scholarly journals Cyclic stretch induces alveolar epithelial barrier dysfunction via calpain-mediated degradation of p120-catenin

2011 ◽  
Vol 301 (2) ◽  
pp. L197-L206 ◽  
Author(s):  
Yuelan Wang ◽  
Richard D. Minshall ◽  
David E. Schwartz ◽  
Guochang Hu
Keyword(s):  
Lung Injury ◽  
Alveolar Epithelial Cells ◽  
Cyclic Stretch ◽  
Epithelial Barrier ◽  
Gap Formation ◽  
Barrier Dysfunction ◽  
P120 Catenin ◽  
Alveolar Epithelial ◽  
Ventilator Induced Lung Injury ◽  
Epithelial Barrier Dysfunction

Lung hyperinflation is known to be an important contributing factor in the pathogenesis of ventilator-induced lung injury. Mechanical stretch causes epithelial barrier dysfunction and an increase in alveolar permeability, although the precise mechanisms have not been completely elucidated. p120-catenin is an adherens junction-associated protein that regulates cell-cell adhesion. In this study, we determined the role of p120-catenin in cyclic stretch-induced alveolar epithelial barrier dysfunction. Cultured alveolar epithelial cells (MLE-12) were subjected to uniform cyclic (0.5 Hz) biaxial stretch from 0 to 8 or 20% change in surface area for 0, 1, 2, or 4 h. At the end of the experiments, cells were lysed to determine p120-catenin expression by Western blot analysis. Immunofluorescence staining of p120-catenin and F-actin was performed to assess the integrity of monolayers and interepithelial gap formation. Compared with unstretched control cells, 20% stretch caused a significant loss in p120-catenin expression, which was coupled to interepithelial gap formation. p120-Catenin knockdown with small interfering RNA (siRNA) dose dependently increased stretch-induced gap formation, whereas overexpression of p120-catenin abolished stretch-induced gap formation. Furthermore, pharmacological calpain inhibition or depletion of calpain-1 with a specific siRNA prevented p120-catenin loss and subsequent stretch-induced gap formation. Our findings demonstrate that p120-catenin plays a critical protective role in cyclic stretch-induced alveolar barrier dysfunction, and, thus, maintenance of p120-catenin expression may be a novel therapeutic strategy for the prevention and treatment of ventilator-induced lung injury.

scholarly journals Ma Xing Shi Gan Decoction Protects against PM2.5-Induced Lung Injury through Suppression of Epithelial-to-Mesenchymal Transition (EMT) and Epithelial Barrier Disruption

2020 ◽  
Vol 2020 ◽  
pp. 1-17
Author(s):  
Ye-fang Wang ◽  
Yu-xiang Fei ◽  
Bo Zhao ◽  
Qi-yang Yin ◽  
Jian-ping Zhu ◽  
...  
Keyword(s):  
Lung Injury ◽  
Epithelial To Mesenchymal Transition ◽  
Cell Model ◽  
Alveolar Epithelial Cell ◽  
Epithelial Barrier ◽  
Barrier Dysfunction ◽  
Mesenchymal Transition ◽  
Epithelial Barrier Dysfunction

This research was designed to explore the effect of Ma Xing Shi Gan decoction (MXD) in alleviating particulate matter less than 2.5 μm in diameter (PM2.5) induced lung injury from the perspective of epithelial barrier protection and inhibition of epithelial-to-mesenchymal transition (EMT). Rats were exposed to PM2.5 to establish a lung injury model in vivo, and a PM2.5-stimulated primary cultured type II alveolar epithelial cell model was introduced in vitro. Our results indicated that MXD alleviated the weight loss and pathologic changes and improved the epithelial barrier dysfunction. MXD also significantly inhibited the TGF-β/Smad3 pathway, increased the level of ZO-1 and claudin-5, and reversed the EMT process. Notably, the protection of MXD was abolished by TGF-β in vitro. Our results indicated that MXD has a protection against PM2.5-induced lung injury. The proposed mechanism is reversing PM2.5-induced EMT through inhibiting TGF-β/Smad3 pathway and then upregulating the expression of tight-junction proteins.

Angiotensin II mediates glutathione depletion, transforming growth factor-β1 expression, and epithelial barrier dysfunction in the alcoholic rat lung

2005 ◽  
Vol 289 (3) ◽  
pp. L363-L370 ◽  
Author(s):  
Rabih I. Bechara ◽  
Andres Pelaez ◽  
Andres Palacio ◽  
Pratibha C. Joshi ◽  
C. Michael Hart ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Angiotensin Ii ◽  
Transforming Growth Factor ◽  
Glutathione Depletion ◽  
Ethanol Ingestion ◽  
Epithelial Barrier ◽  
Barrier Dysfunction ◽  
Alveolar Epithelial ◽  
Epithelial Barrier Dysfunction ◽  
Tgf Β1

Alcohol abuse markedly increases the risk of sepsis-mediated acute lung injury. In a rat model, ethanol ingestion alone (in the absence of any other stress) causes pulmonary glutathione depletion, increased expression of transforming growth factor-β1 (TGF-β1), and alveolar epithelial barrier dysfunction, even though the lung appears grossly normal. However, during endotoxemia, ethanol-fed rats release more activated TGF-β1 into the alveolar space where it can exacerbate epithelial barrier dysfunction and lung edema. Ethanol ingestion activates the renin-angiotensin system, and angiotensin II is capable of inducing oxidative stress and TGF-β1 expression. We determined that lisinopril, an angiotensin-converting enzyme inhibitor that decreases angiotensin II formation, limited lung glutathione depletion, and treatment with either lisinopril or losartan, a selective angiotensin II type 1 receptor blocker, normalized TGF-β1 expression. The glutathione precursor procysteine also prevented TGF-β1 expression, suggesting that TGF-β1 may be induced indirectly by angiotensin II-mediated oxidative stress and glutathione depletion. Importantly, lisinopril treatment normalized barrier function in alveolar epithelial cell monolayers from ethanol-fed rats, and treatment with either lisinopril or losartan normalized alveolar epithelial barrier function in ethanol-fed rats in vivo, as reflected by lung liquid clearance of an intratracheal saline challenge, even during endotoxemia. In parallel, lisinopril treatment limited TGF-β1 protein release into the alveolar space during endotoxemia. Together, these results suggest that angiotensin II mediates oxidative stress and the consequent TGF-β1 expression and alveolar epithelial barrier dysfunction that characterize the alcoholic lung.

scholarly journals Magnitude-dependent effects of cyclic stretch on HGF- and VEGF-induced pulmonary endothelial remodeling and barrier regulation

2008 ◽  
Vol 295 (4) ◽  
pp. L612-L623 ◽  
Author(s):  
Anna A. Birukova ◽  
Nurgul Moldobaeva ◽  
Junjie Xing ◽  
Konstantin G. Birukov
Keyword(s):  
Growth Factor ◽  
Lung Injury ◽  
Synergistic Effects ◽  
Endothelial Permeability ◽  
Small Gtpase ◽  
Cyclic Stretch ◽  
Dependent Manner ◽  
Protective Effects ◽  
Gap Formation ◽  
Barrier Dysfunction

Mechanical ventilation at high tidal volumes compromises the blood-gas barrier and increases lung vascular permeability, which may lead to ventilator-induced lung injury and pulmonary edema. Using pulmonary endothelial cell (ECs) exposed to physiologically [5% cyclic stretch (CS)] and pathologically (18% CS) relevant magnitudes of CS, we evaluated the potential protective effects of hepatocyte growth factor (HGF) on EC barrier dysfunction induced by CS and vascular endothelial growth factor (VEGF). In static culture, HGF enhanced EC barrier function in a Rac-dependent manner and attenuated VEGF-induced EC permeability and paracellular gap formation. The protective effects of HGF were associated with the suppression of Rho-dependent signaling triggered by VEGF. Five percent CS promoted HGF-induced enhancement of the cortical F-actin rim and activation of Rac-dependent signaling, suggesting synergistic barrier-protective effects of physiological CS and HGF. In contrast, 18% CS further enhanced VEGF-induced EC permeability, activation of Rho signaling, and formation of actin stress fibers and paracellular gaps. These effects were attenuated by HGF pretreatment. EC preconditioning at 5% CS before HGF and VEGF further promoted EC barrier maintenance. Our data suggest synergistic effects of HGF and physiological CS in the Rac-mediated mechanisms of EC barrier protection. In turn, HGF reduced the barrier-disruptive effects of VEGF and pathological CS via downregulation of the Rho pathway. These results support the importance of HGF-VEGF balance in control of acute lung injury/acute respiratory distress syndrome severity via small GTPase-dependent regulation of lung endothelial permeability.

Death-associated Protein Kinase 1 Mediates Ventilator-induced Lung Injury in Mice by Promoting Alveolar Epithelial Cell Apoptosis

2020 ◽  
Vol 133 (4) ◽  
pp. 905-918
Author(s):  
Yaxin Wang ◽  
Yiyi Yang ◽  
Lin Chen ◽  
Wei Xiong ◽  
Limin Song ◽  
...  
Keyword(s):  
Epithelial Cell ◽  
Lung Injury ◽  
Tidal Volume ◽  
Cell Apoptosis ◽  
Alveolar Epithelial Cell ◽  
B Cell Lymphoma ◽  
Cyclic Stretch ◽  
Alveolar Epithelial ◽  
Ventilator Induced Lung Injury ◽  
Epithelial Cell Apoptosis

Background Alveolar epithelial cell apoptosis is implicated in the onset of ventilator-induced lung injury. Death-associated protein kinase 1 (DAPK1) is associated with cell apoptosis. The hypothesis was that DAPK1 participates in ventilator-induced lung injury through promoting alveolar epithelial cell apoptosis. Methods Apoptosis of mouse alveolar epithelial cell was induced by cyclic stretch. DAPK1 expression was altered (knockdown or overexpressed) in vitro by using a small interfering RNA or a plasmid, respectively. C57/BL6 male mice (n = 6) received high tidal volume ventilation to establish a lung injury model. Adeno-associated virus transfection of short hairpin RNA and DAPK1 inhibitor repressed DAPK1 expression and activation in lungs, respectively. The primary outcomes were alveolar epithelial cell apoptosis and lung injury. Results Compared with the control group, the 24-h cyclic stretch group showed significantly higher alveolar epithelial cell apoptotic percentage (45 ± 4% fold vs. 6 ± 1% fold; P < 0.0001) and relative DAPK1 expression, and this group also demonstrated a reduced apoptotic percentage after DAPK1 knockdown (27 ± 5% fold vs. 53 ± 8% fold; P < 0.0001). A promoted apoptotic percentage in DAPK1 overexpression was observed without stretching (49 ± 6% fold vs. 14 ± 3% fold; P < 0.0001). Alterations in B-cell lymphoma 2 and B-cell lymphoma 2–associated X are associated with DAPK1 expression. The mice subjected to high tidal volume had higher DAPK1 expression and alveolar epithelial cell apoptotic percentage in lungs compared with the low tidal volume group (43 ± 6% fold vs. 4 ± 2% fold; P < 0.0001). Inhibition of DAPK1 through adeno-associated virus infection or DAPK1 inhibitor treatment appeared to be protective against lung injury with reduced lung injury score, resolved pulmonary inflammation, and repressed alveolar epithelial cell apoptotic percentage (47 ± 4% fold and 48 ± 6% fold; 35 ± 5% fold and 34 ± 4% fold; P < 0.0001, respectively). Conclusions DAPK1 promotes the onset of ventilator-induced lung injury by triggering alveolar epithelial cell apoptosis through intrinsic apoptosis pathway in mice. Editor’s Perspective What We Already Know about This Topic What This Article Tells Us That Is New

scholarly journals HIV-1 transgene expression in rats causes oxidant stress and alveolar epithelial barrier dysfunction

2009 ◽  
Vol 6 (1) ◽  
pp. 1 ◽  
Author(s):  
Coy Lassiter ◽  
Xian Fan ◽  
Pratibha C Joshi ◽  
Barbara A Jacob ◽  
Roy L Sutliff ◽  
...  
Keyword(s):  
Transgene Expression ◽  
Oxidant Stress ◽  
Epithelial Barrier ◽  
Barrier Dysfunction ◽  
Alveolar Epithelial ◽  
Epithelial Barrier Dysfunction ◽  
Hiv 1
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