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Regulation of p53-mediated changes in the uPA-fibrinolytic system and in lung injury by loss of surfactant protein C expression in alveolar epithelial cells
Pulmonary surfactant protein C (SP-C) expression by type II alveolar epithelial cells (AECs) is markedly reduced in diverse types of lung injuries and is often associated with AEC apoptosis. It is unclear whether loss of SP-C contributes to the increased p53 and urokinase-type plasminogen activator (uPA) system cross-talk and apoptosis of AECs. Therefore, we inhibited SP-C expression in human and murine AECs using lentivirus vector expressing shRNA and tested p53 and downstream changes in the uPA-fibrinolytic system. Inhibition of SP-C expression in AECs induced p53 and activated caspase-3, indicating AEC apoptosis. We als...
Source: AJP: Lung Cellular and Molecular Physiology - June 1, 2017 Category: Respiratory Medicine Authors: Puthusseri, B., Marudamuthu, A., Tiwari, N., Fu, J., Idell, S., Shetty, S. Tags: RESEARCH ARTICLE Source Type: research

Annexin A2 contributes to lung injury and fibrosis by augmenting factor Xa fibrogenic activity
In this study, the contribution of annexin A2 in lung injury and fibrosis was investigated. Annexin A2 immunoreactivity was observed in regions of fibrosis, including those associated with fibroblasts in lung tissue of IPF patients. Furthermore, annexin A2 was detected in the conditioned media and an EGTA membrane wash of human lung fibroblast (LF) cultures. Incubation with human plasma (5% vol/vol) or purified FXa (15–50 nM) evoked fibrogenic responses in LF cultures, with FXa increasing interleukin-6 (IL-6) production and cell number by 270 and 46%, respectively (P < 0.05, n = 5–8). The fibrogenic actions ...
Source: AJP: Lung Cellular and Molecular Physiology - May 4, 2017 Category: Respiratory Medicine Authors: Schuliga, M., Jaffar, J., Berhan, A., Langenbach, S., Harris, T., Waters, D., Lee, P. V. S., Grainge, C., Westall, G., Knight, D., Stewart, A. G. Tags: RESEARCH ARTICLE Source Type: research

Inflammation-induced caveolin-1 and BMPRII depletion promotes endothelial dysfunction and TGF-{beta}-driven pulmonary vascular remodeling
Endothelial cell (EC) activation and vascular injury are hallmark features of acute lung injury (ALI) and acute respiratory distress syndrome (ARDS). Caveolin-1 (Cav-1) is highly expressed in pulmonary microvascular ECs and plays a key role in maintaining vascular homeostasis. The aim of this study was to determine if the lung inflammatory response to Escherichia coli lipopolysaccharide (LPS) promotes priming of ECs via Cav-1 depletion and if this contributes to the onset of pulmonary vascular remodeling. To test the hypothesis that depletion of Cav-1 primes ECs to respond to profibrotic signals, C57BL6 wild-type (WT) mice...
Source: AJP: Lung Cellular and Molecular Physiology - May 4, 2017 Category: Respiratory Medicine Authors: Oliveira, S. D. S., Castellon, M., Chen, J., Bonini, M. G., Gu, X., Elliott, M. H., Machado, R. F., Minshall, R. D. Tags: RESEARCH ARTICLE Source Type: research

Effect of {alpha}7 nicotinic acetylcholine receptor activation on cardiac fibroblasts: a mechanism underlying RV fibrosis associated with cigarette smoke exposure
In this study, we evaluated cardiac function and fibrosis in mice exposed to CS and determined mechanisms of smoke-induced changes in CF signaling and fibrosis. AKR mice were exposed to CS for 6 wk followed by echocardiography and evaluation of cardiac hypertrophy, collagen content, and pulmonary muscularization. Proliferation and collagen content were evaluated in primary isolated rat CFs exposed to CS extract (CSE) or nicotine. Markers of cell proliferation, fibrosis, and proliferative signaling were determined by immunoblot or Sircol collagen assay. Mice exposed to CS had significantly decreased RV function, as determin...
Source: AJP: Lung Cellular and Molecular Physiology - May 4, 2017 Category: Respiratory Medicine Authors: Vang, A., Clements, R. T., Chichger, H., Kue, N., Allawzi, A., OConnell, K., Jeong, E.-M., Dudley, S. C., Sakhatskyy, P., Lu, Q., Zhang, P., Rounds, S., Choudhary, G. Tags: RESEARCH ARTICLE Source Type: research

Microencapsulation of Lefty-secreting engineered cells for pulmonary fibrosis therapy in mice
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 fibrosi...
Source: AJP: Lung Cellular and Molecular Physiology - May 4, 2017 Category: Respiratory Medicine Authors: Ma, H., Qiao, S., Wang, Z., Geng, S., Zhao, Y., Hou, X., Tian, W., Chen, X., Yao, L. Tags: RESEARCH ARTICLE Source Type: research

Rhinovirus-bacteria coexposure synergistically induces CCL20 production from human bronchial epithelial cells
Exacerbations of chronic obstructive pulmonary disease are triggered by viral or bacterial pathogens, with human rhinovirus (HRV) and nontypeable Hemophilus influenzae (NTHI) among the most commonly detected pathogens. Patients who suffer from concomitant viral and bacterial infection have more severe exacerbations. The airway epithelial cell is the initial site of viral and bacterial interactions, and CCL20 is an epithelial chemokine that attracts immature dendritic cells to the airways and can act as an antimicrobial. As such, it contributes to innate and adaptive immune responses to infection. We used primary cultures o...
Source: AJP: Lung Cellular and Molecular Physiology - May 4, 2017 Category: Respiratory Medicine Authors: Maciejewski, B. A., Jamieson, K. C., Arnason, J. W., Kooi, C., Wiehler, S., Traves, S. L., Leigh, R., Proud, D. Tags: RESEARCH ARTICLE Source Type: research

Lung epithelial cell focal adhesion kinase signaling inhibits lung injury and fibrosis
Progressive pulmonary fibrosis is a devastating consequence of many acute and chronic insults to the lung. Lung injury leads to alveolar epithelial cell (AEC) death, destruction of the basement membrane, and activation of transforming growth factor-β (TGF-β). There is subsequent resolution of the injury and a coordinated and concurrent initiation of fibrosis. Both of these processes may involve activation of similar intracellular signaling pathways regulated in part by dynamic changes to the extracellular matrix. Matrix signaling can augment the profibrotic fibroblast response to TGF-β. However, similar matr...
Source: AJP: Lung Cellular and Molecular Physiology - May 4, 2017 Category: Respiratory Medicine Authors: Wheaton, A. K., Agarwal, M., Jia, S., Kim, K. K. Tags: RESEARCH ARTICLE Source Type: research

The mast cell-B cell axis in lung vascular remodeling and pulmonary hypertension
Over past years, a critical role for the immune system and, in particular, for mast cells in the pathogenesis of pulmonary hypertension (PH) has emerged. However, the way in which mast cells promote PH is still poorly understood. Here, we investigated the mechanisms by which mast cells may contribute to PH, specifically focusing on the interaction between the innate and adaptive immune response and the role of B cells and autoimmunity. Experiments were performed in Sprague-Dawley rats and B cell-deficient JH-KO rats in the monocrotaline, Sugen/hypoxia, and the aortic banding model of PH. Hemodynamics, cell infiltration, IL...
Source: AJP: Lung Cellular and Molecular Physiology - May 4, 2017 Category: Respiratory Medicine Authors: Breitling, S., Hui, Z., Zabini, D., Hu, Y., Hoffmann, J., Goldenberg, N. M., Tabuchi, A., Buelow, R., Dos Santos, C., Kuebler, W. M. Tags: RESEARCH ARTICLE Source Type: research

Profiling of ARDS pulmonary edema fluid identifies a metabolically distinct subset
In this study, we tested the hypothesis that there exists a subgroup of ARDS patients who exhibit a metabolically distinct profile. We examined undiluted pulmonary edema fluid obtained at the time of endotracheal intubation from 16 clinically phenotyped ARDS patients and 13 control patients with hydrostatic pulmonary edema. Nontargeted metabolic profiling was carried out on the undiluted edema fluid. Univariate and multivariate statistical analyses including principal component analysis (PCA) and partial least squares discriminant analysis (PLS-DA) were conducted to find discriminant metabolites. Seven-hundred and sixty un...
Source: AJP: Lung Cellular and Molecular Physiology - May 4, 2017 Category: Respiratory Medicine Authors: Rogers, A. J., Contrepois, K., Wu, M., Zheng, M., Peltz, G., Ware, L. B., Matthay, M. A. Tags: RESEARCH ARTICLE Source Type: research

Insulin signaling via the PI3-kinase/Akt pathway regulates airway glucose uptake and barrier function in a CFTR-dependent manner
Cystic fibrosis-related diabetes is the most common comorbidity associated with cystic fibrosis (CF) and correlates with increased rates of lung function decline. Because glucose is a nutrient present in the airways of patients with bacterial airway infections and because insulin controls glucose metabolism, the effect of insulin on CF airway epithelia was investigated to determine the role of insulin receptors and glucose transport in regulating glucose availability in the airway. The response to insulin by human airway epithelial cells was characterized by quantitative PCR, immunoblot, immunofluorescence, and glucose upt...
Source: AJP: Lung Cellular and Molecular Physiology - May 4, 2017 Category: Respiratory Medicine Authors: Molina, S. A., Moriarty, H. K., Infield, D. T., Imhoff, B. R., Vance, R. J., Kim, A. H., Hansen, J. M., Hunt, W. R., Koval, M., McCarty, N. A. Tags: RESEARCH ARTICLE Source Type: research

Nonantibiotic macrolides restore airway macrophage phagocytic function with potential anti-inflammatory effects in chronic lung diseases
We reported defective efferocytosis associated with cigarette smoking and/or airway inflammation in chronic lung diseases, including chronic obstructive pulmonary disease, severe asthma, and childhood bronchiectasis. We also showed defects in phagocytosis of nontypeable Haemophilus influenzae (NTHi), a common colonizer of the lower airway in these diseases. These defects could be substantially overcome with low-dose azithromycin; however, chronic use may induce bacterial resistance. The aim of the present study was therefore to investigate two novel macrolides—2'-desoxy-9-(S)-erythromycylamine (GS-459755) and azithro...
Source: AJP: Lung Cellular and Molecular Physiology - May 4, 2017 Category: Respiratory Medicine Authors: Hodge, S., Tran, H. B., Hamon, R., Roscioli, E., Hodge, G., Jersmann, H., Ween, M., Reynolds, P. N., Yeung, A., Treiberg, J., Wilbert, S. Tags: RESEARCH ARTICLE Source Type: research

{beta}2-Microglobulin participates in development of lung emphysema by inducing lung epithelial cell senescence
β2-Microglobulin (β2M), the light chain of the major histocompatibility complex class I (MHC I), has been identified as a proaging factor and is involved in the pathogenesis of neurodegenerative disorders by driving cognitive and regenerative impairments. However, little attention has focused on the effect of β2M in the development of lung emphysema. Here, we found that concentrations of β2M in plasma were significantly elevated in patients with lung emphysema than those in normal control subjects (1.89 ± 0.12 vs. 1.42 ± 0.06 mg/l, P < 0.01). Moreover, the expression of β2M was sig...
Source: AJP: Lung Cellular and Molecular Physiology - May 4, 2017 Category: Respiratory Medicine Authors: Gao, N., Wang, Y., Zheng, C.-M., Gao, Y.-L., Li, H., Li, Y., Fu, T.-T., Xu, L.-L., Wang, W., Ying, S., Huang, K. Tags: RESEARCH ARTICLE Source Type: research

Human airway trypsin-like protease, a serine protease involved in respiratory diseases
More than 2% of all human genes are coding for a complex system of more than 700 proteases and protease inhibitors. Among them, serine proteases play extraordinary, diverse functions in different physiological and pathological processes. The human airway trypsin-like protease (HAT), also referred to as TMPRSS11D and serine 11D, belongs to the emerging family of cell surface proteolytic enzymes, the type II transmembrane serine proteases (TTSPs). Through the cleavage of its four major identified substrates, HAT triggers specific responses, notably in epithelial cells, within the pericellular and extracellular environment, i...
Source: AJP: Lung Cellular and Molecular Physiology - May 4, 2017 Category: Respiratory Medicine Authors: Menou, A., Duitman, J., Flajolet, P., Sallenave, J.-M., Mailleux, A. A., Crestani, B. Tags: REVIEW Source Type: research

Hypoxic proliferation requires EGFR-mediated ERK activation in human pulmonary microvascular endothelial cells
We have previously shown that hypoxic proliferation of human pulmonary microvascular endothelial cells (hPMVECs) depends on epidermal growth factor receptor (EGFR) activation. To determine downstream signaling leading to proliferation, we tested the hypothesis that hypoxia-induced proliferation in hPMVECs would require EGFR-mediated activation of extracellular signal-regulated kinase (ERK) leading to arginase II induction. To test this hypothesis, hPMVECs were incubated in either normoxia (21% O2, 5% CO2) or hypoxia (1% O2, 5% CO2) and Western blotting was performed for EGFR, arginase II, phosphorylated-ERK (pERK), and tot...
Source: AJP: Lung Cellular and Molecular Physiology - May 1, 2017 Category: Respiratory Medicine Authors: White, H. A., Jin, Y., Chicoine, L. G., Chen, B., Liu, Y., Nelin, L. D. Tags: RESEARCH ARTICLE Source Type: research

BMP4 inhibits PDGF-induced proliferation and collagen synthesis via PKA-mediated inhibition of calpain-2 in pulmonary artery smooth muscle cells
In the present study, we investigated the effect of bone morphogenetic protein 4 (BMP4) on PDGF-induced cell proliferation and collagen synthesis in pulmonary artery smooth muscle cells (PASMCs). Normal human PASMCs were incubated with and without PDGF-BB in the absence and presence of BMP4 for 0.5 to 24 h. The protein levels of collagen-I, p-Smad2/3, p-Smad1/5, and intracellular active TGF-β1, calpain activity, and cell proliferation were then measured. The results showed that BMP4 induced an increase in p-Smad1/5 but had no effect on the protein levels of collagen-I, p-Smad2/3, and intracellular active TGF-β1 a...
Source: AJP: Lung Cellular and Molecular Physiology - May 1, 2017 Category: Respiratory Medicine Authors: Cai, P., Kovacs, L., Dong, S., Wu, G., Su, Y. Tags: RESEARCH ARTICLE Source Type: research