Fasudil, a Rho-Kinase Inhibitor, Attenuates Bleomycin-Induced Pulmonary Fibrosis in Mice

Chunguo Jiang,Zhiwei Lu,Zuojun Xu,Hui Huang,Jia Liu,Yanxun Wang

doi:10.3390/ijms13078293

Abstract

The mechanisms underlying the pathogenesis of idiopathic pulmonary fibrosis (IPF) involve multiple pathways, such as inflammation, epithelial mesenchymal transition, coagulation, oxidative stress, and developmental processes. The small GTPase, RhoA, and its target protein, Rho-kinase (ROCK), may interact with other signaling pathways known to contribute to pulmonary fibrosis. This study aimed to determine the beneficial effects and mechanisms of fasudil, a selective ROCK inhibitor, on bleomycin-induced pulmonary fibrosis in mice. Our results showed that the Aschcroft score and hydroxyproline content of the bleomycin-treated mouse lung decreased in response to fasudil treatment. The number of infiltrated inflammatory cells in the bronchoalveolar lavage fluid (BALF) was attenuated by fasudil. In addition, fasudil reduced the production of transforming growth factor-β1 (TGF-β1), connective tissue growth factor (CTGF), alpha-smooth muscle actin (α-SMA), and plasminogen activator inhibitor-1 (PAI-1) mRNA and protein expression in bleomycin-induced pulmonary fibrosis. These findings suggest that fasudil may be a potential therapeutic candidate for the treatment of pulmonary fibrosis.

Highlights

Idiopathic pulmonary fibrosis (IPF) is a specific form of chronic, progressive fibrosing interstitial lung disease of unknown etiology [1]
The effect of fasudil against bleomycin-induced inflammation and fibrosis was examined on day 21 after bleomycin infusion (Figure 1)
A well-alveolized normal histology was observed in the phosphate-buffered saline (PBS) + normal saline (NS)-treated control group

Summary

Introduction

Idiopathic pulmonary fibrosis (IPF) is a specific form of chronic, progressive fibrosing interstitial lung disease of unknown etiology [1]. The mechanisms underlying the pathogenesis of IPF involve multiple pathways, such as inflammation, epithelial mesenchymal transition, coagulation, oxidative stress, and developmental processes, which result in alveolar epithelial cell injury and fibroblast proliferation that leads to abnormal deposition of extracellular collagen [2]. The Rho/ROCK-mediated pathway plays a role in infiltration of inflammatory cells both in vitro and in vivo [5,6]. Transforming growth factor-β1 (TGF-β1) links inflammation to fibrogenesis and is one of the key mediators in the fibrotic process [7]. As a downstream mediator of TGF-β1, connective tissue growth factor (CTGF)

Objectives

Methods

Results

Conclusion