

    Yongchun ZHOU

    2012-08-01

    Full Text Available Background and objective The incidence of Xuanwei lung cancer ranks first in China, and its pathogenesis requires in-depth investigation. This study aims to establish an orthotopic Xuanwei lung cancer severe combined immunodeficiency (SCID mouse model and to provide a basic experimental platform for further study. Methods The Xuanwei lung cancer cell line XWLC-05 was inoculated into the lung tissue of SCID mice in high and low doses. The tumor formation rates, tumor characteristics, spontaneous metastases, and survival times of the mice were observed, taking a subcutaneously transplanted tumor as control. Results The tumor formation rates of the orthotopic transplantation of lung cancer cells in high and low doses were 81% and 83%, respectively, among which mice in the high-dose group appeared cachectic on day 13. Extensive invasion and adhesion were observed in the contralateral lung and thoracic cavity, but no distant metastasis was exhibited. Mice with low-dose cells in the orthotopic transplantation group appeared cachectic and distant metastasis occurred on day 25. The tumor formation rates in the subcutaneous inoculation group by the high and low doses of cells were 100% and 94.5%, respectively, and no distant metastasis was observed. The rate of metastasis within the orthotopic transplantation group and between the orthotopic and subcutaneous inoculation groups showed a significant difference (P<0.05. A significant difference was indicated by the survival rate within and between the groups (P<0.001. Conclusion We successfully established an orthotopic XWLC SCID mouse model, which lays the foundation for a more in-depth study.

  16. Lung Pathologies in a Chronic Inflammation Mouse Model Are Independent of Eosinophil Degranulation.

    Science.gov (United States)

    Jacobsen, Elizabeth A; Ochkur, Sergei I; Doyle, Alfred D; LeSuer, William E; Li, Wen; Protheroe, Cheryl A; Colbert, Dana; Zellner, Katie R; Shen, HuaHao H; Irvin, Charles G; Lee, James J; Lee, Nancy A

    2017-05-15

    The release of eosinophil granule proteins in the lungs of patients with asthma has been dogmatically linked with lung remodeling and airway hyperresponsiveness. However, the demonstrated inability of established mouse models to display the eosinophil degranulation occurring in human subjects has prevented a definitive in vivo test of this hypothesis. To demonstrate in vivo causative links between induced pulmonary histopathologies/lung dysfunction and eosinophil degranulation. A transgenic mouse model of chronic T-helper cell type 2-driven inflammation overexpressing IL-5 from T cells and human eotaxin 2 in the lung (I5/hE2) was used to test the hypothesis that chronic histopathologies and the development of airway hyperresponsiveness occur as a consequence of extensive eosinophil degranulation in the lung parenchyma. Studies targeting specific inflammatory pathways in I5/hE2 mice surprisingly showed that eosinophil-dependent immunoregulative events and not the release of individual secondary granule proteins are the central contributors to T-helper cell type 2-induced pulmonary remodeling and lung dysfunction. Specifically, our studies highlighted a significant role for eosinophil-dependent IL-13 expression. In contrast, extensive degranulation leading to the release of major basic protein-1 or eosinophil peroxidase was not causatively linked to many of the induced pulmonary histopathologies. However, these studies did define a previously unappreciated link between the release of eosinophil peroxidase (but not major basic protein-1) and observed levels of induced airway mucin. These data suggest that improvements observed in patients with asthma responding to therapeutic strategies ablating eosinophils may occur as a consequence of targeting immunoregulatory mechanisms and not by simply eliminating the destructive activities of these purportedly end-stage effector cells.

  17. Mouse lung infection model to assess Rhodococcus equi virulence and vaccine protection.

    Science.gov (United States)

    González-Iglesias, Patricia; Scortti, Mariela; MacArthur, Iain; Hapeshi, Alexia; Rodriguez, Héctor; Prescott, John F; Vazquez-Boland, José A

    2014-08-06

    The pathogenic actinomycete Rhodococcus equi causes severe purulent lung infections in foals and immunocompromised people. Although relatively unsusceptible to R. equi, mice are widely used for in vivo studies with this pathogen. The most commonly employed mouse model is based on systemic (intravenous) infection and determination of R. equi burdens in spleen and liver. Here, we investigated the murine lung for experimental infection studies with R. equi. Using a 10(7)CFU intranasal challenge in BALB/c mice, virulent R. equi consistently survived in quantifiable numbers up to 10 days in the lungs whereas virulence-deficient R. equi bacteria were rapidly cleared. An internally controlled virulence assay was developed in which the test R. equi strains are co-inoculated and monitored in the same mouse. Isogenic R. equi bacteria lacking either the plasmid vapA gene or the entire virulence plasmid were compared using this competitive assay. Both strains showed no significant differences in in vivo fitness in the lung, indicating that the single loss of the virulence factor VapA was sufficient to account for the full attenuation seen in the absence of the virulence plasmid. To test the adequacy of the lung infection model for monitoring R. equi vaccine efficacy, BALB/c mice were immunized with live R. equi and challenged intranasally. Vaccination conferred protection against acute pulmonary challenge with virulent R. equi. Our data indicate that the murine lung infection model provides a useful tool for both R. equi virulence and vaccine studies. Copyright © 2014 Elsevier B.V. All rights reserved.

  18. Differing patterns of P-selectin expression in lung injury

    DEFF Research Database (Denmark)

    Bless, N M; Tojo, S J; Kawarai, H

    1998-01-01

    -selectin. In the immune complex model, upregulation of P-selectin was defined by Northern and Western blot analysis of lung homogenates, by immunostaining of lung tissue, and by vascular fixation of 125I-labeled anti-P-selectin. P-selectin protein was detected by 1 hour (long before detection of mRNA) and expression...

  19. DIFFERENTIAL SUSCEPTIBILITY OF HUMAN SP-B GENETIC VARIANTS ON LUNG INJURY CAUSED BY BACTERIAL PNEUMONIA AND THE EFFECT OF A CHEMICALLY MODIFIED CURCUMIN.

    Science.gov (United States)

    Xu, Yongan; Ge, Lin; Abdel-Razek, Osama; Jain, Sumeet; Liu, Zhiyong; Hong, Yucai; Nieman, Gary; Johnson, Francis; Golub, Lorne M; Cooney, Robert N; Wang, Guirong

    2016-04-01

    Staphylococcus aureus is a common cause of nosocomial pneumonia frequently resulting in acute respiratory distress syndrome (ARDS). Surfactant protein B (SP-B) gene expresses two proteins involved in lowering surface tension and host defense. Genotyping studies demonstrate a significant association between human SP-B genetic variants and ARDS. Curcumins have been shown to attenuate host inflammation in many sepsis models. Our hypothesis is that functional differences of SP-B variants and treatment with curcumin (CMC2.24) modulate lung injury in bacterial pneumonia. Humanized transgenic mice, expressing either SP-B T or C allele without mouse SP-B gene, were used. Bioluminescent labeled S. aureus Xen 36 (50 μL) was injected intratracheally to cause pneumonia. Infected mice received daily CMC2.24 (40 mg/kg) or vehicle alone by oral gavage. Dynamic changes of bacteria were monitored using in vivo imaging system. Histological, cellular, and molecular indices of lung injury were studied in infected mice 48 h after infection. In vivo imaging analysis revealed total flux (bacterial number) was higher in the lung of infected SP-B-C mice compared with infected SP-B-T mice (P pneumonia than mice with SP-B-T allele, and that CMC2.24 attenuates lung injury thus reducing mortality.

  20. Asiaticoside attenuates lipopolysaccharide-induced acute lung injury via down-regulation of NF-κB signaling pathway.

    Science.gov (United States)

    Qiu, Jiaming; Yu, Lijun; Zhang, Xingxing; Wu, Qianchao; Wang, Di; Wang, Xiuzhi; Xia, Cheng; Feng, Haihua

    2015-05-01

    Asiaticoside (AS), a triterpene glycoside isolated from Centella asiatica, has been shown to possess potent anti-inflammatory activity. However, the detailed molecular mechanisms of AS on lipopolysaccharide (LPS)-induced acute lung injury (ALI) model in mice are scanty. The purpose of this study was to evaluate the effect of AS on LPS-induced mouse ALI via down-regulation of NF-κB signaling pathway. We investigated the efficacy of AS on cytokine levels induced by LPS in bronchoalveolar lavage fluid (BALF) and RAW 264.7 cells. The production of cytokine (TNF-α and IL-6) was measured by enzyme-linked immunosorbent assay (ELISA). The lung wet-to-dry weight ratios were measured in LPS-challenged mice, and lung histopathologic changes observed via paraffin section were assessed. To further study the mechanism of AS protective effects on ALI, the activation of NF-κB p65 subunit and the degradation of IκBα were tested by western blot assay. We found that AS treatment at 15, 30 or 45mg/kg dose-dependently attenuated LPS-induced pulmonary inflammation by reducing inflammatory infiltration, histopathological changes, descended cytokine production, and pulmonary edema initiated by LPS. Furthermore, our results suggested that AS suppressed inflammatory responses in LPS-induced ALI through inhibition of the phosphorylation of NF-κB p65 subunit and the degradation of its inhibitor IκBα, and might be a new preventive agent of ALI in the clinical setting.

  1. 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.

  2. Protective Effect of Rhubarb on Endotoxin-Induced Acute Lung Injury

    Institute of Scientific and Technical Information of China (English)

    李春盛; 周景; 桂培春; 何新华

    2001-01-01

    To approach the mechanism of lipopolysaccharide (LPS) in causing acute lung injury (ALI) and the protective effect of rhubarb and dexamethasone, lung specimens were examined with macroscopy, microscopy, electron microscopy and the biological markers of ALI including lung wet/dry weight, the rate of neutrophils and protein content in the pulmonary alveolar lavage fluid, pulmonary capillary permeability and pulmonary alveolar permeability index were observed. The mechanism of the ALI is mainly due to direct injury of alveolar epithelium and pulmonary vascular endothelium. Rhubarb and dexamethasone could significantly reduce the edema of the lung tissue, decrease the red blood cell exudation, neutrophil infiltration and plasma protein exudation in the alveoli and all the biological markers in comparison with the ALI model rats, indicating they have protective action on vascular endothelium and alveolar epithelium.

  3. Pancreatic enzymes in the gut contributing to lung injury after trauma/hemorrhagic shock

    Institute of Scientific and Technical Information of China (English)

    石汉平; 刘正军; 闻英

    2004-01-01

    Objective: To examine whether pancreatic proteolytic enzymes involve in lung injury induced by trauma/hemorrhagic shock (T/HS). Results: Lung permeability, pulmonary myeloperoxidase levels and the ratio of bronchoalveolar lavage fluid protein to plasma protein increased after T/HS, and significantly decreased in intraluminal-ANGD treated but not in intravenous-ANGD treated rats. Histological analysis demonstrated fewer injured villi in the intraluminal-ANGD treated rats compared with those in the control rats. Linear regression analysis revealed that the percentage of injured ileal mucosal villi directly related to pulmonary polymorphic neutrophil sequestration and lung permeability to Evans blue dye. Conclusions: Pancreatic proteolytic enzymes in the ischemic gut may be important toxic factors contributing to lung injury after T/HS.

  4. TGFβ signaling in lung epithelium regulates bleomycin-induced alveolar injury and fibroblast recruitment.

    Science.gov (United States)

    Degryse, Amber L; Tanjore, Harikrishna; Xu, Xiaochuan C; Polosukhin, Vasiliy V; Jones, Brittany R; Boomershine, Chad S; Ortiz, Camila; Sherrill, Taylor P; McMahon, Frank B; Gleaves, Linda A; Blackwell, Timothy S; Lawson, William E

    2011-06-01

    The response of alveolar epithelial cells (AECs) to lung injury plays a central role in the pathogenesis of pulmonary fibrosis, but the mechanisms by which AECs regulate fibrotic processes are not well defined. We aimed to elucidate how transforming growth factor-β (TGFβ) signaling in lung epithelium impacts lung fibrosis in the intratracheal bleomycin model. Mice with selective deficiency of TGFβ receptor 2 (TGFβR2) in lung epithelium were generated and crossed to cell fate reporter mice that express β-galactosidase (β-gal) in cells of lung epithelial lineage. Mice were given intratracheal bleomycin (0.08 U), and the following parameters were assessed: AEC death by terminal deoxynucleotidyl transferase dUTP-mediated nick-end labeling assay, inflammation by total and differential cell counts from bronchoalveolar lavage, fibrosis by scoring of trichrome-stained lung sections, and total lung collagen content. Mice with lung epithelial deficiency of TGFβR2 had improved AEC survival, despite greater lung inflammation, after bleomycin administration. At 3 wk after bleomycin administration, mice with epithelial TGFβR2 deficiency showed a significantly attenuated fibrotic response in the lungs, as determined by semiquantitatve scoring and total collagen content. The reduction in lung fibrosis in these mice was associated with a marked decrease in the lung fibroblast population, both total lung fibroblasts and epithelial-to-mesenchymal transition-derived (S100A4(+)/β-gal(+)) fibroblasts. Attenuation of TGFβ signaling in lung epithelium provides protection from bleomycin-induced fibrosis, indicating a critical role for the epithelium in transducing the profibrotic effects of this cytokine.

  5. Multislice spiral computed tomography to determine the effects of a recruitment maneuver in experimental lung injury

    Energy Technology Data Exchange (ETDEWEB)

    Henzler, Dietrich; Rossaint, Rolf [University Hospital, RWTH Aachen, Anesthesiology Department, Aachen (Germany); Mahnken, Andreas H.; Wildberger, Joachim E.; Guenther, Rolf W. [University Hospital of the RWTH Aachen, Clinic of Diagnostic Radiology, Aachen (Germany); Kuhlen, Ralf [University Hospital of the RWTH Aachen, Operative Intensive Care Department, Aachen (Germany)

    2006-06-15

    Although recruitment of atelectatic lung is a common aim in acute respiratory distress syndrome (ARDS), the effects of a recruitment maneuver have not been assessed quantitatively. By multislice spiral CT (MSCT), we analyzed the changes in lung volumes calculated from the changes in the CT values of hyperinflated (V{sub HYP}), normally (V{sub NORM}), poorly (V{sub POOR}) and nonaerated (V{sub NON}) lung in eight mechanically ventilated pigs with saline lavage-induced acute lung injury before and after a recruitment maneuver. This was compared to single slice analysis near the diaphragm. The increase in aerated lung was mainly for V{sub POOR} and the less in V{sub NORM}. Total lung volume and intrathoracic gas increased. No differences were found for tidal volumes measured by spirometry or determined by CT. The inspiratory-expiratory volume differences were not different after the recruitment maneuver in V{sub NON} (from 62{+-}18 ml to 43{+-}26 ml, P=0.114), and in V{sub NORM} (from 216{+-}51 ml to 251{+-}37 ml, P=0.102). Single slice analysis significantly underestimated the increase in normally and poorly aerated lung. Quantitative analysis of lung volumes by whole lung MSCT revealed the increase of poorly aerated lung as the main mechanism of a standard recruitment maneuver. MSCT can provide additional information as compared to single slice CT. (orig.)

  6. Renal Impairment with Sublethal Tubular Cell Injury in a Chronic Liver Disease Mouse Model.

    Science.gov (United States)

    Ishida, Tokiko; Kotani, Hirokazu; Miyao, Masashi; Kawai, Chihiro; Jemail, Leila; Abiru, Hitoshi; Tamaki, Keiji

    2016-01-01

    The pathogenesis of renal impairment in chronic liver diseases (CLDs) has been primarily studied in the advanced stages of hepatic injury. Meanwhile, the pathology of renal impairment in the early phase of CLDs is poorly understood, and animal models to elucidate its mechanisms are needed. Thus, we investigated whether an existing mouse model of CLD induced by 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) shows renal impairment in the early phase. Renal injury markers, renal histology (including immunohistochemistry for tubular injury markers and transmission electron microscopy), autophagy, and oxidative stress were studied longitudinally in DDC- and standard diet-fed BALB/c mice. Slight but significant renal dysfunction was evident in DDC-fed mice from the early phase. Meanwhile, histological examinations of the kidneys with routine light microscopy did not show definitive morphological findings, and electron microscopic analyses were required to detect limited injuries such as loss of brush border microvilli and mitochondrial deformities. Limited injuries have been recently designated as sublethal tubular cell injury. As humans with renal impairment, either with or without CLD, often show almost normal tubules, sublethal injury has been of particular interest. In this study, the injuries were associated with mitochondrial aberrations and oxidative stress, a possible mechanism for sublethal injury. Intriguingly, two defense mechanisms were associated with this injury that prevent it from progressing to apparent cell death: autophagy and single-cell extrusion with regeneration. Furthermore, the renal impairment of this model progressed to chronic kidney disease with interstitial fibrosis after long-term DDC feeding. These findings indicated that DDC induces renal impairment with sublethal tubular cell injury from the early phase, leading to chronic kidney disease. Importantly, this CLD mouse model could be useful for studying the pathophysiological mechanisms of

  7. Renal Impairment with Sublethal Tubular Cell Injury in a Chronic Liver Disease Mouse Model.

    Directory of Open Access Journals (Sweden)

    Tokiko Ishida

    Full Text Available The pathogenesis of renal impairment in chronic liver diseases (CLDs has been primarily studied in the advanced stages of hepatic injury. Meanwhile, the pathology of renal impairment in the early phase of CLDs is poorly understood, and animal models to elucidate its mechanisms are needed. Thus, we investigated whether an existing mouse model of CLD induced by 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC shows renal impairment in the early phase. Renal injury markers, renal histology (including immunohistochemistry for tubular injury markers and transmission electron microscopy, autophagy, and oxidative stress were studied longitudinally in DDC- and standard diet-fed BALB/c mice. Slight but significant renal dysfunction was evident in DDC-fed mice from the early phase. Meanwhile, histological examinations of the kidneys with routine light microscopy did not show definitive morphological findings, and electron microscopic analyses were required to detect limited injuries such as loss of brush border microvilli and mitochondrial deformities. Limited injuries have been recently designated as sublethal tubular cell injury. As humans with renal impairment, either with or without CLD, often show almost normal tubules, sublethal injury has been of particular interest. In this study, the injuries were associated with mitochondrial aberrations and oxidative stress, a possible mechanism for sublethal injury. Intriguingly, two defense mechanisms were associated with this injury that prevent it from progressing to apparent cell death: autophagy and single-cell extrusion with regeneration. Furthermore, the renal impairment of this model progressed to chronic kidney disease with interstitial fibrosis after long-term DDC feeding. These findings indicated that DDC induces renal impairment with sublethal tubular cell injury from the early phase, leading to chronic kidney disease. Importantly, this CLD mouse model could be useful for studying the

  8. Protective effect of ghrelin against paraquatinduced acute lung injury in mice

    Institute of Scientific and Technical Information of China (English)

    刘瑶

    2014-01-01

    Objective To measure the levels of ghrelin-induced expression or activation of nuclear factor erythroid 2-re-lated factor 2(Nrf2),heme oxygenase-1(HO-1),and NAD(P)H:quinone oxidoreductase 1(NQO1)in the PQ-injured lungs of mice and to evaluate the protective effect of ghrelin against paraquat(PQ)-induced acute lung injury in mice.Methods According to the random number table method,50 ICR mice of clean grade were

  9. Leukotriene biosynthesis inhibition ameliorates acute lung injury following hemorrhagic shock in rats

    Directory of Open Access Journals (Sweden)

    Hadi Najah R

    2011-06-01

    Full Text Available Abstract Background Hemorrhagic shock followed by resuscitation is conceived as an insult frequently induces a systemic inflammatory response syndrome and oxidative stress that results in multiple-organ dysfunction syndrome including acute lung injury. MK-886 is a leukotriene biosynthesis inhibitor exerts an anti inflammatory and antioxidant activity. Objectives The objective of present study was to assess the possible protective effect of MK-886 against hemorrhagic shock-induced acute lung injury via interfering with inflammatory and oxidative pathways. Materials and methods Eighteen adult Albino rats were assigned to three groups each containing six rats: group I, sham group, rats underwent all surgical instrumentation but neither hemorrhagic shock nor resuscitation was done; group II, Rats underwent hemorrhagic shock (HS for 1 hr then resuscitated with Ringer's lactate (1 hr (induced untreated group, HS; group III, HS + MK-886 (0.6 mg/kg i.p. injection 30 min before the induction of HS, and the same dose was repeated just before reperfusion period. At the end of experiment (2 hr after completion of resuscitation, blood samples were collected for measurement of serum tumor necrosis factor-α (TNF-α and interleukin-6 (IL-6. The trachea was then isolated and bronchoalveolar lavage fluid (BALF was carried out for measurement of leukotriene B4 (LTB4, leukotriene C4 (LTC4 and total protein. The lungs were harvested, excised and the left lung was homogenized for measurement of malondialdehyde (MDA and reduced glutathione (GSH and the right lung was fixed in 10% formalin for histological examination. Results MK-886 treatment significantly reduced the total lung injury score compared with the HS group (P 4, LTC4 & total protein compared with the HS group (P P Conclusions The results of the present study reveal that MK-886 may ameliorate lung injury in shocked rats via interfering with inflammatory and oxidative pathways implicating the role of

  10. Effect of partial liquid ventilation on lung function in oleic acid-induced lung injury model of piglets

    Institute of Scientific and Technical Information of China (English)

    ZHANG Ji-zhuo; LI Ling-ke; ZHANG Yan-bo; LI Gang; XU Yu-lin; ZHU Yao-bin

    2013-01-01

    Background Pediatric patients are susceptible to lung injury that does not respond to traditional therapies.Partial liquid ventilation (PLV) has been developed as an alternative ventilatory strategy for treating severe lung injury.The aim of this study is to investigate the effect of PLV on lung function in immature piglets.Methods Acute lung injury was induced in 12 Chinese immature piglets by oleic acid (OA).The animals were randomly assigned to two groups (n=6 each group):(1) conventional mechanical ventilation (MV) group and (2) PLV with FC-77 (10 ml/kg) group.Mean arterial blood pressure (MAP),mean pulmonary arterial pressure (MPAP),central venous pressure (CVP),left atrial pressure (LAP),systemic vascular resistance (SVR),pulmonary vascular resistance (PVR),cardiac output (CO),mean pressure of airway (Paw),dynamic lung compliance (Cydn),and arterial blood gases were measured during the observation period.Results No piglet died in either group with severe lung injury.After four hours of ventilation,pH in the MV group gradually decreased to lower than 7.20,while in the PLV group,pH also gradually decreased but remained higher than 7.20 (P <0.05).Partial pressure of oxygen in artery (PaO2) decreased in both groups,but with a significant difference between the PLV group and MV group (P <0.05).Partial pressure of carbon dioxide in artery (PaCO2) increased in both groups,but with a significant difference between the PLV group and MV group (P <0.05).Paw increased in both groups,but was not significantly different (P >0.05).Cydn decreased in both groups,but without a significant difference (P >0.05).At four hours,heart rate (HR) and MAP in both groups decreased.MPAP in both groups increased,and there was a significant difference between the two groups (P <0.05).CVP was stable in both groups.At four hours,PVR and LAP were increased in both groups.CO was decreased in both groups (P <0.05).SVR was stable during the observation time.Conclusion PLV did not

  11. An official American Thoracic Society research statement: noninfectious lung injury after hematopoietic stem cell transplantation: idiopathic pneumonia syndrome.

    Science.gov (United States)

    Panoskaltsis-Mortari, Angela; Griese, Matthias; Madtes, David K; Belperio, John A; Haddad, Imad Y; Folz, Rodney J; Cooke, Kenneth R

    2011-05-01

    Acute lung dysfunction of noninfectious etiology, known as idiopathic pneumonia syndrome (IPS), is a severe complication following hematopoietic stem cell transplantation (HSCT). Several mouse models have been recently developed to determine the underlying causes of IPS. A cohesive interpretation of experimental data and their relationship to the findings of clinical research studies in humans is needed to better understand the basis for current and future clinical trials for the prevention/treatment of IPS. Our goal was to perform a comprehensive review of the preclinical (i.e., murine models) and clinical research on IPS. An ATS committee performed PubMed and OVID searches for published, peer-reviewed articles using the keywords "idiopathic pneumonia syndrome" or "lung injury" or "pulmonary complications" AND "bone marrow transplant" or "hematopoietic stem cell transplant." No specific inclusion or exclusion criteria were determined a priori for this review. Experimental models that reproduce the various patterns of lung injury observed after HSCT have identified that both soluble and cellular inflammatory mediators contribute to the inflammation engendered during the development of IPS. To date, 10 preclinical murine models of the IPS spectrum have been established using various donor and host strain combinations used to study graft-versus-host disease (GVHD). This, as well as the demonstrated T cell dependency of IPS development in these models, supports the concept that the lung is a target of immune-mediated attack after HSCT. The most developed therapeutic strategy for IPS involves blocking TNF signaling with etanercept, which is currently being evaluated in clinical trials. IPS remains a frequently fatal complication that limits the broader use of allogeneic HSCT as a successful treatment modality. Faced with the clinical syndrome of IPS, one can categorize the disease entity with the appropriate tools, although cases of unclassifiable IPS will remain

  12. Mitigation of Lung Injury after Accidental Exposure to Radiation

    Science.gov (United States)

    Mahmood, J.; Jelveh, S.; Calveley, V.; Zaidi, A.; Doctrow, S. R.; Hill, R. P.

    2011-01-01

    There is a serious need to develop effective mitigators against accidental radiation exposures. In radiation accidents, many people may receive nonuniform whole-body or partial-body irradiation. The lung is one of the more radiosensitive organs, demonstrating pneumonitis and fibrosis that are believed to develop at least partially because of radiation-induced chronic inflammation. Here we addressed the crucial questions of how damage to the lung can be mitigated and whether the response is affected by irradiation to the rest of the body. We examined the widely used dietary supplement genistein given at two dietary levels (750 or 3750 mg/kg) to Fischer rats irradiated with 12 Gy to the lung or 8 Gy to the lung + 4 Gy to the whole body excluding the head and tail (whole torso). We found that genistein had promising mitigating effects on oxidative damage, pneumonitis and fibrosis even at late times (36 weeks) when drug treatment was initiated 1 week after irradiation and stopped at 28 weeks postirradiation. The higher dose of genistein showed no greater beneficial effect. Combined lung and whole-torso irradiation caused more lung-related severe morbidity resulting in euthanasia of the animals than lung irradiation alone. PMID:22013884

  13. A mouse model of human repetitive mild traumatic brain injury

    OpenAIRE

    Kane, Michael J; Pérez, Mariana Angoa; Briggs, Denise I.; Viano, David C.; Kreipke, Christian W.; Kuhn, Donald M.

    2011-01-01

    A novel method for the study of repetitive mild traumatic brain injury (rmTBI) that models the most common form of head injury in humans is presented. Existing animal models of TBI impart focal, severe damage unlike that seen in repeated and mild concussive injuries, and few are configured for repetitive application. Our model is a modification of the Marmarou weight drop method and allows repeated head impacts to lightly anesthetized mice. A key facet of this method is the delivery of an imp...

  14. Lung preservation in experimental ischemia/reperfusion injury and lung transplantation: a comparison of natural and synthetic surfactants.

    Science.gov (United States)

    Knudsen, Lars; Boxler, Laura; Mühlfeld, Christian; Schaefer, Inga-Marie; Becker, Laura; Bussinger, Christine; von Stietencron, Immanuel; Madershahian, Navid; Richter, Joachim; Wahlers, Thorsten; Wittwer, Thorsten; Ochs, Matthias

    2012-01-01

    Surfactant inactivation results from ischemia/reperfusion injury and plays a major role in the pathogenesis of primary graft dysfunction after clinical lung transplantation. Thus, prophylactic administration of exogenous surfactant preparations before the onset of ischemia/reperfusion has proven to be effective in preserving pulmonary structure and function. Various natural and synthetic surfactant preparations exhibit differences regarding the biochemical composition and biophysical properties. In this study we compared the efficacy of preservation of pulmonary structure and function of the natural surfactant preparations Curosurf and Survanta to that of a synthetic surfactant containing an analog of surfactant protein C (SPC-33) in a rat model of ischemia/reperfusion injury. The oxygenation capacity and peak inspiratory pressure during the reperfusion period were recorded. By applying design-based stereology at the light- and electron-microscopic level, pathologic alterations, including alveolar edema, injury of the blood-air barrier and the intra-alveolar as well as intracellular surfactant pools, were quantified. The best oxygenation and preservation of lung structure was achieved with Curosurf. Survanta treatment was associated with the most severe injury of the blood-air barrier, and SPC-33 demonstrated signs of microatelectasis. The intra-alveolar surfactant pool after Curosurf and SPC-33 was dominated by active surfactant subtypes, whereas Survanta was associated with the highest fraction of inactive surfactant. The intracellular surfactant pool did not show any differences between the treatment groups. Taken together, Curosurf achieved the best structural and functional lung preservation, whereas Survanta was inferior to both Curosurf and SPC-33. Copyright © 2012 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.

  15. Cellular changes in bronchoalveolar lavage fluid in hyperoxia-induced lung injury

    Institute of Scientific and Technical Information of China (English)

    Xinbiao HE; Wei ZHAO

    2008-01-01

    It is well known that high concentration oxy-gen exposure is a model of acute lung injury (ALI). However, controversy exists over the mechanism. This study was designed to clarify the cellular characteristics in bronchoalveolar lavage fluid (BALF) and body weight loss of rats exposed to oxygen(>90%). Young male Wistar rats, aged 6 weeks, were divided into three groups: (1) room air group (exposed to room air, n=22); (2) hyperoxia < 48 h group (exposed to over 90% oxygen for less than 48 h, n=18); (3) hyperoxia 66-72 h group (exposed to over 90% oxygen for 66-72 h group, n=7). Compared to the room air group, the total cell counts in the hyperoxia 66-72 h group decreased, whereas the neu-trophils increased significantly. The body weights of the rats exposed to room air continued to increase. However, the body weights of oxygen-exposed rats increased slightly on the first day and weight loss was seen from the second day. All rats were noted to have bilateral pleural effusion in the hyperoxia 66-72 h group. The data suggests that (1) an increase in neutrophil count is an evident feature of hyperoxia-induced lung injury; (2) high concentration oxygen exposure can give rise to anorexia and malnutri-tion, which may play a role in hyperoxia-induced lung injury. Blocking neutrophil influx into lung tissue in the early phase and improving malnutrition are two effective methods to reduce hyperoxic lung injury.

  16. Low positive end-expiratory pressure does not exacerbate nebulized-acid lung injury in dogs.

    Science.gov (United States)

    Pellett, Andrew A; Welsh, David A; deBoisblanc, Bennett P; Lipscomb, Gary; Johnson, Royce W; Lord, Kevin C; Levitzky, Michael G

    2005-03-01

    It is not clear if low end-expiratory pressures contribute to ventilator-induced lung injury in large animals. We sought to determine whether ventilation with a low level of positive end-expiratory pressure (PEEP) worsens preexisting permeability lung injury in dogs. Lung injury was initiated in 20 mongrel dogs by ventilating with nebulized 3N hydrochloric acid until a lower inflection point (LIP) appeared on the respiratory system pressure-volume loop. One group of 10 dogs was then ventilated for 4 hours with PEEP set below the LIP (low PEEP), whereas the remaining group of dogs was ventilated for the same time period with similar tidal volumes but with PEEP set above the LIP (high PEEP). We found histologic evidence of reduced alveolar volumes in the low-PEEP animals. However, there were no differences in neutrophil infiltration, lung lobe weights, pulmonary capillary hemorrhage or congestion, or arterial endothelin-1 concentration between the 2 protocol groups. In conclusion, we were unable to demonstrate that ventilation with PEEP set below the LIP exacerbates hydrochloric acid-induced lung injury in dogs.

  17. Protective effect of heme oxygenase-1 on lung injury induced by erythrocyte instillation in rats

    Institute of Scientific and Technical Information of China (English)

    PANG Qing-feng; ZHOU Qiao-mei; ZENG Si; DOU Li-dong; JI Yong; ZENG Yin-ming

    2008-01-01

    Background Intratracheal instillation of blood induces self-repaired acute lung injury.However,the mechanism of repair has been unclear.Heme-oxygenase (HO)-1,which catalyzes heine breakdown,acts as an inducible defense against oxidative stress and plays an important role in inflammation.The objective of this study was to test the role of HO-1 in lung injury caused by intratracheal instillation of red cells.Methods Forty healthy,male Sprague-Dawley rats were randomly divided into five groups:normal group,saline group,erythrocyte group,erythrocyte+zinc-protoporphyrin (ZnPP,HO-1 inhibitor) group and saline+ZnPP group.At 2 days after intratracheal instillation of red cells,lung tissues and lavage samples were isolated for biochemical determinations and histological measurements.Results Histological analysis revealed that administration of ZnPP worsened the acute lung injury induced by instilled erythrocytes.HO-1 was over-expressed in the erythrocyte group and in the erythrocyte+ZnPP group.Compared with the erythrocyte+ZnPP group,the levels of total protein,lactate dehydrogenase and tumor necrosis factor-α in the lavage were lower (P<0.01),while the level of interleukin-10 was higher in the erythrocyte group (P<0.01).Conclusion HO-1 protects against erythrocyte-induced inflammatory injury in lung.

  18. Effects of alprostadil and iloprost on renal, lung, and skeletal muscle injury following hindlimb ischemia-reperfusion injury in rats.

    Science.gov (United States)

    Erer, Dilek; Özer, Abdullah; Demirtaş, Hüseyin; Gönül, İpek Işık; Kara, Halil; Arpacı, Hande; Çomu, Faruk Metin; Oktar, Gürsel Levent; Arslan, Mustafa; Küçük, Ayşegül

    2016-01-01

    To evaluate the effects of alprostadil (prostaglandin [PGE1] analog) and iloprost (prostacyclin [PGI2] analog) on renal, lung, and skeletal muscle tissues after ischemia reperfusion (I/R) injury in an experimental rat model. Wistar albino rats underwent 2 hours of ischemia via infrarenal aorta clamping with subsequent 2 hours of reperfusion. Alprostadil and iloprost were given starting simultaneously with the reperfusion period. Effects of agents on renal, lung, and skeletal muscle (gastrocnemius) tissue specimens were examined. Renal medullary congestion, cytoplasmic swelling, and mean tubular dilatation scores were significantly lower in the alprostadil-treated group than those found in the I/R-only group (Piloprost-treated groups (P=0.017 and P=0.001; Piloprost-treated group than the scores found in the nontreated I/R group (Piloprost significantly reduce lung tissue I/R injury. Alprostadil has more prominent protective effects against renal I/R injury, while iloprost is superior in terms of protecting the skeletal muscle tissue against I/R injury.

  19. Effects of alprostadil and iloprost on renal, lung, and skeletal muscle injury following hindlimb ischemia–reperfusion injury in rats

    Science.gov (United States)

    Erer, Dilek; Özer, Abdullah; Demirtaş, Hüseyin; Gönül, İpek Işık; Kara, Halil; Arpacı, Hande; Çomu, Faruk Metin; Oktar, Gürsel Levent; Arslan, Mustafa; Küçük, Ayşegül

    2016-01-01

    Objectives To evaluate the effects of alprostadil (prostaglandin [PGE1] analog) and iloprost (prostacyclin [PGI2] analog) on renal, lung, and skeletal muscle tissues after ischemia reperfusion (I/R) injury in an experimental rat model. Materials and methods Wistar albino rats underwent 2 hours of ischemia via infrarenal aorta clamping with subsequent 2 hours of reperfusion. Alprostadil and iloprost were given starting simultaneously with the reperfusion period. Effects of agents on renal, lung, and skeletal muscle (gastrocnemius) tissue specimens were examined. Results Renal medullary congestion, cytoplasmic swelling, and mean tubular dilatation scores were significantly lower in the alprostadil-treated group than those found in the I/R-only group (Palprostadil- and iloprost-treated groups (P=0.017 and P=0.001; PAlprostadil and iloprost significantly reduce lung tissue I/R injury. Alprostadil has more prominent protective effects against renal I/R injury, while iloprost is superior in terms of protecting the skeletal muscle tissue against I/R injury. PMID:27601882

  20. Segmental pulmonary vascular resistances during oleic acid lung injury in rabbits.

    Science.gov (United States)

    Maarek, J M; Grimbert, F

    1994-10-01

    We studied in isolated rabbit lungs the effects of oleic acid (OA) injury on the segmental distribution of vascular resistance. Vascular occlusion pressures were measured in control and OA-injured preparations over 90 min. Capillary filtration coefficient KF,C increased from 0.61 (+/- 0.10) to 0.91 (+/- 0.14) g.min-1.mmHg-1.(100 g)-1 in OA-injured lungs whereas it remained constant in control lungs. Total pulmonary vascular resistance changed little in both control and OA-injured lungs. OA injury resulted in a 15% increase of the double occlusion capillary pressure. In addition, the contribution of the microvascular to the total vascular resistance rose from 8% to 22%. The increase in microvascular resistance was significant 15 min after OA on the arteriolar side and became significant 30 min later on the venular side. Oleic acid injury does not change the total pulmonary vascular resistance but alters the distribution of segmental resistances in the isolated rabbit lung, thereby contributing to the accumulation of lung water in this model of low pressure permeability edema.

  1. Erdosteine ameliorates lung injury induced by transient aortic occlusion in rats.

    Science.gov (United States)

    Kurtoglu, Tunay; Sacar, Mustafa; Inan, Bilal Kaan; Duver, M Harun; Guler, Adem; Ucak, Alper; Us, Melih Hulusi; Yilmaz, Ahmet Turan

    2007-01-01

    The aim of this experimental study was to evaluate the protective effect of erdosteine on lung injury induced by ischaemia-reperfusion (IR) of the lower extremities of rats. Wistar albino rats (n = 21) were divided into three groups. In the IR group (n = 7), the aorta was cross-clamped for two hours, followed by one hour of reperfusion. In the erdosteine group (n = 7), animals were pretreated with erdosteine 100 mg/kg daily via gastric lavage, starting three days before aortic occlusion. In the control group (n 5 7), the lungs were removed and blood samples were taken immediately after sternotomy. No treatment was given in the control and IR groups. After both lungs were removed, biochemical parameters were measured and broncho-alveolar lavage (BAL ) assessment was made. MDA levels and MPO activities in the lung tissue were significantly reduced in the erdosteine group compared to the IR group. BAL assessment revealed decreased neutrophil counts in the erdosteine-treated group. Pretreatment of animals with erdosteine significantly attenuated transient aortic occlusion-induced remote lung injury, characterised by leukocyte accumulation and lipid peroxidation. The results suggest that erdosteine may be beneficial in amelioration of lung injury caused by IR.

  2. RAGE/NF-κB signaling mediates lipopolysaccharide induced acute lung injury in neonate rat model.

    Science.gov (United States)

    Li, Yuhong; Wu, Rong; Tian, Yian; Yu, Min; Tang, Yun; Cheng, Huaipin; Tian, Zhaofang

    2015-01-01

    Lipopolysaccharide (LPS) is known to induce acute lung injury (ALI) and acute respiratory distress syndrome (ARDS). Accumulating data suggest the crucial role of RAGE in the pathogenesis of ALI/ARDS. However, the mechanism by which RAGE mediates inflammatory lung injury in the neonates remains elusive. In this study we established LPS-induced ALI model in neonate rats, and investigated the role of RAGE/NF-κB signaling in mediating ALI. We found that RAGE antibody or bortezomib reduced LPS-induced histopathological abnormalities in the lung and lung damage score. RAGE antibody or bortezomib also reduced TNF-α level in both serum and BALF of the rats. Furthermore, RAGE antibody or bortezomib significantly reduced LPS-induced upregulation of RAGE and NF-κB expression in the lung. In conclusion, we established ALI model in neonate rats to demonstrate that LPS induced inflammatory lung injury via RAGE/NF-κB signaling. Interference with RAGE/NF-κB signaling is a potential approach to prevent and treat sepsis-related ALI/ARDS.

  3. Intercellular Adhension Molecule-1 in the Pathogenesis of Heroin-induced Acute Lung Injury in Rats

    Institute of Scientific and Technical Information of China (English)

    周琼; 白明; 邹世清

    2004-01-01

    The expression of intercellular adhesion molecule-1 (ICAM-1) in the pathogenesis of heroin-induced acute lung injury (ALI) in rats was investigated. The model of ALI was established by intravenous injection of heroin into tail vein in rats. Thirty-six rats were randomly divided into heroin-treated groups (1 h, 2 h, 4 h, 6 h and 24 h) and normal control group. Changes in histopathologic morphology and biological markers of ALI were measured. The expression of ICAM-1in lung tissue was detected by using immunohistochemistry and RT-PCR. The results showed that the W/D ratio and protein contents in BALF of the heroin-treated groups were significantly higher than that of the control group (P<0.01). The histopathological changes in the lung tissue were more obvious in heroin-treated groups. The ICAM-1 protein and mRNA expression in the lung tissue of heroin-treated groups were significantly increased as compared with that of the control group (P<0.01), and correlated with the ALI parameters in a time-dependent manner. Increasing of ICAM-1 expression was involved in the formation of heroin-induced lung injury. Furthermore, the level of expression was positively correlated with the severity of lung injury.

  4. Activated protein C protection from lung inflammation in endotoxin-induced injury.

    Science.gov (United States)

    Pirrone, Federica; Mazzola, Silvia M; Pastore, Camilla; Paltrinieri, Saverio; Sironi, Giuseppe; Riccaboni, Pietro; Viola, Manuela; Passi, Alberto; Clement, Maria G; Albertini, Mariangela

    2008-11-01

    We studied the protection of recombinant human activated protein C (rhAPC) in endotoxin-induced lung inflammation and injury and whether this effect is correlated with modulation of lung matrix metalloproteinase (MMP) activity. We randomly assigned 12 Large White pigs to receive intravenous Escher-ichia coli lipopolysaccharide (LPS; 40 mu g/kg/hr), rhAPC (24 mu g/ kg/hr), or both. We monitored respiratory mechanics and function, cell counts, and cytokine concentrations in bron-choalveolar lavage fluid (BALF). Lung samples were collected for the zymography of MMP-2 and MMP-9 activities and for histology. In septic pigs, rhAPC decreased proMMP-9 release as well as MMP-9 activation, and increased proMMP-2 presence without any evident activation compared with specimens that were given LPS alone. In addition, lung injury in rhAPC-treated animals was significantly attenuated, as shown by higher respiratory compliance, delayed increase in tumor necrosis alfa and interleukin-1beta as well as neutrophil recruitment in the BALF, reduced lung edema, and histologic changes. In conclusion, rhAPC is beneficial in acute lung injury, and the protection may depend, at least in part, on modulation of MMP-2/9 activity.

  5. Apneic oxygenation combined with extracorporeal arteriovenous carbon dioxide removal provides sufficient gas exchange in experimental lung injury

    DEFF Research Database (Denmark)

    Nielsen, Niels Dalsgaard; Kjærgaard, Benedict; Nielsen, Jakob Koefoed

    Background and aim of study We hypothesized that continuous high airway pressure without ventilatory movements (apneic oxygenation), using an open lung approach, combined with extracorporeal, pumpless, arterio-venous, carbon dioxide (CO2) removal would provide adequate gas exchange in acute lung...... injury was induced by repeated lung lavage. Thereafter the tracheal tube was, after a lung recruitment maneuver, connected to 20 cmH2O continuous positive airway pressure (FiO2 = 1.0) for oxygenation of the blood. A pumpless membrane lung (Interventional Lung Assist, NovaLung, Germany) was connected...... In this porcine lung injury model, apneic oxygenation with arteriovenous CO2 removal provided sufficient gas exchange and stable hemodynamics, indicating that the method might have a potential in the treatment of severe ARDS.   Acknowledgements The membrane lungs were kindly provided by Novalung GmbH, Germany....

  6. Carbon black nanoparticle instillation induces sustained inflammation and genotoxicity in mouse lung and liver

    Directory of Open Access Journals (Sweden)

    Bourdon Julie A

    2012-02-01

    Full Text Available Abstract Background Widespread occupational exposure to carbon black nanoparticles (CBNPs raises concerns over their safety. CBNPs are genotoxic in vitro but less is known about their genotoxicity in various organs in vivo. Methods We investigated inflammatory and acute phase responses, DNA strand breaks (SB and oxidatively damaged DNA in C57BL/6 mice 1, 3 and 28 days after a single instillation of 0.018, 0.054 or 0.162 mg Printex 90 CBNPs, alongside sham controls. Bronchoalveolar lavage (BAL fluid was analyzed for cellular composition. SB in BAL cells, whole lung and liver were assessed using the alkaline comet assay. Formamidopyrimidine DNA glycosylase (FPG sensitive sites were assessed as an indicator of oxidatively damaged DNA. Pulmonary and hepatic acute phase response was evaluated by Saa3 mRNA real-time quantitative PCR. Results Inflammation was strongest 1 and 3 days post-exposure, and remained elevated for the two highest doses (i.e., 0.054 and 0.162 mg 28 days post-exposure (P Saa3 mRNA in lung tissue on day 1 (all doses, 3 (all doses and 28 (0.054 and 0.162 mg, but not in liver. Conclusions Deposition of CBNPs in lung induces inflammatory and genotoxic effects in mouse lung that persist considerably after the initial exposure. Our results demonstrate that CBNPs may cause genotoxicity both in the primary exposed tissue, lung and BAL cells, and in a secondary tissue, the liver.

  7. Oleic acid-induced lung injury in rabbits: effect of fibrinogen depletion with Arvin

    Energy Technology Data Exchange (ETDEWEB)

    Allard, M.F.; Doerschuk, C.M.; Brumwell, M.L.; Belzberg, A.; Hogg, J.C.

    1988-03-01

    The role of fibrinogen in the evolution of the increased permeability after oleic acid-induced lung injury was studied in New Zealand White rabbits. Animals depleted of fibrinogen by treatment with Malayan pit viper venom were compared with untreated rabbits immediately and at 1 and 24 h after injury. The increased permeability to albumin and elevated extravascular lung water (EVLW) associated with lung injury returned to control values by 24 h in untreated animals. Fibrinogen-depleted animals had a higher mortality (10/25 vs. 2/17, P less than 0.02) and showed a greater immediate increase in permeability to albumin that returned to control values at 1 and 24 h after injury, as well as trends toward elevated blood-free dry lung weight and larger increases in EVLW that persisted for 24 h. These findings indicate that fibrinogen-related proteins play an important role in controlling the microvascular injury that is produced by oleic acid. However, when these proteins are depleted, other mechanisms partially control the leak at later stages of the repair process.

  8. Hemorrhage and resuscitation induce alterations in cytokine expression and the development of acute lung injury.

    Science.gov (United States)

    Shenkar, R; Coulson, W F; Abraham, E

    1994-03-01

    Acute pulmonary injury occurs frequently following hemorrhage and injury. In order to better examine the sequence of events leading to lung injury in this setting, we investigated lung histology as well as in vivo mRNA levels for cytokines with proinflammatory and immunoregulatory properties (IL-1 beta, IL-6, IL-10, TNF-alpha, TGF-beta, IFN-gamma) over the 3 days following hemorrhage and resuscitation. Significant increases in mRNA levels for IL-1 beta, IL-6, IL-10, and IFN-gamma, but not TNF-alpha, were present among intraparenchymal pulmonary mononuclear cells obtained 1 and 3 days after hemorrhage. Among alveolar macrophages, TNF-alpha and IL-1 beta mRNA levels were increased 3 days after hemorrhage. Few changes in cytokine mRNA levels, with the exception of TNF-alpha at 3 days after hemorrhage, were present among peripheral blood mononuclear cells. Histologic examination of lungs from hemorrhaged animals showed no alterations 1 day after hemorrhage, but neutrophil and mononuclear cell infiltrates, edema, intra-alveolar hemorrhage, and fibrin generation were present 3 days after hemorrhage. These results suggest that hemorrhage-induced enhancement of proinflammatory cytokine gene transcription may be an important mechanism contributing to the frequent development of acute lung injury following blood loss and injury.

  9. Trauma hemorrhagic shock-induced lung injury involves a gut-lymph-induced TLR4 pathway in mice.

    Directory of Open Access Journals (Sweden)

    Diego C Reino

    Full Text Available Injurious non-microbial factors released from the stressed gut during shocked states contribute to the development of acute lung injury (ALI and multiple organ dysfunction syndrome (MODS. Since Toll-like receptors (TLR act as sensors of tissue injury as well as microbial invasion and TLR4 signaling occurs in both sepsis and noninfectious models of ischemia/reperfusion (I/R injury, we hypothesized that factors in the intestinal mesenteric lymph after trauma hemorrhagic shock (T/HS mediate gut-induced lung injury via TLR4 activation.The concept that factors in T/HS lymph exiting the gut recreates ALI is evidenced by our findings that the infusion of porcine lymph, collected from animals subjected to global T/HS injury, into naïve wildtype (WT mice induced lung injury. Using C3H/HeJ mice that harbor a TLR4 mutation, we found that TLR4 activation was necessary for the development of T/HS porcine lymph-induced lung injury as determined by Evan's blue dye (EBD lung permeability and myeloperoxidase (MPO levels as well as the induction of the injurious pulmonary iNOS response. TRIF and Myd88 deficiency fully and partially attenuated T/HS lymph-induced increases in lung permeability respectively. Additional studies in TLR2 deficient mice showed that TLR2 activation was not involved in the pathology of T/HS lymph-induced lung injury. Lastly, the lymph samples were devoid of bacteria, endotoxin and bacterial DNA and passage of lymph through an endotoxin removal column did not abrogate the ability of T/HS lymph to cause lung injury in naïve mice.Our findings suggest that non-microbial factors in the intestinal mesenteric lymph after T/HS are capable of recreating T/HS-induced lung injury via TLR4 activation.

  10. TGF-beta1 Transgenic Mouse Model of Thoracic Irradiation: Modulation of MMP-2 and MMP-9 in the Lung Tissue

    Institute of Scientific and Technical Information of China (English)

    YANG Kunyu; Liu LI; ZHANG Tao; WU Gang; Ruebe Claudia; Ruebe Christian; HU Yu

    2006-01-01

    To investigate the effects of TGF-β1 on the two gelatinases (MMP-2 and MMP-9), and their roles in lung remodeling after irradiation-induced lung injury. Expressions of TGF-β1 were measured with western blot, and expressions of MMP-2 and MMP-9 were analyzed with zymography in a TGF-β1 transgenic mouse model after thoracic irradiation with 12 Gy. We found expressions of TGF-β1 in the lung from the transgenic mice were three folds as compared to those from control mice. With densitometrical analysis, we found a significant decrease in MMP-9 activity in lung homogenates from the transgenic mice as compared with those from non-transgenic control mice 8 weeks after sham-irradiation (relative MMP-9 activity: C: 1.000±0.1091; TG: 0.4772± 0.470 (n=8, P<0.05). But MMP-2 was constitutively expressed in the lung homogenates from the transgenic mice as compared to those from control mice 8 weeks aftersham-irradiation (relative MMP-2 activity 8 weeks after sham-irradiation: C: 1.000±0.1556, TG: 1.0075±0.1472). Eight weeks after thoracic irradiation with 12 Gy, we observed a significant increase of MMP-2 and MMP-9 activity in lung homogenates from both transgenic and normal mice. In TGF-β1 transgenic mice relative MMP-9 activity was increased to 1.5321±0. 2217 folds 8 weeks after thoracic irradiation with 12 Gy as compared to those after sham-irradiation (1.000±0.2153), and relative MMP-2 activity was increased to 1. 7142±0. 4231 folds. Our results show that TGF-β1 itself down-regulates activity of MMP-9, thereby decreases ECM degradation in lungs of TGF-β1 transgenic mice.Also we find that ionizing irradiation upregulates both MMP-2 and MMP-9 activity. Over-expressions of MMP-9 and MMP-2 after lung irradiation are involved in the inflammatory response associated with radiation-induced lung injury, and maybe further in radiation-induced lung fibrosis.

  11. Nitrogen dioxide-induced acute lung injury in sheep.

    Science.gov (United States)

    Januszkiewicz, A J; Mayorga, M A

    1994-05-20

    Lung mechanics, hemodynamics and blood chemistries were assessed in sheep (Ovis aries) before, and up to 24 h following, a 15-20 min exposure to either air (control) or approximately 500 ppm nitrogen dioxide (NO2). Histopathologic examinations of lung tissues were performed 24 h after exposure. Nose-only and lung-only routes of exposure were compared for effects on NO2 pathogenesis. Bronchoalveolar lavage fluids from air- and NO2-exposed sheep were analyzed for biochemical and cellular signs of NO2 insult. The influence of breathing pattern on NO2 dose was also assessed. Five hundred ppm NO2 exposure of intubated sheep (lung-only exposure) was marked by a statistically significant, albeit small, blood methemoglobin increase. The exposure induced an immediate tidal volume decrease, and an increase in both breathing rate and inspired minute ventilation. Pulmonary function, indexed by lung resistance and dynamic lung compliance, progressively deteriorated after exposure. Maximal lung resistance and dynamic lung compliance changes occurred at 24 h post exposure, concomitant with arterial hypoxemia. Bronchoalveolar lavage fluid epithelial cell number and total protein were significantly increased while macrophage number was significantly decreased within the 24 h post-exposure period. Histopathologic examination of lung tissue 24 h after NO2 revealed patchy edema, mild hemorrhage and polymorphonuclear and mononuclear leukocyte infiltration. The NO2 toxicologic profile was significantly attenuated when sheep were exposed to the gas through a face mask (nose-only exposure). Respiratory pattern was not significantly altered, lung mechanics changes were minimal, hypoxemia did not occur, and pathologic evidence of exudation was not apparent in nose-only, NO2-exposed sheep. The qualitative responses of this large animal species to high-level NO2 supports the concept of size dependent species sensitivity to NO2. In addition, when inspired minute ventilation was used as a dose

  12. Pathogenesis of Septic Acute Lung Injury and Strategies for Immuno-Pharmacological Therapy.

    Science.gov (United States)

    1996-10-01

    obtained from septic-NO animals revealed a qualitative reduction in alveolar and septal edema . Although qualitative in nature, parenchyma of septic-NO...pulmonary edema in a model of acute lung injury. Am. Rev. Respir. Dis. 142:1083- 1087. 18. McDonald, R. J. 1991. Pentoxifylline reduces injury to isolated...patients with uncomplicated sepsis and septic shock--comparison with cardiogenic shock. Thromb. Haemost. 58:709-713. 60. Carvalho, A. C., S. DeMarinis

  13. Acute lung injury and ARDS in acute pancreatitis: Mechanisms and potential intervention

    Institute of Scientific and Technical Information of China (English)

    Roland; Andersson

    2010-01-01

    Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) in acute pancreatitis still represents a substantial problem,with a mortality rate in the range of 30%-40%.The present review evaluates underlying pathophysiological mechanisms in both ALI and ARDS and potential clinical implications.Several mediators and pathophysiological pathways are involved during the different phases of ALI and ARDS.The initial exudative phase is characterized by diffuse alveolar damage,microvascular injury and inf...

  14. Nitrogen Dioxide-Induced Acute Lung Injury in Sheep

    Science.gov (United States)

    1994-01-01

    subsequent to inhalation expo- sure. Non- cardiogenic pulmonary edema is produced by brief exposure and unlike hyperoxia (Newman et al., 1983; Fukushima...macrophage number significantly decreased within the 24-h post-exposure period. Examination of lung tissue 24 after NO2 revealed patchy edema , mild hemorrhage...examination of lung tissue 24 h after NO, revealed patchy edema , mild hemorrhage and polymorphonuclear c, and mononuclear leukocyte infiltration. The NO

  15. Dexamethasone pretreatment attenuates lung and kidney injury in cholestatic rats induced by hepatic ischemia/reperfusion.

    Science.gov (United States)

    Zhou, Liangyi; Yao, Xiangqing; Chen, Yanling

    2012-02-01

    Hepatic ischemia followed by reperfusion (IR) results in mild to severe organ injury, in which tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) seem to be involved. Thus, we aim to assess the influence of hepatic ischemia/reperfusion injury on remote organs in addition to cholestasis and consider the possible efficacy of steroid pretreatment in reducing the injury. A common bile duct ligation model was done on 24 male Sprague-Dawley rats. After 7 days, the rats were divided randomly into control group, IR group, and dexamethasone (DEX) group. The IR group showed significant increases in serum alanine aminotransferase, aspartate aminotransferase, and creatinine levels compared with the control and DEX groups. By ELISA techniques, higher levels of TNF-α and IL-1β in lung and kidney tissues were measured in the IR group than in the control and DEX groups, these were verified by immunohistochemistry. The lung histology of the IR group rats showed neutrophil infiltration, interstitial edema, and alveolar wall thickening. Kidney histology of the IR group rats showed vacuolization of the proximal tubular epithelial cells and tubular dilatation with granular eosinophilic casts. Better morphological aspects were observed in the DEX-pretreated animals. Minimal lesions were observed in the control. The results suggest that hepatic ischemia/reperfusion injury in cholestatic rats induced lung and kidney injuries. Pretreatment with dexamethasone reduced the IR-induced injury in addition to cholestasis.

  16. Microarray expression profiles of genes in lung tissues of rats subjected to focal cerebral ischemia-induced lung injury following bone marrow-derived mesenchymal stem cell transplantation.

    Science.gov (United States)

    Hu, Yue; Xiong, Liu-Lin; Zhang, Piao; Wang, Ting-Hua

    2017-01-01

    Ischemia-induced stroke is the most common disease of the nervous system and is associated with a high mortality rate worldwide. Cerebral ischemia may lead to remote organ dysfunction, particular in the lungs, resulting in lung injury. Nowadays, bone marrow-derived mesenchymal stem cells (BMSCs) are widely studied in clinical trials as they may provide an effective solution to the treatment of neurological and cardiac diseases; however, the underlying molecular mechanisms remain unknown. In this study, a model of permanent focal cerebral ischemia-induced lung injury was successfully established and confirmed by neurological evaluation and lung injury scores. We demonstrated that the transplantation of BMSCs (passage 3) via the tail vein into the lung tissues attenuated lung injury. In order to elucidate the underlying molecular mechanisms, we analyzed the gene expression profiles in lung tissues from the rats with focal cerebral ischemia and transplanted with BMSCs using a Gene microarray. Moreover, the Gene Ontology database was employed to determine gene function. We found that the phosphoinositide 3-kinase (PI3K)-AKT signaling pathway, transforming growth factor-β (TGF-β) and platelet-derived growth factor (PDGF) were downregulated in the BMSC transplantation groups, compared with the control group. These results suggested that BMSC transplantation may attenuate lung injury following focal cerebral ischemia and that this effect is associated with the downregulation of TGF-β, PDGF and the PI3K-AKT pathway.

  17. Impact of cigarette smoke on the human and mouse lungs: a gene-expression comparison study.

    Directory of Open Access Journals (Sweden)

    Mathieu C Morissette

    Full Text Available Cigarette smoke is well known for its adverse effects on human health, especially on the lungs. Basic research is essential to identify the mechanisms involved in the development of cigarette smoke-related diseases, but translation of new findings from pre-clinical models to the clinic remains difficult. In the present study, we aimed at comparing the gene expression signature between the lungs of human smokers and mice exposed to cigarette smoke to identify the similarities and differences. Using human and mouse whole-genome gene expression arrays, changes in gene expression, signaling pathways and biological functions were assessed. We found that genes significantly modulated by cigarette smoke in humans were enriched for genes modulated by cigarette smoke in mice, suggesting a similar response of both species. Sixteen smoking-induced genes were in common between humans and mice including six newly reported to be modulated by cigarette smoke. In addition, we identified a new conserved pulmonary response to cigarette smoke in the induction of phospholipid metabolism/degradation pathways. Finally, the majority of biological functions modulated by cigarette smoke in humans were also affected in mice. Altogether, the present study provides information on similarities and differences in lung gene expression response to cigarette smoke that exist between human and mouse. Our results foster the idea that animal models should be used to study the involvement of pathways rather than single genes in human diseases.

  18. Osteopontin protects against hyperoxia-induced lung injury by inhibiting nitric oxide synthases.

    Science.gov (United States)

    Zhang, Xiang-Feng; Liu, Shuang; Zhou, Yu-Jie; Zhu, Guang-Fa; Foda, Hussein D

    2010-04-05

    Exposure of adult mice to more than 95% O(2) produces a lethal injury by 72 hours. Nitric oxide synthase (NOS) is thought to contribute to the pathophysiology of murine hyperoxia-induced acute lung injury (ALI). Osteopontin (OPN) is a phosphorylated glycoprotein produced principally by macrophages. OPN inhibits inducible nitric oxide synthase (iNOS), which generates large amounts of nitric oxide production. However, the relationship between nitric oxide and endogenous OPN in lung tissue during hyperoxia-induced ALI has not yet been elucidated, thus we examined the role that OPN plays in the hyperoxia-induced lung injury and its relationships with NOS. One hundred and forty-four osteopontin knock-out (KO) mice and their matched wild type background control (WT) were exposed in sealed cages > 95% oxygen or room air for 24- 72 hours, and the severity of lung injury was assessed; expression of OPN, endothelial nitric oxide synthase (eNOS) and iNOS mRNA in lung tissues at 24, 48 and 72 hours of hyperoxia were studied by reverse transcription-polymerase chain reaction (RT-PCR); immunohistochemistry (IHC) was performed for the detection of iNOS, eNOS, and OPN protein in lung tissues. OPN KO mice developed more severe acute lung injury at 72 hours of hyperoxia. The wet/dry weight ratio increased to 6.85 +/- 0.66 in the KO mice at 72 hours of hyperoxia as compared to 5.31 +/- 0.92 in the WT group (P < 0.05). iNOS mRNA (48 hours: 1.04 +/- 0.08 vs. 0.63 +/- 0.09, P < 0.01; 72 hours: 0.89 +/- 0.08 vs. 0.72 +/- 0.09, P < 0.05) and eNOS mRNA (48 hours: 0.62 +/- 0.08 vs. 0.43 +/- 0.09, P < 0.05; 72 hours: 0.67 +/- 0.08 vs. 0.45 +/- 0.09, P < 0.05) expression was more significantly increased in OPN KO mice than their matched WT mice when exposed to hyperoxia. IHC study showed higher expression of iNOS (20.54 +/- 3.18 vs. 12.52 +/- 2.46, P < 0.05) and eNOS (19.83 +/- 5.64 vs. 9.45 +/- 3.82, P < 0.05) in lung tissues of OPN KO mice at 72 hours of hyperoxia. OPN can protect against

  19. Flecainide Improve Sepsis Induced Acute Lung Injury by Controlling Inflammatory Response

    Directory of Open Access Journals (Sweden)

    Jia Song

    2016-08-01

    Full Text Available Background: Flecainide is an antiarrhythmic agent that is used primarily in the treatment of cardiac arrhythmias. Some evidences also suggest that flecainide can participate in alveolar fluid clearance and inflammatory responses. This experiment was aimed to evaluate the effects of flecainide on sepsis induced acute lung injury in a rat model. Methods: Rats were treated with subcutaneous infusion of saline or flecainide (0.1 or 0.2 mg/kg/hr by a mini-osmotic pump. Subcutaneous infusion was started 3 hours before and continued until 8 hours after intraperitoneal injection of saline or endotoxin. Animals were sacrificed for analyses of severity of acute lung injury with wet to dry (W/D ratio and lung injury score (LIS in lung and inflammatory responses with level of leukocyte, polymorphonuclear neutrophils (PMNs and inteleukin-8 (IL-8 in bronchoalveolar lavages fluid (BALF. Results: Flecainide markedly improved dose dependently sepsis induced acute lung injury as analysed by W/D ratio (from 2.24 ± 0.11 to 1.76 ± 0.09, p < 0.05 and LIS (from 3 to 1, p < 0.05, and inflammatory response as determined by leukocyte (from 443 ± 127 to 229 ± 95, p < 0.05, PMNs (from 41.43 ± 17.63 to 2.43 ± 2.61, p < 0.05 and IL-8 (from 95.00 ± 15.28 to 40.00 ± 10.21, p < 0.05 in BALF. Conclusions: Flecanide improve sepsis induced acute lung injury in rats by controlling inflammatory responses.

  20. The "Goldilocks Effect" in Cystic Fibrosis: identification of a lung phenotype in the cftr knockout and heterozygous mouse

    Directory of Open Access Journals (Sweden)

    Bates Jason HT

    2004-07-01

    Full Text Available Abstract Background Cystic Fibrosis is a pleiotropic disease in humans with primary morbidity and mortality associated with a lung disease phenotype. However, knockout in the mouse of cftr, the gene whose mutant alleles are responsible for cystic fibrosis, has previously failed to produce a readily, quantifiable lung phenotype. Results Using measurements of pulmonary mechanics, a definitive lung phenotype was demonstrated in the cftr-/- mouse. Lungs showed decreased compliance and increased airway resistance in young animals as compared to cftr+/+ littermates. These changes were noted in animals less than 60 days old, prior to any long term inflammatory effects that might occur, and are consistent with structural differences in the cftr-/- lungs. Surprisingly, the cftr+/- animals exhibited a lung phenotype distinct from either the homozygous normal or knockout genotypes. The heterozygous mice showed increased lung compliance and decreased airway resistance when compared to either homozygous phenotype, suggesting a heterozygous advantage that might explain the high frequency of this mutation in certain populations. Conclusions In the mouse the gene dosage of cftr results in distinct differences in pulmonary mechanics of the adult. Distinct phenotypes were demonstrated in each genotype, cftr-/-, cftr +/-, and cftr+/+. These results are consistent with a developmental role for CFTR in the lung.

  1. Inhaled Nitric Oxide Decreases Leukocyte Trafficking in the Neonatal Mouse Lung During Exposure to >95% Oxygen

    Science.gov (United States)

    Rose, Melissa J.; Stenger, Michael R.; Joshi, Mandar S.; Welty, Stephen E.; Bauer, John Anthony; Nelin, Leif D.

    2010-01-01

    Chronic lung injury in the neonate is termed bronchopulmonary dysplasia (BPD). These patients generally require supplemental oxygen therapy, and hyperoxia has been implicated in the pathogenesis of BPD. The concomitant use of oxygen and inhaled nitric oxide (iNO) may result in the generation of reactive nitrogen species, or may have an anti-inflammatory effect in the neonatal lung. We tested the hypothesis that exposure to >95% O2 in neonatal mice would increase trafficking of leukocytes into the lung, and that the addition of iNO to >95% O2 would decrease this leukocyte trafficking. Hyperoxia resulted in fewer alveoli, increased presence of neutrophils and macrophages, and decreased number of mast cells within the lung parenchyma. Adding iNO to hyperoxia prevented the hyperoxia-induced changes and resulted in the numbers of alveoli, neutrophils, macrophages, and mast cells approximating those found in controls (room air exposure). Intercellular adhesion molecule (ICAM) and monocyte chemotactic protein-1 (MCP-1), two factors responsible for leukocyte recruitment, were upregulated by hyperoxic exposure, but the addition of iNO to the hyperoxic exposure prevented the hyperoxia-induced upregulation of ICAM and MCP-1. These data demonstrate that iNO alters the hyperoxia-induced recruitment of leukocytes into the lung. PMID:19915514

  2. Estrogen receptor hormone agonists limit trauma hemorrhage shock-induced gut and lung injury in rats.

    Directory of Open Access Journals (Sweden)

    Danielle Doucet

    Full Text Available BACKGROUND: Acute lung injury (ALI and the development of the multiple organ dysfunction syndrome (MODS is a major cause of death in trauma patients. Earlier studies in trauma hemorrhagic shock (T/HS have documented that splanchnic ischemia leading to gut inflammation and loss of barrier function is an initial triggering event that leads to gut-induced ARDS and MODS. Since sex hormones have been shown to modulate the response to T/HS and proestrous (PE females are more resistant to T/HS-induced gut and distant organ injury, the goal of our study was to determine the contribution of estrogen receptor (ERalpha and ERbeta in modulating the protective response of female rats to T/HS-induced gut and lung injury. METHODS/PRINCIPAL FINDINGS: The incidence of gut and lung injury was assessed in PE and ovariectomized (OVX female rats subjected to T/HS or trauma sham shock (T/SS as well as OVX rats that were administered estradiol (E2 or agonists for ERalpha or ERbeta immediately prior to resuscitation. Marked gut and lung injury was observed in OVX rats subjected to T/HS as compared to PE rats or E2-treated OVX rats subjected to T/HS. Both ERalpha and ERbeta agonists were equally effective in limiting T/HS-induced morphologic villous injury and bacterial translocation, whereas the ERbeta agonist was more effective than the ERalpha agonist in limiting T/HS-induced lung injury as determined by histology, Evan's blue lung permeability, bronchoalevolar fluid/plasma protein ratio and myeloperoxidase levels. Similarly, treatment with either E2 or the ERbeta agonist attenuated the induction of the intestinal iNOS response in OVX rats subjected to T/HS whereas the ERalpha agonist was only partially protective. CONCLUSIONS/SIGNIFICANCE: Our study demonstrates that estrogen attenuates T/HS-induced gut and lung injury and that its protective effects are mediated by the activation of ERalpha, ERbeta or both receptors.

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

    Energy Technology Data Exchange (ETDEWEB)

    Wang, Chaoyun [School of Pharmaceutical Sciences, Binzhou Medical University, Yantai, Shandong 264003 (China); Huang, Qingxian [Department of Hepatobiliary Surgery, Yantai Yuhuangding Hospital, Yantai, Shandong 264000 (China); Wang, Chunhua; Zhu, Xiaoxi; Duan, Yunfeng; Yuan, Shuai [School of Pharmaceutical Sciences, Binzhou Medical University, Yantai, Shandong 264003 (China); Bai, Xianyong, E-mail: xybai2012@163.com [School of Pharmaceutical Sciences, Binzhou Medical University, Yantai, Shandong 264003 (China)

    2013-11-01

    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{sub 2}), carbon dioxide tension, pH, and the PaO{sub 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{sup 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

  4. Butyrylcholinesterase in guinea pig lung lavage: a novel biomarker to assess lung injury following inhalation exposure to nerve agent VX.

    Science.gov (United States)

    Graham, Jacob R; Wright, Benjamin S; Rezk, Peter E; Gordon, Richard K; Sciuto, Alfred M; Nambiar, Madhusoodana P

    2006-06-01

    Respiratory disturbances play a central role in chemical warfare nerve agent (CWNA) induced toxicity; they are the starting point of mass casualty and the major cause of death. We developed a microinstillation technique of inhalation exposure to nerve agent VX and assessed lung injury by biochemical analysis of the bronchoalveolar lavage fluid (BALF). Here we demonstrate that normal guinea pig BALF has a significant amount of cholinesterase activity. Treatment with Huperzine A, a specific inhibitor of acetylcholinesterase (AChE), showed that a minor fraction of BALF cholinesterase is AChE. Furthermore, treatment with tetraisopropyl pyrophosphoramide (iso-OMPA), a specific inhibitor of butyrylcholinesterase (BChE), inhibited more than 90% of BChE activity, indicating the predominance of BChE in BALF. A predominance of BChE expression in the lung lavage was seen in both genders. Substrate specific inhibition indicated that nearly 30% of the cholinesterase in lung tissue homogenate is AChE. BALF and lung tissue AChE and BChE activities were strongly inhibited in guinea pigs exposed for 5 min to 70.4 and 90.4 microg/m3 VX and allowed to recover for 15 min. In contrast, BALF AChE activity was increased 63% and 128% and BChE activity was increased 77% and 88% after 24 h of recovery following 5 min inhalation exposure to 70.4 microg/m3 and 90.4 mg/m3 VX, respectively. The increase in BALF AChE and BChE activity was dose dependent. Since BChE is synthesized in the liver and present in the plasma, an increase in BALF indicates endothelial barrier injury and leakage of plasma into lung interstitium. Therefore, a measure of increased levels of AChE and BChE in the lung lavage can be used to determine the chronology of barrier damage as well as the extent of lung injury following exposure to chemical warfare nerve agents.

  5. The "Goldilocks Effect" in Cystic Fibrosis: identification of a lung phenotype in the cftr knockout and heterozygous mouse

    OpenAIRE

    Bates Jason HT; Lundblad Lennart KA; Craig Cohen J; Levitzky Michael; Larson Janet E

    2004-01-01

    Abstract Background Cystic Fibrosis is a pleiotropic disease in humans with primary morbidity and mortality associated with a lung disease phenotype. However, knockout in the mouse of cftr, the gene whose mutant alleles are responsible for cystic fibrosis, has previously failed to produce a readily, quantifiable lung phenotype. Results Using measurements of pulmonary mechanics, a definitive lung phenotype was demonstrated in the cftr-/- mouse. Lungs showed decreased compliance and increased a...

  6. Relationship between Notch Receptors and Hyperoxia-induced Lung Injury in Newborn Rats

    Institute of Scientific and Technical Information of China (English)

    2005-01-01

    To investigate role of Notch1-3 in hyperoxia-induced lung injury in newborn rat exposed to 85% O2, SD rat litters born on the 22th day were randomly divided into two groups: room air group and hyperoxia group. The animals were sacrificed 1, 4, 7, 10, 14 and 21 days after continued exposure to oxygen (n=40, oxygen>0.85) or room air (n=40). 6 rats each group were used to assess lung histological changes by HE staining and expression of Notch in lungs by immunohistochemistry. Total RNA was extracted by Trizol reagent from frozen lung tissues. Notch mRNA were measured by reverse transcription polymerase chain reaction (RT-PCR). Our results showed that 7, 14 and 21 days after O2 exposure, hyperoxia group showed lung injury characterized by pulmonary edema, hemorrhage and lung development arrest. Positive staining for Notch1,Notch 2 in hyperoxia group was much lower than those in room air group at all time points (P<0.01, P<0.05), but compared with the controls, the hyperoxia group showed higher expression of Notch3 (P>0.05). Immunostained cells were typically airways epithelia, alveolar epithelial and inflammatory cells, and fibroblasts in hyperoxia group (P<0.01). Notch mRNA levels showed similar change as protein level (P< 0.01). It is concluded that the prolonged exposure to 85 % O2 resulted in abnormal expression of Notch receptors, which might contribute to the pathogenesis of hyperoxia-induced lung injury in newborn rats. The decreased inhibition of Notch1 might be one of the protective reaction and major mechanisms for proliferation/differentiation of type Ⅱ alveolar epithelial cells. The up-regulation of Notch3 activity might result in the lung development arrest of the newborn rats.

  7. Macrophage micro-RNA-155 promotes lipopolysaccharide-induced acute lung injury in mice and rats.

    Science.gov (United States)

    Wang, Wen; Liu, Zhi; Su, Jie; Chen, Wen-Sheng; Wang, Xiao-Wu; Bai, San-Xing; Zhang, Jin-Zhou; Yu, Shi-Qiang

    2016-08-01

    Micro-RNA (miR)-155 is a novel gene regulator with important roles in inflammation. Herein, our study aimed to explore the role of miR-155 in LPS-induced acute lung injury(ALI). ALI in mice was induced by intratracheally delivered LPS. Loss-of-function experiments performed on miR-155 knockout mice showed that miR-155 gene inactivation protected mice from LPS-induced ALI, as manifested by preserved lung permeability and reduced lung inflammation compared with wild-type controls. Bone marrow transplantation experiments identified leukocytes, but not lung parenchymal-derived miR-155-promoted acute lung inflammation. Real-time PCR analysis showed that the expression of miR-155 in lung tissue was greatly elevated in wild-type mice after LPS stimulation. In situ hybridization showed that miR-155 was mainly expressed in alveolar macrophages. In vitro experiments performed in isolated alveolar macrophages and polarized bone marrow-derived macrophages confirmed that miR-155 expression in macrophages was increased in response to LPS stimulation. Conversely, miR-155 gain-of-function in alveolar macrophages remarkably exaggerated LPS-induced acute lung injury. Molecular studies identified the inflammation repressor suppressor of cytokine signaling (SOCS-1) as the downstream target of miR-155. By binding to the 3'-UTR of the SOCS-1 mRNA, miR-155 downregulated SOCS-1 expression, thus, permitting the inflammatory response during lung injury. Finally, we generated a novel miR-155 knockout rat strain and showed that the proinflammatory role of miR-155 was conserved in rats. Our study identified miR-155 as a proinflammatory factor after LPS stimulation, and alveolar macrophages-derived miR-155 has an important role in LPS-induced ALI. Copyright © 2016 the American Physiological Society.

  8. Edaravone attenuates ischemia-reperfusion injury by inhibiting oxidative stress in a canine lung transplantation model

    Institute of Scientific and Technical Information of China (English)

    XU Jin-zhi; SHEN Bao-zhong; LI Ye; ZHANG Tong; XU Wan-hai; LIU Xiao-wei; LU Hong-guang

    2008-01-01

    Background Previous reports have confirmed that edaravone has protective effects against ischemia-reperfusion(IR) injury of many organs.In this study,we investigated the effect of edaravone on preventing IR injury of the lung in a canine lung transplantation model. Methods Twelve weight-matched pairs of random-bred dogs were randomized into two groups.Within each pair,one dog served as donor and the other as recipient.In the study group,prostaglandin EI(PGEl)(8 μg/kg)was injected into the donor pulmonary artery(PA)before occlusion and the donor lungs were flushed with 1.0L of LPD solution containing edaravone(10mg/kg)and stored in the same LPD solution at a temperature of 1.C for 8 hours.The left single lung transplantation was then performed and recipients received intravenous injection with edaravone l 1 0 mg/kg)at the onset of reperfusion.In the control group,edaravone was substituted by the same volume of sterile saline solution.Another six dogs were obtained as normal control group in which left lungs were dissected after thoracotomy without an IR injury.One hour after repeffusion.or after dissection of the left lung,the right lung was excluded from peffusion and ventilation after which,cardiopulmonary parameters were measured.Wet/dry ratios,malondiaIdehyde(MDA)and myeloperoxidase (MPO)levels were assessed and histological analysis of lung tissue performed at the same time.Results All animals survived until the end of the experiment.The study group showed significantly decreased wet/dry ratios(treated:(74.1±4.2)%vs control:(86.8±5.2)%,P<0.01),MDA levels(treated:0.50±0.08 vs control:0.88±0.15,P <0.01)and MPO activity(treated:0.23±0.05 vs control:0.43±0.07,P

  9. Lung injury after cigarette smoking is particle-related

    Science.gov (United States)

    That specific component responsible and the mechanistic pathway for increased human morbidity and mortality after cigarette smoking have yet to be delineated. We propose that 1) injury and disease following cigarette smoking are associated with exposure and retention of particles...

  10. Lung injury after cigarette smoking is particle-related

    Science.gov (United States)

    That specific component responsible and the mechanistic pathway for increased human morbidity and mortality after cigarette smoking have yet to be delineated. We propose that 1) injury and disease following cigarette smoking are associated with exposure and retention of particles...

  11. Bronchoalveolar lavage alterations during prolonged ventilation of patients without acute lung injury.

    Science.gov (United States)

    Tsangaris, I; Lekka, M E; Kitsiouli, E; Constantopoulos, S; Nakos, G

    2003-03-01

    Mechanical ventilation deteriorates previously injured lung, but little is known about its effect on healthy human lung. This work was designed to assess the effect of prolonged mechanical ventilation on bronchoalveolar lavage (BAL) fluid composition of patients without acute lung injury. Twenty-two ventilated patients (tidal volume 8-10 mL x kg(-1), positive end-expiratory pressure 3-5 cmH2O) without lung injury, who did not develop any complication from the respiratory system during the 2-week study period, were studied. They were subjected to three consecutive BALs, the first during 36 h from intubation, the second at the end of the first week of mechanical ventilation and the third at the end of the second week of mechanical ventilation. Total BAL protein increased during mechanical ventilation (148 +/- 62, 381 +/- 288, 353 +/- 215 microg x mL(-1) BAL for the first, second and third BAL, respectively). In contrast, BAL phospholipids decreased (2.7 +/- 1.1, 1.4 +/- 0.6, 1.2 +/- 0.7 microg x mL(-1) BAL, respectively). Large surfactant aggregates were reduced and inflammatory markers, such as platelet activating factor (PAF), PAF-acetylhydrolase and neutrophils, significantly increased after 1 week, but partially remitted after 2 weeks of mechanical ventilation. In summary, this study demonstrates that prolonged mechanical ventilation even of patients without acute lung injury is associated with the presence of inflammatory markers and surfactant alterations.

  12. Acute cigarette smoke exposure causes lung injury in rabbits treated with ibuprofen

    Energy Technology Data Exchange (ETDEWEB)

    Witten, M.L.; Lemen, R.J.; Quan, S.F.; Sobonya, R.E.; Magarelli, J.L.; Bruck, D.C.

    1987-01-01

    We studied lung clearance of aerosolized technetium-labeled diethylenetriamine pentaacetic acid (/sup 99m/TcDTPA), plasma concentrations of 6-keto-PGF1 alpha and thromboxane B2, and pulmonary edema as indices of lung injury in rabbits exposed to cigarette smoke (CSE). Forty-six rabbits were randomly assigned to 4 groups: control sham smoke exposure (SS, N = 9), sham smoke exposure ibuprofen-pretreated (SS-I, N = 10), CSE (N = 9), sham smoke exposure ibuprofen-pretreated (SS-I, N = 10), CSE (N = 9), and CSE ibuprofen-pretreated (CSE-I, N = 19). Ibuprofen (cyclooxygenase eicosanoid inhibitor) was administered as a single daily intramuscular injection (25 mg/kg) for 7 days before the experiment. Cigarette or sham smoke was delivered by syringe in a series of 5, 10, 20, and 30 tidal volume breaths with a 15-min counting period between each subset of breaths to determine /sup 99m/TcDTPA biological half-life (T1/2). In the ibuprofen pretreated group, CSE caused significant decreases in /sup 99m/TcDTPA T1/2 and dynamic lung compliance. Furthermore, these changes in lung function were accompanied by severe injury to type I alveolar cell epithelium, pulmonary edema, and frequently death of the rabbits. These findings suggest that inhibition of the cyclooxygenase pathway before CSE exacerbates lung injury in rabbits.

  13. RAGE deficiency attenuates the protective effect of Lidocaine against sepsis-induced acute lung injury.

    Science.gov (United States)

    Zhang, Zhuo; Zhou, Jie; Liao, Changli; Li, Xiaobing; Liu, Minghua; Song, Daqiang; Jiang, Xian

    2017-04-01

    Lidocaine (Lido) is reported to suppress inflammatory responses and exhibit a therapeutic effect in models of cecal ligation and puncture (CLP)-induced acute lung injury (ALI). The receptor for advanced glycation end product (RAGE) exerts pro-inflammatory effects by enhancing pro-inflammatory cytokine production. However, the precise mechanism by which Lido confers protection against ALI is not clear. ALI was induced in RAGE WT and RAGE knockout (KO) rats using cecal ligation and puncture (CLP) operations for 24 h. The results showed that Lido significantly inhibited CLP-induced lung inflammation and histopathological lung injury. Furthermore, Lido significantly reduced CLP-induced upregulation of HMGB1 and RAGE expression and activation of the NF-κB and MAPK signaling pathways. With the use of RAGE KO rats, we demonstrate here that RAGE deficiency attenuates the protective effect of Lido against CLP-induced lung inflammatory cell infiltration and histopathological lung injury. These results suggest that RAGE deficiency attenuates the protective effect of Lido against CLP-induced ALI by attenuating the pro-inflammatory cytokines production.

  14. TGF-beta, radiation-induced pulmonary Injury and lung cancer

    NARCIS (Netherlands)

    Vujaskovic, Z; Groen, HJM

    2000-01-01

    Purpose: To determine whether changes in TGF-beta plasma levels during radiation therapy may be useful in predicting radiation-induced pulmonary injury and tumour response in non-small-cell lung cancer (NSCLC) patients. Materials and methods: Plasma TGF-beta was investigated in 27 patients with stag

  15. Acute Lung Injury | EU Clinical Trials Register [EU Clinical Trials Register

    Lifescience Database Archive (English)

    Full Text Available rnedUK - MHRA A.2EudraCT number2010-021186-70 A.3Full title of the trial Keratinocyte growth factor in Acute...reviated title of the trial where available Keratinocyte Growth Factor in Acute L...nder investigation E.1.1Medical condition(s) being investigated Acute Lung Injury

  16. Alpha glucocorticoid receptor expression in different experimental rat models of acute lung injury

    OpenAIRE

    Bertorelli,Giuseppina; Pesci, Alberto; Peveri, Silvia; Mergoni, Mario; Corradi, Attilio; Cantoni, Anna Maria; Tincani, Giovanni; Bobbio, Antonio; Rusca, Michele; Carbognani, Paolo

    2008-01-01

    Alpha glucocorticoid receptor expression in different experimental rat models of acute lung injury correspondence: Corresponding author. Tel.: +390521703883; fax: +390521703493. (Carbognani, Paolo) (Carbognani, Paolo) Dipartimento di Clinica Medica - Nefrologia e Scienze della Prevenzione--> , University of Parma--> - ITALY (Bertorelli, Giuseppina) Dipartimento di Clinica Medica - Nefrologia e Scienze della...

  17. A model of hemorrhagic shock and acute lung injury in Landrace-Large White Swine.

    Science.gov (United States)

    Xanthos, Theodoros T; Balkamou, Xanthippi A; Stroumpoulis, Kostantinos I; Pantazopoulos, Ioannis N; Rokas, Georgios I; Agrogiannis, Georgios D; Troupis, Georgios T; Demestiha, Theano D; Skandalakis, Panagiotis N

    2011-04-01

    Traumatic injury is a leading cause of death worldwide for people between 5 and 44 y of age, and it accounts for 10% of all deaths. The incidence of acute lung injury, a life-threatening complication in severely injured trauma patients remains between 30% and 50%. This study describes an experimental protocol of volume-controlled hemorrhage in Landrace-Large White swine. The experimental approach simulated the clinical situation associated with hemorrhagic shock in the trauma patient while providing controlled conditions to maximize reproducibility. The duration of the protocol was 8 h and was divided into 5 distinct phases-stabilization, hemorrhage, maintenance, resuscitation, and observation-after which the swine were euthanized. Lung tissue samples were analyzed histologically. All swine survived the protocol. The hemodynamic responses accurately reflected those seen in humans, and the development of acute lung injury was consistent among all swine. This experimental protocol of hemorrhagic shock and fluid resuscitation in Landrace-Large White swine may be useful for future study of hemorrhagic shock and acute lung injury.

  18. A Model of Hemorrhagic Shock and Acute Lung Injury in Landrace–Large White Swine

    Science.gov (United States)

    Xanthos, Theodoros T; Balkamou, Xanthippi A; Stroumpoulis, Kostantinos I; Pantazopoulos, Ioannis N; Rokas, Georgios I; Agrogiannis, Georgios D; Troupis, Georgios T; Demestiha, Theano D; Skandalakis, Panagiotis N

    2011-01-01

    Traumatic injury is a leading cause of death worldwide for people between 5 and 44 y of age, and it accounts for 10% of all deaths. The incidence of acute lung injury, a life-threatening complication in severely injured trauma patients remains between 30% and 50%. This study describes an experimental protocol of volume-controlled hemorrhage in Landrace–Large White swine. The experimental approach simulated the clinical situation associated with hemorrhagic shock in the trauma patient while providing controlled conditions to maximize reproducibility. The duration of the protocol was 8 h and was divided into 5 distinct phases—stabilization, hemorrhage, maintenance, resuscitation, and observation—after which the swine were euthanized. Lung tissue samples were analyzed histologically. All swine survived the protocol. The hemodynamic responses accurately reflected those seen in humans, and the development of acute lung injury was consistent among all swine. This experimental protocol of hemorrhagic shock and fluid resuscitation in Landrace–Large White swine may be useful for future study of hemorrhagic shock and acute lung injury. PMID:21535927

  19. MEMBRANE-OXYGENATOR PREVENTS LUNG REPERFUSION INJURY IN CANINE CARDIOPULMONARY BYPASS

    NARCIS (Netherlands)

    GU, YJ; WANG, YS; CHIANG, BY; GAO, XD; YE, CX; WILDEVUUR, CRH

    The effect of blood activation on lung reperfusion injury during cardiopulmonary bypass was investigated in 20 dogs with the use of a bubble oxygenator (n = 10) or a membrane oxygenator (n = 10). In the bubble oxygenator group, significant leukocyte and platelet right to left atrium gradients were

  20. Acute lung injury in children : from viral infection and mechanical ventilation to inflammation and apoptosis

    NARCIS (Netherlands)

    Bern, R.A.

    2010-01-01

    Acute lung injury (ALI), ook bekend als acute respiratory distress syndrome (ARDS), is een uitgebreide ontstekingsreactie in beide longen door een longziekte of een aandoening elders in het lichaam. Kinderen lijken minder gevoelig voor de ziekte dan volwassenen, wellicht door de manier waarop de lon

  1. Epidemiology of acute lung injury and acute respiratory distress syndrome in The Netherlands : A survey

    NARCIS (Netherlands)

    Wind, Jan; Versteegt, Jens; Twisk, Jos; van der Werf, Tjip S.; Bindels, Alexander J. G. H.; Spijkstra, Jan-Jaap; Girbes, Armand R. J.; Groeneveld, A. B. Johan

    2007-01-01

    Background: The characteristics, incidence and risk factors for acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) may depend on definitions and geography. Methods: A prospective, 3-day point-prevalence study was performed by a survey of all intensive care units (ICU) in the Neth

  2. The role of selected cytokines and proteins analyzed in bronchoalveolar lavage fluid in lung injury

    Directory of Open Access Journals (Sweden)

    Monika Jedynak

    2014-06-01

    Full Text Available The early organism response to injury or infection involves activation of the innate immune system, in which pattern recognition receptors (PRRs participate. They recognize highly conservative structures that are called pathogen-associated molecular patterns (PAMPs and damage-associated molecular patterns (DAMPs. The interactions between PRRs and PAMPs or DAMPs lead to the activation of transcriptional factors which are responsible for gene expression of inflammatory mediators and synthesis and release of these factors, and result in the development of inflammation. RAGE (receptor for advanced glycation end products and CD163 belonging to PRRs play a significant role in the early immune response in lungs. They are expressed on alveolar epithelial cells and alveolar macrophages, respectively. NK cells are also involved in lung response to injury, though their maturation and the ability to express PRRs depend on the presence of IL-15. Detailed knowledge about these factors enables us to understand the signal pathways that are activated in the course of infectious and noninfectious lung injury. The analysis of these proteins’ concentrations in body fluids creates new possibilities in monitoring lung injury and predicting the results of treatment. In the future, the discussed mediators may become the targets for new forms of treatment in life-threatening respiratory diseases.

  3. Biomarkers of asbestos-induced lung injury: the influence of fiber characteristics and exposure methodology

    Science.gov (United States)

    ATS 2013 Biomarkers of asbestos-induced lung injury: the influence of fiber characteristics and exposure methodology Urmila P Kodavanti, Debora Andrews, Mette C Schaldweiler, Jaime M Cyphert, Darol E Dodd, and Stephen H Gavett NHEERL, U.S. EPA, Research Triangle Park, NC; NIEH...

  4. Complement activation contributes to ventilator-induced lung injury in rats

    NARCIS (Netherlands)

    B. Petersen; T. Busch; J. Gaertner; J.J. Haitsma (Jack); S.C. Krabbendam (Stefan); M. Ebsen (Michael); B.F. Lachmann (Burkhard); U.X. Kaisers

    2016-01-01

    textabstractThe complement system contributes to ventilator induced lung injury (VILI). We hypothesized that pretreatment with the C1 esterase inhibitor (C1INH) Berinert® constrains complement activation consecutively inducing improvements in arterial oxygenation and histological pulmonary damage. A

  5. Acute lung injury in 2003%2003年度急性肺损伤

    Institute of Scientific and Technical Information of China (English)

    Roger G SPRAGG

    2003-01-01

    During the past several decades, clinical investigators world-wide have continued to study the causes,pathophysiology, and treatment strategies for acute lung injury (ALl). This syndrome, which is characterized by nonhydrostatic pulmonary edema and hypoxemia associated with a variety of etiologies, is slowly becoming better understood as a result of these efforts.

  6. Hemodynamic effects of partial liquid ventilation with perfluorocarbon in acute lung injury

    NARCIS (Netherlands)

    R.J.M. Houmes (Robert Jan); S.J.C. Verbrugge (Serge); E. Hendrik (Edwin); B.F. Lachmann (Burkhard)

    1995-01-01

    textabstractObjective: To assess the effect of partial liquid ventilation with perfluorocarbons on hemodynamics and gas exchange in large pigs with induced acute lung injury (ALI). Design: Randomized, prospective, double-control, experimental study. Setting: Experimental intensive care unit of a uni

  7. Activated protein C in the treatment of acute lung injury and acute respiratory distress syndrome

    NARCIS (Netherlands)

    A.D. Cornet; G.P. van Nieuw Amerongen; A. Beishuizen; M.J. Schultz; A.R.J. Girbes; A.B.J. Groeneveld

    2009-01-01

    Background: Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) frequently necessitate mechanical ventilation in the intensive care unit. The syndromes have a high mortality rate and there is at present no treatment specifically directed at the underlying pathogenesis. Central in

  8. The receptor for advanced glycation end products in ventilator-induced lung injury

    NARCIS (Netherlands)

    Kuipers, Maria T; Aslami, Hamid; Tuinman, Pieter Roel; Tuip-de Boer, Anita M; Jongsma, Geartsje; van der Sluijs, Koenraad F; Choi, Goda; Wolthuis, Esther K; Roelofs, Joris Jth; Bresser, Paul; Schultz, Marcus J; van der Poll, Tom; Wieland, Catharina W

    2014-01-01

    BACKGROUND: Mechanical ventilation (MV) can cause ventilator-induced lung injury (VILI). The innate immune response mediates this iatrogenic inflammatory condition. The receptor for advanced glycation end products (RAGE) is a multiligand receptor that can amplify immune and inflammatory responses. W

  9. Early preventive treatment for severe acute pancreatitis combined with lung injury

    Institute of Scientific and Technical Information of China (English)

    刘学民; 刘青光; 潘承恩

    2002-01-01

    @@ Severe acute pancreatitis (SAP) can cause systematic inflammatory response syndrome (SIRS),which leads to injury or failure of the internal organs and systems.1 Among them,acute respiratory distress syndrome(ARDS)is a severe or fatal complication.In this article,the early preventive treatment for SAP combined with lung injure is studied.

  10. Mechanisms and consequences of lung epithelial injury in severe RSV disease

    NARCIS (Netherlands)

    van den Berg, E.

    2015-01-01

    The studies in this thesis have examined mechanisms and consequences of lung epithelial injury in severe RSV disease. In this context, they specifically contribute to the knowledge of apoptosis and the formation of pulmonary edema. The results of our studies underscore the complexity of the mechanis

  11. Biomarkers of asbestos-induced lung injury: the influence of fiber characteristics and exposure methodology

    Science.gov (United States)

    ATS 2013 Biomarkers of asbestos-induced lung injury: the influence of fiber characteristics and exposure methodology Urmila P Kodavanti, Debora Andrews, Mette C Schaldweiler, Jaime M Cyphert, Darol E Dodd, and Stephen H Gavett NHEERL, U.S. EPA, Research Triangle Park, NC; NIEH...

  12. Partial liquid ventilation improves lung function in ventilation-induced lung injury

    NARCIS (Netherlands)

    G.F. Vazquez de Anda; R.A. Lachmann; S.J.C. Verbrugge (Serge); D.A.M.P.J. Gommers (Diederik); J.J. Haitsma (Jack); B.F. Lachmann (Burkhard)

    2001-01-01

    textabstractDisturbances in lung function and lung mechanics are present after ventilation with high peak inspiratory pressures (PIP) and low levels of positive end-expiratory pressure (PEEP). Therefore, the authors investigated whether partial liquid ventilation can re-establish l

  13. Impaired Pulmonary Defense Against Pseudomonas aeruginosa in VEGF Gene Inactivated Mouse Lung

    Science.gov (United States)

    Breen, Ellen C.; Malloy, Jaret L.; Tang, Kechun; Xia, Feng; Fu, Zhenxing; Hancock, Robert E. W.; Overhage, Joerg; Wagner, Peter D.; Spragg, Roger G.

    2012-01-01

    Repeated bacterial and viral infections are known to contribute to worsening lung function in several respiratory diseases, including asthma, cystic fibrosis and chronic obstructive pulmonary disease (COPD). Previous studies have reported alveolar wall cell apoptosis and parenchymal damage in adult pulmonary VEGF gene ablated mice. We hypothesized that VEGF expressed by type II cells is also necessary to provide an effective host defense against bacteria in part by maintaining surfactant homeostasis. Therefore, Pseudomonas aeruginosa (PAO1) levels were evaluated in mice following lung-targeted VEGF gene inactivation, and alterations in VEGF-dependent type II cell function were evaluated by measuring surfactant homeostasis in mouse lungs and isolated type II cells. In VEGF-deficient lungs increased PAO1 levels and pro-inflammatory cytokines, TNFα and IL-6, were detected 24 hours after bacterial instillation compared to control lungs. In vivo lung-targeted VEGF gene deletion (57% decrease in total pulmonary VEGF) did not alter alveolar surfactant or tissue disaturated phosphatidylcholine (DSPC) levels. However, sphingomyelin content, choline phosphate cytidylyltransferase (CCT) mRNA and SP-D expression were decreased. In isolated type II cells an 80% reduction of VEGF protein resulted in decreases in total phospholipids (PL), DSPC, DSPC synthesis, surfactant associated proteins (SP)-B and -D, and the lipid transporters, ABCA1 and Rab3D. TPA-induced DSPC secretion and apoptosis were elevated in VEGF-deficient type II cells. These results suggest a potential protective role for type II cell-expressed VEGF against bacterial initiated infection. PMID:22718316

  14. Diesel exhaust particles are mutagenic in FE1-MutaMouse lung epithelial cells

    DEFF Research Database (Denmark)

    Jacobsen, Nicklas Raun; Møller, Peter; Cohn, Corey Alexander;

    2008-01-01

    The particulate phase of diesel engine exhaust is likely carcinogenic. However, the mechanisms of diesel exhaust particles (DEPs) induced mutagenicity/carcinogenicity are still largely unknown. We determined the mutant frequency following eight repeated 72 h incubations with 37.5 or 75 microg....../ml DEP (NIST SRM 1650) in the FE1-MutaMouse lung epithelial cell line. We measured DEP-induced acellular and intracellular production of reactive oxygen species (ROS) and compared with ROS production induced by carbon black, which we have previously shown is mutagenic in this cell line [N.R. Jacobsen, A.......T. Saber, P. White, P. Moller, G. Pojana, U. Vogel, S. Loft, J. Gingerich, L. Soper, G.R. Douglas, H. Wallin. Increased mutant frequency by carbon black, but not quartz, in the lacZ and cII transgenes of mutamouse lung epithelial cells, Environ. Mol. Mutagen. 48(6) (2007) 451-461]. The mutant frequency...

  15. A functional role for tumor cell heterogeneity in a mouse model of small cell lung cancer.

    Science.gov (United States)

    Calbo, Joaquim; van Montfort, Erwin; Proost, Natalie; van Drunen, Ellen; Beverloo, H Berna; Meuwissen, Ralph; Berns, Anton

    2011-02-15

    Small cell lung cancer (SCLC) is the lung neoplasia with the poorest prognosis, due to its high metastatic potential and chemoresistance upon relapse. Using the previously described mouse model for SCLC, we found that the tumors are often composed of phenotypically different cells with either a neuroendocrine or a mesenchymal marker profile. These cells had a common origin because they shared specific genomic aberrations. The transition from neuroendocrine to mesenchymal phenotype could be achieved by the ectopic expression of oncogenic Ras(V12). Crosstalk between mesenchymal and neuroendocrine cells strongly influenced their behavior. When engrafted as a mixed population, the mesenchymal cells endowed the neuroendocrine cells with metastatic capacity, illustrating the potential relevance of tumor cell heterogeneity in dictating tumor properties.

  16. Cordyceps Militaris Alleviates Severity of Murine Acute Lung Injury Through miRNAs-Mediated CXCR2 Inhibition

    Directory of Open Access Journals (Sweden)

    Sheng Liu

    2015-07-01

    Full Text Available Background/Aims: Acute lung injury (ALI and acute respiratory distress syndrome (ARDS are lethal diseases in humans, and the current treatments have limited therapeutic effects. Cordyceps militaris (CM is a caterpillar-grown traditional medicinal mushroom, and has been used as a natural invigorant for longevity, endurance, and vitality in China. Recently, purified extracts from CM have been shown to have beneficial effects on various diseases including cancer. Nevertheless, a role of CM in ALI has not been examined previously. Methods: Here, we used a bleomycin-induced ALI model to study the effects of CM on the severity of ALI in mice. The levels of CXCR2, a receptor for Interleukin 8 (IL-8 in pulmonary microvascular endothelial cells, were examined in different experimental groups. The levels of microRNA (miR-1321 and miR-3188 were also examined in lung samples and in CM. Adeno-associated viruses carrying miR-1321 and miR-3188 were injected into bleomycin-treated mice for evaluation their effects on the severity of ALI. Results: CM treatment significantly alleviated the severity of bleomycin-induced ALI in mice. The increases in lung CXCR2 by bleomycin were significantly reduced by CM at protein level, but not at mRNA level. CM contained high levels of 2 miRNAs (miR-1321 and miR-3188 that target 3'-UTR of CXCR2 mRNA to inhibit its expression. Overexpression of miR-1321 and miR-3188 in mouse lung through AAV-mediated gene therapy mimicked the effects of CM. Conclusion: CM may alleviate severity of murine ALI through miRNAs-mediated CXCR2 inhibition.

  17. Abdominal Muscle Activity during Mechanical Ventilation Increases Lung Injury in Severe Acute Respiratory Distress Syndrome.

    Directory of Open Access Journals (Sweden)

    Xianming Zhang

    Full Text Available It has proved that muscle paralysis was more protective for injured lung in severe acute respiratory distress syndrome (ARDS, but the precise mechanism is not clear. The purpose of this study was to test the hypothesis that abdominal muscle activity during mechanically ventilation increases lung injury in severe ARDS.Eighteen male Beagles were studied under mechanical ventilation with anesthesia. Severe ARDS was induced by repetitive oleic acid infusion. After lung injury, Beagles were randomly assigned into spontaneous breathing group (BIPAPSB and abdominal muscle paralysis group (BIPAPAP. All groups were ventilated with BIPAP model for 8h, and the high pressure titrated to reached a tidal volume of 6ml/kg, the low pressure was set at 10 cmH2O, with I:E ratio 1:1, and respiratory rate adjusted to a PaCO2 of 35-60 mmHg. Six Beagles without ventilator support comprised the control group. Respiratory variables, end-expiratory volume (EELV and gas exchange were assessed during mechanical ventilation. The levels of Interleukin (IL-6, IL-8 in lung tissue and plasma were measured by qRT-PCR and ELISA respectively. Lung injury scores were determined at end of the experiment.For the comparable ventilator setting, as compared with BIPAPSB group, the BIPAPAP group presented higher EELV (427±47 vs. 366±38 ml and oxygenation index (293±36 vs. 226±31 mmHg, lower levels of IL-6(216.6±48.0 vs. 297.5±71.2 pg/ml and IL-8(246.8±78.2 vs. 357.5±69.3 pg/ml in plasma, and lower express levels of IL-6 mRNA (15.0±3.8 vs. 21.2±3.7 and IL-8 mRNA (18.9±6.8 vs. 29.5±7.9 in lung tissues. In addition, less lung histopathology injury were revealed in the BIPAPAP group (22.5±2.0 vs. 25.2±2.1.Abdominal muscle activity during mechanically ventilation is one of the injurious factors in severe ARDS, so abdominal muscle paralysis might be an effective strategy to minimize ventilator-induce lung injury.

  18. Indium oxide (In2O3) nanoparticles induce progressive lung injury distinct from lung injuries by copper oxide (CuO) and nickel oxide (NiO) nanoparticles.

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    Jeong, Jiyoung; Kim, Jeongeun; Seok, Seung Hyeok; Cho, Wan-Seob

    2016-04-01

    Indium is an essential element in the manufacture of liquid crystal displays and other electronic devices, and several forms of indium compounds have been developed, including nanopowders, films, nanowires, and indium metal complexes. Although there are several reports on lung injury caused by indium-containing compounds, the toxicity of nanoscale indium oxide (In2O3) particles has not been reported. Here, we compared lung injury induced by a single exposure to In2O3 nanoparticles (NPs) to that caused by benchmark high-toxicity nickel oxide (NiO) and copper oxide (CuO) NPs. In2O3 NPs at doses of 7.5, 30, and 90 cm(2)/rat (50, 200, and 600 µg/rat) were administered to 6-week-old female Wistar rats via pharyngeal aspiration, and lung inflammation was evaluated 1, 3, 14, and 28 days after treatment. Neutrophilic inflammation was observed on day 1 and worsened until day 28, and severe pulmonary alveolar proteinosis (PAP) was observed on post-aspiration days 14 and 28. In contrast, pharyngeal aspiration of NiO NPs showed severe neutrophilic inflammation on day 1 and lymphocytic inflammation with PAP on day 28. Pharyngeal aspiration of CuO NPs showed severe neutrophilic inflammation on day 1, but symptoms were completely resolved after 14 days and no PAP was observed. The dose of In2O3 NPs that produced progressive neutrophilic inflammation and PAP was much less than the doses of other toxic particles that produced this effect, including crystalline silica and NiO NPs. These results suggest that occupational exposure to In2O3 NPs can cause severe lung injury.

  19. Autocrine growth factors are involved in branching morphogenesis of mouse lung epithelium.

    Science.gov (United States)

    Okada, Kimiko; Noda, Masatsugu; Nogawa, Hiroyuki

    2013-01-01

    The current model for branching morphogenesis of mouse lung proposes that the epithelium bifurcates as cells pursue separate sources of fibroblast growth factor (FGF) 10, secreted from mesenchymal tissue through interactions with epithelial tissue. If so, it may be assumed that the lung epithelium will grow into a uniform, expanding ball (without branching) when uniformly exposed to a constant concentration of FGF10. To test this hypothesis, we cultured Matrigel-embedded lung epithelium explants in FGF10-supplemented medium while shaking the culture dishes. Shaking cultures with FGF10 resulted in inferior epithelial branching compared to control cultures at rest. However, this effect was unexpectedly accompanied by poor growth rather than by ball-like expansion. When using FGF1, epithelial cultures grew and branched similarly well under either culture condition. Thus, we hypothesized that FGF10 signaling must be mediated by autocrine FGFs, such as FGF1, which might easily diffuse through the culture medium in the shaking culture. Reverse transcription-polymerase chain reaction analyses showed that FGF9 as well as FGF1 were expressed in the epithelium in vivo and in FGF10-stimulated epithelium in vitro, and FGF9 induced epithelial branching at a much lower concentration than FGF10. These results suggest that FGF1 and FGF9 may mediate FGF10 signaling and induce branching in the lung epithelium via autocrine signaling.

  20. Effect of Sodium Ferulate on Fluidity and Morphology of Cell Membrane in Ozone Induced Lung Injury

    Institute of Scientific and Technical Information of China (English)

    2006-01-01

    Objective: To study the effect of sodium ferulate (SF), an active component of Radix Angelica, on lung damage induced by ozone (O3). Methods: Mice model of lung injury was induced by ozone inhalation and treated with SF. The level of lipid peroxide and microviscosity in alveolar epithelial cell membrane of the mice was determined, and the structural change of lung cells was observed by microscopy. Results: Ozone could increase the level of malondialdehyde (MDA) and the microviscosity in alveolar epithelial cell membrane, and induce inflammatory changes in morphologic structure. These abnormal changes were improved after SF administration, which was manifested as alleviation of heightened microviscosity, increase of membrane fluidity, as well as the basically normalized pulmonary cellular structure under microscope. Conclusion: SF has a preventive effect against oxidized pulmonary injury induced by ozone, the action of which could be through scavenging oxygen free radicals, reducing lipid peroxide production, increasing membranous fluidity and mitigating inflammatory changes in cell structure.

  1. [Advances in the study of the relationship between autophagy and sepsis-induced lung injury].

    Science.gov (United States)

    Wang, Xingtong; Li, Hengyu; Xia, Zhaofan

    2014-08-01

    Sepsis is one of the most common pathogenetic causes of acute lung injury (ALI), and at present there is still a lack of effective targeted techniques and methods for its prevention and treatment. Autophagy is a homeostatic mecha- nism common to all eukaryotic cells, including adaption to environment, defense against invasion of pathogens, and maintenance of cellular homeostasis. Autophagy is also involved in a variety of lung-related diseases. In septic lung injury, autophagy not only serves to dissipate dysfunctional organelles, but also inhibits the release of inflammatory cytokines. This review aims at eliciting the role of autophagy in sepsis-induced ALI and further exploring the potential targets of autophagy in inhibiting inflammation, in an effort to provide a new perspective for clinical treatment of sepsis-induced ALI.

  2. Aging promotes pro-fibrotic matrix production and increases fibrocyte recruitment during acute lung injury.

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    Sueblinvong, Viranuj; Neveu, Wendy A; Neujahr, David C; Mills, Stephen T; Rojas, Mauricio; Roman, Jesse; Guidot, David M

    2014-01-01

    Fibrotic lung diseases increase with age. Previously we determined that senescence increases tissue expression of fibronectin EDA (Fn-EDA) and decreases fibroblast expression of Thy-1, and that fibrocytes contribute to fibrosis following bleomycin-induced lung injury in mice. In this study we hypothesized that fibroblasts lacking Thy-1 expression produce an extracellular matrix that promotes fibrocyte retention and myofibroblast transdifferentiation, thereby promoting fibrogenesis. Young and old mice were treated with bleomycin intratracheally; fibrocytes in the bone marrow, blood, and lungs were quantified, and lung fibroblast Thy-1 expression assessed. Bone marrow-derived fibrocytes were cultured on matrices derived from Thy-1(+) or Thy-1(-) fibroblasts ± the pro-fibrotic cytokine TGFβ1. Older mice had more fibrocytes in their bone marrows at baseline and more fibrocytes in their lungs following bleomycin treatment. In parallel, lung fibroblasts in older mice had lower expression of Thy-1 at baseline that increased transiently 7 days after bleomycin treatment but then rapidly waned such that 14 days after bleomycin treatment Thy-1 expression was again markedly lower. Fibrocytes cultured on matrices derived from Thy-1(-) fibroblasts + TGFβ1 had increased gene expression for collagen type 1, fibronectin, Fn-EDA, and α-smooth muscle actin. In parallel, whereas the matrices derived from Thy-1(-) fibroblasts stimulated phosphorylation of Akt in cultured fibrocytes, the matrices derived from Thy-1(+) fibroblasts induced apoptosis. These findings suggest that senescence increases fibrocyte recruitment to the lung following injury and that loss of Thy-1 expression by lung fibroblasts promotes fibrocyte retention and myofibroblast trans-differentiation that renders the "aging lung" susceptible to fibrosis.

  3. [Protective effect of synthetic salidroside on acute lung injury in rats].

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    Huang, Qian; Cai, Yan-Chun; Wei, Xiao-Li; Wu, Jin-Long; Mei, Ru-Huan; Hu, Xiao-Lan

    2017-06-25

    To study the protective effect and mechanism of synthetic salidroside on acute lung injury (ALI) induced by lipopolysaccharide (LPS), male Sprague-Dawley (SD) rats were randomly divided into saline control group, 3 mg/kg LPS model group, different doses of salidroside groups (5, 20 and 80 mg/kg), and 5 mg/kg dexamethasone group. Intratracheal LPS instillation was used to establish the ALI model 0.5 h after intraperitoneal injection of salidroside or dexamethasone, and the rats were sacrificed 6 h later. Lung wet/dry weight ratio (W/D) was calculated. Lung tissue pathology and lung injury score (LIS) were observed and evaluated through hematoxylin and eosin (HE) staining. The centrifugal sediment of bronchoalveolar lavage fluid (BALF) was used to count the polymorphonuclear leukocyte (PMN) number by Wright's staining, and the centrifugal supernatant of BALF was used to determine the contents of protein and inflammatory factors (TNF-α, IL-1β and IL-6). The contents of myeloperoxidase (MPO) and malondialdehyde (MDA) in lung tissue were determined. Western blot was used to detect the expression levels of phosphorylated and total nuclear factor kappa B (NF-κB)/p65 protein in lung tissue. The results showed that, compared with LPS group, the intervention of synthetic salidroside alleviated the pathological damage in lung tissue, decreased the LIS and lung W/D ratio (P salidroside has a protective effect on ALI induced by LPS, and its mechanism is related to inhibiting the phosphorylation of NF-κB and reducing the aggregation of PMN in the lung.

  4. Acute inflammation decreases the expression of connexin 40 in mouse lung.

    Science.gov (United States)

    Rignault, Stéphanie; Haefliger, Jacques-Antoine; Waeber, Bernard; Liaudet, Lucas; Feihl, François

    2007-07-01

    Transmigration of neutrophil polymorphonuclear leukocytes through the microvascular endothelium is a cardinal event of acute inflammation. In vitro, this process can be restricted by gap junctional intercellular communication, but whether it also occurs in vivo is unknown. Connexin 40 (Cx40) is a gap junctional protein abundantly present in the lung, notably in vascular endothelium. We hypothesized that acute lung inflammation would be aggravated in knockout mice genetically deficient in Cx40. This hypothesis was tested in two different models: 1) intranasal instillation of LPS at either supramaximal (50 microg/mouse) or inframaximal dose (0.01 microg/mouse) and 2) pulmonary inflammation as a distant consequence of an abdominal infection caused by cecal ligation and perforation. Pulmonary transmigration of neutrophils was assessed by counting these cells in bronchoalveolar lavage fluid (LPS model) or with the myeloperoxidase assay in homogenates of blood-free tissue (cecal ligation and perforation model). Pulmonary content in Cx40 and Cx43 was evaluated with immunoblots. In wild-type mice, there was a time-dependent decrease of Cx40 expression in both models. The time points for studies with the knockout mice were chosen in such a manner that inflammation was clearly present and Cx40 still largely expressed in wild-type animals. In either model, the development of lung inflammation did not differ between wild-type and Cx40-deficient mice. In conclusion, the pulmonary expression of the Cx40 protein is progressively and markedly decreased in two different murine models of acute lung inflammation, but there is no causal relationship between this process and the pulmonary transmigration of neutrophils.

  5. Natural antioxidant betanin protects rats from paraquat-induced acute lung injury interstitial pneumonia.

    Science.gov (United States)

    Han, Junyan; Ma, Deshun; Zhang, Miao; Yang, Xuelian; Tan, Dehong

    2015-01-01

    The effect of betanin on a rat paraquat-induced acute lung injury (ALI) model was investigated. Paraquat was injected intraperitoneally at a single dose of 20 mg/kg body weight, and betanin (25 and 100 mg/kg/d) was orally administered 3 days before and 2 days after paraquat administration. Rats were sacrificed 24 hours after the last betanin dosage, and lung tissue and bronchoalveolar lavage fluid (BALF) were collected. In rats treated only with paraquat, extensive lung injury characteristic of ALI was observed, including histological changes, elevation of lung : body weight ratio, increased lung permeability, increased lung neutrophilia infiltration, increased malondialdehyde (MDA) and myeloperoxidase (MPO) activity, reduced superoxide dismutase (SOD) activity, reduced claudin-4 and zonula occluden-1 protein levels, increased BALF interleukin (IL-1) and tumor necrosis factor (TNF)-α levels, reduced BALF IL-10 levels, and increased lung nuclear factor kappa (NF-κB) activity. In rats treated with betanin, paraquat-induced ALI was attenuated in a dose-dependent manner. In conclusion, our results indicate that betanin attenuates paraquat-induced ALI possibly via antioxidant and anti-inflammatory mechanisms. Thus, the potential for using betanin as an auxilliary therapy for ALI should be explored further.

  6. Humidifier disinfectant-associated lung injury in adults: Prognostic factors in predicting short-term outcome

    Energy Technology Data Exchange (ETDEWEB)

    Koo, Hyun Jung; Do, Kyung-Hyun; Chae, Eun Jin [University of Ulsan College of Medicine, Department of Radiology and Research Institute of Radiology, Asan Medical Center, Songpa-gu, Seoul (Korea, Republic of); Kim, Hwa Jung [University of Ulsan College of Medicine, Cancer Center, Department of Clinical Epidemiology and Biostatistics, Asan Medical Center, Seoul (Korea, Republic of); Song, Joon Seon; Jang, Se Jin [University of Ulsan College of Medicine, Department of Pathology, Asan Medical Center, Seoul (Korea, Republic of); Hong, Sang-Bum; Huh, Jin Won [University of Ulsan College of Medicine, Department of Pulmonary and Critical Care Medicine, Asan Medical Center, Seoul (Korea, Republic of); Lee, En [Inje University Haundae Paik Hospital, Department of Pediatrics, Busan (Korea, Republic of); Hong, Soo-Jong [University of Ulsan College of Medicine, Department of Pediatrics, Childhood Asthma and Atopy Center, Environmental Health Center, Asan Medical Center, Seoul (Korea, Republic of)

    2017-01-15

    To identify clinical and radiologic findings that affect disease severity and short-term prognosis of humidifier disinfectant-associated lung injury in adults and to compare computed tomography (CT) findings between the patients with and without death or lung transplantation. Fifty-nine adults (mean age, 34 years; M/F = 12:47) were enrolled in this retrospective study. Medical records and prospective surveillance data were used to assess clinical and radiological factors associated with a poor clinical outcome. Multivariate generalized estimating equation models were used to analyse serial CT findings. Overall cumulative major events including lung transplantation and mortality were assessed using the Kaplan-Meier method. Almost half needed ICU admission (47.5 %) and 17 died (28.8 %). Young age, peripartum and low O{sub 2} saturation were factors associated with ICU admission. On initial chest radiographs, consolidation (P < 0.001) and ground-glass opacity (P = 0.01) were significantly noted in patients who required ICU admission. CT findings including consolidation (odds ratio (OR), 1.02), pneumomediastinum (OR, 1.66) and pulmonary interstitial emphysema (OR, 1.61) were the risk factors for lung transplantation and mortality. Clinical and radiologic findings are related to the risks of lung transplantation and mortality of humidifier disinfectant-associated lung injury. Consolidation, pneumomediastinum and pulmonary interstitial emphysema were short-term prognostic CT findings. (orig.)

  7. XB130 deficiency enhances lipopolysaccharide-induced septic response and acute lung injury

    Science.gov (United States)

    Toba, Hiroaki; Tomankova, Tereza; Wang, Yingchun; Bai, Xiaohui; Cho, Hae-Ra; Guan, Zhehong; Adeyi, Oyedele A.; Tian, Feng; Keshavjee, Shaf; Liu, Mingyao

    2016-01-01

    XB130 is a novel oncoprotein that promotes cancer cell survival, proliferation and migration. Its physiological function in vivo is largely unknown. The objective of this study was to determine the role of XB130 in lipopolysaccharide (LPS)-induced septic responses and acute lung injury. LPS was intraperitoneally administrated to Xb130 knockout (KO) and wild type (WT) mice. There was a significant weight loss in KO mice at Day 2 and significantly higher disease scores during the 7 days of observation. The levels of tumor necrosis factor-alpha, monocyte chemoattractant protein-1, interleukin-6 and interleukin-10 in the serum were significantly higher in KO mice at Day 2. In KO mice there were a significantly higher lung injury score, higher wet/dry lung weight ratio, more apoptotic cells and less proliferative cells in the lung. Macrophage infiltration was significantly elevated in the lung of KO mice. There was significantly increased number of p-GSK-3β positive cells in KO mice, which were mainly neutrophils and macrophages. XB130 is expressed in alveolar type I and type II cells in the lung. The expression in these cells was significantly reduced after LPS challenge. XB130 deficiency delayed the recovery from systemic septic responses, and the presence of XB130 in the alveolar epithelial cells may provide protective mechanisms by reducing cell death and promoting cell proliferation, and reducing pulmonary permeability. PMID:27029000

  8. Mesenchymal Stem Cell Derived Secretome and Extracellular Vesicles for Acute Lung Injury and Other Inflammatory Lung Diseases

    Science.gov (United States)

    Monsel, Antoine; Zhu, Ying-gang; Gudapati, Varun; Lim, Hyungsun; Lee, Jae W.

    2017-01-01

    Introduction Acute respiratory distress syndrome is a major cause of respiratory failure in critically ill patients. Despite extensive research into its pathophysiology, mortality remains high. No effective pharmacotherapy exists. Based largely on numerous preclinical studies, administration of mesenchymal stem or stromal cell (MSC) as a therapeutic for acute lung injury holds great promise, and clinical trials are currently underway. However, concern for the use of stem cells, specifically the risk of iatrogenic tumor formation, remains unresolved. Accumulating evidence now suggest that novel cell-free therapies including MSC-derived conditioned medium and extracellular vesicles released from MSCs might constitute compelling alternatives. Areas covered The current review summarizes the preclinical studies testing MSC conditioned medium and/or MSC extracellular vesicles as treatment for acute lung injury and other inflammatory lung diseases. Expert opinion While certain logistical obstacles limit the clinical applications of MSC conditioned medium such as the volume required for treatment, the therapeutic application of MSC extracellular vesicles remains promising, primarily due to ability of extracellular vesicles to maintain the functional phenotype of the parent cell. However, utilization of MSC extracellular vesicles will require large-scale production and standardization concerning identification, characterization and quantification. PMID:27011289

  9. Regulatory T cells reduce acute lung injury fibroproliferation by decreasing fibrocyte recruitment.

    Science.gov (United States)

    Garibaldi, Brian T; D'Alessio, Franco R; Mock, Jason R; Files, D Clark; Chau, Eric; Eto, Yoshiki; Drummond, M Bradley; Aggarwal, Neil R; Sidhaye, Venkataramana; King, Landon S

    2013-01-01

    Acute lung injury (ALI) causes significant morbidity and mortality. Fibroproliferation in ALI results in worse outcomes, but the mechanisms governing fibroproliferation remain poorly understood. Regulatory T cells (Tregs) are important in lung injury resolution. Their role in fibroproliferation is unknown. We sought to identify the role of Tregs in ALI fibroproliferation, using a murine model of lung injury. Wild-type (WT) and lymphocyte-deficient Rag-1(-/-) mice received intratracheal LPS. Fibroproliferation was characterized by histology and the measurement of lung collagen. Lung fibrocytes were measured by flow cytometry. To dissect the role of Tregs in fibroproliferation, Rag-1(-/-) mice received CD4(+)CD25(+) (Tregs) or CD4(+)CD25(-) Tcells (non-Tregs) at the time of LPS injury. To define the role of the chemokine (C-X-C motif) ligand 12 (CXCL12)-CXCR4 pathway in ALI fibroproliferation, Rag-1(-/-) mice were treated with the CXCR4 antagonist AMD3100 to block fibrocyte recruitment. WT and Rag-1(-/-) mice demonstrated significant collagen deposition on Day 3 after LPS. WT mice exhibited the clearance of collagen, but Rag-1(-/-) mice developed persistent fibrosis. This fibrosis was mediated by the sustained epithelial expression of CXCL12 (or stromal cell-derived factor 1 [SDF-1]) that led to increased fibrocyte recruitment. The adoptive transfer of Tregs resolved fibroproliferation by decreasing CXCL12 expression and subsequent fibrocyte recruitment. Blockade of the CXCL12-CXCR4 axis with AMD3100 also decreased lung fibrocytes and fibroproliferation. These results indicate a central role for Tregs in the resolution of ALI fibroproliferation by reducing fibrocyte recruitment along the CXCL12-CXCR4 axis. A dissection of the role of Tregs in ALI fibroproliferation may inform the design of new therapeutic tools for patients with ALI.

  10. Lung T lymphocyte trafficking and activation during ischemic acute kidney injury.

    Science.gov (United States)

    Lie, Mihaela L; White, Laura E; Santora, Rachel J; Park, Jong M; Rabb, Hamid; Hassoun, Heitham T

    2012-09-15

    Despite advances in renal replacement therapy, the mortality rate for acute kidney injury (AKI) remains unacceptably high, likely owing to extrarenal organ dysfunction. Kidney ischemia-reperfusion injury (IRI) activates cellular and soluble mediators that facilitate organ crosstalk and induce caspase-dependent lung apoptosis and injury through a TNFR1-dependent pathway. Given that T lymphocytes mediate local IRI in the kidney and are known to drive TNFR1-mediated apoptosis, we hypothesized that T lymphocytes activated during kidney IRI would traffic to the lung and mediate pulmonary apoptosis during AKI. In an established murine model of kidney IRI, we identified trafficking of CD3+ T lymphocytes to the lung during kidney IRI by flow cytometry and immunohistochemistry. T lymphocytes were primarily of the CD3+CD8+ phenotype; however, both CD3+CD4+ and CD3+CD8+ T lymphocytes expressed CD69 and CD25 activation markers during ischemic AKI. The activated lung T lymphocytes did not demonstrate an increased expression of intracellular TNF-α or surface TNFR1. Kidney IRI induced pulmonary apoptosis measured by caspase-3 activation in wild-type controls, but not in T cell-deficient (T(nu/nu)) mice. Adoptive transfer of murine wild-type T lymphocytes into T(nu/nu) mice restored the injury phenotype with increased cellular apoptosis and lung microvascular barrier dysfunction, suggesting that ischemic AKI-induced pulmonary apoptosis is T cell dependent. Kidney-lung crosstalk during AKI represents a complex biological process, and although T lymphocytes appear to serve a prominent role in the interorgan effects of AKI, further experiments are necessary to elucidate the specific role of activated T cells in modulating pulmonary apoptosis.

  11. Inhaled hydrogen sulfide protects against lipopolysaccharide-induced acute lung injury in mice

    Directory of Open Access Journals (Sweden)

    Faller Simone

    2012-10-01

    Full Text Available Abstract Background Local pulmonary and systemic infections can lead to acute lung injury (ALI. The resulting lung damage can evoke lung failure and multiple organ dysfunction associated with increased mortality. Hydrogen sulfide (H2S appears to represent a new therapeutic approach to ALI. The gas has been shown to mediate potent anti-inflammatory and organ protective effects in vivo. This study was designed to define its potentially protective role in sepsis-induced lung injury. Methods C57BL/6 N mice received lipopolysaccharide (LPS intranasally in the absence or presence of 80 parts per million H2S. After 6 h, acute lung injury was determined by comparative histology. Bronchoalveolar lavage (BAL fluid was analyzed for total protein content and differential cell counting. BAL and serum were further analyzed for interleukin-1β, macrophage inflammatory protein-2, and/or myeloperoxidase glycoprotein levels by enzyme-linked immunosorbent assays. Differences between groups were analyzed by one way analysis of variance. Results Histological analysis revealed that LPS instillation led to increased alveolar wall thickening, cellular infiltration, and to an elevated ALI score. In the presence of H2S these changes were not observed despite LPS treatment. Moreover, neutrophil influx, and pro-inflammatory cytokine release were enhanced in BAL fluid of LPS-treated mice, but comparable to control levels in H2S treated mice. In addition, myeloperoxidase levels were increased in serum after LPS challenge and this was prevented by H2S inhalation. Conclusion Inhalation of hydrogen sulfide protects against LPS-induced acute lung injury by attenuating pro-inflammatory responses.

  12. Role of Kupffer cells in acute hemorrhagic necrotizing pancreatitis-associated lung injury of rats

    Institute of Scientific and Technical Information of China (English)

    Hong-Bin Liu; Nai-Qiang Cui; Dong-Hua Li; Chang Chen

    2006-01-01

    AIM: To investigate the role of Kupffer cells (KCs) in acute hemorrhagic necrotizing pancreatitis-associated lung injury (AHNP-LI).METHODS: Forty-two rats were allocated to four groups [sham operation, AHNP model, gadolinium chloride (GdCl3) pretreatment, GdCl3 control]. In GdCl3pretreatment group, GdCl3 was administered by caudal vein injection 24 h before the AHNP model induction.Blood from the iliac artery, alveolar macrophages and tissues from the pancreas and lung, were collected in six animals per group 3 and 6 h after acute pancreatitis induction. TNF-α, IL-1 of serum, myeloperoxidase (MPO)of lung tissue, NF-κB activation of alveolar macrophages were detected. Serum AST and ALT in sham operation group and GdCl3 control group were tested. In addition,histopathological changes of the pancreas and lung were observed under light microscope.RESULTS: MPO of lung tissue and TNF-α, IL-1 levels of serum were all reduced significantly in GdCl3pretreatment group compared to those in AHNP group(P<0.01). NF-κB activation of alveolar macrophages was also attenuated significantly in GdCl3 pretreatment group compared to that in AHNP group (P<0.01). The pathological injury of the lung was ameliorated obviously in GdCl3 pretreatment group compared to that in AHNP group. Nevertheless, the serum amylase level did not reduce and injury of the pancreas was not prevented in GdCl3 pretreatment group.CONCLUSION: Pulmonary injury induced by AHNP is mediated by KC activation and AHNP-LI can be significantly ameliorated by pretreatment with GdCl3 and KCs play a vital role in AHNP-LI.

  13. Strategies to improve oxygenation in experimental acute lung injury

    NARCIS (Netherlands)

    A. Hartog (Arthur)

    2000-01-01

    textabstractOne of the most important clinical syndromes, in which failure of oxygen uptake in the lung leads to severe hypoxia, is the so-called acute respiratory distress syndrome (ARDS). ARDS is a complex of clinical signs and symptoms which occur following diverse pulmonary or systemic insults,

  14. Altered mucosal immune response after acute lung injury in a murine model of Ataxia Telangiectasia.

    Science.gov (United States)

    Eickmeier, Olaf; Kim, Su Youn; Herrmann, Eva; Döring, Constanze; Duecker, Ruth; Voss, Sandra; Wehner, Sibylle; Hölscher, Christoph; Pietzner, Julia; Zielen, Stefan; Schubert, Ralf

    2014-05-29

    Ataxia telangiectasia (A-T) is a rare but devastating and progressive disorder characterized by cerebellar dysfunction, lymphoreticular malignancies and recurrent sinopulmonary infections. In A-T, disease of the respiratory system causes significant morbidity and is a frequent cause of death. We used a self-limited murine model of hydrochloric acid-induced acute lung injury (ALI) to determine the inflammatory answer due to mucosal injury in Atm (A-T mutated)- deficient mice (Atm(-/-)). ATM deficiency increased peak lung inflammation as demonstrated by bronchoalveolar lavage fluid (BALF) neutrophils and lymphocytes and increased levels of BALF pro-inflammatory cytokines (e.g. IL-6, TNF). Furthermore, bronchial epithelial damage after ALI was increased in Atm(-/-) mice. ATM deficiency increased airway resistance and tissue compliance before ALI was performed. Together, these findings indicate that ATM plays a key role in inflammatory response after airway mucosal injury.

  15. Increased intestinal protein permeability in a model of lung injury induced by phorbol myristate acetate.

    Science.gov (United States)

    St John, R C; Mizer, L A; Weisbrode, S E; Dorinsky, P M

    1991-11-01

    Multiple nonpulmonary organ failure is a frequent complication of the adult respiratory distress syndrome (ARDS), and contributes significantly to the high mortality rate associated with this disorder. Although previous studies suggest that systemic organ injury may be an integral component of ARDS, little is known about the specific functional alterations that occur in these target organs. The present study was designed, therefore, to test the hypothesis that endothelial damage, as assessed by microvascular permeability changes, develops in systemic organs in a model of acute lung injury. To test this postulate, the microvascular permeability for total protein was estimated using the steady-state relationship between the lymph (CL) to plasma (Cp) protein concentration ratio (i.e., CL/Cp) and lymph flow in autoperfused cat ileum preparations. Specifically, CL/Cp was measured in five cats, 2 h after acute lung injury was induced by intravenously administered phorbol myristate acetate (PMA), 15 micrograms/kg, and the results were compared with those of seven time-matched control animals. Prior to PMA infusion, the PaO2/FIO2 ratio was 451 +/- 28 in both groups and remained unchanged (486 +/- 26) in the control group. By contrast, the PaO2/FIO2 ratio fell to 275 +/- 95 after PMA infusion (p less than 0.05). In addition, whereas CL/Cp was 0.099 +/- 0.008 in the control animals, it increased to 0.36 +/- 0.06 in the PMA-injured animals (p less than 0.01). In summary, this study demonstrated that in this model of acute lung injury produced by PMA-induced activation of circulating inflammatory cells, both acute lung injury and systemic organ injury (i.e., morphologic and permeability alterations) occurred.

  16. COMPLEX CLINICAL AND INSTRUMENTAL EVALUATION OF LUNG INJURY IN PATIENTS WITH RHEUMATOID ARTHRITIS

    Directory of Open Access Journals (Sweden)

    I. I. Nesterovich

    2016-01-01

    Full Text Available The damage of the respiratory system is a quite common  extra-articular manifestation  of rheumatoid  arthritis (RA. It is important  to note that its clinical symptoms occur in only 20–30% of patients; however, subclinical forms identified by active screening are observed in 70–80% of patients.Objective: to compare the significance of pulmonary complaints,  the results of physical examination, and the data of instrumental  studies for the detection  of lung injury in patients with RA.Subjects and methods. The study enrolled 70 RA patients (63 women and 7 men aged 24 to 83 years. Only 10% of them had clinically evident lung injury associated with RA. Patients with other pulmonary diseases, such as asthma, chronic obstructive pulmonary disease, etc., were excluded. Physical examination, radiography/fluoroscopy, high-resolution computed  tomography (HRCT, single-photon emission computed  tomography (SPECT of the lung, and lung function testing (LFT with the determination of lung diffusion capacity.Results and discussion. The data of physical examination  were nonspecific and unconvincing.  Pulmonary  complaints (dyspnea, cough, expectoration were seen in 65% of the patients; an objective assessment revealed changes (vesiculotympanitic resonance,  harsh breathing, and pleural friction rub in 40%. The X-ray films/fluorograms  displayed abnormalities (pulmonary fibrosis, focal changes in only 10% of cases. 92% of the patients had lung HRCT  changes including moderate (bronchial  obstruction (40%, rheumatoid  nodules (10%, ground glass opacities (60%, bronchial thickening (20%, pleural effusion (10%, tree-in-bud opacities (3% and severe (pulmonary hypertension  (10%, bronchiectasis (10%, emphysema (5% and lung tissue fibrotic changes as the honeycomb lung (2% ones. SPECT showed local hypoperfusion in the mantle and mediastinal parts of the lungs in 80% of cases. LFT analysis demonstrated reduced lung diffusion capacity in 41% of

  17. Pulmonary microvascular hyperpermeability and expression of vascular endothelial growth factor in smoke inhalation- and pneumonia-induced acute lung injury.

    Science.gov (United States)

    Lange, Matthias; Hamahata, Atsumori; Traber, Daniel L; Connelly, Rhykka; Nakano, Yoshimitsu; Traber, Lillian D; Schmalstieg, Frank C; Herndon, David N; Enkhbaatar, Perenlei

    2012-11-01

    Acute lung injury (ALI) and sepsis are major contributors to the morbidity and mortality of critically ill patients. The current study was designed further evaluate the mechanism of pulmonary vascular hyperpermeability in sheep with these injuries. Sheep were randomized to a sham-injured control group (n=6) or ALI/sepsis group (n=7). The sheep in the ALI/sepsis group received inhalation injury followed by instillation of Pseudomonas aeruginosa into the lungs. These groups were monitored for 24 h. Additional sheep (n=16) received the injury and lung tissue was harvested at different time points to measure lung wet/dry weight ratio, vascular endothelial growth factor (VEGF) mRNA and protein expression as well as 3-nitrotyrosine protein expression in lung homogenates. The injury induced severe deterioration in pulmonary gas exchange, increases in lung lymph flow and protein content, and lung water content (P<0.01 each). These alterations were associated with elevated lung and plasma nitrite/nitrate concentrations, increased tracheal blood flow, and enhanced VEGF mRNA and protein expression in lung tissue as well as enhanced 3-nitrotyrosine protein expression (P<0.05 each). This study describes the time course of pulmonary microvascular hyperpermeability in a clinical relevant large animal model and may improve the experimental design of future studies. Copyright © 2012 Elsevier Ltd and ISBI. All rights reserved.

  18. The Effects of Dexamethasone and L-NAME on Acute Lung Injury in Rats with Lung Contusion.

    Science.gov (United States)

    Kozan, Ahmet; Kilic, Nermin; Alacam, Hasan; Guzel, Ahmet; Guvenc, Tolga; Acikgoz, Mehmet

    2016-10-01

    The therapeutic efficiency of an anti-inflammatory agent, dexamethasone (DXM), and a nitric oxide synthase (NOS) inhibitor, Nitro-L-arginine methyl ester (L-NAME), in lung tissue injury after lung contusion was investigated. Serum levels of tumor necrosis factor-alpha (TNF-α), interleukin-10 (IL-10), YKL-40, an inflammatory peptide, inducible NOS (iNOS), and Clara cell protein 16 (CC-16) were evaluated. Immunohistochemical analyses were also performed, and the lung tissue was examined histopathologically. The study consisted of eight groups of Sprague-Dawley rats (n = 10 in each group), weighing 250-300 g: (1) control, (2) contusion, (3) control + DXM, (4) contusion + DXM, (5) control + L-NAME (6) contusion + L-NAME, (7) control + DXM + L-NAME, and (8) contusion + DXM + L-NAME. A previously developed lung contusion model was used, in addition to the control group. The rats were administered DXM and L-NAME intraperitoneally (i.p.) at doses of 15 and 60 mg/kg/day, respectively. DXM and L-NAME administration decreased the iNOS level in the contusion groups. DXM increased the levels of YKL-40 and IL-10 in both the control and contusion groups, with higher levels in the contusion groups. L-NAME increased the serum level of IL-10 in the lung contusion groups. DXM increased the synthesis of CC-16 in the control and contusion groups. The combined use of a high-dose steroid and NOS inhibitor resulted in the death of the rats. Steroids can increase the level of cytokines, such as YKL-40 and IL-10, and the synthesis of CC-16 and prevent pneumonia, ALI/ARDS, and sepsis in lung contusion.

  19. Effects of low potassium dextran glucose solution on oleic acid-induced acute lung injury in juvenile piglets

    Institute of Scientific and Technical Information of China (English)

    LING Feng; LIU Ying-long; LIU Ai-jun; WANG Dong; WANG Qiang

    2011-01-01

    Background Epithelial dysfunction in lungs plays a key role in the pathogenesis of acute lung injury. The beneficial effects of low potassium dextran glucose solution (LPD) have been reported in lung preservation, and LPD enables injured alveolar pneumocytes to recover. So we hypothesized that systemic administration of LPD may have benefits in treating acute lung injury. We investigated the effects of LPD on arterial blood gas and levels of some cytokines in oleic acid-induced acute lung injury in juvenile piglets.Methods Oleic acid (0.1 ml/kg) was intrapulmonarily administered to healthy anesthetized juvenile piglets. Ten animals were randomly assigned to two groups (n=5 each): oleic acid-induced group (control group) with intravenous infusion of 12.5 ml/kg of lactated Ringer's solution 30 minutes before administration of oleic acid and LPD group with systemic administration of LPD (12.5 ml/kg) 30 minutes before injecting oleic acid. Blood gas variables and concentrations of tumor necrosis factor alpha, endothelin 1 and interleukin 10 were measured before and every 1 hour for 6 hours after initial lung injury.Results Compared with control group, blood pH, partial pressure of arterial oxygen to fraction of inspired oxygen ratio,partial pressure of arterial carbon dioxide, and mean pulmonary arterial pressure in LPD group were improved (P<0.05or 0.01). Six hours after lung injury, concentration of tumor necrosis factor alpha in lung tissue was lower in LPD group than control group (P<0.05). Plasmic concentration of endothelin 1 showed lower in LPD group while plasmic concentration of interleukin 10 showed higher in LPD group (P<0.05).Conclusions Before lung injury, systemic administration of LPD can improve gas exchange, attenuate pulmonary hypertension, decrease plasmic levels of endothelin 1, increase interleukin 10 and decrease concentration of tumor necrosis factor alpha in lung tissue in oleic acid-induced acute lung injury in juvenile piglets.

  20. Multipotent adult progenitor cells decrease cold ischemic injury in ex vivo perfused human lungs: an initial pilot and feasibility study.

    Science.gov (United States)

    La Francesca, Saverio; Ting, Anthony E; Sakamoto, Jason; Rhudy, Jessica; Bonenfant, Nicholas R; Borg, Zachary D; Cruz, Fernanda F; Goodwin, Meagan; Lehman, Nicholas A; Taggart, Jennifer M; Deans, Robert; Weiss, Daniel J

    2014-01-01

    Primary graft dysfunction (PGD) is a significant cause of early morbidity and mortality following lung transplantation. Improved organ preservation techniques will decrease ischemia-reperfusion injury (IRI) contributing to PGD. Adult bone marrow-derived adherent stem cells, including mesenchymal stromal (stem) cells (MSCs) and multipotent adult progenitor cells (MAPCs), have potent anti-inflammatory actions, and we thus postulated that intratracheal MAPC administration during donor lung processing would decrease IRI. The goal of the study was therefore to determine if intratracheal MAPC instillation would decrease lung injury and inflammation in an ex vivo human lung explant model of prolonged cold storage and subsequent reperfusion. Four donor lungs not utilized for transplant underwent 8 h of cold storage (4°C). Following rewarming for approximately 30 min, non-HLA-matched allogeneic MAPCs (1 × 10(7) MAPCs/lung) were bronchoscopically instilled into the left lower lobe (LLL) and vehicle comparably instilled into the right lower lobe (RLL). The lungs were then perfused and mechanically ventilated for 4 h and subsequently assessed for histologic injury and for inflammatory markers in bronchoalveolar lavage fluid (BALF) and lung tissue. All LLLs consistently demonstrated a significant decrease in histologic and BALF inflammation compared to vehicle-treated RLLs. These initial pilot studies suggest that use of non-HLA-matched allogeneic MAPCs during donor lung processing can decrease markers of cold ischemia-induced lung injury.

  1. Recurrent recruitment manoeuvres improve lung mechanics and minimize lung injury during mechanical ventilation of healthy mice.

    Directory of Open Access Journals (Sweden)

    Lucy Kathleen Reiss

    Full Text Available INTRODUCTION: Mechanical ventilation (MV of mice is increasingly required in experimental studies, but the conditions that allow stable ventilation of mice over several hours have not yet been fully defined. In addition, most previous studies documented vital parameters and lung mechanics only incompletely. The aim of the present study was to establish experimental conditions that keep these parameters within their physiological range over a period of 6 h. For this purpose, we also examined the effects of frequent short recruitment manoeuvres (RM in healthy mice. METHODS: Mice were ventilated at low tidal volume V(T = 8 mL/kg or high tidal volume V(T = 16 mL/kg and a positive end-expiratory pressure (PEEP of 2 or 6 cm H(2O. RM were performed every 5 min, 60 min or not at all. Lung mechanics were followed by the forced oscillation technique. Blood pressure (BP, electrocardiogram (ECG, heart frequency (HF, oxygen saturation and body temperature were monitored. Blood gases, neutrophil-recruitment, microvascular permeability and pro-inflammatory cytokines in bronchoalveolar lavage (BAL and blood serum as well as histopathology of the lung were examined. RESULTS: MV with repetitive RM every 5 min resulted in stable respiratory mechanics. Ventilation without RM worsened lung mechanics due to alveolar collapse, leading to impaired gas exchange. HF and BP were affected by anaesthesia, but not by ventilation. Microvascular permeability was highest in atelectatic lungs, whereas neutrophil-recruitment and structural changes were strongest in lungs ventilated with high tidal volume. The cytokines IL-6 and KC, but neither TNF nor IP-10, were elevated in the BAL and serum of all ventilated mice and were reduced by recurrent RM. Lung mechanics, oxygenation and pulmonary inflammation were improved by increased PEEP. CONCLUSIONS: Recurrent RM maintain lung mechanics in their physiological range during low tidal volume ventilation of healthy mice by

  2. Effects of early bronchoalveolar lavage fluid collected from dogs with smoke inhalation injury on the lungs of rats

    Institute of Scientific and Technical Information of China (English)

    NIE Fa-chuan; SU Dong; YANG Zong-cheng; BI Min; HUANG Yue-sheng

    2004-01-01

    Objective: Whether early massive bronchoalveolar lavage can remove the harmful substances from the lungs injured with smoke inhalation remains uncertain. This study was designed to observe the effects of early massive bronchoalveolar lavage fluid (BALF) on the healthy lungs in rats. Methods: Mongrel dogs were inflicted with severe smoke inhalation injury. The injured lungs were lavaged with large amount of normal saline in the first hour after injury and the BALF was collected. The BALF was injected into the healthy lungs of 30 rats (group C) in the dosage of 5 ml/kg. The functions and pathological changes of the lungs were observed 24 h after perfusion with the BALF. The data were compared with those of 23 rats (group B) whose lungs were perfused with the BALF collected from normal dogs and those of 21 rats (group A)whose lungs were perfused with normal saline. Results: The mortality rate 24 h after lung perfusion was higher in group C than in groups A and B. The survivors of group C exhibited fluctuation of respiratory rate (RR), remarkable decrease of PaO2, significantly higher content of lung water, decrease of total static pulmonary compliance and pulmonary expansion index, and increasse of inflammatory cytokines in the tissues of lungs. Only slight mechanic obstructive effect on the airway was observed in rats of group A and B. The pathological changes of the lungs of the rats in group C were similar to those of the dogs with actual smoke inhalation injury. Conclusion: Our findings indicate that the BALF collected from dogs with acute severe smoke inhalation injury in the early stage after injury injured the normal lungs of rats with the bioactive substances in the BALF. These findings show us that it is a valuable therapeutic procedure to apply massive bronchoalveolar fluid lavage in the early stage after inhalation injury.

  3. Effect of inhalation of nebulized NO donor substance on acute hypoxic lung injury in newborn piglets

    Institute of Scientific and Technical Information of China (English)

    XIA Hong-ping; HUANG Guo-ying; ZHU Jian-xing; SUN Bo

    2008-01-01

    Background Birth asphyxia may result in multiple organ dysfunction such as lung injury.Inhalation of nebulized nitric oxide precursor can selectively reduce pulmonary hypertension.However,it is unknown whether such precursors can alleviate lung injury induced by hypoxia.We evaluated the effect of inhalation of nebulized nitroglycerine and sodium nitroprusside on acute hypoxic lung injury in newborn piglets.Methods Acute hypoxic lung injury was induced by inspiring 10% O2 for 1 hour.Twenty-four anaesthetized and mechanically ventilated piglets (5-7 days old) were randomly divided into four groups:(1) group S,not hypoxic;(2) group C,nebulized saline after hypoxia;(3) group NTG,nebulized nitroglycerine after hypoxia;(4) group SNP,nebulized sodium nitroprusside after hypoxia.Respiratory dynamic compliance and resistance of respiratory system were recorded at baseline,0.5 hour and 1 hour of hypoxia;then 0.5 hour,1 hour,3 hours and 5 hours following hypoxia.After nebulization,arterial blood was collected for measuring methaemoglobin and nitrate/nitrite levels.Right lung tissue,wet-dry ratio and myeloperoxidase level were determined.White blood cell count (WBC),total surfactant phospholipids (TPL) and disaturated phosphatidyl choline (DSPC) of the bronchoalveolar lavage fluid (BALF) were calculated,Left lungs were used for examining pathological changes.Results No significant difference was observed in respiratory dynamic compliance,resistance of respiratory system,wet-dry ratio,levels of methaemoglobin and nitrate/nitrite after nebulization,TPL or DSPC/TPL among four groups.WBC in BALF in groups NTG and SNP significantly decreased as compared with group C:similarly for myeloperoxidase level in lung tissue.Lung histological findings showed infiltration of neutrophils in groups NTG and SNP decreased significantly as compared with group C.Conclusion Inhalation of nebulized nitroglycerine or sodium nitroprusside can alleviate the infiltration of neutrophils,while it affects

  4. Sphingosine-1-phosphate receptor 1 agonism attenuates lung ischemia-reperfusion injury

    Science.gov (United States)

    Stone, Matthew L.; Sharma, Ashish K.; Zhao, Yunge; Charles, Eric J.; Huerter, Mary E.; Johnston, William F.; Kron, Irving L.; Lynch, Kevin R.

    2015-01-01

    Outcomes for lung transplantation are the worst of any solid organ, and ischemia-reperfusion injury (IRI) limits both short- and long-term outcomes. Presently no therapeutic agents are available to prevent IRI. Sphingosine 1-phosphate (S1P) modulates immune function through binding to a set of G protein-coupled receptors (S1PR1-5). Although S1P has been shown to attenuate lung IRI, the S1P receptors responsible for protection have not been defined. The present study tests the hypothesis that protection from lung IRI is primarily mediated through S1PR1 activation. Mice were treated with either vehicle, FTY720 (a nonselective S1P receptor agonist), or VPC01091 (a selective S1PR1 agonist and S1PR3 antagonist) before left lung IR. Function, vascular permeability, cytokine expression, neutrophil infiltration, and myeloperoxidase levels were measured in lungs. After IR, both FTY720 and VPC01091 significantly improved lung function (reduced pulmonary artery pressure and increased pulmonary compliance) vs. vehicle control. In addition, FTY720 and VPC01091 significantly reduced vascular permeability, expression of proinflammatory cytokines (IL-6, IL-17, IL-12/IL-23 p40, CC chemokine ligand-2, and TNF-α), myeloperoxidase levels, and neutrophil infiltration compared with control. No significant differences were observed between VPC01091 and FTY720 treatment groups. VPC01091 did not significantly affect elevated invariant natural killer T cell infiltration after IR, and administration of an S1PR1 antagonist reversed VPC01091-mediated protection after IR. In conclusion, VPC01091 and FTY720 provide comparable protection from lung injury and dysfunction after IR. These findings suggest that S1P-mediated protection from IRI is mediated by S1PR1 activation, independent of S1PR3, and that selective S1PR1 agonists may provide a novel therapeutic strategy to prevent lung IRI. PMID:25910934

  5. Systemic Metabolic Impairment and Lung Injury Following Acrolein Inhalation

    Science.gov (United States)

    A single ozone exposure causes pulmonary injury and systemic metabolic alterations through neuronal and hypothalamus pituitary adrenal axis activation. Metabolically impaired Goto Kakizaki (GK) rats with non-obese type-2 diabetes are more sensitive to ozone induced changes than h...

  6. Severe lung injuries due to SO/sub 2/ inhalation

    Energy Technology Data Exchange (ETDEWEB)

    Wunderlich, P.; Leupold, W.; Mittenzwey, K.W.; Rupprecht, E.

    1982-01-01

    By accident a 12 year old boy had to spend 4 hours in a SO/sub 2/-enriched atmosphere (concentration 13.8 mg per cubicmeter = 4.8 ppm). The course of the following intoxication was tetraphasic: 1. acute irritation of the mucous membranes of the upper airways and of the eye: rhinopharyngitis, laryngitis and bronchitis, conjunctivitis and corneal lesions (duration: 5 days), 2. symptom free interval (duration: 3 days), 3. subacute destruction of the low airways and the lung: destructing bronchitis, bronchiolitis, alveolitis, emphysema of the lung, mediastinum and skin, gradual development of bronchiectasis (duration: 9-12 months) and 4. gradual transition into terminal scarification: emphysema of the lung, continuous partial respiratory insufficiency with combined, especially obstructive disturbance of ventilation (without alterations observed during the last 4 years). On occasions of this fateful and therapeutically hardly influenced course recommendations are given for initial general and topical administration of very high doses of corticosteroids in each case of inhalative intoxication as the only measure which probably would have prevented it.

  7. TNF-α mediated increase of HIF-1α inhibits VASP expression, which reduces alveolar-capillary barrier function during acute lung injury (ALI).

    Science.gov (United States)

    Tang, Mengjie; Tian, Yihao; Li, Doulin; Lv, Jiawei; Li, Qun; Kuang, Changchun; Hu, Pengchao; Wang, Ying; Wang, Jing; Su, Ke; Wei, Lei

    2014-01-01

    Acute lung injury (ALI) is an inflammatory disorder associated with reduced alveolar-capillary barrier function and increased pulmonary vascular permeability. Vasodilator-stimulated phosphoprotein (VASP) is widely associated with all types of modulations of cytoskeleton rearrangement-dependent cellular morphology and function, such as adhesion, shrinkage, and permeability. The present studies were conducted to investigate the effects and mechanisms by which tumor necrosis factor-alpha (TNF-α) increases the tight junction permeability in lung tissue associated with acute lung inflammation. After incubating A549 cells for 24 hours with different concentrations (0-100 ng/mL) of TNF-α, 0.1 to 8 ng/mL TNF-α exhibited no significant effect on cell viability compared with the 0 ng/mL TNF-α group (control group). However, 10 ng/mL and 100 ng/mL TNF-α dramatically inhibited the viability of A549 cells compared with the control group (*pTNF-α for 24 hours displayed significantly increased cell permeability (*pinhibition of VASP expression increased the cell permeability (*pTNF-α in lung tissues and serum significantly increased at one hour, and the value reached a peak at four hours. Moreover, the Evans Blue absorption value of the mouse lung tissues reached a peak at four hours. The HIF-1α protein expression level in mouse lung tissues increased significantly at four hours and eight hours (**pTNF-α to inhibit VASP expression and to modulate the acute pulmonary inflammation process, and these molecules play an important role in the impairment of the alveolar-capillary barrier.

  8. Lung injury pathways: Adenosine receptor 2B signaling limits development of ischemic bronchiolitis obliterans organizing pneumonia.

    Science.gov (United States)

    Densmore, John C; Schaid, Terry R; Jeziorczak, Paul M; Medhora, Meetha; Audi, Said; Nayak, Shraddha; Auchampach, John; Dwinell, Melinda R; Geurts, Aron M; Jacobs, Elizabeth R

    2017-02-01

    Purpose/Aim of the Study: Adenosine signaling was studied in bronchiolitis obliterans organizing pneumonia (BOOP) resulting from unilateral lung ischemia. Ischemia was achieved by either left main pulmonary artery or complete hilar ligation. Sprague-Dawley (SD) rats, Dahl salt sensitive (SS) rats and SS mutant rat strains containing a mutation in the A2B adenosine receptor gene (Adora2b) were studied. Adenosine concentrations were measured in bronchoalveolar lavage (BAL) by HPLC. A2A (A2AAR) and A2B adenosine receptor (A2BAR) mRNA and protein were quantified. Twenty-four hours after unilateral PA ligation, BAL adenosine concentrations from ischemic lungs were increased relative to contralateral lungs in SD rats. A2BAR mRNA and protein concentrations were increased after PA ligation while miR27a, a negatively regulating microRNA, was decreased in ischemic lungs. A2AAR mRNA and protein concentrations remained unchanged following ischemia. A2BAR protein was increased in PA ligated lungs of SS rats after 7 days, and 4 h after complete hilar ligation in SD rats. SS-Adora2b mutants showed a greater extent of BOOP relative to SS rats, and greater inflammatory changes. Increased A2BAR and adenosine following unilateral lung ischemia as well as more BOOP in A2BAR mutant rats implicate a protective role for A2BAR signaling in countering ischemic lung injury.

  9. Protective effect of ginsenoside Rg1 on glutamate-induced lung injury

    Institute of Scientific and Technical Information of China (English)

    Li SHEN; Jian-zhong HAN; Chen LI; Shao-jie YUE; Yong LIU; Xiao-qun QIN; Hui-jun LIU; Zi-qiang LUO

    2007-01-01

    Aim: To examine the possible protective effect of ginsenoside Rg1, an active component of ginseng, on lung injury caused by glutamate in vivo. Methods: The lungs of mice receiving glutamate (0.5 g/kg) and/or ginsenoside Rg1 (0.03 g/kg) via intraperitoneal administration were collected. The indexes of lung wet weight/body weight ratios (LW/BW), lung wet/dry weight ratios (W/D), heart rate (HR),and breathing rate (BR) were determined. The activity of nitric oxide synthase(NOS), xanthine oxidase (XOD), superoxide dismutase (SOD), catalase (CAT), the content of NO, and malondialdehyde in the lung homogenate were measured.Results: Treatment with glutamate for 2 h increased LW/BW, W/D, HR, and BR.These changes were nearly abolished by pretreatment with ginsenoside Rg1 for 30 min before glutamate injection. An analysis of the lung homogenate demon-strated the protective effect as evidenced by the inhibition of NOS (12%) and XOD (50%) inactivity, the enhanced activity of SOD (20%) and CAT (25%).Conclusion: Ginsenoside Rg1 has a potential protective role in lung diseases associated with glutamate toxicity.

  10. Expression of aquaporin-1 and aquaporin-3 in lung tissue of rat model with ischemia-reperfusion injury

    Institute of Scientific and Technical Information of China (English)

    ZHAO Song; LI Xiang-nan

    2010-01-01

    @@ End-stage lung diseases are common and frequentlyoccurring diseases which are difficult for clinical treatment. In recent years, lung transplantation has become a widely accepted and effective therapeutic option for patients with the end-stage pulmonary diseases. Early pulmonary edema resulting from ischemia-reperfusion injury accounts for the major part of mortality and morbidity after lung transplantation. The water channel proteins in lung injury have been little studied, and their impact on the formation of pulmonary edema remains unclear. In this study, we established a rat lung ischemia-reperfusion model to study its impact on the expressions of water channel proteins in lung tissue and explore a new approach to lung transplantation in pulmonary edema pathogenesis.

  11. Antioxidant effects of selenium on lung injury in paraquat intoxicated rats

    Science.gov (United States)

    Kim, K.S.; Suh, G.J.; Kwon, W.Y.; Kwak, Y.H.; Lee, Kenneth; Lee, H.J.; Jeong, K.Y.; Lee, M.W.

    2012-01-01

    CONTEXT: Paraquat (PQ) causes lethal intoxication by inducing oxidant injury to the lung. Selenium is a cofactor for glutathione peroxidase (GPx), which is one of the major endogenous antioxidant enzymes. OBJECTIVE: To determine whether selenium post-treatment activates GPx, decreases lung injury, and improves survival in PQ intoxicated rats. MATERIALS AND METHODS: Male Spraque-Dawley rats were categorized into three groups: sham (n = 6), PQ (n = 12), and PQ + Se (n = 12). In the PQ and PQ + Se groups, 50 mg/kg of PQ was administered intraperitoneally. After 10 minutes, 60 μg/kg of Se (PQ + Se) or saline (PQ) was administered via the tail vein. Six rats per group were euthanized 6 hours or 24 hours later. Lung tissues were harvested for the measurement of GPx activity, reduced glutathione (GSH), glutathione disulfide (GSSG) and malondialdehyde (MDA) and for histological analysis. Using separated set of rats, survival of PQ (n = 10) and PQ + Se (n = 10) were observed for 72 hours. RESULTS: GPx activity in the PQ group at the 6-hour and 24-hour time points was lower than in the sham group (p CONCLUSION: Single dose of selenium post-treatment activates GPx and attenuates lipid peroxidation and lung injury early after paraquat intoxication, but does not improve 72 hours of survival.

  12. Rap1 mediates protective effects of iloprost against ventilator-induced lung injury

    Science.gov (United States)

    Birukova, Anna A.; Fu, Panfeng; Xing, Junjie

    2009-01-01

    Prostaglandin I2 (PGI2) has been shown to attenuate vascular constriction, hyperpermeability, inflammation, and acute lung injury. However, molecular mechanisms of PGI2 protective effects on pulmonary endothelial cells (EC) are not well understood. We tested a role of cAMP-activated Epac-Rap1 pathway in the barrier protective effects of PGI2 analog iloprost in the murine model of ventilator-induced lung injury. Mice were treated with iloprost (2 μg/kg) after onset of high tidal volume ventilation (30 ml/kg, 4 h). Bronchoalveolar lavage, histological analysis, and measurements of Evans blue accumulation were performed. In vitro, microvascular EC barrier function was assessed by morphological analysis of agonist-induced gap formation and monitoring of Rho pathway activation and EC permeability. Iloprost reduced bronchoalveolar lavage protein content, neutrophil accumulation, capillary filtration coefficient, and Evans blue albumin extravasation caused by high tidal volume ventilation. Small-interfering RNA-based Rap1 knockdown inhibited protective effects of iloprost. In vitro, iloprost increased barrier properties of lung microvascular endothelium and alleviated thrombin-induced EC barrier disruption. In line with in vivo results, Rap1 depletion attenuated protective effects of iloprost in the thrombin model of EC permeability. These data describe for the first time protective effects for Rap1-dependent signaling against ventilator-induced lung injury and pulmonary endothelial barrier dysfunction. PMID:19850733

  13. A novel, stable and reproducible acute lung injury model induced by oleic acid in immature piglet

    Institute of Scientific and Technical Information of China (English)

    ZHU Yao-bin; LING Feng; ZHANG Yan-bo; LIU Ai-jun; LIU Dong-hai; QIAO Chen-hui; WANG Qiang; LIU Ying-long

    2011-01-01

    Background Young children are susceptible to pulmonary injury,and acute lung injury (ALl) often results in a high mortality and financial costs in pediatric patients.A good ALl model will help us to gain a better understanding of the real pathophysiological picture and to evaluate novel treatment approaches to acute respiratory distress syndrome (ARDS) more accurately and liberally.This study aimed to establish a hemodynamically stable and reproducible model with ALl in piglet induced by oleic acid.Methods Six Chinese mini-piglets were used to establish ALl models by oleic acid.Hemodynamic and pulmonary function data were measured.Histopathological assessment was performed.Results Mean blood pressure,heart rate (HR),cardiac output (CO),central venous pressure (CVP) and left atrial pressure (LAP) were sharply decreased after oleic acid given,while the mean pulmonary arterial pressure (MPAP) was increased in comparison with baseline (P <0.05).pH,arterial partial pressure of O2 (PaO2),PaO2/inspired O2 fraction (FiO2) and lung compliance decreased,while PaCO2 and airway pressure increased in comparison with baseline (P <0.05).The lung histology showed severe inflammation,hyaline membranes,intra-alveolar and interstitial hemorrhage.Conclusion This experiment established a stable model which allows for a diversity of studies on early lung injury.

  14. Activation of nicotinic cholinergic receptors prevents ventilator-induced lung injury in rats.

    Directory of Open Access Journals (Sweden)

    Fabienne Brégeon

    Full Text Available Respiratory distress syndrome is responsible for 40 to 60 percent mortality. An over mortality of about 10 percent could result from additional lung injury and inflammation due to the life-support mechanical ventilation, which stretches the lung. It has been recently demonstrated, in vitro, that pharmacological activation of the alpha 7 nicotinic receptors (α7-nAChR could down regulate intracellular mediators involved in lung cell inflammatory response to stretch. Our aim was to test in vivo the protective effect of the pharmacological activation of the α7-nAChR against ventilator-induced lung injury (VILI. Anesthetized rats were ventilated for two hours with a high stretch ventilation mode delivering a stroke volume large enough to generate 25-cmH(2O airway pressure, and randomly assigned to four groups: pretreated with parenteral injection of saline or specific agonist of the α7-nAChR (PNU-282987, or submitted to bilateral vagus nerve electrostimulation while pre-treated or not with the α7-nAChR antagonist methyllycaconitine (MLA. Controls ventilated with a conventional stroke volume of 10 mL/kg gave reference data. Physiological indices (compliance of the respiratory system, lung weight, blood oxygenation, arterial blood pressure and lung contents of inflammatory mediators (IL-6 measured by ELISA, substance P assessed using HPLC were severely impaired after two hours of high stretch ventilation (sham group. Vagal stimulation was able to maintain the respiratory parameters close to those obtained in Controls and reduced lung inflammation except when associated to nicotinic receptor blockade (MLA, suggesting the involvement of α7-nAChR in vagally-mediated protection against VILI. Pharmacological pre-treatment with PNU-282987 strongly decreased lung injury and lung IL-6 and substance P contents, and nearly abolished the increase in plasmatic IL-6 levels. Pathological examination of the lungs confirmed the physiological differences observed

  15. INDUCTION OF DNA ADDUCTS, TUMORS, AND KI-RAS ONCOGENE MUTATIONS IN STRAIN A/J MOUSE LUNG BY IP. ADMINISTRATION OF DIBENZ[A,H]ANTHRACENE

    Science.gov (United States)

    Induction of DNA adducts, tumors, and Ki-ras oncogene mutations in strain AlJ mouse lung by ip. administration of dibenz[a,h]anthracene Previous studies of polycyclic aromatic hydrocarbon (P AH) induced lung tumors in the strain NJ mouse model system have demonstrated qua...

  16. Aberrant LncRNA Expression Profile in a Contusion Spinal Cord Injury Mouse Model

    Directory of Open Access Journals (Sweden)

    Ya Ding

    2016-01-01

    Full Text Available Long noncoding RNAs (LncRNAs play a crucial role in cell growth, development, and various diseases related to the central nervous system. However, LncRNA differential expression profiles in spinal cord injury are yet to be reported. In this study, we profiled the expression pattern of LncRNAs using a microarray method in a contusion spinal cord injury (SCI mouse model. Compared with a spinal cord without injury, few changes in LncRNA expression levels were noted 1 day after injury. The differential changes in LncRNA expression peaked 1 week after SCI and subsequently declined until 3 weeks after injury. Quantitative real-time polymerase chain reaction (qRT-PCR was used to validate the reliability of the microarray, demonstrating that the results were reliable. Gene ontology (GO analysis indicated that differentially expressed mRNAs were involved in transport, cell adhesion, ion transport, and metabolic processes, among others. Kyoto Encyclopedia of Genes and Genomes (KEGG enrichment analysis showed that the neuroactive ligand-receptor interaction, the PI3K-Akt signaling pathway, and focal adhesions were potentially implicated in SCI pathology. We constructed a dynamic LncRNA-mRNA network containing 264 LncRNAs and 949 mRNAs to elucidate the interactions between the LncRNAs and mRNAs. Overall, the results from this study indicate for the first time that LncRNAs are differentially expressed in a contusion SCI mouse model.

  17. NF-kB activation as a biomarker of light injury using a transgenic mouse model

    Science.gov (United States)

    Pocock, Ginger M.; Boretsky, Adam; Wang, Heuy-Ching; Golden, Dallas; Gupta, Praveena; Vargas, Gracie; Oliver, Jeffrey W.; Motamedi, Massoud

    2012-03-01

    The spatial and temporal activation of NF-kB (p65) was monitored in the retina of a transgenic mouse model (cis-NFkB-EGFP) in vivo after receiving varying grades of laser induced thermal injury in one eye. Baseline images of the retinas from 26 mice were collected prior to injury and up to five months post-exposure using a Heidelberg Spectralis HRA confocal scanning laser ophthalmoscope (cSLO) with a spectral domain optical coherence tomographer (SDOCT). Injured and control eyes were enucleated at discrete time points following laser exposure for cryosectioning to determine localization of NF-kB dependent enhanced green fluorescent protein (EGFP) reporter gene expression within the retina using fluorescence microscopy. In addition, EGFP basal expression in brain and retinal tissue from the cis-NFkB-EGFP was characterized using two-photon imaging. Regions of the retina exposed to threshold and supra-threshold laser damage evaluated using fluorescence cSLO showed increased EGFP fluorescence localized to the exposed region for a duration that was dependent upon the degree of injury. Fluorescence microscopy of threshold damage revealed EGFP localized to the outer nuclear region and retinal pigment epithelial layer. Basal expression of EGFP imaged using two-photon microscopy was heterogeneously distributed throughout brain tissue and confined to the inner retina. Results show cis-NF-kB-EGFP reporter mouse can be used for in vivo studies of light induced injury to the retina and possibly brain injury.

  18. Fetal calcium regulates branching morphogenesis in the developing human and mouse lung: involvement of voltage-gated calcium channels.

    Science.gov (United States)

    Brennan, Sarah C; Finney, Brenda A; Lazarou, Maria; Rosser, Anne E; Scherf, Caroline; Adriaensen, Dirk; Kemp, Paul J; Riccardi, Daniela

    2013-01-01

    Airway branching morphogenesis in utero is essential for optimal postnatal lung function. In the fetus, branching morphogenesis occurs during the pseudoglandular stage (weeks 9-17 of human gestation, embryonic days (E)11.5-16.5 in mouse) in a hypercalcaemic environment (~1.7 in the fetus vs. ~1.1-1.3 mM for an adult). Previously we have shown that fetal hypercalcemia exerts an inhibitory brake on branching morphogenesis via the calcium-sensing receptor. In addition, earlier studies have shown that nifedipine, a selective blocker of L-type voltage-gated Ca(2+) channels (VGCC), inhibits fetal lung growth, suggesting a role for VGCC in lung development. The aim of this work was to investigate the expression of VGCC in the pseudoglandular human and mouse lung, and their role in branching morphogenesis. Expression of L-type (CaV1.2 and CaV1.3), P/Q type (CaV2.1), N-type (CaV2.2), R-type (CaV2.3), and T-type (CaV3.2 and CaV3.3) VGCC was investigated in paraffin sections from week 9 human fetal lungs and E12.5 mouse embryos. Here we show, for the first time, that Cav1.2 and Cav1.3 are expressed in both the smooth muscle and epithelium of the developing human and mouse lung. Additionally, Cav2.3 was expressed in the lung epithelium of both species. Incubating E12.5 mouse lung rudiments in the presence of nifedipine doubled the amount of branching, an effect which was partly mimicked by the Cav2.3 inhibitor, SNX-482. Direct measurements of changes in epithelial cell membrane potential, using the voltage-sensitive fluorescent dye DiSBAC2(3), demonstrated that cyclic depolarisations occur within the developing epithelium and coincide with rhythmic occlusions of the lumen, driven by the naturally occurring airway peristalsis. We conclude that VGCC are expressed and functional in the fetal human and mouse lung, where they play a role in branching morphogenesis. Furthermore, rhythmic epithelial depolarisations evoked by airway peristalsis would allow for branching to match

  19. Fetal calcium regulates branching morphogenesis in the developing human and mouse lung: involvement of voltage-gated calcium channels.

    Directory of Open Access Journals (Sweden)

    Sarah C Brennan

    Full Text Available Airway branching morphogenesis in utero is essential for optimal postnatal lung function. In the fetus, branching morphogenesis occurs during the pseudoglandular stage (weeks 9-17 of human gestation, embryonic days (E11.5-16.5 in mouse in a hypercalcaemic environment (~1.7 in the fetus vs. ~1.1-1.3 mM for an adult. Previously we have shown that fetal hypercalcemia exerts an inhibitory brake on branching morphogenesis via the calcium-sensing receptor. In addition, earlier studies have shown that nifedipine, a selective blocker of L-type voltage-gated Ca(2+ channels (VGCC, inhibits fetal lung growth, suggesting a role for VGCC in lung development. The aim of this work was to investigate the expression of VGCC in the pseudoglandular human and mouse lung, and their role in branching morphogenesis. Expression of L-type (CaV1.2 and CaV1.3, P/Q type (CaV2.1, N-type (CaV2.2, R-type (CaV2.3, and T-type (CaV3.2 and CaV3.3 VGCC was investigated in paraffin sections from week 9 human fetal lungs and E12.5 mouse embryos. Here we show, for the first time, that Cav1.2 and Cav1.3 are expressed in both the smooth muscle and epithelium of the developing human and mouse lung. Additionally, Cav2.3 was expressed in the lung epithelium of both species. Incubating E12.5 mouse lung rudiments in the presence of nifedipine doubled the amount of branching, an effect which was partly mimicked by the Cav2.3 inhibitor, SNX-482. Direct measurements of changes in epithelial cell membrane potential, using the voltage-sensitive fluorescent dye DiSBAC2(3, demonstrated that cyclic depolarisations occur within the developing epithelium and coincide with rhythmic occlusions of the lumen, driven by the naturally occurring airway peristalsis. We conclude that VGCC are expressed and functional in the fetal human and mouse lung, where they play a role in branching morphogenesis. Furthermore, rhythmic epithelial depolarisations evoked by airway peristalsis would allow for branching to

  20. Inflammation and lung maturation from stretch injury in preterm fetal sheep.

    Science.gov (United States)

    Hillman, Noah H; Polglase, Graeme R; Pillow, J Jane; Saito, Masatoshi; Kallapur, Suhas G; Jobe, Alan H

    2011-02-01

    Mechanical ventilation is a risk factor for the development of bronchopulmonary dysplasia in premature infants. Fifteen minutes of high tidal volume (V(T)) ventilation induces inflammatory cytokine expression in small airways and lung parenchyma within 3 h. Our objective was to describe the temporal progression of cytokine and maturation responses to lung injury in fetal sheep exposed to a defined 15-min stretch injury. After maternal anesthesia and hysterotomy, 129-day gestation fetal lambs (n = 7-8/group) had the head and chest exteriorized. Each fetus was intubated, and airway fluid was gently removed. While placental support was maintained, the fetus received ventilation with an escalating V(T) to 15 ml/kg without positive end-expiratory pressure (PEEP) for 15 min using heated, humidified 100% nitrogen. The fetus was then returned to the uterus for 1, 6, or 24 h. Control lambs received a PEEP of 2 cmH(2)O for 15 min. Tissue samples from the lung and systemic organs were evaluated. Stretch injury increased the early response gene Egr-1 and increased expression of pro- and anti-inflammatory cytokines within 1 h. The injury induced granulocyte/macrophage colony-stimulating factor mRNA and matured monocytes to alveolar macrophages by 24 h. The mRNA for the surfactant proteins A, B, and C increased in the lungs by 24 h. The airway epithelium demonstrated dynamic changes in heat shock protein 70 (HSP70) over time. Serum cortisol levels did not increase, and induction of systemic inflammation was minimal. We conclude that a brief period of high V(T) ventilation causes a proinflammatory cascade, a maturation of lung monocytic cells, and an induction of surfactant protein mRNA.

  1. Protective effects of penehyclidine hydrochloride on acute lung injury caused by severe dichlorvos poisoning in swine

    Institute of Scientific and Technical Information of China (English)

    CUI Juan; LI Chun-sheng; HE Xin-hua; SONG Yu-guo

    2013-01-01

    Background Organophosphate poisoning is an important health problem in developing countries which causes death mainly by inducing acute lung injury.In this study,we examined the effects of penehyclidine hydrochloride (PHC),a selective M-receptor inhibitor,on dichlorvos-induced acute lung injury in swine.Methods Twenty-two female swines were randomly divided into control (n=5),dichlorvos (n=6),atropine (n=6),and PHC (n=5) groups.Hemodynamic data,extravascular lung water index (EVLWI),and pulmonary vascular permeability index (PVPI) were monitored; blood gas analysis and acetylcholinesterase (AchE) levels were measured.PaO2/FiO2,cardiac index (Cl),and pulmonary vascular resistance indices (PVRI) were calculated.At termination of the study,pulmonary tissue was collected for ATPase activity determination and wet to dry weight ratio (W/D) testing 6 hours post-poisoning.TUNEL assay,and Bax,Bcl-2,and caspase-3 expression were applied to pulmonary tissue,and histopathology was observed.Results After poisoning,PHC markedly decreased PVRI,increased CI more effectively than atropine.Anticholinergic treatment reduced W/D,apoptosis index (AI),and mitigated injury to the structure of lung; however,PHC reduced AI and caspase-3 expression and improved Bcl-2/Bax more effectively than atropine.Atropine and PHC improved ATPase activities; a significant difference between groups was observed in Ca2+-ATPase activity,but not Na+-K+-ATPase activity.Conclusions The PHC group showed mild impairment in pathology,less apoptotic cells,and little impact on cardiac function compared with the atropine group in dichlorvos-induced acute lung injury.