@article{APS4548,
author = {Xin-qi Peng and Mahendra Damarla and Jarrett Skirball and Stephanie Nonas and Xiao-ying Wang and Eugenia J Han and Emile J Hasan and Xuan Cao and Adel Boueiz and Rachel Damico and Rubin M Tuder and Alfred M Sciuto and Dana R Anderson and Joe GN Garcia and David A Kass and Paul M Hassoun and Jun-tian Zhang},
title = {Protective role of PI3-kinase/Akt/eNOS signaling in mechanical stress through inhibition of p38 mitogenactivated protein kinase in mouse lung},
journal = {Acta Pharmacologica Sinica},
volume = {31},
number = {2},
year = {2016},
keywords = {},
abstract = {Aim: To test the hypothesis that PI3K/Akt/eNOS signaling has a protective role in a murine model of ventilation associated lung injury (VALI) through down-regulation of p38 MAPK signaling.
Methods: Male C57BL/J6 (wild-type, WT) or eNOS knockout mice (eNOS–/–) were exposed to mechanical ventilation (MV) with low (LVT, 7 mL/kg) and high tidal volume (HVT, 20 mL/kg) for 0−4 h. A subset of WT mice was administered the specific inhibitors of PI3K (100 nmol/L Wortmannin [Wort], ip) or of p38 MAPK (SB203580, 2 mg/kg, ip) 1 h before MV. Cultured type II alveolar epithelial cells C10 were exposed to 18% cyclic stretch for 2 h with or without 20 nmol/L Wort pretreatment. At the end of the experiment, the capillary leakage in vivo was assessed by extravasation of Evans blue dye (EBD), wet/dry weight ratio and lung lavage protein concentration. The lung tissue and cell lysate were also collected for protein and histological review.
Results: MV decreased PI3K/Akt phosphorylation and eNOS expression but increased phospho-p38 MAPK expression along with a lung leakage of EBD. Inhibitions of phospho-Akt by Wort worsen the lung edema, whereas inhibition of p38 MAPK kinase restored activation of Akt together with alleviated capillary leakage. eNOS–/– mice showed an exacerbated lung edema and injury. The stretched C10 cells demonstrated that Wort diminished the activation of Akt, but potentiated phosphorylation of MAPK p38.
Conclusion: Our results indicate that PI-3K/Akt/eNOS pathway has significant protective effects in VALI by preventing capillary leakage, and that there is a cross-talk between PI3K/Akt and p38 MAPK pathways in vascular barrier dysfunction resulting from VALI.},
issn = {1745-7254}, url = {http://www.chinaphar.com/article/view/4548}
}