Gallic Acid Induces a Reactive Oxygen Species-Provoked c-Jun NH2-Terminal Kinase-Dependent Apoptosis in Lung Fibroblasts

Chiu-Yuan Chen,Kun-Chieh Chen,Hsiang-Chun Liu,Tsung-Ying Yang,Shih-Lan Hsu

doi:10.1155/2013/613950

Abstract

Idiopathic pulmonary fibrosis is a chronic lung disorder characterized by fibroblasts proliferation and extracellular matrix accumulation. Induction of fibroblast apoptosis therefore plays a crucial role in the resolution of this disease. Gallic acid (3,4,5-trihydroxybenzoic acid), a common botanic phenolic compound, has been reported to induce apoptosis in tumor cell lines and renal fibroblasts. The present study was undertaken to examine the role of mitogen-activated protein kinases (MAPKs) in lung fibroblasts apoptosis induced by gallic acid. We found that treatment with gallic acid resulted in activation of c-Jun NH2-terminal kinase (JNK), extracellular signal-regulated kinase (ERK), and protein kinase B (PKB, Akt), but not p38MAPK, in mouse lung fibroblasts. Inhibition of JNK using pharmacologic inhibitor (SP600125) and genetic knockdown (JNK specific siRNA) significantly inhibited p53 accumulation, reduced PUMA and Fas expression, and abolished apoptosis induced by gallic acid. Moreover, treatment with antioxidants (vitamin C, N-acetyl cysteine, and catalase) effectively diminished gallic acid-induced hydrogen peroxide production, JNK and p53 activation, and cell death. These observations imply that gallic acid-mediated hydrogen peroxide formation acts as an initiator of JNK signaling pathways, leading to p53 activation and apoptosis in mouse lung fibroblasts.

Highlights

Idiopathic pulmonary fibrosis (IPF) is a progressive and usually fatal disorder with a reported median survival of 3 to 6 years from the time of diagnosis [1]
It was found that the inhibition of ATM/p53 activity by pharmacologic and genetic strategies partially blocked the gallic acid-induced apoptotic process [16], indicating that another pathway might be involved in gallic acidtriggered lung fibroblast apoptosis
It has been reported that mitogen-activated protein kinase (MAPK) and phosphoinositide 3-kinase (PI3K)/protein kinase B (PKB/Akt) signaling pathways are the primary intermediates for the induction of apoptosis by oxidative stress [19]

Summary

Introduction

Idiopathic pulmonary fibrosis (IPF) is a progressive and usually fatal disorder with a reported median survival of 3 to 6 years from the time of diagnosis [1]. IPF is characterized by the loss of lung epithelium and the formation of scar tissue within the lungs with accumulation of fibroblasts and myofibroblasts that deposit excessive extracellular matrix including collagen [2]. Increasing evidence shows that the abnormal wound repair process in response to alveolar epithelial injury is responsible for IPF and fibroblastto-myofibroblast differentiation, which represents a key event during tissue repair [2]. In contrast to epithelial cells, fibroblasts derived from IPF lungs are more resistant to apoptosis than normal lung fibroblasts [5]. Immoderate cell loss in the alveolar epithelium may Evidence-Based Complementary and Alternative Medicine be important early in IPF progression, while reduced fibroblasts/myofibroblasts apoptosis has been associated with the formation of fibrotic lesions [6].

Objectives

Methods

Results

Conclusion