TNF-α Mediated Increase of HIF-1α Inhibits VASP Expression, Which Reduces Alveolar-Capillary Barrier Function during Acute Lung Injury ALIReportar como inadecuado




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Acute lung injury ALI is an inflammatory disorder associated with reduced alveolar-capillary barrier function and increased pulmonary vascular permeability. Vasodilator-stimulated phosphoprotein VASP is widely associated with all types of modulations of cytoskeleton rearrangement-dependent cellular morphology and function, such as adhesion, shrinkage, and permeability. The present studies were conducted to investigate the effects and mechanisms by which tumor necrosis factor-alpha TNF-α increases the tight junction permeability in lung tissue associated with acute lung inflammation. After incubating A549 cells for 24 hours with different concentrations 0–100 ng-mL of TNF-α, 0.1 to 8 ng-mL TNF-α exhibited no significant effect on cell viability compared with the 0 ng-mL TNF-α group control group. However, 10 ng-mL and 100 ng-mL TNF-α dramatically inhibited the viability of A549 cells compared with the control group *p<0.05. Monolayer cell permeability assay results indicated that A549 cells incubated with 10 ng-mL TNF-α for 24 hours displayed significantly increased cell permeability *p<0.05. Moreover, the inhibition of VASP expression increased the cell permeability *p<0.05. Pretreating A549 cells with cobalt chloride to mimic a hypoxia environment increased protein expression level of hypoxia inducible factor-1α HIF-1α *p<0.05, whereas protein expression level of VASP decreased significantly *p<0.05. In LPS-induced ALI mice, the concentrations of TNF-α in lung tissues and serum significantly increased at one hour, and the value reached a peak at four hours. Moreover, the Evans Blue absorption value of the mouse lung tissues reached a peak at four hours. The HIF-1α protein expression level in mouse lung tissues increased significantly at four hours and eight hours **p<0.001, whereas the VASP protein expression level decreased significantly **p<0.01. Taken together, our data demonstrate that HIF-1α acts downstream of TNF-α to inhibit VASP expression and to modulate the acute pulmonary inflammation process, and these molecules play an important role in the impairment of the alveolar-capillary barrier.



Autor: Mengjie Tang , Yihao Tian , Doulin Li, Jiawei Lv, Qun Li, Changchun Kuang, Pengchao Hu, Ying Wang, Jing Wang, Ke Su, Lei Wei

Fuente: http://plos.srce.hr/



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