The Anti-Fibrotic Effects of CG-745, an HDAC Inhibitor, in Bleomycin and PHMG-Induced Mouse Models.

Young-Suk Kim,Hak-Ryul Kim,Hyunju Cha,Joong-Myung Cho,Hyo-Jin Kim

doi:10.3390/molecules24152792

Abstract

Idiopathic pulmonary fibrosis (IPF) is a fatal lung disease with poor prognosis and progression to lung fibrosis related to genetic factors as well as environmental factors. In fact, it was discovered that in South Korea many people who used humidifier disinfectants containing polyhexamethylene guanidine (PHMG), died of lung fibrosis. Currently two anti-fibrotic drugs, pirfenidone and nintedanib, have been approved by the FDA, but unfortunately, do not cure the disease. Since the histone deacetylase (HDAC) activity is associated with progression to chronic diseases and with fibrotic phenomena in the kidney, heart and lung tissues, we investigated the anti-fibrotic effects of CG-745, an HDAC inhibitor. After lung fibrosis was induced in two animal models by bleomycin and PHMG instillation, the regulation of fibrosis and epithelial mesenchymal transition (EMT)-related markers was assessed. CG-745 exhibited potent prevention of collagen production, inflammatory cell accumulation, and cytokines release in both models. Additionally, N-cadherin and vimentin expression were lowered significantly by the treatment of CG-745. The anti-fibrotic effects of CG-745 proven by the EMT regulation may suggest a potential therapeutic effect of CG-745 on lung fibrosis.

Highlights

IntroductionIdiopathic pulmonary fibrosis (IPF) is the most common and lethal diffuse fibrosis lung disease
Idiopathic pulmonary fibrosis (IPF) is the most common and lethal diffuse fibrosis lung disease.It is a chronic, progressive, fibrotic interstitial lung disease of unknown cause that occurs frequently in older adults [1,2]
We investigated whether the inhibitory activities and anti-fibrotic effects of CG-745 show any favorable treatment effect on pulmonary fibrosis in animal models induced by bleomycin and polyhexamethylene guanidine (PHMG)

Summary

Introduction

Idiopathic pulmonary fibrosis (IPF) is the most common and lethal diffuse fibrosis lung disease. It is a chronic, progressive, fibrotic interstitial lung disease of unknown cause that occurs frequently in older adults [1,2]. A favored conceptual model of the IPF pathogenesis is that recurrent, subclinical epithelial injury superimposed on accelerated epithelial aging leads to the aberrant repair of the injured alveolus and deposition of interstitial fibrosis by myofibroblasts. The senescence of these alveolar epithelial cells and fibroblasts appears to be a central phenotype that promotes lung fibrosis [3]. IPF is generally induced by the usage of antitumor drug, bleomycin, which causes cell damage, oxidative stress, and activates inflammation to develop IPF in animal models [4].

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