Simvastatin Ameliorates PAK4 Inhibitor-Induced Gut and Lung Injury.

Huiqi Wang,Shuming Pan,Xuan Liu,Zengbin Wu,Dan Liu,Liang Chen,Aihua Fei,Chengjin Gao,Jiameng Chen

doi:10.1155/2017/8314276

Abstract

P21 activated kinase 4 (PAK4), a key regulator of cytoskeletal rearrangement and endothelial microparticles (EMPs), is released after lipopolysaccharide (LPS) stimulation. In addition, it participates in LPS-induced lung injury. In this study, forty-eight Sprague Dawley (SD) rats were divided into two groups, including PAK4 inhibitor (P) and PAK4 inhibitor + simvastatin (P + S) treatment groups. All rats were given PAK4 inhibitor (15 mg/kg/d) orally. Immediately after PAK4 inhibitor administration, simvastatin was injected intraperitoneally to P + S group animals at 20 mg/kg/day. Then, treatment effects on the intestinal mucosal barrier and lung injury caused by PAK4 inhibitor and simvastatin were assessed. The results showed that gut Zonula Occludens- (ZO-) 1, PAK4, mitogen-activated protein kinase 4 (MPAK4), and CD11c protein levels were reduced, while plasma endotoxin levels were increased after administration of PAK4 inhibitor. Furthermore, compared with normal rats, wet-to-dry (W/D) values of lung tissues and circulating EMP levels were increased in the treatment group, while PAK4 and CD11c protein amounts were reduced. Therefore, in this lung injury process induced by PAK4 inhibitor, the protective effects of simvastatin were reflected by intestinal mucosal barrier protection, inflammatory response regulation via CD11c+ cells, and cytoskeleton stabilization. In summary, PAK4 is a key regulator in the pathophysiological process of acute lung injury (ALI) and can be a useful target for ALI treatment.

Highlights

Sepsis is one of the principal causes of death in critical care medicine departments [1]
We previously demonstrated that enhanced circulating endothelial microparticle (EMP) levels [4, 12] result from disorders of the pulmonary vascular endothelial cytoskeleton
We previously demonstrated that simvastatin attenuates LPS-induced acute lung injury (ALI) via cytoskeleton stabilization by regulating the pulmonary Cdc42-P21 activated kinase 4 (PAK4) pathway and altering the levels of circulating endothelial microparticles (EMPs) [4]

Summary

Introduction

Sepsis is one of the principal causes of death in critical care medicine departments [1]. According to SEPSIS 3.0, organ dysfunction is the main characteristic of septic patients, who commonly develop lung failure. Acute lung injury (ALI) can result from multiple intrapulmonary and extrapulmonary pathological stimuli [3], sepsis remains the leading risk factor. Gut barrier dysfunction is very common and considered a component of distant organ failure, including lung injury [6]. The gut and its contents act as a reservoir for bacteria and endotoxins, which can subsequently induce systemic inflammatory response syndrome (SIRS), ALI, and multiple organ dysfunction syndrome (MODS) [7]. Gut barrier dysfunction is one of the main factors in this pathological process, which is considered a loss of intestinal mucosal integrity, leading to bacterial translocation and the release of gut-derived proinflammatory cytokines [8]

Methods

Results

Conclusion