Abstract
Acute Lung Injury (ALI) is a major cause of death in sepsis resulting from Gram‐negative bacterial infection. Polymorphonuclear leukocytes (PMNs) respond to septicemic infection by releasing superoxide anions, which is a major mechanism for bacterial clearance. However, uncontrolled activation of the NADPH oxidase leads to injury to the host tissue, which underscores the importance for the proper regulation of this enzyme. PIP3 dependent Rac exchanger 1 (P‐Rex1), a Rac guanine nucleotide exchange factor, is known for its role in regulating chemoattractant‐induced superoxide production in PMNs through G‐protein coupled receptor (GPCR) signaling. Using P‐Rex1 knockout mice, we found that the LPS‐induced lung injury was significantly reduced as compared to the wild type mice. In addition, we also observed P‐Rex1 expression in lung microvascular endothelial cells, suggesting a function of P‐Rex1 in endothelial cell signaling. siRNA‐mediated knock‐down of P‐Rex1 expression in endothelial cells prevented the increase in endothelial barrier permeability following stimulation with TNF‐alpha, which is a major cytokine released in LPS‐induced sepsis. The altered endothelial permeability is accompanied by a severe ablation of TNF‐alpha‐induced Rac activation and reactive oxygen species (ROS) generation in endothelial cells. From these results, we conclude that TNF‐alpha contributes to lung microvascular permeability through ROS‐mediated disruption of the endothelial junction and P‐Rex1 plays a central role in this process. (Source of research support – NIH)
Published Version
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call