Human pulmonary dirofilariasis coexisting with intercostal neurilemmoma: A case report and literature review

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Chia-Ying Li

2013-10-01

Full Text Available Human pulmonary dirofilariasis (HPD is a rare zoonotic infection caused by Dirofilaria immitis. Dogs are the definite hosts and humans are infected occasionally via a vector, generally a mosquito. Most thoracic neurilemmoma arise in the mediastinum and fewer tumors originate peripherally from the intercostal nerves. Most patients with HPD or thoracic neurilemmoma are asymptomatic and these diseases are often discovered incidentally. We present a 53-year-old female who was found to have a pulmonary nodule and a chest wall nodule during a routine health examination. She underwent a video-assisted thoracoscopic surgery (VATS with partial lung resection and local excision of the chest wall. The pathological examination revealed a coiled, degenerating Dirofilariasis immitis worm surrounded by granulomatous inflammation with caseous necrosis and a neurilemmoma composed of S-100 protein immunoreactive but smooth muscle actin negative spindle cells. Because these diseases are self-limiting and make further treatment unnecessary, video-assisted thoracoscopic surgery (VATS is considered preferable and less invasive for definitive diagnosis and management.

Oestrogen receptor alpha in pulmonary hypertension.

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Wright, Audrey F; Ewart, Marie-Ann; Mair, Kirsty; Nilsen, Margaret; Dempsie, Yvonne; Loughlin, Lynn; Maclean, Margaret R

2015-05-01

Pulmonary arterial hypertension (PAH) occurs more frequently in women with mutations in bone morphogenetic protein receptor type 2 (BMPR2) and dysfunctional BMPR2 signalling underpinning heritable PAH. We have previously shown that serotonin can uncover a pulmonary hypertensive phenotype in BMPR2(+/-) mice and that oestrogen can increase serotinergic signalling in human pulmonary arterial smooth muscle cells (hPASMCs). Hence, here we wished to characterize the expression of oestrogen receptors (ERs) in male and female human pulmonary arteries and have examined the influence of oestrogen and serotonin on BMPR2 and ERα expression. By immunohistochemistry, we showed that ERα, ERβ, and G-protein-coupled receptors are expressed in human pulmonary arteries localizing mainly to the smooth muscle layer which also expresses the serotonin transporter (SERT). Protein expression of ERα protein was higher in female PAH patient hPASMCs compared with male and serotonin also increased the expression of ERα. 17β-estradiol induced proliferation of hPASMCs via ERα activation and this engaged mitogen-activated protein kinase and Akt signalling. Female mice over-expressing SERT (SERT(+) mice) develop PH and the ERα antagonist MPP attenuated the development of PH in normoxic and hypoxic female SERT(+) mice. The therapeutic effects of MPP were accompanied by increased expression of BMPR2 in mouse lung. ERα is highly expressed in female hPASMCs from PAH patients and mediates oestrogen-induced proliferation of hPASMCs via mitogen-activated protein kinase and Akt signalling. Serotonin can increase ERα expression in hPASMCs and antagonism of ERα reverses serotonin-dependent PH in the mouse and increases BMPR2 expression. Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2015. For permissions please email: journals.permissions@oup.com.

Characterization of proximal pulmonary arterial cells from chronic thromboembolic pulmonary hypertension patients

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Quarck Rozenn

2012-03-01

Full Text Available Abstract Background Chronic thromboembolic pulmonary hypertension (CTEPH is associated with proximal pulmonary artery obstruction and vascular remodeling. We hypothesized that pulmonary arterial smooth muscle (PASMC and endothelial cells (PAEC may actively contribute to remodeling of the proximal pulmonary vascular wall in CTEPH. Our present objective was to characterize PASMC and PAEC from large arteries of CTEPH patients and investigate their potential involvement in vascular remodeling. Methods Primary cultures of proximal PAEC and PASMC from patients with CTEPH, with non-thromboembolic pulmonary hypertension (PH and lung donors have been established. PAEC and PASMC have been characterized by immunofluorescence using specific markers. Expression of smooth muscle specific markers within the pulmonary vascular wall has been studied by immunofluorescence and Western blotting. Mitogenic activity and migratory capacity of PASMC and PAEC have been investigated in vitro. Results PAEC express CD31 on their surface, von Willebrand factor in Weibel-Palade bodies and take up acetylated LDL. PASMC express various differentiation markers including α-smooth muscle actin (α-SMA, desmin and smooth muscle myosin heavy chain (SMMHC. In vascular tissue from CTEPH and non-thromboembolic PH patients, expression of α-SMA and desmin is down-regulated compared to lung donors; desmin expression is also down-regulated in vascular tissue from CTEPH compared to non-thromboembolic PH patients. A low proportion of α-SMA positive cells express desmin and SMMHC in the neointima of proximal pulmonary arteries from CTEPH patients. Serum-induced mitogenic activity of PAEC and PASMC, as well as migratory capacity of PASMC, were increased in CTEPH only. Conclusions Modified proliferative and/or migratory responses of PASMC and PAEC in vitro, associated to a proliferative phenotype of PASMC suggest that PASMC and PAEC could contribute to proximal vascular remodeling in CTEPH.

Hyperplastic Growth of Pulmonary Artery Smooth Muscle Cells from Subjects with Pulmonary Arterial Hypertension Is Activated through JNK and p38 MAPK.

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Jamie L Wilson

Full Text Available Smooth muscle in the pulmonary artery of PAH subjects, both idiopathic and hereditary, is characterized by hyperplasia. Smooth muscle cells (HPASMC isolated from subjects with or without PAH retain their in vivo phenotype as illustrated by their expression of alpha-smooth muscle actin and expression of H-caldesmon. Both non PAH and PAH HPASMC display a lengthy, approximately 94h, cell cycle. The HPASMC from both idiopathic and hereditary PAH display an abnormal proliferation characterized by continued growth under non-proliferative, non-growth stimulated conditions. This effector independent proliferation is JNK and p38 MAP kinase dependent. Blocking the activation of either abrogates the HPASMC growth. HPASMC from non PAH donors under quiescent conditions display negligible proliferation but divide upon exposure to growth factors such as PDGF-BB or FGF2 but not EGF. This growth does not involve the MAP kinases. Instead it routes via the tyrosine kinase receptor through mTOR and then 6SK. In the PAH cells PDGF-BB and FGF2 augment the dysregulated cell proliferation, also through mTOR/6SK. Additionally, blocking the activation of mTOR also modulates the MAP kinase promoted dysregulated growth. These results highlight key alterations in the growth of HPASMC from subjects with PAH which contribute to the etiology of the disease and can clearly be targeted at various regulatory points for future therapies.

MicroRNA-143 Activation Regulates Smooth Muscle and Endothelial Cell Crosstalk in Pulmonary Arterial Hypertension.

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Deng, Lin; Blanco, Francisco J; Stevens, Hannah; Lu, Ruifang; Caudrillier, Axelle; McBride, Martin; McClure, John D; Grant, Jenny; Thomas, Matthew; Frid, Maria; Stenmark, Kurt; White, Kevin; Seto, Anita G; Morrell, Nicholas W; Bradshaw, Angela C; MacLean, Margaret R; Baker, Andrew H

2015-10-23

The pathogenesis of pulmonary arterial hypertension (PAH) remains unclear. The 4 microRNAs representing the miR-143 and miR-145 stem loops are genomically clustered. To elucidate the transcriptional regulation of the miR-143/145 cluster and the role of miR-143 in PAH. We identified the promoter region that regulates miR-143/145 microRNA expression in pulmonary artery smooth muscle cells (PASMCs). We mapped PAH-related signaling pathways, including estrogen receptor, liver X factor/retinoic X receptor, transforming growth factor-β (Smads), and hypoxia (hypoxia response element), that regulated levels of all pri-miR stem loop transcription and resulting microRNA expression. We observed that miR-143-3p is selectively upregulated compared with miR-143-5p during PASMC migration. Modulation of miR-143 in PASMCs significantly altered cell migration and apoptosis. In addition, we found high abundance of miR-143-3p in PASMC-derived exosomes. Using assays with pulmonary arterial endothelial cells, we demonstrated a paracrine promigratory and proangiogenic effect of miR-143-3p-enriched exosomes from PASMC. Quantitative polymerase chain reaction and in situ hybridization showed elevated expression of miR-143 in calf models of PAH and in samples from PAH patients. Moreover, in contrast to our previous findings that had not supported a therapeutic role in vivo, we now demonstrate a protective role of miR-143 in experimental pulmonary hypertension in vivo in miR-143-/- and anti-miR-143-3p-treated mice exposed to chronic hypoxia in both preventative and reversal settings. MiR-143-3p modulated both cellular and exosome-mediated responses in pulmonary vascular cells, whereas inhibition of miR-143-3p blocked experimental pulmonary hypertension. Taken together, these findings confirm an important role for the miR-143/145 cluster in PAH pathobiology. © 2015 American Heart Association, Inc.

8,9-Epoxyeicosatrienoic acid analog protects pulmonary artery smooth muscle cells from apoptosis via ROCK pathway

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Ma, Jun; Zhang, Lei; Li, Shanshan; Liu, Shulin; Ma, Cui; Li, Weiyang; Falck, J.R.; Manthati, Vijay L.; Reddy, D. Sudarshan; Medhora, Meetha; Jacobs, Elizabeth R.; Zhu, Daling

2010-01-01

Epoxyeicosatrienoic acids (EETs), metabolites of arachidonic acid (AA) catalyzed by cytochrome P450 (CYP), have many essential biologic roles in the cardiovascular system including inhibition of apoptosis in cardiomyocytes. In the present study, we tested the potential of 8,9-EET and derivatives to protect pulmonary artery smooth muscle cells (PASMCs) from starvation induced apoptosis. We found 8,9-epoxy-eicos-11(Z)-enoic acid (8,9-EET analog (214)), but not 8,9-EET, increased cell viability, decreased activation of caspase-3 and caspase-9, and decreased TUNEL-positive cells or nuclear condensation induced by serum deprivation (SD) in PASMCs. These effects were reversed after blocking the Rho-kinase (ROCK) pathway with Y-27632 or HA-1077. Therefore, 8,9-EET analog (214) protects PASMC from serum deprivation-induced apoptosis, mediated at least in part via the ROCK pathway. Serum deprivation of PASMCs resulted in mitochondrial membrane depolarization, decreased expression of Bcl-2 and enhanced expression of Bax, all effects were reversed by 8,9-EET analog (214) in a ROCK dependent manner. Because 8,9-EET and not the 8,9-EET analog (214) protects pulmonary artery endothelial cells (PAECs), these observations suggest the potential to differentially promote apoptosis or survival with 8,9-EET or analogs in pulmonary arteries.

8,9-Epoxyeicosatrienoic acid analog protects pulmonary artery smooth muscle cells from apoptosis via ROCK pathway

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Ma, Jun; Zhang, Lei; Li, Shanshan [Department of Biopharmaceutical Sciences, College of Pharmacy, Harbin Medical University, 157 Baojian Road, Nangang District, Harbin, Heilongjiang 150081 (China); Liu, Shulin [Department of Biopharmaceutical Sciences, College of Pharmacy, Harbin Medical University, 157 Baojian Road, Nangang District, Harbin, Heilongjiang 150081 (China); Bio-pharmaceutical Key Laboratory of Heilongjiang Province, Harbin 150081 (China); Ma, Cui [Department of Biopharmaceutical Sciences, College of Pharmacy, Harbin Medical University, 157 Baojian Road, Nangang District, Harbin, Heilongjiang 150081 (China); Li, Weiyang [Mudanjiang Medical College, Mudanjiang 157011 (China); Falck, J.R.; Manthati, Vijay L.; Reddy, D. Sudarshan [University of Texas Southwestern Medical Center, Dallas, TX 75390 (United States); Medhora, Meetha; Jacobs, Elizabeth R. [Division of Pulmonary and Critical Care, Department of Medicine, Cardiovascular Center, Medical College of Wisconsin, Milwaukee, WI 53226 (United States); Zhu, Daling, E-mail: dalingz@yahoo.com [Department of Biopharmaceutical Sciences, College of Pharmacy, Harbin Medical University, 157 Baojian Road, Nangang District, Harbin, Heilongjiang 150081 (China); Bio-pharmaceutical Key Laboratory of Heilongjiang Province, Harbin 150081 (China)

2010-08-15

Epoxyeicosatrienoic acids (EETs), metabolites of arachidonic acid (AA) catalyzed by cytochrome P450 (CYP), have many essential biologic roles in the cardiovascular system including inhibition of apoptosis in cardiomyocytes. In the present study, we tested the potential of 8,9-EET and derivatives to protect pulmonary artery smooth muscle cells (PASMCs) from starvation induced apoptosis. We found 8,9-epoxy-eicos-11(Z)-enoic acid (8,9-EET analog (214)), but not 8,9-EET, increased cell viability, decreased activation of caspase-3 and caspase-9, and decreased TUNEL-positive cells or nuclear condensation induced by serum deprivation (SD) in PASMCs. These effects were reversed after blocking the Rho-kinase (ROCK) pathway with Y-27632 or HA-1077. Therefore, 8,9-EET analog (214) protects PASMC from serum deprivation-induced apoptosis, mediated at least in part via the ROCK pathway. Serum deprivation of PASMCs resulted in mitochondrial membrane depolarization, decreased expression of Bcl-2 and enhanced expression of Bax, all effects were reversed by 8,9-EET analog (214) in a ROCK dependent manner. Because 8,9-EET and not the 8,9-EET analog (214) protects pulmonary artery endothelial cells (PAECs), these observations suggest the potential to differentially promote apoptosis or survival with 8,9-EET or analogs in pulmonary arteries.

Iptakalim inhibits PDGF-BB-induced human airway smooth muscle cells proliferation and migration

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Liu, Wenrui; Kong, Hui; Zeng, Xiaoning; Wang, Jingjing; Wang, Zailiang; Yan, Xiaopei; Wang, Yanli; Xie, Weiping, E-mail: wpxie@njmu.edu.cn; Wang, Hong, E-mail: hongwang@njmu.edu.cn

2015-08-15

Chronic airway diseases are characterized by airway remodeling which is attributed partly to the proliferation and migration of airway smooth muscle cells (ASMCs). ATP-sensitive potassium (K{sub ATP}) channels have been identified in ASMCs. Mount evidence has suggested that K{sub ATP} channel openers can reduce airway hyperresponsiveness and alleviate airway remodeling. Opening K{sup +} channels triggers K{sup +} efflux, which leading to membrane hyperpolarization, preventing Ca{sup 2+}entry through closing voltage-operated Ca{sup 2+} channels. Intracellular Ca{sup 2+} is the most important regulator of muscle contraction, cell proliferation and migration. K{sup +} efflux decreases Ca{sup 2+} influx, which consequently influences ASMCs proliferation and migration. As a K{sub ATP} channel opener, iptakalim (Ipt) has been reported to restrain the proliferation of pulmonary arterial smooth muscle cells (PASMCs) involved in vascular remodeling, while little is known about its impact on ASMCs. The present study was designed to investigate the effects of Ipt on human ASMCs and the mechanisms underlying. Results obtained from cell counting kit-8 (CCK-8), flow cytometry and 5-ethynyl-2′-deoxyuridine (EdU) incorporation showed that Ipt significantly inhibited platelet-derived growth factor (PDGF)-BB-induced ASMCs proliferation. ASMCs migration induced by PDGF-BB was also suppressed by Ipt in transwell migration and scratch assay. Besides, the phosphorylation of Ca{sup 2+}/calmodulin-dependent kinase II (CaMKII), extracellular regulated protein kinases 1/2 (ERK1/2), protein kinase B (Akt), and cyclic adenosine monophosphate (cAMP) response element binding protein (CREB) were as well alleviated by Ipt administration. Furthermore, we found that the inhibition of Ipt on the PDGF-BB-induced proliferation and migration in human ASMCs was blocked by glibenclamide (Gli), a selective K{sub ATP} channel antagonist. These findings provide a strong evidence to support that Ipt

Baicalin inhibits hypoxia-induced pulmonary artery smooth muscle cell proliferation via the AKT/HIF-1α/p27-associated pathway.

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Zhang, Lin; Pu, Zhichen; Wang, Junsong; Zhang, Zhifeng; Hu, Dongmei; Wang, Junjie

2014-05-09

Baicalin, a flavonoid compound purified from the dry roots of Scutellaria baicalensis Georgi, has been shown to possess various pharmacological actions. Previous studies have revealed that baicalin inhibits the growth of cancer cells through the induction of apoptosis. Pulmonary arterial hypertension (PAH) is a devastating disease characterized by enhanced pulmonary artery smooth muscle cell (PASMCs) proliferation and suppressed apoptosis. However, the potential mechanism of baicalin in the regulation of PASMC proliferation and the prevention of cardiovascular diseases remains unexplored. To test the effects of baicalin on hypoxia, we used rats treated with or without baicalin (100 mg·kg⁻¹ each rat) at the beginning of the third week after hypoxia. Hemodynamic and pulmonary pathomorphology data showed that right ventricular systolic pressures (RVSP), the weight of the right ventricle/left ventricle plus septum (RV/LV + S) ratio and the medial width of pulmonary arterioles were much higher in chronic hypoxia. However, baicalin treatment repressed the elevation of RVSP, RV/LV + S and attenuated the pulmonary vascular structure remodeling (PVSR) of pulmonary arterioles induced by chronic hypoxia. Additionally, baicalin (10 and 20 μmol·L⁻¹) treatment suppressed the proliferation of PASMCs and attenuated the expression of hypoxia-inducible factor-α (HIF-α) under hypoxia exposure. Meanwhile, baicalin reversed the hypoxia-induced reduction of p27 and increased AKT/protein kinase B phosphorylation p-AKT both in vivo and in vitro. These results suggested that baicalin could effectively attenuate PVSR and hypoxic pulmonary hypertension.

Development of occlusive neointimal lesions in distal pulmonary arteries of endothelin B receptor-deficient rats: a new model of severe pulmonary arterial hypertension.

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Ivy, D Dunbar; McMurtry, Ivan F; Colvin, Kelley; Imamura, Masatoshi; Oka, Masahiko; Lee, Dong-Seok; Gebb, Sarah; Jones, Peter Lloyd

2005-06-07

Human pulmonary arterial hypertension (PAH) is characterized by proliferation of vascular smooth muscle and, in its more severe form, by the development of occlusive neointimal lesions. However, few animal models of pulmonary neointimal proliferation exist, thereby limiting a complete understanding of the pathobiology of PAH. Recent studies of the endothelin (ET) system demonstrate that deficiency of the ET(B) receptor predisposes adult rats to acute and chronic hypoxic PAH, yet these animals fail to develop neointimal lesions. Herein, we determined and thereafter showed that exposure of ET(B) receptor-deficient rats to the endothelial toxin monocrotaline (MCT) leads to the development of neointimal lesions that share hallmarks of human PAH. The pulmonary hemodynamic and morphometric effects of 60 mg/kg MCT in control (MCT(+/+)) and ET(B) receptor-deficient (MCT(sl/sl)) rats at 6 weeks of age were assessed. MCT(sl/sl) rats developed more severe PAH, characterized by elevated pulmonary artery pressure, diminished cardiac output, and right ventricular hypertrophy. In MCT(sl/sl) rats, morphometric evaluation revealed the presence of neointimal lesions within small distal pulmonary arteries, increased medial wall thickness, and decreased arterial-to-alveolar ratio. In keeping with this, barium angiography revealed diminished distal pulmonary vasculature of MCT(sl/sl) rat lungs. Cells within neointimal lesions expressed smooth muscle and endothelial cell markers. Moreover, cells within neointimal lesions exhibited increased levels of proliferation and were located in a tissue microenvironment enriched with vascular endothelial growth factor, tenascin-C, and activated matrix metalloproteinase-9, factors already implicated in human PAH. Finally, assessment of steady state mRNA showed that whereas expression of ET(B) receptors was decreased in MCT(sl/sl) rat lungs, ET(A) receptor expression increased. Deficiency of the ET(B) receptor markedly accelerates the progression of

Development of Occlusive Neointimal Lesions in Distal Pulmonary Arteries of Endothelin B Receptor–Deficient Rats: A New Model of Severe Pulmonary Arterial Hypertension

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Ivy, D. Dunbar; McMurtry, Ivan F.; Colvin, Kelley; Imamura, Masatoshi; Oka, Masahiko; Lee, Dong-Seok; Gebb, Sarah; Jones, Peter Lloyd

2007-01-01

Background Human pulmonary arterial hypertension (PAH) is characterized by proliferation of vascular smooth muscle and, in its more severe form, by the development of occlusive neointimal lesions. However, few animal models of pulmonary neointimal proliferation exist, thereby limiting a complete understanding of the pathobiology of PAH. Recent studies of the endothelin (ET) system demonstrate that deficiency of the ETB receptor predisposes adult rats to acute and chronic hypoxic PAH, yet these animals fail to develop neointimal lesions. Herein, we determined and thereafter showed that exposure of ETB receptor–deficient rats to the endothelial toxin monocrotaline (MCT) leads to the development of neointimal lesions that share hallmarks of human PAH. Methods and Results The pulmonary hemodynamic and morphometric effects of 60 mg/kg MCT in control (MCT+/+) and ETB receptor–deficient (MCTsl/sl) rats at 6 weeks of age were assessed. MCTsl/sl rats developed more severe PAH, characterized by elevated pulmonary artery pressure, diminished cardiac output, and right ventricular hypertrophy. In MCTsl/sl rats, morphometric evaluation revealed the presence of neointimal lesions within small distal pulmonary arteries, increased medial wall thickness, and decreased arterial-to-alveolar ratio. In keeping with this, barium angiography revealed diminished distal pulmonary vasculature of MCTsl/sl rat lungs. Cells within neointimal lesions expressed smooth muscle and endothelial cell markers. Moreover, cells within neointimal lesions exhibited increased levels of proliferation and were located in a tissue microenvironment enriched with vascular endothelial growth factor, tenascin-C, and activated matrix metalloproteinase-9, factors already implicated in human PAH. Finally, assessment of steady state mRNA showed that whereas expression of ETB receptors was decreased in MCTsl/sl rat lungs, ETA receptor expression increased. Conclusions Deficiency of the ETB receptor markedly

Nuclear fusion-independent smooth muscle differentiation of human adipose-derived stem cells induced by a smooth muscle environment.

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Zhang, Rong; Jack, Gregory S; Rao, Nagesh; Zuk, Patricia; Ignarro, Louis J; Wu, Benjamin; Rodríguez, Larissa V

2012-03-01

Human adipose-derived stem cells hASC have been isolated and were shown to have multilineage differentiation capacity. Although both plasticity and cell fusion have been suggested as mechanisms for cell differentiation in vivo, the effect of the local in vivo environment on the differentiation of adipose-derived stem cells has not been evaluated. We previously reported the in vitro capacity of smooth muscle differentiation of these cells. In this study, we evaluate the effect of an in vivo smooth muscle environment in the differentiation of hASC. We studied this by two experimental designs: (a) in vivo evaluation of smooth muscle differentiation of hASC injected into a smooth muscle environment and (b) in vitro evaluation of smooth muscle differentiation capacity of hASC exposed to bladder smooth muscle cells. Our results indicate a time-dependent differentiation of hASC into mature smooth muscle cells when these cells are injected into the smooth musculature of the urinary bladder. Similar findings were seen when the cells were cocultured in vitro with primary bladder smooth muscle cells. Chromosomal analysis demonstrated that microenvironment cues rather than nuclear fusion are responsible for this differentiation. We conclude that cell plasticity is present in hASCs, and their differentiation is accomplished in the absence of nuclear fusion. Copyright © 2011 AlphaMed Press.

Pulmonary capillary recruitment in response to hypoxia in healthy humans: a possible role for hypoxic pulmonary venoconstriction?

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Taylor, Bryan J; Kjaergaard, Jesper; Snyder, Eric M

2011-01-01

We examined mechanisms by which hypoxia may elicit pulmonary capillary recruitment in humans. On separate occasions, twenty-five healthy adults underwent exposure to intravenous saline infusion (30 ml/kg ∼ 15 min) or 17-h normobaric hypoxia ( [FIO2 = 12.5%). Cardiac output (Q) and pulmonary...... capillary blood volume (Vc) were measured before and after saline infusion and hypoxic-exposure by a rebreathing method. Pulmonary artery systolic pressure (sPpa) and left ventricular (LV) diastolic function were assessed before and after hypoxic-exposure via echocardiography. Saline infusion increased Q......Ppa and LV diastolic function. In conclusion, hypoxia-induced pulmonary capillary recruitment in humans is only partly accounted for by changes in Q, sPpa and LV diastolic function. We speculate that hypoxic pulmonary venoconstriction may play a role in such recruitment....

Serotonin Signaling Through the 5-HT1B Receptor and NADPH Oxidase 1 in Pulmonary Arterial Hypertension.

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Hood, Katie Y; Mair, Kirsty M; Harvey, Adam P; Montezano, Augusto C; Touyz, Rhian M; MacLean, Margaret R

2017-07-01

Serotonin can induce human pulmonary artery smooth muscle cell (hPASMC) proliferation through reactive oxygen species (ROS), influencing the development of pulmonary arterial hypertension (PAH). We hypothesize that in PASMCs, serotonin induces oxidative stress through NADPH-oxidase-derived ROS generation and reduced Nrf-2 (nuclear factor [erythroid-derived 2]-like 2) antioxidant systems, promoting vascular injury. HPASMCs from controls and PAH patients, and PASMCs from Nox1 -/- mice, were stimulated with serotonin in the absence/presence of inhibitors of Src kinase, the 5-HT 1B receptor, and NADPH oxidase 1 (Nox1). Markers of fibrosis were also determined. The pathophysiological significance of our findings was examined in vivo in serotonin transporter overexpressing female mice, a model of pulmonary hypertension. We confirmed thatserotonin increased superoxide and hydrogen peroxide production in these cells. For the first time, we show that serotonin increased oxidized protein tyrosine phosphatases and hyperoxidized peroxiredoxin and decreased Nrf-2 and catalase activity in hPASMCs. ROS generation was exaggerated and dependent on cellular Src-related kinase, 5-HT 1B receptor, and the serotonin transporter in human pulmonary artery smooth muscle cells from PAH subjects. Proliferation and extracellular matrix remodeling were exaggerated in human pulmonary artery smooth muscle cells from PAH subjects and dependent on 5-HT 1B receptor signaling and Nox1, confirmed in PASMCs from Nox1 -/- mice. In serotonin transporter overexpressing mice, SB216641, a 5-HT 1B receptor antagonist, prevented development of pulmonary hypertension in a ROS-dependent manner. Serotonin can induce cellular Src-related kinase-regulated Nox1-induced ROS and Nrf-2 dysregulation, contributing to increased post-translational oxidative modification of proteins and activation of redox-sensitive signaling pathways in hPASMCs, associated with mitogenic responses. 5-HT 1B receptors contribute to

Dynamic and diverse changes in the functional properties of vascular smooth muscle cells in pulmonary hypertension.

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Stenmark, Kurt R; Frid, Maria G; Graham, Brian B; Tuder, Rubin M

2018-03-15

Pulmonary hypertension (PH) is the end result of interaction between pulmonary vascular tone and a complex series of cellular and molecular events termed 'vascular remodelling'. The remodelling process, which can involve the entirety of pulmonary arterial vasculature, almost universally involves medial thickening, driven by increased numbers and hypertrophy of its principal cellular constituent, smooth muscle cells (SMCs). It is noted, however that SMCs comprise heterogeneous populations of cells, which can exhibit markedly different proliferative, inflammatory, and extracellular matrix production changes during remodelling. We further consider that these functional changes in SMCs of different phenotype and their role in PH are dynamic and may undergo significant changes over time (which we will refer to as cellular plasticity); no single property can account for the complexity of the contribution of SMC to pulmonary vascular remodelling. Thus, the approaches used to pharmacologically manipulate PH by targeting the SMC phenotype(s) must take into account processes that underlie dominant phenotypes that drive the disease. We present evidence for time- and location-specific changes in SMC proliferation in various animal models of PH; we highlight the transient nature (rather than continuous) of SMC proliferation, emphasizing that the heterogenic SMC populations that reside in different locations along the pulmonary vascular tree exhibit distinct responses to the stresses associated with the development of PH. We also consider that cells that have often been termed 'SMCs' may arise from many origins, including endothelial cells, fibroblasts and resident or circulating progenitors, and thus may contribute via distinct signalling pathways to the remodelling process. Ultimately, PH is characterized by long-lived, apoptosis-resistant SMC. In line with this key pathogenic characteristic, we address the acquisition of a pro-inflammatory phenotype by SMC that is essential

Mycophenolate mofetil attenuates pulmonary arterial hypertension in rats

International Nuclear Information System (INIS)

Suzuki, Chihiro; Takahashi, Masafumi; Morimoto, Hajime; Izawa, Atsushi; Ise, Hirohiko; Hongo, Minoru; Hoshikawa, Yasushi; Ito, Takayuki; Miyashita, Hiroshi; Kobayashi, Eiji; Shimada, Kazuyuki; Ikeda, Uichi

2006-01-01

Pulmonary arterial hypertension (PAH) is characterized by abnormal proliferation of smooth muscle cells (SMCs), leading to occlusion of pulmonary arterioles, right ventricular (RV) hypertrophy, and death. We investigated whether mycophenolate mofetil (MMF), a potent immunosuppresssant, prevents the development of monocrotaline (MCT)-induced PAH in rats. MMF effectively decreased RV systolic pressure and RV hypertrophy, and reduced the medial thickness of pulmonary arteries. MMF significantly inhibited the number of proliferating cell nuclear antigen (PCNA)-positive cells, infiltration of macrophages, and expression of P-selectin and interleukin-6 on the endothelium of pulmonary arteries. The infiltration of T cells and mast cells was not affected by MMF. In vitro experiments revealed that mycophenolic acid (MPA), an active metabolite of MMF, dose-dependently inhibited proliferation of human pulmonary arterial SMCs. MMF attenuated the development of PAH through its anti-inflammatory and anti-proliferative properties. These findings provide new insight into the potential role of immunosuppressants in the treatment of PAH

Pulmonary lymphangioleiomyomatosis - a case report

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Chun-Jie Li

2015-01-01

Full Text Available Pulmonary lymphangioleiomyomatosis (PLAM is a rare disease, occurs in 16-68-year-old women, especially in women of childbearing age. High-resolution computed tomography would be useful for diagnosis of PLAM. Immunohistochemistry of  smooth muscle actin (SMA and HMB-45 smooth muscle cells was positive for smooth muscle cells. Progesterone receptor and estrogen receptor in some smooth muscle cells were positive for some smooth muscle cells. HMB-45-positive diagnosis of the disease is more important.

[Electrophysiological study on rat conduit pulmonary artery smooth muscle cells under normoxia and acute hypoxia].

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Hu, Ying; Zou, Fei; Cai, Chun-Qing; Wu, Hang-Yu; Yun, Hai-Xia; Chen, Yun-Tian; Jin, Guo-En; Ge, Ri-Li

2006-10-25

The present study was designed to investigate the electrophysiological characteristics of rat conduit pulmonary artery smooth muscle cells (PASMCs) and the response to acute hypoxia. PASMCs of the 1st to 2nd order branches in the conduit pulmonary arteries were obtained by enzymatic isolation. The PASMCs were divided into acute hypoxia preconditioned group and normoxia group. Hypoxia solutions were achieved by bubbling with 5% CO2 plus 95% N2 for at least 30 min before cell perfusion. Potassium currents were compared between these two groups using whole-cell patch clamp technique. The total outward current of PASMCs was measured under normoxia condition when iBTX [specific blocking agent of large conductance Ca-activated K(+) (BK(Ca)) channel] and 4-AP [specific blocking agent of delayed rectifier K(+) (K(DR)) channel] were added consequently into bath solution. PASMCs were classified into three types according to their size, shape and electrophysiological characteristics. Type I cells are the smallest with spindle shape, smooth surface and discrete perinuclear bulge. Type II cells show the biggest size with banana-like appearance. Type III cells have the similar size with type I, and present intermediary shape between type I and type II. iBTX had little effect on the total outward current in type I cells, while 4-AP almost completely blocked it. Most of the total outward current in type II cells was inhibited by iBTX, and the remaining was sensitive to 4-AP. In type III cells, the total outward current was sensitive to both iBTX and 4-AP. Acute hypoxia reduced the current in all three types of cells: (1614.8+/-62.5) pA to (892.4+/-33.6) pA for type I cells (Ppotassium current and improves the E(m) in PASMCs. These effects may be involved in the modulation of constriction/relaxation of conduit artery under acute hypoxia. Different distribution of K(DR) and BK(Ca) channels in these three types of PASMCs might account for their different constriction

Potential contribution of phenotypically modulated smooth muscle cells and related inflammation in the development of experimental obstructive pulmonary vasculopathy in rats.

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Shoichiro Otsuki

Full Text Available We tested the hypothesis that phenotypically modulated smooth muscle cells (SMCs and related inflammation are associated with the progression of experimental occlusive pulmonary vascular disease (PVD. Occlusive PVD was induced by combined exposure to a vascular endothelial growth factor receptor tyrosine kinase inhibitor Sugen 5416 and hypobaric hypoxia for 3 weeks in rats, which were then returned to ambient air. Hemodynamic, morphometric, and immunohistochemical studies, as well as gene expression analyses, were performed at 3, 5, 8, and 13 weeks after the initial treatment (n = 78. Experimental animals developed pulmonary hypertension and right ventricular hypertrophy, and exhibited a progressive increase in indices of PVD, including cellular intimal thickening and intimal fibrosis. Cellular intimal lesions comprised α smooth muscle actin (α SMA+, SM1+, SM2+/-, vimentin+ immature SMCs that were covered by endothelial monolayers, while fibrous intimal lesions typically included α SMA+, SM1+, SM2+, vimentin+/- mature SMCs. Plexiform lesions comprised α SMA+, vimentin+, SM1-, SM2- myofibroblasts covered by endothelial monolayers. Immature SMC-rich intimal and plexiform lesions were proliferative and were infiltrated by macrophages, while fibrous intimal lesions were characterized by lower proliferative abilities and were infiltrated by few macrophages. Compared with controls, the number of perivascular macrophages was already higher at 3 weeks and progressively increased during the experimental period; gene expression of pulmonary hypertension-related inflammatory molecules, including IL6, MCP1, MMP9, cathepsin-S, and RANTES, was persistently or progressively up-regulated in lungs of experimental animals. We concluded that phenotypically modulated SMCs and related inflammation are potentially associated with the progression of experimental obstructive PVD.

Lack of bcr and abr promotes hypoxia-induced pulmonary hypertension in mice.

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Min Yu

Full Text Available Bcr and Abr are GTPase activating proteins that specifically downregulate activity of the small GTPase Rac in restricted cell types in vivo. Rac1 is expressed in smooth muscle cells, a critical cell type involved in the pathogenesis of pulmonary hypertension. The molecular mechanisms that underlie hypoxia-associated pulmonary hypertension are not well-defined.Bcr and abr null mutant mice were compared to wild type controls for the development of pulmonary hypertension after exposure to hypoxia. Also, pulmonary arterial smooth muscle cells from those mice were cultured in hypoxia and examined for proliferation, p38 activation and IL-6 production. Mice lacking Bcr or Abr exposed to hypoxia developed increased right ventricular pressure, hypertrophy and pulmonary vascular remodeling. Perivascular leukocyte infiltration in the lungs was increased, and under hypoxia bcr-/- and abr-/- macrophages generated more reactive oxygen species. Consistent with a contribution of inflammation and oxidative stress in pulmonary hypertension-associated vascular damage, Bcr and Abr-deficient animals showed elevated endothelial leakage after hypoxia exposure. Hypoxia-treated pulmonary arterial smooth muscle cells from Bcr- or Abr-deficient mice also proliferated faster than those of wild type mice. Moreover, activated Rac1, phosphorylated p38 and interleukin 6 were increased in these cells in the absence of Bcr or Abr. Inhibition of Rac1 activation with Z62954982, a novel Rac inhibitor, decreased proliferation, p38 phosphorylation and IL-6 levels in pulmonary arterial smooth muscle cells exposed to hypoxia.Bcr and Abr play a critical role in down-regulating hypoxia-induced pulmonary hypertension by deactivating Rac1 and, through this, reducing both oxidative stress generated by leukocytes as well as p38 phosphorylation, IL-6 production and proliferation of pulmonary arterial smooth muscle cells.

Preferential expression and function of voltage-gated, O2-sensitive K+ channels in resistance pulmonary arteries explains regional heterogeneity in hypoxic pulmonary vasoconstriction: ionic diversity in smooth muscle cells.

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Archer, Stephen L; Wu, Xi-Chen; Thébaud, Bernard; Nsair, Ali; Bonnet, Sebastien; Tyrrell, Ben; McMurtry, M Sean; Hashimoto, Kyoko; Harry, Gwyneth; Michelakis, Evangelos D

2004-08-06

Hypoxic pulmonary vasoconstriction (HPV) is initiated by inhibition of O2-sensitive, voltage-gated (Kv) channels in pulmonary arterial smooth muscle cells (PASMCs). Kv inhibition depolarizes membrane potential (E(M)), thereby activating Ca2+ influx via voltage-gated Ca2+ channels. HPV is weak in extrapulmonary, conduit pulmonary arteries (PA) and strong in precapillary resistance arteries. We hypothesized that regional heterogeneity in HPV reflects a longitudinal gradient in the function/expression of PASMC O2-sensitive Kv channels. In adult male Sprague Dawley rats, constrictions to hypoxia, the Kv blocker 4-aminopyridine (4-AP), and correolide, a Kv1.x channel inhibitor, were endothelium-independent and greater in resistance versus conduit PAs. Moreover, HPV was dependent on Kv-inhibition, being completely inhibited by pretreatment with 4-AP. Kv1.2, 1.5, Kv2.1, Kv3.1b, Kv4.3, and Kv9.3. mRNA increased as arterial caliber decreased; however, only Kv1.5 protein expression was greater in resistance PAs. Resistance PASMCs had greater K+ current (I(K)) and a more hyperpolarized E(M) and were uniquely O2- and correolide-sensitive. The O2-sensitive current (active at -65 mV) was resistant to iberiotoxin, with minimal tityustoxin sensitivity. In resistance PASMCs, 4-AP and hypoxia inhibited I(K) 57% and 49%, respectively, versus 34% for correolide. Intracellular administration of anti-Kv1.5 antibodies inhibited correolide's effects. The hypoxia-sensitive, correolide-insensitive I(K) (15%) was conducted by Kv2.1. Anti-Kv1.5 and anti-Kv2.1 caused additive depolarization in resistance PASMCs (Kv1.5>Kv2.1) and inhibited hypoxic depolarization. Heterologously expressed human PASMC Kv1.5 generated an O2- and correolide-sensitive I(K) like that in resistance PASMCs. In conclusion, Kv1.5 and Kv2.1 account for virtually all the O2-sensitive current. HPV occurs in a Kv-enriched resistance zone because resistance PASMCs preferentially express O2-sensitive Kv-channels.

Mediators on human airway smooth muscle.

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Armour, C; Johnson, P; Anticevich, S; Ammit, A; McKay, K; Hughes, M; Black, J

1997-01-01

1. Bronchial hyperresponsiveness in asthma may be due to several abnormalities, but must include alterations in the airway smooth muscle responsiveness and/or volume. 2. Increased responsiveness of airway smooth muscle in vitro can be induced by certain inflammatory cell products and by induction of sensitization (atopy). 3. Increased airway smooth muscle growth can also be induced by inflammatory cell products and atopic serum. 4. Mast cell numbers are increased in the airways of asthmatics and, in our studies, in airway smooth muscle that is sensitized and hyperresponsive. 5. We propose that there is a relationship between mast cells and airway smooth muscle cells which, once an allergic process has been initiated, results in the development of critical features in the lungs in asthma.

Key role of the endothelial TGF-β/ALK1/endoglin signaling pathway in humans and rodents pulmonary hypertension.

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Benoît Gore

Full Text Available Mutations affecting transforming growth factor-beta (TGF-β superfamily receptors, activin receptor-like kinase (ALK-1, and endoglin (ENG occur in patients with pulmonary arterial hypertension (PAH. To determine whether the TGF-β/ALK1/ENG pathway was involved in PAH, we investigated pulmonary TGF-β, ALK1, ALK5, and ENG expressions in human lung tissue and cultured pulmonary-artery smooth-muscle-cells (PA-SMCs and pulmonary endothelial cells (PECs from 14 patients with idiopathic PAH (iPAH and 15 controls. Seeing that ENG was highly expressed in PEC, we assessed the effects of TGF-β on Smad1/5/8 and Smad2/3 activation and on growth factor production by the cells. Finally, we studied the consequence of ENG deficiency on the chronic hypoxic-PH development by measuring right ventricular (RV systolic pressure (RVSP, RV hypertrophy, and pulmonary arteriolar remodeling in ENG-deficient (Eng+/- and wild-type (Eng+/+ mice. We also evaluated the pulmonary blood vessel density, macrophage infiltration, and cytokine expression in the lungs of the animals. Compared to controls, iPAH patients had higher serum and pulmonary TGF-β levels and increased ALK1 and ENG expressions in lung tissue, predominantly in PECs. Incubation of the cells with TGF-β led to Smad1/5/8 phosphorylation and to a production of FGF2, PDGFb and endothelin-inducing PA-SMC growth. Endoglin deficiency protected mice from hypoxic PH. As compared to wild-type, Eng+/- mice had a lower pulmonary vessel density, and no change in macrophage infiltration after exposure to chronic hypoxia despite the higher pulmonary expressions of interleukin-6 and monocyte chemoattractant protein-1. The TGF-β/ALK1/ENG signaling pathway plays a key role in iPAH and experimental hypoxic PH via a direct effect on PECs leading to production of growth factors and inflammatory cytokines involved in the pathogenesis of PAH.

Interleukin-22 Inhibits Bleomycin-Induced Pulmonary Fibrosis

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Minrui Liang

2013-01-01

Full Text Available Pulmonary fibrosis is a progressive and fatal fibrotic disease of the lungs with unclear etiology. Recent insight has suggested that early injury/inflammation of alveolar epithelial cells could lead to dysregulation of tissue repair driven by multiple cytokines. Although dysregulation of interleukin- (IL- 22 is involved in various pulmonary pathophysiological processes, the role of IL-22 in fibrotic lung diseases is still unclear and needs to be further addressed. Here we investigated the effect of IL-22 on alveolar epithelial cells in the bleomycin- (BLM- induced pulmonary fibrosis. BLM-treated mice showed significantly decreased level of IL-22 in the lung. IL-22 produced γδT cells were also decreased significantly both in the tissues of lungs and spleens. Administration of recombinant human IL-22 to alveolar epithelial cell line A549 cells ameliorated epithelial to mesenchymal transition (EMT and partially reversed the impaired cell viability induced by BLM. Furthermore, blockage of IL-22 deteriorated pulmonary fibrosis, with elevated EMT marker (α-smooth muscle actin (α-SMA and overactivated Smad2. Our results indicate that IL-22 may play a protective role in the development of BLM-induced pulmonary fibrosis and may suggest IL-22 as a novel immunotherapy tool in treating pulmonary fibrosis.

Pulmonary disease in patients with human immunodeficiency virus infection

DEFF Research Database (Denmark)

Lundgren, J D; Orholm, Marianne; Lundgren, B

1989-01-01

cause pulmonary disease alone or in combination. Bilateral interstitial infiltrates are the most frequent chest x-ray abnormality and are most frequently caused by infection with Pneumocystis carinii. Cytomegalovirus, Mycobacterium tuberculosis, nonspecific interstitial pneumonitis and pulmonary Kaposi......Pulmonary disease is the most important cause of morbidity and mortality in patients infected with human immunodeficiency virus (HIV). All parts of the hospital system are expected to be involved in the diagnosis and treatment of HIV infected patients in the coming years. Many different processes......'s sarcoma are the most important parts of the differential diagnosis. An aggressive approach to the diagnosis of pulmonary disease in this patient population is indicated in order to provide optimal care and assess new therapies....

Inhibition of DNA nanotube-conjugated mTOR siRNA on the growth of pulmonary arterial smooth muscle cells

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Zaichun You

2015-12-01

Full Text Available Here we provide raw and processed data and methods behind mTOR siRNA loaded DNA nanotubes (siRNA-DNA-NTs in the growth of pulmonary arterial smooth muscle cells (PASMCs under both normoxic and hypoxic condition, and also related to (You et al., Biomaterials, 2015, 67:137–150, [1]. The MTT analysis, Semi-quantitative RT-PCR data presented here were used to probe cytotoxicity of mTOR siRNA-DNA-NT complex in its TAE-Mg2+ buffer. siRNA-DNA-NTs have a lower cytotoxicity and higher transfection efficiency and can, based on inhibition of mTOR expression, decrease PASMCs growth both hypoxic and normal condition.

Slow receptor dissociation kinetics differentiate macitentan from other endothelin receptor antagonists in pulmonary arterial smooth muscle cells.

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John Gatfield

Full Text Available Two endothelin receptor antagonists (ERAs, bosentan and ambrisentan, are currently approved for the treatment of pulmonary arterial hypertension (PAH, a devastating disease involving an activated endothelin system and aberrant contraction and proliferation of pulmonary arterial smooth muscle cells (PASMC. The novel ERA macitentan has recently concluded testing in a Phase III morbidity/mortality clinical trial in PAH patients. Since the association and dissociation rates of G protein-coupled receptor antagonists can influence their pharmacological activity in vivo, we used human PASMC to characterize inhibitory potency and receptor inhibition kinetics of macitentan, ambrisentan and bosentan using calcium release and inositol-1-phosphate (IP(1 assays. In calcium release assays macitentan, ambrisentan and bosentan were highly potent ERAs with K(b values of 0.14 nM, 0.12 nM and 1.1 nM, respectively. Macitentan, but not ambrisentan and bosentan, displayed slow apparent receptor association kinetics as evidenced by increased antagonistic potency upon prolongation of antagonist pre-incubation times. In compound washout experiments, macitentan displayed a significantly lower receptor dissociation rate and longer receptor occupancy half-life (ROt(1/2 compared to bosentan and ambrisentan (ROt(1/2:17 minutes versus 70 seconds and 40 seconds, respectively. Because of its lower dissociation rate macitentan behaved as an insurmountable antagonist in calcium release and IP(1 assays, and unlike bosentan and ambrisentan it blocked endothelin receptor activation across a wide range of endothelin-1 (ET-1 concentrations. However, prolongation of the ET-1 stimulation time beyond ROt(1/2 rendered macitentan a surmountable antagonist, revealing its competitive binding mode. Bosentan and ambrisentan behaved as surmountable antagonists irrespective of the assay duration and they lacked inhibitory activity at high ET-1 concentrations. Thus, macitentan is a competitive

PM2.5 promotes human bronchial smooth muscle cell migration via the sonic hedgehog signaling pathway.

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Ye, Xiuqin; Hong, Wei; Hao, Binwei; Peng, Gongyong; Huang, Lingmei; Zhao, Zhuxiang; Zhou, Yumin; Zheng, Mengning; Li, Chenglong; Liang, Chunxiao; Yi, Erkang; Pu, Jinding; Li, Bing; Ran, Pixin

2018-03-02

The contribution of airway remodeling in chronic obstructive pulmonary disease (COPD) has been well documented, with airway smooth muscle cell proliferation and migration playing a role in the remodeling process. Here, we aimed to verify the effects of fine particulate matter (PM2.5) on human bronchial smooth muscle cell (HBSMC) migration and to explore the underlying signaling pathways. HBSMC apoptosis, proliferation and migration were measured using flow cytometry, cell counting and transwell migration assays, respectively. The role of the hedgehog pathway in cell migration was assessed by western blotting to measure the expression of Sonic hedgehog (Shh), Gli1 and Snail. Furthermore, siRNA was used to knock down Gli1 or Snail expression. PM2.5 induced HBSMC apoptosis in a dose-dependent manner, although certain concentrations of PM2.5 did not induce HBSMC proliferation or apoptosis. Interestingly, cell migration was stimulated by PM2.5 doses far below those that induced apoptosis. Additional experiments revealed that these PM2.5 doses enhanced the expression of Shh, Gli1 and Snail in HBSMCs. Furthermore, PM2.5-induced cell migration and protein expression were enhanced by recombinant Shh and attenuated by cyclopamine. Similar results were obtained by knocking down Gli1 or Snail. These findings suggest that PM2.5, which may exert its effects through the Shh signaling pathway, is necessary for the migration of HBSMCs. These data define a novel role for PM2.5 in airway remodeling in COPD.

A continuum model for pressure-flow relationship in human pulmonary circulation.

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Huang, Wei; Zhou, Qinlian; Gao, Jian; Yen, R T

2011-06-01

A continuum model was introduced to analyze the pressure-flow relationship for steady flow in human pulmonary circulation. The continuum approach was based on the principles of continuum mechanics in conjunction with detailed measurement of vascular geometry, vascular elasticity and blood rheology. The pulmonary arteries and veins were considered as elastic tubes and the "fifth-power law" was used to describe the pressure-flow relationship. For pulmonary capillaries, the "sheet-flow" theory was employed and the pressure-flow relationship was represented by the "fourth-power law". In this paper, the pressure-flow relationship for the whole pulmonary circulation and the longitudinal pressure distribution along the streamlines were studied. Our computed data showed general agreement with the experimental data for the normal subjects and the patients with mitral stenosis and chronic bronchitis in the literature. In conclusion, our continuum model can be used to predict the changes of steady flow in human pulmonary circulation.

α-Trinositol inhibits FGF-stimulated growth of smooth muscle and breast cancer cells

International Nuclear Information System (INIS)

Siren, Matti J.; Vainiomaeki, Maija; Vaeaenaenen, Kalervo; Haerkoenen, Pirkko

2004-01-01

α-Trinositol (D-myo-inositol-1,2,6-trisphosphate), an isomer of the intracellular messenger IP 3 , has been studied for its anti-inflammatory and other effects in animal experiments and in human. The mechanisms of action remain unknown. Several human pathologies are associated with uncontrolled production of fibroblast growth factors (FGFs). FGF-2 induces vascular smooth muscle cell proliferation, which contributes to restenosis after coronary balloon angioplasty. The expression of several FGFs is also increased in tumors. We studied the effects of the water- and lipid-soluble derivatives of α-trinositol on the FGF-2- and/or FGF-8-induced proliferation of human pulmonary artery smooth muscle cells (HPASMC) and S115 mouse breast cancer cells. α-Trinositol decreased the FGF-mediated proliferation of HPASMC and S115 cells. Membrane permeability did not seem obligatory since the lipid-soluble form of α-trinositol was less effective than the water-soluble derivative. These results suggest a new biological function for certain phosphoinositides in the modulation of FGF-regulated processes

Protective roles of pulmonary rehabilitation mixture in experimental pulmonary fibrosis in vitro and in vivo

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Zhang, L.; Ji, Y.X.; Jiang, W.L.; Lv, C.J. [School of Pharmaceutical Sciences, Binzhou Medical University, Yantai (China)

2015-05-08

Abnormal high mobility group protein B1 (HMGB1) activation is involved in the pathogenesis of pulmonary fibrosis. Pulmonary rehabilitation mixture (PRM), which combines extracts from eight traditional Chinese medicines, has very good lung protection in clinical use. However, it is not known if PRM has anti-fibrotic activity. In this study, we investigated the effects of PRM on transforming growth factor-β1 (TGF-β1)-mediated and bleomycin (BLM)-induced pulmonary fibrosis in vitro and in vivo. The effects of PRM on TGF-β1-mediated epithelial-mesenchymal transition (EMT) in A549 cells, on the proliferation of human lung fibroblasts (HLF-1) in vitro, and on BLM-induced pulmonary fibrosis in vivo were investigated. PRM treatment resulted in a reduction of EMT in A549 cells that was associated with attenuating an increase of vimentin and a decrease of E-cadherin. PRM inhibited the proliferation of HLF-1 at an IC{sub 50} of 0.51 µg/mL. PRM ameliorated BLM-induced pulmonary fibrosis in rats, with reduction of histopathological scores and collagen deposition, and a decrease in α-smooth muscle actin (α-SMA) and HMGB1 expression. An increase in receptor for advanced glycation end-product (RAGE) expression was found in BLM-instilled lungs. PRM significantly decreased EMT and prevented pulmonary fibrosis through decreasing HMGB1 and regulating RAGE in vitro and in vivo. PRM inhibited TGF-β1-induced EMT via decreased HMGB1 and vimentin and increased RAGE and E-cadherin levels. In summary, PRM prevented experimental pulmonary fibrosis by modulating the HMGB1/RAGE pathway.

Protective roles of pulmonary rehabilitation mixture in experimental pulmonary fibrosis in vitro and in vivo

International Nuclear Information System (INIS)

Zhang, L.; Ji, Y.X.; Jiang, W.L.; Lv, C.J.

2015-01-01

Abnormal high mobility group protein B1 (HMGB1) activation is involved in the pathogenesis of pulmonary fibrosis. Pulmonary rehabilitation mixture (PRM), which combines extracts from eight traditional Chinese medicines, has very good lung protection in clinical use. However, it is not known if PRM has anti-fibrotic activity. In this study, we investigated the effects of PRM on transforming growth factor-β1 (TGF-β1)-mediated and bleomycin (BLM)-induced pulmonary fibrosis in vitro and in vivo. The effects of PRM on TGF-β1-mediated epithelial-mesenchymal transition (EMT) in A549 cells, on the proliferation of human lung fibroblasts (HLF-1) in vitro, and on BLM-induced pulmonary fibrosis in vivo were investigated. PRM treatment resulted in a reduction of EMT in A549 cells that was associated with attenuating an increase of vimentin and a decrease of E-cadherin. PRM inhibited the proliferation of HLF-1 at an IC 50 of 0.51 µg/mL. PRM ameliorated BLM-induced pulmonary fibrosis in rats, with reduction of histopathological scores and collagen deposition, and a decrease in α-smooth muscle actin (α-SMA) and HMGB1 expression. An increase in receptor for advanced glycation end-product (RAGE) expression was found in BLM-instilled lungs. PRM significantly decreased EMT and prevented pulmonary fibrosis through decreasing HMGB1 and regulating RAGE in vitro and in vivo. PRM inhibited TGF-β1-induced EMT via decreased HMGB1 and vimentin and increased RAGE and E-cadherin levels. In summary, PRM prevented experimental pulmonary fibrosis by modulating the HMGB1/RAGE pathway

Adrenomedullin and adrenotensin regulate collagen synthesis and proliferation in pulmonary arterial smooth muscle cells

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Li, W. [School of Control Science and Engineering, Biomedical Engineering Institute, Shandong University, Jinan, Shandong (China); Kong, Q.Y.; Zhao, C.F. [Department of Pediatrics, Qilu Hospital, Shandong University, Jinan, Shandong (China); Zhao, F. [Department of Medicine, Weill Medical College of Cornell University, New York, NY (United States); Li, F.H.; Xia, W. [Department of Pediatrics, Qilu Hospital, Shandong University, Jinan, Shandong (China); Wang, R. [Key Laboratory of Cardiovascular Remodeling and Function Research, Qilu Hospital, Shandong University, Jinan, Shandong (China); Hu, Y.M. [School of Control Science and Engineering, Biomedical Engineering Institute, Shandong University, Jinan, Shandong (China); Hua, M. [Shandong Institute of Scientific and Technical Information, Jinan, Shandong (China)

2013-12-10

To understand the pathophysiological mechanisms of pulmonary arterial smooth muscle cell (PASMC) proliferation and extracellular-matrix accumulation in the development of pulmonary hypertension and remodeling, this study determined the effects of different doses of adrenomedullin (ADM) and adrenotensin (ADT) on PASMC proliferation and collagen synthesis. The objective was to investigate whether extracellular signal-regulated kinase (ERK1/2) signaling was involved in ADM- and ADT-stimulated proliferation of PASMCs in 4-week-old male Wistar rats (body weight: 100-150 g, n=10). The proliferation of PASMCs was examined by 5-bromo-2-deoxyuridine incorporation. A cell growth curve was generated by the Cell Counting Kit-8 method. Expression of collagen I, collagen III, and phosphorylated ERK1/2 (p-ERK1/2) was evaluated by immunofluorescence. The effects of different concentrations of ADM and ADT on collagen I, collagen III, and p-ERK1/2 protein expression were determined by immunoblotting. We also investigated the effect of PD98059 inhibition on the expression of p-ERK1/2 protein by immunoblotting. ADM dose-dependently decreased cell proliferation, whereas ADT dose-dependently increased it; and ADM and ADT inhibited each other with respect to their effects on the proliferation of PASMCs. Consistent with these results, the expression of collagen I, collagen III, and p-ERK1/2 in rat PASMCs decreased after exposure to ADM but was upregulated after exposure to ADT. PD98059 significantly inhibited the downregulation by ADM and the upregulation by ADT of p-ERK1/2 expression. We conclude that ADM inhibited, and ADT stimulated, ERK1/2 signaling in rat PASMCs to regulate cell proliferation and collagen expression.

miR-143 Activation Regulates Smooth Muscle and Endothelial Cell Crosstalk in Pulmonary Arterial Hypertension

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Stevens, Hannah; Lu, Ruifang; Caudrillier, Axelle; McBride, Martin; McClure, John D; Grant, Jenny; Thomas, Matthew; Frid, Maria; Stenmark, Kurt; White, Kevin; Seto, Anita G.; Morrell, Nicholas W.; Bradshaw, Angela C; MacLean, Margaret R.; Baker, Andrew H.

2015-01-01

Rationale The pathogenesis of PAH remains unclear. The four microRNAs representing the miR-143 and miR-145 stem loops are genomically clustered. Objective To elucidate the transcriptional regulation of the miR-143/145 cluster, and the role of miR-143 in PAH. Methods and Results We identified the promoter region that regulates miR-143/145 miRNA expression in pulmonary artery smooth muscle cells (PASMCs). We mapped PAH-related signalling pathways, including estrogens receptor (ER), liver X factor/retinoic X receptor (LXR/RXR), TGF-β (Smads), and hypoxia (HRE) that regulated levels of all pri-miR stem loop transcription and resulting miRNA expression. We observed that miR-143-3p is selectively upregulated compared to miR-143-5p during PASMC migration. Modulation of miR-143 in PASMCs significantly altered cell migration and apoptosis. In addition, we found high abundance of miR-143-3p in PASMCs-derived exosomes. Using assays with pulmonary arterial endothelial cells (PAECs) we demonstrated a paracrine pro-migratory and pro-angiogenic effect of miR-143-3p enriched exosomes from PASMC. Quantitative PCR and in situ hybridisation showed elevated expression of miR-143 in calf models of PAH as well as in samples from PAH patients. Moreover, in contrast to our previous findings that had not supported a therapeutic role in vivo, we now demonstrate a protective role for miR-143 in experimental PH in vivo in miR-143−/− and antimiR143-3p-treated mice exposed to chronic hypoxia in both preventative and reversal settings. Conclusions miR-143-3p modulated both cellular and exosome-mediated responses in pulmonary vascular cells, while inhibition of miR-143-3p blocked experimental PH. Taken together these findings confirm an important role for the miR-143/145 cluster in PAH pathobiology. PMID:26311719

Tiny plastic lung mimics human pulmonary function

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Careers Inclusion & Diversity Work-Life Balance Career Resources Apply for a Job Postdocs Students Goals Recycling Green Purchasing Pollution Prevention Reusing Water Resources Environmental Management Releases - 2016 » April » Tiny plastic lung mimics human pulmonary function Tiny plastic lung mimics

MicroRNA-222 Promotes the Proliferation of Pulmonary Arterial Smooth Muscle Cells by Targeting P27 and TIMP3

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Ying Xu

2017-08-01

Full Text Available Background/Aims: Aberrant vascular smooth muscle cell (VSMC proliferation plays an important role in the development of pulmonary artery hypertension (PAH. Dysregulated microRNAs (miRNAs, miRs have been implicated in the progression of PAH. miR-222 has a pro-proliferation effect on VSMCs while it has an anti-proliferation effect on vascular endothelial cells (ECs. As the biological function of a single miRNA could be cell-type specific, the role of miR-222 in pulmonary artery smooth muscle cell (PASMC proliferation is not clear and deserves to be explored. Methods: PASMCs were transfected with miR-222 mimic or inhibitor and PASMC proliferation was determined by Western blot for PCNA, Ki-67 and EdU staining, and cell number counting. The target genes of miR-222 including P27 and TIMP3 were determined by luciferase assay and Western blot. In addition, the functional rescue experiments were performed based on miR-222 inhibitor and siRNAs to target genes. Results: miR-222 mimic promoted PASMC proliferation while miR-222 inhibitor decreased that. TIMP3 was identified to be a direct target gene of miR-222 based on luciferase assay. Meanwhile, P27 and TIMP3 were up-regulated by miR-222 inhibitor and down-regulated by miR-222 mimic. Moreover, P27 siRNA and TIMP3 siRNA could both attenuate the anti-proliferation effect of miR-222 inhibitor in PASMCs, supporting that P27 and TIMP3 are at least partially responsible for the regulatory effect of miR-222 in PASMCs. Conclusion: miR-222 promotes PASMC proliferation at least partially through targeting P27 and TIMP3.

Milrinone relaxes pulmonary veins in guinea pigs and humans.

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Annette D Rieg

Full Text Available INTRODUCTION: The phosphodiesterase-III inhibitor milrinone improves ventricular contractility, relaxes pulmonary arteries and reduces right ventricular afterload. Thus, it is used to treat heart failure and pulmonary hypertension (PH. However, its action on pulmonary veins (PVs is not defined, although particularly PH due to left heart disease primarily affects the pulmonary venous bed. We examined milrinone-induced relaxation in PVs from guinea pigs (GPs and humans. MATERIAL AND METHODS: Precision-cut lung slices (PCLS were prepared from GPs or from patients undergoing lobectomy. Milrinone-induced relaxation was studied by videomicroscopy in naïve PVs and in PVs pre-constricted with the ETA-receptor agonist BP0104. Baseline luminal area was defined as 100%. Intracellular cAMP was measured by ELISA and milrinone-induced changes of segmental vascular resistances were studied in the GP isolated perfused lung (IPL. RESULTS: In the IPL (GP, milrinone (10 µM lowered the postcapillary resistance of pre-constricted vessels. In PCLS (GP, milrinone relaxed naïve and pre-constricted PVs (120% and this relaxation was attenuated by inhibition of protein kinase G (KT 5823, adenyl cyclase (SQ 22536 and protein kinase A (KT 5720, but not by inhibition of NO-synthesis (L-NAME. In addition, milrinone-induced relaxation was dependent on the activation of K ATP-, BK Ca (2+- and Kv-channels. Human PVs also relaxed to milrinone (121%, however only if pre-constricted. DISCUSSION: Milrinone relaxes PVs from GPs and humans. In GPs, milrinone-induced relaxation is based on K ATP-, BK Ca (2+- and Kv-channel-activation and on cAMP/PKA/PKG. The relaxant properties of milrinone on PVs lead to reduced postcapillary resistance and hydrostatic pressures. Hence they alleviate pulmonary edema and suggest beneficial effects of milrinone in PH due to left heart disease.

Milrinone relaxes pulmonary veins in guinea pigs and humans.

Science.gov (United States)

Rieg, Annette D; Suleiman, Said; Perez-Bouza, Alberto; Braunschweig, Till; Spillner, Jan W; Schröder, Thomas; Verjans, Eva; Schälte, Gereon; Rossaint, Rolf; Uhlig, Stefan; Martin, Christian

2014-01-01

The phosphodiesterase-III inhibitor milrinone improves ventricular contractility, relaxes pulmonary arteries and reduces right ventricular afterload. Thus, it is used to treat heart failure and pulmonary hypertension (PH). However, its action on pulmonary veins (PVs) is not defined, although particularly PH due to left heart disease primarily affects the pulmonary venous bed. We examined milrinone-induced relaxation in PVs from guinea pigs (GPs) and humans. Precision-cut lung slices (PCLS) were prepared from GPs or from patients undergoing lobectomy. Milrinone-induced relaxation was studied by videomicroscopy in naïve PVs and in PVs pre-constricted with the ETA-receptor agonist BP0104. Baseline luminal area was defined as 100%. Intracellular cAMP was measured by ELISA and milrinone-induced changes of segmental vascular resistances were studied in the GP isolated perfused lung (IPL). In the IPL (GP), milrinone (10 µM) lowered the postcapillary resistance of pre-constricted vessels. In PCLS (GP), milrinone relaxed naïve and pre-constricted PVs (120%) and this relaxation was attenuated by inhibition of protein kinase G (KT 5823), adenyl cyclase (SQ 22536) and protein kinase A (KT 5720), but not by inhibition of NO-synthesis (L-NAME). In addition, milrinone-induced relaxation was dependent on the activation of K ATP-, BK Ca (2+)- and Kv-channels. Human PVs also relaxed to milrinone (121%), however only if pre-constricted. Milrinone relaxes PVs from GPs and humans. In GPs, milrinone-induced relaxation is based on K ATP-, BK Ca (2+)- and Kv-channel-activation and on cAMP/PKA/PKG. The relaxant properties of milrinone on PVs lead to reduced postcapillary resistance and hydrostatic pressures. Hence they alleviate pulmonary edema and suggest beneficial effects of milrinone in PH due to left heart disease.

Directional asymmetries in human smooth pursuit eye movements.

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Ke, Sally R; Lam, Jessica; Pai, Dinesh K; Spering, Miriam

2013-06-27

Humans make smooth pursuit eye movements to bring the image of a moving object onto the fovea. Although pursuit accuracy is critical to prevent motion blur, the eye often falls behind the target. Previous studies suggest that pursuit accuracy differs between motion directions. Here, we systematically assess asymmetries in smooth pursuit. In experiment 1, binocular eye movements were recorded while observers (n = 20) tracked a small spot of light moving along one of four cardinal or diagonal axes across a featureless background. We analyzed pursuit latency, acceleration, peak velocity, gain, and catch-up saccade latency, number, and amplitude. In experiment 2 (n = 22), we examined the effects of spatial location and constrained stimulus motion within the upper or lower visual field. Pursuit was significantly faster (higher acceleration, peak velocity, and gain) and smoother (fewer and later catch-up saccades) in response to downward versus upward motion in both the upper and the lower visual fields. Pursuit was also more accurate and smoother in response to horizontal versus vertical motion. CONCLUSIONS. Our study is the first to report a consistent up-down asymmetry in human adults, regardless of visual field. Our findings suggest that pursuit asymmetries are adaptive responses to the requirements of the visual context: preferred motion directions (horizontal and downward) are more critical to our survival than nonpreferred ones.

Endothelial and Smooth Muscle Cell Interaction via FoxM1 Signaling Mediates Vascular Remodeling and Pulmonary Hypertension.

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Dai, Zhiyu; Zhu, Maggie M; Peng, Yi; Jin, Hua; Machireddy, Narsa; Qian, Zhijian; Zhang, Xianming; Zhao, You-Yang

2018-04-17

Angioproliferative vasculopathy is a hallmark of pulmonary arterial hypertension (PAH). However, little is known how endothelial cell (EC) and smooth muscle cell (SMC) crosstalk regulates the angioproliferative vascular remodeling. We aimed to investigate the role of EC and SMC interaction and underlying signaling pathways in PH development. SMC-specific Foxm1 or Cxcr4 knockout mice, EC-specific Foxm1 or Egln1 knockout mice, as well as EC-specific Egln1/Cxcl12 double knockout mice were used to assess the role of FoxM1 on SMC proliferation and PH. Lung tissues and cells from PAH patients were employed to validate clinical relevance. FoxM1 inhibitor Thiostrepton was used in Sugen 5416/hypoxia- and monocrotaline-challenged rats. FoxM1 expression was markedly upregulated in lungs and pulmonary arterial SMCs of idiopathic PAH patients and 4 discrete PH rodent models. Mice with SMC- (but not EC-) specific deletion of Foxm1 were protected from hypoxia- or Sugen 5416/hypoxia-induced PH. The upregulation of FoxM1 in SMCs induced by multiple EC-derived factors (PDGF-B, CXCL12, ET-1 and MIF) mediated SMC proliferation. Genetic deletion of endothelial Cxcl12 in Egln1Tie2Cre mice or loss of its cognate receptor Cxcr4 in SMCs in hypoxia-treated mice inhibited FoxM1 expression, SMC proliferation and PH. Accordingly, pharmacological inhibition of FoxM1 inhibited severe PH in both Sugen 5416/hypoxia and monocrotaline-challenged rats. Multiple factors derived from dysfunctional ECs induced FoxM1 expression in SMCs and activated FoxM1-dependent SMC proliferation which contributes to pulmonary vascular remodeling and PH. Thus, targeting FoxM1 signaling represents a novel strategy for treatment of IPAH.

Enhanced elastin synthesis and maturation in human vascular smooth muscle tissue derived from induced-pluripotent stem cells.

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Eoh, Joon H; Shen, Nian; Burke, Jacqueline A; Hinderer, Svenja; Xia, Zhiyong; Schenke-Layland, Katja; Gerecht, Sharon

2017-04-01

Obtaining vascular smooth muscle tissue with mature, functional elastic fibers is a key obstacle in tissue-engineered blood vessels. Poor elastin secretion and organization leads to a loss of specialization in contractile smooth muscle cells, resulting in over proliferation and graft failure. In this study, human induced-pluripotent stem cells (hiPSCs) were differentiated into early smooth muscle cells, seeded onto a hybrid poly(ethylene glycol) dimethacrylate/poly (l-lactide) (PEGdma-PLA) scaffold and cultured in a bioreactor while exposed to pulsatile flow, towards maturation into contractile smooth muscle tissue. We evaluated the effects of pulsatile flow on cellular organization as well as elastin expression and assembly in the engineered tissue compared to a static control through immunohistochemistry, gene expression and functionality assays. We show that culturing under pulsatile flow resulted in organized and functional hiPSC derived smooth muscle tissue. Immunohistochemistry analysis revealed hiPSC-smooth muscle tissue with robust, well-organized cells and elastic fibers and the supporting microfibril proteins necessary for elastic fiber assembly. Through qRT-PCR analysis, we found significantly increased expression of elastin, fibronectin, and collagen I, indicating the synthesis of necessary extracellular matrix components. Functionality assays revealed that hiPSC-smooth muscle tissue cultured in the bioreactor had an increased calcium signaling and contraction in response to a cholinergic agonist, significantly higher mature elastin content and improved mechanical properties in comparison to the static control. The findings presented here detail an effective approach to engineering elastic human vascular smooth muscle tissue with the functionality necessary for tissue engineering and regenerative medicine applications. Obtaining robust, mature elastic fibers is a key obstacle in tissue-engineered blood vessels. Human induced-pluripotent stem cells have

Pulmonary lymphangioleiomyomatosis

International Nuclear Information System (INIS)

Shawki, Hilal B.; Muhammad, Shakir M.; Reda, Amal N.; Abdulla, Thair S.; Ardalan, Delaram M.

2007-01-01

A 38-year-old Iraqi female, presented with one-year history of exertional dyspnea and exercise intolerance, without systemic or constitutional symptoms. Clinical examination revealed bilateral basal crackles with signs suggestive of left side pleural effusion, chest x-ray showed left sided pleural effusion, and diffuse bilateral basal pulmonary shadowing. Her biochemical analysis, hematological tests, electrocardiogram and echocardiography were normal, aspiration of the fluid revealed a chylothorax, the radiological shadowing was proved by computed tomography scan of the chest to be diffuse cystic lesions involving mostly lower lobes. Open lung biopsy showed dilated lymphatic vessels with surrounding inflammatory cells and smooth muscle fibers consistently with the diagnosis of pulmonary lymphangioleiomyomatosis. (author)

Hypoxia, leukocytes, and the pulmonary circulation.

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Stenmark, Kurt R; Davie, Neil J; Reeves, John T; Frid, Maria G

2005-02-01

Data are rapidly accumulating in support of the idea that circulating monocytes and/or mononuclear fibrocytes are recruited to the pulmonary circulation of chronically hypoxic animals and that these cells play an important role in the pulmonary hypertensive process. Hypoxic induction of monocyte chemoattractant protein-1, stromal cell-derived factor-1, vascular endothelial growth factor-A, endothelin-1, and tumor growth factor-beta(1) in pulmonary vessel wall cells, either directly or indirectly via signals from hypoxic lung epithelial cells, may be a critical first step in the recruitment of circulating leukocytes to the pulmonary circulation. In addition, hypoxic stress appears to induce release of increased numbers of monocytic progenitor cells from the bone marrow, and these cells may have upregulated expression of receptors for the chemokines produced by the lung circulation, which thus facilitates their specific recruitment to the pulmonary site. Once present, macrophages/fibrocytes may exert paracrine effects on resident pulmonary vessel wall cells stimulating proliferation, phenotypic modulation, and migration of resident fibroblasts and smooth muscle cells. They may also contribute directly to the remodeling process through increased production of collagen and/or differentiation into myofibroblasts. In addition, they could play a critical role in initiating and/or supporting neovascularization of the pulmonary artery vasa vasorum. The expanded vasa network may then act as a conduit for further delivery of circulating mononuclear cells to the pulmonary arterial wall, creating a feedforward loop of pathological remodeling. Future studies will need to determine the mechanisms that selectively induce leukocyte/fibrocyte recruitment to the lung circulation under hypoxic conditions, their direct role in the remodeling process via production of extracellular matrix and/or differentiation into myofibroblasts, their impact on the phenotype of resident smooth muscle

Reactive Oxygen and Nitrogen Species in the Development of Pulmonary Hypertension

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David J.R. Fulton

2017-07-01

Full Text Available Pulmonary arterial hypertension (PAH is a progressive disease of the lung vasculature that involves the loss of endothelial function together with inappropriate smooth muscle cell growth, inflammation, and fibrosis. These changes underlie a progressive remodeling of blood vessels that alters flow and increases pulmonary blood pressure. Elevated pressures in the pulmonary artery imparts a chronic stress on the right ventricle which undergoes compensatory hypertrophy but eventually fails. How PAH develops remains incompletely understood and evidence for the altered production of reactive oxygen and nitrogen species (ROS, RNS respectively in the pulmonary circulation has been well documented. There are many different types of ROS and RNS, multiple sources, and collective actions and interactions. This review summarizes past and current knowledge of the sources of ROS and RNS and how they may contribute to the loss of endothelial function and changes in smooth muscle proliferation in the pulmonary circulation.

Experimental model of human corpus cavernosum smooth muscle relaxation

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Rommel P. Regadas

2010-08-01

Full Text Available PURPOSE: To describe a technique for en bloc harvesting of the corpus cavernosum, cavernous artery and urethra from transplant organ donors and contraction-relaxation experiments with corpus cavernosum smooth muscle. MATERIALS AND METHODS: The corpus cavernosum was dissected to the point of attachment with the crus penis. A 3 cm segment (corpus cavernosum and urethra was isolated and placed in ice-cold sterile transportation buffer. Under magnification, the cavernous artery was dissected. Thus, 2 cm fragments of cavernous artery and corpus cavernosum were obtained. Strips measuring 3 x 3 x 8 mm3 were then mounted vertically in an isolated organ bath device. Contractions were measured isometrically with a Narco-Biosystems force displacement transducer (model F-60, Narco-Biosystems, Houston, TX, USA and recorded on a 4-channel Narco-Biosystems desk model polygraph. RESULTS: Phenylephrine (1µM was used to induce tonic contractions in the corpus cavernosum (3 - 5 g tension and cavernous artery (0.5 - 1g tension until reaching a plateau. After precontraction, smooth muscle relaxants were used to produce relaxation-response curves (10-12M to 10-4 M. Sodium nitroprusside was used as a relaxation control. CONCLUSION: The harvesting technique and the smooth muscle contraction-relaxation model described in this study were shown to be useful instruments in the search for new drugs for the treatment of human erectile dysfunction.

Neurophysiology and Neuroanatomy of Smooth Pursuit in Humans

Science.gov (United States)

Lencer, Rebekka; Trillenberg, Peter

2008-01-01

Smooth pursuit eye movements enable us to focus our eyes on moving objects by utilizing well-established mechanisms of visual motion processing, sensorimotor transformation and cognition. Novel smooth pursuit tasks and quantitative measurement techniques can help unravel the different smooth pursuit components and complex neural systems involved…

A method for smoothing segmented lung boundary in chest CT images

Science.gov (United States)

Yim, Yeny; Hong, Helen

2007-03-01

To segment low density lung regions in chest CT images, most of methods use the difference in gray-level value of pixels. However, radiodense pulmonary vessels and pleural nodules that contact with the surrounding anatomy are often excluded from the segmentation result. To smooth lung boundary segmented by gray-level processing in chest CT images, we propose a new method using scan line search. Our method consists of three main steps. First, lung boundary is extracted by our automatic segmentation method. Second, segmented lung contour is smoothed in each axial CT slice. We propose a scan line search to track the points on lung contour and find rapidly changing curvature efficiently. Finally, to provide consistent appearance between lung contours in adjacent axial slices, 2D closing in coronal plane is applied within pre-defined subvolume. Our method has been applied for performance evaluation with the aspects of visual inspection, accuracy and processing time. The results of our method show that the smoothness of lung contour was considerably increased by compensating for pulmonary vessels and pleural nodules.

Biliverdin reductase/bilirubin mediates the anti-apoptotic effect of hypoxia in pulmonary arterial smooth muscle cells through ERK1/2 pathway

International Nuclear Information System (INIS)

Song, Shasha; Wang, Shuang; Ma, Jun; Yao, Lan; Xing, Hao; Zhang, Lei; Liao, Lin; Zhu, Daling

2013-01-01

Inhibition of pulmonary arterial smooth muscle cell (PASMC) apoptosis induced by hypoxia plays an important role in pulmonary arterial remodeling leading to aggravate hypoxic pulmonary arterial hypertension. However, the mechanisms of hypoxia acting on PASMC apoptosis remain exclusive. Biliverdin reductase (BVR) has many essential biologic roles in physiological and pathological processes. Nevertheless, it is unclear whether the hypoxia-induced inhibition on PASMC apoptosis is mediated by BVR. In the present work, we found BVR majorly localized in PASMCs and was up-regulated in levels of protein and mRNA by hypoxia. Then we studied the contribution of BVR to anti-apoptotic response of hypoxia in PASMCs. Our results showed that siBVR, blocking generation of bilirubin, reversed the effect of hypoxia on enhancing cell survival and apoptotic protein (Bcl-2, procasepase-9, procasepase-3) expression, preventing nuclear shrinkage, DNA fragmentation and mitochondrial depolarization in starved PASMCs, which were recovered by exogenous bilirubin. Moreover, the inhibitory effect of bilirubin on PASMC apoptosis under hypoxic condition was blocked by the inhibitor of ERK1/2 pathway. Taken together, our data indicate that BVR contributes to the inhibitory process of hypoxia on PASMC apoptosis, which is mediated by bilirubin through ERK1/2 pathway. Highlights: • BVR expresses in PASMC and is up-regulated by hypoxia in protein and mRNA levels. • BVR/bilirubin contribute to the inhibitive process of hypoxia on PASMC apoptosis. • Bilirubin protects PASMC from apoptosis under hypoxia via ERK1/2 pathway

Biliverdin reductase/bilirubin mediates the anti-apoptotic effect of hypoxia in pulmonary arterial smooth muscle cells through ERK1/2 pathway

Energy Technology Data Exchange (ETDEWEB)

Song, Shasha [Department of Biopharmaceutical Sciences, College of Pharmacy, Harbin Medical, University (Daqing), Daqing 163319 (China); Wang, Shuang [Department of Biopharmaceutical Sciences, College of Pharmacy, Harbin Medical, University (Daqing), Daqing 163319 (China); Biopharmaceutical Key Laboratory of Heilongjiang Province, Harbin 150081 (China); Ma, Jun; Yao, Lan; Xing, Hao; Zhang, Lei; Liao, Lin [Department of Biopharmaceutical Sciences, College of Pharmacy, Harbin Medical, University (Daqing), Daqing 163319 (China); Zhu, Daling, E-mail: dalingz@yahoo.com [Department of Biopharmaceutical Sciences, College of Pharmacy, Harbin Medical, University (Daqing), Daqing 163319 (China); Biopharmaceutical Key Laboratory of Heilongjiang Province, Harbin 150081 (China)

2013-08-01

Inhibition of pulmonary arterial smooth muscle cell (PASMC) apoptosis induced by hypoxia plays an important role in pulmonary arterial remodeling leading to aggravate hypoxic pulmonary arterial hypertension. However, the mechanisms of hypoxia acting on PASMC apoptosis remain exclusive. Biliverdin reductase (BVR) has many essential biologic roles in physiological and pathological processes. Nevertheless, it is unclear whether the hypoxia-induced inhibition on PASMC apoptosis is mediated by BVR. In the present work, we found BVR majorly localized in PASMCs and was up-regulated in levels of protein and mRNA by hypoxia. Then we studied the contribution of BVR to anti-apoptotic response of hypoxia in PASMCs. Our results showed that siBVR, blocking generation of bilirubin, reversed the effect of hypoxia on enhancing cell survival and apoptotic protein (Bcl-2, procasepase-9, procasepase-3) expression, preventing nuclear shrinkage, DNA fragmentation and mitochondrial depolarization in starved PASMCs, which were recovered by exogenous bilirubin. Moreover, the inhibitory effect of bilirubin on PASMC apoptosis under hypoxic condition was blocked by the inhibitor of ERK1/2 pathway. Taken together, our data indicate that BVR contributes to the inhibitory process of hypoxia on PASMC apoptosis, which is mediated by bilirubin through ERK1/2 pathway. Highlights: • BVR expresses in PASMC and is up-regulated by hypoxia in protein and mRNA levels. • BVR/bilirubin contribute to the inhibitive process of hypoxia on PASMC apoptosis. • Bilirubin protects PASMC from apoptosis under hypoxia via ERK1/2 pathway.

Spatial differences of cellular origins and in vivo hypoxia modify contractile properties of pulmonary artery smooth muscle cells: lessons for arterial tissue engineering.

Science.gov (United States)

Hall, S M; Soueid, A; Smith, T; Brown, R A; Haworth, S G; Mudera, V

2007-01-01

Tissue engineering of functional arteries is challenging. Within the pulmonary artery wall, smooth muscle cells (PASMCs) have site-specific developmental and functional phenotypes, reflecting differing contractile roles. The force generated by PASMCs isolated from the inner 25% and outer 50% of the media of intrapulmonary elastic arteries from five normal and eight chronically hypoxic (hypertensive) 14 day-old piglets was quantified in a three-dimensional (3D) collagen construct, using a culture force monitor. Outer medial PASMCs from normal piglets exerted more force (528 +/- 50 dynes) than those of hypoxic piglets (177 +/- 42 dynes; p engineering of major blood vessels.

Single photon emission computed tomography study of human pulmonary perfusion: preliminary findings

Energy Technology Data Exchange (ETDEWEB)

Carratu, L; Sofia, M [Naples Univ. (Italy). Facolta di Medicina e Chirurgia; Salvatore, M; Muto, P; Ariemma, G [Istituto Nazionale per la Prevenzione, Lo Studio e La Cura dei Tumori Fondazione Pascale, Naples (Italy); Lopez-Majano, V [Cook County Hospital, Chicago, IL (USA). Nuclear Medicine Div.

1984-02-01

Single photon emission computed tomography (SPECT) was performed with /sup 99/Tcsup(m)-albumin macroaggregates to study human pulmonary perfusion in healthy subjects and patients with respiratory diseases such as chronic obstructive pulmonary disease (COPD) and lung neoplasms. The reconstructed SPECT data was displayed in coronal, transverse, sagittal plane sections and compared to conventional perfusion scans. The SPECT data gave more complicated anatomical information about the extent of damage and morphology of the pulmonary vascular bed. In healthy subjects and COPD patients, qualitative and quantitative assessment of pulmonary perfusion could be obtained from serial SPECT scans with respect to distribution and relative concentration of the injected radiopharmaceutical. Furthermore, SPECT of pulmonary perfusion has been useful in detecting the extent of damage to the pulmonary circulation. This is useful for the preoperative evaluation and staging of lung cancer.

Angiogenesis is induced by airway smooth muscle strain.

Science.gov (United States)

Hasaneen, Nadia A; Zucker, Stanley; Lin, Richard Z; Vaday, Gayle G; Panettieri, Reynold A; Foda, Hussein D

2007-10-01

Angiogenesis is an important feature of airway remodeling in both chronic asthma and chronic obstructive pulmonary disease (COPD). Airways in those conditions are exposed to excessive mechanical strain during periods of acute exacerbations. We recently reported that mechanical strain of human airway smooth muscle (HASM) led to an increase in their proliferation and migration. Sustained growth in airway smooth muscle in vivo requires an increase in the nutritional supply to these muscles, hence angiogenesis. In this study, we examined the hypothesis that cyclic mechanical strain of HASM produces factors promoting angiogenic events in the surrounding vascular endothelial cells. Our results show: 1) a significant increase in human lung microvascular endothelial cell (HMVEC-L) proliferation, migration, and tube formation following incubation in conditioned media (CM) from HASM cells exposed to mechanical strain; 2) mechanical strain of HASM cells induced VEGF expression and release; 3) VEGF neutralizing antibodies inhibited the proliferation, migration, and tube formations of HMVEC-L induced by the strained airway smooth muscle CM; 4) mechanical strain of HASM induced a significant increase in hypoxia-inducible factor-1alpha (HIF-1alpha) mRNA and protein, a transcription factor required for VEGF gene transcription; and 5) mechanical strain of HASM induced HIF-1alpha/VEGF through dual phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) and ERK pathways. In conclusion, exposing HASM cells to mechanical strain induces signal transduction pathway through PI3K/Akt/mTOR and ERK pathways that lead to an increase in HIF-1alpha, a transcription factor required for VEGF expression. VEGF release by mechanical strain of HASM may contribute to the angiogenesis seen with repeated exacerbation of asthma and COPD.

The flavonoid quercetin reverses pulmonary hypertension in rats.

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Daniel Morales-Cano

Full Text Available Quercetin is a dietary flavonoid which exerts vasodilator, antiplatelet and antiproliferative effects and reduces blood pressure, oxidative status and end-organ damage in humans and animal models of systemic hypertension. We hypothesized that oral quercetin treatment might be protective in a rat model of pulmonary arterial hypertension. Three weeks after injection of monocrotaline, quercetin (10 mg/kg/d per os or vehicle was administered for 10 days to adult Wistar rats. Quercetin significantly reduced mortality. In surviving animals, quercetin decreased pulmonary arterial pressure, right ventricular hypertrophy and muscularization of small pulmonary arteries. Classic biomarkers of pulmonary arterial hypertension such as the downregulated expression of lung BMPR2, Kv1.5, Kv2.1, upregulated survivin, endothelial dysfunction and hyperresponsiveness to 5-HT were unaffected by quercetin. Quercetin significantly restored the decrease in Kv currents, the upregulation of 5-HT2A receptors and reduced the Akt and S6 phosphorylation. In vitro, quercetin induced pulmonary artery vasodilator effects, inhibited pulmonary artery smooth muscle cell proliferation and induced apoptosis. In conclusion, quercetin is partially protective in this rat model of PAH. It delayed mortality by lowering PAP, RVH and vascular remodeling. Quercetin exerted effective vasodilator effects in isolated PA, inhibited cell proliferation and induced apoptosis in PASMCs. These effects were associated with decreased 5-HT2A receptor expression and Akt and S6 phosphorylation and partially restored Kv currents. Therefore, quercetin could be useful in the treatment of PAH.

Effect of prepro-calcitonin gene-related peptide-expressing endothelial progenitor cells on pulmonary hypertension.

Science.gov (United States)

Zhao, Qiang; Liu, Zixiong; Wang, Zhe; Yang, Cheng; Liu, Jun; Lu, Jun

2007-08-01

Calcitonin gene-related peptide (CGRP) is a potent smooth muscle cell proliferation inhibitor and vasodilator. It is now believed that CGRP plays an important role in maintaining a low pulmonary vascular resistance. We evaluated the therapeutic effect of intravenously administered CGRP-expressing endothelial progenitor cells (EPCs) on left-to-right shunt-induced pulmonary hypertension in rats. Endothelial progenitor cells were obtained from cultured human peripheral blood mononuclear cells. The genetic sequence for CGRP was subcloned into cultured EPCs by human expression plasmid. Pulmonary hypertension was established in immunodeficient rats with an abdominal aorta to inferior vena cava shunt operation. The transfected EPCs were injected through the left jugular vein at 10 weeks after the shunt operation. Mean pulmonary artery pressure and total pulmonary vascular resistance were detected with right cardiac catheterization at 4 weeks. The distribution of EPCs in the lung tissue was examined with immunofluorescence technique. Histopathologic changes in the structure of the pulmonary arteries was observed with electron microscopy and subjected to computerized image analysis. The lungs of rats transplanted with CGRP-expressing EPCs demonstrated a decrease in both mean pulmonary artery pressure (17.64 +/- 0.79 versus 22.08 +/- 0.95 mm Hg; p = 0.018) and total pulmonary vascular resistance (1.26 +/- 0.07 versus 2.45 +/- 0.18 mm Hg x min/mL; p = 0.037) at 4 weeks. Immunofluorescence revealed that intravenously administered cells were incorporated into the pulmonary vasculature. Pulmonary vascular remodeling was remarkably attenuated with the administration of CGRP-expressing EPCs. The transplantation of CGRP-expressing EPCs may effectively attenuate established pulmonary hypertension and exert reversal effects on pulmonary vascular remodeling. Our findings suggest that the therapy based on the combination of both CGRP transfection and EPCs may be a potentially useful

SOD2 Activity Is not Impacted by Hyperoxia in Murine Neonatal Pulmonary Artery Smooth Muscle Cells and Mice

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Anita Gupta

2015-03-01

Full Text Available Pulmonary hypertension (PH complicates bronchopulmonary dysplasia (BPD in 25% of infants. Superoxide dismutase 2 (SOD2 is an endogenous mitochondrial antioxidant, and overexpression protects against acute lung injury in adult mice. Little is known about SOD2 in neonatal lung disease and PH. C57Bl/6 mice and isogenic SOD2+/+ and SOD2−/+ mice were placed in room air (control or 75% O2 (chronic hyperoxia, CH for 14 days. Right ventricular hypertrophy (RVH was assessed by Fulton’s index. Medial wall thickness (MWT and alveolar area were assessed on formalin fixed lung sections. Pulmonary artery smooth muscle cells (PASMC were placed in 21% or 95% O2 for 24 h. Lung and PASMC protein were analyzed for SOD2 expression and activity. Oxidative stress was measured with a mitochondrially-targeted sensor, mitoRoGFP. CH lungs have increased SOD2 expression, but unchanged activity. SOD2−/+ PASMC have decreased expression and activity at baseline, but increased SOD2 expression in hyperoxia. Hyperoxia increased mitochondrial ROS in SOD2+/+ and SOD2−/+ PASMC. SOD2+/+ and SOD2−/+ CH pups induced SOD2 expression, but not activity, and developed equivalent increases in RVH, MWT, and alveolar area. Since SOD2−/+ mice develop equivalent disease, this suggests other antioxidant systems may compensate for partial SOD2 expression and activity in the neonatal period during hyperoxia-induced oxidative stress.

Effects and mechanism of oridonin on pulmonary hypertension induced by chronic hypoxia-hypercapnia in rats.

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Wang, Liang-Xing; Sun, Yu; Chen, Chan; Huang, Xiao-Ying; Lin, Quan; Qian, Guo-Qing; Dong, Wei; Chen, Yan-Fan

2009-06-20

Pulmonary arterial hypertension (PAH) is characterized by suppressing apoptosis and enhancing cell proliferation in the vascular wall. Inducing pulmonary artery smooth muscle cells (PASMC) apoptosis had been regarded as a therapeutic approach for PAH. Oridonin can cause apoptosis in many cell lines, while little has been done to evaluate its effect on PASMC. Thirty male Sprague-Dawley rats were randomly assigned to three groups: normal control (NC); hypoxia-hypercapnia (HH); Hypoxia-hypercapnia + oridonin (HHO). Rats were exposed to hypoxia-hypercapnia for four weeks. Cultured human PASMC (HPASMC) were assigned to three groups: normoxia (NO); hypoxia (HY); hypoxia + oridonin (HO). The mean pulmonary artery pressure, mass ratio of right ventricle over left ventricle plus septum (RV/(LV + S)), the ratio of thickness of the pulmonary arteriole wall to vascular external diameter (WT%) and the ratio of the vessel wall area to the total area (WA%) were measured. Morphologic changes of pulmonary arteries were observed under light and electron microscopes. The apoptotic characteristics in vitro and in vivo were detected. The mPAP, RV/(LV + S), WT%, and WA% in the HH group were significantly greater than those in the NC (P HHO groups (P HHO groups; and the expression of Bcl-2 in group HH was greater than that in the NC and HHO groups. HPASMC mitochondrial membrane potentials in group HO was lower than in group HY (P < 0.01), and cyt-C in the cytoplasm, AI, and caspase-9 in the HO group were greater than that in the HY group (P < 0.01), but the expression of Bcl-2 in the HO group was less than that in the HY group (P < 0.05). The results suggest that oridonin can lower pulmonary artery pressure effectively, and inhibit pulmonary artery structural remodeling by inducing smooth cell apoptosis via a mitochondria-dependent pathway.

Tomographic findings of acute pulmonary toxoplasmosis in immunocompetent patients.

Science.gov (United States)

de Souza Giassi, Karina; Costa, Andre Nathan; Apanavicius, Andre; Teixeira, Fernando Bin; Fernandes, Caio Julio Cesar; Helito, Alfredo Salim; Kairalla, Ronaldo Adib

2014-11-25

Toxoplasmosis is one of the most common human zoonosis, and is generally benign in most of the individuals. Pulmonary involvement is common in immunocompromised subjects, but very rare in immunocompetents and there are scarce reports of tomographic findings in the literature. The aim of the study is to describe three immunocompetent patients diagnosed with acute pulmonary toxoplasmosis and their respective thoracic tomographic findings. Acute toxoplasmosis was diagnosed according to the results of serological tests suggestive of recent primary infection and the absence of an alternative etiology. From 2009 to 2013, three patients were diagnosed with acute respiratory failure secondary to acute toxoplasmosis. The patients were two female and one male, and were 38, 56 and 36 years old. Similarly they presented a two-week febrile illness and progressive dyspnea before admission. Laboratory tests demonstrated lymphocytosis, slight changes in liver enzymes and high inflammatory markers. Tomographic findings were bilateral smooth septal and peribronchovascular thickening (100%), ground-glass opacities (100%), atelectasis (33%), random nodules (33%), lymph node enlargement (33%) and pleural effusion (66%). All the patients improved their symptoms after treatment, and complete resolution of tomographic findings were found in the followup. These cases provide a unique description of the presentation and evolution of pulmonary tomographic manifestations of toxoplasmosis in immunocompetent patients. Toxoplasma pneumonia manifests with fever, dyspnea and a non-productive cough that may result in respiratory failure. In animal models, changes were described as interstitial pneumonitis with focal infiltrates of neutrophils that can finally evolve into a pattern of diffuse alveolar damage with focal necrosis. The tomographic findings are characterized as ground glass opacities, smooth septal and marked peribronchovascular thickening; and may mimic pulmonary congestion

Rapid effects of phytoestrogens on human colonic smooth muscle are mediated by oestrogen receptor beta.

LENUS (Irish Health Repository)

Hogan, A M

2012-02-01

Epidemiological studies have correlated consumption of dietary phytoestrogens with beneficial effects on colon, breast and prostate cancers. Genomic and non-genomic mechanisms are responsible for anti-carcinogenic effects but, until now, the effect on human colon was assumed to be passive and remote. No direct effect on human colonic smooth muscle has previously been described. Institutional research board approval was granted. Histologically normal colon was obtained from the proximal resection margin of colorectal carcinoma specimens. Circular smooth muscle strips were microdissected and suspended under 1g of tension in organ baths containing oxygenated Krebs solution at 37 degrees C. After an equilibration period, tissues were exposed to diarylpropionitrile (DPN) (ER beta agonist) and 1,3,5-tris(4-hydroxyphenyl)-4-propyl-1H-pyrazole (PPT) (ER alpha agonist) or to the synthetic phytoestrogen compounds genistein (n=8), daidzein (n=8), fisetin (n=8) and quercetin (n=8) in the presence or absence of fulvestrant (oestrogen receptor antagonist). Mechanism of action was investigated by inhibition of downstream pathways. The cholinergic agonist carbachol was used to induce contractile activity. Tension was recorded isometrically. Phytoestrogens inhibit carbachol-induced colonic contractility. In keeping with a non-genomic, rapid onset direct action, the effect was within minutes, reversible and similar to previously described actions of 17 beta oestradiol. No effect was seen in the presence of fulvestrant indicating receptor modulation. While the DPN exerted inhibitory effects, PPT did not. The effect appears to be reliant on a p38\\/mitogen activated protein kinase mediated induction of nitric oxide production in colonic smooth muscle. The present data set provides the first description of a direct effect of genistein, daidzein, fisetin and quercetin on human colonic smooth muscle. The presence of ER in colonic smooth muscle has been functionally proven and the beta

Radiological case. Pulmonary Lymphangioleiomyomatosis

International Nuclear Information System (INIS)

Rivera Bernal, Aura Lucia; Carrillo Bayona, Jorge Alberto; Ojeda Leon, Paulina

2004-01-01

Lymphangioleiomyomatosis is a rare disorder, which affects principally the pulmonary parenchyma of young women at a reproductive age, and is pathologically characterized by the interstitial proliferation of smooth muscle and formation of cysts in the lung. We present the case of a 35-year-old woman that has a lymphangioleiomyomatosis diagnosis

Upregulated copper transporters in hypoxia-induced pulmonary hypertension.

Directory of Open Access Journals (Sweden)

Adriana M Zimnicka

Full Text Available Pulmonary vascular remodeling and increased arterial wall stiffness are two major causes for the elevated pulmonary vascular resistance and pulmonary arterial pressure in patients and animals with pulmonary hypertension. Cellular copper (Cu plays an important role in angiogenesis and extracellular matrix remodeling; increased Cu in vascular smooth muscle cells has been demonstrated to be associated with atherosclerosis and hypertension in animal experiments. In this study, we show that the Cu-uptake transporter 1, CTR1, and the Cu-efflux pump, ATP7A, were both upregulated in the lung tissues and pulmonary arteries of mice with hypoxia-induced pulmonary hypertension. Hypoxia also significantly increased expression and activity of lysyl oxidase (LOX, a Cu-dependent enzyme that causes crosslinks of collagen and elastin in the extracellular matrix. In vitro experiments show that exposure to hypoxia or treatment with cobalt (CoCl2 also increased protein expression of CTR1, ATP7A, and LOX in pulmonary arterial smooth muscle cells (PASMC. In PASMC exposed to hypoxia or treated with CoCl2, we also confirmed that the Cu transport is increased using 64Cu uptake assays. Furthermore, hypoxia increased both cell migration and proliferation in a Cu-dependent manner. Downregulation of hypoxia-inducible factor 1α (HIF-1α with siRNA significantly attenuated hypoxia-mediated upregulation of CTR1 mRNA. In summary, the data from this study indicate that increased Cu transportation due to upregulated CTR1 and ATP7A in pulmonary arteries and PASMC contributes to the development of hypoxia-induced pulmonary hypertension. The increased Cu uptake and elevated ATP7A also facilitate the increase in LOX activity and thus the increase in crosslink of extracellular matrix, and eventually leading to the increase in pulmonary arterial stiffness.

Human lung mast cells modulate the functions of airway smooth muscle cells in asthma.

Science.gov (United States)

Alkhouri, H; Hollins, F; Moir, L M; Brightling, C E; Armour, C L; Hughes, J M

2011-09-01

Activated mast cell densities are increased on the airway smooth muscle in asthma where they may modulate muscle functions and thus contribute to airway inflammation, remodelling and airflow obstruction. To determine the effects of human lung mast cells on the secretory and proliferative functions of airway smooth muscle cells from donors with and without asthma. Freshly isolated human lung mast cells were stimulated with IgE/anti-IgE. Culture supernatants were collected after 2 and 24 h and the mast cells lysed. The supernatants/lysates were added to serum-deprived, subconfluent airway smooth muscle cells for up to 48 h. Released chemokines and extracellular matrix were measured by ELISA, proliferation was quantified by [(3) H]-thymidine incorporation and cell counting, and intracellular signalling by phospho-arrays. Mast cell 2-h supernatants reduced CCL11 and increased CXCL8 and fibronectin production from both asthmatic and nonasthmatic muscle cells. Leupeptin reversed these effects. Mast cell 24-h supernatants and lysates reduced CCL11 release from both muscle cell types but increased CXCL8 release by nonasthmatic cells. The 24-h supernatants also reduced asthmatic, but not nonasthmatic, muscle cell DNA synthesis and asthmatic cell numbers over 5 days through inhibiting extracellular signal-regulated kinase (ERK) and phosphatidylinositol (PI3)-kinase pathways. However, prostaglandins, thromboxanes, IL-4 and IL-13 were not involved in reducing the proliferation. Mast cell proteases and newly synthesized products differentially modulated the secretory and proliferative functions of airway smooth muscle cells from donors with and without asthma. Thus, mast cells may modulate their own recruitment and airway smooth muscle functions locally in asthma. © 2011 John Wiley & Sons A/S.

A new model of progressive pulmonary fibrosis in rats

Energy Technology Data Exchange (ETDEWEB)

Last, J.A.; Gelzleichter, T.R.; Pinkerton, K.E.; Walker, R.M.; Witschi, H. (Univ. of California, Davis (United States))

1993-08-01

Sprague-Dawley rats were exposed for 6 h daily to 0.8 ppm of ozone and 14.4 ppm of nitrogen dioxide. Approximately 7 to 10 wk after the initiation of exposure, animals began to demonstrate respiratory insufficiency and severe weight loss. About half of the rats died between Days 55 and 78 of exposure; no overt ill effects were observed in animals exposed to filtered air, to ozone alone, or to nitrogen dioxide. Biochemical findings in animals exposed to ozone and nitrogen dioxide included increased lung content of DNA, protein, collagen, and elastin, which was about 300% higher than the control values. The collagen-specific crosslink hydroxy-pyridinium, a biomarker for mature collagen in the lung, was decreased by about 40%. These results are consistent with extensive breakdown and remodeling of the lung parenchyma and its associated vasculature. Histopathologic evaluation showed severe fibrosis, alveolar collapse, honeycombing, macrophage and mast cell accumulation, vascular smooth muscle hypertrophy, and other indications of severe progressive interstitial pulmonary fibrosis and end-stage lung disease. This unique animal model of progressive pulmonary fibrosis resembles the final stages of human idiopathic pulmonary fibrosis and should facilitate studying underlying mechanisms and potential therapy of progressive pulmonary fibrosis.

miR-140-5p regulates hypoxia-mediated human pulmonary artery smooth muscle cell proliferation, apoptosis and differentiation by targeting Dnmt1 and promoting SOD2 expression

Energy Technology Data Exchange (ETDEWEB)

Zhang, Yanwei; Xu, Jing, E-mail: xujingdoc@163.com

2016-04-22

miR-140-5p is down-regulated in patients with pulmonary arterial hypertension (PAH) and experimental models of PAH, and inhibits hypoxia-mediated pulmonary artery smooth muscle cell (PASMC) proliferation in vitro. Delivery of synthetic miR-140-5p prevents and treats established, experimental PAH. DNA methyltransferase 1 (Dnmt1) is up-regulated in PAH associated human PASMCs (HPASMCs), which promotes the development of PAH by hypermethylation of CpG islands within the promoter for superoxide dismutase 2 (SOD2) and down-regulating SOD2 expression. We searched for miR-140-5p targets using TargetScan, PicTar and MiRanda tools, and found that Dnmt1 is a potential target of miR-140-5p. Based on these findings, we speculated that miR-140-5p might target Dnmt1 and regulate SOD2 expression to regulate hypoxia-mediated HPASMC proliferation, apoptosis and differentiation. We detected the expression of miR-140-5p, Dnmt1 and SOD2 by quantitative real-time polymerase chain reaction (qRT-PCR) and western blot assays, respectively, and found down-regulation of miR-140-5p and SOD2 and up-regulation of Dnmt1 exist in PAH tissues and hypoxia-mediated HPASMCs. Cell proliferation, apoptosis and differentiation detection showed that miR-140-5p inhibits proliferation and promotes apoptosis and differentiation of HPASMCs in hypoxia, while the effect of Dnmt1 on hypoxia-mediated HPASMCs is reversed. Luciferase assay confirmed that miR-140-5p targets Dnmt1 directly. An inverse correlation is also found between miR-140-5p and Dnmt1 in HPASMCs. In addition, we further investigated whether miR-140-5p and Dnmt1 regulate HPASMC proliferation, apoptosis and differentiation by regulating SOD2 expression, and the results confirmed our speculation. Taken together, these results indicated that miR-140-5p at least partly targets Dnmt1 and regulates SOD2 expression to inhibit proliferation and promote apoptosis and differentiation of HPASMCs in hypoxia. - Highlights: • miR-140-5p and SOD2 are down

Beneficial Effects of Renal Denervation on Pulmonary Vascular Remodeling in Experimental Pulmonary Artery Hypertension.

Science.gov (United States)

Qingyan, Zhao; Xuejun, Jiang; Yanhong, Tang; Zixuan, Dai; Xiaozhan, Wang; Xule, Wang; Zongwen, Guo; Wei, Hu; Shengbo, Yu; Congxin, Huang

2015-07-01

Activation of both the sympathetic nervous system and the renin-angiotensin-aldosterone system is closely associated with pulmonary arterial hypertension. We hypothesized that renal denervation decreases renin-angiotensin-aldosterone activity and inhibits the progression of pulmonary arterial hypertension. Twenty-two beagles were randomized into 3 groups. The dogs' pulmonary dynamics were measured before and 8 weeks after injection of 0.1mL/kg dimethylformamide (control dogs) or 2mg/kg dehydromonocrotaline (pulmonary arterial hypertension and pulmonary arterial hypertension + renal denervation dogs). Eight weeks after injection, neurohormone levels and pulmonary tissue morphology were measured. Levels of plasma angiotensin II and endothelin-1 were significantly increased after 8 weeks in the pulmonary arterial hypertension dogs and were higher in the lung tissues of these dogs than in those of the control and renal denervation dogs (mean [standard deviation] angiotensin II: 65 [9.8] vs 38 [6.7], 46 [8.1]; endothelin-1: 96 [10.3] vs 54 [6.2], 67 [9.4]; P < .01). Dehydromonocrotaline increased the mean pulmonary arterial pressure (16 [3.4] mmHg vs 33 [7.3] mmHg; P < .01), and renal denervation prevented this increase. Pulmonary smooth muscle cell proliferation was higher in the pulmonary arterial hypertension dogs than in the control and pulmonary arterial hypertension + renal denervation dogs. Renal denervation attenuates pulmonary vascular remodeling and decreases pulmonary arterial pressure in experimental pulmonary arterial hypertension. The effect of renal denervation may contribute to decreased neurohormone levels. Copyright © 2014 Sociedad Española de Cardiología. Published by Elsevier España, S.L.U. All rights reserved.

Expression of WNT5A in Idiopathic Pulmonary Fibrosis and Its Control by TGF-β and WNT7B in Human Lung Fibroblasts.

Science.gov (United States)

Newman, Donna R; Sills, W Shane; Hanrahan, Katherine; Ziegler, Amanda; Tidd, Kathleen McGinnis; Cook, Elizabeth; Sannes, Philip L

2016-02-01

The wingless (Wnt) family of signaling ligands contributes significantly to lung development and is highly expressed in patients with usual interstitial pneumonia (UIP). We sought to define the cellular distribution of Wnt5A in the lung tissue of patients with idiopathic pulmonary fibrosis (IPF) and the signaling ligands that control its expression in human lung fibroblasts and IPF myofibroblasts. Tissue sections from 40 patients diagnosed with IPF or UIP were probed for the immunolocalization of Wnt5A. Further, isolated lung fibroblasts from normal or IPF human lungs, adenovirally transduced for the overexpression or silencing of Wnt7B or treated with TGF-β1 or its inhibitor, were analyzed for Wnt5A protein expression. Wnt5A was expressed in IPF lungs by airway and alveolar epithelium, smooth muscle cells, endothelium, and myofibroblasts of fibroblastic foci and throughout the interstitium. Forced overexpression of Wnt7B with or without TGF-β1 treatment significantly increased Wnt5A protein expression in normal human smooth muscle cells and fibroblasts but not in IPF myofibroblasts where Wnt5A was already highly expressed. The results demonstrate a wide distribution of Wnt5A expression in cells of the IPF lung and reveal that it is significantly increased by Wnt7B and TGF-β1, which, in combination, could represent key signaling pathways that modulate the pathogenesis of IPF. © 2016 The Histochemical Society.

Regulation of GPCR-mediated smooth muscle contraction : implications for asthma and pulmonary hypertension

NARCIS (Netherlands)

Wright, D B; Tripathi, S; Sikarwar, A; Santosh, K T; Perez-Zoghbi, J; Ojo, O O; Irechukwu, N; Ward, J P T; Schaafsma, D

Contractile G-protein-coupled receptors (GPCRs) have emerged as key regulators of smooth muscle contraction, both under healthy and diseased conditions. This brief review will discuss some key topics and novel insights regarding GPCR-mediated airway and vascular smooth muscle contraction as

Bioenergetic profile of human coronary artery smooth muscle cells and effect of metabolic intervention.

Directory of Open Access Journals (Sweden)

Mingming Yang

Full Text Available Bioenergetics of artery smooth muscle cells is critical in cardiovascular health and disease. An acute rise in metabolic demand causes vasodilation in systemic circulation while a chronic shift in bioenergetic profile may lead to vascular diseases. A decrease in intracellular ATP level may trigger physiological responses while dedifferentiation of contractile smooth muscle cells to a proliferative and migratory phenotype is often observed during pathological processes. Although it is now possible to dissect multiple building blocks of bioenergetic components quantitatively, detailed cellular bioenergetics of artery smooth muscle cells is still largely unknown. Thus, we profiled cellular bioenergetics of human coronary artery smooth muscle cells and effects of metabolic intervention. Mitochondria and glycolysis stress tests utilizing Seahorse technology revealed that mitochondrial oxidative phosphorylation accounted for 54.5% of ATP production at rest with the remaining 45.5% due to glycolysis. Stress tests also showed that oxidative phosphorylation and glycolysis can increase to a maximum of 3.5 fold and 1.25 fold, respectively, indicating that the former has a high reserve capacity. Analysis of bioenergetic profile indicated that aging cells have lower resting oxidative phosphorylation and reduced reserve capacity. Intracellular ATP level of a single cell was estimated to be over 1.1 mM. Application of metabolic modulators caused significant changes in mitochondria membrane potential, intracellular ATP level and ATP:ADP ratio. The detailed breakdown of cellular bioenergetics showed that proliferating human coronary artery smooth muscle cells rely more or less equally on oxidative phosphorylation and glycolysis at rest. These cells have high respiratory reserve capacity and low glycolysis reserve capacity. Metabolic intervention influences both intracellular ATP concentration and ATP:ADP ratio, where subtler changes may be detected by the latter.

Human eosinophil–airway smooth muscle cell interactions

Directory of Open Access Journals (Sweden)

J. Margaret Hughes

2000-01-01

Full Text Available Eosinophils are present throughout the airway wall of asthmatics. The nature of the interaction between human airway smooth muscle cells (ASMC and eosinophils was investigated in this study. We demonstrated, using light microscopy, that freshly isolated eosinophils from healthy donors rapidly attach to ASMC in vitro. Numbers of attached eosinophils were highest at 2 h, falling to 50% of maximum by 20 h. Eosinophil attachment at 2 h was reduced to 72% of control by anti-VCAM-1, and to 74% at 20 h by anti-ICAM-1. Pre-treatment of ASMC for 24 h with TNF-α, 10 nM, significantly increased eosinophil adhesion to 149 and 157% of control after 2 and 20 h. These results provide evidence that eosinophil interactions with ASMC involve VCAM-1 and ICAM-1 and are modulated by TNF-α.

Melatonin suppresses acrolein-induced IL-8 production in human pulmonary fibroblasts.

Science.gov (United States)

Kim, Gun-Dong; Lee, Seung Eun; Kim, Tae-Ho; Jin, Young-Ho; Park, Yong Seek; Park, Cheung-Seog

2012-04-01

Cigarette smoke (CS) causes harmful alterations in the lungs and airway structures and functions that characterize chronic obstructive pulmonary disease (COPD). In addition to COPD, active cigarette smoking causes other respiratory diseases and diminishes health status. Furthermore, recent studies show that, α, β-unsaturated aldehyde acrolein in CS induces the production of interleukin (IL)-8, which is known to be related to bronchitis, rhinitis, pulmonary fibrosis, and asthma. In addition, lung and pulmonary fibroblasts secrete IL-8, which has a chemotactic effect on leukocytes, and which in turn, play a critical role in lung inflammation. On the other hand, melatonin regulates circadian rhythm homeostasis in humans and has many other effects, which include antioxidant and anti-inflammatory effects, as demonstrated by the reduced expressions of iNOS, IL-1β, and IL-6 and increased glutathione (GSH) and superoxide dismutase activities. In this study, we investigated whether melatonin suppresses acrolein-induced IL-8 secretion in human pulmonary fibroblasts (HPFs). It was found that acrolein-induced IL-8 production was accompanied by increased levels of phosphorylation of Akt and extracellular signal-regulated kinases (ERK1/2) in HPFs, and that melatonin suppressed IL-8 production in HPFs. These results suggest that melatonin suppresses acrolein-induced IL-8 production via ERK1/2 and phosphatidylinositol 3-kinase (PI3K)/Akt signal inhibition in HPFs. © 2011 John Wiley & Sons A/S.

Calcification of human vascular smooth muscle cells: associations with osteoprotegerin expression and acceleration by high-dose insulin

DEFF Research Database (Denmark)

Olesen, Ping; Knudsen, Kirsten Quyen Nguyen; Wogensen, Lise

2007-01-01

Arterial medial calcifications occur often in diabetic individuals as part of the diabetic macroangiopathy. The pathogenesis is unknown, but the presence of calcifications predicts risk of cardiovascular events. We examined the effects of insulin on calcifying smooth muscle cells in vitro...... and measured the expression of the bone-related molecule osteoprotegerin (OPG). Human vascular smooth muscle cells (VSMCs) were grown from aorta from kidney donors. Induction of calcification was performed with beta-glycerophosphate. The influence of insulin (200 microU/ml or 1,000 microU/ml) on calcification...... calcification in human smooth muscle cells from a series of donors after variable time in culture. Decreased OPG amounts were observed from the cells during the accelerated calcification phase. High dose of insulin (1,000 microU/ml) accelerated the calcification, whereas lower concentrations (200 microU/ml) did...

Human induced pluripotent stem cell-derived vascular smooth muscle cells

DEFF Research Database (Denmark)

Ayoubi, Sohrab; Sheikh, Søren P; Eskildsen, Tilde V

2017-01-01

. To this end, human induced pluripotent stem cells (hiPSCs) have generated great enthusiasm, and have been a driving force for development of novel strategies in drug discovery and regenerative cell-therapy for the last decade. Hence, investigating the mechanisms underlying the differentiation of hi......PSCs into specialized cell types such as cardiomyocytes, endothelial cells, and vascular smooth muscle cells (VSMCs) may lead to a better understanding of developmental cardiovascular processes and potentiate progress of safe autologous regenerative therapies in pathological conditions. In this review, we summarize...

Transforming growth factor. beta. sub 1 is present at sites of extracellular matrix gene expression in human pulmonary fibrosis

Energy Technology Data Exchange (ETDEWEB)

Broekelmann, T.J.; Limper, A.H.; McDonald, J.A. (Washington Univ., St. Louis, MO (United States)); Colby, T.V. (Mayo Clinic, Rochester, MN (United States))

1991-08-01

Idiopathic pulmonary fibrosis is an inexorably fatal disorder characterized by connective tissue deposition within the terminal air spaces resulting in loss of lung function and eventual respiratory failure. Previously, the authors demonstrated that foci of activated fibroblasts expressing high levels of fibronectin, procollagen, and smooth muscle actin and thus resembling those found in healing wounds are responsible for the connective tissue deposition and scarring in idiopathic pulmonary fibrosis. Using in situ hybridization and immunohistochemistry, they now demonstrate the presence of transforming growth factor {beta}{sub 1} (TGF-{beta}{sub 1}), a potent profibrotic cytokine, in the foci containing these activated fibroblasts. These results suggest that matrix-associated TGF-{beta}{sub 1} may serve as a stimulus for the persistent expression of connective tissue genes. One potential source of the TGF-{beta}{sub 1} is the alveolar macrophage, and they demonstrate the expression of abundant TGF-{beta}{sub 1} mRNA in alveolar macrophages in lung tissue from patients with idiopathic pulmonary fibrosis.

RhoA–Rho kinase and Platelet Activating Factor Stimulation of Ovine Fetal Pulmonary Vascular Smooth Muscle Cell Proliferation

Science.gov (United States)

Renteria, Lissette S.; Austin, Monique; Lazaro, Mariecon; Andrews, Mari Ashley; Lustina, Jennessee; Raj, J. Usha; Ibe, Basil O.

2013-01-01

Objectives Platelet Activating Factor (PAF) is produced by pulmonary vascular smooth muscle Cells (PVSMC). We studied effect of Rho kinase on PAF stimulation of PVSMC proliferation in an attempt to understand a role for RhoA/Rho kinase on PAF-induced ovine fetal pulmonary vascular remodeling. Our hypothesis is that PAF acts through Rho kinase, as one of its downstream signaling, to induce arterial (SMC-PA) and venous (SMC-PV) growth in the hypoxic lung environment of the fetus in utero. Materials and methods Rho kinase and MAPK effects on PAF receptor (PAFR)-mediated cell growth and PAFR expression were studied by DNA synthesis, Western and immunocytochemistry. Effects of constructs T19N and G14V on PAF-induced cell proliferation was also studied. Results Hypoxia increased PVSMC proliferation and the Rho kinase inhibitors, Y-27632 and Fasudil (HA-1077) as well as MAPK inhibitors PD 98059 and SB 203580 attenuated PAF stimulation of cell proliferation. RhoA T19N and G14V stimulated cell proliferation, but co-incubation with PAF did not affect proliferative effects of the constructs. PAFR protein expression was significantly down-regulated in both cell types by both Y-27632 and HA-1077 with comparable profiles. Also cells treated with Y-27632 showed less PAF receptor fluorescence with significant disruption of the cell morphology. Conclusions Our results show that Rho kinase nonspecifically modulates PAFR-mediated responses via a translational modification of PAFR protein and suggest that, in vivo, activation of Rho kinase by PAF may be one other pathway to sustain PAFR-mediated PVSMC growth. PMID:24033386

RhoA-Rho kinase and platelet-activating factor stimulation of ovine foetal pulmonary vascular smooth muscle cell proliferation.

Science.gov (United States)

Renteria, L S; Austin, M; Lazaro, M; Andrews, M A; Lustina, J; Raj, J U; Ibe, B O

2013-10-01

Platelet-activating factor (PAF) is produced by pulmonary vascular smooth muscle cells (PVSMC). We studied effects of Rho kinase on PAF stimulation of PVSMC proliferation in an attempt to understand the role of RhoA/Rho kinase on PAF-induced ovine foetal pulmonary vascular remodelling. Our hypothesis is that PAF acts through Rho kinase, as one of its downstream signals, to induce arterial (SMC-PA) and venous (SMC-PV) cell proliferation in the hypoxic lung environment of the foetus, in utero. Rho kinase and MAPK effects on PAF receptor (PAFR)-mediated cell population expansion, and PAFR expression, were studied by DNA synthesis, western blot analysis and immunocytochemistry. Effects of constructs T19N and G14V on PAF-induced cell proliferation were also investigated. Hypoxia increased PVSMC proliferation and Rho kinase inhibitors, Y-27632 and Fasudil (HA-1077) as well as MAPK inhibitors PD 98059 and SB 203580 attenuated PAF stimulation of cell proliferation. RhoA T19N and G14V stimulated cell proliferation, but co-incubation with PAF did not affect proliferative effects of the constructs. PAFR protein expression was significantly downregulated in both cell types by both Y-27632 and HA-1077, with comparable profiles. Also, cells treated with Y-27632 had less PAF receptor fluorescence with significant disruption of cell morphology. Our results show that Rho kinase non-specifically modulated PAFR-mediated responses by a translational modification of PAFR protein, and suggest that, in vivo, activation of Rho kinase by PAF may be a further pathway to sustain PAFR-mediated PVSMC proliferation. © 2013 John Wiley & Sons Ltd.

A new paradigm for the role of smooth muscle cells in the human cervix.

Science.gov (United States)

Vink, Joy Y; Qin, Sisi; Brock, Clifton O; Zork, Noelia M; Feltovich, Helen M; Chen, Xiaowei; Urie, Paul; Myers, Kristin M; Hall, Timothy J; Wapner, Ronald; Kitajewski, Jan K; Shawber, Carrie J; Gallos, George

2016-10-01

Premature cervical remodeling resulting in spontaneous preterm birth may begin with premature failure or relaxation at the internal os (termed "funneling"). To date, we do not understand why the internal os fails or why funneling occurs in some cases of premature cervical remodeling. Although the human cervix is thought to be mostly collagen with minimal cellular content, cervical smooth muscle cells are present in the cervix and can cause cervical tissue contractility. To understand why the internal os relaxes or why funneling occurs in some cases of premature cervical remodeling, we sought to evaluate cervical smooth muscle cell content and distribution throughout human cervix and correlate if cervical smooth muscle organization influences regional cervical tissue contractility. Using institutional review board-approved protocols, nonpregnant women cervix, whole cervical slices were obtained from the internal os, midcervix, and external os and immunostained with smooth muscle actin. To correlate tissue structure with function, whole slices from the internal and external os were stimulated to contract with 1 μmol/L of oxytocin in organ baths. In separate samples, we tested if the cervix responds to a common tocolytic, nifedipine. Cervical slices from the internal os were treated with oxytocin alone or oxytocin + increasing doses of nifedipine to generate a dose response and half maximal inhibitory concentration. Student t test was used where appropriate. Cervical tissue was collected from 41 women. Immunohistochemistry showed cervical smooth muscle cells at the internal and external os expressed mature smooth muscle cell markers and contraction-associated proteins. The cervix exhibited a gradient of cervical smooth muscle cells. The area of the internal os contained 50-60% cervical smooth muscle cells that were circumferentially organized in the periphery of the stroma, which may resemble a sphincter-like pattern. The external os contained approximately 10

Overexpression of functional TrkA receptors after internalisation in human airway smooth muscle cells.

Science.gov (United States)

Freund-Michel, Véronique; Frossard, Nelly

2008-10-01

Trafficking of the TrkA receptor after stimulation by NGF is of emerging importance in structural cells in the context of airway inflammatory diseases. We have recently reported the expression of functional TrkA receptors in human airway smooth muscle cells (HASMC). We have here studied the TrkA trafficking mechanisms in these cells. TrkA disappearance from the cell membrane was induced within 5 min of NGF (3pM) stimulation. Co-immunoprecipitation of clathrin-TrkA was revealed, and TrkA internalisation inhibited either by clathrin inhibitors or by siRNA inducing downregulation of endogenous clathrin. TrkA internalised receptors were totally degraded in lysosomes, with no recycling phenomenon. Newly synthesized TrkA receptors were thereafter re-expressed at the cell membrane within 10 h. TrkA re-synthesis was inhibited by blockade of clathrin-dependent internalisation, but not of TrkA receptors lysosomal degradation. Finally, we observed that NGF multiple stimulations progressively increased TrkA expression in HASMC, which was associated with an increase in NGF/TrkA-dependent proliferation. In conclusion, we show here the occurrence of clathrin-dependent TrkA internalisation and lysosomal degradation in the airway smooth muscle, followed by upregulated re-synthesis of functional TrkA receptors and increased proliferative effect in the human airway smooth muscle. This may have pathophysiological consequences in airway inflammatory diseases.

Protocatechuic aldehyde ameliorates experimental pulmonary fibrosis by modulating HMGB1/RAGE pathway

Energy Technology Data Exchange (ETDEWEB)

Zhang, Liang, E-mail: countryspring@sina.com; Ji, Yunxia, E-mail: 413499057@qq.com; Kang, Zechun, E-mail: davidjiangwl@163.com; Lv, Changjun, E-mail: Lucky_lcj@sina.com; Jiang, Wanglin, E-mail: jwl518@163.com

2015-02-15

An abnormal high mobility group box 1 (HMGB1) activation and a decrease in receptor for advanced glycation end-product (RAGE) play a key role in the pathogenesis of pulmonary fibrosis. Protocatechuic aldehyde (PA) is a naturally occurring compound, which is extracted from the degradation of phenolic acids. However, whether PA has anti-fibrotic functions is unknown. In this study, the effects of PA on the transforming growth factor-β1 (TGF-β1)-mediated epithelial–mesenchymal transition (EMT) in A549 cells, on the apoptosis of human type I alveolar epithelial cells (AT I), on the proliferation of human lung fibroblasts (HLF-1) in vitro, and on bleomycin (BLM)-induced pulmonary fibrosis in vivo were investigated. PA treatment resulted in a reduction of EMT in A549 cells with a decrease in vimentin and HMGB, an increase of E-cadherin and RAGE, a reduction of HLF-1 proliferation with a decrease of fibroblast growth factor 2 (FGF-2) and platelet-derived growth factor (PDGF). Apoptosis of AT I was attenuated with an increase of RAGE. PA ameliorated BLM-induced pulmonary fibrosis in rats with a reduction of histopathological scores and collagen deposition, and a lower FGF-2, PDGF, α-smooth muscle actin (α-SMA) and HMGB1 expression, whereas higher RAGE was found in BLM-instilled lungs. Through the decrease of HGMB1 and the regulation of RAGE, PA reversed the EMT, inhibited HLF-1 proliferation as well as reduced apoptosis in AT I, and prevented pulmonary fibrosis in vivo. Collectively, our results demonstrate that PA prevents experimental pulmonary fibrosis by modulating HMGB1/RAGE pathway. - Highlights: • PA prevents EMT, reduces the apoptosis of AT1 in vitro. • PA decreases proliferation of HLF-1, reduces PDGF and FGF expression in vitro. • PA prevents experimental pulmonary fibrosis by modulating the HMGB1/RAGE pathway.

Protocatechuic aldehyde ameliorates experimental pulmonary fibrosis by modulating HMGB1/RAGE pathway

International Nuclear Information System (INIS)

Zhang, Liang; Ji, Yunxia; Kang, Zechun; Lv, Changjun; Jiang, Wanglin

2015-01-01

An abnormal high mobility group box 1 (HMGB1) activation and a decrease in receptor for advanced glycation end-product (RAGE) play a key role in the pathogenesis of pulmonary fibrosis. Protocatechuic aldehyde (PA) is a naturally occurring compound, which is extracted from the degradation of phenolic acids. However, whether PA has anti-fibrotic functions is unknown. In this study, the effects of PA on the transforming growth factor-β1 (TGF-β1)-mediated epithelial–mesenchymal transition (EMT) in A549 cells, on the apoptosis of human type I alveolar epithelial cells (AT I), on the proliferation of human lung fibroblasts (HLF-1) in vitro, and on bleomycin (BLM)-induced pulmonary fibrosis in vivo were investigated. PA treatment resulted in a reduction of EMT in A549 cells with a decrease in vimentin and HMGB, an increase of E-cadherin and RAGE, a reduction of HLF-1 proliferation with a decrease of fibroblast growth factor 2 (FGF-2) and platelet-derived growth factor (PDGF). Apoptosis of AT I was attenuated with an increase of RAGE. PA ameliorated BLM-induced pulmonary fibrosis in rats with a reduction of histopathological scores and collagen deposition, and a lower FGF-2, PDGF, α-smooth muscle actin (α-SMA) and HMGB1 expression, whereas higher RAGE was found in BLM-instilled lungs. Through the decrease of HGMB1 and the regulation of RAGE, PA reversed the EMT, inhibited HLF-1 proliferation as well as reduced apoptosis in AT I, and prevented pulmonary fibrosis in vivo. Collectively, our results demonstrate that PA prevents experimental pulmonary fibrosis by modulating HMGB1/RAGE pathway. - Highlights: • PA prevents EMT, reduces the apoptosis of AT1 in vitro. • PA decreases proliferation of HLF-1, reduces PDGF and FGF expression in vitro. • PA prevents experimental pulmonary fibrosis by modulating the HMGB1/RAGE pathway

PDGF Promotes the Warburg Effect in Pulmonary Arterial Smooth Muscle Cells via Activation of the PI3K/AKT/mTOR/HIF-1α Signaling Pathway

Directory of Open Access Journals (Sweden)

Yunbin Xiao

2017-07-01

Full Text Available Background/Aims: The enhanced proliferation of pulmonary arterial smooth muscle cells (PASMCs is a central pathological component in pulmonary arterial hypertension (PAH. Both the Warburg effect and platelet-derived growth factor (PDGF are involved in the proliferation of PASMCs. However, the mechanism underlying the crosstalk between the Warburg effect and PDGF during PASMC proliferation is still unknown. We hypothesized that PDGF promotes the Warburg effect via activating the phosphatidylinositol 3-kinase (PI3K signaling pathway and hypoxia-inducible factor 1-α (HIF-1α in proliferative PASMCs. Methods: PASMCs were derived from pulmonary arteries of SD rats; cell viability, the presence of metabolites, and metabolic enzyme activities assay were determined by MTT assays, kit assays and western blot analysis, respectively. Results: PDGF promoted PASMC proliferation in a dose- and time-dependent manner, accompanied by an enhanced Warburg effect. Treatment with PDGFR antagonists, Warburg effect inhibitor and PDK1 inhibitor significantly inhibited PI3K signaling activation, HIF-1α expression and PASMC proliferation induced by PDGF, respectively. Furthermore, treatment with PI3K signaling pathway inhibitors remarkably suppressed PDGF-induced PASMC proliferation and the Warburg effect. Conclusion: microplate reader (Biotek, Winooski The Warburg effect plays a critical role in PDGF-induced PASMC proliferation and is mediated by activation of the PI3K signaling pathway and HIF-1α.

Basic studies on the estimation of the capacitance of human pulmonary 'venous' system using radionuclide angiocardiography

International Nuclear Information System (INIS)

Fujiwara, Hideki; Gotoh, Kohshi; Suzuki, Takahiko; Ohsumi, Yukio; Yagi, Yasuo; Hirakawa, Senri

1993-01-01

To establish the methodology to assess the capacitance of human pulmonary 'venous' system, using radionuclide angiocardiography and passive leg elevation, some basic aspects of the method were investigated. The pulmonary 'venous' system consisted of pulmonary veins and the left atrium. A short segment of the volume-pressure curve in human pulmonary 'venous' system was obtained as a line connecting the 2 points. (1) Pulmonary 'venous' volume-mean pulmonary capillary wedge pressure plot (P 'V' V-PCW plot) in supine position, where P 'V' V=0.7 x PBV. Pulmonary blood volume (PBV) was obtained by radionuclide angiocardiography, while mean pulmonary capillary wedge pressure (PCW) was simultaneously recorded by a floating catheter. (2) ΔP 'V' V-ΔPCW relation where ΔP 'V' V=0.8 x ΔPBV. Increment of the pulmonary blood volume (ΔPBV) during passive elevation of legs was measured from the baseline PBV and the percentage increase in the radioactivity over the right anterior chest during the leg elevation, after correction for (a) radioactivity from chest wall origin, and for (b) attenuation of the radioactive beams by the lung and the anterior chest wall. ΔPCW was the increase in PCW during leg elevation. The present study focussed on the details of the two corrections, (a) and (b), using, in parts, mechanical models. The present study also focussed on the reproducibility of the ΔP 'V' V, ΔPCW and Cp'v' (compliance of the pulmonary 'venous' system). The coefficient of variation was ±23% in ΔP 'V' V, ±18% in ΔPCW and ±18% in Cp'v', indicating a fair degree of reproducibility. (author)

Progenitor cells in pulmonary vascular remodeling

Science.gov (United States)

Yeager, Michael E.; Frid, Maria G.; Stenmark, Kurt R.

2011-01-01

Pulmonary hypertension is characterized by cellular and structural changes in the walls of pulmonary arteries. Intimal thickening and fibrosis, medial hypertrophy and fibroproliferative changes in the adventitia are commonly observed, as is the extension of smooth muscle into the previously non-muscularized vessels. A majority of these changes are associated with the enhanced presence of α-SM-actin+ cells and inflammatory cells. Atypical abundances of functionally distinct endothelial cells, particularly in the intima (plexiform lesions), and also in the perivascular regions, are also described. At present, neither the origin(s) of these cells nor the molecular mechanisms responsible for their accumulation, in any of the three compartments of the vessel wall, have been fully elucidated. The possibility that they arise from either resident vascular progenitors or bone marrow–derived progenitor cells is now well established. Resident vascular progenitor cells have been demonstrated to exist within the vessel wall, and in response to certain stimuli, to expand and express myofibroblastic, endothelial or even hematopoietic markers. Bone marrow–derived or circulating progenitor cells have also been shown to be recruited to sites of vascular injury and to assume both endothelial and SM-like phenotypes. Here, we review the data supporting the contributory role of vascular progenitors (including endothelial progenitor cells, smooth muscle progenitor cells, pericytes, and fibrocytes) in vascular remodeling. A more complete understanding of the processes by which progenitor cells modulate pulmonary vascular remodeling will undoubtedly herald a renaissance of therapies extending beyond the control of vascular tonicity and reduction of pulmonary artery pressure. PMID:22034593

Differential gene expression profiling of human adipose stem cells differentiating into smooth muscle-like cells by TGFβ1/BMP4

Energy Technology Data Exchange (ETDEWEB)

Elçin, Ayşe Eser; Parmaksiz, Mahmut; Dogan, Arin; Seker, Sukran; Durkut, Serap; Dalva, Klara; Elçin, Yaşar Murat, E-mail: elcinmurat@gmail.com

2017-03-15

Regenerative repair of the vascular system is challenging from the perspectives of translational medicine and tissue engineering. There are fundamental hurdles in front of creating bioartificial arteries, which involve recaputilation of the three-layered structure under laboratory settings. Obtaining and maintaining smooth muscle characteristics is an important limitation, as the transdifferentiated cells fail to display mature phenotype. This study aims to shed light on the smooth muscle differentiation of human adipose stem cells (hASCs). To this end, we first acquired hASCs from lipoaspirate samples. Upon characterization, the cells were induced to differentiate into smooth muscle (SM)-like cells using a variety of inducer combinations. Among all, TGFβ1/BMP4 combination had the highest differentiation efficiency, based on immunohistochemical analyses. hSM-like cell samples were compared to hASCs and to the positive control, human coronary artery-smooth muscle cells (hCA-SMCs) through gene transcription profiling. Microarray findings revealed the activation of gene groups that function in smooth muscle differentiation, signaling pathways, extracellular modeling and cell proliferation. Our results underline the effectiveness of the growth factors and suggest some potential variables for detecting the SM-like cell characteristics. Evidence in transcriptome level was used to evaluate the TGFβ1/BMP4 combination as a previously unexplored effector for the smooth muscle differentiation of adipose stem cells. - Highlights: • Human adipose stem cells (hASCs) were isolated, characterized and cultured. • Growth factor combinations were evaluated for their effectiveness in differentiation using IHC. • hASCs were differentiated into smooth muscle (SM)-like cells using TGF-β1 and BMP4 combination. • Microarray analysis was performed for hASCs, SM-like cells and coronary artery-SMCs. • Microarray data was used to perform hierarchical clustering and interpretation

Primary pulmonary choriocarcinoma after human chorionic gonadotropin normalization following hydatidiform mole

DEFF Research Database (Denmark)

Maestá, Izildinha; Leite, Fábio Vicente; Michelin, Odair Carlito

2010-01-01

BACKGROUND: Primary pulmonary choriocarcinoma (PPC) is rare and frequently leads to death. CASES: Two young patients presented with previous molar pregnancy and spontaneous serum human chorionic gonadotropin (hCG) normalization. Patient 1 was referred to our center after partial response to chemo...

Restoration of uridine 5′-triphosphate-suppressed delayed rectifying K+ currents by an NO activator KMUP-1 involves RhoA/Rho kinase signaling in pulmonary artery smooth muscle cells

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Zen-Kong Dai

2016-12-01

Full Text Available We have demonstrated that KMUP-1 (7-[2-[4-(2-chlorobenzenepiperazinyl]ethyl]-1,3-dimethylxanthine blunts monocrotaline-induced pulmonary arterial hypertension by altering Ca2+ sensitivity, K+-channel function, endothelial nitric oxide synthase activity, and RhoA/Rho kinase (ROCK expression. This study further investigated whether KMUP-1 impedes uridine 5′-triphosphate (UTP-inhibited delayed rectifying K+ (KDR current in rat pulmonary arteries involved the RhoA/ROCK signaling. Pulmonary artery smooth muscle cells (PASMCs were enzymatically dissociated from rat pulmonary arteries. KMUP-1 (30μM attenuated UTP (30μM-mediated membrane depolarization and abolished UTP-enhanced cytosolic Ca2+ concentration. Whole-cell patch-clamp electrophysiology was used to monitor KDR currents. A voltage-dependent KDR current was isolated and shown to consist of a 4-aminopyridine (5mM-sensitive component and an insensitive component. The 4-aminopyridine sensitive KDR current was suppressed by UTP (30μM. The ROCK inhibitor Y27632 (30μM abolished the ability of UTP to inhibit the KDR current. Like Y27632, KMUP-1 (30μM similarly abolished UTP-inhibited KDR currents. Superfused protein kinase A and protein kinase G inhibitors (KT5720, 300nM and KT5823, 300nM did not affect UTP-inhibited KDR currents, but the currents were restored by adding KMUP-1 (30μM to the superfusate. KMUP-1 reversal of KDR current inhibition by UTP predominantly involves the ROCK inhibition. The results indicate that the RhoA/ROCK signaling pathway plays a key role in eliciting PASMCs depolarization caused by UTP, which would result in pulmonary artery constriction. KMUP-1 blocks UTP-mediated PASMCs depolarization, suggesting that it would prevent abnormal pulmonary vasoconstriction.

Role of catechins on ET-1 induced stimulation of PLD and NADPH oxidase activities in pulmonary smooth muscle cells: Determination of the probable mechanism by molecular docking studies.

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Chakraborti, Sajal; Sarkar, Jaganmay; Bhuyan, Rajabrata; Chakraborti, Tapati

2017-12-05

Treatment of human pulmonary artery smooth muscle cells with ET-1 stimulated PLD and NADPH oxidase activities, which were inhibited upon pretreatment with bosentan (ET-1 receptor antagonist), FIPI (PLD inhibitor), apocynin (NADPH oxidase inhibitor) and EGCG & ECG (catechins having galloyl group), but not EGC & EC (catechins devoid of galloyl group). Herein, we determined the probable mechanism by which the galloyl group containing catechins inhibit ET-1 induced stimulation of PLD activity by molecular docking analyses based on our biochemical studies. ET-1 induced stimulation of PLD activity was inhibited by SecinH3 (inhibitor of cytohesin). Arf-6 and cytohesin-1 were associated in the cell membrane, which was not inhibited by the catechins during ET-1 treatment to the cells. However, EGCG and ECG inhibited binding of GTPγS with Arf-6 even in presence of cytohesin-1. The molecular docking analyses revealed that the galloyl group containing catechins (EGCG/ECG) with cytohesin1-Arf6GDP, but not the non-galloyl-containing catechins (EGC and EC), prevents GDP/GTP exchange in Arf-6 which seems to be an important mechanism for inhibition of ET-1 induced activation of PLD and subsequently increase in NADPH oxidase activities.

LC/MS/MS data analysis of the human uterine smooth muscle S-nitrosoproteome fingerprint in pregnancy, labor, and preterm labor

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Craig C. Ulrich

2015-09-01

Full Text Available The data described in this article is the subject of an article in the American Journal of Physiology: Cell Physiology, titled “The Human Uterine Smooth Muscle S-nitrosoproteome Fingerprint in Pregnancy, Labor, and Preterm Labor” (doi:10.1152/ajpcell.00198.2013 (Ulrich et al., 2013 [1]. The data described is a large scale mass spectrometry data set that defines the human uterine smooth muscle S-nitrosoproteome differences among laboring, non-laboring, preterm laboring tissue after treatment with S-nitrosoglutathione.

Molecular imaging of the human pulmonary vascular endothelium in pulmonary hypertension: a phase II safety and proof of principle trial

Energy Technology Data Exchange (ETDEWEB)

Harel, Francois [Montreal Heart Institute, Research Center, Montreal, QC (Canada); Universite de Montreal, Department of Nuclear Medicine, Montreal, Quebec (Canada); Langleben, David; Abikhzer, Gad [McGill University, Lady Davis Institute and Jewish General Hospital, Montreal, Quebec (Canada); Provencher, Steve; Guimond, Jean [Institut Universitaire de Cardiologie et de Pneumologie de Quebec, Quebec (Canada); Fournier, Alain; Letourneau, Myriam [INRS-Institut Armand-Frappier, Laval, Quebec (Canada); Finnerty, Vincent; Nguyen, Quang T.; Levac, Xavier [Montreal Heart Institute, Research Center, Montreal, QC (Canada); Mansour, Asmaa; Guertin, Marie-Claude [Montreal Health Innovation Coordination Center, Montreal, QC (Canada); Dupuis, Jocelyn [Montreal Heart Institute, Research Center, Montreal, QC (Canada); Universite de Montreal, Department of Medicine, Montreal, Quebec (Canada)

2017-07-15

The adrenomedullin receptor is densely expressed in the pulmonary vascular endothelium. PulmoBind, an adrenomedullin receptor ligand, was developed for molecular diagnosis of pulmonary vascular disease. We evaluated the safety of PulmoBind SPECT imaging and its capacity to detect pulmonary vascular disease associated with pulmonary hypertension (PH) in a human phase II study. Thirty patients with pulmonary arterial hypertension (PAH, n = 23) or chronic thromboembolic PH (CTEPH, n = 7) in WHO functional class II (n = 26) or III (n = 4) were compared to 15 healthy controls. Lung SPECT was performed after injection of 15 mCi {sup 99m}Tc-PulmoBind in supine position. Qualitative and semi-quantitative analyses of lung uptake were performed. Reproducibility of repeated testing was evaluated in controls after 1 month. PulmoBind injection was well tolerated without any serious adverse event. Imaging was markedly abnormal in PH with ∝50% of subjects showing moderate to severe heterogeneity of moderate to severe extent. The abnormalities were unevenly distributed between the right and left lungs as well as within each lung. Segmental defects compatible with pulmonary embolism were present in 7/7 subjects with CTEPH and in 2/23 subjects with PAH. There were no segmental defects in controls. The PulmoBind activity distribution index, a parameter indicative of heterogeneity, was elevated in PH (65% ± 28%) vs. controls (41% ± 13%, p = 0.0003). In the only subject with vasodilator-responsive idiopathic PAH, PulmoBind lung SPECT was completely normal. Repeated testing 1 month later in healthy controls was well tolerated and showed no significant variability of PulmoBind distribution. In this phase II study, molecular SPECT imaging of the pulmonary vascular endothelium using {sup 99m}Tc-PulmoBind was safe. PulmoBind showed potential to detect both pulmonary embolism and abnormalities indicative of pulmonary vascular disease in PAH. Phase III studies with this novel tracer and

Endothelin B receptor blockade attenuates pulmonary vasodilation in oxygen-ventilated fetal lambs.

Science.gov (United States)

Ivy, D Dunbar; Lee, Dong-Seok; Rairigh, Robyn L; Parker, Thomas A; Abman, Steven H

2004-01-01

Endothelin-1 (ET-1) contributes to the regulation of pulmonary vascular tone in the normal ovine fetus and in models of perinatal pulmonary hypertension. In the fetal lamb lung, the effects of ET-1 depend on the balance of at least two endothelin receptor subtypes: ETA and ETB. ETA receptors are located on smooth muscle cells and mediate vasoconstriction and smooth muscle proliferation. Stimulation of endothelial ETB receptors causes vasodilation through release of nitric oxide and also functions to remove ET-1 from the circulation. However, whether activation of ETB receptors contributes to the fall in pulmonary vascular tone at birth is unknown. To determine the role of acute ETB receptor blockade in pulmonary vasodilation in response to birth-related stimuli, we studied the hemodynamic effects of selective ETB receptor blockade with BQ-788 during mechanical ventilation with low (<10%) and high FiO2 (100%) in near-term fetal sheep. Intrapulmonary infusion of BQ-788 did not change left pulmonary artery (LPA) blood flow and pulmonary vascular resistance (PVR) at baseline. In comparison with controls, BQ-788 treatment attenuated the rise in LPA flow with low and high FiO2 ventilation (p <0.001 vs. control for each FiO2 concentration). PVR progressively decreased during mechanical ventilation with low and high FiO2 in both groups, but PVR remained higher after BQ-788 treatment throughout the study period (p <0.001). We conclude that selective ETB receptor blockade attenuates pulmonary vasodilation at birth. We speculate that ETB receptor stimulation contributes to pulmonary vasodilation at birth in the ovine fetus.

Hypoxia-induced mitogenic factor (HIMF/FIZZ1/RELM alpha recruits bone marrow-derived cells to the murine pulmonary vasculature.

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Daniel J Angelini

2010-06-01

Full Text Available Pulmonary hypertension (PH is a disease of multiple etiologies with several common pathological features, including inflammation and pulmonary vascular remodeling. Recent evidence has suggested a potential role for the recruitment of bone marrow-derived (BMD progenitor cells to this remodeling process. We recently demonstrated that hypoxia-induced mitogenic factor (HIMF/FIZZ1/RELM alpha is chemotactic to murine bone marrow cells in vitro and involved in pulmonary vascular remodeling in vivo.We used a mouse bone marrow transplant model in which lethally irradiated mice were rescued with bone marrow transplanted from green fluorescent protein (GFP(+ transgenic mice to determine the role of HIMF in recruiting BMD cells to the lung vasculature during PH development. Exposure to chronic hypoxia and pulmonary gene transfer of HIMF were used to induce PH. Both models resulted in markedly increased numbers of BMD cells in and around the pulmonary vasculature; in several neomuscularized small (approximately 20 microm capillary-like vessels, an entirely new medial wall was made up of these cells. We found these GFP(+ BMD cells to be positive for stem cell antigen-1 and c-kit, but negative for CD31 and CD34. Several of the GFP(+ cells that localized to the pulmonary vasculature were alpha-smooth muscle actin(+ and localized to the media layer of the vessels. This finding suggests that these cells are of mesenchymal origin and differentiate toward myofibroblast and vascular smooth muscle. Structural location in the media of small vessels suggests a functional role in the lung vasculature. To examine a potential mechanism for HIMF-dependent recruitment of mesenchymal stem cells to the pulmonary vasculature, we performed a cell migration assay using cultured human mesenchymal stem cells (HMSCs. The addition of recombinant HIMF induced migration of HMSCs in a phosphoinosotide-3-kinase-dependent manner.These results demonstrate HIMF-dependent recruitment of BMD

Inhibition effect of Bifidobacterium longum, Lactobacillus acidophilus, Streptococcus thermophilus and Enterococcus faecalis and their related products on human colonic smooth muscle in vitro.

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Jing Gong

Full Text Available To investigate the effects of four strains, generally used in clinic, including Bifidobacterium longum, Lactobacillus acidophilus, Streptococcus thermophilus and Enterococcus faecalis, and their related products on human colonic smooth muscle in vitro.Human colonic circular muscle strips obtained from disease-free margins of resected segments from 25 patients with colorectal cancer were isometrically examined in a constant-temperature organ bath and exposed to different concentrations of living bacteria, sonicated cell fractions and cell-free supernatant (CFS. The area under the curve (AUC representing the contractility of smooth muscle strips was calculated.(1 The four living probiotics inhibited the contractility of human colonic muscle strips only at high concentration (1010 CFUs/mL, all P0.05.Four common probiotics related products, including the sonicated cell fractions and the CFS, obviously inhibited human colonic smooth muscles strips contraction in a dose-dependent manner. Only high concentration living probiotics (1010 CFUs/mL can inhibit the colonic smooth muscles strips contraction. The NO pathway may be partly involved in the inhibitory effect of CFS from Streptococcus thermophilus and Enterococcus faecalis.

C-type natriuretic peptide ameliorates pulmonary fibrosis by acting on lung fibroblasts in mice.

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Kimura, Toru; Nojiri, Takashi; Hino, Jun; Hosoda, Hiroshi; Miura, Koichi; Shintani, Yasushi; Inoue, Masayoshi; Zenitani, Masahiro; Takabatake, Hiroyuki; Miyazato, Mikiya; Okumura, Meinoshin; Kangawa, Kenji

2016-02-19

Pulmonary fibrosis has high rates of mortality and morbidity; however, no effective pharmacological therapy has been established. C-type natriuretic peptide (CNP), a member of the natriuretic peptide family, selectively binds to the transmembrane guanylyl cyclase (GC)-B receptor and exerts anti-inflammatory and anti-fibrotic effects in various organs through vascular endothelial cells and fibroblasts that have a cell-surface GC-B receptor. Given the pathophysiological importance of fibroblast activation in pulmonary fibrosis, we hypothesized that the anti-fibrotic and anti-inflammatory effects of exogenous CNP against bleomycin (BLM)-induced pulmonary fibrosis were exerted in part by the effect of CNP on pulmonary fibroblasts. C57BL/6 mice were divided into two groups, CNP-treated (2.5 μg/kg/min) and vehicle, to evaluate BLM-induced (1 mg/kg) pulmonary fibrosis and inflammation. A periostin-CNP transgenic mouse model exhibiting CNP overexpression in fibroblasts was generated and examined for the anti-inflammatory and anti-fibrotic effects of CNP via fibroblasts in vivo. Additionally, we assessed CNP attenuation of TGF-β-induced differentiation into myofibroblasts by using immortalized human lung fibroblasts stably expressing GC-B receptors. Furthermore, to investigate whether CNP acts on human lung fibroblasts in a clinical setting, we obtained primary-cultured fibroblasts from surgically resected lungs of patients with lung cancer and analyzed levels of GC-B mRNA transcription. CNP reduced mRNA levels of the profibrotic cytokines interleukin (IL)-1β and IL-6, as well as collagen deposition and the fibrotic area in lungs of mice with bleomycin-induced pulmonary fibrosis. Furthermore, similar CNP effects were observed in transgenic mice exhibiting fibroblast-specific CNP overexpression. In cultured-lung fibroblasts, CNP treatment attenuated TGF-β-induced phosphorylation of Smad2 and increased mRNA and protein expression of α-smooth muscle actin and SM22�

Differentiation of Human Adipose Derived Stem Cells into Smooth Muscle Cells Is Modulated by CaMKIIγ

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Kaisaier Aji

2016-01-01

Full Text Available The multifunctional Ca2+/calmodulin-dependent protein kinase II (CaMKII is known to participate in maintenance and switches of smooth muscle cell (SMC phenotypes. However, which isoform of CaMKII is involved in differentiation of adult mesenchymal stem cells into contractile SMCs remains unclear. In the present study, we detected γ isoform of CaMKII in differentiation of human adipose derived stem cells (hASCs into SMCs that resulted from treatment with TGF-β1 and BMP4 in combination for 7 days. The results showed that CaMKIIγ increased gradually during differentiation of hASCs as determined by real-time PCR and western blot analysis. The siRNA-mediated knockdown of CaMKIIγ decreased the protein levels and transcriptional levels of smooth muscle contractile markers (a-SMA, SM22a, calponin, and SM-MHC, while CaMKIIγ overexpression increases the transcriptional and protein levels of smooth muscle contractile markers. These results suggested that γ isoform of CaMKII plays a significant role in smooth muscle differentiation of hASCs.

[Pulmonary arterial hypertension associated to human immunodeficiency virus].

Science.gov (United States)

Sandoval-Gutiérrez, José Luis; Santos-Martínez, Luis Efren; Rodríguez-Silverio, Juan; Baranda-Tovar, Francisco Martín; Rivera-Rosales, Rosa María; Flores-Murrieta, Francisco Javier

2015-01-01

From the advent of the highly effective antiretroviral treatment, the life expectancy of patients with human immunodeficiency virus has increased significantly. At present, the causes of death are non-infectious complications. Between them, the pulmonary arterial hypertension has a special importance. It is important early detection to establish the therapeutic, with the objective of preventing a fatal outcome to future. Copyright © 2013 Instituto Nacional de Cardiología Ignacio Chávez. Published by Masson Doyma México S.A. All rights reserved.

CD16(+) monocytes with smooth muscle cell characteristics are reduced in human renal chronic transplant dysfunction

NARCIS (Netherlands)

Boersema, M.; van den Born, Joost; van Ark, J.; Harms, Geertruida; Seelen, M. A.; van Dijk, M. C. R. F.; van Goor, H.; Navis, G. J.; Popa, E. R.; Hillebrands, J. L.

In chronic transplant dysfunction (CTD), persistent (allo)immune-mediated inflammation eventually leads to tissue remodeling including neointima formation in intragraft arteries. We previously showed that recipient-derived neointimal alpha-SMA(+) smooth muscle-like cells are present in human renal

Basally activated nonselective cation currents regulate the resting membrane potential in human and monkey colonic smooth muscle

Science.gov (United States)

Dwyer, Laura; Rhee, Poong-Lyul; Lowe, Vanessa; Zheng, Haifeng; Peri, Lauren; Ro, Seungil; Sanders, Kenton M.

2011-01-01

Resting membrane potential (RMP) plays an important role in determining the basal excitability of gastrointestinal smooth muscle. The RMP in colonic muscles is significantly less negative than the equilibrium potential of K+, suggesting that it is regulated not only by K+ conductances but by inward conductances such as Na+ and/or Ca2+. We investigated the contribution of nonselective cation channels (NSCC) to the RMP in human and monkey colonic smooth muscle cells (SMC) using voltage- and current-clamp techniques. Qualitative reverse transcriptase-polymerase chain reaction was performed to examine potential molecular candidates for these channels among the transient receptor potential (TRP) channel superfamily. Spontaneous transient inward currents and holding currents were recorded in human and monkey SMC. Replacement of extracellular Na+ with equimolar tetraethylammonium or Ca2+ with Mn2+ inhibited basally activated nonselective cation currents. Trivalent cations inhibited these channels. Under current clamp, replacement of extracellular Na+ with N-methyl-d-glucamine or addition of trivalent cations caused hyperpolarization. Three unitary conductances of NSCC were observed in human and monkey colonic SMC. Molecular candidates for basally active NSCC were TRPC1, C3, C4, C7, M2, M4, M6, M7, V1, and V2 in human and monkey SMC. Comparison of the biophysical properties of these TRP channels with basally active NSCC (bINSCC) suggests that TRPM4 and specific TRPC heteromultimer combinations may underlie the three single-channel conductances of bINSCC. In conclusion, these findings suggest that basally activated NSCC contribute to the RMP in human and monkey colonic SMC and therefore may play an important role in determining basal excitability of colonic smooth muscle. PMID:21566016

Hemodynamic, pulmonary vascular, and myocardial abnormalities secondary to pharmacologic constriction of the fetal ductus arteriosus. A possible mechanism for persistent pulmonary hypertension and transient tricuspid insufficiency in the newborn infant.

Science.gov (United States)

Levin, D L; Mills, L J; Weinberg, A G

1979-08-01

The prostaglandin synthetase inhibitor indomethacin was given orally or intravenously to pregnant ewes. This resulted in a significant rise in the fetal pulmonary-to-systemic arterial mean blood pressure difference across the ductus arteriosus, presumably secondary to constriction of the ductus arteriosus. In five experiments the pressure difference could be promptly but temporarily reversed by the administration of prostaglandin E1 (PGE1) into the fetal inferior vena cava. Fetal lungs from study and control animals were fixed by perfusion at measured pulmonary arterial mean blood pressure, and fifth-generation resistance vessels were studied. The medial width/external diameter ratio was significantly increased in the study vs the control lungs due to increased smooth muscle and decreased external diameter. In addition, study fetuses had acute degenerative myocardial changes in the tricuspid valve papillary muscles, the right ventricular free wall and the interventricular septum. Similar changes were not seen in control fetuses. Indomethacin administration during pregnancy causes constriction of the fetal ductus arteriosus, fetal pulmonary arterial hypertension, and right ventricular damage. If severe, this may cause rapid fetal death. If less severe, in the newborn infant, this mechanism may be one cause of persistent pulmonary hypertension due to vasoconstriction and increased pulmonary arterial smooth muscle and/or tricuspid insufficiency due to papillary muscle infarction.

JAK2 mediates lung fibrosis, pulmonary vascular remodelling and hypertension in idiopathic pulmonary fibrosis: an experimental study.

Science.gov (United States)

Milara, Javier; Ballester, Beatriz; Morell, Anselm; Ortiz, José L; Escrivá, Juan; Fernández, Estrella; Perez-Vizcaino, Francisco; Cogolludo, Angel; Pastor, Enrique; Artigues, Enrique; Morcillo, Esteban; Cortijo, Julio

2018-06-01

Pulmonary hypertension (PH) is a common disorder in patients with idiopathic pulmonary fibrosis (IPF) and portends a poor prognosis. Recent studies using vasodilators approved for PH have failed in improving IPF mainly due to ventilation ( V )/perfusion ( Q ) mismatching and oxygen desaturation. Janus kinase type 2 (JAK2) is a non-receptor tyrosine kinase activated by a broad spectrum of profibrotic and vasoactive mediators, but its role in PH associated to PH is unknown. The study of JAK2 as potential target to treat PH in IPF. JAK2 expression was increased in pulmonary arteries (PAs) from IPF (n=10; 1.93-fold; P=0.0011) and IPF+PH (n=9; 2.65-fold; Ppulmonary artery endothelial cells (HPAECs) and human pulmonary artery smooth muscle cells (HPASMCs) from patients with IPF in vitro treated with the JAK2 inhibitor JSI-124 or siRNA-JAK2 and stimulated with transforming growth factor beta. Both JSI-124 and siRNA-JAK2 inhibited the HPAEC to mesenchymal transition and the HPASMCs to myofibroblast transition and proliferation. JAK2 inhibition induced small PA relaxation in precision-cut lung slice experiments. PA relaxation was dependent of the large conductance calcium-activated potassium channel (BK Ca ). JAK2 inhibition activated BK Ca channels and reduced intracellular Ca 2+ . JSI-124 1 mg/kg/day, reduced bleomycin-induced lung fibrosis, PA remodelling, right ventricular hypertrophy, PA hypertension and V / Q mismatching in rats. The animal studies followed the ARRIVE guidelines. JAK2 participates in PA remodelling and tension and may be an attractive target to treat IPF associated to PH. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

Immunohistochemical examination of plexiform-like complex vascular lesions in the lungs of broiler chickens selected for susceptibility to idiopathic pulmonary arterial hypertension.

Science.gov (United States)

Hamal, Krishna R; Erf, Gisela F; Anthony, Nicholas B; Wideman, Robert F

2012-01-01

Idiopathic pulmonary arterial hypertension (IPAH) is a disease of unknown cause that is characterized by elevated pulmonary arterial pressure and pulmonary vascular resistance, and by extensive vascular remodelling. In human IPAH patients, remodelling of the pulmonary vasculature results in the formation of plexiform lesions in the terminal pulmonary arterioles. Various molecules are expressed in the human plexiform lesions, including alpha smooth muscle actin, von Willebrand factor, vascular endothelial growth factor, vascular endothelial growth factor receptor type 2, hypoxia inducible factor-1α, survivin, tenascin, collagen, fibronectin, and various immune/inflammatory cells such as, cytotoxic lymphocytes, B lymphocytes, MHC class II cells, and monocytes/macrophages are also present. Plexiform lesions rarely develop in the lungs of laboratory animals, but plexiform-like complex vascular lesions (CVL) do develop spontaneously in the lungs of broiler chickens from an IPAH-susceptible line. To examine angioproliferative and immune-system-related activities associated with CVL in broiler lungs, paraformaldehyde-fixed, paraffin-embedded lung sections from 8-week-old to 24-week-old broiler chickens were stained immunohistochemically using monoclonal or polyclonal antibodies specific for angioproliferative molecules and immune/inflammatory cells. The CVL in the lungs of broiler chickens exhibited positive staining for both angioproliferative molecules and immune/inflammatory cells. These observations combined with the close histological resemblance of broiler CVL to the plexiform lesions of human IPAH patients further validates chickens from our IPAH-susceptible line as an excellent animal model of spontaneous plexogenic arteriopathy.

In-depth evaluation of commercially available human vascular smooth muscle cells phenotype: Implications for vascular tissue engineering

Energy Technology Data Exchange (ETDEWEB)

Timraz, Sara B.H., E-mail: sara.timraz@kustar.ac.ae [Department of Biomedical Engineering, Khalifa University, PO Box 127788, Abu Dhabi (United Arab Emirates); Farhat, Ilyas A.H., E-mail: ilyas.farhat@outlook.com [Department of Applied Mathematics and Sciences, Khalifa University, PO Box 127788, Abu Dhabi (United Arab Emirates); Alhussein, Ghada, E-mail: ghada.alhussein@kustar.ac.ae [Department of Biomedical Engineering, Khalifa University, PO Box 127788, Abu Dhabi (United Arab Emirates); Christoforou, Nicolas, E-mail: nicolas.christoforou@kustar.ac.ae [Department of Biomedical Engineering, Khalifa University, PO Box 127788, Abu Dhabi (United Arab Emirates); Department of Biomedical Engineering, Duke University, Durham, NC 27708 (United States); Teo, Jeremy C.M., E-mail: jeremy.teo@kustar.ac.ae [Department of Biomedical Engineering, Khalifa University, PO Box 127788, Abu Dhabi (United Arab Emirates)

2016-05-01

In vitro research on vascular tissue engineering has extensively used isolated primary human or animal smooth muscle cells (SMC). Research programs that lack such facilities tend towards commercially available primary cells sources. Here, we aim to evaluate the capacity of commercially available human SMC to maintain their contractile phenotype, and determine if dedifferentiation towards the synthetic phenotype occurs in response to conventional cell culture and passaging without any external biochemical or mechanical stimuli. Lower passage SMC adopted a contractile phenotype marked by a relatively slower proliferation rate, higher expression of proteins of the contractile apparatus and smoothelin, elongated morphology, and reduced deposition of collagen types I and III. As the passage number increased, migratory capacity was enhanced, average cell speed, total distance and net distance travelled increased up to passage 8. Through the various assays, corroborative evidence pinpoints SMC at passage 7 as the transition point between the contractile and synthetic phenotypes, while passage 8 distinctly and consistently exhibited characteristics of synthetic phenotype. This knowledge is particularly useful in selecting SMC of appropriate passage number for the target vascular tissue engineering application, for example, a homeostatic vascular graft for blood vessel replacement versus recreating atherosclerotic blood vessel model in vitro. - Highlights: • Ability of human smooth muscle cells to alter phenotype in culture is evaluated. • Examined the effect of passaging human smooth muscle cells on phenotype. • Phenotype is assessed based on morphology, proliferation, markers, and migration. • Multi-resolution assessment methodology, single-cell and cell-population. • Lower and higher passages than P7 adopted a contractile and synthetic phenotype respectively.

In-depth evaluation of commercially available human vascular smooth muscle cells phenotype: Implications for vascular tissue engineering

International Nuclear Information System (INIS)

Timraz, Sara B.H.; Farhat, Ilyas A.H.; Alhussein, Ghada; Christoforou, Nicolas; Teo, Jeremy C.M.

2016-01-01

In vitro research on vascular tissue engineering has extensively used isolated primary human or animal smooth muscle cells (SMC). Research programs that lack such facilities tend towards commercially available primary cells sources. Here, we aim to evaluate the capacity of commercially available human SMC to maintain their contractile phenotype, and determine if dedifferentiation towards the synthetic phenotype occurs in response to conventional cell culture and passaging without any external biochemical or mechanical stimuli. Lower passage SMC adopted a contractile phenotype marked by a relatively slower proliferation rate, higher expression of proteins of the contractile apparatus and smoothelin, elongated morphology, and reduced deposition of collagen types I and III. As the passage number increased, migratory capacity was enhanced, average cell speed, total distance and net distance travelled increased up to passage 8. Through the various assays, corroborative evidence pinpoints SMC at passage 7 as the transition point between the contractile and synthetic phenotypes, while passage 8 distinctly and consistently exhibited characteristics of synthetic phenotype. This knowledge is particularly useful in selecting SMC of appropriate passage number for the target vascular tissue engineering application, for example, a homeostatic vascular graft for blood vessel replacement versus recreating atherosclerotic blood vessel model in vitro. - Highlights: • Ability of human smooth muscle cells to alter phenotype in culture is evaluated. • Examined the effect of passaging human smooth muscle cells on phenotype. • Phenotype is assessed based on morphology, proliferation, markers, and migration. • Multi-resolution assessment methodology, single-cell and cell-population. • Lower and higher passages than P7 adopted a contractile and synthetic phenotype respectively.

Mechanism by which nuclear factor-kappa beta (NF-kB regulates ovine fetal pulmonary vascular smooth muscle cell proliferation

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Uchenna D. Ogbozor

2015-09-01

Full Text Available Platelet activating factor (PAF modulates ovine fetal pulmonary hemodynamic. PAF acts through its receptors (PAFR in pulmonary vascular smooth muscle cells (PVSMC to phosphorylate and induce nuclear translocation of NF-kB p65 leading to PVSMC proliferation. However, the interaction of NF-kB p65 and PAF in the nuclear domain to effect PVSMC cell growth is not clearly defined. We used siRNA-dependent translation initiation arrest to study a mechanism by which NF-kB p65 regulates PAF stimulation of PVSMC proliferation. Our hypotheses are: (a PAF induces NF-kB p65 DNA binding and (b NF-kB p65 siRNA attenuates PAF stimulation of PVSMC proliferation. For DNA binding, cells were fed 10 nM PAF with and without PAFR antagonists WEB 2170, CV 3988 or BN 52021 and incubated for 12 h. DNA binding was measured by specific ELISA. For NF-kB p65 siRNA effect, starved cells transfected with the siRNA were incubated for 24 h with and without 10 nM PAF. Cell proliferation was measured by DNA synthesis while expression of NF-kB p65 and PAFR protein was measured by Western blotting. In both studies, the effect of 10% FBS alone was used as the positive control. In general, PAF stimulated DNA binding which was inhibited by PAFR antagonists. siRNAs to NF-kB p65 and PAFR significantly attenuated cell proliferation compared to 10% FBS and PAF effect. Inclusion of PAF in siRNA-treated cells did not reverse inhibitory effect of NF-kB p65 siRNA on DNA synthesis. PAFR expression was inhibited in siRNA-treated cells. These data show that PAF-stimulation of PVSMC proliferation occurs via a PAFR-NF-kB p65 linked pathway.

Mechanism by which nuclear factor-kappa beta (NF-kB) regulates ovine fetal pulmonary vascular smooth muscle cell proliferation.

Science.gov (United States)

Ogbozor, Uchenna D; Opene, Michael; Renteria, Lissette S; McBride, Shaemion; Ibe, Basil O

2015-09-01

Platelet activating factor (PAF) modulates ovine fetal pulmonary hemodynamic. PAF acts through its receptors (PAFR) in pulmonary vascular smooth muscle cells (PVSMC) to phosphorylate and induce nuclear translocation of NF-kB p65 leading to PVSMC proliferation. However, the interaction of NF-kB p65 and PAF in the nuclear domain to effect PVSMC cell growth is not clearly defined. We used siRNA-dependent translation initiation arrest to study a mechanism by which NF-kB p65 regulates PAF stimulation of PVSMC proliferation. Our hypotheses are: (a) PAF induces NF-kB p65 DNA binding and (b) NF-kB p65 siRNA attenuates PAF stimulation of PVSMC proliferation. For DNA binding, cells were fed 10 nM PAF with and without PAFR antagonists WEB 2170, CV 3988 or BN 52021 and incubated for 12 h. DNA binding was measured by specific ELISA. For NF-kB p65 siRNA effect, starved cells transfected with the siRNA were incubated for 24 h with and without 10 nM PAF. Cell proliferation was measured by DNA synthesis while expression of NF-kB p65 and PAFR protein was measured by Western blotting. In both studies, the effect of 10% FBS alone was used as the positive control. In general, PAF stimulated DNA binding which was inhibited by PAFR antagonists. siRNAs to NF-kB p65 and PAFR significantly attenuated cell proliferation compared to 10% FBS and PAF effect. Inclusion of PAF in siRNA-treated cells did not reverse inhibitory effect of NF-kB p65 siRNA on DNA synthesis. PAFR expression was inhibited in siRNA-treated cells. These data show that PAF-stimulation of PVSMC proliferation occurs via a PAFR-NF-kB p65 linked pathway.

The cancer theory of pulmonary arterial hypertension

Science.gov (United States)

Boucherat, Olivier; Vitry, Geraldine; Trinh, Isabelle; Paulin, Roxane; Provencher, Steeve; Bonnet, Sebastien

2017-01-01

Pulmonary arterial hypertension (PAH) remains a mysterious killer that, like cancer, is characterized by tremendous complexity. PAH development occurs under sustained and persistent environmental stress, such as inflammation, shear stress, pseudo-hypoxia, and more. After inducing an initial death of the endothelial cells, these environmental stresses contribute with time to the development of hyper-proliferative and apoptotic resistant clone of cells including pulmonary artery smooth muscle cells, fibroblasts, and even pulmonary artery endothelial cells allowing vascular remodeling and PAH development. Molecularly, these cells exhibit many features common to cancer cells offering the opportunity to exploit therapeutic strategies used in cancer to treat PAH. In this review, we outline the signaling pathways and mechanisms described in cancer that drive PAH cells’ survival and proliferation and discuss the therapeutic potential of antineoplastic drugs in PAH. PMID:28597757

Human Pulmonary Infection by the Zoonotic Metastrongylus salmi Nematode. The First Reported Case in the Americas

OpenAIRE

Calvopina, Manuel; Caballero, Henry; Morita, Tatsushi; Korenaga, Masataka

2016-01-01

Pulmonary metastrongylosis, a zoonotic disease found primarily in pigs, is caused by eight different species of the cosmopolitan nematode Metastrongylus genus. To date, only four human cases have been reported, all from Europe. Herein, a severe case of pulmonary infection caused by Metastrongylus salmi in an Ecuadorian man, with successful treatment with ivermectin, is described.

Revisiting the Role of TRP, Orai, and ASIC Channels in the Pulmonary Arterial Response to Hypoxia

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Roberto V. Reyes

2018-05-01

Full Text Available The pulmonary arteries are exquisitely responsive to oxygen changes. They rapidly and proportionally contract as arterial PO2 decrease, and they relax as arterial PO2 is re-established. The hypoxic pulmonary vasoconstriction (HPV is intrinsic since it does not require neural or endocrine factors, as evidenced in isolated vessels. On the other hand, pulmonary arteries also respond to sustained hypoxia with structural and functional remodeling, involving growth of smooth muscle medial layer and later recruitment of adventitial fibroblasts, secreted mitogens from endothelium and changes in the response to vasoconstrictor and vasodilator stimuli. Hypoxic pulmonary arterial vasoconstriction and remodeling are relevant biological responses both under physiological and pathological conditions, to explain matching between ventilation and perfusion, fetal to neonatal transition of pulmonary circulation and pulmonary artery over-constriction and thickening in pulmonary hypertension. Store operated channels (SOC and receptor operated channels (ROC are plasma membrane cationic channels that mediate calcium influx in response to depletion of internal calcium stores or receptor activation, respectively. They are involved in both HPV and pathological remodeling since their pharmacological blockade or genetic suppression of several of the Stim, Orai, TRP, or ASIC proteins in SOC or ROC complexes attenuate the calcium increase, the tension development, the pulmonary artery smooth muscle proliferation, and pulmonary arterial hypertension. In this Mini Review, we discussed the evidence obtained in in vivo animal models, at the level of isolated organ or cells of pulmonary arteries, and we identified and discussed the questions for future research needed to validate these signaling complexes as targets against pulmonary hypertension.

Smooth Muscle-Like Cells Generated from Human Mesenchymal Stromal Cells Display Marker Gene Expression and Electrophysiological Competence Comparable to Bladder Smooth Muscle Cells.

Science.gov (United States)

Brun, Juliane; Lutz, Katrin A; Neumayer, Katharina M H; Klein, Gerd; Seeger, Tanja; Uynuk-Ool, Tatiana; Wörgötter, Katharina; Schmid, Sandra; Kraushaar, Udo; Guenther, Elke; Rolauffs, Bernd; Aicher, Wilhelm K; Hart, Melanie L

2015-01-01

The use of mesenchymal stromal cells (MSCs) differentiated toward a smooth muscle cell (SMC) phenotype may provide an alternative for investigators interested in regenerating urinary tract organs such as the bladder where autologous smooth muscle cells cannot be used or are unavailable. In this study we measured the effects of good manufacturing practice (GMP)-compliant expansion followed by myogenic differentiation of human MSCs on the expression of a range of contractile (from early to late) myogenic markers in relation to the electrophysiological parameters to assess the functional role of the differentiated MSCs and found that differentiation of MSCs associated with electrophysiological competence comparable to bladder SMCs. Within 1-2 weeks of myogenic differentiation, differentiating MSCs significantly expressed alpha smooth muscle actin (αSMA; ACTA2), transgelin (TAGLN), calponin (CNN1), and smooth muscle myosin heavy chain (SM-MHC; MYH11) according to qRT-PCR and/or immunofluorescence and Western blot. Voltage-gated Na+ current levels also increased within the same time period following myogenic differentiation. In contrast to undifferentiated MSCs, differentiated MSCs and bladder SMCs exhibited elevated cytosolic Ca2+ transients in response to K+-induced depolarization and contracted in response to K+ indicating functional maturation of differentiated MSCs. Depolarization was suppressed by Cd2+, an inhibitor of voltage-gated Ca2+-channels. The expression of Na+-channels was pharmacologically identified as the Nav1.4 subtype, while the K+ and Ca2+ ion channels were identified by gene expression of KCNMA1, CACNA1C and CACNA1H which encode for the large conductance Ca2+-activated K+ channel BKCa channels, Cav1.2 L-type Ca2+ channels and Cav3.2 T-type Ca2+ channels, respectively. This protocol may be used to differentiate adult MSCs into smooth muscle-like cells with an intermediate-to-late SMC contractile phenotype exhibiting voltage-gated ion channel

Smooth Muscle-Like Cells Generated from Human Mesenchymal Stromal Cells Display Marker Gene Expression and Electrophysiological Competence Comparable to Bladder Smooth Muscle Cells.

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Juliane Brun

Full Text Available The use of mesenchymal stromal cells (MSCs differentiated toward a smooth muscle cell (SMC phenotype may provide an alternative for investigators interested in regenerating urinary tract organs such as the bladder where autologous smooth muscle cells cannot be used or are unavailable. In this study we measured the effects of good manufacturing practice (GMP-compliant expansion followed by myogenic differentiation of human MSCs on the expression of a range of contractile (from early to late myogenic markers in relation to the electrophysiological parameters to assess the functional role of the differentiated MSCs and found that differentiation of MSCs associated with electrophysiological competence comparable to bladder SMCs. Within 1-2 weeks of myogenic differentiation, differentiating MSCs significantly expressed alpha smooth muscle actin (αSMA; ACTA2, transgelin (TAGLN, calponin (CNN1, and smooth muscle myosin heavy chain (SM-MHC; MYH11 according to qRT-PCR and/or immunofluorescence and Western blot. Voltage-gated Na+ current levels also increased within the same time period following myogenic differentiation. In contrast to undifferentiated MSCs, differentiated MSCs and bladder SMCs exhibited elevated cytosolic Ca2+ transients in response to K+-induced depolarization and contracted in response to K+ indicating functional maturation of differentiated MSCs. Depolarization was suppressed by Cd2+, an inhibitor of voltage-gated Ca2+-channels. The expression of Na+-channels was pharmacologically identified as the Nav1.4 subtype, while the K+ and Ca2+ ion channels were identified by gene expression of KCNMA1, CACNA1C and CACNA1H which encode for the large conductance Ca2+-activated K+ channel BKCa channels, Cav1.2 L-type Ca2+ channels and Cav3.2 T-type Ca2+ channels, respectively. This protocol may be used to differentiate adult MSCs into smooth muscle-like cells with an intermediate-to-late SMC contractile phenotype exhibiting voltage-gated ion

Cultured smooth muscle cells of the human vesical sphincter are more sensitive to histamine than are detrusor smooth muscle cells.

Science.gov (United States)

Neuhaus, Jochen; Oberbach, Andreas; Schwalenberg, Thilo; Stolzenburg, Jens-Uwe

2006-05-01

To compare histamine receptor expression in cultured smooth muscle cells from the human detrusor and internal sphincter using receptor-specific agonists. Smooth muscle cells from the bladder dome and internal sphincter were cultured from 5 male patients undergoing cystectomy for bladder cancer therapy. Calcium transients in cells stimulated with carbachol, histamine, histamine receptor 1 (H1R)-specific heptanecarboxamide (HTMT), dimaprit (H2R), and R-(alpha)-methylhistamine (H3R) were measured by calcium imaging. Histamine receptor proteins were detected by Western blot analysis and immunocytochemistry. H1R, H2R, and H3R expression was found in tissue and cultured cells. Carbachol stimulated equal numbers of detrusor and sphincter cells (60% and 51%, respectively). Histamine stimulated significantly more cells than carbachol in detrusor (100%) and sphincter (99.34%) cells. Calcium responses to carbachol in detrusor and sphincter cells were comparable and did not differ from those to histamine in detrusor cells. However, histamine and specific agonists stimulated more sphincter cells than did carbachol (P <0.001), and the calcium increase was greater in sphincter cells than in detrusor cells. Single cell analysis revealed comparable H2R responses in detrusor and sphincter cells, but H1R and H3R-mediated calcium reactions were significantly greater in sphincter cells. Histamine very effectively induces calcium release in smooth muscle cells. In sphincter cells, histamine is even more effective than carbachol regarding the number of reacting cells and the intracellular calcium increase. Some of the variability in the outcome of antihistaminic interstitial cystitis therapies might be caused by the ineffectiveness of the chosen antihistaminic or unintentional weakening of sphincteric function.

Human Pulmonary Infection by the Zoonotic Metastrongylus salmi Nematode. The First Reported Case in the Americas

Science.gov (United States)

Calvopina, Manuel; Caballero, Henry; Morita, Tatsushi; Korenaga, Masataka

2016-01-01

Pulmonary metastrongylosis, a zoonotic disease found primarily in pigs, is caused by eight different species of the cosmopolitan nematode Metastrongylus genus. To date, only four human cases have been reported, all from Europe. Herein, a severe case of pulmonary infection caused by Metastrongylus salmi in an Ecuadorian man, with successful treatment with ivermectin, is described. PMID:27382078

Massive Pulmonary Embolism: Treatment with Thrombus Fragmentation and Local Fibrinolysis with Recombinant Human-Tissue Plasminogen Activator

International Nuclear Information System (INIS)

Stock, Klaus Wilhelm; Jacob, Augustinus Ludwig; Schnabel, Karl Jakob; Bongartz, Georg; Steinbrich, Wolfgang

1997-01-01

Purpose: To report the results of thrombus fragmentation in combination with local fibrinolysis using recombinant human-tissue plasminogen activator (rtPA) in patients with massive pulmonary embolism. Methods: Five patients with massive pulmonary embolism were treated with thrombus fragmentation followed by intrapulmonary injection of rtPA. Clot fragmentation was performed with a guidewire, angiographic catheter, and balloon catheter. Three patients had undergone recent surgery; one of them received a reduced dosage of rtPA. Results: All patients survived and showed clinical improvement with a resultant significant (p < 0.05) decrease in the pulmonary blood pressure (mean systolic pulmonary blood pressure before treatment, 49 mmHg; 4 hr after treatment, 28 mmHg). Angiographic follow-up in three patients revealed a decrease in thrombus material and an increase in pulmonary perfusion. Two patients developed retroperitoneal hematomas requiring transfusion. Conclusion: Clot fragmentation and local fibrinolysis with rtPA was an effective therapy for massive pulmonary embolism. Bleeding at the puncture site was a frequent complication

Live attenuated Francisella novicida vaccine protects against Francisella tularensis pulmonary challenge in rats and non-human primates.

Directory of Open Access Journals (Sweden)

Ping Chu

2014-10-01

Full Text Available Francisella tularensis causes the disease tularemia. Human pulmonary exposure to the most virulent form, F. tularensis subsp. tularensis (Ftt, leads to high morbidity and mortality, resulting in this bacterium being classified as a potential biothreat agent. However, a closely-related species, F. novicida, is avirulent in healthy humans. No tularemia vaccine is currently approved for human use. We demonstrate that a single dose vaccine of a live attenuated F. novicida strain (Fn iglD protects against subsequent pulmonary challenge with Ftt using two different animal models, Fischer 344 rats and cynomolgus macaques (NHP. The Fn iglD vaccine showed protective efficacy in rats, as did a Ftt iglD vaccine, suggesting no disadvantage to utilizing the low human virulent Francisella species to induce protective immunity. Comparison of specific antibody profiles in vaccinated rat and NHP sera by proteome array identified a core set of immunodominant antigens in vaccinated animals. This is the first report of a defined live attenuated vaccine that demonstrates efficacy against pulmonary tularemia in a NHP, and indicates that the low human virulence F. novicida functions as an effective tularemia vaccine platform.

Interstitial cells of Cajal in human small intestine. Ultrastructural identification and organization between the main smooth muscle layers

DEFF Research Database (Denmark)

Rumessen, J J; Thuneberg, L

1991-01-01

with elastin fibers. The organization shown in this study strongly supports the concept of interstitial cells of Cajal as important regulatory cells also in the human small intestine. The characteristic cytology and organization of interstitial cells of Cajal may provide a basis for future morphological......Previous morphological and electrophysiological studies have supported the hypothesis that interstitial cells of Cajal have important regulatory (pacemaker) functions in the gut. In the current study, interstitial cells of Cajal associated with Auerbach's plexus in human small intestine were...... studied. Freshly resected intestine was examined by light and electron microscopy. The interstitial cells of Cajal resembled modified smooth muscle cells. They had caveolae and dense bodies, an incomplete basal lamina, a very well-developed smooth endoplasmic reticulum, and abundant intermediate (10 nm...

Pediatric Pulmonary Abscess

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Kyle Barbour

2018-04-01

Full Text Available History of present illness: A 6-year-old previously healthy male presented to the emergency department with three days of left upper quadrant abdominal pain. Family endorsed one week of fevers, cough productive of yellow sputum, and non-bilious, non-bloody emesis. He denied shortness of breath and chest pain. On exam, the patient was febrile with otherwise normal vital signs. He had diffuse tenderness to his abdomen but clear lungs. Laboratory studies revealed leukocytosis to 25,000/mm3 with a left shift. Significant findings: Upright posterior-anterior plain chest films show a left lower lobe consolidation with an air-fluid level and a single septation consistent with a pulmonary abscess (white arrows. A small left pleural effusion was also present, seen as blunting of the left costophrenic angle and obscuration of the left hemidiaphragm (black arrows. Discussion: Pediatric pulmonary abscesses are rare, most commonly caused by aspiration, and the majority consequently arise in dependent portions of the lung.1 The most common pathogens in children are Streptococcus pneumoniaeand Staphylococcus aureus.1 Immunocompromised patients and those with existing pulmonary disease more commonly contract Pseudomonas aeruginosaor Bacteroides, and fungal pathogens are possible.1 Common symptoms include tachypnea, fever, and cough. Imaging is necessary to distinguish pulmonary abscesses from pneumonia, empyema, pneumatocele, and other etiologies. Plain film radiography may miss up to 18% of pulmonary abscesses yet is often the first modality to visualize an intrathoracic abnormality.2 If seen, pulmonary abscesses most often appear as consolidations with air-fluid levels. Generally, pulmonary abscesses are round with irregular, thick walls, whereas empyemas are elliptical with smooth, thin walls.3 However, these characteristics cannot definitively distinguish these processes.2 Advantages of plain films include being low cost and easily obtained. Computed

Humane metapneumovirus (HMPV) associated pulmonary infections in immunocompromised adults—Initial CT findings, disease course and comparison to respiratory-syncytial-virus (RSV) induced pulmonary infections

International Nuclear Information System (INIS)

Syha, R.; Beck, R.; Hetzel, J.; Ketelsen, D.; Grosse, U.; Springer, F.; Horger, M.

2012-01-01

Aim: To describe computed tomography (CT)-imaging findings in human metapneumovirus (HMPV)-related pulmonary infection as well as their temporal course and to analyze resemblances/differences to pulmonary infection induced by the closely related respiratory-syncytial-virus (RSV) in immunocompromised patients. Materials and methods: Chest-CT-scans of 10 HMPV PCR-positive patients experiencing pulmonary symptoms were evaluated retrospectively with respect to imaging findings and their distribution and results were then compared with data acquired in 13 patients with RSV pulmonary infection. Subsequently, we analyzed the course of chest-findings in HMPV patients. Results: In HMPV, 8/10 patients showed asymmetric pulmonary findings, whereas 13/13 patients with RSV-pneumonia presented more symmetrical bilateral pulmonary infiltrates. Image analysis yielded in HMPV patients following results: ground-glass-opacity (GGO) (n = 6), parenchymal airspace consolidations (n = 5), ill-defined nodular-like centrilobular opacities (n = 9), bronchial wall thickening (n = 8). In comparison, results in RSV patients were: GGO (n = 10), parenchymal airspace consolidations (n = 9), ill-defined nodular-like centrilobular opacities (n = 10), bronchial wall thickening (n = 4). In the course of the disease, signs of acute HMPV interstitial pneumonia regressed transforming temporarily in part into findings compatible with bronchitis/bronchiolitis. Conclusions: Early chest-CT findings in patients with HMPV-related pulmonary symptoms are compatible with asymmetric acute interstitial pneumonia accompanied by signs of bronchitis; the former transforming with time into bronchitis and bronchiolitis before they resolve. On the contrary, RSV-induced pulmonary infection exhibits mainly symmetric acute interstitial pneumonia.

Humane metapneumovirus (HMPV) associated pulmonary infections in immunocompromised adults—Initial CT findings, disease course and comparison to respiratory-syncytial-virus (RSV) induced pulmonary infections

Energy Technology Data Exchange (ETDEWEB)

Syha, R., E-mail: roland.syha@med.uni-tuebingen.de [Department of Diagnostic Radiology, Eberhard-Karls-University, Hoppe-Seyler-Str.3, 72076 Tübingen (Germany); Beck, R. [Institute of Medical Virology, Eberhard-Karls-University, Elfriede-Authorn-Str. 6, 72076 Tübingen (Germany); Hetzel, J. [Department of Medical Oncology and Hematology, Eberhard-Karls-University, Otfried-Müller-Str. 10, 72070 Tübingen (Germany); Ketelsen, D.; Grosse, U.; Springer, F.; Horger, M. [Department of Diagnostic Radiology, Eberhard-Karls-University, Hoppe-Seyler-Str.3, 72076 Tübingen (Germany)

2012-12-15

Aim: To describe computed tomography (CT)-imaging findings in human metapneumovirus (HMPV)-related pulmonary infection as well as their temporal course and to analyze resemblances/differences to pulmonary infection induced by the closely related respiratory-syncytial-virus (RSV) in immunocompromised patients. Materials and methods: Chest-CT-scans of 10 HMPV PCR-positive patients experiencing pulmonary symptoms were evaluated retrospectively with respect to imaging findings and their distribution and results were then compared with data acquired in 13 patients with RSV pulmonary infection. Subsequently, we analyzed the course of chest-findings in HMPV patients. Results: In HMPV, 8/10 patients showed asymmetric pulmonary findings, whereas 13/13 patients with RSV-pneumonia presented more symmetrical bilateral pulmonary infiltrates. Image analysis yielded in HMPV patients following results: ground-glass-opacity (GGO) (n = 6), parenchymal airspace consolidations (n = 5), ill-defined nodular-like centrilobular opacities (n = 9), bronchial wall thickening (n = 8). In comparison, results in RSV patients were: GGO (n = 10), parenchymal airspace consolidations (n = 9), ill-defined nodular-like centrilobular opacities (n = 10), bronchial wall thickening (n = 4). In the course of the disease, signs of acute HMPV interstitial pneumonia regressed transforming temporarily in part into findings compatible with bronchitis/bronchiolitis. Conclusions: Early chest-CT findings in patients with HMPV-related pulmonary symptoms are compatible with asymmetric acute interstitial pneumonia accompanied by signs of bronchitis; the former transforming with time into bronchitis and bronchiolitis before they resolve. On the contrary, RSV-induced pulmonary infection exhibits mainly symmetric acute interstitial pneumonia.

Proliferation and extracellular matrix synthesis of smooth muscle cells cultured from human coronary atherosclerotic and restenotic lesions

NARCIS (Netherlands)

D.C. MacLeod (Donald); B.H. Strauss (Bradley); J. Escaned (Javier); V.A.W.M. Umans (Victor); R-J. van Suylen (Robert-Jan); A. Verkerk (Anton); P.J. de Feyter (Pim); P.W.J.C. Serruys (Patrick); M. de Jong (Marcel)

1994-01-01

textabstractOBJECTIVES. The purpose of this study was to examine the proliferative capacity and extracellular matrix synthesis of human coronary plaque cells in vitro. BACKGROUND. Common to both primary atherosclerosis and restenosis are vascular smooth muscle cell proliferation and production of

Adenovirus-assisted lipofection: efficient in vitro gene transfer of luciferase and cytosine deaminase to human smooth muscle cells.

Science.gov (United States)

Kreuzer, J; Denger, S; Reifers, F; Beisel, C; Haack, K; Gebert, J; Kübler, W

1996-07-01

Smooth muscle cells (SMC) are a central cell type involved in multiple processes of coronary artery diseases including restenosis and therefore are major target cells for different aspects of gene transfer. Previous attempts to transfect primary arterial cells using different techniques like liposomes, CaPO4 and electroporation resulted in only low transfection efficiency. The development of recombinant adenoviruses dramatically improved the delivery of foreign genes into different cell types including SMC. However, cloning and identification of recombinants remain difficult and time-consuming techniques. The present study demonstrates that a complex consisting of reporter plasmid encoding firefly luciferase (pLUC), polycationic liposomes and replication-deficient adenovirus was able to yield very high in vitro transfection of primary human smooth muscle cells under optimized conditions. The technique of adenovirus-assisted lipofection (AAL) increases transfer and expression of plasmid DNA in human smooth muscle cells in vitro up to 1000-fold compared to lipofection. To verify the applicability of AAL for gene transfer into human smooth muscle cells we studied a gene therapy approach to suppress proliferation of SMC in vitro, using the prokaryotic cytosine deaminase gene (CD) which enables transfected mammalian cells to deaminate 5-fluorocytosine (5-FC) to the highly toxic 5-fluorouracil (5-FU). The effect of a transient CD expression on RNA synthesis was investigated by means of a cotransfection with a RSV-CD expression plasmid and the luciferase reporter plasmid. Western blot analysis demonstrated high expression of CD protein in transfected SMC. Cotransfected SMC demonstrated two-fold less luciferase activity in the presence of 5-FC (5 mmol/l) after 48 h compared to cells transfected with a non-CD coding plasmid. The data demonstrate that a transient expression of CD could be sufficient to reduce the capacity of protein synthesis in human SMC. This simple and

Selexipag in the treatment of pulmonary arterial hypertension: design, development, and therapy

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Hardin EA

2016-11-01

Full Text Available Elizabeth Ashley Hardin,1 Kelly M Chin2 1Department of Internal Medicine, Division of Cardiology, 2Department of Internal Medicine, Division of Pulmonary and Critical Care Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA Abstract: Pulmonary arterial hypertension is characterized by abnormalities in the small pulmonary arteries including increased vasoconstriction, vascular remodeling, proliferation of smooth muscle cells, and in situ thrombosis. Selexipag, a novel, oral prostacyclin receptor agonist, has been shown to improve hemodynamics in a phase II clinical trial and reduce clinical worsening in a large phase III clinical trial involving patients with pulmonary arterial hypertension. In this paper, we describe the prostacyclin signaling pathway, currently available oral prostanoid medications, and the development and clinical use of selexipag. Keywords: selexipag, pulmonary arterial hypertension, prostacyclin

LPS, but not Angiotensin ll, lnduces Direct Pro-lnflammatory Effects in Cultured Mouse Arteries and Human Endothelial and Vascular Smooth Muscle Cells

DEFF Research Database (Denmark)

Outzen, Emilie M; Zaki, Marina; Mehryar, Rahila

2017-01-01

resistance-sized arteries (MRA) supported by experiments in cultured human primary endothelial and vascular smooth muscle cells. Results showed that 24-hr organ culture of mouse MRA with 10 nM Ang II had, unlike 100 ng/mL LPS, no effects on IL-6 or MCP-1 secretion, VCAM1 mRNA expression or endothelial......]-Ang II had no concentration- or time-dependent effects on IL-6 and MCP-1 secretion in human umbilical vein endothelial cells (HUVEC) and human aortic smooth muscle cells (HASMC). AGTR1 or AGTR2 mRNA expression were undetectable in HUVEC, whereas HASMC expressed only AGTR1 mRNA. In summary, contrary...... rights reserved....

Human Pulmonary Infection by the Zoonotic Metastrongylus salmi Nematode. The First Reported Case in the Americas.

Science.gov (United States)

Calvopina, Manuel; Caballero, Henry; Morita, Tatsushi; Korenaga, Masataka

2016-10-05

Pulmonary metastrongylosis, a zoonotic disease found primarily in pigs, is caused by eight different species of the cosmopolitan nematode Metastrongylus genus. To date, only four human cases have been reported, all from Europe. Herein, a severe case of pulmonary infection caused by Metastrongylus salmi in an Ecuadorian man, with successful treatment with ivermectin, is described. © The American Society of Tropical Medicine and Hygiene.

Defective angiogenesis delays thrombus resolution: a potential pathogenetic mechanism underlying chronic thromboembolic pulmonary hypertension

Science.gov (United States)

Panzenboeck, Adelheid; Winter, Max P; Schubert, Uwe; Voswinckel, Robert; Frey, Maria K; Jakowitsch, Johannes; Alimohammadi, Arman; Hobohm, Lukas; Mangold, Andreas; Bergmeister, Helga; Sibilia, Maria; Wagner, Erwin F; Mayer, Eckhard; Klepetko, Walter; Hoelzenbein, Thomas J; Preissner, Klaus T; Lang, Irene M

2015-01-01

Objective Restoration of patency is a natural target of vascular remodeling following venous thrombosis that involves vascular endothelial cells and smooth muscle cells as well as leukocytes. Acute pulmonary emboli usually resolve within six months. However, in some instances, thrombi transform into fibrous vascular obstructions, resulting in occlusion of the deep veins, or in chronic thromboembolic pulmonary hypertension (CTEPH). We proposed that dysregulated thrombus angiogenesis may contribute to thrombus persistence. Approach and Results Mice with an endothelial-cell-specific conditional deletion of vascular endothelial growth factor receptor 2/kinase insert domain protein receptor (VEGF-R2/Kdr) were utilized in a model of stagnant flow venous thrombosis closely resembling human deep vein thrombosis. Biochemical and functional analyses were performed on pulmonary endarterectomy specimens from patients with CTEPH, a human model of non-resolving venous thromboembolism. Endothelial cell-specific deletion of Kdr and subsequent ablation of thrombus vascularization delayed thrombus resolution. In accordance with these findings, organized human CTEPH thrombi were largely devoid of vascular structures. Several vessel-specific genes such as KDR, vascular endothelial cadherin and podoplanin were expressed at lower levels in white CTEPH thrombi than in organizing deep vein thrombi and organizing thrombi from aortic aneurysms. In addition, red CTEPH thrombi attenuated the angiogenic response induced by VEGF. Conclusions In the present work, we propose a mechanism of thrombus non-resolution demonstrating that endothelial cell-specific deletion of Kdr abates thrombus vessel formation, misguiding thrombus resolution. Medical conditions associated with the development of CTEPH may be compromising early thrombus angiogenesis. PMID:24526692

Restenosis after balloon valvuloplasty in a dog with pulmonary stenosis.

Science.gov (United States)

Sunahara, Hiroshi; Fujii, Yoko; Sugimoto, Keisuke; Aoki, Takuma; Sugahara, Gou; Shirota, Kinji

2015-01-01

A two-month-old female Chihuahua was diagnosed as severe pulmonary valvular stenosis (PS). Although balloon valvuloplasty (BV) was successfully performed, restenosis was observed 19 months after the procedure. Euthanasia was chosen due to low output syndrome during the surgical repair attempted when the dog was 5 years old. Postmortem examination revealed markedly thickened pulmonary valve due to the increase of extracellular matrix which might be produced by increased α smooth muscle actin-positive myofibroblasts. The thickening of the valve was associated with restriction of the valve's motion, resulting in restenosis in the present case. This is the first case report documented histopathological and immunohistochemical findings of the restenotic pulmonary valve in dogs with PS after BV.

Theophylline prevents NAD+ depletion via PARP-1 inhibition in human pulmonary epithelial cells

International Nuclear Information System (INIS)

Moonen, Harald J.J.; Geraets, Liesbeth; Vaarhorst, Anika; Bast, Aalt; Wouters, Emiel F.M.; Hageman, Geja J.

2005-01-01

Oxidative DNA damage, as occurs during exacerbations in chronic obstructive pulmonary disease (COPD), highly activates the nuclear enzyme poly(ADP-ribose)polymerase-1 (PARP-1). This can lead to cellular depletion of its substrate NAD + , resulting in an energy crisis and ultimately in cell death. Inhibition of PARP-1 results in preservation of the intracellular NAD + pool, and of NAD + -dependent cellular processes. In this study, PARP-1 activation by hydrogen peroxide decreased intracellular NAD + levels in human pulmonary epithelial cells, which was found to be prevented in a dose-dependent manner by theophylline, a widely used compound in the treatment of COPD. This enzyme inhibition by theophylline was confirmed in an ELISA using purified human PARP-1 and was found to be competitive by nature. These findings provide new mechanistic insights into the therapeutic effect of theophylline in oxidative stress-induced lung pathologies

Preventive effect of interferon-γ of Chinese genotype on radiation pulmonary fibrosis

International Nuclear Information System (INIS)

Sun Li; Song Liangwen; Liu Tao; Zhang Yong; Yin Jiye; Diao Ruiying

2006-01-01

Objective: To investigate the inhibitive effect of Interferon-γ (γ-IFN) of Chinese genotype on proliferation of human lung fibroblast (HLF) induced by radiation, and examine its possible mechanism and role in prevention and treatment of radiation pulmonary fibrosis. Methods: The proliferation of HLF was determined by MTT assay, the expression of γ-smooth muscle actin (αa-SMA) and the synthesis of collagen type IV by immunocytochemistry assays. Results: Chinese α-IFN was observed to inhibit, proportionally to irradiation dose, the proliferation of HLF induced by 60 Co γ-irradiation. The expression of γ-SMA was remarkable in cytoplasmic matrix after the irradiation, suggesting that irradiation could induce the transformation from fibroblast (FB) to myofibroblast (MFB). The expression of collagen IV was increased with irradiation. Compared with the irradiated group, the expression of collagen IV was lower when γ-IFN was administered before being irradiated. Conclusion: 60 Co γ irradiation can induce pulmonary fibrosis by promoting the proliferation of HLF, inducing the transformation from FB to MFB, and increasing the excreting of collagen type IV. γ-IFN can prevent pulmonary fibrosis by effectively inhibiting the abnormal proliferation of HLF and the excessive synthesis of collagen IV after irradiation. (authors)

Tyrosine phosphorylation of Kv1.5 is upregulated in intrauterine growth retardation rats with exaggerated pulmonary hypertension

Directory of Open Access Journals (Sweden)

L.C. Fu

2017-09-01

Full Text Available Intrauterine growth retardation (IUGR is associated with the development of adult-onset diseases, including pulmonary hypertension. However, the underlying mechanism of the early nutritional insult that results in pulmonary vascular dysfunction later in life is not fully understood. Here, we investigated the role of tyrosine phosphorylation of voltage-gated potassium channel 1.5 (Kv1.5 in this prenatal event that results in exaggerated adult vascular dysfunction. A rat model of chronic hypoxia (2 weeks of hypoxia at 12 weeks old following IUGR was used to investigate the physiological and structural effect of intrauterine malnutrition on the pulmonary artery by evaluating pulmonary artery systolic pressure and vascular diameter in male rats. Kv1.5 expression and tyrosine phosphorylation in pulmonary artery smooth muscle cells (PASMCs were determined. We found that IUGR increased mean pulmonary artery pressure and resulted in thicker pulmonary artery smooth muscle layer in 14-week-old rats after 2 weeks of hypoxia, while no difference was observed in normoxia groups. In the PASMCs of IUGR-hypoxia rats, Kv1.5 mRNA and protein expression decreased while that of tyrosine-phosphorylated Kv1.5 significantly increased. These results demonstrate that IUGR leads to exaggerated chronic hypoxia pulmonary arterial hypertension (CH-PAH in association with decreased Kv1.5 expression in PASMCs. This phenomenon may be mediated by increased tyrosine phosphorylation of Kv1.5 in PASMCs and it provides new insight into the prevention and treatment of IUGR-related CH-PAH.

Pulmonary vein and atrial wall pathology in human total anomalous pulmonary venous connection

NARCIS (Netherlands)

Douglas, Yvonne L.; Jongbloed, Monique R. M.; den Hartog, Wietske C. E.; Bartelings, Margot M.; Bogers, Ad J. J. C.; Ebels, Tjark; DeRuiter, Marco C.; Gittenberger-de Groot, Adriana C.

2009-01-01

Background: Normally, the inside of the left atrial (LA) body and pulmonary veins (PVs) is lined by vessel wall tissue covered by myocardium. In total anomalous pulmonary venous connection (TAPVC), no connection of the PVs with the LA body exists. These veins have an increased incidence of PV

Aspirin reduces lipopolysaccharide-induced pulmonary inflammation in human models of ARDS.

Science.gov (United States)

Hamid, U; Krasnodembskaya, A; Fitzgerald, M; Shyamsundar, M; Kissenpfennig, A; Scott, C; Lefrancais, E; Looney, M R; Verghis, R; Scott, J; Simpson, A J; McNamee, J; McAuley, D F; O'Kane, C M

2017-11-01

Platelets play an active role in the pathogenesis of acute respiratory distress syndrome (ARDS). Animal and observational studies have shown aspirin's antiplatelet and immunomodulatory effects may be beneficial in ARDS. To test the hypothesis that aspirin reduces inflammation in clinically relevant human models that recapitulate pathophysiological mechanisms implicated in the development of ARDS. Healthy volunteers were randomised to receive placebo or aspirin 75  or 1200 mg (1:1:1) for seven days prior to lipopolysaccharide (LPS) inhalation, in a double-blind, placebo-controlled, allocation-concealed study. Bronchoalveolar lavage (BAL) was performed 6 hours after inhaling 50 µg of LPS. The primary outcome measure was BAL IL-8. Secondary outcome measures included markers of alveolar inflammation (BAL neutrophils, cytokines, neutrophil proteases), alveolar epithelial cell injury, systemic inflammation (neutrophils and plasma C-reactive protein (CRP)) and platelet activation (thromboxane B2, TXB2). Human lungs, perfused and ventilated ex vivo (EVLP) were randomised to placebo or 24 mg aspirin and injured with LPS. BAL was carried out 4 hours later. Inflammation was assessed by BAL differential cell counts and histological changes. In the healthy volunteer (n=33) model, data for the aspirin groups were combined. Aspirin did not reduce BAL IL-8. However, aspirin reduced pulmonary neutrophilia and tissue damaging neutrophil proteases (Matrix Metalloproteinase (MMP)-8/-9), reduced BAL concentrations of tumour necrosis factor α and reduced systemic and pulmonary TXB2. There was no difference between high-dose and low-dose aspirin. In the EVLP model, aspirin reduced BAL neutrophilia and alveolar injury as measured by histological damage. These are the first prospective human data indicating that aspirin inhibits pulmonary neutrophilic inflammation, at both low and high doses. Further clinical studies are indicated to assess the role of aspirin in the

Inhalable delivery of AAV-based MRP4/ABCC4 silencing RNA prevents monocrotaline-induced pulmonary hypertension

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Caroline Claude

Full Text Available The ATP-binding cassette transporter MRP4 (encoded by ABCC4 regulates membrane cyclic nucleotides concentrations in arterial cells including smooth muscle cells. MRP4/ABCC4 deficient mice display a reduction in smooth muscle cells proliferation and a prevention of pulmonary hypertension in response to hypoxia. We aimed to study gene transfer of a MRP4/ABCC4 silencing RNA via intratracheal delivery of aerosolized adeno-associated virus 1 (AAV1.shMRP4 or AAV1.control in a monocrotaline-induced model of pulmonary hypertension in rats. Gene transfer was performed at the time of monocrotaline administration and the effect on the development of pulmonary vascular remodeling was assessed 35 days later. AAV1.shMRP4 dose-dependently reduced right ventricular systolic pressure and hypertrophy with a significant reduction with the higher doses (i.e., >1011 DRP/animal as compared to AAV1.control. The higher dose of AAV1.shMRP4 was also associated with a significant reduction in distal pulmonary arteries remodeling. AAV1.shMRP4 was finally associated with a reduction in the expression of ANF, a marker of cardiac hypertrophy. Collectively, these results support a therapeutic potential for downregulation of MRP4 for the treatment of pulmonary artery hypertension.

Effects of the dual TP receptor antagonist and thromboxane synthase inhibitor EV-077 on human endothelial and vascular smooth muscle cells

International Nuclear Information System (INIS)

Petri, Marcelo H.; Tellier, Céline; Michiels, Carine; Ellertsen, Ingvill; Dogné, Jean-Michel; Bäck, Magnus

2013-01-01

Highlights: •EV-077 reduced TNF-α induced inflammation in endothelial cells. •The thromboxane mimetic U69915 enhanced vascular smooth muscle cell proliferation. •EV-077 inhibited smooth muscle cell proliferation. -- Abstract: The prothrombotic mediator thromboxane A 2 is derived from arachidonic acid metabolism through the cyclooxygenase and thromboxane synthase pathways, and transduces its effect through the thromboxane prostanoid (TP) receptor. The aim of this study was to determine the effect of the TP receptor antagonist and thromboxane synthase inhibitor EV-077 on inflammatory markers in human umbilical vein endothelial cells and on human coronary artery smooth muscle cell proliferation. To this end, mRNA levels of different proinflammatory mediators were studied by real time quantitative PCR, supernatants were analyzed by enzyme immune assay, and cell proliferation was assessed using WST-1. EV-077 significantly decreased mRNA levels of ICAM-1 and PTX3 after TNFα incubation, whereas concentrations of 6-keto PGF1α in supernatants of endothelial cells incubated with TNFα were significantly increased after EV-077 treatment. Although U46619 did not alter coronary artery smooth muscle cell proliferation, this thromboxane mimetic enhanced the proliferation induced by serum, insulin and growth factors, which was significantly inhibited by EV-077. In conclusion, EV-077 inhibited TNFα-induced endothelial inflammation and reduced the enhancement of smooth muscle cell proliferation induced by a thromboxane mimetic, supporting that the thromboxane pathway may be associated with early atherosclerosis in terms of endothelial dysfunction and vascular hypertrophy

Effects of the dual TP receptor antagonist and thromboxane synthase inhibitor EV-077 on human endothelial and vascular smooth muscle cells

Energy Technology Data Exchange (ETDEWEB)

Petri, Marcelo H. [Department of Medicine, Karolinska Institutet and Center for Molecular Medicine, Karolinska University Hospital, Stockholm (Sweden); Tellier, Céline; Michiels, Carine [NARILIS, URBC, University of Namur, Namur (Belgium); Ellertsen, Ingvill [Department of Medicine, Karolinska Institutet and Center for Molecular Medicine, Karolinska University Hospital, Stockholm (Sweden); Dogné, Jean-Michel [Department of Pharmacy, Namur Thrombosis and Hemostasis Center, University of Namur, Namur (Belgium); Bäck, Magnus, E-mail: Magnus.Back@ki.se [Department of Medicine, Karolinska Institutet and Center for Molecular Medicine, Karolinska University Hospital, Stockholm (Sweden)

2013-11-15

Highlights: •EV-077 reduced TNF-α induced inflammation in endothelial cells. •The thromboxane mimetic U69915 enhanced vascular smooth muscle cell proliferation. •EV-077 inhibited smooth muscle cell proliferation. -- Abstract: The prothrombotic mediator thromboxane A{sub 2} is derived from arachidonic acid metabolism through the cyclooxygenase and thromboxane synthase pathways, and transduces its effect through the thromboxane prostanoid (TP) receptor. The aim of this study was to determine the effect of the TP receptor antagonist and thromboxane synthase inhibitor EV-077 on inflammatory markers in human umbilical vein endothelial cells and on human coronary artery smooth muscle cell proliferation. To this end, mRNA levels of different proinflammatory mediators were studied by real time quantitative PCR, supernatants were analyzed by enzyme immune assay, and cell proliferation was assessed using WST-1. EV-077 significantly decreased mRNA levels of ICAM-1 and PTX3 after TNFα incubation, whereas concentrations of 6-keto PGF1α in supernatants of endothelial cells incubated with TNFα were significantly increased after EV-077 treatment. Although U46619 did not alter coronary artery smooth muscle cell proliferation, this thromboxane mimetic enhanced the proliferation induced by serum, insulin and growth factors, which was significantly inhibited by EV-077. In conclusion, EV-077 inhibited TNFα-induced endothelial inflammation and reduced the enhancement of smooth muscle cell proliferation induced by a thromboxane mimetic, supporting that the thromboxane pathway may be associated with early atherosclerosis in terms of endothelial dysfunction and vascular hypertrophy.

Role of Spm-Cer-S1P signalling pathway in MMP-2 mediated U46619-induced proliferation of pulmonary artery smooth muscle cells: protective role of epigallocatechin-3-gallate.

Science.gov (United States)

Chowdhury, Animesh; Sarkar, Jaganmay; Chakraborti, Tapati; Chakraborti, Sajal

2015-10-01

During remodelling of pulmonary artery, marked proliferation of pulmonary artery smooth muscle cells (PASMCs) occurs, which contributes to pulmonary hypertension. Thromboxane A2 (TxA2) has been shown to produce pulmonary hypertension. The present study investigates the inhibitory effect of epigallocatechin-3-gallate (EGCG) on the TxA2 mimetic, U46619-induced proliferation of PASMCs. U46619 at a concentration of 10 nM induces maximum proliferation of bovine PASMCs. Both pharmacological and genetic inhibitors of p(38)MAPK, NF-κB and MMP-2 significantly inhibit U46619-induced cell proliferation. EGCG markedly abrogate U46619-induced p(38)MAPK phosphorylation, NF-κB activation, proMMP-2 expression and activation, and also the cell proliferation. U46619 causes an increase in the activation of sphingomyelinase (SMase) and sphingosine kinase (SPHK) and also increase sphingosine 1 phosphate (S1P) level. U46619 also induces phosphorylation of ERK1/2, which phosphorylates SPHK leading to an increase in S1P level. Both pharmacological and genetic inhibitors of SMase and SPHK markedly inhibit U46619-induced cell proliferation. Additionally, pharmacological and genetic inhibitors of MMP-2 markedly abrogate U46619-induced SMase activity and S1P level. EGCG markedly inhibit U46619-induced SMase activity, ERK1/2 and SPHK phosphorylation and S1P level in the cells. Overall, Sphingomyeline-Ceramide-Sphingosine-1-phosphate (Spm-Cer-S1P) signalling axis plays an important role in MMP-2 mediated U46619-induced proliferation of PASMCs. Importantly, EGCG inhibits U46619 induced increase in MMP-2 activation by modulating p(38)MAPK-NFκB pathway and subsequently prevents the cell proliferation. Copyright © 2015 John Wiley & Sons, Ltd.

A Clinicopathological Analysis of Pulmonary Lymphangioleiomyomatosis

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Jun GAO

2011-04-01

Full Text Available Background and objective Pulmonary lymphangioleiomyomatosis (PLAM is a rare tumor with unique clinicopathological features. The aim of this study is to investigate the clinicopathological features, the diagnosis and differential diagnosis of pulmonary lymphangioleiomyomatosis. Methods Three cases of PLAM were analyzed by light microscopy, immunohistochemistry and their clinical data, and the relative literatures were reviewed. Results Three cases of patients suffered from PLAM were the women in their reproductive aged, from 27 years to 45 years (mean 37.7 years, two cases of the HRCT showed bilateral diffuse cystic airspaces changed, and one case was the pneumothorax. The histopathological examination revealed the tumor was composed of the variably sized cystic spaces are lined by plaque-like or nodular aggregates of endothelial cells and the hyperplasia, smooth-muscle-like spindle cells which was along with the bronchi and the vessels. The immunohistochemistry showed that Des, Caldes, SMA, MSA, HMB-45, CD63, Vim, ER and PR were positive in the hyperplasia spindle cells, and there was no expression of MRAT-1. The FVIII, CD34 were positive in the capillary endothelial cells, and the D2-40 was positive in the lymphatic vessels. All the patients were alive without the recrudescence of the PLAM since the diagnosis, about 3 months to 25 months, and there was no LAM in their other systems. Conclusion The most significant histopathological feature of pulmonary lymphangioleiomyomatosis was the progressive invasion of smooth muscle cells into the lymphatic vessels, and the blood vessels. The majority of the cases occur in the lungs of the women in the predominantly premenopausal and middle-age. It is a poor prognosis due to the progressive respiratory failure.

Benzo(a)pyrene activation and detoxification by human pulmonary alveolar macrophages and lymphocytes

International Nuclear Information System (INIS)

Marshall, M.V.; McLemore, T.L.; Martin, R.R.; Marshall, M.H.; Wray, N.P.; Busbee, D.L.; Cantrell, E.T.; Arnott, M.S.; Griffin, A.C.

1980-01-01

Comparisons of pulmonary alveolar macrophages and circulating lymphocytes from five smokers and five nonsmokers for their ability to metabolize benzo(a)pyrene as determined by high pressure liquid chromatography were carried out. Utilizing this approach, further investigation of activation and detoxification by several human cell types could provide the basis for more precise and comprehensive studies of carcinogen and drug metabolism in the human lung, and for a better assessment of cancer risk in selected populations

Invasive Pulmonary Aspergillosis-mimicking Tuberculosis.

Science.gov (United States)

Kim, Sung-Han; Kim, Mi Young; Hong, Sun In; Jung, Jiwon; Lee, Hyun Joo; Yun, Sung-Cheol; Lee, Sang-Oh; Choi, Sang-Ho; Kim, Yang Soo; Woo, Jun Hee

2015-07-01

Pulmonary tuberculosis is occasionally confused with invasive pulmonary aspergillosis (IPA) in transplant recipients, since clinical suspicion and early diagnosis of pulmonary tuberculosis and IPA rely heavily on imaging modes such as computed tomography (CT). We therefore investigated IPA-mimicking tuberculosis in transplant recipients. All adult transplant recipients who developed tuberculosis or IPA at a tertiary hospital in an intermediate tuberculosis-burden country during a 6-year period were enrolled. First, we tested whether experienced radiologists could differentiate pulmonary tuberculosis from IPA. Second, we determined which radiologic findings could help us differentiate them. During the study period, 28 transplant recipients developed pulmonary tuberculosis after transplantation, and 80 patients developed IPA after transplantation. Two experienced radiologists scored blindly 28 tuberculosis and 50 randomly selected IPA cases. The sensitivities of radiologists A and B for IPA were 78% and 68%, respectively (poor agreement, kappa value = 0.25). The sensitivities of radiologists A and B for tuberculosis were 64% and 61%, respectively (excellent agreement, kappa value = 0.77). We then compared the CT findings of the 28 patients with tuberculosis and 80 patients with IPA. Infarct-shaped consolidations and smooth bronchial wall thickening were more frequent in IPA, and mass-shaped consolidations and centrilobular nodules (tuberculosis. Certain CT findings appear to be helpful in differentiating between IPA and tuberculosis. Nevertheless, the CT findings of about one-third of pulmonary tuberculosis cases in transplant recipients are very close to those of IPA. © The Author 2015. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

Protective effect of fenspiride on the bronchi in rats with chronic obstructive pulmonary disease.

Science.gov (United States)

Kuzubova, N A; Lebedeva, E S; Fedin, A N; Dvorakovskaya, I V; Titova, O N

2013-06-01

We studied the effect of a non-steroidal anti-inflammatory drug fenspiride on contractive activity of bronchial smooth muscles on the model of chronic obstructive pulmonary disease of rats induced by 60-day exposure to nitrogen dioxide. The administration of fenspiride during the acute stage of the disease (day 15) abolished the constricting effect of the pollutant on the bronchial smooth muscles. Dilatation effect of fenspiride in a low dose (0.15 mg/kg) was mediated by its interaction with nerve endings of bronchial capsaicin-sensitive nerve C-fibers. The interaction of drug with receptors of C-fibers prevented neurogenic inflammation, which was confirmed by the absence of structural changes in the lungs typical of this pathology. The broncholytic effect of fenspiride in a high dose (15 mg/kg) was mediated by not only afferent pathways, but also its direct relaxing action on smooth muscle cells. The observed anti-inflammatory and bronchodilatation effect of fenspiride in very low doses can be used for prevention of chronic obstructive pulmonary disease in risk-group patients contacting with aggressive environmental factors.

The pathogenesis of bleomycin-induced lung injury in animals and its applicability to human idiopathic pulmonary fibrosis.

Science.gov (United States)

Williamson, James D; Sadofsky, Laura R; Hart, Simon P

2015-03-01

Idiopathic pulmonary fibrosis (IPF) is a devastating disease of unknown etiology, for which there is no curative pharmacological therapy. Bleomycin, an anti-neoplastic agent that causes lung fibrosis in human patients has been used extensively in rodent models to mimic IPF. In this review, we compare the pathogenesis and histological features of human IPF and bleomycin-induced pulmonary fibrosis (BPF) induced in rodents by intratracheal delivery. We discuss the current understanding of IPF and BPF disease development, from the contribution of alveolar epithelial cells and inflammation to the role of fibroblasts and cytokines, and draw conclusions about what we have learned from the intratracheal bleomycin model of lung fibrosis.

High-resolution computed tomography findings in eight patients with hantavirus pulmonary syndrome

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Barbosa, Diego de Lacerda; Hochhegger, Bruno; Souza Junior, Arthur Soares; Zanetti, Glaucia; Escuissato, Dante Luiz; Meirelles, Gustavo de Souza Portes; Funari, Marcelo Buarque de Gusmao; Marchiori, Edson, E-mail: edmarchiori@gmail.com [Universidade Federal do Rio de Janeiro (UFRJ), Rio de Janeiro, RJ (Brazil); Santa Casa de Porto Alegre, Porto Alegre, RS (Brazil); Faculdade de Medicina de Sao Jose do Rio Preto (FAMERP), SP (Brazil); Ultra X, Sao Jose do Rio Preto, SP (Brazil); Universidade Federal do Parana (UFPR), Curitiba, PR (Brazil); Universidade Federal de Sao Paulo (UNIFESP), Sao Paulo, SP (Brazil); Grupo Fleury, Sao Paulo, SP (Brazil); Universidade de Sao Paulo (FM/USP), Sao Paulo, SP (Brazil). Faculdade de Medicina

2017-05-15

Objective: The purpose of this study was to describe the high-resolution computed tomography (HRCT) findings in patients with hantavirus pulmonary syndrome (HPS). Materials and Methods: We retrospectively reviewed HRCT findings from eight cases of HPS. All patients were men, aged 19-70 (mean, 41.7) years. Diagnoses were established by serological test (enzyme-linked immunosorbent assay) in all patients. Two chest radiologists analyzed the images and reached decisions by consensus. Results: The predominant HRCT findings were ground-glass opacities (GGOs) and smooth inter- and intralobular septal thickening, found in all eight cases; however, the crazy-paving pattern was found in only three cases. Pleural effusion and peribronchovascular thickening were observed in five patients. The abnormalities were bilateral in all patients. Conclusion: The predominant HRCT findings in patients with HPS were GGOs and smooth inter- and intralobular septal thickening, which probably correlate with the histopathologic findings of pulmonary edema. (author)

High-resolution computed tomography findings in eight patients with hantavirus pulmonary syndrome

International Nuclear Information System (INIS)

Barbosa, Diego de Lacerda; Hochhegger, Bruno; Souza Junior, Arthur Soares; Zanetti, Glaucia; Escuissato, Dante Luiz; Meirelles, Gustavo de Souza Portes; Funari, Marcelo Buarque de Gusmao; Marchiori, Edson; Santa Casa de Porto Alegre, Porto Alegre, RS; Faculdade de Medicina de Sao Jose do Rio Preto; Ultra X, Sao Jose do Rio Preto, SP; Universidade Federal do Parana; Universidade Federal de Sao Paulo; Grupo Fleury, Sao Paulo, SP; Universidade de Sao Paulo

2017-01-01

Objective: The purpose of this study was to describe the high-resolution computed tomography (HRCT) findings in patients with hantavirus pulmonary syndrome (HPS). Materials and Methods: We retrospectively reviewed HRCT findings from eight cases of HPS. All patients were men, aged 19-70 (mean, 41.7) years. Diagnoses were established by serological test (enzyme-linked immunosorbent assay) in all patients. Two chest radiologists analyzed the images and reached decisions by consensus. Results: The predominant HRCT findings were ground-glass opacities (GGOs) and smooth inter- and intralobular septal thickening, found in all eight cases; however, the crazy-paving pattern was found in only three cases. Pleural effusion and peribronchovascular thickening were observed in five patients. The abnormalities were bilateral in all patients. Conclusion: The predominant HRCT findings in patients with HPS were GGOs and smooth inter- and intralobular septal thickening, which probably correlate with the histopathologic findings of pulmonary edema. (author)

Pulmonary Lymphangioleiomyomatosis. Presentation of 3 cases and revision of the literature

International Nuclear Information System (INIS)

Pedrozo Pupo, John C; Robinson, Eugenia; Gaviria, Alejandro; Ojeda Leon, Paulina; Pacheco, Pedro M

2000-01-01

We present three cases of women with pulmonary Iymphangioleiomyomatosis diagnosis, a 47-year-old woman whose initial manifestation was pneumothorax, a 40-year-old woman with progressive dyspnoea and other a 45-year-old woman with pneumothorax. Lymphangioleiomyomatosis is a rare lung disease that afflicts young women childbearing age and premenopausal. It is characterized pathologically by the proliferation of atypical pulmonary interstitial smooth muscle and by cyst formation. Unknown origin usually leads to progressive deterioration of lung function and eventual death from failure. It occurs in women of reproductive age and people with tuberous sclerosis

Oxytocin receptors expressed and coupled to Ca2+ signalling in a human vascular smooth muscle cell line.

Science.gov (United States)

Yazawa, H; Hirasawa, A; Horie, K; Saita, Y; Iida, E; Honda, K; Tsujimoto, G

1996-03-01

1. In a human vascular smooth muscle cell line (HVSMC), binding experiments with [3H]-arginine8-vasopressin (AVP) have shown the existence of a homogeneous population of binding sites with affinity (Kd value) of 0.65 nM and a maximum number of binding sites (Bmax) of 122 fmol mg-1 protein. 2. Nonlabelled compounds compete for [3H]-AVP binding in the HVSMC membrane with an order of potency of oxytocin > lyspressin > or = AVP > Thr4, Gly7-oxytocin > (beta-mercapto-beta-beta-cyclopentamethylenepropionyl-O-Me Tyr2, Arg8) vasopressin > desmopressin > OPC21268 > OPC31260. This order was markedly different from that observed in rat vascular smooth muscle cells (A10), a well-established V1A receptor system. 3. In HVSMC both oxytocin and AVP increased inositol 1,4,5-trisphosphate (IP3) production and [Ca2+]i response, but the efficacy of the responses was greater for oxytocin than AVP. 4. Reverse transcription-polymerase chain reaction (RT-PCR) assay detected only oxytocin receptor but not V1A or V2 receptors in HVSMC, whereas only V1A receptors were found in A10 cells. 5. In conclusion, in HVSMC only oxytocin receptors are expressed among the vasopressin receptor family, and they coupled to phosphatidyl inositol (PI) turnover/Ca2+ signalling. This unexpected observation should provide new insight into the functional role of the oxytocin receptor in a human vascular smooth muscle cell line.

Anti-CTGF single-chain variable fragment dimers inhibit human airway smooth muscle (ASM) cell proliferation by down-regulating p-Akt and p-mTOR levels.

Science.gov (United States)

Gao, Wei; Cai, Liting; Xu, Xudong; Fan, Juxiang; Xue, Xiulei; Yan, Xuejiao; Qu, Qinrong; Wang, Xihua; Zhang, Chen; Wu, Guoqiu

2014-01-01

Connective tissue growth factor (CTGF) contributes to airway smooth muscle (ASM) cell hyperplasia in asthma. Humanized single-chain variable fragment antibody (scFv) was well characterized as a CTGF antagonist in the differentiation of fibroblast into myofibroblast and pulmonary fibrosis in our previous studies. To further improve the bioactivity of scFv, we constructed a plasmid to express scFv-linker-matrilin-6×His fusion proteins that could self-assemble into the scFv dimers by disulfide bonds in matrilin under non-reducing conditions. An immunoreactivity assay demonstrated that the scFv dimer could highly bind to CTGF in a concentration-dependent manner. The MTT and EdU assay results revealed that CTGF (≥10 ng/mL) promoted the proliferation of ASM cells, and this effect was inhibited when the cells were treated with anti-CTGF scFv dimer. The western blot analysis results showed that increased phosphorylation of Akt and mTOR induced by CTGF could be suppressed by this scFv dimer. Based on these findings, anti-CTGF scFv dimer may be a potential agent for the prevention of airway remodeling in asthma.

Tissue-Engineered Vascular Rings from Human iPSC-Derived Smooth Muscle Cells

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Biraja C. Dash

2016-07-01

Full Text Available There is an urgent need for an efficient approach to obtain a large-scale and renewable source of functional human vascular smooth muscle cells (VSMCs to establish robust, patient-specific tissue model systems for studying the pathogenesis of vascular disease, and for developing novel therapeutic interventions. Here, we have derived a large quantity of highly enriched functional VSMCs from human induced pluripotent stem cells (hiPSC-VSMCs. Furthermore, we have engineered 3D tissue rings from hiPSC-VSMCs using a facile one-step cellular self-assembly approach. The tissue rings are mechanically robust and can be used for vascular tissue engineering and disease modeling of supravalvular aortic stenosis syndrome. Our method may serve as a model system, extendable to study other vascular proliferative diseases for drug screening. Thus, this report describes an exciting platform technology with broad utility for manufacturing cell-based tissues and materials for various biomedical applications.

Autoradiographic localization of calcitonin gene-related peptide (CGRP) binding sites in human and guinea pig lung

International Nuclear Information System (INIS)

Mak, J.C.; Barnes, P.J.

1988-01-01

125 I-Human calcitonin gene-related peptide (hCGRP) binding sites were localized in human and guinea pig lungs by an autoradiographic method. Scatchard analysis of saturation experiments from slide-mounted sections of guinea pig lung displayed specific 125 I-hCGRP binding sites with a dissociation constant (Kd) of 0.72 +/- 0.05 nM (mean +/- S.E.M., n = 3) and a maximal number of binding sites (Bmax) of 133.4 +/- 5.6 fmol/mg protein. In both human and guinea pig lung, autoradiography revealed that CGRP binding sites were widely distributed, with particularly dense labeling over bronchial and pulmonary blood vessels of all sizes and alveolar walls. Airway smooth muscle and epithelium of large airways was sparsely labeled but no labeling was found over submucosal glands. This localization corresponds well to the reported pattern of CGRP-like immunoreactive innervation. The findings of localization of CGRP binding sites on bronchial and pulmonary blood vessels indicate that CGRP may be important in the regulation of airway and pulmonary blood flow

[The effect of calcitonin gene-related peptide on collagen accumulation in pulmonary arteries of rats with hypoxic pulmonary arterial hypertension].

Science.gov (United States)

Li, Xian-Wei; Du, Jie; Li, Yuan-Jian

2013-03-01

To observe the effect of calcitonin gene-related peptide (CGRP) on pulmonary vascular collagen accumulation in hypoxia rats in order to study the effect of CGRP on hypoxic pulmonary vascular structural remodeling and its possible mechanism. Rats were acclimated for 1 week, and then were randomly divided into three groups: normoxia group, hypoxia group, and hypoxia plus capsaicin group. Pulmonary arterial hypertension was induced by hypoxia in rats. Hypoxia plus capsaicin group, rats were given capsaicin (50 mg/(kg x d), s.c) 4 days before hypoxia to deplete endogenous CGRP. Hypoxia (3% O2) stimulated proliferation of pulmonary arterial smooth muscle cells (PASMCs) and proliferation was measured by BrdU marking. The expression levels of CGRP, phosphorylated ERK1/2 (p-ERK1/ 2), collagen I and collagen III were detected by real-time PCR or Western blot. Right ventricle systolic pressure (RVSP) and mean pulmonary arterial pressure (mPAP) of pulmonary arterial hypertension (PAH) rats induced by hypoxia were higher than those of normoxia rats. By HE and Masson staining, it was demonstrated that hypoxia also significantly induced hypertrophy of pulmonary arteries and increased level of collagen accumulation. Hypoxia dramatically decreased the CGRP level and increased the expression of p-ERK1/2, collagen I, collagen III in pulmonary arteries. All these effects of hypoxia were further aggravated by pre-treatment of rats with capsaicin. CGRP concentration-dependently inhibited hypoxia-induced proliferation of PASMCs, markedly decreased the expression of p-ERK1/2, collagen I and collagen III. All these effects of CGRP were abolished in the presence of CGRP8-37. These results suggest that CGRP might inhibit hypoxia-induced PAH and pulmonary vascular remodeling, through inhibiting phosphorylation of ERK1/2 and alleviating the collagen accumulation of pulmonary arteries.

Cocaine-induced pulmonary changes: HRCT findings

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Renata Rocha de Almeida

2015-08-01

Full Text Available AbstractObjective: To evaluate HRCT scans of the chest in 22 patients with cocaine-induced pulmonary disease.Methods: We included patients between 19 and 52 years of age. The HRCT scans were evaluated by two radiologists independently, discordant results being resolved by consensus. The inclusion criterion was an HRCT scan showing abnormalities that were temporally related to cocaine use, with no other apparent causal factors.Results:In 8 patients (36.4%, the clinical and tomographic findings were consistent with "crack lung", those cases being studied separately. The major HRCT findings in that subgroup of patients included ground-glass opacities, in 100% of the cases; consolidations, in 50%; and the halo sign, in 25%. In 12.5% of the cases, smooth septal thickening, paraseptal emphysema, centrilobular nodules, and the tree-in-bud pattern were identified. Among the remaining 14 patients (63.6%, barotrauma was identified in 3 cases, presenting as pneumomediastinum, pneumothorax, and hemopneumothorax, respectively. Talcosis, characterized as perihilar conglomerate masses, architectural distortion, and emphysema, was diagnosed in 3 patients. Other patterns were found less frequently: organizing pneumonia and bullous emphysema, in 2 patients each; and pulmonary infarction, septic embolism, eosinophilic pneumonia, and cardiogenic pulmonary edema, in 1 patient each.Conclusions: Pulmonary changes induced by cocaine use are varied and nonspecific. The diagnostic suspicion of cocaine-induced pulmonary disease depends, in most of the cases, on a careful drawing of correlations between clinical and radiological findings.

Cocaine-induced pulmonary changes: HRCT findings

International Nuclear Information System (INIS)

Almeida, Renata Rocha de; Zanetti, Glaucia; Marchiori, Edson; Souza, Luciana Soares de; Silva, Jorge Luiz Pereira e; Mancano, Alexandre Dias; Nobre, Luiz Felipe; Hochhegger, Bruno; Marchiori, Edson

2015-01-01

Objective: To evaluate HRCT scans of the chest in 22 patients with cocaine-induced pulmonary disease. Methods: We included patients between 19 and 52 years of age. The HRCT scans were evaluated by two radiologists independently, discordant results being resolved by consensus. The inclusion criterion was an HRCT scan showing abnormalities that were temporally related to cocaine use, with no other apparent causal factors. Results: In 8 patients (36.4%), the clinical and tomographic findings were consistent with 'crack lung', those cases being studied separately. The major HRCT findings in that subgroup of patients included ground-glass opacities, in 100% of the cases; consolidations, in 50%; and the halo sign, in 25%. In 12.5% of the cases, smooth septal thickening, paraseptal emphysema, centrilobular nodules, and the tree-in-bud pattern were identified. Among the remaining 14 patients (63.6%), barotrauma was identified in 3 cases, presenting as pneumomediastinum, pneumothorax, and hemopneumothorax, respectively. Talcosis, characterized as perihilar conglomerate masses, architectural distortion, and emphysema, was diagnosed in 3 patients. Other patterns were found less frequently: organizing pneumonia and bullous emphysema, in 2 patients each; and pulmonary infarction, septic embolism, eosinophilic pneumonia, and cardiogenic pulmonary edema, in 1 patient each. Conclusions: Pulmonary changes induced by cocaine use are varied and nonspecific. The diagnostic suspicion of cocaine-induced pulmonary disease depends, in most of the cases, on a careful drawing of correlations between clinical and radiological findings. (author)

Cocaine-induced pulmonary changes: HRCT findings

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Almeida, Renata Rocha de; Zanetti, Glaucia; Marchiori, Edson, E-mail: edmarchiori@gmail.com [Universidade Federal do Rio de Janeiro (UFRJ), RJ (Brazil). Programa de Pos-Graduacao em Radiologia; Souza Junior, Arthur Soares [Faculdade de Medicina de Petropolis, Petropolis, RJ (Brazil); Souza, Luciana Soares de [Ultra-X, Sao Jose do Rio Preto, SP (Brazil); Silva, Jorge Luiz Pereira e [Universidade Federal da Bahia (UFBA), Salvador (Brazil). Dep. de Medicina e Apoio Diagnostico; Escuissato, Dante Luiz [Universidade Federal do Parana (UFPR), Curitiba (Brazil). Dept. de Clinica Medica; Irion, Klaus Loureiro [Liverpool Heart and Chest Hospital NHS Foundation Trust, Liverpool (United Kingdom); Mancano, Alexandre Dias [Hospital Anchieta, Taguatinga, DF (Brazil); Nobre, Luiz Felipe [Universidade Federal de Santa Catarina (UFSC), Florianopolis, SC (Brazil); Hochhegger, Bruno [Universidade Federal de Ciencias da Saude de Porto Alegre, Porto Alegre, RS (Brazil); Marchiori, Edson [Universidade Federal Fluminense (UFF), Niteroi, RJ (Brazil)

2015-07-15

Objective: To evaluate HRCT scans of the chest in 22 patients with cocaine-induced pulmonary disease. Methods: We included patients between 19 and 52 years of age. The HRCT scans were evaluated by two radiologists independently, discordant results being resolved by consensus. The inclusion criterion was an HRCT scan showing abnormalities that were temporally related to cocaine use, with no other apparent causal factors. Results: In 8 patients (36.4%), the clinical and tomographic findings were consistent with 'crack lung', those cases being studied separately. The major HRCT findings in that subgroup of patients included ground-glass opacities, in 100% of the cases; consolidations, in 50%; and the halo sign, in 25%. In 12.5% of the cases, smooth septal thickening, paraseptal emphysema, centrilobular nodules, and the tree-in-bud pattern were identified. Among the remaining 14 patients (63.6%), barotrauma was identified in 3 cases, presenting as pneumomediastinum, pneumothorax, and hemopneumothorax, respectively. Talcosis, characterized as perihilar conglomerate masses, architectural distortion, and emphysema, was diagnosed in 3 patients. Other patterns were found less frequently: organizing pneumonia and bullous emphysema, in 2 patients each; and pulmonary infarction, septic embolism, eosinophilic pneumonia, and cardiogenic pulmonary edema, in 1 patient each. Conclusions: Pulmonary changes induced by cocaine use are varied and nonspecific. The diagnostic suspicion of cocaine-induced pulmonary disease depends, in most of the cases, on a careful drawing of correlations between clinical and radiological findings. (author)

Activation of endothelial and epithelial K(Ca) 2.3 calcium-activated potassium channels by NS309 relaxes human small pulmonary arteries and bronchioles

DEFF Research Database (Denmark)

Kroigaard, Christel; Dalsgaard, Thomas; Nielsen, Gorm

2012-01-01

BACKGROUND AND PURPOSE: Small (K(Ca) 2) and intermediate (K(Ca) 3.1) conductance calcium-activated potassium channels (K(Ca) ) may contribute to both epithelium- and endothelium-dependent relaxations, but this has not been established in human pulmonary arteries and bronchioles. Therefore, we inv...... targets for treatment of pulmonary hypertension and chronic obstructive pulmonary disease....

Polyvinylpyrrolidone-Capped Silver Nanoparticle Inhibits Infection of Carbapenem-Resistant Strain of Acinetobacter baumannii in the Human Pulmonary Epithelial Cell

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Vishvanath Tiwari

2017-08-01

Full Text Available Acinetobacter baumannii, an opportunistic ESKAPE pathogen, causes respiratory and urinary tract infections. Its prevalence increases gradually in the clinical setup. Pathogenicity of Acinetobacter is significantly influenced by its ability to infect and survive in human pulmonary cells. Therefore, it is important to study the infection of A. baumannii in human pulmonary host cell (A-549, monitoring surface interacting and internalized bacteria. It was found that during infection of A. baumannii, about 40% bacteria adhered to A-549, whereas 20% got internalized inside pulmonary cell and induces threefold increase in the reactive oxygen species production. We have synthesized polyvinylpyrrolidone (PVP-capped AgNPs using chemical methods and tested its efficacy against carbapenem-resistant strain of A. baumannii. PVP-capped silver nanoparticles (PVP-AgNPs (30 µM have shown antibacterial activity against carbapenem-resistant strain of A. baumannii and this concentration does not have any cytotoxic effect on the human pulmonary cell line (IC50 is 130 µM. Similarly, PVP-AgNPs treatment decreases 80% viability of intracellular bacteria, decreases adherence of A. baumannii to A-549 (40 to 2.2%, and decreases intracellular concentration (20 to 1.3% of A. baumannii. This concludes that PVP-AgNPs can be developed as a substitute for carbapenem to control the infection caused by carbapenem-resistant A. baumannii.

Modulation of cGMP by human HO-1 retrovirus gene transfer in pulmonary microvessel endothelial cells.

Science.gov (United States)

Abraham, Nader G; Quan, Shuo; Mieyal, Paul A; Yang, Liming; Burke-Wolin, Theresa; Mingone, Christopher J; Goodman, Alvin I; Nasjletti, Alberto; Wolin, Michael S

2002-11-01

Carbon monoxide (CO) stimulates guanylate cyclase (GC) and increases guanosine 3',5'-cyclic monophosphate (cGMP) levels. We transfected rat-lung pulmonary endothelial cells with a retrovirus-mediated human heme oxygenase (hHO)-1 gene. Pulmonary cells that expressed hHO-1 exhibited a fourfold increase in HO activity associated with decreases in the steady-state levels of heme and cGMP without changes in soluble GC (sGC) and endothelial nitric oxide synthase (NOS) proteins or basal nitrite production. Heme elicited significant increases in CO production and intracellular cGMP levels in both pulmonary endothelial and pulmonary hHO-1-expressing cells. N(omega)-nitro-L-arginine methyl ester (L-NAME), an inhibitor of NOS, significantly decreased cGMP levels in heme-treated pulmonary endothelial cells but not heme-treated hHO-1-expressing cells. In the presence of exogenous heme, CO and cGMP levels in hHO-1-expressing cells exceeded the corresponding levels in pulmonary endothelial cells. Acute exposure of endothelial cells to SnCl2, which is an inducer of HO-1, increased cGMP levels, whereas chronic exposure decreased heme and cGMP levels. These results indicate that prolonged overexpression of HO-1 ultimately decreases sGC activity by limiting the availability of cellular heme. Heme activates sGC and enhances cGMP levels via a mechanism that is largely insensitive to NOS inhibition.

Doppler ultrasonography of the human fetal pulmonary circulation

NARCIS (Netherlands)

J.A.M. Laudij (Jacqueline)

2000-01-01

textabstractPulmonary hypoplasia is a condition characterized by a decrease in the number of lung cells, airways and alveoli with a resulting decrease in organ size and weight. The reported incidence of pulmonary hypoplasia in the general population is about 1 per 1000 live births and it is one of

NOX4 mediates BMP4-induced upregulation of TRPC1 and 6 protein expressions in distal pulmonary arterial smooth muscle cells.

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Qian Jiang

Full Text Available Our previous studies demonstrated that bone morphogenetic protein 4 (BMP4 mediated, elevated expression of canonical transient receptor potential (TRPC largely accounts for the enhanced proliferation in pulmonary arterial smooth muscle cells (PASMCs. In the present study, we sought to determine the signaling pathway through which BMP4 up-regulates TRPC expression.We employed recombinant human BMP4 (rhBMP4 to determine the effects of BMP4 on NADPH oxidase 4 (NOX4 and reactive oxygen species (ROS production in rat distal PASMCs. We also designed small interfering RNA targeting NOX4 (siNOX4 and detected whether NOX4 knockdown affects rhBMP4-induced ROS, TRPC1 and 6 expression, cell proliferation and intracellular Ca2+ determination in PASMCs.In rhBMP4 treated rat distal PASMCs, NOX4 expression was (226.73±11.13 %, and the mean ROS level was (123.65±1.62 % of that in untreated control cell. siNOX4 transfection significantly reduced rhBMP4-induced elevation of the mean ROS level in PASMCs. Moreover, siNOX4 transfection markedly reduced rhBMP4-induced elevation of TRPC1 and 6 proteins, basal [Ca2+]i and SOCE. Furthermore, compared with control group (0.21±0.001, the proliferation of rhBMP4 treated cells was significantly enhanced (0.41±0.001 (P<0.01. However, such increase was attenuated by knockdown of NOX4. Moreover, external ROS (H2O2 100 µM, 24 h rescued the effects of NOX4 knockdown, which included the declining of TRPC1 and 6 expression, basal intracellular calcium concentration ([Ca2+]i and store-operated calcium entry (SOCE, suggesting that NOX4 plays as an important mediator in BMP4-induced proliferation and intracellular calcium homeostasis.These results suggest that BMP4 may increase ROS level, enhance TRPC1 and 6 expression and proliferation by up-regulating NOX4 expression in PASMCs.

CT findings of pulmonary cryptococcosis in immunocompetent children

International Nuclear Information System (INIS)

Wang Bei; Peng Yun; Zhou Chunjun; Zhao Shunying

2012-01-01

Objective: The aim of our study was to study the CT findings of cryptococcosis in immunocompetent children. Methods: CT scan and clinical data of 21 immunocompetent children with proven pulmonary cryptococcosis were retrospectively collected and analyzed. Results: The CT scans demonstrated 1 mm subpleural nodule in the lingula of left lung in 1 patient and multiple nodules in 20 patients.Of 20 patients with multiple nodules, peripheral or subpleural distribution was found in 12 patients,and diffuse distribution in 8 patients. Of 20 patients with multiple nodules,Nodules of < 10 mm was found in 18 patients,< 3 mm in 14 patients, and > 10 mm in 2 patients. Round nodular with smooth margin was detected in 15 of 20 patients with multiple nodules. Lymphadenopathy was found in 17 patients including 3 patients with mild contrast enhancement and 2 patients with circular enhancement. Extrapulmonary lesions distributing in liver, spleen, kidney, and the nervous system were found in 14 patients. In follow-up, 1 patient died and 20 patients fully recovered. Conclusions: Pulmonary multiple nodules with lymphadenopathy is the characteristic CT findings in immunocompetent children with pulmonary cryptococcosis which is prone to involve multiple extra-pulmonary organs. (authors)

Drug-induced pulmonary arterial hypertension: a recent outbreak

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Gérald Simonneau

2013-09-01

Full Text Available Pulmonary arterial hypertension (PAH is a rare disorder characterised by progressive obliteration of the pulmonary microvasculature resulting in elevated pulmonary vascular resistance and premature death. According to the current classification PAH can be associated with exposure to certain drugs or toxins, particularly to appetite suppressant intake drugs, such as aminorex, fenfluramine derivatives and benfluorex. These drugs have been confirmed to be risk factors for PAH and were withdrawn from the market. The supposed mechanism is an increase in serotonin levels, which was demonstrated to act as a growth factor for the pulmonary artery smooth muscle cells. Amphetamines, phentermine and mazindol were less frequently used, but are considered possible risk factors, for PAH. Dasatinib, dual Src/Abl kinase inhibitor, used in the treatment of chronic myelogenous leukaemia was associated with cases of severe PAH, potentially in part reversible after dasatinib withdrawal. Recently, several studies have raised the issue of potential endothelial dysfunction that could be induced by interferon, and a few cases of PAH have been reported with interferon therapy. PAH remains a rare complication of these drugs, suggesting possible individual susceptibility, and further studies are needed to identify patients at risk of drug-induced PAH.

Anorexigen-induced pulmonary hypertension and the serotonin (5-HT hypothesis: lessons for the future in pathogenesis

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Adnot Serge

2002-01-01

Full Text Available Abstract Epidemiological studies have established that fenfluramine, D-fenfluramine, and aminorex, but not other appetite suppressants, increase the risk of primary pulmonary hypertension (PH. One current hypothesis suggests that fenfluramine-like medications may act through interactions with the serotonin (5-hydroxytryptamine [5-HT] transporter (5-HTT located on pulmonary artery smooth muscle cells and responsible for the mitogenic action of 5-HT. Anorexigens may contribute to PH by boosting 5-HT levels in the bloodstream, directly stimulating smooth muscle cell growth, or altering 5-HTT expression. We suggest that individuals with a high basal level of 5-HTT expression related to the presence of the long 5-HTT gene promoter variant may be particularly susceptible to one or more of these potential mechanisms of appetite-suppressant-related PH.

Liposomal nanoparticles encapsulating iloprost exhibit enhanced vasodilation in pulmonary arteries

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Jain PP

2014-07-01

Full Text Available Pritesh P Jain,1 Regina Leber,1,2 Chandran Nagaraj,1 Gerd Leitinger,3 Bernhard Lehofer,4 Horst Olschewski,1,5 Andrea Olschewski,1,6 Ruth Prassl,1,4 Leigh M Marsh11Ludwig Boltzmann Institute for Lung Vascular Research, 2Biophysics Division, Institute of Molecular Biosciences, University of Graz, 3Research Unit Electron Microscopic Techniques, Institute of Cell Biology, Histology, and Embryology, 4Institute of Biophysics, 5Division of Pulmonology, Department of Internal Medicine, 6Department of Anesthesiology and Intensive Care Medicine, Medical University of Graz, Graz, AustriaAbstract: Prostacyclin analogues are standard therapeutic options for vasoconstrictive diseases, including pulmonary hypertension and Raynaud’s phenomenon. Although effective, these treatment strategies are expensive and have several side effects. To improve drug efficiency, we tested liposomal nanoparticles as carrier systems. In this study, we synthesized liposomal nanoparticles tailored for the prostacyclin analogue iloprost and evaluated their pharmacologic efficacy on mouse intrapulmonary arteries, using a wire myograph. The use of cationic lipids, stearylamine, or 1,2-di-(9Z-octadecenoyl-3-trimethylammonium-propane (DOTAP in liposomes promoted iloprost encapsulation to at least 50%. The addition of cholesterol modestly reduced iloprost encapsulation. The liposomal nanoparticle formulations were tested for toxicity and pharmacologic efficacy in vivo and ex vivo, respectively. The liposomes did not affect the viability of human pulmonary artery smooth muscle cells. Compared with an equivalent concentration of free iloprost, four out of the six polymer-coated liposomal formulations exhibited significantly enhanced vasodilation of mouse pulmonary arteries. Iloprost that was encapsulated in liposomes containing the polymer polyethylene glycol exhibited concentration-dependent relaxation of arteries. Strikingly, half the concentration of iloprost in liposomes elicited

PKA and Epac cooperate to augment bradykinin-induced interleukin-8 release from human airway smooth muscle cells

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Halayko Andrew J

2009-09-01

Full Text Available Abstract Background Airway smooth muscle contributes to the pathogenesis of pulmonary diseases by secreting inflammatory mediators such as interleukin-8 (IL-8. IL-8 production is in part regulated via activation of Gq-and Gs-coupled receptors. Here we study the role of the cyclic AMP (cAMP effectors protein kinase A (PKA and exchange proteins directly activated by cAMP (Epac1 and Epac2 in the bradykinin-induced IL-8 release from a human airway smooth muscle cell line and the underlying molecular mechanisms of this response. Methods IL-8 release was assessed via ELISA under basal condition and after stimulation with bradykinin alone or in combination with fenoterol, the Epac activators 8-pCPT-2'-O-Me-cAMP and Sp-8-pCPT-2'-O-Me-cAMPS, the PKA activator 6-Bnz-cAMP and the cGMP analog 8-pCPT-2'-O-Me-cGMP. Where indicated, cells were pre-incubated with the pharmacological inhibitors Clostridium difficile toxin B-1470 (GTPases, U0126 (extracellular signal-regulated kinases ERK1/2 and Rp-8-CPT-cAMPS (PKA. The specificity of the cyclic nucleotide analogs was confirmed by measuring phosphorylation of the PKA substrate vasodilator-stimulated phosphoprotein. GTP-loading of Rap1 and Rap2 was evaluated via pull-down technique. Expression of Rap1, Rap2, Epac1 and Epac2 was assessed via western blot. Downregulation of Epac protein expression was achieved by siRNA. Unpaired or paired two-tailed Student's t test was used. Results The β2-agonist fenoterol augmented release of IL-8 by bradykinin. The PKA activator 6-Bnz-cAMP and the Epac activator 8-pCPT-2'-O-Me-cAMP significantly increased bradykinin-induced IL-8 release. The hydrolysis-resistant Epac activator Sp-8-pCPT-2'-O-Me-cAMPS mimicked the effects of 8-pCPT-2'-O-Me-cAMP, whereas the negative control 8-pCPT-2'-O-Me-cGMP did not. Fenoterol, forskolin and 6-Bnz-cAMP induced VASP phosphorylation, which was diminished by the PKA inhibitor Rp-8-CPT-cAMPS. 6-Bnz-cAMP and 8-pCPT-2'-O-Me-cAMP induced GTP

Connective tissue growth factor stimulates the proliferation, migration and differentiation of lung fibroblasts during paraquat-induced pulmonary fibrosis.

Science.gov (United States)

Yang, Zhizhou; Sun, Zhaorui; Liu, Hongmei; Ren, Yi; Shao, Danbing; Zhang, Wei; Lin, Jinfeng; Wolfram, Joy; Wang, Feng; Nie, Shinan

2015-07-01

It is well established that paraquat (PQ) poisoning can cause severe lung injury during the early stages of exposure, finally leading to irreversible pulmonary fibrosis. Connective tissue growth factor (CTGF) is an essential growth factor that is involved in tissue repair and pulmonary fibrogenesis. In the present study, the role of CTGF was examined in a rat model of pulmonary fibrosis induced by PQ poisoning. Histological examination revealed interstitial edema and extensive cellular thickening of interalveolar septa at the early stages of poisoning. At 2 weeks after PQ administration, lung tissue sections exhibited a marked thickening of the alveolar walls with an accumulation of interstitial cells with a fibroblastic appearance. Masson's trichrome staining revealed a patchy distribution of collagen deposition, indicating pulmonary fibrogenesis. Western blot analysis and immunohistochemical staining of tissue samples demonstrated that CTGF expression was significantly upregulated in the PQ-treated group. Similarly, PQ treatment of MRC-5 human lung fibroblast cells caused an increase in CTGF in a dose-dependent manner. Furthermore, the addition of CTGF to MRC-5 cells triggered cellular proliferation and migration. In addition, CTGF induced the differentiation of fibroblasts to myofibroblasts, as was evident from increased expression of α-smooth muscle actin (α-SMA) and collagen. These findings demonstrate that PQ causes increased CTGF expression, which triggers proliferation, migration and differentiation of lung fibroblasts. Therefore, CTGF may be important in PQ-induced pulmonary fibrogenesis, rendering this growth factor a potential pharmacological target for reducing lung injury.

The pulmonary vasculature in a neonatal porcine model with increased pulmonary blood flow and pressure

DEFF Research Database (Denmark)

Stenbøg, Elisabeth Vidstid; Steinbruchel, Daniel Andreas; Thomsen, Anne Bloch

2001-01-01

Introduction: Hypertension and hyperperfusion of the pulmonary vascular bed in the setting of congenital cardiac malformations may lead to progressive pulmonary vascular disease. To improve the understanding of the basic mechanisms of this disease, there is a need for clinically relevant animal....... By three months of age, nearly all shunts had closed spontaneously, and haemodynamics were normal. Ligation of the left pulmonary artery resulted in a normal total pulmonary blood flow, despite only the right lung being perfused, and a 33% increase in systolic pulmonary arterial pressure...... in humans. Elevated circulating levels of endothelin were associated with abnormal haemodynamics rather than abnormal pathology. These findings could be valuable for future studies on the pathogenesis of hypertensive pulmonary vascular disease associated with congenital cardiac malformations....

Variations in alveolar partial pressure for carbon dioxide and oxygen have additive not synergistic acute effects on human pulmonary vasoconstriction.

Science.gov (United States)

Croft, Quentin P P; Formenti, Federico; Talbot, Nick P; Lunn, Daniel; Robbins, Peter A; Dorrington, Keith L

2013-01-01

The human pulmonary vasculature constricts in response to hypercapnia and hypoxia, with important consequences for homeostasis and adaptation. One function of these responses is to direct blood flow away from poorly-ventilated regions of the lung. In humans it is not known whether the stimuli of hypercapnia and hypoxia constrict the pulmonary blood vessels independently of each other or whether they act synergistically, such that the combination of hypercapnia and hypoxia is more effective than the sum of the responses to each stimulus on its own. We independently controlled the alveolar partial pressures of carbon dioxide (Paco 2) and oxygen (Pao 2) to examine their possible interaction on human pulmonary vasoconstriction. Nine volunteers each experienced sixteen possible combinations of four levels of Paco 2 (+6, +1, -4 and -9 mmHg, relative to baseline) with four levels of Pao 2 (175, 100, 75 and 50 mmHg). During each of these sixteen protocols Doppler echocardiography was used to evaluate cardiac output and systolic tricuspid pressure gradient, an index of pulmonary vasoconstriction. The degree of constriction varied linearly with both Paco 2 and the calculated haemoglobin oxygen desaturation (1-So2). Mixed effects modelling delivered coefficients defining the interdependence of cardiac output, systolic tricuspid pressure gradient, ventilation, Paco 2 and So2. No interaction was observed in the effects on pulmonary vasoconstriction of carbon dioxide and oxygen (p>0.64). Direct effects of the alveolar gases on systolic tricuspid pressure gradient greatly exceeded indirect effects arising from concurrent changes in cardiac output.

Human mast cell and airway smooth muscle cell interactions: implications for asthma.

Science.gov (United States)

Page, S; Ammit, A J; Black, J L; Armour, C L

2001-12-01

Asthma is characterized by inflammation, hyperresponsiveness, and remodeling of the airway. Human mast cells (HMCs) play a central role in all of these changes by releasing mediators that cause exaggerated bronchoconstriction, induce human airway smooth muscle (HASM) cell proliferation, and recruit and activate inflammatory cells. Moreover, the number of HMCs present on asthmatic HASM is increased compared with that on nonasthmatic HASM. HASM cells also have the potential to actively participate in the inflammatory process by synthesizing cytokines and chemokines and expressing surface molecules, which have the capacity to perpetuate the inflammatory mechanisms present in asthma. This review specifically examines how the mediators of HMCs have the capacity to modulate many functions of HASM; how the synthetic function of HASM, particularly through the release and expression of stem cell factor, has the potential to influence HMC number and activation in an extraordinarily potent and proinflammatory manner; and how these interactions between HMCs and HASM have potential consequences for airway structure and inflammation relevant to the disease process of asthma.

Increased proinflammatory responses from asthmatic human airway smooth muscle cells in response to rhinovirus infection

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King Nicholas JC

2006-05-01

Full Text Available Abstract Background Exacerbations of asthma are associated with viral respiratory tract infections, of which rhinoviruses (RV are the predominant virus type. Airway smooth muscle is important in asthma pathogenesis, however little is known about the potential interaction of RV and human airway smooth muscle cells (HASM. We hypothesised that rhinovirus induction of inflammatory cytokine release from airway smooth muscle is augmented and differentially regulated in asthmatic compared to normal HASM cells. Methods HASM cells, isolated from either asthmatic or non-asthmatic subjects, were infected with rhinovirus. Cytokine production was assayed by ELISA, ICAM-1 cell surface expression was assessed by FACS, and the transcription regulation of IL-6 was measured by luciferase activity. Results RV-induced IL-6 release was significantly greater in HASM cells derived from asthmatic subjects compared to non-asthmatic subjects. This response was RV specific, as 5% serum- induced IL-6 release was not different in the two cell types. Whilst serum stimulated IL-8 production in cells from both subject groups, RV induced IL-8 production in only asthmatic derived HASM cells. The transcriptional induction of IL-6 was differentially regulated via C/EBP in the asthmatic and NF-κB + AP-1 in the non-asthmatic HASM cells. Conclusion This study demonstrates augmentation and differential transcriptional regulation of RV specific innate immune response in HASM cells derived from asthmatic and non-asthmatics, and may give valuable insight into the mechanisms of RV-induced asthma exacerbations.

Oxidative and nonoxidative metabolism of polycyclic aromatic hydrocarbons in rabbit and chicken aortas and in human fetal smooth-muscle cells

International Nuclear Information System (INIS)

Bond, J.A.; Kocan, R.M.; Benditt, E.P.; Juchau, M.R.

1980-01-01

A description of the various enzyme systems in aortas of rabbits and chickens and in human fetal smooth muscle cells in culture which are responsible overall for the metabolism of F, 12-dimethylbenz(a)anthracene and benzo(a)pyrene-4, 5-oxide are provided

Hypoxia-induced DNA hypermethylation in human pulmonary fibroblasts is associated with Thy-1 promoter methylation and the development of a pro-fibrotic phenotype

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Robinson Claire M

2012-08-01

Full Text Available Abstract Background Pulmonary fibrosis is a debilitating and lethal disease with no effective treatment options. Understanding the pathological processes at play will direct the application of novel therapeutic avenues. Hypoxia has been implicated in the pathogenesis of pulmonary fibrosis yet the precise mechanism by which it contributes to disease progression remains to be fully elucidated. It has been shown that chronic hypoxia can alter DNA methylation patterns in tumour-derived cell lines. This epigenetic alteration can induce changes in cellular phenotype with promoter methylation being associated with gene silencing. Of particular relevance to idiopathic pulmonary fibrosis (IPF is the observation that Thy-1 promoter methylation is associated with a myofibroblast phenotype where loss of Thy-1 occurs alongside increased alpha smooth muscle actin (α-SMA expression. The initial aim of this study was to determine whether hypoxia regulates DNA methylation in normal human lung fibroblasts (CCD19Lu. As it has been reported that hypoxia suppresses Thy-1 expression during lung development we also studied the effect of hypoxia on Thy-1 promoter methylation and gene expression. Methods CCD19Lu were grown for up to 8 days in hypoxia and assessed for global changes in DNA methylation using flow cytometry. Real-time PCR was used to quantify expression of Thy-1, α-SMA, collagen I and III. Genomic DNA was bisulphite treated and methylation specific PCR (MSPCR was used to examine the methylation status of the Thy-1 promoter. Results Significant global hypermethylation was detected in hypoxic fibroblasts relative to normoxic controls and was accompanied by increased expression of myofibroblast markers. Thy-1 mRNA expression was suppressed in hypoxic cells, which was restored with the demethylating agent 5-aza-2′-deoxycytidine. MSPCR revealed that Thy-1 became methylated following fibroblast exposure to 1% O2. Conclusion These data suggest that global and

Role of human pulmonary fibroblast-derived MCP-1 in cell activation and migration in experimental silicosis

International Nuclear Information System (INIS)

Liu, Xueting; Fang, Shencun; Liu, Haijun; Wang, Xingang; Dai, Xiaoniu; Yin, Qing; Yun, Tianwei; Wang, Wei; Zhang, Yingming; Liao, Hong; Zhang, Wei; Yao, Honghong; Chao, Jie

2015-01-01

Background: Silicosis is a systemic disease caused by inhaling silicon dioxide (SiO 2 ). Phagocytosis of SiO 2 in the lung initiates an inflammatory cascade that results in fibroblast proliferation and migration and subsequent fibrosis. Clinical evidence indicates that the activation of alveolar macrophages by SiO 2 produces rapid and sustained inflammation that is characterized by the generation of monocyte chemotactic protein 1 (MCP-1), which induces fibrosis. Pulmonary fibroblast-derived MCP-1 may play a critical role in fibroblast proliferation and migration. Methods and results: Experiments using primary cultured adult human pulmonary fibroblasts (HPF-a) demonstrated the following results: 1) SiO 2 treatment resulted in the rapid and sustained induction of MCP-1 as well as the elevation of the CC chemokine receptor type 2 (CCR2) protein levels; 2) pretreatment of HPF-a with RS-102895, a specific CCR2 inhibitor, abolished the SiO 2 -induced increase in cell activation and migration in both 2D and 3D culture systems; and 3) RNA interference targeting CCR2 prevented the SiO 2 -induced increase in cell migration. Conclusion: These data demonstrated that the up-regulation of pulmonary fibroblast-derived MCP-1 is involved in pulmonary fibroblast migration induced by SiO 2 . CCR2 was also up-regulated in response to SiO 2 , and this up-regulation facilitated the effect of MCP-1 on fibroblasts. Our study deciphered the link between fibroblast-derived MCP-1 and SiO 2 -induced cell migration. This finding provides novel insight into the potential of MCP-1 in the development of novel therapeutic strategies for silicosis. - Highlights: • Role of pulmonary fibroblast-derived MCP-1 in experimental silicosis was studied. • SiO 2 induced MCP-1 release from cultured human pulmonary fibroblast (HPF-a). • SiO 2 directly activated HPF-a via the MCP-1/CCR2 pathway. • SiO 2 increased HPF-a migration in both 2D and 3D model via the MCP-1/CCR2 pathway. • RNA-i of MCP-1/CCR2

Role of human pulmonary fibroblast-derived MCP-1 in cell activation and migration in experimental silicosis

Energy Technology Data Exchange (ETDEWEB)

Liu, Xueting [Department of Physiology, Medical School of Southeast University, Nanjing, Jiangsu 210009 (China); Fang, Shencun [Nine Department of Respiratory Medicine, Nanjing Chest Hospital, Nanjing, Jiangsu 210029 (China); Liu, Haijun [Neurobiology Laboratory, New Drug Screening Centre, China Pharmaceutical University, Nanjing, Jiangsu 210009 (China); Wang, Xingang; Dai, Xiaoniu; Yin, Qing; Yun, Tianwei [Department of Physiology, Medical School of Southeast University, Nanjing, Jiangsu 210009 (China); Wang, Wei; Zhang, Yingming [Nine Department of Respiratory Medicine, Nanjing Chest Hospital, Nanjing, Jiangsu 210029 (China); Liao, Hong [Neurobiology Laboratory, New Drug Screening Centre, China Pharmaceutical University, Nanjing, Jiangsu 210009 (China); Zhang, Wei [Department of Physiology, Medical School of Southeast University, Nanjing, Jiangsu 210009 (China); Yao, Honghong [Department of Pharmacology, Medical School of Southeast University, Nanjing, Jiangsu 210009 (China); Chao, Jie, E-mail: chaojie@seu.edu.cn [Department of Physiology, Medical School of Southeast University, Nanjing, Jiangsu 210009 (China)

2015-10-15

Background: Silicosis is a systemic disease caused by inhaling silicon dioxide (SiO{sub 2}). Phagocytosis of SiO{sub 2} in the lung initiates an inflammatory cascade that results in fibroblast proliferation and migration and subsequent fibrosis. Clinical evidence indicates that the activation of alveolar macrophages by SiO{sub 2} produces rapid and sustained inflammation that is characterized by the generation of monocyte chemotactic protein 1 (MCP-1), which induces fibrosis. Pulmonary fibroblast-derived MCP-1 may play a critical role in fibroblast proliferation and migration. Methods and results: Experiments using primary cultured adult human pulmonary fibroblasts (HPF-a) demonstrated the following results: 1) SiO{sub 2} treatment resulted in the rapid and sustained induction of MCP-1 as well as the elevation of the CC chemokine receptor type 2 (CCR2) protein levels; 2) pretreatment of HPF-a with RS-102895, a specific CCR2 inhibitor, abolished the SiO{sub 2}-induced increase in cell activation and migration in both 2D and 3D culture systems; and 3) RNA interference targeting CCR2 prevented the SiO{sub 2}-induced increase in cell migration. Conclusion: These data demonstrated that the up-regulation of pulmonary fibroblast-derived MCP-1 is involved in pulmonary fibroblast migration induced by SiO{sub 2}. CCR2 was also up-regulated in response to SiO{sub 2}, and this up-regulation facilitated the effect of MCP-1 on fibroblasts. Our study deciphered the link between fibroblast-derived MCP-1 and SiO{sub 2}-induced cell migration. This finding provides novel insight into the potential of MCP-1 in the development of novel therapeutic strategies for silicosis. - Highlights: • Role of pulmonary fibroblast-derived MCP-1 in experimental silicosis was studied. • SiO{sub 2} induced MCP-1 release from cultured human pulmonary fibroblast (HPF-a). • SiO{sub 2} directly activated HPF-a via the MCP-1/CCR2 pathway. • SiO{sub 2} increased HPF-a migration in both 2D and 3D

The chemokine and scavenger receptor CXCL16/SR-PSOX is expressed in human vascular smooth muscle cells and is induced by interferon γ

International Nuclear Information System (INIS)

Wagsaeter, Dick; Olofsson, Peder S.; Norgren, Lars; Stenberg, Bjoern; Sirsjoe, Allan

2004-01-01

Atherosclerosis is an inflammatory disease that is characterised by the involvement of chemokines that are important for the recruitment of leukocytes and scavenger receptors that mediate foam cell formation. Several cytokines are involved in the regulation of chemokines and scavenger receptors in atherosclerosis. CXCL16 is a chemokine and scavenger receptor and found in macrophages in human atherosclerotic lesions. Using double-labelled immunohistochemistry, we identified that smooth muscle cells in human lesions express CXCL16. We then analysed the effects of IFN-γ, TNF-α, IL-12, IL-15, IL-18, and LPS on CXCL16 expression in cultured aortic smooth muscle cells. IFN-γ was the most potent CXCL16 inducer and increased mRNA, soluble form, membrane form, and total cellular levels of CXCL16. The IFN-γ induction of CXCL16 was also associated with increased uptake of oxLDL into these cells. Taken together, smooth muscle cells express CXCL16 in atherosclerotic lesions, which may play a role in the attraction of T cells to atherosclerotic lesions and contribute to the cellular internalisation of modified LDL

Multiple P2Y receptors couple to calcium-dependent, chloride channels in smooth muscle cells of the rat pulmonary artery

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Gurney Alison M

2005-10-01

Full Text Available Abstract Background Uridine 5'-triphosphate (UTP and uridine 5'-diphosphate (UDP act via P2Y receptors to evoke contraction of rat pulmonary arteries, whilst adenosine 5'-triphosphate (ATP acts via P2X and P2Y receptors. Pharmacological characterisation of these receptors in intact arteries is complicated by release and extracellular metabolism of nucleotides, so the aim of this study was to characterise the P2Y receptors under conditions that minimise these problems. Methods The perforated-patch clamp technique was used to record the Ca2+-dependent, Cl- current (ICl,Ca activated by P2Y receptor agonists in acutely dissociated smooth muscle cells of rat small (SPA and large (LPA intrapulmonary arteries, held at -50 mV. Contractions to ATP were measured in isolated muscle rings. Data were compared by Student's t test or one way ANOVA. Results ATP, UTP and UDP (10-4M evoked oscillating, inward currents (peak = 13–727 pA in 71–93% of cells. The first current was usually the largest and in the SPA the response to ATP was significantly greater than those to UTP or UDP (P -1 and changed little during agonist application. The non-selective P2 receptor antagonist suramin (10-4M abolished currents evoked by ATP in SPA (n = 4 and LPA (n = 4, but pyridoxalphosphate-6-azophenyl-2',4'-disulphonic acid (PPADS (10-4M, also a non-selective P2 antagonist, had no effect (n = 4, 5 respectively. Currents elicited by UTP (n = 37 or UDP (n = 14 were unaffected by either antagonist. Contractions of SPA evoked by ATP were partially inhibited by PPADS (n = 4 and abolished by suramin (n = 5. Both antagonists abolished the contractions in LPA. Conclusion At least two P2Y subtypes couple to ICl,Ca in smooth muscle cells of rat SPA and LPA, with no apparent regional variation in their distribution. The suramin-sensitive, PPADS-resistant site activated by ATP most resembles the P2Y11 receptor. However, the suramin- and PPADS-insensitive receptor activated by UTP and UDP

circHIPK2-mediated σ-1R promotes endoplasmic reticulum stress in human pulmonary fibroblasts exposed to silica.

Science.gov (United States)

Cao, Zhouli; Xiao, Qingling; Dai, Xiaoniu; Zhou, Zewei; Jiang, Rong; Cheng, Yusi; Yang, Xiyue; Guo, Huifang; Wang, Jing; Xi, Zhaoqing; Yao, Honghong; Chao, Jie

2017-12-13

Silicosis is characterized by fibroblast accumulation and excessive deposition of extracellular matrix. Although the roles of SiO 2 -induced chemokines and cytokines released from alveolar macrophages have received significant attention, the direct effects of SiO 2 on protein production and functional changes in pulmonary fibroblasts have been less extensively studied. Sigma-1 receptor, which has been associated with cell proliferation and migration in the central nervous system, is expressed in the lung, but its role in silicosis remains unknown. To elucidate the role of sigma-1 receptor in fibrosis induced by silica, both the upstream molecular mechanisms and the functional effects on cell proliferation and migration were investigated. Both molecular biological assays and pharmacological techniques, combined with functional experiments, such as migration and proliferation, were applied in human pulmonary fibroblasts from adults to analyze the molecular and functional changes induced by SiO 2 . SiO 2 induced endoplasmic reticulum stress in association with enhanced expression of sigma-1 receptor. Endoplasmic reticulum stress promoted migration and proliferation of human pulmonary fibroblasts-adult exposed to SiO 2 , inducing the development of silicosis. Inhibition of sigma-1 receptor ameliorated endoplasmic reticulum stress and fibroblast functional changes induced by SiO 2 . circHIPK2 is involved in the regulation of sigma-1 receptor in human pulmonary fibroblasts-adult exposed to SiO 2 . Our study elucidated a link between SiO 2 -induced fibrosis and sigma-1 receptor signaling, thereby providing novel insight into the potential use of sigma-1 receptor/endoplasmic reticulum stress in the development of novel therapeutic strategies for silicosis treatment.

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

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Izziki Mohamed

2009-01-01

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

Antiproliferative effect of UTP on human arterial and venous smooth muscle cells.

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White, P J; Kumari, R; Porter, K E; London, N J; Ng, L L; Boarder, M R

2000-12-01

We have investigated the hypothesis that responses associated with proliferation are regulated by extracellular nucleotides such as ATP and UTP in cultured human vascular smooth muscle cells (VSMC) derived from internal mammary artery (IMA) and saphenous vein (SV). Platelet-derived growth factor (PDGF), ATP, and UTP each generated an increase in cytosolic free Ca(2+) concentration ([Ca(2+)](i)) in both IMA- and SV-derived cells in the absence of detectable inositol 1,4,5-trisphosphate production. ATP alone had no effect on [(3)H]thymidine incorporation into DNA, but with a submaximal concentration of PDGF it raised [(3)H]thymidine incorporation in SV- but not IMA-derived cells. UTP alone also was without effect on [(3)H]thymidine incorporation or cell number. However, in both SV- and IMA-derived cells, UTP reduced the PDGF-stimulated [(3)H]thymidine response and PDGF-stimulated cell proliferation. This cannot be explained by an inhibitory effect on the p42/p44 mitogen-activated protein kinase (MAPK) cascade, since this response to PDGF was not attenuated by UTP. We conclude that, in human VSMC of both arterial and venous origin, UTP acts as an anti-proliferative regulator.

Antioxidant mechanism of Rutin on hypoxia-induced pulmonary arterial cell proliferation.

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Li, Qian; Qiu, Yanli; Mao, Min; Lv, Jinying; Zhang, Lixin; Li, Shuzhen; Li, Xia; Zheng, Xiaodong

2014-11-18

Reactive oxygen species (ROS) are involved in the pathologic process of pulmonary arterial hypertension as either mediators or inducers. Rutin is a type of flavonoid which exhibits significant scavenging properties on oxygen radicals both in vitro and in vivo. In this study, we proposed that rutin attenuated hypoxia-induced pulmonary artery smooth muscle cell (PASMC) proliferation by scavenging ROS. Immunofluorescence data showed that rutin decreased the production of ROS, which was mainly generated through mitochondria and NADPH oxidase 4 (Nox4) in pulmonary artery endothelial cells (PAECs). Western blot results provided further evidence on rutin increasing expression of Nox4 and hypoxia-inducible factor-1α (HIF-1α). Moreover, cell cycle analysis by flow cytometry indicated that proliferation of PASMCs triggered by hypoxia was also repressed by rutin. However, N-acetyl-L-cysteine (NAC), a scavenger of ROS, abolished or diminished the capability of rutin in repressing hypoxia-induced cell proliferation. These data suggest that rutin shows a potential benefit against the development of hypoxic pulmonary arterial hypertension by inhibiting ROS, subsequently preventing hypoxia-induced PASMC proliferation.

Antioxidant Mechanism of Rutin on Hypoxia-Induced Pulmonary Arterial Cell Proliferation

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Qian Li

2014-11-01

Full Text Available Reactive oxygen species (ROS are involved in the pathologic process of pulmonary arterial hypertension as either mediators or inducers. Rutin is a type of flavonoid which exhibits significant scavenging properties on oxygen radicals both in vitro and in vivo. In this study, we proposed that rutin attenuated hypoxia-induced pulmonary artery smooth muscle cell (PASMC proliferation by scavenging ROS. Immunofluorescence data showed that rutin decreased the production of ROS, which was mainly generated through mitochondria and NADPH oxidase 4 (Nox4 in pulmonary artery endothelial cells (PAECs. Western blot results provided further evidence on rutin increasing expression of Nox4 and hypoxia-inducible factor-1α (HIF-1α. Moreover, cell cycle analysis by flow cytometry indicated that proliferation of PASMCs triggered by hypoxia was also repressed by rutin. However, N-acetyl-L-cysteine (NAC, a scavenger of ROS, abolished or diminished the capability of rutin in repressing hypoxia-induced cell proliferation. These data suggest that rutin shows a potential benefit against the development of hypoxic pulmonary arterial hypertension by inhibiting ROS, subsequently preventing hypoxia-induced PASMC proliferation.

Effects of acute ethanol exposure on cytokine production by primary airway smooth muscle cells

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Kaphalia, Lata; Kalita, Mridul [Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Internal Medicine, University of Texas Medical Branch, Galveston, TX (United States); Kaphalia, Bhupendra S. [Department of Pathology, University of Texas Medical Branch, Galveston, TX (United States); Calhoun, William J., E-mail: William.Calhoun@utmb.edu [Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Internal Medicine, University of Texas Medical Branch, Galveston, TX (United States)

2016-02-01

Both chronic and binge alcohol abuse can be significant risk factors for inflammatory lung diseases such as acute respiratory distress syndrome and chronic obstructive pulmonary disease. However, metabolic basis of alcohol-related lung disease is not well defined, and may include key metabolites of ethanol [EtOH] in addition to EtOH itself. Therefore, we investigated the effects of EtOH, acetaldehyde [ACE], and fatty acid ethyl esters [FAEEs] on oxidative stress, endoplasmic reticulum (ER) stress, AMP-activated protein kinase (AMPK) signaling and nuclear translocation of phosphorylated (p)-NF-κB p65 in primary human airway smooth muscle (HASM) cells stimulated to produce cytokines using LPS exposure. Both FAEEs and ACE induced evidence of cellular oxidative stress and ER stress, and increased p-NF-κB in nuclear extracts. EtOH and its metabolites decreased p-AMPKα activation, and induced expression of fatty acid synthase, and decreased expression of sirtuin 1. In general, EtOH decreased secretion of IP-10, IL-6, eotaxin, GCSF, and MCP-1. However, FAEEs and ACE increased these cytokines, suggesting that both FAEEs and ACE as compared to EtOH itself are proinflammatory. A direct effect of EtOH could be consistent with blunted immune response. Collectively, these two features of EtOH exposure, coupled with the known inhibition of innate immune response in our model might explain some clinical manifestations of EtOH exposure in the lung. - Highlights: • Metabolic basis for EtOH toxicity was studied in human airway smooth muscle (HASM) cells. • In HASM cells, EtOH metabolites were found to be relatively more toxic than EtOH itself. • EtOH metabolites mediate deactivation of AMPK via oxidative stress and ER stress. • EtOH metabolites were found to be more proinflammatory than EtOH itself in HASM cells.

Effects of acute ethanol exposure on cytokine production by primary airway smooth muscle cells

International Nuclear Information System (INIS)

Kaphalia, Lata; Kalita, Mridul; Kaphalia, Bhupendra S.; Calhoun, William J.

2016-01-01

Both chronic and binge alcohol abuse can be significant risk factors for inflammatory lung diseases such as acute respiratory distress syndrome and chronic obstructive pulmonary disease. However, metabolic basis of alcohol-related lung disease is not well defined, and may include key metabolites of ethanol [EtOH] in addition to EtOH itself. Therefore, we investigated the effects of EtOH, acetaldehyde [ACE], and fatty acid ethyl esters [FAEEs] on oxidative stress, endoplasmic reticulum (ER) stress, AMP-activated protein kinase (AMPK) signaling and nuclear translocation of phosphorylated (p)-NF-κB p65 in primary human airway smooth muscle (HASM) cells stimulated to produce cytokines using LPS exposure. Both FAEEs and ACE induced evidence of cellular oxidative stress and ER stress, and increased p-NF-κB in nuclear extracts. EtOH and its metabolites decreased p-AMPKα activation, and induced expression of fatty acid synthase, and decreased expression of sirtuin 1. In general, EtOH decreased secretion of IP-10, IL-6, eotaxin, GCSF, and MCP-1. However, FAEEs and ACE increased these cytokines, suggesting that both FAEEs and ACE as compared to EtOH itself are proinflammatory. A direct effect of EtOH could be consistent with blunted immune response. Collectively, these two features of EtOH exposure, coupled with the known inhibition of innate immune response in our model might explain some clinical manifestations of EtOH exposure in the lung. - Highlights: • Metabolic basis for EtOH toxicity was studied in human airway smooth muscle (HASM) cells. • In HASM cells, EtOH metabolites were found to be relatively more toxic than EtOH itself. • EtOH metabolites mediate deactivation of AMPK via oxidative stress and ER stress. • EtOH metabolites were found to be more proinflammatory than EtOH itself in HASM cells.

Overexpression of transforming growth factor-β1 in fetal monkey lung results in prenatal pulmonary fibrosis

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Tarantal, A.F.; Chen, H.; Shi, T.T.; Lu, C-H.; Fang, A.B.; Buckley, S.; Kolb, M.; Gauldie, J.; Warburton, D.; Shi, W.

2011-01-01

Altered transforming growth factor (TGF)-β expression levels have been linked to a variety of human respiratory diseases, including bronchopulmonary dysplasia and pulmonary fibrosis. However, a causative role for aberrant TGF-β in neonatal lung diseases has not been defined in primates. Exogenous and transient TGF-β1 overexpression in fetal monkey lung was achieved by transabdominal ultrasound-guided fetal intrapulmonary injection of adenoviral vector expressing TGF-β1 at the second or third trimester of pregnancy. The lungs were then harvested near term, and fixed for histology and immunohistochemistry. Lung hypoplasia was observed where TGF-β1 was overexpressed during the second trimester. The most clearly marked phenotype consisted of severe pulmonary and pleural fibrosis, which was independent of the gestational time point when TGF-β1 was overexpressed. Increased cell proliferation, particularly in α-smooth muscle actin-positive myofibroblasts, was detected within the fibrotic foci. But epithelium to mesenchyme transdifferentiation was not detected. Massive collagen fibres were deposited on the inner and outer sides of the pleural membrane, with an intact elastin layer in the middle. This induced fibrotic pathology persisted even after adenoviral-mediated TGF-β1 overexpression was no longer evident. Therefore, overexpression of TGF-β1 within developing fetal monkey lung results in severe and progressive fibrosis in lung parenchyma and pleural membrane, in addition to pulmonary hypoplasia. PMID:20351039

Stimulation of aortic smooth muscle cell mitogenesis by serotonin

International Nuclear Information System (INIS)

Nemecek, G.M.; Coughlin, S.R.; Handley, D.A.; Moskowitz, M.A.

1986-01-01

Bovine aortic smooth muscle cells in vitro responded to 1 nM to 10 μM serotonin with increased incorporation of [ 3 H]thymidine into DNA. The mitogenic effect of serotonin was half-maximal at 80 nM and maximal above 1 μM. At a concentration of 1 μM, serotonin stimulated smooth muscle cell mitogenesis to the same extent as human platelet-derived growth factor (PDGF) at 12 ng/ml. Tryptamine was ≅ 1/10th as potent as serotonin as a mitogen for smooth muscle cells. Other indoles that are structurally related to serotonin (D- and L-tryptophan, 5-hydroxy-L-tryptophan, N-acetyl-5-hydroxytryptamine, melatonin, 5-hydroxyindoleacetic acid, and 5-hydroxytryptophol) and quipazine were inactive. The stimulatory effect of serotonin on smooth muscle cell DNA synthesis required prolonged (20-24 hr) exposure to the agonist and was attenuated in the presence of serotonin D receptor antagonists. When smooth muscle cells were incubated with submaximal concentrations of serotonin and PDGF, synergistic rather than additive mitogenic responses were observed. These data indicate that serotonin has a significant mitogenic effect on smooth muscle cells in vitro, which appears to be mediated by specific plasma membrane receptors

Primary intimal sarcoma of the pulmonary artery 1 case report and retrospective analysis of 20 cases published in China

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Guo Lingchuan; Chen Yanbin

2012-01-01

Objective: To explore the clinical and histopathological features of primary, intimal sarcoma of the pulmonary artery. Methods: One case of primary intimal sarcoma of the pulmonary artery diagnosed in our hospital and 20 cases published openly in China were analysed retrospectively. Results: The clinical presentation of primary intimal sarcoma of the pulmonary artery was progressive dyspnea, cough, chest pain, syncope, bloody phlegm, fever and fatigue. From the radiological finding, its signs were of pulmonary, artery dilation, reduced pulmonary vasculature and cardiomegaly, soft tissue mass near the right ventricle outflow tract. Histological examination of intimal sarcoma of the pulmonary artery revealed a poorly differentiated mesenchymal tumor of fibroblastic or myofibroblastic differentiation, consisting of mildly atypical spindle cells with atypia, mitosis, and nuclear polymorphism. Immunohistochemical analysis showed positive staining with antibodies against vimentin, alpha-smooth muscle actin, while negative for desmin. Conclusion: Primary, intimal sarcoma of the pulmonary artery has atypical clinical and radiological manifestation with poor prognosis, its definite diagnosis depends on histopathology. (authors)

Mycobacterial and nonbacterial pulmonary complications in hospitalized patients with human immunodeficiency virus infection: A prospective, cohort study

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Afessa Bekele

2001-09-01

Full Text Available Abstract Background A prospective observational study was done to describe nonbacterial pulmonary complications in hospitalized patients with human immunodeficiency virus (HIV infection. Methods The study included 1,225 consecutive hospital admissions of 599 HIV-infected patients treated from April 1995 through March 1998. Data included demographics, risk factors for HIV infection, Acute Physiology and Chronic Health Evaluation (APACHE II score, pulmonary complications, CD4+ lymphocyte count, hospital stay and case-fatality rate. Results Patient age (mean ± SD was 38.2 ± 8.9 years, 62% were men, and 84% were African American. The median APACHE II score was 14, and median CD4+ lymphocyte count was 60/μL. Pulmonary complications were Pneumocystis carinii pneumonia (85 in 78 patients, Mycobacterium avium complex (51 in 38, Mycobacterium tuberculosis (40 in 35, Mycobacterium gordonae (11 in 11, Mycobacterium kansasii (10 in 9, Cytomegalovirus (10 in 10, Nocardia asteroides (3 in 3, fungus ball (2 in 2, respiratory syncytial virus (1, herpes simplex virus (1, Histoplasma capsulatum (1, lymphoma (3 in 3, bronchogenic carcinoma (2 in 2, and Kaposi sarcoma (1. The case-fatality rate of patients was 11% with Pneumocystis carinii pneumonia; 5%, Mycobacterium tuberculosis; 6%, Mycobacterium avium complex; and 7%, noninfectious pulmonary complications. Conclusion Most pulmonary complications in hospitalized patients with HIV are from Pneumocystis and mycobacterial infection.

Tetraspanin CD9 regulates cell contraction and actin arrangement via RhoA in human vascular smooth muscle cells.

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Michael J Herr

Full Text Available The most prevalent cardiovascular diseases arise from alterations in vascular smooth muscle cell (VSMC morphology and function. Tetraspanin CD9 has been previously implicated in regulating vascular pathologies; however, insight into how CD9 may regulate adverse VSMC phenotypes has not been provided. We utilized a human model of aortic smooth muscle cells to understand the consequences of CD9 deficiency on VSMC phenotypes. Upon knocking down CD9, the cells developed an abnormally small and rounded morphology. We determined that this morphological change was due to a lack of typical parallel actin arrangement. We also found similar total RhoA but decreased GTP-bound (active RhoA levels in CD9 deficient cells. As a result, cells lacking a full complement of CD9 were less contractile than their control treated counterparts. Upon restoration of RhoA activity in the CD9 deficient cells, the phenotype was reversed and cell contraction was restored. Conversely, inhibition of RhoA activity in the control cells mimicked the CD9-deficient cell phenotype. Thus, alteration in CD9 expression was sufficient to profoundly disrupt cellular actin arrangement and endogenous cell contraction by interfering with RhoA signaling. This study provides insight into how CD9 may regulate previously described vascular smooth muscle cell pathophysiology.

Ginsenoside Rb1 Attenuates Agonist-Induced Contractile Response via Inhibition of Store-Operated Calcium Entry in Pulmonary Arteries of Normal and Pulmonary Hypertensive Rats

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Rui-Xing Wang

2015-03-01

Full Text Available Background: Pulmonary hypertension (PH is characterized by sustained vasoconstriction, enhanced vasoreactivity and vascular remodeling, which leads to right heart failure and death. Despite several treatments are available, many forms of PH are still incurable. Ginsenoside Rb1, a principle active ingredient of Panax ginseng, exhibits multiple pharmacological effects on cardiovascular system, and suppresses monocrotaline (MCT-induced right heart hypertrophy. However, its effect on the pulmonary vascular functions related to PH is unknown. Methods: We examined the vasorelaxing effects of ginsenoside Rb1 on endothelin-1 (ET-1 induced contraction of pulmonary arteries (PAs and store-operated Ca2+ entry (SOCE in pulmonary arterial smooth muscle cells (PASMCs from chronic hypoxia (CH and MCT-induced PH. Results: Ginsenoside Rb1 elicited concentration-dependent relaxation of ET-1-induced PA contraction. The vasorelaxing effect was unaffected by nifedipine, but abolished by the SOCE blocker Gd3+. Ginsenoside Rb1 suppressed cyclopiazonic acid (CPA-induced PA contraction, and CPA-activated cation entry and Ca2+ transient in PASMCs. ET-1 and CPA-induced contraction, and CPA-activated cation entry and Ca2+ transients were enhanced in PA and PASMCs of CH and MCT-treated rats; the enhanced responses were abolished by ginsenoside Rb1. Conclusion: Ginsenoside Rb1 attenuates ET-1-induced contractile response via inhibition of SOCE, and it can effectively antagonize the enhanced pulmonary vasoreactivity in PH.

Human herpes virus-8 DNA in bronchoalveolar lavage samples from patients with AIDS-associated pulmonary Kaposi's sarcoma

DEFF Research Database (Denmark)

Benfield, T L; Dodt, K K; Lundgren, Jens Dilling

1997-01-01

Kaposi's sarcoma (KS) is the most frequent AIDS-associated neoplasm, and often disseminates to visceral organs, including the lungs. An ante-mortem diagnosis of pulmonary KS is difficult. Recently, DNA sequences resembling a new human herpes virus (HHV-8), have been identified in various forms...

Scanning electron microscopy of vascular corrosion casts and histologic examination of pulmonary microvasculature in dogs with dirofilariosis.

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Ninomiya, Hiroyoshi; Wakao, Yoshito

2002-11-01

To characterize structural changes in pulmonary vessels of dogs with dirofilariosis. 8 dogs with dirofilariosis and 2 unaffected control dogs. Pulmonary artery pressure was measured in affected dogs, and dogs then were euthanatized. Scanning electron microscopy was used to examine vascular corrosion casts of pulmonary vasculature. Tissue sections of pulmonary vasculature were evaluated by use of histologic examination. Pulmonary artery pressure was higher in dogs with severely affected pulmonary vessels. In tissue sections, dilatation, as well as lesions in the tunica intima and proliferative lesions resulting in constriction or obstruction, were frequently observed in branches of the pulmonary artery. Numerous dilated bronchial arteries were observed around affected pulmonary arteries. Hyperplastic venous sphincters were observed in small pulmonary veins and venules. In corrosion casts, affected pulmonary lobar arteries had dilatation, pruning, abnormal tapering, constriction, and obstruction. In small arteries and arterioles, surface structures representing aneurisms and edema were seen. Bronchial arteries were well developed and extremely dilated, and they formed numerous anastomoses with pulmonary arteries at all levels, from the pulmonary trunk to peripheral vessels. Capillaries in the lungs were dilated with little structural change. Small pulmonary veins and venules had irregular annular constrictions that were caused by hyperplastic smooth muscle cells of venous sphincters. Scanning electron microscopy of microvascular casts delineated links between the bronchial and pulmonary circulations in dogs with dirofilariosis. Results of scanning electron microscopy provided a structural explanation for the development of pulmonary circulatory disturbances and pulmonary hypertension in dogs affected by dirofilariosis.

cDNA, deduced polypeptide structure and chromosomal assignment of human pulmonary surfactant proteolipid, SPL(pVal)

International Nuclear Information System (INIS)

Glasser, S.W.; Korfhagen, T.R.; Weaver, T.E.; Clark, J.C.; Pilot-Matias, T.; Meuth, J.; Fox, J.L.; Whitsett, J.A.

1988-01-01

In hyaline membrane disease of premature infants, lack of surfactant leads to pulmonary atelectasis and respiratory distress. Hydrophobic surfactant proteins of M/sub r/ = 5000-14,000 have been isolated from mammalian surfactants which enhance the rate of spreading and the surface tension lowering properties of phospholipids during dynamic compression. The authors have characterized the amino-terminal amino acid sequence of pulmonary proteolipids from ether/ethanol extracts of bovine, canine, and human surfactant. Two distinct peptides were identified and termed SPL(pVal) and SPL(Phe). An oligonucleotide probe based on the valine-rich amino-terminal amino acid sequence of SPL(pVal) was utilized to isolate cDNA and genomic DNA encoding the human protein, termed surfactant proteolipid SPL(pVal) on the basis of its unique polyvaline domain. The primary structure of a precursor protein of 20,870 daltons, containing the SPL(pVal) peptide, was deduced from the nucleotide sequence of the cDNAs. Hybrid-arrested translation and immunoprecipitation of labeled translation products of human mRNA demonstrated a precursor protein, the active hydrophobic peptide being produced by proteolytic processing. Two classes of cDNAs encoding SPL(pVal) were identified. Human SPL(pVal) mRNA was more abundant in the adult than in fetal lung. The SPL(pVal) gene locus was assigned to chromosome 8

Applying cybernetic technology to diagnose human pulmonary sounds.

Science.gov (United States)

Chen, Mei-Yung; Chou, Cheng-Han

2014-06-01

Chest auscultation is a crucial and efficient method for diagnosing lung disease; however, it is a subjective process that relies on physician experience and the ability to differentiate between various sound patterns. Because the physiological signals composed of heart sounds and pulmonary sounds (PSs) are greater than 120 Hz and the human ear is not sensitive to low frequencies, successfully making diagnostic classifications is difficult. To solve this problem, we constructed various PS recognition systems for classifying six PS classes: vesicular breath sounds, bronchial breath sounds, tracheal breath sounds, crackles, wheezes, and stridor sounds. First, we used a piezoelectric microphone and data acquisition card to acquire PS signals and perform signal preprocessing. A wavelet transform was used for feature extraction, and the PS signals were decomposed into frequency subbands. Using a statistical method, we extracted 17 features that were used as the input vectors of a neural network. We proposed a 2-stage classifier combined with a back-propagation (BP) neural network and learning vector quantization (LVQ) neural network, which improves classification accuracy by using a haploid neural network. The receiver operating characteristic (ROC) curve verifies the high performance level of the neural network. To expand traditional auscultation methods, we constructed various PS diagnostic systems that can correctly classify the six common PSs. The proposed device overcomes the lack of human sensitivity to low-frequency sounds and various PS waves, characteristic values, and a spectral analysis charts are provided to elucidate the design of the human-machine interface.

Neutrophil-Derived MMP-8 Drives AMPK-Dependent Matrix Destruction in Human Pulmonary Tuberculosis

Science.gov (United States)

Ong, Catherine W. M.; Elkington, Paul T.; Brilha, Sara; Ugarte-Gil, Cesar; Tome-Esteban, Maite T.; Tezera, Liku B.; Pabisiak, Przemyslaw J.; Moores, Rachel C.; Sathyamoorthy, Tarangini; Patel, Vimal; Gilman, Robert H.; Porter, Joanna C.; Friedland, Jon S.

2015-01-01

Pulmonary cavities, the hallmark of tuberculosis (TB), are characterized by high mycobacterial load and perpetuate the spread of M. tuberculosis. The mechanism of matrix destruction resulting in cavitation is not well defined. Neutrophils are emerging as key mediators of TB immunopathology and their influx are associated with poor outcomes. We investigated neutrophil-dependent mechanisms involved in TB-associated matrix destruction using a cellular model, a cohort of 108 patients, and in separate patient lung biopsies. Neutrophil-derived NF-kB-dependent matrix metalloproteinase-8 (MMP-8) secretion was up-regulated in TB and caused matrix destruction both in vitro and in respiratory samples of TB patients. Collagen destruction induced by TB infection was abolished by doxycycline, a licensed MMP inhibitor. Neutrophil extracellular traps (NETs) contain MMP-8 and are increased in samples from TB patients. Neutrophils lined the circumference of human pulmonary TB cavities and sputum MMP-8 concentrations reflected TB radiological and clinical disease severity. AMPK, a central regulator of catabolism, drove neutrophil MMP-8 secretion and neutrophils from AMPK-deficient patients secrete lower MMP-8 concentrations. AMPK-expressing neutrophils are present in human TB lung biopsies with phospho-AMPK detected in nuclei. These data demonstrate that neutrophil-derived MMP-8 has a key role in the immunopathology of TB and is a potential target for host-directed therapy in this infectious disease. PMID:25996154

Neutrophil-Derived MMP-8 Drives AMPK-Dependent Matrix Destruction in Human Pulmonary Tuberculosis.

Science.gov (United States)

Ong, Catherine W M; Elkington, Paul T; Brilha, Sara; Ugarte-Gil, Cesar; Tome-Esteban, Maite T; Tezera, Liku B; Pabisiak, Przemyslaw J; Moores, Rachel C; Sathyamoorthy, Tarangini; Patel, Vimal; Gilman, Robert H; Porter, Joanna C; Friedland, Jon S

2015-05-01

Pulmonary cavities, the hallmark of tuberculosis (TB), are characterized by high mycobacterial load and perpetuate the spread of M. tuberculosis. The mechanism of matrix destruction resulting in cavitation is not well defined. Neutrophils are emerging as key mediators of TB immunopathology and their influx are associated with poor outcomes. We investigated neutrophil-dependent mechanisms involved in TB-associated matrix destruction using a cellular model, a cohort of 108 patients, and in separate patient lung biopsies. Neutrophil-derived NF-kB-dependent matrix metalloproteinase-8 (MMP-8) secretion was up-regulated in TB and caused matrix destruction both in vitro and in respiratory samples of TB patients. Collagen destruction induced by TB infection was abolished by doxycycline, a licensed MMP inhibitor. Neutrophil extracellular traps (NETs) contain MMP-8 and are increased in samples from TB patients. Neutrophils lined the circumference of human pulmonary TB cavities and sputum MMP-8 concentrations reflected TB radiological and clinical disease severity. AMPK, a central regulator of catabolism, drove neutrophil MMP-8 secretion and neutrophils from AMPK-deficient patients secrete lower MMP-8 concentrations. AMPK-expressing neutrophils are present in human TB lung biopsies with phospho-AMPK detected in nuclei. These data demonstrate that neutrophil-derived MMP-8 has a key role in the immunopathology of TB and is a potential target for host-directed therapy in this infectious disease.

Evidence Supports Tradition: The in Vitro Effects of Roman Chamomile on Smooth Muscles

Directory of Open Access Journals (Sweden)

Zsolt Sándor

2018-04-01

Full Text Available The dried flowers of Chamaemelum nobile (L. All. have been used in traditional medicine for different conditions related to the spasm of the gastrointestinal system. However, there have been no experimental studies to support the smooth muscle relaxant effect of this plant. The aim of our research was to assess the effects of the hydroethanolic extract of Roman chamomile, its fractions, four of its flavonoids (apigenin, luteolin, hispidulin, and eupafolin, and its essential oil on smooth muscles. The phytochemical compositions of the extract and its fractions were characterized and quantified by HPLC-DAD, the essential oil was characterized by GC and GC-MS. Neuronally mediated and smooth muscle effects were tested in isolated organ bath experiments on guinea pig, rat, and human smooth muscle preparations. The crude herbal extract induced an immediate, moderate, and transient contraction of guinea pig ileum via the activation of cholinergic neurons of the gut wall. Purinoceptor and serotonin receptor antagonists did not influence this effect. The more sustained relaxant effect of the extract, measured after pre-contraction of the preparations, was remarkable and was not affected by an adrenergic beta receptor antagonist. The smooth muscle-relaxant activity was found to be associated with the flavonoid content of the fractions. The essential oil showed only the relaxant effect, but no contracting activity. The smooth muscle-relaxant effect was also detected on rat gastrointestinal tissues, as well as on strip preparations of human small intestine. These results suggest that Roman chamomile extract has a direct and prolonged smooth muscle-relaxant effect on guinea pig ileum which is related to its flavonoid content. In some preparations, a transient stimulation of enteric cholinergic motoneurons was also detected. The essential oil also had a remarkable smooth muscle relaxant effect in this setting. Similar relaxant effects were also detected on

Evidence Supports Tradition: The in Vitro Effects of Roman Chamomile on Smooth Muscles.

Science.gov (United States)

Sándor, Zsolt; Mottaghipisheh, Javad; Veres, Katalin; Hohmann, Judit; Bencsik, Tímea; Horváth, Attila; Kelemen, Dezső; Papp, Róbert; Barthó, Loránd; Csupor, Dezső

2018-01-01

The dried flowers of Chamaemelum nobile (L.) All. have been used in traditional medicine for different conditions related to the spasm of the gastrointestinal system. However, there have been no experimental studies to support the smooth muscle relaxant effect of this plant. The aim of our research was to assess the effects of the hydroethanolic extract of Roman chamomile, its fractions, four of its flavonoids (apigenin, luteolin, hispidulin, and eupafolin), and its essential oil on smooth muscles. The phytochemical compositions of the extract and its fractions were characterized and quantified by HPLC-DAD, the essential oil was characterized by GC and GC-MS. Neuronally mediated and smooth muscle effects were tested in isolated organ bath experiments on guinea pig, rat, and human smooth muscle preparations. The crude herbal extract induced an immediate, moderate, and transient contraction of guinea pig ileum via the activation of cholinergic neurons of the gut wall. Purinoceptor and serotonin receptor antagonists did not influence this effect. The more sustained relaxant effect of the extract, measured after pre-contraction of the preparations, was remarkable and was not affected by an adrenergic beta receptor antagonist. The smooth muscle-relaxant activity was found to be associated with the flavonoid content of the fractions. The essential oil showed only the relaxant effect, but no contracting activity. The smooth muscle-relaxant effect was also detected on rat gastrointestinal tissues, as well as on strip preparations of human small intestine. These results suggest that Roman chamomile extract has a direct and prolonged smooth muscle-relaxant effect on guinea pig ileum which is related to its flavonoid content. In some preparations, a transient stimulation of enteric cholinergic motoneurons was also detected. The essential oil also had a remarkable smooth muscle relaxant effect in this setting. Similar relaxant effects were also detected on other visceral

Airway reactivity in chronic obstructive pulmonary disease. Failure of in vivo methacholine responsiveness to correlate with cholinergic, adrenergic, or nonadrenergic responses in vitro.

Science.gov (United States)

Taylor, S M; Paré, P D; Armour, C L; Hogg, J C; Schellenberg, R R

1985-07-01

This study aimed to determine whether in vivo airways hyperreactivity was manifested by either enhanced bronchial smooth muscle responses to contractile stimuli or by deficient responses to relaxant stimuli in vitro. Quantitative responses to nebulized methacholine were obtained in 12 human subjects prior to pulmonary resection. The provocative concentration of methacholine producing a 20% reduction in FEV1 (PC20) was calculated, and these values were compared with in vitro responses of bronchial smooth muscle strips from the surgical specimens. Both contractile cholinergic responses and relaxant nonadrenergic noncholinergic dose-response data were obtained for the in vitro bronchial specimens by electrical field stimulation. In addition, cumulative dose responses were obtained to exogenously added methacholine, the beta-adrenergic agonist salbutamol, and the adenylate cyclase activator forskolin. Despite a wide range of PC20 values, the in vivo airway responsiveness did not correlate with any of the in vitro responses examined, suggesting that airway reactivity is not due solely to the responsiveness of smooth muscle to contractile agonists nor to a localized deficiency in the nonadrenergic inhibitory system, beta-adrenergic inhibition, or abnormal cyclic-AMP-mediated pathways of relaxation.

Non-invasive estimation of the human pulmonary blood volume with gamma camera and RI-angiocardiography

International Nuclear Information System (INIS)

Goto, Koshi; Hirano, Akihiko; Hirakawa, Senri

1981-01-01

A new, non-invasive method for the estimation of the human pulmonary blood volume (PBV), existing between the pulmonary artery bifurcation (PAB) and the left atrium (LA), has been developed in this laboratory, in the form of PBV = PPT sub(RCG) x 0.77 x CO, equation (6), given in Appendix. This was an extension of the classical Stewart-Hamilton method of indicator dilution, applied to radioisotope angiocardiography. Using a gamma-camera, the radio-isotope (99 m Tc-albumin) dilution curves were recorded externally at the region of PAB, LA and LV (left ventricle), among other things, in human subjects in supine position. The mean transit time (MTT) was determined for each region, and the difference in MTT, e.g., ΔMTT sub(PAB-LA), was measured. We calculated PBV between PAB and LA as PBV = ΔMTT sub(PAB-LA) x CO, equation (1) given in Appendix. Empirical time relations between ΔMTT sub(PAB-LA) and PPT sub(RCG) were examined in mechanical models and human subjects, through several steps represented by equations (2) to (5), given in Appendix, and our tentatively final formula was equation (6). The values of PBV estimated in this way were in good agreement with those of PBV measured invasively in the past, using two injection sites (PA and LA) and one sampling site (artery). (author)

Estrogen receptor beta signaling inhibits PDGF induced human airway smooth muscle proliferation.

Science.gov (United States)

Ambhore, Nilesh Sudhakar; Katragadda, Rathnavali; Raju Kalidhindi, Rama Satyanarayana; Thompson, Michael A; Pabelick, Christina M; Prakash, Y S; Sathish, Venkatachalem

2018-04-20

Airway smooth muscle (ASM) cell hyperplasia driven by persistent inflammation is a hallmark feature of remodeling in asthma. Sex steroid signaling in the lungs is of considerable interest, given epidemiological data showing more asthma in pre-menopausal women and aging men. Our previous studies demonstrated that estrogen receptor (ER) expression increases in asthmatic human ASM; however, very limited data are available regarding differential roles of ERα vs. ERβ isoforms in human ASM cell proliferation. In this study, we evaluated the effect of selective ERα and ERβ modulators on platelet-derived growth factor (PDGF)-stimulated ASM proliferation and the mechanisms involved. Asthmatic and non-asthmatic primary human ASM cells were treated with PDGF, 17β-estradiol, ERα-agonist and/or ERβ-agonist and/or G-protein-coupled estrogen receptor 30 (GPR30/GPER) agonist and proliferation was measured using MTT and CyQuant assays followed by cell cycle analysis. Transfection of small interfering RNA (siRNA) ERα and ERβ significantly altered the human ASM proliferation. The specificity of siRNA transfection was confirmed by Western blot analysis. Gene and protein expression of cell cycle-related antigens (PCNA and Ki67) and C/EBP were measured by RT-PCR and Western analysis, along with cell signaling proteins. PDGF significantly increased ASM proliferation in non-asthmatic and asthmatic cells. Treatment with PPT showed no significant effect on PDGF-induced proliferation, whereas WAY interestingly suppressed proliferation via inhibition of ERK1/2, Akt, and p38 signaling. PDGF-induced gene expression of PCNA, Ki67 and C/EBP in human ASM was significantly lower in cells pre-treated with WAY. Furthermore, WAY also inhibited PDGF-activated PCNA, C/EBP, cyclin-D1, and cyclin-E. Overall, we demonstrate ER isoform-specific signaling in the context of ASM proliferation. Activation of ERβ can diminish remodeling in human ASM by inhibiting pro-proliferative signaling pathways

Isorhynchophylline protects against pulmonary arterial hypertension and suppresses PASMCs proliferation

International Nuclear Information System (INIS)

Guo, Haipeng; Zhang, Xin; Cui, Yuqian; Deng, Wei; Xu, Dachun; Han, Hui; Wang, Hao; Chen, Yuguo; Li, Yu; Wu, Dawei

2014-01-01

Highlights: • We focus on PASMCs proliferation in the pathogenesis of PAH. • Isorhynchophylline inhibited PASMCs proliferation and alleviated PAH. • IRN blocked PDGF-Rβ phosphorylation and its downstream signal transduction. • IRN regulated cyclins and CDKs to arrest cell cycle in the G0/G1 phase. • We reported IRN has the potential to be a candidate for PAH treatment. - Abstract: Increased pulmonary arterial smooth muscle cells (PASMCs) proliferation is a key pathophysiological component of pulmonary vascular remodeling in pulmonary arterial hypertension (PAH). Isorhynchophylline (IRN) is a tetracyclic oxindole alkaloid isolated from the Chinese herbal medicine Uncaria rhynchophylla. It has long been used clinically for treatment of cardiovascular and cerebrovascular diseases. However, very little is known about whether IRN can influence the development of PAH. Here we examined the effect of IRN on monocrotaline (MCT) induced PAH in rats. Our data demonstrated that IRN prevented MCT induced PAH in rats, as assessed by right ventricular (RV) pressure, the weight ratio of RV to (left ventricular + septum) and RV hypertrophy. IRN significantly attenuated the percentage of fully muscularized small arterioles, the medial wall thickness, and the expression of smooth muscle α-actin (α-SMA) and proliferating cell nuclear antigen (PCNA). In vitro studies, IRN concentration-dependently inhibited the platelet-derived growth factor (PDGF)-BB-induced proliferation of PASMCs. Fluorescence-activated cell-sorting analysis showed that IRN caused G0/G1 phase cell cycle arrest. IRN-induced growth inhibition was associated with downregulation of Cyclin D1 and CDK6 as well as an increase in p27Kip1 levels in PDGF-BB-stimulated PASMCs. Moreover, IRN negatively modulated PDGF-BB-induced phosphorylation of PDGF-Rβ, ERK1/2, Akt/GSK3β, and signal transducers and activators of transcription 3 (STAT3). These results demonstrate that IRN could inhibit PASMCs proliferation and

Isorhynchophylline protects against pulmonary arterial hypertension and suppresses PASMCs proliferation

Energy Technology Data Exchange (ETDEWEB)

Guo, Haipeng; Zhang, Xin [Department of Critical Care Medicine, Qilu Hospital of Shandong University, Jinan 250012 (China); Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Chinese Ministry of Health, Qilu Hospital of Shandong University, Jinan 250012 (China); Cui, Yuqian [Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Chinese Ministry of Health, Qilu Hospital of Shandong University, Jinan 250012 (China); Deng, Wei [Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan 430060 (China); Xu, Dachun [Department of Cardiology, Shanghai Tenth People’s Hospital of Tongji University, Shanghai 200072 (China); Han, Hui; Wang, Hao [Department of Critical Care Medicine, Qilu Hospital of Shandong University, Jinan 250012 (China); Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Chinese Ministry of Health, Qilu Hospital of Shandong University, Jinan 250012 (China); Chen, Yuguo [Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Chinese Ministry of Health, Qilu Hospital of Shandong University, Jinan 250012 (China); Li, Yu, E-mail: qlliyu@126.com [Department of Respiratory, Qilu Hospital of Shandong University, Jinan 250012 (China); Wu, Dawei, E-mail: wdwu55@163.com [Department of Critical Care Medicine, Qilu Hospital of Shandong University, Jinan 250012 (China); Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Chinese Ministry of Health, Qilu Hospital of Shandong University, Jinan 250012 (China)

2014-07-18

Highlights: • We focus on PASMCs proliferation in the pathogenesis of PAH. • Isorhynchophylline inhibited PASMCs proliferation and alleviated PAH. • IRN blocked PDGF-Rβ phosphorylation and its downstream signal transduction. • IRN regulated cyclins and CDKs to arrest cell cycle in the G0/G1 phase. • We reported IRN has the potential to be a candidate for PAH treatment. - Abstract: Increased pulmonary arterial smooth muscle cells (PASMCs) proliferation is a key pathophysiological component of pulmonary vascular remodeling in pulmonary arterial hypertension (PAH). Isorhynchophylline (IRN) is a tetracyclic oxindole alkaloid isolated from the Chinese herbal medicine Uncaria rhynchophylla. It has long been used clinically for treatment of cardiovascular and cerebrovascular diseases. However, very little is known about whether IRN can influence the development of PAH. Here we examined the effect of IRN on monocrotaline (MCT) induced PAH in rats. Our data demonstrated that IRN prevented MCT induced PAH in rats, as assessed by right ventricular (RV) pressure, the weight ratio of RV to (left ventricular + septum) and RV hypertrophy. IRN significantly attenuated the percentage of fully muscularized small arterioles, the medial wall thickness, and the expression of smooth muscle α-actin (α-SMA) and proliferating cell nuclear antigen (PCNA). In vitro studies, IRN concentration-dependently inhibited the platelet-derived growth factor (PDGF)-BB-induced proliferation of PASMCs. Fluorescence-activated cell-sorting analysis showed that IRN caused G0/G1 phase cell cycle arrest. IRN-induced growth inhibition was associated with downregulation of Cyclin D1 and CDK6 as well as an increase in p27Kip1 levels in PDGF-BB-stimulated PASMCs. Moreover, IRN negatively modulated PDGF-BB-induced phosphorylation of PDGF-Rβ, ERK1/2, Akt/GSK3β, and signal transducers and activators of transcription 3 (STAT3). These results demonstrate that IRN could inhibit PASMCs proliferation and

Smooth manifolds

CERN Document Server

Sinha, Rajnikant

2014-01-01

This book offers an introduction to the theory of smooth manifolds, helping students to familiarize themselves with the tools they will need for mathematical research on smooth manifolds and differential geometry. The book primarily focuses on topics concerning differential manifolds, tangent spaces, multivariable differential calculus, topological properties of smooth manifolds, embedded submanifolds, Sard’s theorem and Whitney embedding theorem. It is clearly structured, amply illustrated and includes solved examples for all concepts discussed. Several difficult theorems have been broken into many lemmas and notes (equivalent to sub-lemmas) to enhance the readability of the book. Further, once a concept has been introduced, it reoccurs throughout the book to ensure comprehension. Rank theorem, a vital aspect of smooth manifolds theory, occurs in many manifestations, including rank theorem for Euclidean space and global rank theorem. Though primarily intended for graduate students of mathematics, the book ...

Oxytocin receptors expressed and coupled to Ca2+ signalling in a human vascular smooth muscle cell line.

OpenAIRE

Yazawa, H.; Hirasawa, A.; Horie, K.; Saita, Y.; Iida, E.; Honda, K.; Tsujimoto, G.

1996-01-01

1. In a human vascular smooth muscle cell line (HVSMC), binding experiments with [3H]-arginine8-vasopressin (AVP) have shown the existence of a homogeneous population of binding sites with affinity (Kd value) of 0.65 nM and a maximum number of binding sites (Bmax) of 122 fmol mg-1 protein. 2. Nonlabelled compounds compete for [3H]-AVP binding in the HVSMC membrane with an order of potency of oxytocin > lyspressin > or = AVP > Thr4, Gly7-oxytocin > (beta-mercapto-beta-beta-cyclopentamethylenep...

A role for mitochondrial oxidants in stress-induced premature senescence of human vascular smooth muscle cells

Directory of Open Access Journals (Sweden)

Yogita Mistry

2013-01-01

Full Text Available Mitochondria are a major source of cellular oxidants and have been implicated in aging and associated pathologies, notably cardiovascular diseases. Vascular cell senescence is observed in experimental and human cardiovascular pathologies. Our previous data highlighted a role for angiotensin II in the induction of telomere-dependent and -independent premature senescence of human vascular smooth muscle cells and suggested this was due to production of superoxide by NADPH oxidase. However, since a role for mitochondrial oxidants was not ruled out we hypothesise that angiotensin II mediates senescence by mitochondrial superoxide generation and suggest that inhibition of superoxide may prevent vascular smooth muscle cell aging in vitro. Cellular senescence was induced using a stress-induced premature senescence protocol consisting of three successive once-daily exposure of cells to 1×10−8 mol/L angiotensin II and was dependent upon the type-1 angiotensin II receptor. Angiotensin stimulated NADPH-dependent superoxide production as estimated using lucigenin chemiluminescence in cell lysates and this was attenuated by the mitochondrial electron transport chain inhibitor, rotenone. Angiotensin also resulted in an increase in mitoSOX fluorescence indicating stimulation of mitochondrial superoxide. Significantly, the induction of senescence by angiotensin II was abrogated by rotenone and by the mitochondria-targeted superoxide dismutase mimetic, mitoTEMPO. These data suggest that mitochondrial superoxide is necessary for the induction of stress-induced premature senescence by angiotensin II and taken together with other data suggest that mitochondrial cross-talk with NADPH oxidases, via as yet unidentified signalling pathways, is likely to play a key role.

GM-CSF production from human airway smooth muscle cells is potentiated by human serum

Directory of Open Access Journals (Sweden)

Maria B. Sukkar

2000-01-01

Full Text Available Recent evidence suggests that airway smooth muscle cells (ASMC actively participate in the airway inflammatory process in asthma. Interleukin–1β (IL–1β and tumour necrosis factor–α (TNF–α induce ASMC to release inflammatory mediators in vitro. ASMC mediator release in vivo, however, may be influenced by features of the allergic asthmatic phenotype. We determined whether; (1 allergic asthmatic serum (AAS modulates ASMC mediator release in response to IL–1β and TNF–α, and (2 IL–1β/TNF–α prime ASMC to release mediators in response to AAS. IL–5 and GMCSF were quantified by ELISA in culture supernatants of; (1 ASMC pre-incubated with either AAS, non-allergic non-asthmatic serum (NAS or MonomedTM (a serum substitute and subsequently stimulated with IL–1β and TNF–α and (2 ASMC stimulated with IL–1β/TNF–α and subsequently exposed to either AAS, NAS or MonomedTM. IL-1g and TNF–α induced GM-CSF release in ASMC pre-incubated with AAS was not greater than that in ASMC pre-incubated with NAS or MonomedTM. IL–1β and TNF–α, however, primed ASMC to release GM-CSF in response to human serum. GM-CSF production following IL–1β/TNF–α and serum exposure (AAS or NAS was significantly greater than that following IL–1β /TNF–α and MonomedTM exposure or IL–1β/TNF–α exposure only. Whilst the potentiating effects of human serum were not specific to allergic asthma, these findings suggest that the secretory capacity of ASMC may be up-regulated during exacerbations of asthma, where there is evidence of vascular leakage.

Smooth Tubercle Bacilli: Neglected Opportunistic Tropical Pathogens

Directory of Open Access Journals (Sweden)

Djaltou eAboubaker

2016-01-01

Full Text Available Smooth tubercle bacilli (STB including ‘‘Mycobacterium canettii’’ are members of the Mycobacterium tuberculosis complex (MTBC which cause non-contagious tuberculosis in human. This group comprises less than one hundred isolates characterized by smooth colonies and cordless organisms. Most STB isolates have been obtained from patients exposed to the Republic of Djibouti but seven isolates, including the three seminal ones obtained by Georges Canetti between 1968 and 1970, were recovered from patients in France, Madagascar, Sub-Sahara East Africa and French Polynesia. STB form a genetically heterogeneous group of MTBC organisms with large 4.48 ± 0.05 Mb genomes which may link Mycobacterium kansasii to MTBC organisms. Lack of inter-human transmission suggested a yet unknown environmental reservoir. Clinical data indicate a respiratory tract route of contamination and the digestive tract as an alternative route of contamination. Further epidemiological and clinical studies are warranted to elucidate areas of uncertainty regarding these unusual mycobacteria and the tuberculosis they cause.

TIMP-1 stimulates proliferation of human aortic smooth muscle cells and Ras effector pathways

International Nuclear Information System (INIS)

Akahane, Takemi; Akahane, Manabu; Shah, Amy; Thorgeirsson, Unnur P.

2004-01-01

Tissue inhibitor of metalloproteinases-1 (TIMP-1) is a multifunctional protein, which is found in most tissues and body fluids. Here, we demonstrated that recombinant TIMP-1 but not the synthetic matrix metalloproteinase inhibitor, GM6001, stimulated proliferation of human aortic smooth muscle cells (AoSMC) in a dose-dependent manner. The mitogenic effect was associated with activation of Ras, increased phosphorylation of ERK, and stimulation of cyclin D1 expression. The phosphatidylinositol 3-kinase (PI3K) signaling pathway was also involved since the PI3K inhibitor, LY294002, abolished the TIMP-1-mediated growth stimulation. These data suggest that TIMP-1 activates Ras, which then turns on the ERK and PI3K signaling pathways to promote cell cycle progression of the AoSMC

Effect of Fenspiride on Bronchial Smooth Muscle of Rats with Chronic Obstructive Pulmonary Disease

OpenAIRE

Kuzubova, Nataliya A.; Lebedeva, Elena S.; Fedin, Anatoliy N.; Dvorakovskaya, Ivetta V.; Preobrazhenskaya, Tatiana N.; Titova, Olga N.

2013-01-01

Chronic obstructive pulmonary disease (COPD) is among the leading causes of morbidity and mortality worldwide. Glucocorticoids are currently the most applicable anti-inflammatory treatment for COPD. However, a subset of COPD subjects is relatively insensitive to this treatment. Fenspiride, a non-corticosteroid anti-inflammatory drug, has been described to have beneficial effects in patients with COPD, although the mechanism of its action is not well known. The effect of fenspiride on contract...

Simvastatin enhances bone morphogenetic protein receptor type II expression

International Nuclear Information System (INIS)

Hu Hong; Sung, Arthur; Zhao, Guohua; Shi, Lingfang; Qiu Daoming; Nishimura, Toshihiko; Kao, Peter N.

2006-01-01

Statins confer therapeutic benefits in systemic and pulmonary vascular diseases. Bone morphogenetic protein (BMP) receptors serve essential signaling functions in cardiovascular development and skeletal morphogenesis. Mutations in BMP receptor type II (BMPR2) are associated with human familial and idiopathic pulmonary arterial hypertension, and pathologic neointimal proliferation of vascular endothelial and smooth muscle cells within small pulmonary arteries. In severe experimental pulmonary hypertension, simvastatin reversed disease and conferred a 100% survival advantage. Here, modulation of BMPR2 gene expression by simvastatin is characterized in human embryonic kidney (HEK) 293T, pulmonary artery smooth muscle, and lung microvascular endothelial cells (HLMVECs). A 1.4 kb BMPR2 promoter containing Egr-1 binding sites confers reporter gene activation in 293T cells which is partially inhibited by simvastatin. Simvastatin enhances steady-state BMPR2 mRNA and protein expression in HLMVEC, through posttranscriptional mRNA stabilization. Simvastatin induction of BMPR2 expression may improve BMP-BMPR2 signaling thereby enhancing endothelial differentiation and function

IgM response to a human Pneumocystis carinii surface antigen in HIV-infected patients with pulmonary symptoms

DEFF Research Database (Denmark)

Lundgren, Bettina; Kovacs, J A; Mathiesen, Lars Reinhardt

1993-01-01

We have developed an ELISA to detect IgM antibodies to a major human Pneumocystis carinii surface antigen (gp95), and investigated the IgM response in 128 HIV-infected patients who underwent bronchoscopy for evaluation of pulmonary symptoms. Only 5 (4%) patients had IgM antibodies to P. carinii g...

TNF-α activates death pathway in human aorta smooth muscle cell in the presence of 7-ketocholesterol

International Nuclear Information System (INIS)

Lee, Hyun Sun; Chang, Jong Sun; Baek, Jin Ah; Chung, Mi Yeon; Lee, Han Cheol; Rhim, Byung Yong; Sok, Dai Eun; Rho, Mun-Chual; Kim, Young Kook; Kim, Koanhoi

2005-01-01

This study was undertaken to investigate whether a physiologically compatible concentration of 7-ketocholesterol had any effect on human vascular smooth muscle cells (HVSMCs). We found that 7-ketocholesterol changed the viability of human aorta smooth muscle cells (HAoSMC) not by cytotoxicity but by activation of tumor necrosis factor-α receptor (TNFR)-mediated death. Whereas TNF-α did not affect the viability in the presence of 7α-hydroxycholesterol or cholesterol, the cytokine induced HAoSMC death in the presence of 7-ketocholesterol as detected by morphology, viability, and fragmentation of chromosomal DNA. The HAoSMC death was inhibited by a neutralizing anti-TNF receptor 1 (TNFR1) antibody and by the caspase inhibitors of z-VAD and z-DEVD. Activations of caspase-8 and -3 were detected from dying HAoSMCs. 7-Ketocholesterol inhibited translocation of the nuclear factor κB (NF-κB) subunits of p65 and p50 from the cytosol into the nucleus, increase of NF-κB activity, and expression of caspase-8 homolog Fas ligand interleukin-1-converting enzyme inhibitory protein by TNF-α. We also found that X-chromosome-linked inhibitor of apoptosis protein was degraded in dying HAoSMC. The present study proposes that 7-ketocholesterol would contribute to the disappearance of HVSMC in the atherosclerotic lesions by enhancing receptor-mediated death. This is the first report demonstrating induction of TNF-α-mediated death by oxysterol in cells

Definition, classification, and epidemiology of pulmonary arterial hypertension.

Science.gov (United States)

Hoeper, Marius M

2009-08-01

Pulmonary arterial hypertension (PAH) is a distinct subgroup of pulmonary hypertension that comprises idiopathic PAH, familial/heritable forms, and PAH associated with connective tissue disease, congenital heart disease, portal hypertension, human immunodeficiency virus (HIV) infection, and some other conditions. The hemodynamic definition of PAH was recently revised: PAH is now defined by a mean pulmonary artery pressure at rest > or =25 mm Hg in the presence of a pulmonary capillary wedge pressure or =30 mm Hg during exercise) that was used in the old definition of PAH has been removed because there are no robust data that would allow defining an upper limit of normal for the pulmonary pressure during exercise. The revised classification of pulmonary hypertension still consists of five major groups: (1) PAH, (2) pulmonary hypertension due to left heart disease, (3) pulmonary hypertension due to chronic lung disease and/or hypoxia, (4) chronic thromboembolic pulmonary hypertension, and (5) miscellaneous forms. Modifications have been made in some of these groups, such as the addition of schistosomiasis-related pulmonary hypertension and pulmonary hypertension in patients with chronic hemolytic anemia to group 1.

TGF-beta1 inhibits Cx43 expression and formation of functional syncytia in cultured smooth muscle cells from human detrusor.

Science.gov (United States)

Neuhaus, Jochen; Heinrich, Marco; Schwalenberg, Thilo; Stolzenburg, Jens-Uwe

2009-02-01

Human detrusor smooth muscle cells (hBSMCs) are coupled by connexin 43 (Cx43)-positive gap junctions to form functional syncytia. Gap junctional communication likely is necessary for synchronised detrusor contractions and is supposed to be altered in voiding disturbances. Other authors have shown that the pleiotropic cytokine TGF-beta1 upregulates Cx43 expression in human aortic smooth muscle cells. In this study, we examined the TGF-beta1 effects on Cx43 expression in cultured hBSMCs. hBSMC cultures, established from patients undergoing cystectomy, were treated with recombinant human TGF-beta1. Cx43 expression was then examined by Western blotting, real-time PCR, and immunocytochemistry. Dye-injection experiments were used to study the size of functional syncytia. Dye-coupling experiments revealed stable formation of functional syncytia in passaged cell cultures (P1-P4). Stimulation with TGF-beta1 led to significant reduction of Cx43 immunoreactivity and coupling. Cx43 protein expression was significantly downregulated and Cx43 mRNA was only 30% of the control level. Interestingly, low phosphorylation species of Cx43 were particularly affected. Our experiments demonstrated a significant down regulation of connexin 43 by TGF-beta1 in cultured hBSMCs. These findings support the view that TGF-beta1 is involved in the pathophysiology of urinary bladder dysfunction.

Serotonin transporter is not required for the development of severe pulmonary hypertension in the Sugen hypoxia rat model

NARCIS (Netherlands)

de Raaf, Michiel Alexander; Kroeze, Yvet; Middelman, Anthonieke; de Man, Frances S.; de Jong, Helma; Vonk-Noordegraaf, Anton; de Korte, Chris; Voelkel, Norbert F.; Homberg, Judith; Bogaard, Harm Jan

2015-01-01

Increased serotonin serum levels have been proposed to play a key role in pulmonary arterial hypertension (PAH) by regulating vessel tone and vascular smooth muscle cell proliferation. An intact serotonin system, which critically depends on a normal function of the serotonin transporter (SERT), is

The influence of propofol, remifentanil and lidocaine on the tone of human bronchial smooth muscle.

Science.gov (United States)

Rogliani, Paola; Calzetta, Luigino; Rendina, Erino A; Massullo, Domenico; Dauri, Mario; Rinaldi, Barbara; Capuano, Annalisa; Matera, Maria Gabriella

2013-06-01

Bronchoscopy is generally a safe procedure, but the induction of anaesthesia can induce bronchospasm. Consequently we investigated the influence of propofol, remifentanil and lidocaine on the tone of the human bronchial smooth muscle. The influence of propofol, remifentanil and lidocaine on the contractile response of human bronchial smooth muscle to electrical field stimulation (EFS) has been evaluated. The role of capsaicin-sensitive sensory nerves and of inducible nitric oxide synthase has also been assessed. Furthermore, the interaction between these three dugs has been measured by Bliss Independence (BI) theory. Statistical significance (P < 0.05) was assessed by Student's t test or ANOVA. Propofol (1.3 μg ml(-1)) and lidocaine (1 mg ml(-1)) reduced the baseline tone of bronchial rings (-14.45 ± 4.53% and -33.40 ± 1.07%, respectively, P < 0.05), whereas remifentanil had not such effect. Aminoguanidine prevented the relaxant effect of propofol. Propofol did not alter the bronchial contractile response to EFS following 30 min of treatment, whereas remifentanil enhanced the bronchial tension (133.83 ± 9.38%, control 101.93 ± 6.82%, P < 0.05 P < 0.05) and lidocaine completely abolished the contractility at 1 mg ml(-1) (P < 0.05). The desensitization of capsaicin-sensitive sensory nerves normalized the hyperresponsiveness induced by remifentanil (-26.77 ± 1.68%, P < 0.05). Significant BI antagonism (P < 0.001) was detected for propofol and lidocaine on the bronchial hyperresponsiveness induced by remifentanil. Propofol and remifentanil may be used safely for bronchoscopy, although remifentanil should be associated with propofol or lidocaine to prevent the potential opioid-mediated bronchospasm. Copyright © 2013 Elsevier Ltd. All rights reserved.

Smooth polyhedral surfaces

KAUST Repository

Gü nther, Felix; Jiang, Caigui; Pottmann, Helmut

2017-01-01

Polyhedral surfaces are fundamental objects in architectural geometry and industrial design. Whereas closeness of a given mesh to a smooth reference surface and its suitability for numerical simulations were already studied extensively, the aim of our work is to find and to discuss suitable assessments of smoothness of polyhedral surfaces that only take the geometry of the polyhedral surface itself into account. Motivated by analogies to classical differential geometry, we propose a theory of smoothness of polyhedral surfaces including suitable notions of normal vectors, tangent planes, asymptotic directions, and parabolic curves that are invariant under projective transformations. It is remarkable that seemingly mild conditions significantly limit the shapes of faces of a smooth polyhedral surface. Besides being of theoretical interest, we believe that smoothness of polyhedral surfaces is of interest in the architectural context, where vertices and edges of polyhedral surfaces are highly visible.

Smooth polyhedral surfaces

KAUST Repository

Günther, Felix

2017-03-15

Polyhedral surfaces are fundamental objects in architectural geometry and industrial design. Whereas closeness of a given mesh to a smooth reference surface and its suitability for numerical simulations were already studied extensively, the aim of our work is to find and to discuss suitable assessments of smoothness of polyhedral surfaces that only take the geometry of the polyhedral surface itself into account. Motivated by analogies to classical differential geometry, we propose a theory of smoothness of polyhedral surfaces including suitable notions of normal vectors, tangent planes, asymptotic directions, and parabolic curves that are invariant under projective transformations. It is remarkable that seemingly mild conditions significantly limit the shapes of faces of a smooth polyhedral surface. Besides being of theoretical interest, we believe that smoothness of polyhedral surfaces is of interest in the architectural context, where vertices and edges of polyhedral surfaces are highly visible.

Signal transduction in the development of pulmonary arterial hypertension

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Malenfant, Simon; Neyron, Anne-Sophie; Paulin, Roxane; Potus, François; Meloche, Jolyane; Provencher, Steeve; Bonnet, Sébastien

2013-01-01

Pulmonary arterial hypertension (PAH) is a unique disease. Properly speaking, it is not a disease of the lung. It can be seen more as a microvascular disease occurring mainly in the lungs and affecting the heart. At the cellular level, the PAH paradigm is characterized by inflammation, vascular tone imbalance, pulmonary arterial smooth muscle cell proliferation and resistance to apoptosis and the presence of in situ thrombosis. At a clinical level, the aforementioned abnormal vascular properties alter physically the pulmonary circulation and ventilation, which greatly influence the right ventricle function as it highly correlates with disease severity. Consequently, right heart failure remains the principal cause of death within this cohort of patients. While current treatment modestly improve patients’ conditions, none of them are curative and, as of today, new therapies are lacking. However, the future holds potential new therapies that might have positive influence on the quality of life of the patient. This article will first review the clinical presentation of the disease and the different molecular pathways implicated in the pathobiology of PAH. The second part will review tomorrow's future putative therapies for PAH. PMID:24015329

SmoothMoves : Smooth pursuits head movements for augmented reality

NARCIS (Netherlands)

Esteves, Augusto; Verweij, David; Suraiya, Liza; Islam, Rasel; Lee, Youryang; Oakley, Ian

2017-01-01

SmoothMoves is an interaction technique for augmented reality (AR) based on smooth pursuits head movements. It works by computing correlations between the movements of on-screen targets and the user's head while tracking those targets. The paper presents three studies. The first suggests that head

Pulmonary Hypertension and Pulmonary Vasodilators.

Science.gov (United States)

Keller, Roberta L

2016-03-01

Pulmonary hypertension in the perinatal period can present acutely (persistent pulmonary hypertension of the newborn) or chronically. Clinical and echocardiographic diagnosis of acute pulmonary hypertension is well accepted but there are no broadly validated criteria for echocardiographic diagnosis of pulmonary hypertension later in the clinical course, although there are significant populations of infants with lung disease at risk for this diagnosis. Contributing cardiovascular comorbidities are common in infants with pulmonary hypertension and lung disease. It is not clear who should be treated without confirmation of pulmonary vascular disease by cardiac catheterization, with concurrent evaluation of any contributing cardiovascular comorbidities. Copyright © 2016 Elsevier Inc. All rights reserved.

Smoothing a Piecewise-Smooth: An Example from Plankton Population Dynamics

DEFF Research Database (Denmark)

Piltz, Sofia Helena

2016-01-01

In this work we discuss a piecewise-smooth dynamical system inspired by plankton observations and constructed for one predator switching its diet between two different types of prey. We then discuss two smooth formulations of the piecewise-smooth model obtained by using a hyperbolic tangent funct...... function and adding a dimension to the system. We compare model behaviour of the three systems and show an example case where the steepness of the switch is determined from a comparison with data on freshwater plankton....

Protein S is protective in pulmonary fibrosis.

Science.gov (United States)

Urawa, M; Kobayashi, T; D'Alessandro-Gabazza, C N; Fujimoto, H; Toda, M; Roeen, Z; Hinneh, J A; Yasuma, T; Takei, Y; Taguchi, O; Gabazza, E C

2016-08-01

Essentials Epithelial cell apoptosis is critical in the pathogenesis of idiopathic pulmonary fibrosis. Protein S, a circulating anticoagulant, inhibited apoptosis of lung epithelial cells. Overexpression of protein S in lung cells reduced bleomycin-induced pulmonary fibrosis. Intranasal therapy with exogenous protein S ameliorated bleomycin-induced pulmonary fibrosis. Background Pulmonary fibrosis is the terminal stage of interstitial lung diseases, some of them being incurable and of unknown etiology. Apoptosis plays a critical role in lung fibrogenesis. Protein S is a plasma anticoagulant with potent antiapoptotic activity. The role of protein S in pulmonary fibrosis is unknown. Objectives To evaluate the clinical relevance of protein S and its protective role in pulmonary fibrosis. Methods and Results The circulating level of protein S was measured in patients with pulmonary fibrosis and controls by the use of enzyme immunoassays. Pulmonary fibrosis was induced with bleomycin in transgenic mice overexpressing human protein S and wild-type mice, and exogenous protein S or vehicle was administered to wild-type mice; fibrosis was then compared in both models. Patients with pulmonary fibrosis had reduced circulating levels of protein S as compared with controls. Inflammatory changes, the levels of profibrotic cytokines, fibrosis score, hydroxyproline content in the lungs and oxygen desaturation were significantly reduced in protein S-transgenic mice as compared with wild-type mice. Wild-type mice treated with exogenous protein S showed significant decreases in the levels of inflammatory and profibrotic markers and fibrosis in the lungs as compared with untreated control mice. After bleomycin infusion, mice overexpressing human protein S showed significantly low caspase-3 activity, enhanced expression of antiapoptotic molecules and enhanced Akt and Axl kinase phosphorylation as compared with wild-type counterparts. Protein S also inhibited apoptosis of alveolar

Biological, pathobiological and bioclinical bases of pulmonary surfactant metabolism in the human species

International Nuclear Information System (INIS)

Garcia, Alfonso; Ojeda, Paulina

2008-01-01

The surfactant metabolism dysfunction pulmonary (SMDP), classically termed as Pulmonary Alveolar Proteinosis (PAP) are a unusual respiratory disorder characterized by abundant and excessive accumulation of surfactant-derived phospholipids and protein components in the pulmonary alveoli and distal airways, with disturbances associated secondary of pulmonary gas exchange and engendering respiratory insufficiency. At least three general pathophysiologic mechanisms may lead to the characteristic feature of PAP: Primary (idiopathic, essential, acquired or adult), secondary and congenital.

Preventive and curative effects of dicaffeoylquinic acid on early pulmonary fibrosis in mice

International Nuclear Information System (INIS)

Liu Tao; Song Liangwen; Dong Junxing; Huang Shanying; Li Yang

2005-01-01

Objective: To explore the effect of dicaffeoylquinic acid (IBE5) on prevention and treatment of pulmonary fibrosis induced by bleomycin (BLM) in mice and its mechanism. Methods: Hydroxyproline content determination, imaging analysis, collagen I and III assay, α-smooth muscle actin (α-SMA) and matrix metalloproteinase 7 (MMP-7 ) immunohistochemistry were performed. Results: 1)Hydroxyproline content decreased in fibrotic lung tissue after administration of IBE5(P<0.05). 2)The number of pulmonary alveoli reduced, alveolus interstitium was thickened and collagen deposition and fibrosis were formed in lung tissue of BLM group. The break of pulmonary alveoli and extension of pulmonary fibrosis were decreased by use of IBE5 (P<0.05). 3)A lot of collagen I and III were synthesized in lung interstitium in BLM group and their quantity was reduced in IBE5 group (P<0.05). 4) In BLM group, α-SMA expression increased and located in myofibroblasts in fibrotic area, and MMP7 immunohistochemical signal was located in myofibroblasts also. They were decreased in IBE5 group(P<0.05). Conclusion: IBE5 plays a preventive and curative role in pulmonary fibrosis by inhibition of transformation of fibroblasts towards myofibroblasts and MMP7 expression. (authors)

Metabolism of benzo[a]pyrene and 7,12-dimethylbenz[a]anthracene in cultured human fetal aortic smooth muscle cells

International Nuclear Information System (INIS)

Bond, J.A.; Kocan, R.M.; Benditt, E.P.; Juchau, M.R.

1979-01-01

Cultured human fetal aortic smooth muscle cells derived from the abdominal aorta converted benzo[a]pyrene (BaP) and 7,12-dimethylbenz[a]anthracene (DMBA) via cytochrome P-450-dependent monooxygenation to metabolites detectable by both a highly sensitive radiometric assay and high pressure liquid chromatography (HPLC). Cells incubated with 3 H-BaP transformed this substrate primarily to phenols. 14 C-DMBA was converted to metabolites that cochromatographed with 12-hydroxymethyl-methylbenz[a]anthracene, 7-hydroxymethyl-12-methylbenz[a]anthracene, 7- 7,12-dihydroxymethylbenz[a]anthracene, and trans-8,9-dihydrodiol-7,12-DMBA. Exposure of cells in culture to 13 μM 1,2-benz[a]anthracene resulted in increased oxidative metabolism of both BaP and DMBA. In the case of BaP, total phenol formation was increased, while with DMBA all metabolites detected by HPLC were increased. Support for the potential role of metabolism of polycyclic aromatic hydrocarbons by aortic smooth muscle cells in the etiology of atherosclerosis was obtained

Probable initial pulmonary lymphangioleiomyomatosis and mediastinal lymphangioleiomyoma

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M. Pontes

2014-03-01

Full Text Available A 68‐year‐old woman was submitted to a mediastinal lymphangioleiomyoma resection found in a follow‐up study of lower left lung resection due to bronchiectasis complicated by chylothorax. This led to a revaluation of the pulmonary specimen that revealed, in addition to inflammatory bronchiectasis, small spindle cell nodules in the lung parenchyma, similar to minute pulmonary meningothelial‐like nodules, but with smooth muscle actin immunohistochemical positivity. The possibility of initial pulmonary development of lymphangioleiomyomatosis is discussed. Resumo: Uma mulher de 68 anos foi submetida a uma ressecção de um linfangioleiomioma mediastinal observado na monitorização de uma lobectomia inferior esquerda devido a bronquiectasia, complicada por quilotórax. Isto levou a uma reavaliação do espécime pulmonar que revelou, além da bronquiectasia inflamatória, nódulos pequenos de células fusiformes no parênquima pulmonar, semelhantes a nódulos pulmonares de tipo meningotelial, mas com positividade imunohistoquímica para actina do músculo liso. A hipótese de desenvolvimento inicial de linfangioleiomiomatose pulmonar é discutida. Keywords: Mediastinal, Lymphangioleiomyoma, Lymphangioleiomyomatosis, Palavras‐chave: Mediastinal, Linfangioleiomioma, Linfangioleiomiomatose

Immunohistochemical characterization of endometriosis-associated smooth muscle cells in human peritoneal endometriotic lesions.

Science.gov (United States)

Barcena de Arellano, Maria L; Gericke, Jessica; Reichelt, Uta; Okuducu, Ali Fuat; Ebert, Andreas D; Chiantera, Vito; Schneider, Achim; Mechsner, Sylvia

2011-10-01

Smooth muscle cells (SMC) are common components of endometriotic lesions. SMC have been characterized previously in peritoneal, ovarian and deep infiltrating endometriotic lesions and adenomyosis. The aim of this retrospective study was to investigate the extent of differentiation in endometriosis-associated SMC (EMaSMC) in peritoneal endometriotic lesions. We obtained biopsies from peritoneal endometriotic lesions (n = 60) and peritoneal sites distant from the endometriotic lesion (n = 60), as well as healthy peritoneum from patients without endometriosis (control tissue, n = 10). These controls were hysterectomy specimens from patients without endometriosis or adenomyosis. Histopathological examination of peritoneal specimens using antibodies against oxytocin receptor (OTR), vasopressin receptor (VPR), smooth muscle myosin heavy chain (SM-MHC), estrogen receptor (ER) or progesterone receptor (PR) was performed. To identify SMC and their level of differentiation, antibodies for smooth muscle actin desmin and caldesmon were used. SMC were detected in all endometriotic lesions. SMC were more abundant in unaffected peritoneum of women with endometriosis (38%) compared with women without endometriosis (6%; P endometriosis.

Ureter smooth muscle cell orientation in rat is predominantly longitudinal.

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Bart Spronck

Full Text Available In ureter peristalsis, the orientation of the contracting smooth muscle cells is essential, yet current descriptions of orientation and composition of the smooth muscle layer in human as well as in rat ureter are inconsistent. The present study aims to improve quantification of smooth muscle orientation in rat ureters as a basis for mechanistic understanding of peristalsis. A crucial step in our approach is to use two-photon laser scanning microscopy and image analysis providing objective, quantitative data on smooth muscle cell orientation in intact ureters, avoiding the usual sectioning artifacts. In 36 rat ureter segments, originating from a proximal, middle or distal site and from a left or right ureter, we found close to the adventitia a well-defined longitudinal smooth muscle orientation. Towards the lamina propria, the orientation gradually became slightly more disperse, yet the main orientation remained longitudinal. We conclude that smooth muscle cell orientation in rat ureter is predominantly longitudinal, though the orientation gradually becomes more disperse towards the proprial side. These findings do not support identification of separate layers. The observed longitudinal orientation suggests that smooth muscle contraction would rather cause local shortening of the ureter, than cause luminal constriction. However, the net-like connective tissue of the ureter wall may translate local longitudinal shortening into co-local luminal constriction, facilitating peristalsis. Our quantitative, minimally invasive approach is a crucial step towards more mechanistic insight into ureter peristalsis, and may also be used to study smooth muscle cell orientation in other tube-like structures like gut and blood vessels.

Ureter smooth muscle cell orientation in rat is predominantly longitudinal.

Science.gov (United States)

Spronck, Bart; Merken, Jort J; Reesink, Koen D; Kroon, Wilco; Delhaas, Tammo

2014-01-01

In ureter peristalsis, the orientation of the contracting smooth muscle cells is essential, yet current descriptions of orientation and composition of the smooth muscle layer in human as well as in rat ureter are inconsistent. The present study aims to improve quantification of smooth muscle orientation in rat ureters as a basis for mechanistic understanding of peristalsis. A crucial step in our approach is to use two-photon laser scanning microscopy and image analysis providing objective, quantitative data on smooth muscle cell orientation in intact ureters, avoiding the usual sectioning artifacts. In 36 rat ureter segments, originating from a proximal, middle or distal site and from a left or right ureter, we found close to the adventitia a well-defined longitudinal smooth muscle orientation. Towards the lamina propria, the orientation gradually became slightly more disperse, yet the main orientation remained longitudinal. We conclude that smooth muscle cell orientation in rat ureter is predominantly longitudinal, though the orientation gradually becomes more disperse towards the proprial side. These findings do not support identification of separate layers. The observed longitudinal orientation suggests that smooth muscle contraction would rather cause local shortening of the ureter, than cause luminal constriction. However, the net-like connective tissue of the ureter wall may translate local longitudinal shortening into co-local luminal constriction, facilitating peristalsis. Our quantitative, minimally invasive approach is a crucial step towards more mechanistic insight into ureter peristalsis, and may also be used to study smooth muscle cell orientation in other tube-like structures like gut and blood vessels.

Endogenous laminin is required for human airway smooth muscle cell maturation

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Tran Thai

2006-09-01

Full Text Available Abstract Background Airway smooth muscle (ASM contraction underlies acute bronchospasm in asthma. ASM cells can switch between a synthetic-proliferative phenotype and a contractile phenotype. While the effects of extracellular matrix (ECM components on modulation of ASM cells to a synthetic phenotype have been reported, the role of ECM components on maturation of ASM cells to a contractile phenotype in adult lung is unclear. As both changes in ECM components and accumulation of contractile ASM are features of airway wall remodelling in asthma, we examined the role of the ECM protein, laminin, in the maturation of contractile phenotype in human ASM cells. Methods Human ASM cells were made senescence-resistant by stable expression of human telomerase reverse transcriptase. Maturation to a contractile phenotype was induced by 7-day serum deprivation, as assessed by immunoblotting for desmin and calponin. The role of laminin on ASM maturation was investigated by comparing the effects of exogenous laminin coated on culture plates, and of soluble laminin peptide competitors. Endogenous expression of laminin chains during ASM maturation was also measured. Results Myocyte binding to endogenously expressed laminin was required for ASM phenotype maturation, as laminin competing peptides (YIGSR or GRGDSP significantly reduced desmin and calponin protein accumulation that otherwise occurs with prolonged serum deprivation. Coating of plastic cell culture dishes with different purified laminin preparations was not sufficient to further promote accumulation of desmin or calponin during 7-day serum deprivation. Expression of α2, β1 and γ1 laminin chains by ASM cells was specifically up-regulated during myocyte maturation, suggesting a key role for laminin-2 in the development of the contractile phenotype. Conclusion While earlier reports suggest exogenously applied laminin slows the spontaneous modulation of ASM to a synthetic phenotype, we show for the

Computational Fluid Dynamics Modeling of the Human Pulmonary Arteries with Experimental Validation.

Science.gov (United States)

Bordones, Alifer D; Leroux, Matthew; Kheyfets, Vitaly O; Wu, Yu-An; Chen, Chia-Yuan; Finol, Ender A

2018-05-21

Pulmonary hypertension (PH) is a chronic progressive disease characterized by elevated pulmonary arterial pressure, caused by an increase in pulmonary arterial impedance. Computational fluid dynamics (CFD) can be used to identify metrics representative of the stage of PH disease. However, experimental validation of CFD models is often not pursued due to the geometric complexity of the model or uncertainties in the reproduction of the required flow conditions. The goal of this work is to validate experimentally a CFD model of a pulmonary artery phantom using a particle image velocimetry (PIV) technique. Rapid prototyping was used for the construction of the patient-specific pulmonary geometry, derived from chest computed tomography angiography images. CFD simulations were performed with the pulmonary model with a Reynolds number matching those of the experiments. Flow rates, the velocity field, and shear stress distributions obtained with the CFD simulations were compared to their counterparts from the PIV flow visualization experiments. Computationally predicted flow rates were within 1% of the experimental measurements for three of the four branches of the CFD model. The mean velocities in four transversal planes of study were within 5.9 to 13.1% of the experimental mean velocities. Shear stresses were qualitatively similar between the two methods with some discrepancies in the regions of high velocity gradients. The fluid flow differences between the CFD model and the PIV phantom are attributed to experimental inaccuracies and the relative compliance of the phantom. This comparative analysis yielded valuable information on the accuracy of CFD predicted hemodynamics in pulmonary circulation models.

Alteration of pulmonary blood flow in tetralogy of Fallot; Pre- and postoperative study with macroaggregates of [sup 99m]Tc-labeled human serum albumin

Energy Technology Data Exchange (ETDEWEB)

Hashimoto, Kazuhiro; Matsui, Michihiko; Kurosawa, Hiromi; Arai, Tatsuta (Jikei Univ., Tokyo (Japan). School of Medicine); Nakamura, Yuzuru

1992-10-01

The pulmonary blood distribution was examined in 17 patients with tetralogy of Fallot (TOF) pre and postoperatively with macroaggregates of [sup 99m]TC-labeled human serum albumin. Most of the patients with TOF demonstrated an abnormal preoperative distribution pattern. The abnormalities included not only an unbalanced distribution between the right and left lungs but also a maldistribution of peripheral vessels in each lung. The right/left lung counts ratio and pulmonary peripheral index (calculated in order to express the severity of peripheral maldistribution) correlated neither to the diameter nor the cross-sectional area of either right or left pulmonary arteries which were measured angiographically. Postoperatively, the pulmonary blood was shunted toward the developed side of the lung which further contributed to maldistribution of blood flow and unbalanced pulmonary growth. Since the patients with an unbalanced pulmonary blood distribution demonstrated a higher right ventricular pressure one year after the operation, a palliative operation facilitating the growth of the underdeveloped side of the lung might be considered as an effective procedure to precede intracardiac repair. (author).

Cis-acting sequences from a human surfactant protein gene confer pulmonary-specific gene expression in transgenic mice

Energy Technology Data Exchange (ETDEWEB)

Korfhagen, T.R.; Glasser, S.W.; Wert, S.E.; Bruno, M.D.; Daugherty, C.C.; McNeish, J.D.; Stock, J.L.; Potter, S.S.; Whitsett, J.A. (Cincinnati College of Medicine, OH (USA))

1990-08-01

Pulmonary surfactant is produced in late gestation by developing type II epithelial cells lining the alveolar epithelium of the lung. Lack of surfactant at birth is associated with respiratory distress syndrome in premature infants. Surfactant protein C (SP-C) is a highly hydrophobic peptide isolated from pulmonary tissue that enhances the biophysical activity of surfactant phospholipids. Like surfactant phospholipid, SP-C is produced by epithelial cells in the distal respiratory epithelium, and its expression increases during the latter part of gestation. A chimeric gene containing 3.6 kilobases of the promoter and 5{prime}-flanking sequences of the human SP-C gene was used to express diphtheria toxin A. The SP-C-diphtheria toxin A fusion gene was injected into fertilized mouse eggs to produce transgenic mice. Affected mice developed respiratory failure in the immediate postnatal period. Morphologic analysis of lungs from affected pups showed variable but severe cellular injury confined to pulmonary tissues. Ultrastructural changes consistent with cell death and injury were prominent in the distal respiratory epithelium. Proximal components of the tracheobronchial tree were not severely affected. Transgenic animals were of normal size at birth, and structural abnormalities were not detected in nonpulmonary tissues. Lung-specific diphtheria toxin A expression controlled by the human SP-C gene injured type II epithelial cells and caused extensive necrosis of the distal respiratory epithelium. The absence of type I epithelial cells in the most severely affected transgenic animals supports the concept that developing type II cells serve as precursors to type I epithelial cells.

Thymosin Beta 4 protects mice from monocrotaline-induced pulmonary hypertension and right ventricular hypertrophy.

Directory of Open Access Journals (Sweden)

Chuanyu Wei

Full Text Available Pulmonary hypertension (PH is a progressive vascular disease of pulmonary arteries that impedes ejection of blood by the right ventricle. As a result there is an increase in pulmonary vascular resistance and pulmonary arterial pressure causing right ventricular hypertrophy (RVH and RV failure. The pathology of PAH involves vascular cell remodeling including pulmonary arterial endothelial cell (PAEC dysfunction and pulmonary arterial smooth muscle cell (PASMC proliferation. Current therapies are limited to reverse the vascular remodeling. Investigating a key molecule is required for development of new therapeutic intervention. Thymosin beta-4 (Tβ4 is a ubiquitous G-actin sequestering protein with diverse biological function and promotes wound healing and modulates inflammatory responses. However, it remains unknown whether Tβ4 has any protective role in PH. The purpose of this study is to evaluate the whether Tβ4 can be used as a vascular-protective agent. In monocrotaline (MCT-induced PH mouse model, we showed that mice treated with Tβ4 significantly attenuated the systolic pressure and RVH, compared to the MCT treated mice. Our data revealed for the first time that Tβ4 selectively targets Notch3-Col 3A-CTGF gene axis in preventing MCT-induced PH and RVH. Our study may provide pre-clinical evidence for Tβ4 and may consider as vasculo-protective agent for the treatment of PH induced RVH.

Asthma causes inflammation of human pulmonary arteries and decreases vasodilatation induced by prostaglandin I2 analogs.

Science.gov (United States)

Foudi, Nabil; Badi, Aouatef; Amrane, Mounira; Hodroj, Wassim

2017-12-01

Asthma is a chronic inflammatory disease associated with increased cardiovascular events. This study assesses the presence of inflammation and the vascular reactivity of pulmonary arteries in patients with acute asthma. Rings of human pulmonary arteries obtained from non-asthmatic and asthmatic patients were set up in organ bath for vascular tone monitoring. Reactivity was induced by vasoconstrictor and vasodilator agents. Protein expression of inflammatory markers was detected by western blot. Prostanoid releases and cyclic adenosine monophosphate (cAMP) levels were quantified using specific enzymatic kits. Protein expression of cluster of differentiation 68, intercellular adhesion molecule-1, vascular cell adhesion molecule-1, and cyclooxygenase-2 was significantly increased in arteries obtained from asthmatic patients. These effects were accompanied by an alteration of vasodilatation induced by iloprost and treprostinil, a decrease in cAMP levels and an increase in prostaglandin (PG) E 2 and PGI 2 synthesis. The use of forskolin (50 µmol/L) has restored the vasodilatation and cAMP release. No difference was observed between the two groups in reactivity induced by norepinephrine, angiotensin II, PGE 2 , KCl, sodium nitroprusside, and acetylcholine. Acute asthma causes inflammation of pulmonary arteries and decreases vasodilation induced by PGI 2 analogs through the impairment of cAMP pathway.

Update on the clinical utility of sildenafil in the treatment of pulmonary arterial hypertension

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Gautam V Ramani

2010-05-01

Full Text Available Gautam V Ramani, Myung H ParkUniversity of Maryland, Baltimore, MD, USAAbstract: Sildenafil is an orally administered phosphodiesterase type 5 inhibitor that is approved for the treatment of pulmonary arterial hypertension (PAH. The hemodynamic effects of sildenafil are mitigated primarily via potentiating the effects of endogenous nitric oxide, leading to smooth muscle cell relaxation and reductions in pulmonary arterial pressures and pulmonary vascular resistance. When added to standard background therapy in patients with idiopathic or associated PAH from congenital heart disease, anorexigen use, or connective tissue disease, sildenafil treatment results in improved exercise capacity as measured by 6 minute walk distance, improved hemodynamics, and favorable changes in quality of life. Sildenafil use is contraindicated with concomitant nitrate administration, and caution should be exercised when used in combination with antihypertensive agents due to risks of precipitating hypotension. Side effects are generally mild, and include flushing, headaches, and epistaxis. The combination of sildenafil with intravenous epoprostenol is safe and well tolerated, and further improves exercise capacity. Sildenafil is approved only for treatment of PAH, and although emerging data suggest a potential role in treating other types of pulmonary hypertension, larger trials are required to confirm these findings. Keywords: sildenafil, pulmonary arterial hypertension, phosphodiesterase type 5 inhibitor

Lung scintigraphy with nonspecific human immunoglobulin G (99mTc-HIG) in the evaluation of pulmonary involvement in connective tissue diseases: correlation with pulmonary function tests (PFTs) and high-resolution computed tomography (HRCT)

International Nuclear Information System (INIS)

Kostopoulos, C.; Toubanakis, C.; Mamoulakis, C.; Gialafos, E.; Mavrikakis, M.; Koutsikos, J.; Zerva, C.; Leondi, A.; Moulopoulos, L.A.; Sfikakis, P.P.

2008-01-01

In patients with connective tissue diseases (CTD), the early detection and evaluation of the severity of the pulmonary involvement is mandatory. High-resolution computed tomography (HRCT) and pulmonary function tests (PFTs) are considered to be valuable noninvasive diagnostic modalities. Radiopharmaceuticals have also been used for this purpose. Our aim was the evaluation of technetium-labeled human polyclonal immunoglobulin G (HIG) lung scintigraphy in the early detection and assessment of the severity of the pulmonary involvement in CTD patients. Fifty-two nonsmoking CTD patients were studied by PFTs, HRCT, and HIG. According to PFTs, patients were divided in group A (impaired PFTs - abnormal pulmonary function) and group B (normal pulmonary function). Semiquantitative analysis was done on HIG and HRCT and corresponding scores were obtained. Significant difference was found between HIG scores in the two groups (0.6 ± 0.07 vs 0.51 ± 0.08, P < 0.001). There was a statistically significant negative correlation between HIG scores and PFTs results and a positive correlation between HIG and HRCT scores. HIG demonstrated similar clinical performance to HRCT. At the best cut-off levels of their score (0.56 and 7, respectively), HIG had a superior sensitivity (77.5 vs 57.5%) with lower specificity (75 vs 91.7%). The combination of the two methods increased the sensitivity of abnormal findings at the expense of specificity. HIG scintigraphy can be used in the early detection and evaluation of the severity of the pulmonary involvement in CTD, whereas, when used in combination with HRCT, the detection of affected patients can be further improved. (orig.)

Expression of smooth muscle and non-muscle myosin heavy chain isoforms in cultured vascular smooth muscle cells

International Nuclear Information System (INIS)

Rovner, A.S.; Murphy, R.A.; Owens, G.K.

1986-01-01

Immunocytochemical studies of cultured smooth muscle cells (SMCs) have disagreed on the nature of myosin expression. This investigation was undertaken to test for the presence of heterogeneous myosin heavy chain (MHC) isoforms in cell culture as a possible explanation for these results. Previously, Rovner et al. detected two MHCs in intact smooth muscles which differed in molecular weight by ca. 4000 daltons (SM1 and SM2) using a 3-4% acrylamide gradient SDS gel system. When sub-confluent primary cultures of rat aorta SMCs were assayed by this system, SM1 and SM2 were seen, along with large amounts of a third, unique MHC, NM, which closely resembled the MHC from human platelet in size and antigenicity. Data from 35 S-methionine autoradiograms showed that the log growth phase SMC cultures were producing almost exclusively NM, but the growth arrest, post-confluent cultures synthesized increased relative amounts of the SM MHC forms and contained comparable amounts of SM1, SM2, and NM. The same patterns of MHC synthesis were seen in sub-passaged SMCs. The expression of the SM-specific forms of myosin in quiescent, post-confluent cultures parallels that of smooth muscle actin suggesting that density induced growth arrest promotes cytodifferentiation in cultured vascular SMCs

Hypoxia-induced pulmonary vascular remodeling requires recruitment of circulating mesenchymal precursors of a monocyte/macrophage lineage.

Science.gov (United States)

Frid, Maria G; Brunetti, Jacqueline A; Burke, Danielle L; Carpenter, Todd C; Davie, Neil J; Reeves, John T; Roedersheimer, Mark T; van Rooijen, Nico; Stenmark, Kurt R

2006-02-01

Vascular remodeling in chronic hypoxic pulmonary hypertension includes marked fibroproliferative changes in the pulmonary artery (PA) adventitia. Although resident PA fibroblasts have long been considered the primary contributors to these processes, we tested the hypothesis that hypoxia-induced pulmonary vascular remodeling requires recruitment of circulating mesenchymal precursors of a monocyte/macrophage lineage, termed fibrocytes. Using two neonatal animal models (rats and calves) of chronic hypoxic pulmonary hypertension, we demonstrated a dramatic perivascular accumulation of mononuclear cells of a monocyte/macrophage lineage (expressing CD45, CD11b, CD14, CD68, ED1, ED2). Many of these cells produced type I collagen, expressed alpha-smooth muscle actin, and proliferated, thus exhibiting mesenchymal cell characteristics attributed to fibrocytes. The blood-borne origin of these cells was confirmed in experiments wherein circulating monocytes/macrophages of chronically hypoxic rats were in vivo-labeled with DiI fluorochrome via liposome delivery and subsequently identified in the remodeled pulmonary, but not systemic, arterial adventitia. The DiI-labeled cells that appeared in the vessel wall expressed monocyte/macrophage markers and procollagen. Selective depletion of this monocytic cell population, using either clodronate-liposomes or gadolinium chloride, prevented pulmonary adventitial remodeling (ie, production of collagen, fibronectin, and tenascin-C and accumulation of myofibroblasts). We conclude that circulating mesenchymal precursors of a monocyte/macrophage lineage, including fibrocytes, are essential contributors to hypoxia-induced pulmonary vascular remodeling.

Disruption of the Hepcidin/Ferroportin Regulatory System Causes Pulmonary Iron Overload and Restrictive Lung Disease

Directory of Open Access Journals (Sweden)

Joana Neves

2017-06-01

Full Text Available Emerging evidence suggests that pulmonary iron accumulation is implicated in a spectrum of chronic lung diseases. However, the mechanism(s involved in pulmonary iron deposition and its role in the in vivo pathogenesis of lung diseases remains unknown. Here we show that a point mutation in the murine ferroportin gene, which causes hereditary hemochromatosis type 4 (Slc40a1C326S, increases iron levels in alveolar macrophages, epithelial cells lining the conducting airways and lung parenchyma, and in vascular smooth muscle cells. Pulmonary iron overload is associated with oxidative stress, restrictive lung disease with decreased total lung capacity and reduced blood oxygen saturation in homozygous Slc40a1C326S/C326S mice compared to wild-type controls. These findings implicate iron in lung pathology, which is so far not considered a classical iron-related disorder.

Polysaccharide from Fuzi protects against Ox-LDL-induced calcification of human vascular smooth muscle cells by increasing autophagic activity

Science.gov (United States)

Liao, Lizhen; Zhuang, Xiaodong; Li, Weidong; Su, Qibiao; Zhao, Jie; Liu, Ying

2018-01-01

Polysaccharide from Fuzi (FPS) is a water-soluble polysaccharide isolated from the traditional Chinese herbal medicine Fuzi. It has been demonstrated to protect hepatocytes against ischemia-reperfusion injury through its potent antioxidant effects, and to attenuate starvation-induced cytotoxicity in H9c2 cells by increasing autophagic activity. In the present study, Alizarin Red S staining was used to detect mineral deposition and reverse transcription-quantitative polymerase chain reaction was used to detect the core binding factor α1 and smooth muscle 22α mRNA expression. To analyze autophagic activity, western blotting was used to detect microtubule-associated protein 1A/1B light chain 3 and nucleoporin P62 expression. In addition, green fluorescent protein-LC3 dots-per-cell was observed by fluorescence microscopy. It was demonstrated that oxidized low-density lipoprotein (Ox-LDL) could increase the calcification of human vascular smooth muscle cells (VSMCs) in a concentration-dependent manner, and that FPS treatment had a significant protective effect against Ox-LDL-induced calcification of human VSMCs. Furthermore, FPS treatment alleviated the Ox-LDL-induced downregulation of autophagic activity, and the protective effect of FPS on Ox-LDL-induced calcification was attenuated by the autophagy inhibitor 3-methyladenine. In conclusion, the present study demonstrated for the first time to the best of the authors' knowledge that FPS can protect against Ox-LDL-induced vascular calcification in human VSMCs, and that this likely occurs via the activation of autophagy. This supports the hypothesis that autophagy may be an endogenous protective mechanism counteracting vascular calcification, and that FPS may be used as a potential therapeutic for vascular calcification. PMID:29393437

Pulmonary infection by Rhodococcus equi presenting with positive Ziehl-Neelsen stain in a patient with human immunodeficiency virus: a case report

OpenAIRE

Spiliopoulou, Anastasia; Assimakopoulos, Stelios F; Foka, Antigoni; Kolonitsiou, Fevronia; Lagadinou, Maria; Petinaki, Efthimia; Anastassiou, Evangelos D; Spiliopoulou, Iris; Marangos, Markos

2014-01-01

Introduction Patients with human immunodeficiency virus carry a significant risk of contracting opportunistic infections. The worldwide increased incidence of tuberculosis has instituted pulmonary tuberculosis as an important diagnostic consideration in patients with human immunodeficiency virus presenting with lower respiratory tract infection. A positive result on the readily-available Ziehl-Neelsen stain usually leads to the initiation of antituberculous treatment, since tuberculosis may e...

Expression and function of K(V)2-containing channels in human urinary bladder smooth muscle.

Science.gov (United States)

Hristov, Kiril L; Chen, Muyan; Afeli, Serge A Y; Cheng, Qiuping; Rovner, Eric S; Petkov, Georgi V

2012-06-01

The functional role of the voltage-gated K(+) (K(V)) channels in human detrusor smooth muscle (DSM) is largely unexplored. Here, we provide molecular, electrophysiological, and functional evidence for the expression of K(V)2.1, K(V)2.2, and the electrically silent K(V)9.3 subunits in human DSM. Stromatoxin-1 (ScTx1), a selective inhibitor of K(V)2.1, K(V)2.2, and K(V)4.2 homotetrameric channels and of K(V)2.1/9.3 heterotetrameric channels, was used to examine the role of these channels in human DSM function. Human DSM tissues were obtained during open bladder surgeries from patients without a history of overactive bladder. Freshly isolated human DSM cells were studied using RT-PCR, immunocytochemistry, live-cell Ca(2+) imaging, and the perforated whole cell patch-clamp technique. Isometric DSM tension recordings of human DSM isolated strips were conducted using tissue baths. RT-PCR experiments showed mRNA expression of K(V)2.1, K(V)2.2, and K(V)9.3 (but not K(V)4.2) channel subunits in human isolated DSM cells. K(V)2.1 and K(V)2.2 protein expression was confirmed by Western blot analysis and immunocytochemistry. Perforated whole cell patch-clamp experiments revealed that ScTx1 (100 nM) inhibited the amplitude of the voltage step-induced K(V) current in freshly isolated human DSM cells. ScTx1 (100 nM) significantly increased the intracellular Ca(2+) level in DSM cells. In human DSM isolated strips, ScTx1 (100 nM) increased the spontaneous phasic contraction amplitude and muscle force, and enhanced the amplitude of the electrical field stimulation-induced contractions within the range of 3.5-30 Hz stimulation frequencies. These findings reveal that ScTx1-sensitive K(V)2-containing channels are key regulators of human DSM excitability and contractility and may represent new targets for pharmacological or genetic intervention for bladder dysfunction.

A subpopulation of smooth muscle cells, derived from melanocyte-competent precursors, prevents patent ductus arteriosus.

Directory of Open Access Journals (Sweden)

Ichiro Yajima

Full Text Available BACKGROUND: Patent ductus arteriosus is a life-threatening condition frequent in premature newborns but also present in some term infants. Current mouse models of this malformation generally lead to perinatal death, not reproducing the full phenotypic spectrum in humans, in whom genetic inheritance appears complex. The ductus arteriosus (DA, a temporary fetal vessel that bypasses the lungs by shunting the aortic arch to the pulmonary artery, is constituted by smooth muscle cells of distinct origins (SMC1 and SMC2 and many fewer melanocytes. To understand novel mechanisms preventing DA closure at birth, we evaluated the importance of cell fate specification in SMC that form the DA during embryonic development. Upon specific Tyr::Cre-driven activation of Wnt/β-catenin signaling at the time of cell fate specification, melanocytes replaced the SMC2 population of the DA, suggesting that SMC2 and melanocytes have a common precursor. The number of SMC1 in the DA remained similar to that in controls, but insufficient to allow full DA closure at birth. Thus, there was no cellular compensation by SMC1 for the loss of SMC2. Mice in which only melanocytes were genetically ablated after specification from their potential common precursor with SMC2, demonstrated that differentiated melanocytes themselves do not affect DA closure. Loss of the SMC2 population, independent of the presence of melanocytes, is therefore a cause of patent ductus arteriosus and premature death in the first months of life. Our results indicate that patent ductus arteriosus can result from the insufficient differentiation, proliferation, or contractility of a specific smooth muscle subpopulation that shares a common neural crest precursor with cardiovascular melanocytes.

A Subpopulation of Smooth Muscle Cells, Derived from Melanocyte-Competent Precursors, Prevents Patent Ductus Arteriosus

Science.gov (United States)

Puig, Isabel; Champeval, Delphine; Kumasaka, Mayuko; Belloir, Elodie; Bonaventure, Jacky; Mark, Manuel; Yamamoto, Hiroaki; Taketo, Mark M.; Choquet, Philippe; Etchevers, Heather C.; Beermann, Friedrich; Delmas, Véronique; Monassier, Laurent; Larue, Lionel

2013-01-01

Background Patent ductus arteriosus is a life-threatening condition frequent in premature newborns but also present in some term infants. Current mouse models of this malformation generally lead to perinatal death, not reproducing the full phenotypic spectrum in humans, in whom genetic inheritance appears complex. The ductus arteriosus (DA), a temporary fetal vessel that bypasses the lungs by shunting the aortic arch to the pulmonary artery, is constituted by smooth muscle cells of distinct origins (SMC1 and SMC2) and many fewer melanocytes. To understand novel mechanisms preventing DA closure at birth, we evaluated the importance of cell fate specification in SMC that form the DA during embryonic development. Upon specific Tyr::Cre-driven activation of Wnt/β-catenin signaling at the time of cell fate specification, melanocytes replaced the SMC2 population of the DA, suggesting that SMC2 and melanocytes have a common precursor. The number of SMC1 in the DA remained similar to that in controls, but insufficient to allow full DA closure at birth. Thus, there was no cellular compensation by SMC1 for the loss of SMC2. Mice in which only melanocytes were genetically ablated after specification from their potential common precursor with SMC2, demonstrated that differentiated melanocytes themselves do not affect DA closure. Loss of the SMC2 population, independent of the presence of melanocytes, is therefore a cause of patent ductus arteriosus and premature death in the first months of life. Our results indicate that patent ductus arteriosus can result from the insufficient differentiation, proliferation, or contractility of a specific smooth muscle subpopulation that shares a common neural crest precursor with cardiovascular melanocytes. PMID:23382837

Classification of smooth Fano polytopes

DEFF Research Database (Denmark)

Øbro, Mikkel

A simplicial lattice polytope containing the origin in the interior is called a smooth Fano polytope, if the vertices of every facet is a basis of the lattice. The study of smooth Fano polytopes is motivated by their connection to toric varieties. The thesis concerns the classification of smooth...... Fano polytopes up to isomorphism. A smooth Fano -polytope can have at most vertices. In case of vertices an explicit classification is known. The thesis contains the classification in case of vertices. Classifications of smooth Fano -polytopes for fixed exist only for . In the thesis an algorithm...... for the classification of smooth Fano -polytopes for any given is presented. The algorithm has been implemented and used to obtain the complete classification for ....

A cyclic GMP-dependent calcium-activated chloride current in smooth-muscle cells from rat mesenteric resistance arteries

DEFF Research Database (Denmark)

Matchkov, Vladimir; Aalkjær, Christian; Nilsson, Holger

2004-01-01

We have previously demonstrated the presence of a cyclic GMP (cGMP)-dependent calcium-activated inward current in vascular smooth-muscle cells, and suggested this to be of importance in synchronizing smooth-muscle contraction. Here we demonstrate the characteristics of this current. Using......M) in the pipette solution. The current was found to be a calcium-activated chloride current with an absolute requirement for cyclic GMP (EC50 6.4 microM). The current could be activated by the constitutively active subunit of PKG. Current activation was blocked by the protein kinase G antagonist Rp-8-Br-PET-cGMP...... differed from those of the calcium-activated chloride current in pulmonary myocytes, which was cGMP-independent, exhibited a high sensitivity to inhibition by niflumic acid, was unaffected by zinc ions, and showed outward current rectification as has previously been reported for this current. Under...

Contribution of Fetal, but Not Adult, Pulmonary Mesothelium to Mesenchymal Lineages in Lung Homeostasis and Fibrosis.

Science.gov (United States)

von Gise, Alexander; Stevens, Sean M; Honor, Leah B; Oh, Jin Hee; Gao, Chi; Zhou, Bin; Pu, William T

2016-02-01

The lung is enveloped by a layer of specialized epithelium, the pulmonary mesothelium. In other organs, mesothelial cells undergo epithelial-mesenchymal transition and contribute to organ stromal cells. The contribution of pulmonary mesothelial cells (PMCs) to the developing lung has been evaluated with differing conclusions. PMCs have also been indirectly implicated in lung fibrosis in the progressive, fatal lung disease idiopathic pulmonary fibrosis. We used fetal or postnatal genetic pulse labeling of PMCs to assess their fate in murine development, normal lung homeostasis, and models of pulmonary fibrosis. We found that most fetal PMC-derived mesenchymal cells (PMCDCs) expressed markers of pericytes and fibroblasts, only a small minority expressed smooth muscle markers, and none expressed endothelial cell markers. Postnatal PMCs did not contribute to lung mesenchyme during normal lung homeostasis or in models of lung fibrosis. However, fetal PMCDCs were abundant and actively proliferating within fibrotic regions in lung fibrosis models, suggesting that they actively participate in the fibrotic process. These data clarify the role of fetal and postnatal PMCDCs in lung development and disease.

Pulmonary artery-to-pulmonary artery anastomoses: angiographic demonstration in patients with chronic thromboembolic pulmonary hypertension

International Nuclear Information System (INIS)

Hodson, J.; Graham, A.; Hughes, J.M.B.; Gibbs, J.S.R.; Jackson, J.E.

2006-01-01

AIM: To describe direct pulmonary artery-to-pulmonary artery anastomoses seen at pulmonary angiography in patients with chronic thromboembolic pulmonary hypertension and discuss their possible significance. MATERIALS AND METHODS: Between 1 August 2000 and 31 July 2004 43 patients (male-to-female ratio 25:18) with a diagnosis of chronic thromboembolic pulmonary hypertension (CTEPH) underwent selective pulmonary angiography to assess the extent of disease and suitability for surgical pulmonary endarterectomy. The mean pulmonary artery pressure ranged from 27-84 mmHg (average of 51 mmHg). Selective bilateral digital subtraction pulmonary angiograms performed in all individuals were reviewed for the presence of intrapulmonary collaterals. RESULTS: In 15 of the 43 patients (male-to-female ratio =7:8) definite (n=12) or probable (n=3) pulmonary artery-to-pulmonary artery anastomoses were demonstrated. Of the remaining 28 patients in whom intrapulmonary collaterals were not seen it was felt that in 16 the angiograms were of insufficient diagnostic quality (grades 4-5) to exclude their presence. Twelve patients, eight of whom had angiograms of sufficient diagnostic quality (grades 1-3), demonstrated one or more areas of luxury perfusion but intrapulmonary collaterals were not seen. CONCLUSION: Direct pulmonary artery-to-pulmonary artery anastomoses were demonstrated in patients with chronic thromboembolic pulmonary hypertension, which to our knowledge have not been previously described. The importance of these collateral vessels is unclear but they may play a role in the maintenance of pulmonary parenchymal viability in patients with chronic pulmonary embolic disease. The rate of development of these collaterals and their prognostic significance in patients with chronic thromboembolic pulmonary hypertension are areas worthy of further study

Pulmonary artery-to-pulmonary artery anastomoses: angiographic demonstration in patients with chronic thromboembolic pulmonary hypertension

Energy Technology Data Exchange (ETDEWEB)

Hodson, J. [Department of Imaging, Imperial College School of Medicine, Hammersmith Hospital, Du Cane Road, London (United Kingdom); Graham, A. [Department of Imaging, Imperial College School of Medicine, Hammersmith Hospital, Du Cane Road, London (United Kingdom); Hughes, J.M.B. [Department of Respiratory Medicine, Imperial College School of Medicine, Hammersmith Hospital, Du Cane Road, London (United Kingdom); Gibbs, J.S.R. [Department of Cardiology, Imperial College School of Medicine, Hammersmith Hospital, Du Cane Road, London (United Kingdom); Jackson, J.E. [Department of Imaging, Imperial College School of Medicine, Hammersmith Hospital, Du Cane Road, London (United Kingdom)]. E-mail: jejackson@hhnt.org

2006-03-15

AIM: To describe direct pulmonary artery-to-pulmonary artery anastomoses seen at pulmonary angiography in patients with chronic thromboembolic pulmonary hypertension and discuss their possible significance. MATERIALS AND METHODS: Between 1 August 2000 and 31 July 2004 43 patients (male-to-female ratio 25:18) with a diagnosis of chronic thromboembolic pulmonary hypertension (CTEPH) underwent selective pulmonary angiography to assess the extent of disease and suitability for surgical pulmonary endarterectomy. The mean pulmonary artery pressure ranged from 27-84 mmHg (average of 51 mmHg). Selective bilateral digital subtraction pulmonary angiograms performed in all individuals were reviewed for the presence of intrapulmonary collaterals. RESULTS: In 15 of the 43 patients (male-to-female ratio =7:8) definite (n=12) or probable (n=3) pulmonary artery-to-pulmonary artery anastomoses were demonstrated. Of the remaining 28 patients in whom intrapulmonary collaterals were not seen it was felt that in 16 the angiograms were of insufficient diagnostic quality (grades 4-5) to exclude their presence. Twelve patients, eight of whom had angiograms of sufficient diagnostic quality (grades 1-3), demonstrated one or more areas of luxury perfusion but intrapulmonary collaterals were not seen. CONCLUSION: Direct pulmonary artery-to-pulmonary artery anastomoses were demonstrated in patients with chronic thromboembolic pulmonary hypertension, which to our knowledge have not been previously described. The importance of these collateral vessels is unclear but they may play a role in the maintenance of pulmonary parenchymal viability in patients with chronic pulmonary embolic disease. The rate of development of these collaterals and their prognostic significance in patients with chronic thromboembolic pulmonary hypertension are areas worthy of further study.

The Impact of Immunosenescence on Pulmonary Disease.

LENUS (Irish Health Repository)

Murray, Michelle A

2015-08-01

The global population is aging with significant gains in life expectancy particularly in the developed world. Consequently, greater focus on understanding the processes that underlie physiological aging has occurred. Key facets of advancing age include genomic instability, telomere shortening, epigenetic changes, and declines in immune function termed immunosenescence. Immunosenescence and its associated chronic low grade systemic "inflamm-aging" contribute to the development and progression of pulmonary disease in older individuals. These physiological processes predispose to pulmonary infection and confer specific and unique clinical phenotypes observed in chronic respiratory disease including late-onset asthma, chronic obstructive pulmonary disease, and pulmonary fibrosis. Emerging concepts of the gut and airway microbiome further complicate the interrelationship between host and microorganism particularly from an immunological perspective and especially so in the setting of immunosenescence. This review focuses on our current understanding of the aging process, immunosenescence, and how it can potentially impact on various pulmonary diseases and the human microbiome.

Fasudil and DETA NONOate, Loaded in a Peptide-Modified Liposomal Carrier, Slow PAH Progression upon Pulmonary Delivery.

Science.gov (United States)

Rashid, Jahidur; Nahar, Kamrun; Raut, Snehal; Keshavarz, Ali; Ahsan, Fakhrul

2018-05-07

We investigated the feasibility of a combination therapy comprising fasudil, a Rho-kinase inhibitor, and DETA NONOate (diethylenetriamine NONOate, DN), a long-acting nitric oxide donor, both loaded in liposomes modified with a homing peptide, CAR (CARSKNKDC), in the treatment of pulmonary arterial hypertension (PAH). We first prepared and characterized unmodified and CAR-modified liposomes of fasudil and DN. Using individual drugs alone or a mixture of fasudil and DN as controls, we studied the efficacy of the two liposomal preparations in reducing mean pulmonary arterial pressure (mPAP) in monocrotaline (MCT) and SUGEN-hypoxia-induced PAH rats. We also conducted morphometric studies (degree of muscularization, arterial medial wall thickness, and collagen deposition) after treating the PAH rats with test and control formulations. When the rats were treated acutely and chronically, the reduction in mPAP was more pronounced in the liposomal formulation-treated rats than in plain drug-treated rats. CAR-modified liposomes were more selective in reducing mPAP than unmodified liposomes of the drugs. Both drugs, formulated in CAR-modified liposomes, reduced the degree of muscularization, medial arterial wall thickness, and collagen deposition more than the combination of plain drugs did. As seen with the in vivo data, CAR-modified liposomes of fasudil or DN increased the levels of the vasodilatory signaling molecule, cGMP, in the smooth muscle cells of PAH-afflicted human pulmonary arteries. Overall, fasudil and DN, formulated in liposomes, could be used as a combination therapy for a better management of PAH.

Human case of visceral larva migrans syndrome: pulmonary and hepatic involvement

Directory of Open Access Journals (Sweden)

Almatary A. M.

2016-12-01

Full Text Available Visceral Larva Migrans (VLM syndrome is commonly caused by larvae of roundworms Toxocara canis or Toxocara cati. Human toxocarosis is a soil-transmitted zoonosis, which may result in partial or general pathological changes in host tissues. We reported a case of 14-year-old boy presented with severe dry cough without dyspnea, mild chest and abdominal pain with general fatigue. Examination of peripheral blood showed marked increase in eosinophils. The chest radiography showed an infiltrative shadow in the lung fields. Chest CT demonstrated multiple opacities in both lungs. Abdominal CT showed multiple low attenuation areas in the liver. Ultrasound guided liver biopsy revealed granulomas with severe eosinophilic infiltration. The boy was treated with albendazole and responded radically. It is worth mentioning that this is the first case of hepato-pulmonary VLM syndrome in Egypt.

Hypoxia-induced pulmonary vascular remodeling: cellular and molecular mechanisms.

Science.gov (United States)

Stenmark, Kurt R; Fagan, Karen A; Frid, Maria G

2006-09-29

Chronic hypoxic exposure induces changes in the structure of pulmonary arteries, as well as in the biochemical and functional phenotypes of each of the vascular cell types, from the hilum of the lung to the most peripheral vessels in the alveolar wall. The magnitude and the specific profile of the changes depend on the species, sex, and the developmental stage at which the exposure to hypoxia occurred. Further, hypoxia-induced changes are site specific, such that the remodeling process in the large vessels differs from that in the smallest vessels. The cellular and molecular mechanisms vary and depend on the cellular composition of vessels at particular sites along the longitudinal axis of the pulmonary vasculature, as well as on local environmental factors. Each of the resident vascular cell types (ie, endothelial, smooth muscle, adventitial fibroblast) undergo site- and time-dependent alterations in proliferation, matrix protein production, expression of growth factors, cytokines, and receptors, and each resident cell type plays a specific role in the overall remodeling response. In addition, hypoxic exposure induces an inflammatory response within the vessel wall, and the recruited circulating progenitor cells contribute significantly to the structural remodeling and persistent vasoconstriction of the pulmonary circulation. The possibility exists that the lung or lung vessels also contain resident progenitor cells that participate in the remodeling process. Thus the hypoxia-induced remodeling of the pulmonary circulation is a highly complex process where numerous interactive events must be taken into account as we search for newer, more effective therapeutic interventions. This review provides perspectives on each of the aforementioned areas.

Mycobacterium Szulgai Pulmonary Infection: Case Report of an Uncommon Pathogen in Korea

International Nuclear Information System (INIS)

Kim, Jeong Jae; Lee, Jae Chun; Jeong, Sun Young

2014-01-01

Mycobacterium szulgai (M. szulgai) is an unusual pathogen in a human non-tuberculous mycobacterial infection. Pulmonary infection due to M. szulgai may be clinically and radiologically confused with active pulmonary tuberculosis. In contrast to other non-tuberculous mycobacteria, M. szulgai infection is well controlled by combination antimycobacterial therapy. Most of the previously reported cases of M. szulgai pulmonary infection showed cavitary upper lobe infiltrates. We herein describe a case of pulmonary M. szulgai infection that shows clinical and radiological presentations similar to active pulmonary tuberculosis.

Mycobacterium Szulgai Pulmonary Infection: Case Report of an Uncommon Pathogen in Korea

Energy Technology Data Exchange (ETDEWEB)

Kim, Jeong Jae; Lee, Jae Chun; Jeong, Sun Young [Jeju National University School of Medicine, Jeju (Korea, Republic of)

2014-10-15

Mycobacterium szulgai (M. szulgai) is an unusual pathogen in a human non-tuberculous mycobacterial infection. Pulmonary infection due to M. szulgai may be clinically and radiologically confused with active pulmonary tuberculosis. In contrast to other non-tuberculous mycobacteria, M. szulgai infection is well controlled by combination antimycobacterial therapy. Most of the previously reported cases of M. szulgai pulmonary infection showed cavitary upper lobe infiltrates. We herein describe a case of pulmonary M. szulgai infection that shows clinical and radiological presentations similar to active pulmonary tuberculosis.

The Critical Role of Pulmonary Arterial Compliance in Pulmonary Hypertension

Science.gov (United States)

Prins, Kurt W.; Pritzker, Marc R.; Scandurra, John; Volmers, Karl; Weir, E. Kenneth

2016-01-01

The normal pulmonary circulation is a low-pressure, high-compliance system. Pulmonary arterial compliance decreases in the presence of pulmonary hypertension because of increased extracellular matrix/collagen deposition in the pulmonary arteries. Loss of pulmonary arterial compliance has been consistently shown to be a predictor of increased mortality in patients with pulmonary hypertension, even more so than pulmonary vascular resistance in some studies. Decreased pulmonary arterial compliance causes premature reflection of waves from the distal pulmonary vasculature, leading to increased pulsatile right ventricular afterload and eventually right ventricular failure. Evidence suggests that decreased pulmonary arterial compliance is a cause rather than a consequence of distal small vessel proliferative vasculopathy. Pulmonary arterial compliance decreases early in the disease process even when pulmonary artery pressure and pulmonary vascular resistance are normal, potentially enabling early diagnosis of pulmonary vascular disease, especially in high-risk populations. With the recognition of the prognostic importance of pulmonary arterial compliance, its impact on right ventricular function, and its contributory role in the development and progression of distal small-vessel proliferative vasculopathy, pulmonary arterial compliance is an attractive target for the treatment of pulmonary hypertension. PMID:26848601

Docosahexaenoic acid inhibits monocrotaline-induced pulmonary hypertension via attenuating endoplasmic reticulum stress and inflammation.

Science.gov (United States)

Chen, Rui; Zhong, Wei; Shao, Chen; Liu, Peijing; Wang, Cuiping; Wang, Zhongqun; Jiang, Meiping; Lu, Yi; Yan, Jinchuan

2018-02-01

Endoplasmic reticulum (ER) stress and inflammation contribute to pulmonary hypertension (PH) pathogenesis. Previously, we confirmed that docosahexaenoic acid (DHA) could improve hypoxia-induced PH. However, little is known about the link between DHA and monocrotaline (MCT)-induced PH. Our aims were, therefore, to evaluate the effects and molecular mechanisms of DHA on MCT-induced PH in rats. Rat PH was induced by MCT. Rats were treated with DHA daily in the prevention group (following MCT injection) and the reversal group (after MCT injection for 2 wk) by gavage. After 4 wk, mean pulmonary arterial pressure (mPAP), right ventricular (RV) hypertrophy index, and morphological and immunohistochemical analyses were evaluated. Rat pulmonary artery smooth muscle cells (PASMCs) were used to investigate the effects of DHA on cell proliferation stimulated by platelet-derived growth factor (PDGF)-BB. DHA decreased mPAP and attenuated pulmonary vascular remodeling and RV hypertrophy, which were associated with suppressed ER stress. DHA blocked the mitogenic effect of PDGF-BB on PASMCs and arrested the cell cycle via inhibiting nuclear factor of activated T cells-1 (NFATc1) expression and activation and regulating cell cycle-related proteins. Moreover, DHA ameliorated inflammation in lung and suppressed macrophage and T lymphocyte accumulation in lung and adventitia of resistance pulmonary arteries. These findings suggest that DHA could protect against MCT-induced PH by reducing ER stress, suppressing cell proliferation and inflammation.

Contrast and assimilation in motion perception and smooth pursuit eye movements.

Science.gov (United States)

Spering, Miriam; Gegenfurtner, Karl R

2007-09-01

The analysis of visual motion serves many different functions ranging from object motion perception to the control of self-motion. The perception of visual motion and the oculomotor tracking of a moving object are known to be closely related and are assumed to be controlled by shared brain areas. We compared perceived velocity and the velocity of smooth pursuit eye movements in human observers in a paradigm that required the segmentation of target object motion from context motion. In each trial, a pursuit target and a visual context were independently perturbed simultaneously to briefly increase or decrease in speed. Observers had to accurately track the target and estimate target speed during the perturbation interval. Here we show that the same motion signals are processed in fundamentally different ways for perception and steady-state smooth pursuit eye movements. For the computation of perceived velocity, motion of the context was subtracted from target motion (motion contrast), whereas pursuit velocity was determined by the motion average (motion assimilation). We conclude that the human motion system uses these computations to optimally accomplish different functions: image segmentation for object motion perception and velocity estimation for the control of smooth pursuit eye movements.

[Pulmonary cystic disease may be a rare complication to recurrent respiratory human papilloma virus infection].

Science.gov (United States)

Laurberg, Peter Thaysen; Weinreich, Ulla M Øller

2014-12-08

A 19-year-old woman with a history of juvenile laryngeal papillomatosis (JLP), treated since childhood with multiple resections, was admitted with symptoms of pneumonia. A chest X-ray and CAT-scan revealed multiple lung cysts and a bronchoalveolar lavage detected human papilloma virus 11. The patient responded well to antibiotics. A body plethysmography showed small lung volumes and low diffusion capacity for carbon monoxide, but normal volume diffusion capacity divided by alveolar volume. Pulmonary cystic disease should be considered when patients with JLP have symptoms of pneumonia.

Eradication of Human Hepatic and Pulmonary Melanoma Metastases in SCID Mice by Antibody--Interleukin 2 Fusion Proteins

Science.gov (United States)

Becker, Jurgen C.; Pancook, James D.; Gillies, Stephen D.; Mendelsohn, John; Reisfeld, Ralph A.

1996-04-01

Antibody--cytokine fusion proteins combine the unique targeting ability of antibodies with the multifunctional activity of cytokines. Here, we demonstrate the therapeutic efficacy of such constructs for the treatment of hepatic and pulmonary metastases of different melanoma cell lines. Two antibody--interleukin 2 (IL-2) fusion proteins, ch225-IL2 and ch14.18-IL2, constructed by fusion of a synthetic sequence coding for human IL-2 to the carboxyl end of the Cγ 1 gene of the corresponding antibodies, were tested for their therapeutic efficacy against xenografted human melanoma in vivo. Tumorspecific fusion proteins completely inhibited the growth of hepatic and pulmonary metastases in C.B-17 scid/scid mice previously reconstituted with human lymphokine-activated killer cells, whereas treatment with combinations of the corresponding antibodies plus recombinant IL-2 only reduced the tumor load. Even when treatment with fusion proteins was delayed up to 8 days after inoculation of tumor cells, it still resulted in complete eradication of micrometastases that were established at that time point. Selection of tumor cell lines expressing or lacking the targeted antigen of the administered fusion protein proved the specificity of the observed antitumor effect. Biodistribution analysis demonstrated that the tumorspecific fusion protein accumulated not only in subcutaneous tumors but also in lungs and livers affected with micrometastases. Survival times of animals treated with the fusion protein were more than doubled as compared to those treated with the combination of the corresponding antibody plus IL-2. Our data demonstrate that an immunotherapeutic approach using cytokines targeted by antibodies to tumor sites has potent effects against disseminated human melanoma.

CXCR1 regulates pulmonary anti-Pseudomonas host defense

Science.gov (United States)

Carevic, M.; Öz, H.; Fuchs, K.; Laval, J.; Schroth, C.; Frey, N.; Hector, A.; Bilich, T.; Haug, M.; Schmidt, A.; Autenrieth, S. E.; Bucher, K.; Beer-Hammer, S.; Gaggar, A.; Kneilling, M.; Benarafa, C.; Gao, J.; Murphy, P.; Schwarz, S.; Moepps, B.; Hartl, D.

2016-01-01

Pseudomonas aeruginosa is a key opportunistic pathogen causing disease in cystic fibrosis (CF) and other lung diseases such as chronic obstructive pulmonary disease (COPD). However, the pulmonary host defense mechanisms regulating anti-Pseudomonas aeruginosa immunity remain incompletely understood. Here we demonstrate, by studying an airway Pseudomonas aeruginosa infection model, in vivo bioluminescence imaging, neutrophil effector responses and human airway samples, that the chemokine receptor CXCR1 regulates pulmonary host defense against Pseudomonas aeruginosa. Mechanistically, CXCR1 regulated anti-Pseudomonas neutrophil responses through modulation of reactive oxygen species and interference with toll-like receptor 5 expression. These studies define CXCR1 as a novel non-canonical chemokine receptor that regulates pulmonary anti-Pseudomonas host defense with broad implications for CF, COPD and other infectious lung diseases. PMID:26950764

Pulmonary malakoplakia associated with immunodeficiency by HTLV-1 and HIV

Directory of Open Access Journals (Sweden)

Manuela Madruga

2014-08-01

Full Text Available Malakoplakia is a rare chronic inflammatory disease often confused with neoplasia. In this paper we report two cases of pulmonary Malakoplakia, both with typical clinical diagnosis of tuberculosis and lung cancer. A patient with human T-lymphotropic virus type I (HTLV-1 and diagnosis of adult T-cell leukemia/lymphoma, and another patient with human immunodeficiency virus (HIV, which was treated for tuberculosis, but, after pulmonary lobectomy, was evidenced Rodococosis equi, progressed to death.

Pulmonary tuberculosis in patients with idiopathic pulmonary fibrosis

Energy Technology Data Exchange (ETDEWEB)

Chung, Myung Jin; Goo, Jin Mo E-mail: jmgoo@plaza.snu.ac.kr; Im, Jung-Gi

2004-11-01

Objectives: Patients with idiopathic pulmonary fibrosis (IPF) have an increased risk of pulmonary tuberculosis. However, detecting pulmonary tuberculosis may be difficult due to the underlying fibrosis. The aim of this report is to describe the radiological and clinical findings of pulmonary tuberculosis in patients with idiopathic pulmonary fibrosis. Materials and methods: We reviewed 143 consecutive patients in whom IPF was diagnosed by either the histological or radio-clinical criteria. Among them, nine patients were histologically (n=2) or bacteriologically (n=7) confirmed to have active pulmonary tuberculosis. The location and patterns of pulmonary tuberculosis were examined on a thin section CT scan. Results: The most common thin section CT findings were subpleural nodules (n=6; mean diameter, 3.2 cm) and a lobar or segmental consolidation (n=3). The lesions were located most commonly in the right lower lobe (n=4). The incidence of tuberculosis in patients with idiopathic pulmonary fibrosis was more than five times higher than that of the general population. Conclusion: The atypical manifestation of pulmonary tuberculosis is common in patients with idiopathic pulmonary fibrosis, which may mimic lung cancer or bacterial pneumonia.

Pulmonary tuberculosis in patients with idiopathic pulmonary fibrosis

International Nuclear Information System (INIS)

Chung, Myung Jin; Goo, Jin Mo; Im, Jung-Gi

2004-01-01

Objectives: Patients with idiopathic pulmonary fibrosis (IPF) have an increased risk of pulmonary tuberculosis. However, detecting pulmonary tuberculosis may be difficult due to the underlying fibrosis. The aim of this report is to describe the radiological and clinical findings of pulmonary tuberculosis in patients with idiopathic pulmonary fibrosis. Materials and methods: We reviewed 143 consecutive patients in whom IPF was diagnosed by either the histological or radio-clinical criteria. Among them, nine patients were histologically (n=2) or bacteriologically (n=7) confirmed to have active pulmonary tuberculosis. The location and patterns of pulmonary tuberculosis were examined on a thin section CT scan. Results: The most common thin section CT findings were subpleural nodules (n=6; mean diameter, 3.2 cm) and a lobar or segmental consolidation (n=3). The lesions were located most commonly in the right lower lobe (n=4). The incidence of tuberculosis in patients with idiopathic pulmonary fibrosis was more than five times higher than that of the general population. Conclusion: The atypical manifestation of pulmonary tuberculosis is common in patients with idiopathic pulmonary fibrosis, which may mimic lung cancer or bacterial pneumonia

Cue-dependent memory-based smooth-pursuit in normal human subjects: importance of extra-retinal mechanisms for initial pursuit.

Science.gov (United States)

Ito, Norie; Barnes, Graham R; Fukushima, Junko; Fukushima, Kikuro; Warabi, Tateo

2013-08-01

Using a cue-dependent memory-based smooth-pursuit task previously applied to monkeys, we examined the effects of visual motion-memory on smooth-pursuit eye movements in normal human subjects and compared the results with those of the trained monkeys. These results were also compared with those during simple ramp-pursuit that did not require visual motion-memory. During memory-based pursuit, all subjects exhibited virtually no errors in either pursuit-direction or go/no-go selection. Tracking eye movements of humans and monkeys were similar in the two tasks, but tracking eye movements were different between the two tasks; latencies of the pursuit and corrective saccades were prolonged, initial pursuit eye velocity and acceleration were lower, peak velocities were lower, and time to reach peak velocities lengthened during memory-based pursuit. These characteristics were similar to anticipatory pursuit initiated by extra-retinal components during the initial extinction task of Barnes and Collins (J Neurophysiol 100:1135-1146, 2008b). We suggest that the differences between the two tasks reflect differences between the contribution of extra-retinal and retinal components. This interpretation is supported by two further studies: (1) during popping out of the correct spot to enhance retinal image-motion inputs during memory-based pursuit, pursuit eye velocities approached those during simple ramp-pursuit, and (2) during initial blanking of spot motion during memory-based pursuit, pursuit components appeared in the correct direction. Our results showed the importance of extra-retinal mechanisms for initial pursuit during memory-based pursuit, which include priming effects and extra-retinal drive components. Comparison with monkey studies on neuronal responses and model analysis suggested possible pathways for the extra-retinal mechanisms.

Tungstate-targeting of BKαβ1 channels tunes ERK phosphorylation and cell proliferation in human vascular smooth muscle.

Directory of Open Access Journals (Sweden)

Ana Isabel Fernández-Mariño

Full Text Available Despite the substantial knowledge on the antidiabetic, antiobesity and antihypertensive actions of tungstate, information on its primary target/s is scarce. Tungstate activates both the ERK1/2 pathway and the vascular voltage- and Ca2+-dependent large-conductance BKαβ1 potassium channel, which modulates vascular smooth muscle cell (VSMC proliferation and function, respectively. Here, we have assessed the possible involvement of BKαβ1 channels in the tungstate-induced ERK phosphorylation and its relevance for VSMC proliferation. Western blot analysis in HEK cell lines showed that expression of vascular BKαβ1 channels potentiates the tungstate-induced ERK1/2 phosphorylation in a Gi/o protein-dependent manner. Tungstate activated BKαβ1 channels upstream of G proteins as channel activation was not altered by the inhibition of G proteins with GDPβS or pertussis toxin. Moreover, analysis of Gi/o protein activation measuring the FRET among heterologously expressed Gi protein subunits suggested that tungstate-targeting of BKαβ1 channels promotes G protein activation. Single channel recordings on VSMCs from wild-type and β1-knockout mice indicated that the presence of the regulatory β1 subunit was essential for the tungstate-mediated activation of BK channels in VSMCs. Moreover, the specific BK channel blocker iberiotoxin lowered tungstate-induced ERK phosphorylation by 55% and partially reverted (by 51% the tungstate-produced reduction of platelet-derived growth factor (PDGF-induced proliferation in human VSMCs. Our observations indicate that tungstate-targeting of BKαβ1 channels promotes activation of PTX-sensitive Gi proteins to enhance the tungstate-induced phosphorylation of ERK, and inhibits PDGF-stimulated cell proliferation in human vascular smooth muscle.

Bayesian Exponential Smoothing.

OpenAIRE

Forbes, C.S.; Snyder, R.D.; Shami, R.S.

2000-01-01

In this paper, a Bayesian version of the exponential smoothing method of forecasting is proposed. The approach is based on a state space model containing only a single source of error for each time interval. This model allows us to improve current practices surrounding exponential smoothing by providing both point predictions and measures of the uncertainty surrounding them.

Effects of altitude and exercise on pulmonary capillary integrity: evidence for subclinical high-altitude pulmonary edema.

Science.gov (United States)

Eldridge, Marlowe W; Braun, Ruedi K; Yoneda, Ken Y; Walby, William F

2006-03-01

Strenuous exercise may be a significant contributing factor for development of high-altitude pulmonary edema, particularly at low or moderate altitudes. Thus we investigated the effects of heavy cycle ergometer exercise (90% maximal effort) under hypoxic conditions in which the combined effects of a marked increase in pulmonary blood flow and nonuniform hypoxic pulmonary vasoconstriction could add significantly to augment the mechanical stress on the pulmonary microcirculation. We postulated that intense exercise at altitude would result in an augmented permeability edema. We recruited eight endurance athletes and examined their bronchoalveolar lavage fluid (BALF) for red blood cells (RBCs), protein, inflammatory cells, and soluble mediators at 2 and 26 h after intense exercise under normoxic and hypoxic conditions. After heavy exercise, under all conditions, the athletes developed a permeability edema with high BALF RBC and protein concentrations in the absence of inflammation. We found that exercise at altitude (3,810 m) caused significantly greater leakage of RBCs [9.2 (SD 3.1)x10(4) cells/ml] into the alveolar space than that seen with normoxic exercise [5.4 (SD 1.2)x10(4) cells/ml]. At altitude, the 26-h postexercise BALF revealed significantly higher RBC and protein concentrations, suggesting an ongoing capillary leak. Interestingly, the BALF profiles following exercise at altitude are similar to that of early high-altitude pulmonary edema. These findings suggest that pulmonary capillary disruption occurs with intense exercise in healthy humans and that hypoxia augments the mechanical stresses on the pulmonary microcirculation.

Anti-smooth muscle antibody

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... gov/ency/article/003531.htm Anti-smooth muscle antibody To use the sharing features on this page, please enable JavaScript. Anti-smooth muscle antibody is a blood test that detects the presence ...

Smooth functors vs. differential forms

NARCIS (Netherlands)

Schreiber, U.; Waldorf, K.

2011-01-01

We establish a relation between smooth 2-functors defined on the path 2-groupoid of a smooth manifold and differential forms on this manifold. This relation can be understood as a part of a dictionary between fundamental notions from category theory and differential geometry. We show that smooth

Non-infective pulmonary disease in HIV-positive children

International Nuclear Information System (INIS)

Theron, Salomine; Andronikou, Savvas; George, Reena; Plessis, Jaco du; Hayes, Murray; Mapukata, Ayanda; Goussard, Pierre; Gie, Robert

2009-01-01

It is estimated that over 90% of children infected with human immunodeficiency virus (HIV) live in the developing world and particularly in sub-Saharan Africa. Pulmonary disease is the most common clinical feature of acquired immunodeficiency syndrome (AIDS) in infants and children causing the most morbidity and mortality, and is the primary cause of death in 50% of cases. Children with lung disease are surviving progressively longer because of earlier diagnosis and antiretroviral treatment and, therefore, thoracic manifestations have continued to change and unexpected complications are being encountered. It has been reported that 33% of HIV-positive children have chronic changes on chest radiographs by the age of 4 years. Lymphocytic interstitial pneumonitis is common in the paediatric HIV population and is responsible for 30-40% of pulmonary disease. HIV-positive children also have a higher incidence of pulmonary malignancies, including lymphoma and pulmonary Kaposi sarcoma. Immune reconstitution inflammatory syndrome is seen after highly active antiretroviral treatment. Complications of pulmonary infections, aspiration and rarely interstitial pneumonitis are also seen. This review focuses on the imaging findings of non-infective chronic pulmonary disease. (orig.)

Expression and proliferation profiles of PKC, JNK and p38MAPK in physiologically stretched human bladder smooth muscle cells

International Nuclear Information System (INIS)

Wazir, Romel; Luo, De-Yi; Dai, Yi; Yue, Xuan; Tian, Ye; Wang, Kun-Jie

2013-01-01

Highlights: •Stretch induces proliferation in human bladder smooth muscle cells (HBSMC). •5% Equibiaxial elongation produces maximum proliferation. •Physiologic stretch decreases apoptotic cell death. •PKC is involved in functional modulation of bladder. •JNK and p38 are not involved in proliferating HBSMC. -- Abstract: Objective: To determine protein kinase C (PKC), c-Jun NH2-Terminal Kinase (JNK) and P38 mitogen-activated protein kinases (p38MAPK) expression levels and effects of their respective inhibitors on proliferation of human bladder smooth muscle cells (HBSMCs) when physiologically stretched in vitro. Materials and methods: HBSMCs were grown on silicone membrane and stretch was applied under varying conditions; (equibiaxial elongation: 2.5%, 5%, 10%, 15%, 20%, 25%), (frequency: 0.05, 0.1, 0.2, 0.5, 1 Hz). Optimal physiological stretch was established by assessing proliferation with 5-Bromo-2-deoxyuridine (BrdU) assay and flow cytometry. PKC, JNK and p38 expression levels were analyzed by Western blot. Specificity was maintained by employing specific inhibitors; (GF109203X for PKC, SP600125 for JNK and SB203580 for p38MAPK), in some experiments. Results: Optimum proliferation was observed at 5% equibiaxial stretch (BrdU: 0.837 ± 0.026 (control) to 1.462 ± 0.023)%, (P 0.05 SP600125) and (1.461 ± 0.01, P > 0.05 SB203580). These findings show that mechanical stretch can promote magnitude-dependent proliferative modulation through PKC and possibly JNK but not via p38MAPK in hBSMCs

Pulmonary capillary haemangiomatosis: a rare cause of pulmonary hypertension.

Science.gov (United States)

Babu, K Anand; Supraja, K; Singh, Raj B

2014-01-01

Pulmonary capillary haemangiomatosis (PCH) is a rare disorder of unknown aetiology, characterised by proliferating capillaries that invade the pulmonary interstitium, alveolar septae and the pulmonary vasculature. It is often mis-diagnosed as primary pulmonary hypertension and pulmonary veno-occlusive disease. Pulmonary capillary haemangiomatosis is a locally aggressive benign vascular neoplasm of the lung. We report the case of a 19-year-old female who was referred to us in the early post-partum period with severe pulmonary artery hypertension, which was diagnosed as PCH by open lung biopsy.

PPARγ agonist pioglitazone reverses pulmonary hypertension and prevents right heart failure via fatty acid oxidation.

Science.gov (United States)

Legchenko, Ekaterina; Chouvarine, Philippe; Borchert, Paul; Fernandez-Gonzalez, Angeles; Snay, Erin; Meier, Martin; Maegel, Lavinia; Mitsialis, S Alex; Rog-Zielinska, Eva A; Kourembanas, Stella; Jonigk, Danny; Hansmann, Georg

2018-04-25

Right ventricular (RV) heart failure is the leading cause of death in pulmonary arterial hypertension (PAH). Peroxisome proliferator-activated receptor γ (PPARγ) acts as a vasoprotective metabolic regulator in smooth muscle and endothelial cells; however, its role in the heart is unclear. We report that deletion of PPARγ in cardiomyocytes leads to biventricular systolic dysfunction and intramyocellular lipid accumulation in mice. In the SU5416/hypoxia (SuHx) rat model, oral treatment with the PPARγ agonist pioglitazone completely reverses severe PAH and vascular remodeling and prevents RV failure. Failing RV cardiomyocytes exhibited mitochondrial disarray and increased intramyocellular lipids (lipotoxicity) in the SuHx heart, which was prevented by pioglitazone. Unbiased ventricular microRNA (miRNA) arrays, mRNA sequencing, and lipid metabolism studies revealed dysregulation of cardiac hypertrophy, fibrosis, myocardial contractility, fatty acid transport/oxidation (FAO), and transforming growth factor-β signaling in the failing RV. These epigenetic, transcriptional, and metabolic alterations were modulated by pioglitazone through miRNA/mRNA networks previously not associated with PAH/RV dysfunction. Consistently, pre-miR-197 and pre-miR-146b repressed genes that drive FAO ( Cpt1b and Fabp4 ) in primary cardiomyocytes. We recapitulated our major pathogenic findings in human end-stage PAH: (i) in the pressure-overloaded failing RV (miR-197 and miR-146b up-regulated), (ii) in peripheral pulmonary arteries (miR-146b up-regulated, miR-133b down-regulated), and (iii) in plexiform vasculopathy (miR-133b up-regulated, miR-146b down-regulated). Together, PPARγ activation can normalize epigenetic and transcriptional regulation primarily related to disturbed lipid metabolism and mitochondrial morphology/function in the failing RV and the hypertensive pulmonary vasculature, representing a therapeutic approach for PAH and other cardiovascular/pulmonary diseases. Copyright

PPARγ ligand ciglitazone inhibits TNFα-induced ICAM-1 in human airway smooth muscle cells

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Chien-Da Huang

2014-08-01

Full Text Available Background: Modification of human airway smooth muscle (ASM function by proinflammatory cytokines has been regarded as a potential mechanism underlying bronchial hyperresponsiveness in asthma. Human ASM cells express intercellular adhesion molecule (ICAM-1 in response to cytokines. Synthetic ligands for peroxisome proliferator-activated receptor (PPARγ reportedly possess anti-inflammatory and immunomodulatory properties. In this study, we examined whether ciglitazone, a synthetic PPARγ ligand, can modulate the basal and tumor necrosis factor (TNFα-induced ICAM1 gene expression in human ASM cells. Methods: Human ASM cells were treated with TNFα. ICAM-1 expression was assessed by flow cytometry and reverse transcriptase-polymerase chain reaction (RT-PCR analysis. PPARγ activity was inhibited by target-specific small interfering (si RNA targeting PPARγ and GW9662, a PPARγ antagonist. Activity of nuclear factor (NF-κB was assessed by using immunoblot analysis, immune-confocal images, and electrophoretic mobility shift assay (EMSA. Results: By flow cytometry, ciglitazone alone had no effect on ICAM-1 expression in ASM cells, but inhibited ICAM-1 expression in response to TNFα (10 ng/ml in a dose-dependent manner (1-10 μM. It also inhibited TNFα-induced ICAM1 gene expression by RT-PCR analysis. Knockdown of PPARγ gene by target-specific siRNA targeting PPARγ enhanced ICAM-1 expression and the inhibitory effect of ciglitazone on TNFα-induced ICAM-1 expression was reversed by PPARγ siRNA and GW9662. SN-50 (10 μg/ml, an inhibitor for nuclear translocation of NF-κB, inhibited TNFα-induced ICAM-1 expression. Ciglitazone did not prevent TNFα-induced degradation of the cytosolic inhibitor of NF-κB (IκB, but inhibited the nuclear translocation of p65 induced by TNFα and suppressed the NF-κB/DNA binding activity. Conclusion: These findings suggest that ciglitazone inhibits TNFα-induced ICAM1 gene expression in human ASM cells through

Pneumocystis jirovecii colonization in chronic pulmonary disease

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Gutiérrez S.

2011-05-01

Full Text Available Pneumocystis jirovecii causes pneumonia in immunosuppressed individuals. However, it has been reported the detection of low levels of Pneumocystis DNA in patients without signs and symptoms of pneumonia, which likely represents colonization. Several studies performed in animals models and in humans have demonstrated that Pneumocystis induces a local and a systemic response in the host. Since P. jirovecii colonization has been found in patients with chronic pulmonary diseases it has been suggested that P. jirovecii may play a role in the physiopathology and progression of those diseases. In this report we revise P. jirovecii colonization in different chronic pulmonary diseases such us, chronic obstructive pulmonary disease, interstitial lung diseases, cystic fibrosis and lung cancer.

Interstitial cells of Cajal in human small intestine. Ultrastructural identification and organization between the main smooth muscle layers

DEFF Research Database (Denmark)

Rumessen, Jüri Johannes; Thuneberg, Lars

1991-01-01

Anatomy, interstitial cells of Cajal, small intestine, gut motility, pacemaker cells, smooth muscle......Anatomy, interstitial cells of Cajal, small intestine, gut motility, pacemaker cells, smooth muscle...

Pulmonary endarterectomy outputs in chronic thromboembolic pulmonary hypertension.

Science.gov (United States)

López Gude, María Jesús; Pérez de la Sota, Enrique; Pérez Vela, Jose Luís; Centeno Rodríguez, Jorge; Muñoz Guijosa, Christian; Velázquez, María Teresa; Alonso Chaterina, Sergio; Hernández González, Ignacio; Escribano Subías, Pilar; Cortina Romero, José María

2017-07-07

Pulmonary thromboendarterectomy surgery is the treatment of choice for patients with chronic thromboembolic pulmonary hypertension; extremely high pulmonary vascular resistance constitutes a risk factor for hospital mortality. The objective of this study was to analyze the immediate and long-term results of the surgical treatment of chronic thromboembolic pulmonary hypertension in patients with very severe pulmonary hypertension. Since February 1996, we performed 160 pulmonary thromboendarterectomies. We divided the patient population in 2 groups: group 1, which included 40 patients with pulmonary vascular resistance≥1090dyn/sec/cm -5 , and group 2, which included the remaining 120 patients. Hospital mortality (15 vs. 2.5%), reperfusion pulmonary edema (33 vs. 14%) and heart failure (23 vs. 3.3%) were all higher in group 1; however, after one year of follow-up, there were no significant differences in the clinical, hemodynamic and echocardiographic conditions of both groups. Survival rate after 5 years was 77% in group 1 and 92% in group 2 (P=.033). After the learning curve including the 46 first patients, there was no difference in hospital mortality (3.8 vs. 2.3%) or survival rate after 5 years (96.2% in group 1 and 96.2% in group 2). Pulmonary thromboendarterectomy is linked to significantly higher morbidity and mortality rates in patients with severe chronic thromboembolic pulmonary hypertension. Nevertheless, these patients benefit the same from the procedure in the mid-/long-term. In our experience, after the learning curve, this surgery is safe in severe pulmonary hypertension and no level of pulmonary vascular resistance should be an absolute counter-indication for this surgery. Copyright © 2017 Elsevier España, S.L.U. All rights reserved.

Ozone exposure and pulmonary effects in panel and human clinical studies: Considerations for design and interpretation.

Science.gov (United States)

Rohr, Annette C

2018-04-01

A wealth of literature exists regarding the pulmonary effects of ozone, a photochemical pollutant produced by the reaction of nitrogen oxide and volatile organic precursors in the presence of sunlight. This paper focuses on epidemiological panel studies and human clinical studies of ozone exposure, and discusses issues specific to this pollutant that may influence study design and interpretation as well as other, broader considerations relevant to ozone-health research. The issues are discussed using examples drawn from the wider literature. The recent panel and clinical literature is also reviewed. Health outcomes considered include lung function, symptoms, and pulmonary inflammation. Issues discussed include adversity, reversibility, adaptation, variability in ozone exposure metric used and health outcomes evaluated, co-pollutants in panel studies, influence of temperature in panel studies, and multiple comparisons. Improvements in and standardization of panel study approaches are recommended to facilitate comparisons between studies as well as meta-analyses. Additional clinical studies at or near the current National Ambient Air Quality Standard (NAAQS) of 70 ppb are recommended, as are clinical studies in sensitive subpopulations such as asthmatics. The pulmonary health impacts of ozone exposure have been well documented using both epidemiological and chamber study designs. However, there are a number of specific methodological and related issues that should be considered when interpreting the results of these studies and planning additional research, including the standardization of exposure and health metrics to facilitate comparisons among studies.

The role of inflammation in hypoxic pulmonary hypertension: from cellular mechanisms to clinical phenotypes

Science.gov (United States)

Poth, Jens M.; Fini, Mehdi A.; Olschewski, Andrea; El Kasmi, Karim C.; Stenmark, Kurt R.

2014-01-01

Hypoxic pulmonary hypertension (PH) comprises a heterogeneous group of diseases sharing the common feature of chronic hypoxia-induced pulmonary vascular remodeling. The disease is usually characterized by mild to moderate pulmonary vascular remodeling that is largely thought to be reversible compared with the progressive irreversible disease seen in World Health Organization (WHO) group I disease. However, in these patients, the presence of PH significantly worsens morbidity and mortality. In addition, a small subset of patients with hypoxic PH develop “out-of-proportion” severe pulmonary hypertension characterized by pulmonary vascular remodeling that is irreversible and similar to that in WHO group I disease. In all cases of hypoxia-related vascular remodeling and PH, inflammation, particularly persistent inflammation, is thought to play a role. This review focuses on the effects of hypoxia on pulmonary vascular cells and the signaling pathways involved in the initiation and perpetuation of vascular inflammation, especially as they relate to vascular remodeling and transition to chronic irreversible PH. We hypothesize that the combination of hypoxia and local tissue factors/cytokines (“second hit”) antagonizes tissue homeostatic cellular interactions between mesenchymal cells (fibroblasts and/or smooth muscle cells) and macrophages and arrests these cells in an epigenetically locked and permanently activated proremodeling and proinflammatory phenotype. This aberrant cellular cross-talk between mesenchymal cells and macrophages promotes transition to chronic nonresolving inflammation and vascular remodeling, perpetuating PH. A better understanding of these signaling pathways may lead to the development of specific therapeutic targets, as none are currently available for WHO group III disease. PMID:25416383

Smoothness in Binomial Edge Ideals

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Hamid Damadi

2016-06-01

Full Text Available In this paper we study some geometric properties of the algebraic set associated to the binomial edge ideal of a graph. We study the singularity and smoothness of the algebraic set associated to the binomial edge ideal of a graph. Some of these algebraic sets are irreducible and some of them are reducible. If every irreducible component of the algebraic set is smooth we call the graph an edge smooth graph, otherwise it is called an edge singular graph. We show that complete graphs are edge smooth and introduce two conditions such that the graph G is edge singular if and only if it satisfies these conditions. Then, it is shown that cycles and most of trees are edge singular. In addition, it is proved that complete bipartite graphs are edge smooth.

Oxygenation decreases elastin secretion from rat ductus arteriosus smooth muscle cells.

Science.gov (United States)

Kawakami, Shoji; Minamisawa, Susumu

2015-08-01

The ductus arteriosus (DA), a fetal arterial connection between the main pulmonary artery and the descending aorta, normally closes immediately after birth. The oxygen concentration in the blood rises after birth, and in the DA this increase in oxygen concentration causes functional closure, which is induced by smooth muscle contraction. Previous studies have demonstrated that hypoxia and/or oxygenation affect vascular remodeling of various vessels. Therefore, we hypothesized that the rise in oxygen concentration would affect the vascular structure of the DA due to production of proteins secreted from DA smooth muscle cells (SMC). Liquid chromatography-tandem mass spectrometry was used to comprehensively investigate the secreted proteins in the supernatant of rat DA SMC harvested under hypoxic conditions (1% oxygen) or under normoxic conditions (21% oxygen). We found that the rise in oxygen concentration reduced the secretion of elastin from DA SMC. On reverse transcription-polymerase chain reaction, the expression of elastin mRNA was not significantly changed in DA SMC from hypoxic to normoxic conditions. Given that elastin forms internal elastic lamina and elastic fibers in the vascular muscle layers, and that a rise in oxygen concentration reduced the secretion of elastin, this suggests that the rise in blood oxygen concentration after birth reduces the secretion of elastin, and therefore may play a role in DA structural remodeling after birth. © 2015 Japan Pediatric Society.

Picfeltarraenin IA inhibits lipopolysaccharide-induced inflammatory cytokine production by the nuclear factor-κB pathway in human pulmonary epithelial A549 cells.

Science.gov (United States)

Shi, Rong; Wang, Qing; Ouyang, Yang; Wang, Qian; Xiong, Xudong

2016-02-01

The present study aimed to investigate the effect of picfeltarraenin IA (IA) on respiratory inflammation by analyzing its effect on interleukin (IL)-8 and prostaglandin E2 (PGE2) production. The expression of cyclooxygenase 2 (COX2) in human pulmonary adenocarcinoma epithelial A549 cells in culture was also examined. Human pulmonary epithelial A549 cells and the human monocytic leukemia THP-1 cell line were used in the current study. Cell viability was measured using a methylthiazol tetrazolium assay. The production of IL-8 and PGE2 was investigated using an enzyme-linked immunosorbent assay. The expression of COX2 and nuclear factor-κB (NF-κB)-p65 was examined using western blot analysis. Treatment with lipopolysaccharide (LPS; 10 µg/ml) resulted in the increased production of IL-8 and PGE2, and the increased expression of COX2 in the A549 cells. Furthermore, IA (0.1-10 µmol/l) significantly inhibited PGE2 production and COX2 expression in cells with LPS-induced IL-8, in a concentration-dependent manner. The results suggested that IA downregulates LPS-induced COX2 expression, and inhibits IL-8 and PGE2 production in pulmonary epithelial cells. Additionally, IA was observed to suppress the expression of COX2 in THP-1 cells, and also to regulate the expression of COX2 via the NF-κB pathway in the A549 cells, but not in the THP-1 cells. These results indicate that IA regulates LPS-induced cytokine release in A549 cells via the NF-κB pathway.

Assessing the utility of autofluorescence-based pulmonary optical endomicroscopy to predict the malignant potential of solitary pulmonary nodules in humans

Science.gov (United States)

Seth, Sohan; Akram, Ahsan R.; McCool, Paul; Westerfeld, Jody; Wilson, David; McLaughlin, Stephen; Dhaliwal, Kevin; Williams, Christopher K. I.

2016-08-01

Solitary pulmonary nodules are common, often incidental findings on chest CT scans. The investigation of pulmonary nodules is time-consuming and often leads to protracted follow-up with ongoing radiological surveillance, however, clinical calculators that assess the risk of the nodule being malignant exist to help in the stratification of patients. Furthermore recent advances in interventional pulmonology include the ability to both navigate to nodules and also to perform autofluorescence endomicroscopy. In this study we assessed the efficacy of incorporating additional information from label-free fibre-based optical endomicrosopy of the nodule on assessing risk of malignancy. Using image analysis and machine learning approaches, we find that this information does not yield any gain in predictive performance in a cohort of patients. Further advances with pulmonary endomicroscopy will require the addition of molecular tracers to improve information from this procedure.

Partial anomalous pulmonary venous return in patients with pulmonary hypertension

International Nuclear Information System (INIS)

Sung, Won-kyung; Au, Virginia; Rose, Anand

2012-01-01

Anomalous pulmonary venous return is an uncommon congenital malformation, and may be partial or total. Partial anomalous pulmonary venous return (PAPVR) is more common than total anomalous pulmonary venous return, and is often associated with other congenital cardiac anomalies. Whilst many patients with PAPVR remain asymptomatic, some may present in later age with symptoms related to left-to-right shunt, right heart failure and pulmonary hypertension. We report two cases of PAPVR detected on Computed Tomography Pulmonary Angiogram (CTPA) for the work up of pulmonary hypertension. The cases demonstrate that, although uncommon, partial anomalous pulmonary venous return can be a contributing factor to pulmonary hypertension and pulmonary veins should be carefully examined when reading a CTPA study.

Pulmonary biomarkers in chronic obstructive pulmonary disease

NARCIS (Netherlands)

Barnes, Peter J.; Chowdhury, Badrul; Kharitonov, Sergei A.; Magnussen, Helgo; Page, Clive P.; Postma, Dirkje; Saetta, Marina

2006-01-01

There has been increasing interest in using pulmonary biomarkers to understand and monitor the inflammation in the respiratory tract of patients with chronic obstructive pulmonary disease (COPD). In this Pulmonary Perspective we discuss the merits of the various approaches by reviewing the current

Essential Roles of Raf/Extracellular Signal-regulated Kinase/Mitogen-activated Protein Kinase Pathway, YY1, and Ca2+ Influx in Growth Arrest of Human Vascular Smooth Muscle Cells by Bilirubin*

Science.gov (United States)

Stoeckius, Marlon; Erat, Anna; Fujikawa, Tatsuya; Hiromura, Makoto; Koulova, Anna; Otterbein, Leo; Bianchi, Cesario; Tobiasch, Edda; Dagon, Yossi; Sellke, Frank W.; Usheva, Anny

2012-01-01

The biological effects of bilirubin, still poorly understood, are concentration-dependent ranging from cell protection to toxicity. Here we present data that at high nontoxic physiological concentrations, bilirubin inhibits growth of proliferating human coronary artery smooth muscle cells by three events. It impairs the activation of Raf/ERK/MAPK pathway and the cellular Raf and cyclin D1 content that results in retinoblastoma protein hypophosphorylation on amino acids S608 and S780. These events impede the release of YY1 to the nuclei and its availability to regulate the expression of genes and to support cellular proliferation. Moreover, altered calcium influx and calpain II protease activation leads to proteolytical degradation of transcription factor YY1. We conclude that in the serum-stimulated human vascular smooth muscle primary cell cultures, bilirubin favors growth arrest, and we propose that this activity is regulated by its interaction with the Raf/ERK/MAPK pathway, effect on cyclin D1 and Raf content, altered retinoblastoma protein profile of hypophosphorylation, calcium influx, and YY1 proteolysis. We propose that these activities together culminate in diminished 5 S and 45 S ribosomal RNA synthesis and cell growth arrest. The observations provide important mechanistic insight into the molecular mechanisms underlying the transition of human vascular smooth muscle cells from proliferative to contractile phenotype and the role of bilirubin in this transition. PMID:22262839

Smooth halos in the cosmic web

Energy Technology Data Exchange (ETDEWEB)

Gaite, José, E-mail: jose.gaite@upm.es [Physics Dept., ETSIAE, IDR, Universidad Politécnica de Madrid, Pza. Cardenal Cisneros 3, E-28040 Madrid (Spain)

2015-04-01

Dark matter halos can be defined as smooth distributions of dark matter placed in a non-smooth cosmic web structure. This definition of halos demands a precise definition of smoothness and a characterization of the manner in which the transition from smooth halos to the cosmic web takes place. We introduce entropic measures of smoothness, related to measures of inequality previously used in economy and with the advantage of being connected with standard methods of multifractal analysis already used for characterizing the cosmic web structure in cold dark matter N-body simulations. These entropic measures provide us with a quantitative description of the transition from the small scales portrayed as a distribution of halos to the larger scales portrayed as a cosmic web and, therefore, allow us to assign definite sizes to halos. However, these ''smoothness sizes'' have no direct relation to the virial radii. Finally, we discuss the influence of N-body discreteness parameters on smoothness.

Smooth halos in the cosmic web

International Nuclear Information System (INIS)

Gaite, José

2015-01-01

Dark matter halos can be defined as smooth distributions of dark matter placed in a non-smooth cosmic web structure. This definition of halos demands a precise definition of smoothness and a characterization of the manner in which the transition from smooth halos to the cosmic web takes place. We introduce entropic measures of smoothness, related to measures of inequality previously used in economy and with the advantage of being connected with standard methods of multifractal analysis already used for characterizing the cosmic web structure in cold dark matter N-body simulations. These entropic measures provide us with a quantitative description of the transition from the small scales portrayed as a distribution of halos to the larger scales portrayed as a cosmic web and, therefore, allow us to assign definite sizes to halos. However, these ''smoothness sizes'' have no direct relation to the virial radii. Finally, we discuss the influence of N-body discreteness parameters on smoothness

Identification of human pulmonary alkaline phosphatase isoenzymes.

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Capelli, A; Cerutti, C G; Lusuardi, M; Donner, C F

1997-04-01

An increase of alkaline phosphatase (ALP) activity has been observed in the bronchoalveolar lavage fluid (BALF) of patients affected by pulmonary fibrosis in chronic interstitial lung disorders. To characterize the ALP isoenzymes in such cases, we used gel filtration, agarose gel electrophoresis, heat and amino acid inhibition assays, wheat-germ agglutinin (WGA) precipitation, and an immunoassay specific for the bone-isoform of ALP. Only one anodic band representing a high-molecular-weight isoform of ALP (Mr approximately 2,000 kDa) was observed on electrophoresis of BALF. The inhibition assay results were consistent for a tissue-nonspecific isoenzyme sensitive to a temperature of 56 degrees C (71.9 +/- 2.5% inhibition) and to homoarginine (65.7 +/- 1.9%), and resistant to L-phenylalanine and L-leucine. Less than 13% of ALP activity was heat-stable. After incubation of BALF specimens with glycosyl-phosphatidylinositol-phospholipase D plus Nonidet P-40, or with phosphatidylinositol-phospholipase C alone, an electrophoretic cathodic band (Mr approximately 220 kDa) appeared near the bone band of a standard serum. With the WGA assay, 84.4 +/- 3.3% of ALP precipitated and the band disappeared. After immunoassay for the bone isoform, a mean of less than 5% enzyme activity was measured. We conclude that the ALP found in BALF is a pulmonary isoform of a tissue nonspecific isoenzyme.

Pulmonary venous remodeling in COPD-pulmonary hypertension and idiopathic pulmonary arterial hypertension

DEFF Research Database (Denmark)

Andersen, Kasper Hasseriis; Andersen, Claus Bøgelund; Gustafsson, Finn

2017-01-01

Pulmonary vascular arterial remodeling is an integral and well-understood component of pulmonary hypertension (PH). In contrast, morphological alterations of pulmonary veins in PH are scarcely described. Explanted lungs (n = 101) from transplant recipients with advanced chronic obstructive...... pulmonary disease (COPD) and idiopathic pulmonary arterial hypertension (IPAH) were analyzed for venous vascular involvement according to a pre-specified, semi-quantitative grading scheme, which categorizes the intensity of venous remodeling in three groups of incremental severity: venous hypertensive (VH......) grade 0 = characterized by an absence of venous vascular remodeling; VH grade 1 = defined by a dominance of either arterialization or intimal fibrosis; and VH grade 2 = a substantial composite of arterialization and intimal fibrosis. Patients were grouped according to clinical and hemodynamic...

Cardiac, skeletal, and smooth muscle mitochondrial respiration: are all mitochondria created equal?

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Park, Song-Young; Gifford, Jayson R; Andtbacka, Robert H I; Trinity, Joel D; Hyngstrom, John R; Garten, Ryan S; Diakos, Nikolaos A; Ives, Stephen J; Dela, Flemming; Larsen, Steen; Drakos, Stavros; Richardson, Russell S

2014-08-01

Unlike cardiac and skeletal muscle, little is known about vascular smooth muscle mitochondrial respiration. Therefore, the present study examined mitochondrial respiratory rates in smooth muscle of healthy human feed arteries and compared with that of healthy cardiac and skeletal muscles. Cardiac, skeletal, and smooth muscles were harvested from a total of 22 subjects (53 ± 6 yr), and mitochondrial respiration was assessed in permeabilized fibers. Complex I + II, state 3 respiration, an index of oxidative phosphorylation capacity, fell progressively from cardiac to skeletal to smooth muscles (54 ± 1, 39 ± 4, and 15 ± 1 pmol·s(-1)·mg(-1), P respiration rates were normalized by CS (respiration per mitochondrial content), oxidative phosphorylation capacity was no longer different between the three muscle types. Interestingly, complex I state 2 normalized for CS activity, an index of nonphosphorylating respiration per mitochondrial content, increased progressively from cardiac to skeletal to smooth muscles, such that the respiratory control ratio, state 3/state 2 respiration, fell progressively from cardiac to skeletal to smooth muscles (5.3 ± 0.7, 3.2 ± 0.4, and 1.6 ± 0.3 pmol·s(-1)·mg(-1), P respiration highlight the existence of intrinsic functional differences between these muscle mitochondria. This likely influences the efficiency of oxidative phosphorylation and could potentially alter ROS production.

Measurement of regional pulmonary blood volume in patients with increased pulmonary blood flow or pulmonary arterial hypertension

International Nuclear Information System (INIS)

Wollmer, P.; Rozcovek, A.; Rhodes, C.G.; Allan, R.M.; Maseri, A.

1984-01-01

The effects of chronic increase in pulmonary blood flow and chronic pulmonary hypertension on regional pulmonary blood volume was measured in two groups of patients. One group of patients had intracardiac, left-to-right shunts without appreciable pulmonary hypertension, and the other consisted of patients with Eisenmenger's syndrome or primary pulmonary hypertension, i.e. patients with normal or reduced blood flow and severe pulmonary hypertension. A technique based on positron tomography was used to measure lung density (by transmission scanning) and regional pulmonary blood volume (after inhalation of /sup 11/CO). The distribution of pulmonary blood volume was more uniform in patients with chronic increase in pulmonary blood flow than in normal subjects. There were also indications of an absolute increase in intrapulmonary blood volume by about 15%. In patients with chronic pulmonary arterial hypertension, the distribution of pulmonary blood volume was also abnormally uniform. There was, however, no indication that overall intrapulmonary blood volume was substantially different from normal subjects. The abnormally uniform distribution of pulmonary blood volume can be explained by recruitment and/or dilatation of vascular beds. Intrapulmonary blood volume appears to be increased in patients with intracardiac, left-to-right shunts. With the development of pulmonary hypertension, intrapulmonary blood volume falls, which may be explained by reactive changes in the vasculature and/or obliteration of capillaries

When a pulmonary embolism is not a pulmonary embolism: a rare case of primary pulmonary leiomyosarcoma

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Nargiz Muganlinskaya

2015-12-01

Full Text Available Arterial leiomyosarcomas account for up to 21% of vascular leiomyosarcomas, with 56% of arterial leiomyosarcomas occurring in the pulmonary artery. While isolated cases of primary pulmonary artery leiomyosarcoma document survival up to 36 months after treatment, these uncommon, aggressive tumors are highly lethal, with 1-year survival estimated at 20% from the onset of symptoms. We discuss a rare case of a pulmonary artery leiomyosarcoma that was originally diagnosed as a pulmonary embolism (PE. A 72-year-old Caucasian female was initially diagnosed with ‘saddle pulmonary embolism’ based on computerized tomographic angiography of the chest 2 months prior to admission and placed on anticoagulation. Dyspnea escalated, and serial computed tomography scans showed cardiomegaly with pulmonary emboli involving the right and left main pulmonary arteries with extension into the right and left upper and lower lobe branches. An echocardiogram on admission showed severe pulmonary hypertension with a pulmonary artery pressure of 82.9 mm Hg, and a severely enlarged right ventricle. Respiratory distress and multiorgan failure developed and, unfortunately, the patient expired. Autopsy showed a lobulated, yellow mass throughout the main pulmonary arteries measuring 13 cm in diameter. The mass extended into the parenchyma of the right upper lobe. On microscopy, the mass was consistent with a high-grade primary pulmonary artery leiomyosarcoma. Median survival of patients with primary pulmonary artery leiomyosarcoma without surgery is one and a half months, and mortality is usually due to right-sided heart failure. Pulmonary artery leiomyosarcoma is a rare but highly lethal disease commonly mistaken for PE. Thus, we recommend clinicians to suspect this malignancy when anticoagulation fails to relieve initial symptoms. In conclusion, early detection and suspicion of pulmonary artery leiomyosarcoma should be considered in patients refractory to anticoagulation

HRCT appearances of pulmonary interstitial diseases. The pathologic basis and clinical diagnostic significance

International Nuclear Information System (INIS)

Ma Daqing; Li Tieyi; Guan Yansheng; He Wen; Nie Yongkang

1999-01-01

Objective: To evaluate the CT appearances, the pathologic basis and diagnostic significance of pulmonary interstitial diseases. methods: 14 isolated lungs with interstitial diseases were obtained at autopsy and surgery. The lungs were inflated and fixed. HRCT and 1 cm thin slice soft X-ray radiograph were performed and then histologic examination was done. HRCT images of 72 cases with interstitial diseases were analysed. The HRCT appearances of 10 cases were followed up for 1.5-7.0 years. Results: According to HRCT-pathologic correlation, pulmonary interstitial diseases had the following HRCT findings: (1) Intralobular interstitial thickening (33 cases, 46%), including fine linear, reticular and radiating appearances and the interface sign. (2) Interlobular septal thickening (24 cases, 33%). (3) Thickening of bronchovesicular bundles (35 cases, 49%), with coarse, blurred or smooth bundle, and nodular shape. (4) Subpleural lines (31 cases, 43%). (5) Ground-glass opacity (22 cases, 31%) with peripheral, diffuse or locular distribution. (6) Honeycombing (27 cases, 38%), having sizes: 5 mm. Of the 10 cases with follow-up, 2 cases became normal on CT and 8 cases progressing to honeycombed lung. Conclusions: The HRCT findings of pulmonary interstitial diseases represent abnormalities of axial, peripheral and septal interstitium. Interstitial fibrosis of the lung can be differentiated from that without fibrosis by HRCT. Ground-glass opacity, intralobular interstitial thickening and subpleural lines are preliminary findings of pulmonary interstitial fibrosis

Comparison of some nonlinear smoothing methods

International Nuclear Information System (INIS)

Bell, P.R.; Dillon, R.S.

1977-01-01

Due to the poor quality of many nuclear medicine images, computer-driven smoothing procedures are frequently employed to enhance the diagnostic utility of these images. While linear methods were first tried, it was discovered that nonlinear techniques produced superior smoothing with little detail suppression. We have compared four methods: Gaussian smoothing (linear), two-dimensional least-squares smoothing (linear), two-dimensional least-squares bounding (nonlinear), and two-dimensional median smoothing (nonlinear). The two dimensional least-squares procedures have yielded the most satisfactorily enhanced images, with the median smoothers providing quite good images, even in the presence of widely aberrant points

Pulmonary blood flow distribution measured by radionuclide computed tomography

International Nuclear Information System (INIS)

Maeda, H.; Itoh, H.; Ishii, Y.

1982-01-01

Distributions of pulmonary blood flow per unit lung volume were measured in sitting patients with a radionuclide computed tomography (RCT) by intravenously administered Tc-99m macroaggregates of human serum albumin (MAA). Four different types of distribution were distinguished, among which a group referred as type 2 had a three zonal blood flow distribution as previously reported (West and co-workers, 1964). The pulmonary arterial pressure (Pa) and the venous pressure (Pv) were determined in this group of distribution. These values showed satifactory agreements with the pulmonary artery pressure (Par) and the capillary wedged pressure (Pcw) measured by Swan-Ganz catheter in eighteen supine patients. Those good correlations enable to establish a noninvasive methodology for measurement of pulmonary vascular pressures

Lymphatics in lymphangioleiomyomatosis and idiopathic pulmonary fibrosis

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Souheil El-Chemaly

2012-09-01

Full Text Available The primary function of the lymphatic system is absorbing and transporting macromolecules and immune cells to the general circulation, thereby regulating fluid, nutrient absorption and immune cell trafficking. Lymphangiogenesis plays an important role in tissue inflammation and tumour cell dissemination. Lymphatic involvement is seen in lymphangioleiomyomatosis (LAM and idiopathic pulmonary fibrosis (IPF. LAM, a disease primarily affecting females, involves the lung (cystic destruction, kidney (angiomyolipoma and axial lymphatics (adenopathy and lymphangioleiomyoma. LAM occurs sporadically or in association with tuberous sclerosis complex (TSC. Cystic lung destruction results from proliferation of LAM cells, which are abnormal smooth muscle-like cells with mutations in the TSC1 or TSC2 gene. Lymphatic abnormalities arise from infiltration of LAM cells into the lymphatic wall, leading to damage or obstruction of lymphatic vessels. Benign appearing LAM cells possess metastatic properties and are found in the blood and other body fluids. IPF is a progressive lung disease resulting from fibroblast proliferation and collagen deposition. Lymphangiogenesis is associated with pulmonary destruction and disease severity. A macrophage subset isolated from IPF bronchoalveolar lavage fluid (BALF express lymphatic endothelial cell markers in vitro, in contrast to the same macrophage subset from normal BALF. Herein, we review lymphatic involvement in LAM and IPF.

Mitochondrial Complex IV Subunit 4 Isoform 2 Is Essential for Acute Pulmonary Oxygen Sensing.

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Sommer, Natascha; Hüttemann, Maik; Pak, Oleg; Scheibe, Susan; Knoepp, Fenja; Sinkler, Christopher; Malczyk, Monika; Gierhardt, Mareike; Esfandiary, Azadeh; Kraut, Simone; Jonas, Felix; Veith, Christine; Aras, Siddhesh; Sydykov, Akylbek; Alebrahimdehkordi, Nasim; Giehl, Klaudia; Hecker, Matthias; Brandes, Ralf P; Seeger, Werner; Grimminger, Friedrich; Ghofrani, Hossein A; Schermuly, Ralph T; Grossman, Lawrence I; Weissmann, Norbert

2017-08-04

Acute pulmonary oxygen sensing is essential to avoid life-threatening hypoxemia via hypoxic pulmonary vasoconstriction (HPV) which matches perfusion to ventilation. Hypoxia-induced mitochondrial superoxide release has been suggested as a critical step in the signaling pathway underlying HPV. However, the identity of the primary oxygen sensor and the mechanism of superoxide release in acute hypoxia, as well as its relevance for chronic pulmonary oxygen sensing, remain unresolved. To investigate the role of the pulmonary-specific isoform 2 of subunit 4 of the mitochondrial complex IV (Cox4i2) and the subsequent mediators superoxide and hydrogen peroxide for pulmonary oxygen sensing and signaling. Isolated ventilated and perfused lungs from Cox4i2 -/- mice lacked acute HPV. In parallel, pulmonary arterial smooth muscle cells (PASMCs) from Cox4i2 -/- mice showed no hypoxia-induced increase of intracellular calcium. Hypoxia-induced superoxide release which was detected by electron spin resonance spectroscopy in wild-type PASMCs was absent in Cox4i2 -/- PASMCs and was dependent on cysteine residues of Cox4i2. HPV could be inhibited by mitochondrial superoxide inhibitors proving the functional relevance of superoxide release for HPV. Mitochondrial hyperpolarization, which can promote mitochondrial superoxide release, was detected during acute hypoxia in wild-type but not Cox4i2 -/- PASMCs. Downstream signaling determined by patch-clamp measurements showed decreased hypoxia-induced cellular membrane depolarization in Cox4i2 -/- PASMCs compared with wild-type PASMCs, which could be normalized by the application of hydrogen peroxide. In contrast, chronic hypoxia-induced pulmonary hypertension and pulmonary vascular remodeling were not or only slightly affected by Cox4i2 deficiency, respectively. Cox4i2 is essential for acute but not chronic pulmonary oxygen sensing by triggering mitochondrial hyperpolarization and release of mitochondrial superoxide which, after conversion

Pulmonary histiocytosis X - imaging aspects of pulmonary involvement

International Nuclear Information System (INIS)

Sabedotti, Ismail Fernando; Maeda, Lucimara; Ferreira, Daniel Miranda; Montandon, Cristiano; Marins, Jose Luiz C.

1999-01-01

Pulmonary histiocytosis X is an idiopathic disease which is and uncommon but important cause of pulmonary fibrosis in young adults. Chest radiographs and high resolution computed tomographic (HRCT) scans of the lungs of 7 patients diagnosed as pulmonary histiocytosis X were examined retrospectively. The authors reviewed the pathologic, clinical and radiographic features of pulmonary histiocytosis X, focusing on differential diagnosis and disease progression. Pulmonary histiocytosis X can be suspected on the basis of chest radiographic findings; predominantly upper lobe nodules and cysts present an increased sensitivity and are virtually pathognomonic of this disorder. Chest HRCT allows good assessment of the evolution of pulmonary histiocytosis X and is also valuable in distinguishing histiocytosis from other disorders that produces nodules or cysts. (author)

The Expression of NOX4 in Smooth Muscles of Small Airway Correlates with the Disease Severity of COPD.

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Liu, Xianyan; Hao, Binwei; Ma, Ailing; He, Jinxi; Liu, Xiaoming; Chen, Juan

Airway smooth muscle (ASM) remodeling is a hallmark in chronic obstructive pulmonary disease (COPD), and nicotinamide-adenine dinucleotide phosphate (NADPH) oxidases (NOXs) produced reactive oxygen species (ROS) play a crucial role in COPD pathogenesis. In the present study, the expression of NOX4 and its correlation with the ASM hypertrophy/hyperplasia, clinical pulmonary functions, and the expression of transforming growth factor β (TGF- β ) in the ASM of COPD small airways were investigated by semiquantitative morphological and/or immunohistochemistry staining methods. The results showed that an elevated expression of NOX4 and TGF- β , along with an increased volume of ASM mass, was found in the ASM of small airways in COPD patients. The abundance of NOX4 protein in the ASM was increased with disease severity and inversely correlated with the pulmonary functions in COPD patients. In addition, the expression of NOX4 and ASM marker α -SMA was colocalized, and the increased NOX4 expression was found to accompany an upregulated expression of TGF- β in the ASM of small airways of COPD lung. These results indicate that NOX4 may be a key regulator in ASM remodeling of small airway, in part through a mechanism interacting with TGF- β signaling in the pathogenesis of COPD, which warrants further investigation.

Inhibition of human arterial smooth muscle (HASM) cell proliferation and collagen synthesis by protamine

International Nuclear Information System (INIS)

Drucker, D.E.; Graham, M.F.; Diegelmann, R.F.; Greenfield, L.J.

1986-01-01

Atherosclerotic plaques result from vascular smooth muscle cell proliferation and collagen deposition. The authors have been studying factors which modulate HASM cell proliferation and collagen synthesis. HASM cells were isolated from the media of normal human thoracic and infrarenal aortas and grown in vitro. Cell numbers were determined by direct counting and collagen synthesis was measured by incorporation of 3 H-proline into collagenase-digestible protein. In this study, protamine (200 μg/ml) was tested and found to cause a 55% reduction of HASM cell proliferation which was reversible when the cells were returned to control medium or when heparin (100 μg/ml) was added with protamine. Protamine caused a constant 33% decrease in non-collagen protein (NCP) synthesis per cell. In contrast, collagen synthesis was inhibited in dose dependent fashion (88% reduction at 200 μg/ml). Protamine blocks HASM cell proliferation and specifically inhibits collagen production. The exact mechanism of this inhibition is unclear but may be related to a transcriptional event since protamine has a high affinity for DNA

Targeted expression of heme oxygenase-1 prevents the pulmonary inflammatory and vascular responses to hypoxia

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Minamino, Tohru; Christou, Helen; Hsieh, Chung-Ming; Liu, Yuxiang; Dhawan, Vijender; Abraham, Nader G.; Perrella, Mark A.; Mitsialis, S. Alex; Kourembanas, Stella

2001-07-01

Chronic hypoxia causes pulmonary hypertension with smooth muscle cell proliferation and matrix deposition in the wall of the pulmonary arterioles. We demonstrate here that hypoxia also induces a pronounced inflammation in the lung before the structural changes of the vessel wall. The proinflammatory action of hypoxia is mediated by the induction of distinct cytokines and chemokines and is independent of tumor necrosis factor- signaling. We have previously proposed a crucial role for heme oxygenase-1 (HO-1) in protecting cardiomyocytes from hypoxic stress, and potent anti-inflammatory properties of HO-1 have been reported in models of tissue injury. We thus established transgenic mice that constitutively express HO-1 in the lung and exposed them to chronic hypoxia. HO-1 transgenic mice were protected from the development of both pulmonary inflammation as well as hypertension and vessel wall hypertrophy induced by hypoxia. Significantly, the hypoxic induction of proinflammatory cytokines and chemokines was suppressed in HO-1 transgenic mice. Our findings suggest an important protective function of enzymatic products of HO-1 activity as inhibitors of hypoxia-induced vasoconstrictive and proinflammatory pathways.

Pulmonary arteriography by digital subtraction angiographic method in cyanotic heart disease with pulmonary stenosis or pulmonary atresia

International Nuclear Information System (INIS)

Kobayashi, Junjiro; Hirose, Hajime; Nakano, Susumu

1985-01-01

Pulmonary arteriography was performed by digital subtraction angiographic (DSA) method in 10 patients with cyanotic heart disease associated with pulmonary stenosis or pulmonary atresia. Ten patients consisted of five patients with tetralogy of Fallot, three with single ventricle and pulmonary stenosis, and two with pseudotruncus arteriosus. Hepato-clavicular position was taken in four patients. Pulmonary artery and its main branches were opacified and recognized clearly, and their diameter could be measured accurately with a small amount of contrast medium. There was a good correlation between the diameter of pulmonary artery measured by DSA and that measured by conventional pulmonary arteriography. DSA is a useful method for evaluating the size and the stenosis of pulmonary artery especially in small cyanotic infants. (author)

Platelet-activating factor synthesis and receptor-mediated signaling are downregulated in ovine newborn lungs: relevance in postnatal pulmonary adaptation and persistent pulmonary hypertension of the newborn.

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Renteria, L S; Cruz, E; Ibe, B O

2013-12-01

Platelet-activating factor (PAF) is a phospholipid with a wide range of biological activities. We studied PAF metabolism and PAF receptor (PAFR) signaling in perinatal ovine lungs to understand PAF's role in transition of the perinatal pulmonary hemodynamics and pathophysiology of persistent pulmonary hypertension of the newborn. We hypothesized that downregulation of PAF synthesis with upregulation of PAF catabolism by acetylhydrolase (PAF-Ah) in the newborn lung is needed for fetus-to-newborn pulmonary adaptation. Studies were conducted on fetal and newborn lamb pulmonary arteries (PA), veins (PV) and smooth muscle cells (SMC). PAF metabolism, PAFR binding and cell proliferation were studied by cell culture; gene expression was studied by qPCR. Fetal lungs synthesized 60% more PAF than newborn lungs. Compared with the fetal PVs and SMCs, PAF-Ah activity in newborn was 40-60% greater. PAF-Ah mRNA expression in newborn vessels was different from the expression by fetal PA. PAF-Ah gene clone activity confirmed deletion of hypoxia-sensitive site. PAFR mRNA expression by the PVs and SMC-PV of the fetus and newborn was greater than by corresponding PAs and SMC-PA. Q-PCR study of PAFR expression by the SMC-PV of both groups was greater than SMC-PA. Fetal SMCs bound more PAF than the newborn SMCs. PAFR antagonist, CV-3988, inhibited PAFR binding and DNA synthesis by the fetal SMCs, but augmented binding and DNA synthesis by newborn cells. We show different PAF-PAFR mediated effects in perinatal lungs, suggesting both transcriptional and translational regulation of PAF-Ah and PAFR expression in the perinatal lamb lungs. These indicate that the downregulation of PAF-mediated effects postnatally protects against persistent pulmonary hypertension of the newborn.

Hypoxia Inducible Factor Signaling and Experimental Persistent Pulmonary Hypertension of the Newborn: A Therapeutic Opportunity

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Stephen eWedgwood

2015-03-01

Full Text Available BACKGROUND: Mitochondrial reactive oxygen species levels and nuclear factor kappa-light-chain-enhancer of activated B cells (NFκB activity are increased in a lamb model of persistent pulmonary hypertension of the newborn (PPHN. These events can trigger hypoxia inducible factor (HIF signaling in response to hypoxia, which has been shown to contribute to pulmonary vascular remodeling in rodent models of pulmonary hypertension. However the role of HIF signaling in chronic intrauterine pulmonary hypertension is not well understood.AIM: To determine if HIF signaling is increased in the lamb model of PPHN, and to identify the underlying mechanisms. RESULTS: PPHN was induced in lambs by antenatal ligation of the ductus arteriosus at 128 days gestation. After 9 days, lungs and pulmonary artery smooth muscle cells (PASMC were isolated from control and PPHN lambs. HIF-1α expression was increased in PPHN lungs and HIF activity was increased in PPHN PASMC relative to controls. Hypoxia increased HIF activity to a greater degree in PPHN vs. control PASMC. Control PASMC were exposed to cyclic stretch at 1Hz and 15% elongation for 24h, as an in vitro model of vascular stress. Stretch increased HIF activity, which was attenuated by inhibition of mitochondrial complex III and NFκB.CONCLUSION: Increased HIF signaling in PPHN is triggered by stretch, via mechanisms involving mitochondrial ROS and NFκB. Hypoxia substantially amplifies HIF activity in PPHN vascular cells. Targeting these signaling molecules may attenuate and reverse pulmonary vascular remodeling associated with PPHN.

Alteration of pulmonary blood flow in tetralogy of Fallot

International Nuclear Information System (INIS)

Hashimoto, Kazuhiro; Matsui, Michihiko; Kurosawa, Hiromi; Arai, Tatsuta; Nakamura, Yuzuru.

1992-01-01

The pulmonary blood distribution was examined in 17 patients with tetralogy of Fallot (TOF) pre and postoperatively with macroaggregates of 99m TC-labeled human serum albumin. Most of the patients with TOF demonstrated an abnormal preoperative distribution pattern. The abnormalities included not only an unbalanced distribution between the right and left lungs but also a maldistribution of peripheral vessels in each lung. The right/left lung counts ratio and pulmonary peripheral index (calculated in order to express the severity of peripheral maldistribution) correlated neither to the diameter nor the cross-sectional area of either right or left pulmonary arteries which were measured angiographically. Postoperatively, the pulmonary blood was shunted toward the developed side of the lung which further contributed to maldistribution of blood flow and unbalanced pulmonary growth. Since the patients with an unbalanced pulmonary blood distribution demonstrated a higher right ventricular pressure one year after the operation, a palliative operation facilitating the growth of the underdeveloped side of the lung might be considered as an effective procedure to precede intracardiac repair. (author)

Vagal innervation is required for pulmonary function phenotype in Htr4-/- mice.

Science.gov (United States)

House, John S; Nichols, Cody E; Li, Huiling; Brandenberger, Christina; Virgincar, Rohan S; DeGraff, Laura M; Driehuys, Bastiaan; Zeldin, Darryl C; London, Stephanie J

2017-04-01

Human genome-wide association studies have identified over 50 loci associated with pulmonary function and related phenotypes, yet follow-up studies to determine causal genes or variants are rare. Single nucleotide polymorphisms in serotonin receptor 4 ( HTR4 ) are associated with human pulmonary function in genome-wide association studies and follow-up animal work has demonstrated that Htr4 is causally associated with pulmonary function in mice, although the precise mechanisms were not identified. We sought to elucidate the role of neural innervation and pulmonary architecture in the lung phenotype of Htr4 -/- animals. We report here that the Htr4 -/- phenotype in mouse is dependent on vagal innervation to the lung. Both ex vivo tracheal ring reactivity and in vivo flexiVent pulmonary functional analyses demonstrate that vagotomy abrogates the Htr4 -/- airway hyperresponsiveness phenotype. Hyperpolarized 3 He gas magnetic resonance imaging and stereological assessment of wild-type and Htr4 -/- mice reveal no observable differences in lung volume, inflation characteristics, or pulmonary microarchitecture. Finally, control of breathing experiments reveal substantive differences in baseline breathing characteristics between mice with/without functional HTR4 in breathing frequency, relaxation time, flow rate, minute volume, time of inspiration and expiration and breathing pauses. These results suggest that HTR4's role in pulmonary function likely relates to neural innervation and control of breathing. Copyright © 2017 the American Physiological Society.

A 310-bp minimal promoter mediates smooth muscle cell-specific expression of telokin.

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Smith, A F; Bigsby, R M; Word, R A; Herring, B P

1998-05-01

A cell-specific promoter located in an intron of the smooth muscle myosin light chain kinase gene directs transcription of telokin exclusively in smooth muscle cells. Transgenic mice were generated in which a 310-bp rabbit telokin promoter fragment, extending from -163 to +147, was used to drive expression of simian virus 40 large T antigen. Smooth muscle-specific expression of the T-antigen transgene paralleled that of the endogenous telokin gene in all smooth muscle tissues except uterus. The 310-bp promoter fragment resulted in very low levels of transgene expression in uterus; in contrast, a transgene driven by a 2.4-kb fragment (-2250 to +147) resulted in high levels of transgene expression in uterine smooth muscle. Telokin expression levels correlate with the estrogen status of human myometrial tissues, suggesting that deletion of an estrogen response element (ERE) may account for the low levels of transgene expression driven by the 310-bp rabbit telokin promoter in uterine smooth muscle. Experiments in A10 smooth muscle cells directly showed that reporter gene expression driven by the 2.4-kb, but not 310-bp, promoter fragment could be stimulated two- to threefold by estrogen. This stimulation was mediated through an ERE located between -1447 and -1474. Addition of the ERE to the 310-bp fragment restored estrogen responsiveness in A10 cells. These data demonstrate that in addition to a minimal 310-bp proximal promoter at least one distal cis-acting regulatory element is required for telokin expression in uterine smooth muscle. The distal element may include an ERE between -1447 and -1474.

Mechanisms responsible for the acceleration of pulmonary V̇O2 on-kinetics in humans after prolonged endurance training.

Science.gov (United States)

Zoladz, Jerzy A; Grassi, Bruno; Majerczak, Joanna; Szkutnik, Zbigniew; Korostyński, Michal; Grandys, Marcin; Jarmuszkiewicz, Wieslawa; Korzeniewski, Bernard

2014-11-01

The effect of prolonged endurance training on the pulmonary V̇O2 on- and off-kinetics in humans, in relation to muscle mitochondria biogenesis, is investigated. Eleven untrained physically active men (means±SD: age 22.4±1.5 years, V̇O2peak 3,187±479 ml/min) performed endurance cycling training (4 sessions per week) lasting 20 wk. Training shortened τp of the pulmonary V̇O2 on-kinetics during moderate-intensity cycling by ∼19% from 28.3±5.2 to 23.0±4.0 s (P=0.005). τp of the pulmonary V̇O2 off-kinetics decreased by ∼11% from 33.7±7.2 to 30.0±6.6 (P=0.02). Training increased (in vastus lateralis muscle) mitochondrial DNA copy number in relation to nuclear DNA (mtDNA/nDNA) (+53%) (P=0.014), maximal citrate synthase (CS) activity (+38%), and CS protein content (+38%) (P=0.004), whereas maximal cytochrome c oxidase (COX) activity after training tended to be only slightly (+5%) elevated (P=0.08). By applying to the experimental data, our computer model of oxidative phosphorylation (OXPHOS) and using metabolic control analysis, we argue that COX activity is a much better measure of OXPHOS intensity than CS activity. According to the model, in the present study a training-induced increase in OXPHOS activity accounted for about 0-10% of the decrease in τp of muscle and pulmonary V̇O2 for the on-transient, whereas the remaining 90-100% is caused by an increase in each-step parallel activation of OXPHOS. Copyright © 2014 the American Physiological Society.

Chronic Embolic Pulmonary Hypertension Caused by Pulmonary Embolism and Vascular Endothelial Growth Factor Inhibition.

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Neto-Neves, Evandro M; Brown, Mary B; Zaretskaia, Maria V; Rezania, Samin; Goodwill, Adam G; McCarthy, Brian P; Persohn, Scott A; Territo, Paul R; Kline, Jeffrey A

2017-04-01

Our understanding of the pathophysiological basis of chronic thromboembolic pulmonary hypertension (CTEPH) will be accelerated by an animal model that replicates the phenotype of human CTEPH. Sprague-Dawley rats were administered a combination of a single dose each of plastic microspheres and vascular endothelial growth factor receptor antagonist in polystyrene microspheres (PE) + tyrosine kinase inhibitor SU5416 (SU) group. Shams received volume-matched saline; PE and SU groups received only microspheres or SU5416, respectively. PE + SU rats exhibited sustained pulmonary hypertension (62 ± 13 and 53 ± 14 mmHg at 3 and 6 weeks, respectively) with reduction of the ventriculoarterial coupling in vivo coincident with a large decrement in peak rate of oxygen consumption during aerobic exercise, respectively. PE + SU produced right ventricular hypokinesis, dilation, and hypertrophy observed on echocardiography, and 40% reduction in right ventricular contractile function in isolated perfused hearts. High-resolution computed tomographic pulmonary angiography and Ki-67 immunohistochemistry revealed abundant lung neovascularization and cellular proliferation in PE that was distinctly absent in the PE + SU group. We present a novel rodent model to reproduce much of the known phenotype of CTEPH, including the pivotal pathophysiological role of impaired vascular endothelial growth factor-dependent vascular remodeling. This model may reveal a better pathophysiological understanding of how PE transitions to CTEPH in human treatments. Copyright © 2017 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

Pulmonary biology of anti-interleukin 5 antibodies

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RW Egan

1997-12-01

Full Text Available Interleukin 5 (IL-5 is a critical cytokine for the maturation of eosinophil precursors to eosinophils in the bone marrow and those eosinophils then accumulate in the lungs during asthma. We have studied anti IL-5 antibodies on allergic responses in mice, guinea pigs and monkeys and are extending this experiment into humans with a humanized antibody. In a monkey model of pulmonary inflammation and airway hyperreactivity, we found that the TRFK-5 antibody blocked both responses for three months following a single dose of 0.3 mg/kg, i.v. This antibody also blocked lung eosinophilia in mice by inhibiting release from the bone marrow. To facilitate multiple dosing and to reduce immunogenicity in humans, we prepared Sch 55700, a humanized antibody against IL-5. Sch 55700 was also active against lung eosinophilia in allergic monkeys and mice and against pulmonary eosinophilia and airway hyperresponsiveness in guinea pigs. Furthermore, as opposed to steroids, Sch 55700 did not cause immunosuppression in guinea pigs. Studies with this antibody in humans will be critical to establishing the therapeutic potential of IL-5 inhibition.

Propylthiouracil Attenuates Experimental Pulmonary Hypertension via Suppression of Pen-2, a Key Component of Gamma-Secretase.

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Ying-Ju Lai

Full Text Available Gamma-secretase-mediated Notch3 signaling is involved in smooth muscle cell (SMC hyper-activity and proliferation leading to pulmonary arterial hypertension (PAH. In addition, Propylthiouracil (PTU, beyond its anti-thyroid action, has suppressive effects on atherosclerosis and PAH. Here, we investigated the possible involvement of gamma-secretase-mediated Notch3 signaling in PTU-inhibited PAH. In rats with monocrotaline-induced PAH, PTU therapy improved pulmonary arterial hypertrophy and hemodynamics. In vitro, treatment of PASMCs from monocrotaline-treated rats with PTU inhibited their proliferation and migration. Immunocyto, histochemistry, and western blot showed that PTU treatment attenuated the activation of Notch3 signaling in PASMCs from monocrotaline-treated rats, which was mediated via inhibition of gamma-secretase expression especially its presenilin enhancer 2 (Pen-2 subunit. Furthermore, over-expression of Pen-2 in PASMCs from control rats increased the capacity of migration, whereas knockdown of Pen-2 with its respective siRNA in PASMCs from monocrotaline-treated rats had an opposite effect. Transfection of PASMCs from monocrotaline-treated rats with Pen-2 siRNA blocked the inhibitory effect of PTU on PASMC proliferation and migration, reflecting the crucial role of Pen-2 in PTU effect. We present a novel cell-signaling paradigm in which overexpression of Pen-2 is essential for experimental pulmonary arterial hypertension to promote motility and growth of smooth muscle cells. Propylthiouracil attenuates experimental PAH via suppression of the gamma-secretase-mediated Notch3 signaling especially its presenilin enhancer 2 (Pen-2 subunit. These findings provide a deep insight into the pathogenesis of PAH and a novel therapeutic strategy.

Pulmonary capillary pressure in pulmonary hypertension.

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Souza, Rogerio; Amato, Marcelo Britto Passos; Demarzo, Sergio Eduardo; Deheinzelin, Daniel; Barbas, Carmen Silvia Valente; Schettino, Guilherme Paula Pinto; Carvalho, Carlos Roberto Ribeiro

2005-04-01

Pulmonary capillary pressure (PCP), together with the time constants of the various vascular compartments, define the dynamics of the pulmonary vascular system. Our objective in the present study was to estimate PCPs and time constants of the vascular system in patients with idiopathic pulmonary arterial hypertension (IPAH), and compare them with these measures in patients with acute respiratory distress syndrome (ARDS). We conducted the study in two groups of patients with pulmonary hypertension: 12 patients with IPAH and 11 with ARDS. Four methods were used to estimate the PCP based on monoexponential and biexponential fitting of pulmonary artery pressure decay curves. PCPs in the IPAH group were considerably greater than those in the ARDS group. The PCPs measured using the four methods also differed significantly, suggesting that each method measures the pressure at a different site in the pulmonary circulation. The time constant for the slow component of the biexponential fit in the IPAH group was significantly longer than that in the ARDS group. The PCP in IPAH patients is greater than normal but methodological limitations related to the occlusion technique may limit interpretation of these data in isolation. Different disease processes may result in different times for arterial emptying, with resulting implications for the methods available for estimating PCP.

Pulmonary edema

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... congestion; Lung water; Pulmonary congestion; Heart failure - pulmonary edema ... Pulmonary edema is often caused by congestive heart failure . When the heart is not able to pump efficiently, blood ...

Smooth and non-smooth travelling waves in a nonlinearly dispersive Boussinesq equation

International Nuclear Information System (INIS)

Shen Jianwei; Xu Wei; Lei Youming

2005-01-01

The dynamical behavior and special exact solutions of nonlinear dispersive Boussinesq equation (B(m,n) equation), u tt -u xx -a(u n ) xx +b(u m ) xxxx =0, is studied by using bifurcation theory of dynamical system. As a result, all possible phase portraits in the parametric space for the travelling wave system, solitary wave, kink and anti-kink wave solutions and uncountably infinite many smooth and non-smooth periodic wave solutions are obtained. It can be shown that the existence of singular straight line in the travelling wave system is the reason why smooth waves converge to cusp waves, finally. When parameter are varied, under different parametric conditions, various sufficient conditions guarantee the existence of the above solutions are given

Reversal of reflex pulmonary vasoconstriction induced by main pulmonary arterial distension.

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Juratsch, C E; Grover, R F; Rose, C E; Reeves, J T; Walby, W F; Laks, M M

1985-04-01

Distension of the main pulmonary artery (MPA) induces pulmonary hypertension, most probably by neurogenic reflex pulmonary vasoconstriction, although constriction of the pulmonary vessels has not actually been demonstrated. In previous studies in dogs with increased pulmonary vascular resistance produced by airway hypoxia, exogenous arachidonic acid has led to the production of pulmonary vasodilator prostaglandins. Hence, in the present study, we investigated the effect of arachidonic acid in seven intact anesthetized dogs after pulmonary vascular resistance was increased by MPA distention. After steady-state pulmonary hypertension was established, arachidonic acid (1.0 mg/min) was infused into the right ventricle for 16 min; 15-20 min later a 16-mg bolus of arachidonic acid was injected. MPA distension was maintained throughout the study. Although the infusion of arachidonic acid significantly lowered the elevated pulmonary vascular resistance induced by MPA distension, the pulmonary vascular resistance returned to control levels only after the bolus injection of arachidonic acid. Notably, the bolus injection caused a biphasic response which first increased the pulmonary vascular resistance transiently before lowering it to control levels. In dogs with resting levels of pulmonary vascular resistance, administration of arachidonic acid in the same manner did not alter the pulmonary vascular resistance. It is concluded that MPA distension does indeed cause reflex pulmonary vasoconstriction which can be reversed by vasodilator metabolites of arachidonic acid. Even though this reflex may help maintain high pulmonary vascular resistance in the fetus, its function in the adult is obscure.

A Novel Genomic Signature with Translational Significance for Human Idiopathic Pulmonary Fibrosis

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Tedrow, John; de Bernard, Simon; Birker-Robaczewska, Magdalena; Gibson, Kevin F.; Guardela, Brenda Juan; Hess, Patrick; Klenk, Axel; Lindell, Kathleen O.; Poirey, Sylvie; Renault, Bérengère; Rey, Markus; Weber, Edgar; Nayler, Oliver; Kaminski, Naftali

2015-01-01

The bleomycin-induced rodent lung fibrosis model is commonly used to study mechanisms of lung fibrosis and to test potential therapeutic interventions, despite the well recognized dissimilarities to human idiopathic pulmonary fibrosis (IPF). Therefore, in this study, we sought to identify genomic commonalities between the gene expression profiles from 100 IPF lungs and 108 control lungs that were obtained from the Lung Tissue Research Consortium, and rat lungs harvested at Days 3, 7, 14, 21, 28, 42, and 56 after bleomycin instillation. Surprisingly, the highest gene expression similarity between bleomycin-treated rat and IPF lungs was observed at Day 7. At this point of maximal rat–human commonality, we identified a novel set of 12 disease-relevant translational gene markers (C6, CTHRC1, CTSE, FHL2, GAL, GREM1, LCN2, MMP7, NELL1, PCSK1, PLA2G2A, and SLC2A5) that was able to separate almost all patients with IPF from control subjects in our cohort and in two additional IPF/control cohorts (GSE10667 and GSE24206). Furthermore, in combination with diffusing capacity of carbon monoxide measurements, four members of the translational gene marker set contributed to stratify patients with IPF according to disease severity. Significantly, pirfenidone attenuated the expression change of one (CTHRC1) translational gene marker in the bleomycin-induced lung fibrosis model, in transforming growth factor-β1–treated primary human lung fibroblasts and transforming growth factor-β1–treated human epithelial A549 cells. Our results suggest that a strategy focused on rodent model–human disease commonalities may identify genes that could be used to predict the pharmacological impact of therapeutic interventions, and thus facilitate the development of novel treatments for this devastating lung disease. PMID:25029475

Pulmonary tuberculosis

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TB; Tuberculosis - pulmonary; Mycobacterium - pulmonary ... Pulmonary TB is caused by the bacterium Mycobacterium tuberculosis (M tuberculosis) . TB is contagious. This means the bacteria is easily spread from an infected person ...

Differential expression of caveolin-1 in human myometrial and uterine leiomyoma smooth muscle.

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Zhou, Yu; Ren, Yuanyuan; Cui, Lihua; Li, Zongjin; Zhu, Yingjun; Lin, Wanjun; Wang, Yuebing

2014-11-01

Uterine leiomyomas, the most common neoplasms of the female genital tract, are benign tumors of the uterus arising from the smooth muscle cells (SMCs) of the myometrium with an involvement of estrogen. Caveolin-1 (Cav-1), a major protein component in caveolae membrane lipid rafts, is down-regulated in several estrogen-related cancer cells, and overexpression of Cav-1 inhibits proliferation of cancer cells and vascular SMCs as well. Therefore, we hypothesize that Cav-1 is down-regulated in human uterine leiomyoma. Western blot using tissues from clinical patients showed that Cav-1 expression was significantly lower or undetectable in uterine leiomyoma compared with their matched myometrium (P leiomyomas was also significantly lower as detected by reverse transcription-quantitative polymerase chain reaction analysis (P = .001). To further study the underlying mechanism, we performed primary cell culture, and found that the expression of Cav-1 remained low in cultured leiomyoma SMCs (P = .009). Serum withdrawal did not change Cav-1 expression in leiomyoma SMCs, but increased expression in myometrial SMCs (P = .006). 17-β estradiol inhibited the expression of Cav-1 protein (P = .047) and mRNA (P = .007) in leiomyoma SMCs, whereas it stimulated expression in myometrial SMCs (P = .043). 17-β estradiol, although activating the mitogen-activated protein kinase pathway in both SMCs, did not stimulate their proliferation. We conclude that human uterine leiomyomas in vitro express low levels of Cav-1, which may result from estrogen inhibition. This effect of estrogen may contribute to the pathogenesis of uterine leiomyoma. Further studies in vivo are needed to verify these results. Copyright © 2014 Elsevier Inc. All rights reserved.

Fetal human airway smooth muscle cell production of leukocyte chemoattractants is differentially regulated by fluticasone.

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Pearson, Helen; Britt, Rodney D; Pabelick, Christine M; Prakash, Y S; Amrani, Yassine; Pandya, Hitesh C

2015-12-01

Adult human airway smooth muscle (ASM) produce cytokines involved in recruitment and survival of leukocytes within airway walls. Cytokine generation by adult ASM is glucocorticoid-sensitive. Whether developing lung ASM produces cytokines in a glucocorticoid-sensitive fashion is unknown. Cultured fetal human ASM cells stimulated with TNF-α (0-20 ng/ml) were incubated with TNF-α receptor-blocking antibodies, fluticasone (1 and 100 nm), or vehicle. Supernatants and cells were assayed for the production of CCL5, CXCL10, and CXCL8 mRNA and protein and glucocorticoid receptor phosphorylation. CCL5, CXCL10, and CXCL8 mRNA and protein production by fetal ASM cell was significantly and dose-dependently following TNF-α treatment. Cytokine mRNA and protein production were effectively blocked by TNF-α R1 and R2 receptor neutralizing antibodies but variably inhibited by fluticasone. TNF-α-induced TNF-R1 and R2 receptor mRNA expression was only partially attenuated by fluticasone. Glucocorticoid receptor phosphorylation at serine (Ser) 211 but not at Ser 226 was enhanced by fluticasone. Production of CCL5, CXCL10, and CXCL8 by fetal ASM appears to involve pathways that are both qualitatively and mechanistically distinct to those described for adult ASM. The findings imply developing ASM has potential to recruit leukocyte into airways and, therefore, of relevance to childhood airway diseases.

Birth weight and characteristics of endothelial and smooth muscle cell cultures from human umbilical cord vessels

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Lurbe Empar

2009-04-01

Full Text Available Abstract Background Low birth weight has been related to an increased risk for developing high blood pressure in adult life. The molecular and cellular analysis of umbilical cord artery and vein may provide information about the early vascular characteristics of an individual. We have assessed several phenotype characteristics of the four vascular cell types derived from human umbilical cords of newborns with different birth weight. Further follow-up studies could show the association of those vascular properties with infancy and adulthood blood pressure. Methods Endothelial and smooth muscle cell cultures were obtained from umbilical cords from two groups of newborns of birth weight less than 2.8 kg or higher than 3.5 kg. The expression of specific endothelial cell markers (von Willebrand factor, CD31, and the binding and internalization of acetylated low-density lipoprotein and the smooth muscle cell specific α-actin have been evaluated. Cell culture viability, proliferation kinetic, growth fraction (expression of Ki67 and percentage of senescent cells (detection of β-galactosidase activity at pH 6.0 have been determined. Endothelial cell projection area was determined by morphometric analysis of cell cultures after CD31 immunodetection. Results The highest variation was found in cell density at the confluence of endothelial cell cultures derived from umbilical cord arteries (66,789 ± 5,093 cells/cm2 vs. 45,630 ± 11,927 cells/cm2, p 2, p Conclusion The analysis of umbilical cord artery endothelial cells, which demonstrated differences in cell size related to birth weight, can provide hints about the cellular and molecular links between lower birth weight and increased adult high blood pressure risk.

Identification of G-Protein-Coupled Receptors (GPCRs) in Pulmonary Artery Smooth Muscle Cells as Novel Therapeutic Targets

Science.gov (United States)

2017-10-01

who do not have pulmonary hypertension (PH) Completed 12/2015 lb. Prepare RNA and cDNA from PASMCs and use Taqman GPCR arrays to identify and quantify...expression of GPCRs with known physiologic agonists .Completed 5/2017 le. Prepare RNA and cDNA from commercially available coronary artery and...Isolate and culture PASMCs from 8 (4 male; 4 female) 3 -month old rats and mice, prepare RNA and cDNA and assess expression of GPCRs with known

Resembling a viper: implications of mimicry for conservation of the endangered smooth snake.

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Valkonen, Janne K; Mappes, Johanna

2014-12-01

The phenomenon of Batesian mimicry, where a palatable animal gains protection against predation by resembling an unpalatable model, has been a core interest of evolutionary biologists for 150 years. An extensive range of studies has focused on revealing mechanistic aspects of mimicry (shared education and generalization of predators) and the evolutionary dynamics of mimicry systems (co-operation vs. conflict) and revealed that protective mimicry is widespread and is important for individual fitness. However, according to our knowledge, there are no case studies where mimicry theories have been applied to conservation of mimetic species. Theoretically, mimicry affects, for example, frequency dependency of predator avoidance learning and human induced mortality. We examined the case of the protected, endangered, nonvenomous smooth snake (Coronella austriaca) that mimics the nonprotected venomous adder (Vipera berus), both of which occur in the Åland archipelago, Finland. To quantify the added predation risk on smooth snakes caused by the rarity of vipers, we calculated risk estimates from experimental data. Resemblance of vipers enhances survival of smooth snakes against bird predation because many predators avoid touching venomous vipers. Mimetic resemblance is however disadvantageous against human predators, who kill venomous vipers and accidentally kill endangered, protected smooth snakes. We found that the effective population size of the adders in Åland is very low relative to its smooth snake mimic (28.93 and 41.35, respectively).Because Batesian mimicry is advantageous for the mimic only if model species exist in sufficiently high numbers, it is likely that the conservation program for smooth snakes will fail if adders continue to be destroyed. Understanding the population consequences of mimetic species may be crucial to the success of endangered species conservation. We suggest that when a Batesian mimic requires protection, conservation planners should

Targeting Interleukin-13 with Tralokinumab Attenuates Lung Fibrosis and Epithelial Damage in a Humanized SCID Idiopathic Pulmonary Fibrosis Model

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Zhang, Huilan; Oak, Sameer R.; Coelho, Ana Lucia; Herath, Athula; Flaherty, Kevin R.; Lee, Joyce; Bell, Matt; Knight, Darryl A.; Martinez, Fernando J.; Sleeman, Matthew A.; Herzog, Erica L.; Hogaboam, Cory M.

2014-01-01

The aberrant fibrotic and repair responses in the lung are major hallmarks of idiopathic pulmonary fibrosis (IPF). Numerous antifibrotic strategies have been used in the clinic with limited success, raising the possibility that an effective therapeutic strategy in this disease must inhibit fibrosis and promote appropriate lung repair mechanisms. IL-13 represents an attractive target in IPF, but its disease association and mechanism of action remains unknown. In the present study, an overexpression of IL-13 and IL-13 pathway markers was associated with IPF, particularly a rapidly progressive form of this disease. Targeting IL-13 in a humanized experimental model of pulmonary fibrosis using tralokinumab (CAT354) was found to therapeutically block aberrant lung remodeling in this model. However, targeting IL-13 was also found to promote lung repair and to restore epithelial integrity. Thus, targeting IL-13 inhibits fibrotic processes and enhances repair processes in the lung. PMID:24325475

Balloon Pulmonary Angioplasty in Chronic Thromboembolic Pulmonary Hypertension: New Horizons in the Interventional Management of Pulmonary Embolism.

Science.gov (United States)

Rivers-Bowerman, Michael D; Zener, Rebecca; Jaberi, Arash; de Perrot, Marc; Granton, John; Moriarty, John M; Tan, Kong T

2017-09-01

Chronic thromboembolic pulmonary hypertension (CTEPH) is an underdiagnosed potential complication of acute or recurrent pulmonary thromboembolic disease. Multiple studies suggest that up to 5% of patients with acute pulmonary thromboembolic disease go on to develop CTEPH. The prognosis of untreated CTEPH is poor, but advances in medical and surgical treatments over the past few decades have improved patient outcomes. The gold standard and curative treatment for CTEPH is pulmonary endarterectomy; however, some patients are inoperable and others who have undergone pulmonary endarterectomy experience persistent or recurrent pulmonary hypertension despite medical therapy. In recent years, balloon pulmonary angioplasty has emerged as a primary and adjunctive treatment for these CTEPH patients at expert or specialized centers. This review outlines an approach to balloon pulmonary angioplasty for CTEPH, including clinical presentation and evaluation; patient selection and indications; treatment planning; equipment and technique; overcoming technical challenges; recognition and management of complications; postprocedural care and clinical follow-up; and expected outcomes. Copyright © 2017 Elsevier Inc. All rights reserved.

Pulmonary lymphangioleiomyomatosis as a pulmonary manifestation of tuberous sclerosis - a case report-

International Nuclear Information System (INIS)

Lee, Young Rahn; Kang, Eun Young; Lee, Nam Joon; Suh, Won Hyuck

1991-01-01

Pulmonary lymphangioleiomyomatosis is a very rare disease mainly arising in reproductive-aged women. Pulmonary lymphangioleiomyomatosis as a pulmonary involvement of tuberous sclerosis is found in only 1 out of 100 patients. Pulmonary involvement in pulmonary lymphangioleiomyomatosis itself and that as a pulmonary manifestation of tuberous sclerosis has been considered very similar with regard to clinical, radiologic, and pathologic manifestations. We report 1 case of pulmonary lymphangioleiomyomatosis as a pulmonary manifestation of tuberous sclerosis in a 39-year-old Korean woman

Adiponectin attenuates lung fibroblasts activation and pulmonary fibrosis induced by paraquat.

Science.gov (United States)

Yao, Rong; Cao, Yu; He, Ya-rong; Lau, Wayne Bond; Zeng, Zhi; Liang, Zong-an

2015-01-01

Pulmonary fibrosis is one of the most common complications of paraquat (PQ) poisoning, which demands for more effective therapies. Accumulating evidence suggests adiponectin (APN) may be a promising therapy against fibrotic diseases. In the current study, we determine whether the exogenous globular APN isoform protects against pulmonary fibrosis in PQ-treated mice and human lung fibroblasts, and dissect the responsible underlying mechanisms. BALB/C mice were divided into control group, PQ group, PQ + low-dose APN group, and PQ + high-dose APN group. Mice were sacrificed 3, 7, 14, and 21 days after PQ treatment. We compared pulmonary histopathological changes among different groups on the basis of fibrosis scores, TGF-β1, CTGF and α-SMA pulmonary content via Western blot and real-time quantitative fluorescence-PCR (RT-PCR). Blood levels of MMP-9 and TIMP-1 were determined by ELISA. Human lung fibroblasts WI-38 were divided into control group, PQ group, APN group, and APN receptor (AdipoR) 1 small-interfering RNA (siRNA) group. Fibroblasts were collected 24, 48, and 72 hours after PQ exposure for assay. Cell viability and apoptosis were determined via Kit-8 (CCK-8) and fluorescein Annexin V-FITC/PI double labeling. The protein and mRNA expression level of collagen type III, AdipoR1, and AdipoR2 were measured by Western blot and RT-PCR. APN treatment significantly decreased the lung fibrosis scores, protein and mRNA expression of pulmonary TGF-β1, CTGF and α-SMA content, and blood MMP-9 and TIMP-1 in a dose-dependent manner (ppulmonary fibrosis in a dose-dependent manner, via suppression of lung fibroblast activation. Functional AdipoR1 are expressed by human WI-38 lung fibroblasts, suggesting potential future clinical applicability of APN against pulmonary fibrosis.

Plasma-derived human C1-esterase inhibitor does not prevent mechanical ventilation-induced pulmonary complement activation in a rat model of Streptococcus pneumoniae pneumonia

NARCIS (Netherlands)

de Beer, F. M.; Aslami, H.; Hoeksma, J.; van Mierlo, G.; Wouters, D.; Zeerleder, S.; Roelofs, J. J. T. H.; Juffermans, N. P.; Schultz, M. J.; Lagrand, W. K.

2014-01-01

Mechanical ventilation has the potential to cause lung injury, and the role of complement activation herein is uncertain. We hypothesized that inhibition of the complement cascade by administration of plasma-derived human C1-esterase inhibitor (C1-INH) prevents ventilation-induced pulmonary

Vascular smooth muscle modulates endothelial control of vasoreactivity via reactive oxygen species production through myoendothelial communications.

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Marie Billaud

Full Text Available BACKGROUND: Endothelial control of vascular smooth muscle plays a major role in the resulting vasoreactivity implicated in physiological or pathological circulatory processes. However, a comprehensive understanding of endothelial (EC/smooth muscle cells (SMC crosstalk is far from complete. Here, we have examined the role of gap junctions and reactive oxygen species (ROS in this crosstalk and we demonstrate an active contribution of SMC to endothelial control of vasomotor tone. METHODOLOGY/PRINCIPAL FINDINGS: In small intrapulmonary arteries, quantitative RT-PCR, Western Blot analyses and immunofluorescent labeling evidenced connexin (Cx 37, 40 and 43 in EC and/or SMC. Functional experiments showed that the Cx-mimetic peptide targeted against Cx 37 and Cx 43 ((37,43Gap27 (1 reduced contractile and calcium responses to serotonin (5-HT simultaneously recorded in pulmonary arteries and (2 abolished the diffusion in SMC of carboxyfluorescein-AM loaded in EC. Similarly, contractile and calcium responses to 5-HT were decreased by superoxide dismutase and catalase which, catabolise superoxide anion and H(2O(2, respectively. Both Cx- and ROS-mediated effects on the responses to 5-HT were reversed by L-NAME, a NO synthase inhibitor or endothelium removal. Electronic paramagnetic resonance directly demonstrated that 5-HT-induced superoxide anion production originated from the SMC. Finally, whereas 5-HT increased NO production, it also decreased cyclic GMP content in isolated intact arteries. CONCLUSIONS/SIGNIFICANCE: These data demonstrate that agonist-induced ROS production in SMC targeting EC via myoendothelial gap junctions reduces endothelial NO-dependent control of pulmonary vasoreactivity. Such SMC modulation of endothelial control may represent a signaling pathway controlling vasoreactivity under not only physiological but also pathological conditions that often implicate excessive ROS production.

Preliminary studies of pulmonary perfusion scanning in patients with pulmonary hypertension

International Nuclear Information System (INIS)

Shi Rongfang; Liu Xiujie; Wang Yanqun

1986-01-01

A comparative analysis of pulmonary perfusion scanning through cardiac catheterization of 57 patients including 32 patients with congenital heart disease, 8 patients with chronic pulmonary thromboembolism and 7 patients with primary pulmonary hypertension is reported. The lung scintigram obtained with In-113m or Tc-99m-MAA represents the distribution of pulmonary blood. It has been found that the lung scintigram was abnormal in patients of congenital heart disease with pulmonary hypertension (i. e. pulmonary artery pressure between 41-80 mmHg) and the extent of radoiactive regional defects is proportional to the level of pulmonary hypertension. The results of the analysis indicated that pulmonary perfusion scanning being a noninvasive technique would be a useful method in evaluating the level of pulmonary hypertension in patients with left to right shunt before and after surgical operation

Effect of connective tissue growth factor (CTGF) expression on radiation pulmonary fibrosis in rats

International Nuclear Information System (INIS)

Huang Shanying; Song Liangwen; Zhang Yong; Sun Li; Li Yang

2005-01-01

Objective: To explore the effect of connective tissue growth factor (CTGF) on initiation of radiation pulmonary fibrosis (RPF) and the relation to α-smooth muscle actin (α-SMA). Methods: The promotive effect of CTGF on proliferation of human lung fibroblasts (HLF) by 5 Gy of 60 Co γ-rays was determined by MTT colorimetry. The expressions of CTGF and α-SMA in HLF were observed by Western blot. Changes of collagen I and III in rat lungs were determined by Sirius red staining and polarization microscopy. Expressions of CTGF and α-SMA in RPF were observed with immunohisto-chemistry and analysis. Results: Expressions of CTGF and α-SMA were increased. CTGF reached its peak at 24 h after irradiation, whereas α-SMA still kept at a high level 72 h after irradiation. A small amount of collagen was produced in rat lung one month after irradiation, in which type III collagen was the primary component. However, a large amount of collagen was produced in rat lung 3-6 months after irradiation, in which type I was dominant. CTGF began to expression 1 week after irradiation in proliferative fibroblasts of rat lung, and it was most evident 3 months after irradiation. α-SMA began to express in proliferative myofibroblasts 1 week after irradiation, and the high peek was reached at 3 months after irradiation. Conclusion: Irradiation can induce expression of CTGF in pulmonary tissue and the later can promote the transformation of fibroblasts to myofibroblasts, strengthen the ability of synthesis and secretion of type I and III collagen. (authors)

Transport mechanisms at the pulmonary mucosa: implications for drug delivery.

Science.gov (United States)

Nickel, Sabrina; Clerkin, Caoimhe G; Selo, Mohammed Ali; Ehrhardt, Carsten

2016-01-01

Over the past years, a significant number of papers have substantiated earlier findings proposing a role for drug transporter proteins in pulmonary drug disposition. Whilst the majority of reports present data from in vitro models, a growing number of publications advance the field by introducing sophisticated ex vivo and in vivo techniques. In a few cases, evidence from clinical studies in human volunteers is complementing the picture. In this review, recent advances in pulmonary drug transporter research are critically evaluated. Transporter expression data in tissues and cell-based in vitro models is summarized and information on transport activity assessed. Novel techniques allowing for better quantification of transporter-related effects following pulmonary delivery are also described. Different tissue and cell populations of the lung have distinct transporter expression patterns. Whether these patterns are affected by disease, gender and smoking habits requires further clarification. Transporters have been found to have an impact on drug absorption processes, at least in vitro. Recent ex vivo experiments using isolated, perfused lung models, however, suggest that mainly efflux pumps have significant effects on absorption into the pulmonary circulation. Whether these rodent-based ex vivo models predict the human situation is basis for further research.

Axial flow velocity patterns in a normal human pulmonary artery model: pulsatile in vitro studies.

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Sung, H W; Yoganathan, A P

1990-01-01

It has been clinically observed that the flow velocity patterns in the pulmonary artery are directly modified by disease. The present study addresses the hypothesis that altered velocity patterns relate to the severity of various diseases in the pulmonary artery. This paper lays a foundation for that analysis by providing a detailed description of flow velocity patterns in the normal pulmonary artery, using flow visualization and laser Doppler anemometry techniques. The studies were conducted in an in vitro rigid model in a right heart pulse duplicator system. In the main pulmonary artery, a broad central flow field was observed throughout systole. The maximum axial velocity (150 cm s-1) was measured at peak systole. In the left pulmonary artery, the axial velocities were approximately evenly distributed in the perpendicular plane. However, in the bifurcation plane, they were slightly skewed toward the inner wall at peak systole and during the deceleration phase. In the right pulmonary artery, the axial velocity in the perpendicular plane had a very marked M-shaped profile at peak systole and during the deceleration phase, due to a pair of strong secondary flows. In the bifurcation plane, higher axial velocities were observed along the inner wall, while lower axial velocities were observed along the outer wall and in the center. Overall, relatively low levels of turbulence were observed in all the branches during systole. The maximum turbulence intensity measured was at the boundary of the broad central flow field in the main pulmonary artery at peak systole.

multiscale smoothing in supervised statistical learning

Indian Academy of Sciences (India)

Optimum level of smoothing is chosen based on the entire training sample, while a good choice of smoothing parameter may also depend on the observation to be classified. One may like to assess the strength of evidence in favor of different competing class at different scale of smoothing. In allows only one single ...

Solitary pulmonary nodule by pulmonary hematoma under warfarin therapy

International Nuclear Information System (INIS)

Scheppach, W.; Kulke, H.; Liebau, G.; Braun, H.; Wuerzburg Univ.

1983-01-01

Pulmonary hematoma is a rare cause of a pulmonary nodule. Mostly it results from penetrating or blunt chest injuries. The case of a patient is reported, whose chest X-ray showed a pulmonary nodule suspected of malignancy. This patient was maintained permanently on anticoagulants (warfarin derivates) after cardiac valve replacement with a prosthesis. A definite diagnosis could not be established by non-invasive methods. A needle biopsy of the lung was impracticable because of the location of the pulmonary lesion; an exploratory thoracotomy could not be carried out due to a general indication of nonoperability. Control examinations showed that the pulmonary nodule had vanished completely within four months. In consideration of the patient's clinical situation it can be concluded that the pulmonary lesion was caused by a hematoma of the lung. (orig.) [de

Solitary pulmonary nodule by pulmonary hematoma under warfarin therapy

Energy Technology Data Exchange (ETDEWEB)

Scheppach, W.; Kulke, H.; Liebau, G.; Braun, H.

1983-06-01

Pulmonary hematoma is a rare cause of a pulmonary nodule. Mostly it results from penetrating or blunt chest injuries. The case of a patient is reported, whose chest X-ray showed a pulmonary nodule suspected of malignancy. This patient was maintained permanently on anticoagulants (warfarin derivates) after cardiac valve replacement with a prosthesis. A definite diagnosis could not be established by non-invasive methods. A needle biopsy of the lung was impracticable because of the location of the pulmonary lesion; an exploratory thoracotomy could not be carried out due to a general indication of nonoperability. Control examinations showed that the pulmonary nodule had vanished completely within four months. In consideration of the patient's clinical situation it can be concluded that the pulmonary lesion was caused by a hematoma of the lung.

A Primary Pulmonary Glomus Tumor: A Case Report and Review of the Literature

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Yasushi Ariizumi

2012-01-01

Full Text Available A case of a glomus tumor originating from the lung is reported. A 43-year-old female had undergone resection of a right lung tumor following a clinical diagnosis of carcinoid, sclerosing hemangioma, or other sarcoma. Histologically, the tumor comprised uniform small round to oval cells with centrally located nucleus, a clear cytoplasm, and apparent cell borders. The tumor also showed a focally hemangiopericytomatous pattern with irregularly branching or dilated vessels. Electron microscopy revealed smooth muscle differentiation of the tumor cells. Immunostaining further revealed that the tumor cells expressed smooth muscle actin, h-caldesmon, muscle specific actin (HHF-35, but not cytokeratin, epithelial membrane antigen, synaptophysin, or chromogranin A. Based on these findings, a diagnosis of primary pulmonary glomus tumor was established. Glomus tumors of the lung are very rare and only 21 cases have been reported to date. The histological features of the present tumor and the relevant literature are discussed.

Valsartan attenuates pulmonary hypertension via suppression of mitogen activated protein kinase signaling and matrix metalloproteinase expression in rodents.

Science.gov (United States)

Lu, Yuyan; Guo, Haipeng; Sun, Yuxi; Pan, Xin; Dong, Jia; Gao, Di; Chen, Wei; Xu, Yawei; Xu, Dachun

2017-08-01

It has previously been demonstrated that the renin-angiotensin system is involved in the pathogenesis and development of pulmonary hypertension (PH). However, the efficacy of angiotensin II type I (AT1) receptor blockers in the treatment of PH is variable. The present study examined the effects of the AT1 receptor blocker valsartan on monocrotaline (MCT)‑induced PH in rats and chronic hypoxia‑induced PH in mice. The results demonstrated that valsartan markedly attenuated development of PH in rats and mice, as indicated by reduced right ventricular systolic pressure, diminished lung vascular remodeling and decreased right ventricular hypertrophy, compared with vehicle treated animals. Immunohistochemical analyses of proliferating cell nuclear antigen expression revealed that valsartan suppressed smooth muscle cell proliferation. Western blot analysis demonstrated that valsartan limited activation of p38, c‑Jun N‑terminal kinase 1/2 and extracellular signal‑regulated kinase 1/2 signaling pathways and significantly reduced MCT‑induced upregulation of pulmonary matrix metalloproteinases‑2 and ‑9, and transforming growth factor‑β1 expression. The results suggested that valsartan attenuates development of PH in rodents by reducing expression of extracellular matrix remodeling factors and limiting smooth muscle cell proliferation to decrease pathological vascular remodeling. Therefore, valsartan may be a valuable future therapeutic approach for the treatment of PH.

Smoothness of limit functors

Indian Academy of Sciences (India)

Abstract. Let S be a scheme. Assume that we are given an action of the one dimen- sional split torus Gm,S on a smooth affine S-scheme X. We consider the limit (also called attractor) subfunctor Xλ consisting of points whose orbit under the given action. 'admits a limit at 0'. We show that Xλ is representable by a smooth ...

Transit of micro-bubbles through the pulmonary circulation of Thoroughbred horses during exercise.

Science.gov (United States)

La Gerche, A; Daffy, J R; Mooney, D J; Forbes, G; Davie, A J

2013-10-01

It has been observed that microbubbles may pass through the pulmonary circulation of dogs and humans during exercise. In humans, this phenomenon has been associated with lower pulmonary artery pressures, enhanced right ventricular function and greater exercise capacity. In the exercising Thoroughbred horse, extraordinarily high cardiac outputs exert significant pulmonary vascular stresses. The aim of this study was to determine, using contrast echocardiography, whether Thoroughbred horses performing strenuous exercise developed pulmonary transit of agitated contrast microbubbles (PTAC). At rest, agitated contrast was observed in the right ventricle, but not in the left ventricle. However, post-exercise microbubbles were observed in the left ventricle, confirming the occurrence of PTAC with exercise but not at rest. Further investigation is warranted to investigate whether this phenomenon may be associated with superior physiology and performance measures as has been implicated in other species. Copyright © 2013 Elsevier Ltd. All rights reserved.

Introduction to Pulmonary Fibrosis

Science.gov (United States)

... page: Introduction to Pulmonary Fibrosis What Is Pulmonary Fibrosis? Pulmonary fibrosis is a disease where there is scarring ... of pulmonary fibrosis. Learn more How Is Pulmonary Fibrosis Diagnosed? Pulmonary fibrosis can be difficult to diagnose, so it ...

Cytoskeletal defects in Bmpr2-associated pulmonary arterial hypertension.

Science.gov (United States)

Johnson, Jennifer A; Hemnes, Anna R; Perrien, Daniel S; Schuster, Manfred; Robinson, Linda J; Gladson, Santhi; Loibner, Hans; Bai, Susan; Blackwell, Tom R; Tada, Yuji; Harral, Julie W; Talati, Megha; Lane, Kirk B; Fagan, Karen A; West, James

2012-03-01

The heritable form of pulmonary arterial hypertension (PAH) is typically caused by a mutation in bone morphogenic protein receptor type 2 (BMPR2), and mice expressing Bmpr2 mutations develop PAH with features similar to human disease. BMPR2 is known to interact with the cytoskeleton, and human array studies in PAH patients confirm alterations in cytoskeletal pathways. The goal of this study was to evaluate cytoskeletal defects in BMPR2-associated PAH. Expression arrays on our Bmpr2 mutant mouse lungs revealed cytoskeletal defects as a prominent molecular consequence of universal expression of a Bmpr2 mutation (Rosa26-Bmpr2(R899X)). Pulmonary microvascular endothelial cells cultured from these mice have histological and functional cytoskeletal defects. Stable transfection of different BMPR2 mutations into pulmonary microvascular endothelial cells revealed that cytoskeletal defects are common to multiple BMPR2 mutations and are associated with activation of the Rho GTPase, Rac1. Rac1 defects are corrected in cell culture and in vivo through administration of exogenous recombinant human angiotensin-converting enzyme 2 (rhACE2). rhACE2 reverses 77% of gene expression changes in Rosa26-Bmpr2(R899X) transgenic mice, in particular, correcting defects in cytoskeletal function. Administration of rhACE2 to Rosa26-Bmpr2(R899X) mice with established PAH normalizes pulmonary pressures. Together, these findings suggest that cytoskeletal function is central to the development of BMPR2-associated PAH and that intervention against cytoskeletal defects may reverse established disease.

A Model of the Smooth Pursuit Eye Movement with Prediction and Learning

Directory of Open Access Journals (Sweden)

Davide Zambrano

2010-01-01

Full Text Available Smooth pursuit is one of the five main eye movements in humans, consisting of tracking a steadily moving visual target. Smooth pursuit is a good example of a sensory-motor task that is deeply based on prediction: tracking a visual target is not possible by correcting the error between the eye and the target position or velocity with a feedback loop, but it is only possible by predicting the trajectory of the target. This paper presents a model of smooth pursuit based on prediction and learning. It starts from amodel of the neuro-physiological system proposed by Shibata and Schaal (Shibata et al., Neural Networks, vol. 18, pp. 213-224, 2005. The learning component added here decreases the prediction time in the case of target dynamics already experienced by the system. In the implementation described here, the convergence time is, after the learning phase, 0.8 s.

Treatment of pulmonary brucellosis: a systematic review.

Science.gov (United States)

Solera, Javier; Solís García Del Pozo, Julián

2017-01-01

Pulmonary involvement is a rare, focal complication of human brucellosis. The aim of this review is to describe clinical and radiologic features, treatment administered and clinical course of these patients. Areas covered: We conducted a systematic search of scientific reports of brucellosis with pulmonary involvement published from January 1985 to July 2016. Four main patterns of disease were observed: pneumonia, pleural effusion, nodules and interstitial pattern. Cough and fever were the most common symptoms. Brucella spp. culture was obtained from blood (50%) or pleural fluid. Treatment is based on the same antibiotics and combinations of antibiotics as for patients with acute no complicated brucellosis. The most frequent antimicrobial combination was doxycycline and rifampin for six weeks. The clinical course was favorable in most reports, and mortality was remarkably low (Brucellosis from other pulmonary infections, such as tuberculosis, sometimes posed an added diagnostic challenge.

Bone morphogenetic proteins regulate osteoprotegerin and its ligands in human vascular smooth muscle cells

DEFF Research Database (Denmark)

Knudsen, Kirsten Quyen Nguyen; Olesen, Ping; Ledet, Thomas

2007-01-01

The bone-related protein osteoprotegerin (OPG) may be involved in the development of vascular calcifications, especially in diabetes, where it has been found in increased amounts in the arterial wall. Experimental studies suggest that members of the TGF-superfamily are involved in the transformat......The bone-related protein osteoprotegerin (OPG) may be involved in the development of vascular calcifications, especially in diabetes, where it has been found in increased amounts in the arterial wall. Experimental studies suggest that members of the TGF-superfamily are involved...... in the transformation of human vascular smooth muscle cells (HVSMC) to osteoblast-like cells. In this study, we evaluated the effect of BMP-2, BMP-7 and transforming growth factor beta (TGF-beta1) on the secretion and mRNA expression of OPG and its ligands receptor activator of nuclear factor-kappabeta ligand (RANKL......) and TNF-related apoptosis-inducing ligand (TRAIL) in HVSMC. All three growth factors decreased OPG protein production significantly; these results were paralleled by reduced OPG mRNA expression. TRAIL mRNA levels were also decreased. RANKL mRNA expression declined when treated with TGF-beta1 but were...

Measurement of pulmonary vascular resistance of Fontan candidates with pulmonary arterial distortion by means of pulmonary perfusion imaging

International Nuclear Information System (INIS)

Park, In-Sam; Mizukami, Ayumi; Tomimatsu, Hirofumi; Kondou, Chisato; Nakanishi, Toshio; Nakazawa, Makoto; Momma, Kazuo

1998-01-01

We measured the distribution of blood flow to the right (R) and left lung (L) by means of pulmonary perfusion imaging and calculated pulmonary vascular resistance (Rp) in 13 patients, whose right and left pulmonary artery pressures were different by 2 to 9 mmHg due to pulmonary arterial distortion (5 interruption, 8 stenosis). The right lung/left lung blood flow ratio was determined and from the ratio and the total pulmonary blood flow, which was determined using the Fick's principle, the absolute values of right and left pulmonary blood flow were calculated. Using the right and left pulmonary blood flow and the right and left pulmonary arterial pressures, right and left pulmonary vascular resistance were calculated, separately. Vascular resistance of the whole lung (Rp) was then calculated using the following equation. 1/(Rp of total lung)=1/(Rp of right lung)+1/(Rp of left lung). Rp calculated from this equation was 1.8+/-0.8 U·m 2 and all values were less than 3 U·m 2 (range 0.3-2.8). Rp estimated from the conventional method using the total pulmonary blood flow and pulmonary arterial pressures, without using the right/left blood flow ratio, ranging from 0.4 to 3.8 U·m 2 and 5 of 13 patients showed Rp>3 U·m 2 . All patients underwent Fontan operation successfully. These data indicated that this method is useful to estimate Rp and to determine the indication of Fontan operation in patients with pulmonary arterial distortions. (author)

Pulmonary Fibrosis Foundation

Science.gov (United States)

... submissions. MORE We Imagine a World Without Pulmonary Fibrosis The Pulmonary Fibrosis Foundation mobilizes people and resources to provide ... its battle against the deadly lung disease, pulmonary fibrosis (PF). PULMONARY FIBROSIS WALK SURPASSES PARTICIPATION AND FUNDRAISING GOALS Nearly ...

Increased oxidative stress and severe arterial remodeling induced by permanent high-flow challenge in experimental pulmonary hypertension

Directory of Open Access Journals (Sweden)

Fadel Elie

2011-09-01

Full Text Available Abstract Background Involvement of inflammation in pulmonary hypertension (PH has previously been demonstrated and recently, immune-modulating dendritic cells (DCs infiltrating arterial lesions in patients suffering from idiopathic pulmonary arterial hypertension (IPAH and in experimental monocrotaline-induced PH have been reported. Occurrence of perivascular inflammatory cells could be linked to local increase of oxidative stress (OS, as it has been shown for systemic atherosclerosis. The impact of OS on vascular remodeling in PH is still to be determined. We hypothesized, that augmented blood-flow could increase OS and might thereby contribute to DC/inflammatory cell-recruitment and smooth-muscle-cell-proliferation. Methods We applied a monocrotaline-induced PH-model and combined it with permanent flow-challenge. Thirty Sprague-Dawley rats were assigned to following groups: control, monocrotaline-exposure (MCT, monocrotaline-exposure/pneumonectomy (MCT/PE. Results Hemodynamic exploration demonstrated most severe effects in MCT/PE, corresponding in histology to exuberant medial and adventitial remodeling of pulmonary muscular arteries, and intimal remodeling of smaller arterioles; lung-tissue PCR evidenced increased expression of DCs-specific fascin, CD68, proinflammatory cytokines (IL-6, RANTES, fractalkine in MCT/PE and to a lesser extent in MCT. Major OS enzyme NOX-4 was maximal in MCT/PE. Antioxidative stress enzymes Mn-SOD and glutathion-peroxidase-1 were significantly elevated, while HO-1 showed maximal expression in MCT with significant decrease in MCT/PE. Catalase was decreased in MCT and MCT/PE. Expression of NOX-4, but also of MN-SOD in MCT/PE was mainly attributed to a highly increased number of interstitial and perivascular CXCR4/SDF1 pathway-recruited mast-cells. Stress markers malonedialdehyde and nitrotyrosine were produced in endothelial cells, medial smooth muscle and perivascular leucocytes of hypertensive vasculature

Pulmonary agenesis

OpenAIRE

Oyola, Mercedes; Pontificia Universidad Javeriana; Gordillo, Gisel; Pontificia Universidad Javeriana; García, Carlos A.; Pontificia Universidad Javeriana; Torres, David; Pontificia Universidad Javeriana

2009-01-01

Pulmonary agenesis is an infrequent pathology which occurs predominantly among females with no lateral preference. We report on the case of a newborn male diagnosed with prenatal diaphragm hernia though at birth seemed more likely either to be a congenital cystic adenomatoid malformation (congenital pulmonary airway malformation) or pulmonary agenesis. The patient died six days after birth and necropsy confirmed pulmonary agenesis. La agenesia pulmonar es una alteración poco frecuente, con...

Pulmonary Artery Dissection: A Fatal Complication of Pulmonary Hypertension

Directory of Open Access Journals (Sweden)

Chuanchen Zhang

2016-01-01

Full Text Available Pulmonary artery dissection is extremely rare but it is a really life-threatening condition when it happens. Most patients die suddenly from major bleeding or tamponade caused by direct rupture into mediastinum or retrograde into the pericardial sac. What we are reporting is a rare case of a 46-year-old female patient whose pulmonary artery dissection involves both the pulmonary valve and right pulmonary artery. The patient had acute chest pain and severe dyspnea, and the diagnosis of pulmonary artery dissection was confirmed by ultrasonography and CT angiography. Moreover, its etiology, clinical manifestations, and management are also discussed in this article.

Histamine receptors in human detrusor smooth muscle cells: physiological properties and immunohistochemical representation of subtypes.

Science.gov (United States)

Neuhaus, Jochen; Weimann, Annett; Stolzenburg, Jens-Uwe; Dawood, Waled; Schwalenberg, Thilo; Dorschner, Wolfgang

2006-06-01

The potent inflammatory mediator histamine is released from activated mast cells in interstitial cystitis (IC). Here, we report on the histamine receptor subtypes involved in the intracellular calcium response of cultured smooth muscle cells (cSMC). Fura-2 was used to monitor the calcium response in cSMC, cultured from human detrusor biopsies. The distribution of histamine receptor subtypes was addressed by immunocytochemistry in situ and in vitro. Histamine stimulated a maximum of 92% of the cells (n=335), being more effective than carbachol (70%, n=920). HTMT (H1R-agonist), dimaprit (H2R) and MTH (H3R) lead to significant lower numbers of reacting cells (60, 48 and 54%). Histamine receptor immunoreactivity (H1R, H2R, H3R, H4R) was found in situ and in vitro. Histamine-induced calcium increase is mediated by distinct histamine receptors. Thus, pre-therapeutic evaluation of histamine receptor expression in IC patients may help to optimize therapy by using a patient-specific cocktail of subtype-specific histamine receptor antagonists.

Lung beta-adrenoceptors in pulmonary hypertension. A study of biopsy specimens in children with congenital heart disease

International Nuclear Information System (INIS)

Lopes, A.A.; Liberato, M.H.; Brentani, M.M.; Aiello, V.D.; Riso, A.A.; Ebaid, M.

1991-01-01

Characteristics of beta-adrenoceptors were analyzed using radioligand-binding techniques with 3H-dihydroalprenolol in lung specimens from 11 children with pulmonary hypertension (median age, three years) undergoing surgical repair of congenital heart defects and four pediatric control subjects (median age, five years) undergoing thoracotomy for removal of neoplasms or cysts. Scatchard analysis of 3H-DHA binding to lung membranes showed similar values of the dissociation constant in both groups (Kd = 0.72 +/- 0.22 nM in patients vs 1.22 +/- 0.22 nM in controls; p = NS). The receptor density was significantly increased in patients in comparison with controls, with respective values of 164 +/- 19 and 95 +/- 13 fmol/mg of protein (p less than 0.025), and correlated directly with mean pulmonary arterial pressure (r = 0.82; p less than 0.0005). No significant relationship was observed between receptor number and pulmonary arterial medial thickness. Thus, the increase in receptor density in these patients may be related to adaptative changes in cells other than vascular smooth muscle

Calcium dynamics in vascular smooth muscle

OpenAIRE

Amberg, Gregory C.; Navedo, Manuel F.

2013-01-01

Smooth muscle cells are ultimately responsible for determining vascular luminal diameter and blood flow. Dynamic changes in intracellular calcium are a critical mechanism regulating vascular smooth muscle contractility. Processes influencing intracellular calcium are therefore important regulators of vascular function with physiological and pathophysiological consequences. In this review we discuss the major dynamic calcium signals identified and characterized in vascular smooth muscle cells....

Cellular, pharmacological, and biophysical evaluation of explanted lungs from a patient with sickle cell disease and severe pulmonary arterial hypertension.

Science.gov (United States)

Rogers, Natasha M; Yao, Mingyi; Sembrat, John; George, M Patricia; Knupp, Heather; Ross, Mark; Sharifi-Sanjani, Maryam; Milosevic, Jadranka; St Croix, Claudette; Rajkumar, Revathi; Frid, Maria G; Hunter, Kendall S; Mazzaro, Luciano; Novelli, Enrico M; Stenmark, Kurt R; Gladwin, Mark T; Ahmad, Ferhaan; Champion, Hunter C; Isenberg, Jeffrey S

2013-12-01

Pulmonary hypertension is recognized as a leading cause of morbidity and mortality in patients with sickle cell disease (SCD). We now report benchtop phenotyping from the explanted lungs of the first successful lung transplant in SCD. Pulmonary artery smooth muscle cells (PASMCs) cultured from the explanted lungs were analyzed for proliferate capacity, superoxide (O2 (•-)) production, and changes in key pulmonary arterial hypertension (PAH)-associated molecules and compared with non-PAH PASMCs. Upregulation of several pathologic processes persisted in culture in SCD lung PASMCs in spite of cell passage. SCD lung PASMCs showed growth factor- and serum-independent proliferation, upregulation of matrix genes, and increased O2 (•-) production compared with control cells. Histologic analysis of SCD-associated PAH arteries demonstrated increased and ectopically located extracellular matrix deposition and degradation of elastin fibers. Biomechanical analysis of these vessels confirmed increased arterial stiffening and loss of elasticity. Functional analysis of distal fifth-order pulmonary arteries from these lungs demonstrated increased vasoconstriction to an α1-adrenergic receptor agonist and concurrent loss of both endothelial-dependent and endothelial-independent vasodilation compared with normal pulmonary arteries. This is the first study to evaluate the molecular, cellular, functional, and mechanical changes in end-stage SCD-associated PAH.

The Relationship between Intellectual Capital and Income Smoothing and Stock Returns (Case in Medical Companies

Directory of Open Access Journals (Sweden)

Dr. H. Vakilifard

2013-05-01

Full Text Available This article examines the relationship between intellectual capital, income smoothing and stock returns. We are capturing income smoothing through total accruals. Income smoothing firms have significantly higher abnormal returns around earnings announcement. In the knowledge economy, intellectual capital has become one of the primary sources of competitive advantage for a firm. Given the remarkable shift in the underlying production factors of a business within the new knowledge economy, it is important for firms to be aware of the elements of intellectual capital that would lead to value creation. So we associated relationship between intellectual capital and income smoothing and stock returns. The sample includes 108 firm-year observations from 2006 to 2011.We have used five variables: three variables to measure IC, and two variables to measure stock returns and income smoothing. Initial data analyses were conducted through SPSS. The results of our study showed that there was relationship between physical capital and stock returns but they did not provide support for the positive relationship between structural capital, human capital and firm’s financial performance.

Retrograde pulmonary arteriography

International Nuclear Information System (INIS)

Calcaterra, G.; Lam, J.; Losekoot, T.G.

1984-01-01

The authors performed retrograde pulmonary arteriography by means of a pulmonary venous wedge injection in 10 patients with no demonstrable intrapericardial pulmonary arteries by 'conventional' angiographic techniques. In all cases but one, the procedure demonstrated the feasibility of a further operation. No complications were observed. Retrograde pulmonary arteriography is an important additional method for determining the existence of surgically accessible pulmonary arteries when other techniques have failed. (Auth.)

Generation and characterization of human smooth muscle cell lines derived from atherosclerotic plaque.

Science.gov (United States)

Bonin, L R; Madden, K; Shera, K; Ihle, J; Matthews, C; Aziz, S; Perez-Reyes, N; McDougall, J K; Conroy, S C

1999-03-01

The study of atherogenesis in humans has been restricted by the limited availability and brief in vitro life span of plaque smooth muscle cells (SMCs). We describe plaque SMC lines with extended life spans generated by the expression of the human papillomavirus (HPV)-16 E6 and E7 genes, which has been shown to extend the life span of normal adult human aortic SMCs. Resulting cell lines (pdSMC1A and 2) demonstrated at least 10-fold increases in life span; pdSMC1A became immortal. The SMC identity of both pdSMC lines was confirmed by SM22 mRNA expression. pdSMC2 were generally diploid but with various structural and numerical alterations; pdSMC1A demonstrated several chromosomal abnormalities, most commonly -Y, +7, -13, anomalies previously reported in both primary pdSMCs and atherosclerotic tissue. Confluent pdSMC2 appeared grossly similar to HPV-16 E6/E7-expressing normal adult aortic SMCs (AASMCs), exhibiting typical SMC morphology/growth patterns; pdSMC1A displayed irregular cell shape/organization with numerous mitotic figures. Dedifferentiation to a synthetic/proliferative phenotype has been hypothesized as a critical step in atherogenesis, because rat neonatal SMCs and adult intimal SMCs exhibit similar gene expression patterns. To confirm that our pdSMC lines likewise express this apparent plaque phenotype, osteopontin, platelet-derived growth factor B, and elastin mRNA levels were determined in pdSMC1A, pdSMC2, and AASMCs. However, no significant increases in osteopontin or platelet-derived growth factor B expression levels were observed in either pdSMC compared with AASMCs. pdSMC2 alone expressed high levels of elastin mRNA. Lower levels of SM22 mRNA in pdSMC1A suggested greater dedifferentiation and/or additional population doublings in pdSMC1A relative to pdSMC2. Both pdSMC lines (particularly 1A) demonstrated high message levels for matrix Gla protein, previously reported to be highly expressed by human neointimal SMCs in vitro. These results describe 2

Evaluation of pulmonary artery flow in acute massive pulmonary thromboembolism with MRI

International Nuclear Information System (INIS)

Li Yongzhong; Li Kuncheng; Zhao Xigang; Zhao Hong

2004-01-01

Objective: To probe into the value of MR imaging in evaluating the pulmonary artery hemodynamics and pulmonary artery pressure in acute massive pulmonary embolism. Methods: MR studies were performed in 21 patients with acute massive pulmonary embolism (diagnosed by contrast enhanced MR pulmonary angiography) and 20 healthy volunteers. The pulmonary artery hemodynamic parameters, such as the diameters of main and right pulmonary artery, peak velocity, average velocity, flow volume, flow patterns, and ejection acceleration time in main pulmonary artery were measured. The findings in patients and volunteers were compared. The hemodynamic parameters in patients were correlated with mean pulmonary artery pressure acquired with right heart catheterization. Results: The diameters of main pulmonary artery (2.93 vs 2.52 cm) and right pulmonary artery (2.49 vs 1.92 cm) in patients and volunteers showed significant differences (t=3.55, P<0.01 and t=4.19, P<0.01, respectively); Peak velocity (85.29 vs 100.63 cm/s), average velocity (11.00 vs 17.12 cm/s), flow volume (89.15 vs 98.96 ml/s), and ejection acceleration time (105.09 vs 163.85 ms) in main pulmonary artery were significantly different between patients and volunteers (t values were 2.89, 6.37, 2.21, and 9.46, respectively; P values were 0.01, <0.01, 0.03, and <0.01, respectively). The peak velocity-time curve of main pulmonary artery acquired with velocity encoded cine of MR in patients demonstrated earlier and lower peak velocity as well as abnormal retrograde flow. In addition, linear correlations were seen between the mean pulmonary pressure and the diameter of main pulmonary artery (r=0.62, P=0.001), diameter of right pulmonary artery (r=0.63, P=0.001), and ejection acceleration time (r=-0.55, P=0.005). Conclusion: MR imaging is a promising technique not only for the detection of pulmonary thromboemboli but also for the evaluation of hemodynamic parameters in pulmonary hypertension. (author)

Pulmonary artery pulse pressure and wave reflection in chronic pulmonary thromboembolism and primary pulmonary hypertension.

Science.gov (United States)

Castelain, V; Hervé, P; Lecarpentier, Y; Duroux, P; Simonneau, G; Chemla, D

2001-03-15

The purpose of this time-domain study was to compare pulmonary artery (PA) pulse pressure and wave reflection in chronic pulmonary thromboembolism (CPTE) and primary pulmonary hypertension (PPH). Pulmonary artery pressure waveform analysis provides a simple and accurate estimation of right ventricular afterload in the time-domain. Chronic pulmonary thromboembolism and PPH are both responsible for severe pulmonary hypertension. Chronic pulmonary thromboembolism and PPH predominantly involve proximal and distal arteries, respectively, and may lead to differences in PA pressure waveform. High-fidelity PA pressure was recorded in 14 patients (7 men/7 women, 46 +/- 14 years) with CPTE (n = 7) and PPH (n = 7). We measured thermodilution cardiac output, mean PA pressure (MPAP), PA pulse pressure (PAPP = systolic - diastolic PAP) and normalized PAPP (nPAPP = PPAP/MPAP). Wave reflection was quantified by measuring Ti, that is, the time between pressure upstroke and the systolic inflection point (Pi), deltaP, that is, the systolic PAP minus Pi difference, and the augmentation index (deltaP/PPAP). At baseline, CPTE and PPH had similar cardiac index (2.4 +/- 0.4 vs. 2.5 +/- 0.5 l/min/m2), mean PAP (59 +/- 9 vs. 59 +/- 10 mm Hg), PPAP (57 +/- 13 vs. 53 +/- 13 mm Hg) and nPPAP (0.97 +/- 0.16 vs. 0.89 +/- 0.13). Chronic pulmonary thromboembolism had shorter Ti (90 +/- 17 vs. 126 +/- 16 ms, p PPAP (0.26 +/- 0.01 vs. 0.09 +/- 0.07, p < 0.01). Our study indicated that: 1) CPTE and PPH with severe pulmonary hypertension had similar PA pulse pressure, and 2) wave reflection is elevated in both groups, and CPTE had increased and anticipated wave reflection as compared with PPH, thus suggesting differences in the pulsatile component of right ventricular afterload.

Quercetin Inhibits Pulmonary Arterial Endothelial Cell Transdifferentiation Possibly by Akt and Erk1/2 Pathways

Directory of Open Access Journals (Sweden)

Shian Huang

2017-01-01

Full Text Available This study aimed to investigate the effects and mechanisms of quercetin on pulmonary arterial endothelial cell (PAEC transdifferentiation into smooth muscle-like cells. TGF-β1-induced PAEC transdifferentiation models were applied to evaluate the pharmacological actions of quercetin. PAEC proliferation was detected with CCK8 method and BurdU immunocytochemistry. Meanwhile, the identification and transdifferentiation of PAECs were determined by FVIII immunofluorescence staining and α-SMA protein expression. The related mechanism was elucidated based on the levels of Akt and Erk1/2 signal pathways. As a result, quercetin effectively inhibited the TGF-β1-induced proliferation and transdifferentiation of the PAECs and activation of Akt/Erk1/2 cascade in the cells. In conclusion, quercetin is demonstrated to be effective for pulmonary arterial hypertension (PAH probably by inhibiting endothelial transdifferentiation possibly via modulating Akt and Erk1/2 expressions.

Angiostatic factors in the pulmonary endarterectomy material from chronic thromboembolic pulmonary hypertension patients cause endothelial dysfunction.

Directory of Open Access Journals (Sweden)

Diana Zabini

Full Text Available Chronic thromboembolic pulmonary hypertension (CTEPH is a rare disease with persistent thrombotic occlusion or stenosis of the large pulmonary arteries resulting in pulmonary hypertension. Surgical removal of the neointimal layer of these vessels together with the non-resolved thrombus consisting of organized collagen-rich fibrotic areas with partly recanalized regions is the treatment of choice (pulmonary endarterectomy, PEA. The present study investigates endothelial cells isolated from such material as well as factors present in the surgical PEA material, which may contribute to impairment of recanalization and thrombus non-resolution. We observed muscularized vessels and non-muscularized vessels in the PEA material. The isolated endothelial cells from the PEA material showed significantly different calcium homeostasis as compared to pulmonary artery endothelial cells (hPAECs from normal controls. In the supernatant (ELISA as well as on the tissue level (histochemical staining of the PEA material, platelet factor 4 (PF4, collagen type I and interferon-gamma-inducible 10 kD protein (IP-10 were detected. CXCR3, the receptor for PF4 and IP-10, was particularly elevated in the distal parts of the PEA material as compared to human control lung (RT-PCR. PF4, collagen type I and IP-10 caused significant changes in calcium homeostasis and affected the cell proliferation, migration and vessel formation in hPAECs. The presence of angiostatic factors like PF4, collagen type I and IP-10, as recovered from the surgical PEA material from CTEPH patients, may lead to changes in calcium homeostasis and endothelial dysfunction.

Clinical characteristics and epidemiology of pulmonary pseudallescheriasis

NARCIS (Netherlands)

Kantarcioglu, A.S.; de Hoog, G.S.; Guarro, J.

2012-01-01

Background: Some members of the Pseudallescheria (anamorph Scedosporium) have emerged as an important cause of life-threatening infections in humans. These fungi may reach the lungs and bronchial tree causing a wide range of manifestations, from colonization of airways to deep pulmonary infections.

Pulmonary hemorrhage resulting from leptospirosis

Directory of Open Access Journals (Sweden)

Mauro Razuk Filho

2016-07-01

Full Text Available Leptospirosis is one of the most widespread zoonoses in the world, although the mechanisms responsible for the pathogenesis of spirochetes of the genus Leptospira are largely unknown. Human infection occurs either by direct contact with infected animals or indirectly, through contact with water or soil contaminated with urine, as the spirochetes easily penetrate human skin. The present report exposes the case of a female patient, diagnosed with leptospirosis after having had contact with a dog infected by Leptospira sp. that developed pulmonary hemorrhage, acute respiratory distress syndrome and acute renal failure.

p53/PUMA expression in human pulmonary fibroblasts mediates cell activation and migration in silicosis.

Science.gov (United States)

Wang, Wei; Liu, Haijun; Dai, Xiaoniu; Fang, Shencun; Wang, Xingang; Zhang, Yingming; Yao, Honghong; Zhang, Xilong; Chao, Jie

2015-11-18

Phagocytosis of SiO2 into the lung causes an inflammatory cascade that results in fibroblast proliferation and migration, followed by fibrosis. Clinical evidence has indicated that the activation of alveolar macrophages by SiO2 produces rapid and sustained inflammation characterized by the generation of monocyte chemotactic protein 1, which, in turn, induces fibrosis. However, the details of events downstream of monocyte chemotactic protein 1 activity in pulmonary fibroblasts remain unclear. Here, to elucidate the role of p53 in fibrosis induced by silica, both the upstream molecular mechanisms and the functional effects on cell proliferation and migration were investigated. Experiments using primary cultured adult human pulmonary fibroblasts led to the following results: 1) SiO2 treatment resulted in a rapid and sustained increase in p53 and PUMA protein levels; 2) the MAPK and PI3K pathways were involved in the SiO2-induced alteration of p53 and PUMA expression; and 3) RNA interference targeting p53 and PUMA prevented the SiO2-induced increases in fibroblast activation and migration. Our study elucidated a link between SiO2-induced p53/PUMA expression in fibroblasts and cell migration, thereby providing novel insight into the potential use of p53/PUMA in the development of novel therapeutic strategies for silicosis treatment.

[Pulmonary function in patients with infiltrative pulmonary tuberculosis].

Science.gov (United States)

Nefedov, V B; Popova, L A; Shergina, E A

2007-01-01

Vital capacity (VC), forced vital capacity (FVC), forced expiratory volume in 1 second (FEV1), FEV1/VC%, PEF, MEF25, MEF50, MEF75, TLC, TGV, pulmonary residual volume (PRV), R(aw), R(in),, R(ex), DLCO-SB, DLCO-SS, PaO2, and PaCO2 were determined in 103 patients with infiltrative pulmonary tuberculosis. Pulmonary dysfunction was detected in 83.5% of the patients. Changes were found in lung volumes and capacities in 63.1%, impaired bronchial patency and pulmonary gas exchange dysfunction were in 60.2 and 41.7%, respectively. The changes in pulmonary volumes and capacities appeared as increased PRV, decreased VC and FVC, and decreased and increased TGV and TLC; impaired bronchial patency presented as decreased PEF, MEF25, MEF50, MEF75, FEV1/VC% and increased R(aw) R(in), and R(ex); pulmonary gas exchange dysfunction manifested itself as reduced DLCO-SB, DLCO-SS, and PaO2 and decreased and increased PaCO2. The magnitude of the observed functional changes was generally slight. Significant disorders were observed rarely and very pronounced ones were exceptional.

[Pulmonary function in patients with disseminated pulmonary tuberculosis].

Science.gov (United States)

Nefedov, V B; Shergina, E A; Popova, L A

2007-01-01

Vital capacity (VC), forced vital capacity (FVC), forced expiratory volume in 1 second (FEV1), FEV1/VC%, PEF, MEF25%, MEF50%, MEF75%, TLS, TGV, pulmonary residual volume (PRV), Raw, Rin, Rex, DLCO-SB, DLCO-SS, PaO2, and PaCO2 were determined in 29 patients with disseminated pulmonary tuberculosis. Pulmonary dysfunction was detected in 93.1% of the patients. Changes were found in lung volumes and capacities in 65.5%, impaired bronchial patency and pulmonary gas exchange dysfunction were in 79.3 and 37.9%, respectively. The changes in pulmonary volumes and capacities appeared as increased PRV, decreased VC, FVC, and TLS, decreased and increased TGV; impaired bronchial patency presented as decreased PEF, MEF25%, MEF50%, MEF75%, and FEV1/VC% and increased Raw, Rin, and Rex; pulmonary gas exchange dysfunction manifested itself as reduced DLCO-SS and PaO2 and decreased and increased PaCO2. The observed functional changes varied from slight to significant and pronounced with a preponderance of small disorders, a lower detection rate of significant disorders, and rare detection of very pronounced ones.

Effect of smoothing on robust chaos.

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Deshpande, Amogh; Chen, Qingfei; Wang, Yan; Lai, Ying-Cheng; Do, Younghae

2010-08-01

In piecewise-smooth dynamical systems, situations can arise where the asymptotic attractors of the system in an open parameter interval are all chaotic (e.g., no periodic windows). This is the phenomenon of robust chaos. Previous works have established that robust chaos can occur through the mechanism of border-collision bifurcation, where border is the phase-space region where discontinuities in the derivatives of the dynamical equations occur. We investigate the effect of smoothing on robust chaos and find that periodic windows can arise when a small amount of smoothness is present. We introduce a parameter of smoothing and find that the measure of the periodic windows in the parameter space scales linearly with the parameter, regardless of the details of the smoothing function. Numerical support and a heuristic theory are provided to establish the scaling relation. Experimental evidence of periodic windows in a supposedly piecewise linear dynamical system, which has been implemented as an electronic circuit, is also provided.

[Acute neurogenic pulmonary edema].

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Roquefeuil, B

1975-01-01

Neurogenic edema, in the strict sense of the term, has at the present time practically not benefitted from precise hemodynamic investigations in human clinical practice, and owing to this fact, authors still classify them under the heading "mixed edema or of unknown pathogenesis". In contrast with this lack of information in man, animal experimental works are surprising by their coherence and the experimental facility of producing neurogenic edema (cranial hypertension by a small inflatable balloon and cisternal infection of fibrin). If one excludes the now ancient vagal theories (CAMERON 1949; CAMPBELL, 1949) which were never confirmed, all of the most recent experimental works (SARNOFF, 1952; DUCKER, 1968; LUISADA, 1967; MORITZ, 1974) confirm the adrenergic disorder of central origin during neurogenic A.P.E. which from the hemodynamic standpoint is like an authentic hemodynamic A.P.E. with raised left atrial pressure, pulmonary venous pressure and pulmonary capillary pressure.

Intermediate filaments in smooth muscle from pregnant and non-pregnant human uterus.

OpenAIRE

Leoni, P; Carli, F; Halliday, D

1990-01-01

The intermediate filament proteins desmin and vimentin from pregnant and non-pregnant uterine muscle and smooth-muscle cells in culture were analysed using SDS/PAGE. The desmin content in uterine muscle increases dramatically during pregnancy, whereas vimentin remains unchanged or changes very little. When muscle cells are kept in culture, a considerable increase in vimentin content is observed as compared with vimentin in freshly isolated non-pregnant uterine tissue. Our results strengthen t...

Rho-Kinase Inhibition Ameliorates Dasatinib-Induced Endothelial Dysfunction and Pulmonary Hypertension

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Csilla Fazakas

2018-05-01

Full Text Available The multi-kinase inhibitor dasatinib is used for treatment of imatinib-resistant chronic myeloid leukemia, but is prone to induce microvascular dysfunction. In lung this can manifest as capillary leakage with pleural effusion, pulmonary edema or even pulmonary arterial hypertension. To understand how dasatinib causes endothelial dysfunction we examined the effects of clinically relevant concentrations of dasatinib on both human pulmonary arterial macro- and microvascular endothelial cells (ECs. The effects of dasatinib was compared to imatinib and nilotinib, two other clinically used BCR/Abl kinase inhibitors that do not inhibit Src. Real three-dimensional morphology and high resolution stiffness mapping revealed softening of both macro- and microvascular ECs upon dasatinib treatment, which was not observed in response to imatinib. In a dose-dependent manner, dasatinib decreased transendothelial electrical resistance/impedance and caused a permeability increase as well as disruption of tight adherens junctions in both cell types. In isolated perfused and ventilated rat lungs, dasatinib increased mean pulmonary arterial pressure, which was accompanied by a gain in lung weight. The Rho-kinase inhibitor Y27632 partly reversed the dasatinib-induced changes in vitro and ex vivo, presumably by acting downstream of Src. Co-administration of the Rho-kinase inhibitor Y27632 completely blunted the increased pulmonary pressure in response to dasatinib. In conclusion, a dasatinib-induced permeability increase in human pulmonary arterial macro- and microvascular ECs might explain many of the adverse effects of dasatinib in patients. Rho-kinase inhibition might be suitable to ameliorate these effects.

Smooth surfaces from rational bilinear patches

KAUST Repository

Shi, Ling

2014-01-01

Smooth freeform skins from simple panels constitute a challenging topic arising in contemporary architecture. We contribute to this problem area by showing how to approximate a negatively curved surface by smoothly joined rational bilinear patches. The approximation problem is solved with help of a new computational approach to the hyperbolic nets of Huhnen-Venedey and Rörig and optimization algorithms based on it. We also discuss its limits which lie in the topology of the input surface. Finally, freeform deformations based on Darboux transformations are used to generate smooth surfaces from smoothly joined Darboux cyclide patches; in this way we eliminate the restriction to surfaces with negative Gaussian curvature. © 2013 Elsevier B.V.

Functional vascular smooth muscle cells derived from human induced pluripotent stem cells via mesenchymal stem cell intermediates

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Bajpai, Vivek K.; Mistriotis, Panagiotis; Loh, Yuin-Han; Daley, George Q.; Andreadis, Stelios T.

2012-01-01

Aims Smooth muscle cells (SMC) play an important role in vascular homeostasis and disease. Although adult mesenchymal stem cells (MSC) have been used as a source of contractile SMC, they suffer from limited proliferation potential and culture senescence, particularly when originating from older donors. By comparison, human induced pluripotent stem cells (hiPSC) can provide an unlimited source of functional SMC for autologous cell-based therapies and for creating models of vascular disease. Our goal was to develop an efficient strategy to derive functional, contractile SMC from hiPSC. Methods and results We developed a robust, stage-wise, feeder-free strategy for hiPSC differentiation into functional SMC through an intermediate stage of multipotent MSC, which could be coaxed to differentiate into fat, bone, cartilage, and muscle. At this stage, the cells were highly proliferative and displayed higher clonogenic potential and reduced senescence when compared with parental hair follicle mesenchymal stem cells. In addition, when exposed to differentiation medium, the myogenic proteins such as α-smooth muscle actin, calponin, and myosin heavy chain were significantly upregulated and displayed robust fibrillar organization, suggesting the development of a contractile phenotype. Indeed, tissue constructs prepared from these cells exhibited high levels of contractility in response to receptor- and non-receptor-mediated agonists. Conclusion We developed an efficient stage-wise strategy that enabled hiPSC differentiation into contractile SMC through an intermediate population of clonogenic and multipotent MSC. The high yield of MSC and SMC derivation suggests that our strategy may facilitate an acquisition of the large numbers of cells required for regenerative medicine or for studying vascular disease pathophysiology. PMID:22941255

Smooth leader or sharp follower? Playing the mirror game with a robot.

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Kashi, Shir; Levy-Tzedek, Shelly

2018-01-01

The increasing number of opportunities for human-robot interactions in various settings, from industry through home use to rehabilitation, creates a need to understand how to best personalize human-robot interactions to fit both the user and the task at hand. In the current experiment, we explored a human-robot collaborative task of joint movement, in the context of an interactive game. We set out to test people's preferences when interacting with a robotic arm, playing a leader-follower imitation game (the mirror game). Twenty two young participants played the mirror game with the robotic arm, where one player (person or robot) followed the movements of the other. Each partner (person and robot) was leading part of the time, and following part of the time. When the robotic arm was leading the joint movement, it performed movements that were either sharp or smooth, which participants were later asked to rate. The greatest preference was given to smooth movements. Half of the participants preferred to lead, and half preferred to follow. Importantly, we found that the movements of the robotic arm primed the subsequent movements performed by the participants. The priming effect by the robot on the movements of the human should be considered when designing interactions with robots. Our results demonstrate individual differences in preferences regarding the role of the human and the joint motion path of the robot and the human when performing the mirror game collaborative task, and highlight the importance of personalized human-robot interactions.

Pulmonary function testing in HTLV-I and HTLV-II infected humans: a cohort study

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Garratty George

2003-07-01

Full Text Available Abstract Background HTLV-I infection has been linked to lung pathology and HTLV-II has been associated with an increased incidence of pneumonia and acute bronchitis. However it is unknown whether HTLV-I or -II infection alters pulmonary function. Methods We performed pulmonary function testing on HTLV-I, HTLV-II and HTLV seronegative subjects from the HTLV outcomes study (HOST, including vital capacity (VC, forced expiratory volume in one second (FEV1, and diffusing lung capacity for carbon monoxide (DLCO corrected for hemoglobin and lung volume. Multivariable analysis adjusted for differences in age, gender, race/ethnicity, height and smoking history. Results Mean (standard deviation pulmonary function values among the 257 subjects were as follows: FVC = 3.74 (0.89 L, FEV1 = 2.93 (0.67 L, DLCOcorr = 23.82 (5.89 ml/min/mmHg, alveolar ventilation (VA = 5.25 (1.20 L and DLCOcorr/VA = 4.54 (0.87 ml/min/mmHg/L. There were no differences in FVC, FEV1 and DLCOcorr/VA by HTLV status. For DLCOcorr, HTLV-I and HTLV-II subjects had slightly lower values than seronegatives, but neither difference was statistically significant after adjustment for confounding. Conclusions There was no difference in measured pulmonary function and diffusing capacity in generally healthy HTLV-I and HTLV-II subjects compared to seronegatives. These results suggest that previously described HTLV-associated abnormalities in bronchoalveolar cells and fluid may not affect pulmonary function.

Pulmonary tissue volume, cardiac output, and diffusing capacity in sustained microgravity

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Verbanck, S.; Larsson, H.; Linnarsson, D.; Prisk, G. K.; West, J. B.; Paiva, M.

1997-01-01

In microgravity (microG) humans have marked changes in body fluids, with a combination of an overall fluid loss and a redistribution of fluids in the cranial direction. We investigated whether interstitial pulmonary edema develops as a result of a headward fluid shift or whether pulmonary tissue fluid volume is reduced as a result of the overall loss of body fluid. We measured pulmonary tissue volume (Vti), capillary blood flow, and diffusing capacity in four subjects before, during, and after 10 days of exposure to microG during spaceflight. Measurements were made by rebreathing a gas mixture containing small amounts of acetylene, carbon monoxide, and argon. Measurements made early in flight in two subjects showed no change in Vti despite large increases in stroke volume (40%) and diffusing capacity (13%) consistent with increased pulmonary capillary blood volume. Late in-flight measurements in four subjects showed a 25% reduction in Vti compared with preflight controls (P volume, to the extent that it was no longer significantly different from preflight control. Diffusing capacity remained elevated (11%; P pulmonary perfusion and pulmonary capillary blood volume, interstitial pulmonary edema does not result from exposure to microG.

[Studies on the interaction of blood components with ultra-smooth polymer surfaces

Energy Technology Data Exchange (ETDEWEB)

Carlson, T.H. [New Mexico Univ., Albuquerque, NM (United States). School of Medicine

1989-04-17

This report is in three parts, though each is briefly described data is provided. The three parts address (1) radioiodination of human thrombin and fibrinogen; (2) interaction of blood components with ultra- smooth polymer surfaces; and (3) initial studies of Tecoflex and treated Tecoflex cups with normal serum samples.

CT pulmonary angiography of adult pulmonary vascular diseases: Technical considerations and interpretive pitfalls

International Nuclear Information System (INIS)

Taslakian, Bedros; Latson, Larry A.; Truong, Mylene T.; Aaltonen, Eric; Shiau, Maria C.; Girvin, Francis; Alpert, Jeffrey B.; Wickstrom, Maj; Ko, Jane P.

2016-01-01

Highlights: • CTPA plays a key role in the evaluation of pulmonary vascular diseases. • Improvements in CT technology have improved visualization of pulmonary arteries. • Knowledge of the technical pitfalls is essential for accurate diagnosis. • Dual energy CT imaging enables parenchymal iodine evaluation. • An awareness of the entities affecting the pulmonary arteries is important. - Abstract: Computed tomography pulmonary angiography (CTPA) has become the primary imaging modality for evaluating the pulmonary arteries. Although pulmonary embolism is the primary indication for CTPA, various pulmonary vascular abnormalities can be detected in adults. Knowledge of these disease entities and understanding technical pitfalls that can occur when performing CTPA are essential to enable accurate diagnosis and allow timely management. This review will cover a spectrum of acquired abnormalities including pulmonary embolism due to thrombus and foreign bodies, primary and metastatic tumor involving the pulmonary arteries, pulmonary hypertension, as well as pulmonary artery aneurysms and stenoses. Additionally, methods to overcome technical pitfalls and interventional treatment options will be addressed.

CT pulmonary angiography of adult pulmonary vascular diseases: Technical considerations and interpretive pitfalls

Energy Technology Data Exchange (ETDEWEB)

Taslakian, Bedros, E-mail: bedros.taslakian@nyumc.org [Department of Radiology, NYU Langone Medical Center, NY (United States); Latson, Larry A., E-mail: larry.latson@nyumc.org [Department of Radiology, NYU Langone Medical Center, NY (United States); Truong, Mylene T., E-mail: mtruong@mdanderson.org [Department of Radiology, University of Texas, MD Anderson Cancer Center, TX (United States); Aaltonen, Eric, E-mail: Eric.Aaltonen@nyumc.org [Department of Radiology, NYU Langone Medical Center, NY (United States); Shiau, Maria C., E-mail: Maria.Shiau@nyumc.org [Department of Radiology, NYU Langone Medical Center, NY (United States); Girvin, Francis, E-mail: Francis.Girvin@nyumc.org [Department of Radiology, NYU Langone Medical Center, NY (United States); Alpert, Jeffrey B., E-mail: Jeffrey.Alpert@nyumc.org [Department of Radiology, NYU Langone Medical Center, NY (United States); Wickstrom, Maj, E-mail: Maj.Wickstrom@nyumc.org [Department of Radiology, NYU Langone Medical Center, NY (United States); Ko, Jane P., E-mail: Jane.Ko@nyumc.org [Department of Radiology, NYU Langone Medical Center, NY (United States)

2016-11-15

Highlights: • CTPA plays a key role in the evaluation of pulmonary vascular diseases. • Improvements in CT technology have improved visualization of pulmonary arteries. • Knowledge of the technical pitfalls is essential for accurate diagnosis. • Dual energy CT imaging enables parenchymal iodine evaluation. • An awareness of the entities affecting the pulmonary arteries is important. - Abstract: Computed tomography pulmonary angiography (CTPA) has become the primary imaging modality for evaluating the pulmonary arteries. Although pulmonary embolism is the primary indication for CTPA, various pulmonary vascular abnormalities can be detected in adults. Knowledge of these disease entities and understanding technical pitfalls that can occur when performing CTPA are essential to enable accurate diagnosis and allow timely management. This review will cover a spectrum of acquired abnormalities including pulmonary embolism due to thrombus and foreign bodies, primary and metastatic tumor involving the pulmonary arteries, pulmonary hypertension, as well as pulmonary artery aneurysms and stenoses. Additionally, methods to overcome technical pitfalls and interventional treatment options will be addressed.

Microencapsulation of Lefty-secreting engineered cells for pulmonary fibrosis therapy in mice.

Science.gov (United States)

Ma, Hongge; Qiao, Shupei; Wang, Zeli; Geng, Shuai; Zhao, Yufang; Hou, Xiaolu; Tian, Weiming; Chen, Xiongbiao; Yao, Lifen

2017-05-01

Idiopathic pulmonary fibrosis (IPF) is a progressive disease that causes unremitting deposition of extracellular matrix proteins, thus resulting in distortion of the pulmonary architecture and impaired gas exchange. Associated with high morbidity and mortality, IPF is generally refractory to current pharmacological therapies. Lefty A, a potent inhibitor of transforming growth factor-β signaling, has been shown to have promising antifibrotic ability in vitro for the treatment of renal fibrosis and other potential organ fibroses. Here, we determined whether Lefty A can attenuate bleomycin (BLM)-induced pulmonary fibrosis in vivo based on a novel therapeutic strategy where human embryonic kidney 293 (HEK293) cells are genetically engineered with the Lefty A-associated GFP gene. The engineered HEK293 cells were encapsulated in alginate microcapsules and then subcutaneously implanted in ICR mice that had 1 wk earlier been intratracheally administered BLM to induce pulmonary fibrosis. The severity of fibrosis in lung tissue was assessed using pathological morphology and collagen expression to examine the effect of Lefty A released from the microencapsulated cells. The engineered HEK293 cells with Lefty A significantly reduced the expression of connective tissue growth factor and collagen type I mRNA, lessened the morphological fibrotic effects induced by BLM, and increased the expression of matrix metalloproteinase-9. This illustrates that engineered HEK293 cells with Lefty A can attenuate pulmonary fibrosis in vivo, thus providing a novel method to treat human pulmonary fibrotic disease and other organ fibroses. Copyright © 2017 the American Physiological Society.

Adiponectin attenuates lung fibroblasts activation and pulmonary fibrosis induced by paraquat.

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Rong Yao

Full Text Available Pulmonary fibrosis is one of the most common complications of paraquat (PQ poisoning, which demands for more effective therapies. Accumulating evidence suggests adiponectin (APN may be a promising therapy against fibrotic diseases. In the current study, we determine whether the exogenous globular APN isoform protects against pulmonary fibrosis in PQ-treated mice and human lung fibroblasts, and dissect the responsible underlying mechanisms. BALB/C mice were divided into control group, PQ group, PQ + low-dose APN group, and PQ + high-dose APN group. Mice were sacrificed 3, 7, 14, and 21 days after PQ treatment. We compared pulmonary histopathological changes among different groups on the basis of fibrosis scores, TGF-β1, CTGF and α-SMA pulmonary content via Western blot and real-time quantitative fluorescence-PCR (RT-PCR. Blood levels of MMP-9 and TIMP-1 were determined by ELISA. Human lung fibroblasts WI-38 were divided into control group, PQ group, APN group, and APN receptor (AdipoR 1 small-interfering RNA (siRNA group. Fibroblasts were collected 24, 48, and 72 hours after PQ exposure for assay. Cell viability and apoptosis were determined via Kit-8 (CCK-8 and fluorescein Annexin V-FITC/PI double labeling. The protein and mRNA expression level of collagen type III, AdipoR1, and AdipoR2 were measured by Western blot and RT-PCR. APN treatment significantly decreased the lung fibrosis scores, protein and mRNA expression of pulmonary TGF-β1, CTGF and α-SMA content, and blood MMP-9 and TIMP-1 in a dose-dependent manner (p<0.05. Pretreatment with APN significantly attenuated the reduced cell viability and up-regulated collagen type III expression induced by PQ in lung fibroblasts, (p<0.05. APN pretreatment up-regulated AdipoR1, but not AdipoR2, expression in WI-38 fibroblasts. AdipoR1 siRNA abrogated APN-mediated protective effects in PQ-exposed fibroblasts. Taken together, our data suggests APN protects against PQ-induced pulmonary fibrosis in a

Endothelial nanomedicine for the treatment of pulmonary disease.

Science.gov (United States)

Brenner, Jacob S; Greineder, Colin; Shuvaev, Vladimir; Muzykantov, Vladimir

2015-02-01

Even though pulmonary diseases are among the leading causes of morbidity and mortality in the world, exceedingly few life-prolonging therapies have been developed for these maladies. Relief may finally come from nanomedicine and targeted drug delivery. Here, we focus on four conditions for which the pulmonary endothelium plays a pivotal role: acute respiratory distress syndrome, primary graft dysfunction occurring immediately after lung transplantation, pulmonary arterial hypertension and pulmonary embolism. For each of these diseases, we first evaluate the targeted drug delivery approaches that have been tested in animals. Then we suggest a 'need specification' for each disease: a list of criteria (e.g., macroscale delivery method, stability, etc.) that nanomedicine agents must meet in order to warrant human clinical trials and investment from industry. For the diseases profiled here, numerous nanomedicine agents have shown promise in animal models. However, to maximize the chances of creating products that reach patients, nanomedicine engineers and clinicians must work together and use each disease's need specification to guide the design of practical and effective nanomedicine agents.

Bifurcations of non-smooth systems

Science.gov (United States)

Angulo, Fabiola; Olivar, Gerard; Osorio, Gustavo A.; Escobar, Carlos M.; Ferreira, Jocirei D.; Redondo, Johan M.

2012-12-01

Non-smooth systems (namely piecewise-smooth systems) have received much attention in the last decade. Many contributions in this area show that theory and applications (to electronic circuits, mechanical systems, …) are relevant to problems in science and engineering. Specially, new bifurcations have been reported in the literature, and this was the topic of this minisymposium. Thus both bifurcation theory and its applications were included. Several contributions from different fields show that non-smooth bifurcations are a hot topic in research. Thus in this paper the reader can find contributions from electronics, energy markets and population dynamics. Also, a carefully-written specific algebraic software tool is presented.

[Pulmonary hypertension in human immunodeficiency virus-infected patients: the role of antiretroviral therapy].

Science.gov (United States)

Olalla, Julián; Urdiales, Daniel; Pombo, Marta; del Arco, Alfonso; de la Torre, Javier; Prada, José Luis

2014-03-20

Pulmonary arterial hypertension (PAH) is a serious disorder, more prevalent in patients infected with human immunodeficiency virus (HIV). It is not entirely clear what role is played by highly active antiretroviral therapy (HAART) in PAH development or course. Our aim was to describe PAH prevalence in a series of HIV-infected patients and identify possible links with cumulative and current use of different antiretrovirals. Cross-sectional study of a cohort of HIV-infected patients attending a hospital in southern Spain. Demographic data, data on HIV infection status and on cumulative and recent antiretroviral treatment were recorded. Transthoracic echocardiography was performed in all study participants. PAH was defined as pulmonary artery systolic pressure of 36mmHg or more. A total of 400 patients participated in the study; 178 presented with tricuspid regurgitation and 22 of these presented with PAH (5.5%). No differences were encountered in age, sex, CD4 lymphocytes, proportion of naive patients or patients with AIDS. No differences were encountered in cumulative use of antiretrovirals. However, recent use of lamivudine was associated with a greater presence of PAH, whereas recent use of tenofovir and emtricitabine was associated with a lower presence of PAH. Logistic regression analysis was performed including the use of lamivudine, emtricitabine and tenofovir. Only recent use of tenofovir was associated with a lower presence of PAH (odds ratio 0.31; 95% confidence interval: 0.17-0.84). PAH prevalence in our study was similar to others series. Current use of tenofovir may be associated with lower PAH prevalence. Copyright © 2012 Elsevier España, S.L. All rights reserved.

SREBP inhibits VEGF expression in human smooth muscle cells

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Motoyama, Koka [Metabolism, Endocrinology and Molecular Medicine, Osaka City University Graduate School of Medicine, Osaka (Japan); Fukumoto, Shinya [Metabolism, Endocrinology and Molecular Medicine, Osaka City University Graduate School of Medicine, Osaka (Japan); Koyama, Hidenori [Metabolism, Endocrinology and Molecular Medicine, Osaka City University Graduate School of Medicine, Osaka (Japan); Emoto, Masanori [Metabolism, Endocrinology and Molecular Medicine, Osaka City University Graduate School of Medicine, Osaka (Japan); Shimano, Hitoshi [Department of Internal Medicine, Institute of Clinical Medicine, University of Tsukuba, Ibaraki (Japan); Maemura, Koji [Department of Cardiovascular Medicine, Graduate School of Medicine, University of Tokyo, Tokyo (Japan); Nishizawa, Yoshiki [Metabolism, Endocrinology and Molecular Medicine, Osaka City University Graduate School of Medicine, Osaka (Japan)

2006-03-31

Sterol regulatory element-binding proteins (SREBPs) are transcription factors that regulate expression of genes encoding enzymes for lipid biosynthesis. SREBPs are activated by HMG-CoA reductase inhibitors (statins). Statins have been also reported to suppress vascular endothelial growth factor (VEGF) expression in vascular smooth muscle cells (VSMCs). Therefore, we hypothesized that SREBPs are involved in statin-mediated regulation of VEGF production in VSMCs. SREBP1 was robustly expressed, and was activated by atorvastatin in VSMCs, as demonstrated by increased levels of the mature nuclear form of SREBP1, and increased promoter activities of a reporter containing sterol regulatory elements by atorvastatin. Moreover, overexpression of SREBP1a dose-dependently suppressed VEGF promoter activity. Site-specific mutation or deletion of the proximal Sp1 sites reduced the inhibitory effects of SREBP1a on VEGF promoter activity. These data demonstrated that SREBP1, activated by atorvastatin, suppressed VEGF expression through the indirect interaction with the proximal tandem Sp1 sites in VSMCs.

SREBP inhibits VEGF expression in human smooth muscle cells

International Nuclear Information System (INIS)

Motoyama, Koka; Fukumoto, Shinya; Koyama, Hidenori; Emoto, Masanori; Shimano, Hitoshi; Maemura, Koji; Nishizawa, Yoshiki

2006-01-01

Sterol regulatory element-binding proteins (SREBPs) are transcription factors that regulate expression of genes encoding enzymes for lipid biosynthesis. SREBPs are activated by HMG-CoA reductase inhibitors (statins). Statins have been also reported to suppress vascular endothelial growth factor (VEGF) expression in vascular smooth muscle cells (VSMCs). Therefore, we hypothesized that SREBPs are involved in statin-mediated regulation of VEGF production in VSMCs. SREBP1 was robustly expressed, and was activated by atorvastatin in VSMCs, as demonstrated by increased levels of the mature nuclear form of SREBP1, and increased promoter activities of a reporter containing sterol regulatory elements by atorvastatin. Moreover, overexpression of SREBP1a dose-dependently suppressed VEGF promoter activity. Site-specific mutation or deletion of the proximal Sp1 sites reduced the inhibitory effects of SREBP1a on VEGF promoter activity. These data demonstrated that SREBP1, activated by atorvastatin, suppressed VEGF expression through the indirect interaction with the proximal tandem Sp1 sites in VSMCs

The impact of faceplate surface characteristics on detection of pulmonary nodules

Science.gov (United States)

Toomey, R. J.; Ryan, J. T.; McEntee, M. F.; McNulty, J.; Evanoff, M. G.; Cuffe, F.; Yoneda, T.; Stowe, J.; Brennan, P. C.

2009-02-01

Introduction In order to prevent specular reflections, many monitor faceplates have features such as tiny dimples on their surface to diffuse ambient light incident on the monitor, however, this "anti-glare" surface may also diffuse the image itself. The purpose of the study was to determine whether the surface characteristics of monitor faceplates influence the detection of pulmonary nodules under low and high ambient lighting conditions. Methods and Materials Separate observer performance studies were conducted at each of two light levels (250 lux). Twelve examining radiologists with the American Board of Radiology participated in the darker condition and eleven in the brighter condition. All observers read on both smooth "glare" and dimpled "anti-glare" faceplates in a single lighting condition. A counterbalanced methodology was utilized to minimise memory effects. In each reading, observers were presented with thirty chest images in random order, of which half contained a single simulated pulmonary nodule. They were asked to give their confidence that each image did or did not contain a nodule and to mark the suspicious location. ROC analysis was applied to resultant data. Results No statistically significant differences were seen in the trapezoidal area under the ROC curve (AUC), sensitivity, specificity or average time per case at either light level for chest specialists or radiologists from other specialities. Conclusion The characteristics of the faceplate surfaces do not appear to affect detection of pulmonary nodules. Further work into other image types is being conducted.

Estimation of pulmonary water distribution and pulmonary congestion by computed tomography

International Nuclear Information System (INIS)

Morooka, Nobuhiro; Watanabe, Shigeru; Masuda, Yoshiaki; Inagaki, Yoshiaki

1982-01-01

Computed tomography (CT) of the lung in normal subjects and patients with congestive heart failure was performed in the supine position with deep inspiration to obtain pulmonary CT values and images. The mean CT value in normal subjects was higher in the posterior than anterior lung field, presumably because blood vessels were more dilated in the former than the latter due to the effects of gravity. The mean pulmonary CT value in patients with congestive heart failure was significantly increased possibly due to an increase in blood flow per unit lung volume arising from either pulmonary congestion or pulmonary interstitial and alveolar edema. The mean pulmonary CT value increased parallel to the severity of pulmonary congestion, interstitial or alveolar edema and was well correlated with the pulmonary arterial wedge pressure, indicating that such a correlation was a valuable tool in assessing therapeutic effects. The results of the present study indicatethat pulmonary CT is useful for the noninvasive estimation of intrapulmonary water content and its distribution, thereby providing an effective diagnostic clue to various conditions in congestive heart failure. (author)

Histopathology of the great vessels in patients with pulmonary arterial hypertension in association with congenital heart disease: large pulmonary arteries matter too.

Science.gov (United States)

Prapa, Matina; McCarthy, Karen P; Dimopoulos, Konstantinos; Sheppard, Mary N; Krexi, Dimitra; Swan, Lorna; Wort, S John; Gatzoulis, Michael A; Ho, Siew Yen

2013-10-03

Pulmonary arterial hypertension (PAH) is considered primarily a disease of the distal pulmonary arteries whereas little is known on the effect of long-standing pulmonary hypertension on the larger proximal pulmonary arteries. This study aims to investigate the structural changes in the great arteries of adults who developed PAH in association with congenital heart disease (CHD), with severe cases termed Eisenmenger syndrome. We performed macroscopic and light microscopy analyses on the great arteries of 10 formalin-fixed human hearts from patients with PAH/CHD and compared them to age-matched healthy controls. A detailed histology grading score was used to assess the severity of medial wall abnormalities. Severe atherosclerotic lesions were found macroscopically in the elastic pulmonary arteries of 4 PAH/CHD specimens and organised thrombi in 3; none were present in the controls. Significant medial wall abnormalities were present in the pulmonary trunk (PT), including fibrosis (80%), and atypical elastic pattern (80%). Cyst-like formations were present in less than one third of patients and were severe in a single case leading to wall rupture. The cumulative PT histology grading score was significantly higher in PAH/CHD cases compared to controls (parteries. These abnormalities are likely to affect haemodynamics and contribute to morbidity and mortality in this cohort. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

Lung irradiation induces pulmonary vascular remodelling resembling pulmonary arterial hypertension

NARCIS (Netherlands)

Ghobadi, G.; Bartelds, B.; van der Veen, S. J.; Dickinson, M. G.; Brandenburg, S.; Berger, R. M. F.; Langendijk, J. A.; Coppes, R. P.; van Luijk, P.

Background Pulmonary arterial hypertension (PAH) is a commonly fatal pulmonary vascular disease that is often diagnosed late and is characterised by a progressive rise in pulmonary vascular resistance resulting from typical vascular remodelling. Recent data suggest that vascular damage plays an

Persistent diffuse pulmonary interstitial emphysema mimicking pulmonary emphysema

OpenAIRE

Demura, Y; Ishizaki, T; Nakanishi, M; Ameshima, S; Itoh, H

2009-01-01

A 69-year-old male non-smoker with a history of atopic asthma presented with symptoms suggestive of chronic obstructive pulmonary disease and this appeared to be corroborated by lung function testing and a chest radiograph. However, a chest CT showed no evidence of pulmonary emphysema and instead demonstrated free air along the bronchovascular sheaths indicative of pulmonary interstistial emphysema, possibly caused by repeated prior exacerbations of asthma. His lung function tests and symptom...

A SAS IML Macro for Loglinear Smoothing

Science.gov (United States)

Moses, Tim; von Davier, Alina

2011-01-01

Polynomial loglinear models for one-, two-, and higher-way contingency tables have important applications to measurement and assessment. They are essentially regarded as a smoothing technique, which is commonly referred to as loglinear smoothing. A SAS IML (SAS Institute, 2002a) macro was created to implement loglinear smoothing according to…

Mechanical stretch modulates microRNA 21 expression, participating in proliferation and apoptosis in cultured human aortic smooth muscle cells.

Directory of Open Access Journals (Sweden)

Jian tao Song

Full Text Available OBJECTIVES: Stretch affects vascular smooth muscle cell proliferation and apoptosis, and several responsible genes have been proposed. We tested whether the expression of microRNA 21 (miR-21 is modulated by stretch and is involved in stretch-induced proliferation and apoptosis of human aortic smooth muscle cells (HASMCs. METHODS AND RESULTS: RT-PCR revealed that elevated stretch (16% elongation, 1 Hz increased miR-21 expression in cultured HASMCs, and moderate stretch (10% elongation, 1 Hz decreased the expression. BrdU incorporation assay and cell counting showed miR-21 involved in the proliferation of HASMCs mediated by stretch, likely by regulating the expression of p27 and phosphorylated retinoblastoma protein (p-Rb. FACS analysis revealed that the complex of miR-21 and programmed cell death protein 4 (PDCD4 participated in regulating apoptosis with stretch. Stretch increased the expression of primary miR-21 and pre-miR-21 in HASMCs. Electrophoretic mobility shift assay (EMSA demonstrated that stretch increased NF-κB and AP-1 activities in HASMCs, and blockade of AP-1 activity by c-jun siRNA significantly suppressed stretch-induced miR-21 expression. CONCLUSIONS: Cyclic stretch modulates miR-21 expression in cultured HASMCs, and miR-21 plays important roles in regulating proliferation and apoptosis mediated by stretch. Stretch upregulates miR-21 expression at least in part at the transcription level and AP-1 is essential for stretch-induced miR-21 expression.

Stimulatory interactions between human coronary smooth muscle cells and dendritic cells.

Directory of Open Access Journals (Sweden)

Sara Paccosi

Full Text Available Despite inflammatory and immune mechanisms participating to atherogenesis and dendritic cells (DCs driving immune and non-immune tissue injury response, the interactions between DCs and vascular smooth muscle cells (VSMCs possibly relevant to vascular pathology including atherogenesis are still unclear. To address this issue, immature DCs (iDCs generated from CD14+ cells isolated from healthy donors were matured either with cytokines (mDCs, or co-cultured (ccDCs with human coronary artery VSMCs (CASMCs using transwell chambers. Co-culture induced DC immunophenotypical and functional maturation similar to cytokines, as demonstrated by flow cytometry and mixed lymphocyte reaction. In turn, factors from mDCs and ccDCs induced CASMC migration. MCP-1 and TNFα, secreted from DCs, and IL-6 and MCP-1, secreted from CASMCs, were primarily involved. mDCs adhesion to CASMCs was enhanced by CASMC pre-treatment with IFNγ and TNFα ICAM-1 and VCAM-1 were involved, since the expression of specific mRNAs for these molecules increased and adhesion was inhibited by neutralizing antibodies to the counter-receptors CD11c and CD18. Adhesion was also inhibited by CASMC pre-treatment with the HMG-CoA-reductase inhibitor atorvastatin and the PPARγ agonist rosiglitazone, which suggests a further mechanism for the anti-inflammatory action of these drugs. Adhesion of DCs to VSMCs was shown also in vivo in rat carotid 7 to 21 days after crush and incision injury. The findings indicate that DCs and VSMCs can interact with reciprocal stimulation, possibly leading to perpetuate inflammation and vascular wall remodelling, and that the interaction is enhanced by a cytokine-rich inflammatory environment and down-regulated by HMGCoA-reductase inhibitors and PPARγ agonists.

MicroRNA Mediated Chemokine Responses in Human Airway Smooth Muscle Cells.

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Mythili Dileepan

Full Text Available Airway smooth muscle (ASM cells play a critical role in the pathophysiology of asthma due to their hypercontractility and their ability to proliferate and secrete inflammatory mediators. microRNAs (miRNAs are gene regulators that control many signaling pathways and thus serve as potential therapeutic alternatives for many diseases. We have previously shown that miR-708 and miR-140-3p regulate the MAPK and PI3K signaling pathways in human ASM (HASM cells following TNF-α exposure. In this study, we investigated the regulatory effect of these miRNAs on other asthma-related genes. Microarray analysis using the Illumina platform was performed with total RNA extracted from miR-708 (or control miR-transfected HASM cells. Inhibition of candidate inflammation-associated gene expression was further validated by qPCR and ELISA. The most significant biologic functions for the differentially expressed gene set included decreased inflammatory response, cytokine expression and signaling. qPCR revealed inhibition of expression of CCL11, CXCL10, CCL2 and CXCL8, while the release of CCL11 was inhibited in miR-708-transfected cells. Transfection of cells with miR-140-3p resulted in inhibition of expression of CCL11, CXCL12, CXCL10, CCL5 and CXCL8 and of TNF-α-induced CXCL12 release. In addition, expression of RARRES2, CD44 and ADAM33, genes known to contribute to the pathophysiology of asthma, were found to be inhibited in miR-708-transfected cells. These results demonstrate that miR-708 and miR-140-3p exert distinct effects on inflammation-associated gene expression and biological function of ASM cells. Targeting these miRNA networks may provide a novel therapeutic mechanism to down-regulate airway inflammation and ASM proliferation in asthma.

Stretching human mesenchymal stromal cells on stiffness-customized collagen type I generates a smooth muscle marker profile without growth factor addition

Science.gov (United States)

Rothdiener, Miriam; Hegemann, Miriam; Uynuk-Ool, Tatiana; Walters, Brandan; Papugy, Piruntha; Nguyen, Phong; Claus, Valentin; Seeger, Tanja; Stoeckle, Ulrich; Boehme, Karen A.; Aicher, Wilhelm K.; Stegemann, Jan P.; Hart, Melanie L.; Kurz, Bodo; Klein, Gerd; Rolauffs, Bernd

2016-10-01

Using matrix elasticity and cyclic stretch have been investigated for inducing mesenchymal stromal cell (MSC) differentiation towards the smooth muscle cell (SMC) lineage but not in combination. We hypothesized that combining lineage-specific stiffness with cyclic stretch would result in a significantly increased expression of SMC markers, compared to non-stretched controls. First, we generated dense collagen type I sheets by mechanically compressing collagen hydrogels. Atomic force microscopy revealed a nanoscale stiffness range known to support myogenic differentiation. Further characterization revealed viscoelasticity and stable biomechanical properties under cyclic stretch with >99% viable adherent human MSC. MSCs on collagen sheets demonstrated a significantly increased mRNA but not protein expression of SMC markers, compared to on culture flasks. However, cyclic stretch of MSCs on collagen sheets significantly increased both mRNA and protein expression of α-smooth muscle actin, transgelin, and calponin versus plastic and non-stretched sheets. Thus, lineage-specific stiffness and cyclic stretch can be applied together for inducing MSC differentiation towards SMCs without the addition of recombinant growth factors or other soluble factors. This represents a novel stimulation method for modulating the phenotype of MSCs towards SMCs that could easily be incorporated into currently available methodologies to obtain a more targeted control of MSC phenotype.

Income and Consumption Smoothing among US States

DEFF Research Database (Denmark)

Sørensen, Bent; Yosha, Oved

within regions but not between regions. This suggests that capital markets transcend regional barriers while credit markets are regional in their nature. Smoothing within the club of rich states is accomplished mainly via capital markets whereas consumption smoothing is dominant within the club of poor...... states. The fraction of a shock to gross state products smoothed by the federal tax-transfer system is the same for various regions and other clubs of states. We calculate the scope for consumption smoothing within various regions and clubs, finding that most gains from risk sharing can be achieved...

Balloon pulmonary angioplasty: a treatment option for inoperable patients with chronic thromboembolic pulmonary hypertension

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Aiko eOgawa

2015-02-01

Full Text Available In chronic thromboembolic pulmonary hypertension, stenoses or obstructions of the pulmonary arteries due to organized thrombi can cause an elevation in pulmonary artery resistance, which in turn can result in pulmonary hypertension. Chronic thromboembolic pulmonary hypertension can be cured surgically by pulmonary endarterectomy; however, patients deemed unsuitable for pulmonary endarterectomy due to lesion, advanced age, or comorbidities have a poor prognosis and limited treatment options. Recently, advances have been made in balloon pulmonary angioplasty for these patients, and this review highlights this recent progress.

Assessment of smoothed spectra using autocorrelation function

International Nuclear Information System (INIS)

Urbanski, P.; Kowalska, E.

2006-01-01

Recently, data and signal smoothing became almost standard procedures in the spectrometric and chromatographic methods. In radiometry, the main purpose to apply smoothing is minimisation of the statistical fluctuation and avoid distortion. The aim of the work was to find a qualitative parameter, which could be used, as a figure of merit for detecting distortion of the smoothed spectra, based on the linear model. It is assumed that as long as the part of the raw spectrum removed by the smoothing procedure (v s ) will be of random nature, the smoothed spectrum can be considered as undistorted. Thanks to this feature of the autocorrelation function, drifts of the mean value in the removed noise vs as well as its periodicity can be more easily detected from the autocorrelogram than from the original data

Microtissues Enhance Smooth Muscle Differentiation and Cell Viability of hADSCs for Three Dimensional Bioprinting

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Jin Yipeng

2017-07-01

Full Text Available Smooth muscle differentiated human adipose derived stem cells (hADSCs provide a crucial stem cell source for urinary tissue engineering, but the induction of hADSCs for smooth muscle differentiation still has several issues to overcome, including a relatively long induction time and equipment dependence, which limits access to abundant stem cells within a short period of time for further application. Three-dimensional (3D bioprinting holds great promise in regenerative medicine due to its controllable construction of a designed 3D structure. When evenly mixed with bioink, stem cells can be spatially distributed within a bioprinted 3D structure, thus avoiding drawbacks such as, stem cell detachment in a conventional cell-scaffold strategy. Notwithstanding the advantages mentioned above, cell viability is often compromised during 3D bioprinting, which is often due to pressure during the bioprinting process. The objective of our study was to improve the efficiency of hADSC smooth muscle differentiation and cell viability of a 3D bioprinted structure. Here, we employed the hanging-drop method to generate hADSC microtissues in a smooth muscle inductive medium containing human transforming growth factor β1 and bioprinted the induced microtissues onto a 3D structure. After 3 days of smooth muscle induction, the expression of α-smooth muscle actin and smoothelin was higher in microtissues than in their counterpart monolayer cultured hADSCs, as confirmed by immunofluorescence and western blotting analysis. The semi-quantitative assay showed that the expression of α-smooth muscle actin (α-SMA was 0.218 ± 0.077 in MTs and 0.082 ± 0.007 in Controls; smoothelin expression was 0.319 ± 0.02 in MTs and 0.178 ± 0.06 in Controls. Induced MTs maintained their phenotype after the bioprinting process. Live/dead and cell count kit 8 assays showed that cell viability and cell proliferation in the 3D structure printed with microtissues were higher at all time

Pulmonary arterial lesions in explanted lungs after transplantation correlate with severity of pulmonary hypertension in chronic obstructive pulmonary disease

DEFF Research Database (Denmark)

Carlsen, Jørn; Andersen, Kasper Hasseriis; Boesgaard, Søren

2013-01-01

BACKGROUND: Pulmonary vascular findings are largely unreported in end-stage chronic obstructive pulmonary disease (COPD). METHODS: Pulmonary vascular lesions in explanted lungs from 70 patients with COPD/emphysema or α-1-antitrypsin deficiency were analyzed retrospectively. Patients were stratified...... of pulmonary vascular lesions in COPD correlate with the severity of PH. Morphologic lesions similar to those characteristic of IPAH can be observed as PH in COPD progresses to levels characteristic of IPAH....... by the presence and severity of pulmonary hypertension (PH) assessed by right-heart catheterization in 3 hemodynamically distinct groups: (1) non-PH (mean pulmonary arterial pressure [mPAP]50 mm Hg; median HE Grade 4 (range 3-6), with generalized arterial dilatation and plexiform lesions. CONCLUSIONS: The extent...

Grainyhead-like 2 (GRHL2) distribution reveals novel pathophysiological differences between human idiopathic pulmonary fibrosis and mouse models of pulmonary fibrosis

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Mahavadi, Poornima; Sasikumar, Satish; Cushing, Leah; Hyland, Tessa; Rosser, Ann E.; Riccardi, Daniela; Lu, Jining; Kalin, Tanya V.; Kalinichenko, Vladimir V.; Guenther, Andreas; Ramirez, Maria I.; Pardo, Annie; Selman, Moisés; Warburton, David

2013-01-01

Chronic injury of alveolar lung epithelium leads to epithelial disintegrity in idiopathic pulmonary fibrosis (IPF). We had reported earlier that Grhl2, a transcriptional factor, maintains alveolar epithelial cell integrity by directly regulating components of adherens and tight junctions and thus hypothesized an important role of GRHL2 in pathogenesis of IPF. Comparison of GRHL2 distribution at different stages of human lung development showed its abundance in developing lung epithelium and in adult lung epithelium. However, GRHL2 is detected in normal human lung mesenchyme only at early fetal stage (week 9). Similar mesenchymal reexpression of GRHL2 was also observed in IPF. Immunofluorescence analysis in serial sections from three IPF patients revealed at least two subsets of alveolar epithelial cells (AEC), based on differential GRHL2 expression and the converse fluorescence intensities for epithelial vs. mesenchymal markers. Grhl2 was not detected in mesenchyme in intraperitoneal bleomycin-induced injury as well as in spontaneously occurring fibrosis in double-mutant HPS1 and HPS2 mice, whereas in contrast in a radiation-induced fibrosis model, with forced Forkhead box M1 (Foxm1) expression, an overlap of Grhl2 with a mesenchymal marker was observed in fibrotic regions. Grhl2's role in alveolar epithelial cell plasticity was confirmed by altered Grhl2 gene expression analysis in IPF and further validated by in vitro manipulation of its expression in alveolar epithelial cell lines. Our findings reveal important pathophysiological differences between human IPF and specific mouse models of fibrosis and support a crucial role of GRHL2 in epithelial activation in lung fibrosis and perhaps also in epithelial plasticity. PMID:24375798

Smooth surfaces from rational bilinear patches

KAUST Repository

Shi, Ling; Wang, Jun; Pottmann, Helmut

2014-01-01

Smooth freeform skins from simple panels constitute a challenging topic arising in contemporary architecture. We contribute to this problem area by showing how to approximate a negatively curved surface by smoothly joined rational bilinear patches

Pulmonary Hypertension Overview

Science.gov (United States)

... well as sleep apnea, are common causes of secondary pulmonary hypertension. Other causes include the following: Congestive heart failure Birth defects in the heart Chronic pulmonary thromboembolism (blood clots in the pulmonary arteries) Acquired immunodeficiency syndrome ( ...

Familial Pulmonary Fibrosis

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... Education & Training Home Conditions Familial Pulmonary Fibrosis Familial Pulmonary Fibrosis Make an Appointment Find a Doctor Ask a ... more members within the same family have Idiopathic Pulmonary Fibrosis (IPF) or any other form of Idiopathic Interstitial ...

Enhanced magnetic resonance pulmonary perfusion imaging in diagnosing pulmonary embolism: preliminary investigation

International Nuclear Information System (INIS)

Huang Xiaoyong; Du Jing; Zhang Zhaoqi; Guo Xi; Yan Zixu; Jiang Hong; Wang Wei

2005-01-01

Objective: This study was designed to investigate the sensitivity and specificity of magnetic resonance pulmonary perfusion imaging (MRPP) in diagnosing pulmonary embolism (PE) compared with enhanced magnetic resonance pulmonary angiography (MRPA) and pulmonary radionuclide perfusion imaging. Methods: Fourteen patients were definitely diagnosed as PE, whose ages were from 19 to 71 years old and mean 45.5 ± 19.8 years old. All patients under went MRPA and MRPP and 3 patients were examined again after thrombolytic treatment. Five patients underwent pulmonary radionuclide perfusion imaging. Setting ROI in top, middle, bottom of lung area and abnormal area respectively, we detected signal intensity and time-signal curve to obtain the transformation rate of signal (TROS) during perfusion peak value. Results: In 14 pulmonary embolism patients, MRPA found 62 branches of pulmonary artery obstruction. Fifty-five abnormal pulmonary perfusion zones were found by MRPP, and the above results were very alike. The coincidence was 88.71%. In 14 cases, MRPP could show 25 subsegments lesion below segments. In 5 patients who had both results Of MRPP and ECT at the same time. MRPP shows 33 perfusion defect zones and 37 segments were found by ECT, the sensitivity was 89.19%. After thrombolytic treatment, both the status of the affected pulmonary artery improved markedly and perfusion defect zones reduced obviously in 3 cases by MRPP and MRPA. TROS in normal perfusion zones perfusion defect zones and low perfusion zones had significant difference (t=22.882, P<0.01). Conclusion: Contrast enhanced MR pulmonary perfusion can show both perfusion defect zones and low perfusion zones in pulmonary embolism. Time-signal curve can show the period of maximum no perfusion zones in pulmonary artery embolism zones. And the amplitude of fluctuation is small with miminum TROS. MRPP has significant values especially in showing pulmonary artery embolism in segments and subsegments. Using both MRPP and

A comparative analysis of pulmonary ventilation-perfusion imaging with pulmonary angiography in the diagnosis of pulmonary embolism

International Nuclear Information System (INIS)

Wang Jincheng; Mi Hongzhi; Wang Qian; Zhang Weijun; Lu Biao; Yang Hao; Ding Jian; Lu Yao

2001-01-01

Objective: To assess the value of ventilation-perfusion imaging in the diagnosis of pulmonary embolism (PE). Methods: Thirty consecutive patients with clinically suspected pulmonary embolism were studied, male: female 15:15, mean age was (36.2 +- 13.9) years. The chest radiograms were obtained in all 30 patients. All patients underwent radionuclide ventilation-perfusion imaging and pulmonary angiography. Results: Of the 30 patients, 22 with lobe, multiple segment or multi-subsegment perfusion defects and normal or nearly normal ventilation images were reported as PE. 20 of them were confirmed to be with PE by pulmonary angiography, 2 patients were not confirmed. Eight of 30 patients with multiple perfusion defects, ventilative abnormalities were reported as non-PE and the diagnoses were confirmed by pulmonary angiography. The sensitivity, specificity and accuracy of diagnosis of PE by ventilation-perfusion imaging was 100%, 80.0% and 93.3% respectively. Conclusions: (1) Ventilation-perfusion imaging is one of the most valuable methods in the diagnosis of PE. (2) The results suggest that pulmonary embolism can be diagnosed non-invasively in most patients on the basis of clinical manifestation, chest radiograms and ventilation-perfusion imaging findings. (3) Pulmonary angiography is required while clinical manifestation and ventilation-perfusion imaging findings are discordant with each other

Pulmonary embolism in pregnancy: comparison of pulmonary CT angiography and lung scintigraphy.

LENUS (Irish Health Repository)

Ridge, Carole A

2012-02-01

OBJECTIVE: The purpose of this study was to retrospectively compare the diagnostic adequacy of lung scintigraphy with that of pulmonary CT angiography (CTA) in the care of pregnant patients with suspected pulmonary embolism. MATERIALS AND METHODS: Patient characteristics, radiology report content, additional imaging performed, final diagnosis, and diagnostic adequacy were recorded for pregnant patients consecutively referred for lung scintigraphy or pulmonary CTA according to physician preference. Measurements of pulmonary arterial enhancement were performed on all pulmonary CTA images of pregnant patients. Lung scintigraphy and pulmonary CTA studies deemed inadequate for diagnosis at the time of image acquisition were further assessed, and the cause of diagnostic inadequacy was determined. The relative contribution of the inferior vena cava to the right side of the heart was measured on nondiagnostic CTA images and compared with that on CTA images of age-matched nonpregnant women, who were the controls. RESULTS: Twenty-eight pulmonary CTA examinations were performed on 25 pregnant patients, and 25 lung scintigraphic studies were performed on 25 pregnant patients. Lung scintigraphy was more frequently adequate for diagnosis than was pulmonary CTA (4% vs 35.7%) (p = 0.0058). Pulmonary CTA had a higher diagnostic inadequacy rate among pregnant than nonpregnant women (35.7% vs 2.1%) (p < 0.001). Transient interruption of contrast material by unopacified blood from the inferior vena cava was identified in eight of 10 nondiagnostic pulmonary CTA studies. CONCLUSION: We found that lung scintigraphy was more reliable than pulmonary CTA in pregnant patients. Transient interruption of contrast material by unopacified blood from the inferior vena cava is a common finding at pulmonary CTA of pregnant patients.

Inhalation of activated protein C inhibits endotoxin-induced pulmonary inflammation in mice independent of neutrophil recruitment

NARCIS (Netherlands)

Slofstra, S. H.; Groot, A. P.; Maris, N. A.; Reitsma, P. H.; Cate, H. Ten; Spek, C. A.

2006-01-01

BACKGROUND AND PURPOSE: Intravenous administration of recombinant human activated protein C (rhAPC) is known to reduce lipopolysaccharide (LPS)-induced pulmonary inflammation by attenuating neutrophil chemotaxis towards the alveolar compartment. Ideally, one would administer rhAPC in pulmonary

TAX SMOOTHING: TESTS ON INDONESIAN DATA

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Rudi Kurniawan

2011-01-01

Full Text Available This paper contributes to the literature of public debt management by testing for tax smoothing behaviour in Indonesia. Tax smoothing means that the government smooths the tax rate across all future time periods to minimize the distortionary costs of taxation over time for a given path of government spending. In a stochastic economy with an incomplete bond market, tax smoothing implies that the tax rate approximates a random walk and changes in the tax rate are nearly unpredictable. For that purpose, two tests were performed. First, random walk behaviour of the tax rate was examined by undertaking unit root tests. The null hypothesis of unit root cannot be rejected, indicating that the tax rate is nonstationary and, hence, it follows a random walk. Second, the predictability of the tax rate was examined by regressing changes in the tax rate on its own lagged values and also on lagged values of changes in the goverment expenditure ratio, and growth of real output. They are found to be not significant in predicting changes in the tax rate. Taken together, the present evidence seems to be consistent with the tax smoothing, therefore provides support to this theory.

Right pulmonary aplasia, aberrant left pulmonary artery, and bronchopulmonary sequestration with an esophageal bronchus

International Nuclear Information System (INIS)

Lee, Peter; McCauley, Roy; Westra, Sjirk; Baba, Timothy

2006-01-01

Pulmonary aplasia and bronchopulmonary foregut malformations in which a patent communication between the foregut and the pulmonary system is present are rare congenital abnormalities. Pulmonary aplasia associated with a pulmonary sling is an even rarer abnormality. We report a unique case of right pulmonary aplasia, aberrant left pulmonary artery, and bronchopulmonary sequestration with an esophageal bronchus diagnosed by multidetector helical CT. (orig.)

Haemophilus influenzae genome evolution during persistence in the human airways in chronic obstructive pulmonary disease.

Science.gov (United States)

Pettigrew, Melinda M; Ahearn, Christian P; Gent, Janneane F; Kong, Yong; Gallo, Mary C; Munro, James B; D'Mello, Adonis; Sethi, Sanjay; Tettelin, Hervé; Murphy, Timothy F

2018-04-03

Nontypeable Haemophilus influenzae (NTHi) exclusively colonize and infect humans and are critical to the pathogenesis of chronic obstructive pulmonary disease (COPD). In vitro and animal models do not accurately capture the complex environments encountered by NTHi during human infection. We conducted whole-genome sequencing of 269 longitudinally collected cleared and persistent NTHi from a 15-y prospective study of adults with COPD. Genome sequences were used to elucidate the phylogeny of NTHi isolates, identify genomic changes that occur with persistence in the human airways, and evaluate the effect of selective pressure on 12 candidate vaccine antigens. Strains persisted in individuals with COPD for as long as 1,422 d. Slipped-strand mispairing, mediated by changes in simple sequence repeats in multiple genes during persistence, regulates expression of critical virulence functions, including adherence, nutrient uptake, and modification of surface molecules, and is a major mechanism for survival in the hostile environment of the human airways. A subset of strains underwent a large 400-kb inversion during persistence. NTHi does not undergo significant gene gain or loss during persistence, in contrast to other persistent respiratory tract pathogens. Amino acid sequence changes occurred in 8 of 12 candidate vaccine antigens during persistence, an observation with important implications for vaccine development. These results indicate that NTHi alters its genome during persistence by regulation of critical virulence functions primarily by slipped-strand mispairing, advancing our understanding of how a bacterial pathogen that plays a critical role in COPD adapts to survival in the human respiratory tract.

IgM response to a human Pneumocystis carinii surface antigen in HIV-infected patients with pulmonary symptoms

DEFF Research Database (Denmark)

Lundgren, Bettina; Kovacs, J A; Mathiesen, Lars Reinhardt

1993-01-01

We have developed an ELISA to detect IgM antibodies to a major human Pneumocystis carinii surface antigen (gp95), and investigated the IgM response in 128 HIV-infected patients who underwent bronchoscopy for evaluation of pulmonary symptoms. Only 5 (4%) patients had IgM antibodies to P. carinii gp...... response to gp95. These patients also showed an increase in IgG antibodies to gp95 and had microbiologically proven PCP. Prior to the development of the IgM response, IgG antibodies to gp95 were detectable in all 3 patients. Thus, HIV-infected patients with PCP seldom produce IgM antibodies to the major...

Smoothing of respiratory motion traces for motion-compensated radiotherapy.

Science.gov (United States)

Ernst, Floris; Schlaefer, Alexander; Schweikard, Achim

2010-01-01

The CyberKnife system has been used successfully for several years to radiosurgically treat tumors without the need for stereotactic fixation or sedation of the patient. It has been shown that tumor motion in the lung, liver, and pancreas can be tracked with acceptable accuracy and repeatability. However, highly precise targeting for tumors in the lower abdomen, especially for tumors which exhibit strong motion, remains problematic. Reasons for this are manifold, like the slow tracking system operating at 26.5 Hz, and using the signal from the tracking camera "as is." Since the motion recorded with the camera is used to compensate for system latency by prediction and the predicted signal is subsequently used to infer the tumor position from a correlation model based on x-ray imaging of gold fiducials around the tumor, camera noise directly influences the targeting accuracy. The goal of this work is to establish the suitability of a new smoothing method for respiratory motion traces used in motion-compensated radiotherapy. The authors endeavor to show that better prediction--With a lower rms error of the predicted signal--and/or smoother prediction is possible using this method. The authors evaluated six commercially available tracking systems (NDI Aurora, PolarisClassic, Polaris Vicra, MicronTracker2 H40, FP5000, and accuTrack compact). The authors first tracked markers both stationary and while in motion to establish the systems' noise characteristics. Then the authors applied a smoothing method based on the a trous wavelet decomposition to reduce the devices' noise level. Additionally, the smoothed signal of the moving target and a motion trace from actual human respiratory motion were subjected to prediction using the MULIN and the nLMS2 algorithms. The authors established that the noise distribution for a static target is Gaussian and that when the probe is moved such as to mimic human respiration, it remains Gaussian with the exception of the FP5000 and the

Smoothing of respiratory motion traces for motion-compensated radiotherapy

International Nuclear Information System (INIS)

Ernst, Floris; Schlaefer, Alexander; Schweikard, Achim

2010-01-01

Purpose: The CyberKnife system has been used successfully for several years to radiosurgically treat tumors without the need for stereotactic fixation or sedation of the patient. It has been shown that tumor motion in the lung, liver, and pancreas can be tracked with acceptable accuracy and repeatability. However, highly precise targeting for tumors in the lower abdomen, especially for tumors which exhibit strong motion, remains problematic. Reasons for this are manifold, like the slow tracking system operating at 26.5 Hz, and using the signal from the tracking camera ''as is''. Since the motion recorded with the camera is used to compensate for system latency by prediction and the predicted signal is subsequently used to infer the tumor position from a correlation model based on x-ray imaging of gold fiducials around the tumor, camera noise directly influences the targeting accuracy. The goal of this work is to establish the suitability of a new smoothing method for respiratory motion traces used in motion-compensated radiotherapy. The authors endeavor to show that better prediction--With a lower rms error of the predicted signal--and/or smoother prediction is possible using this method. Methods: The authors evaluated six commercially available tracking systems (NDI Aurora, PolarisClassic, Polaris Vicra, MicronTracker2 H40, FP5000, and accuTrack compact). The authors first tracked markers both stationary and while in motion to establish the systems' noise characteristics. Then the authors applied a smoothing method based on the a trous wavelet decomposition to reduce the devices' noise level. Additionally, the smoothed signal of the moving target and a motion trace from actual human respiratory motion were subjected to prediction using the MULIN and the nLMS 2 algorithms. Results: The authors established that the noise distribution for a static target is Gaussian and that when the probe is moved such as to mimic human respiration, it remains Gaussian with the

Experimental study of pulmonary thromboembolism ischemia-reperfusion injury in canine model

International Nuclear Information System (INIS)

Li Jianjun; Zhai Renyou; Zhang Dongpo; Huang Qiang; Yu Ping; Dai Dingke; Bao Na

2009-01-01

Objective: To establish a canine model of pulmonary thromboembolism ischemia- reperfusion injury (PTE IRI) that may be used for imaging study. Methods: Ten male and 10 female healthy mongrel canines with (18.6±0.8) kg/body weight, were used. A Swan-Ganz catheter was introduced into the right internal jugular vein via a preset percutaneous sheath using the Seldinger technique, and then was with further insertion the pulmonary artery. Balloon occlusion of the right inferior lobe pulmonary artery for 4 hours was followed by removing the catheter and ending with 4 hours of reperfusion. CT was performed before ischemia, 4 h after ischemia and 4 h after reperfusion. At last, dogs were killed and the bilateral inferior lung tissues were prepared for the examination by light and electronic microscopy. Results: All canine models were successfully developed pulmonary thromboembolism ischemia-reperfusion injury. The examination of CT, light and electron microscopy consistently indicated the presence of permeability pulmonary edema after reperfusion. Conclusions: A closed-chest canine model in vivo of pulmonary thromboembolism ischemia-reperfusion injury can be established with virtual pathophysiological process in human and be as well as for imaging experimental study. (authors)

Pulmonary Arterial Hypertension

Science.gov (United States)

... heart). This type of pulmonary hypertension was called “secondary pulmonary hypertension” but is now referred to as PH, because the cause is known to be from lung disease, heart disease, or chronic thromboemboli (blood clots). Pulmonary Arterial Hypertension (PAH) used to be ...

miR-1 is increased in pulmonary hypertension and downregulates Kv1.5 channels in rat pulmonary arteries.

Science.gov (United States)

Mondejar-Parreño, Gema; Callejo, María; Barreira, Bianca; Morales-Cano, Daniel; Esquivel-Ruiz, Sergio; Moreno, Laura; Cogolludo, Angel; Perez-Vizcaino, Francisco

2018-05-02

■The expression of miR-1 is increased in lungs from the Hyp/Su5416 PAH rat model. ■PASMC from this animal model are more depolarised and show decreased expression and activity of Kv1.5. ■miR-1 directly targets Kv1.5 channels, reduces Kv1.5 activity and induces membrane depolarization. ■Antagomir-1 prevents Kv1.5 channel downregulation and the depolarization induced by hypoxia/Su5416 exposition. Impairment of voltage-dependent potassium channel (Kv) plays a central role in the development of cardiovascular diseases, including pulmonary arterial hypertension (PAH). MicroRNAs (miRNAs) are non-coding RNAs that regulate gene expression by binding to the 3'-UTR region of specific mRNAs. The aim of this study was to analyze the effects of miR-1 on Kv channel function in pulmonary arteries (PA). Kv channel activity was studied in PA from healthy animals transfected with miR-1 or scrambled-miR. Kv currents were studied using the whole-cell configuration of patch-clamp technique. The characterization of the Kv1.5 currents was performed with the selective inhibitor DPO-1. miR-1 expression was increased and Kv1.5 channels were decreased in lungs from a rat model of PAH induced by hypoxia and Su5416. miR-1 transfection increased cell capacitance, reduced Kv1.5 currents and induced membrane depolarization in isolated pulmonary artery smooth muscle cells (PASMCs). Luciferase reporter assay indicated that KCNA5, which encodes Kv1.5 channels, is a direct target gene of miR-1. Incubation of PA with Su5416 and hypoxia (3% O 2 ) increased miR-1 and induced a decline in Kv1.5 currents, which was prevented by antagomiR-1. In conclusion, these data indicate that miR-1 induces PASMC hypertrophy and reduces the activity and expression of Kv channels, suggesting a pathophysiological role in PAH. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

Nodular smooth muscle metaplasia in multiple peritoneal endometriosis

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