Decreased expression of antioxidant enzymes and increased expression of chemokines in COPD lung

doi:10.1016/j.pupt.2006.06.006

Pulmonary Pharmacology & Therapeutics

Volume 20, Issue 5, October 2007, Pages 596-605

https://doi.org/10.1016/j.pupt.2006.06.006 Get rights and content

Abstract

The involvement of inflammation in the pathogenesis of chronic obstructive pulmonary disease (COPD) has been investigated using samples from relatively central airways such as airway biopsies, but there have been fewer studies in the peripheral lung, which is thought to be the main site of the disease process. To determine the molecules that relate to the mechanisms underlying the pathogenesis of COPD, we evaluated the mRNA expression of inflammatory cytokines, chemokines, oxidant enzymes, antioxidant enzymes, proteinases and antiproteinases in peripheral lung tissues from 33 COPD and non-COPD subjects who were undergoing lung resection for lung cancer using an RT-PCR technique.

Among the 42 studied candidate genes, the expressions of mRNA for catalase, glutathion S-transferase P1 (GSTP1), glutathion S-transferase M1 (GSTM1), microsomal epoxide hydrolase (mEPHX) and tissue inhibitor of metalloproteinase 2 (TIMP2) were significantly decreased in COPD lung tissues compared with those in non-COPD tissues, and most of these decreases were significantly correlated with the degree of airflow limitation. On the other hand, the expressions of mRNA for interleukin 1β (IL-1β), interleukin 8 (IL-8), growth-related oncogene-α (Gro-α) and monocyte chemotactic protein-1 (MCP-1) were significantly increased in COPD lungs. Most of these changes were also associated with cigarette smoking.

These data suggest that an impairment of protective mechanisms against oxidants and xenobiotics, in addition to the upregulation of CXC- and CC-chemokines, may be associated with cigarette smoking and involved in the inflammatory process of COPD.

Introduction

Chronic obstructive pulmonary disease (COPD) is a disease characterized by airway inflammation and progressive airflow limitation that is not fully reversible. The morbidity and mortality of the disease have increased in recent years and it is a serious public health problem in many countries throughout the world [1]. Abnormal inflammatory responses of the lungs against noxious gases and particles, such as cigarette smoke, are thought to cause small airway disease, namely obstructive bronchiolitis, and parenchymal destruction, leading to the pathophysiologic changes of COPD such as airflow limitation [2]. Although the precise mechanisms of these processes have not been fully clarified, several mechanisms have been suggested to contribute to the disease process.

The cellular inflammatory response in COPD is characterized by increases in neutrophils, macrophages and CD8-positive T lymphocytes in the lungs [3]. Inflammatory mediators from these cells and epithelial cells contribute to interactions among these cells and cause the pathophysiological changes of COPD including mucus hypersecretion, fibrosis, and parenchymal destruction [4]. Oxidative stress, which may result from excessive oxidants and/or impaired antioxidant activities, is thought to be one of the major causes of inflammation and injury in diseased lungs. Oxidative stress arises during the inflammatory process in the lung and also from the environment. Both endogenous reactive oxygen species released from inflammatory cells such as neutrophils and macrophages and oxidant compounds in cigarette smoke or air pollution cause injuries to lung tissues [5]. These harmful molecules are eliminated by antioxidant enzyme activities in normal lungs [6]. In COPD lungs, these protective mechanisms seem to be impaired. Another mechanism in the COPD pathogenesis is an imbalance of proteinase and antiproteinase. α₁-antitrypsin has been shown to be involved in the structural changes in COPD, and a number of proteinases and antiproteinases have been reported to play roles in the inflammatory process in COPD [7].

The involvement of inflammation, oxidative stress and a proteinase/antiproteinase imbalance in the pathogenesis of COPD has been investigated using samples from COPD subjects. Many studies employing samples from relatively central airways such as airway biopsies and induced sputum have revealed an alteration in the formation of inflammatory mediators, oxidant, antioxidant, proteinase and antiproteinase in COPD airways. However, there have been fewer studies in the peripheral lung, which is thought to be the main site of the disease process.

In this study, we evaluated the expressions of 42 genes for inflammatory cytokines, chemokines, oxidant enzymes, antioxidant enzymes, proteinases and antiproteinases in peripheral lung tissues from COPD and non-COPD subjects. We found decreased mRNA expressions for catalase, glutathion S-transferase P1 (GSTP1), glutathion S-transferase M1 (GSTM1), microsomal epoxide hydrolase (mEPHX) and tissue inhibitor of metalloproteinase 2 (TIMP2) and increased expressions for interleukin 1β (IL-1β), interleukin 8 (IL-8), growth-related oncogene-α (Gro-α) and monocyte chemotactic protein-1 (MCP-1) in the COPD lung. Most of these changes were associated with the degree of airflow limitation and cigarette smoking.

Section snippets

Subjects

Thirty-three patients with or without COPD who were undergoing lung resection for lung cancer took part in the study after giving written informed consent. This study was approved by the Tohoku University Committee on Clinical Investigations and by the Ethics Review Board of Miyagi Prefectural Cancer Center. According to the presence or absence of COPD and a history of smoking, the subjects were divided into three groups: 10 non-COPD subjects who never smoked, 9 non-COPD smokers and 14 COPD

mRNA expressions of the 42 studied candidate genes

Table 3 shows all the data of the mRNA amounts observed in this study. We found some significant differences between COPD and non-COPD subjects. The expressions of mRNA for catalase, GSTP1, mEPHX, GSTM1 and TIMP2 were significantly decreased in COPD lung tissues compared with those in non-COPD tissues. On the other hand, the mRNA expressions for IL-1β, IL-8, Gro-α and MCP-1 were significantly increased in COPD compared with non-COPD. None of the other studied genes showed significant changes in

Discussion

In this study, we observed decreased expressions of mRNA for catalase, GSTP1, GSTM1, mEPHX and TIMP2 and increased expressions of mRNA for IL-1β, IL-8, Gro-α and MCP-1 in peripheral lungs from patients with COPD. Most of these changes in mRNA expressions were associated with the degree of airflow limitation and with the cigarette smoking habit.

Although the precise mechanisms of the pathogenesis of COPD have not been fully elucidated, it is thought that the inflammatory responses of the lungs

Acknowledgements

We are grateful to Drs. Kaoru Koike and Shinsaku Ueda for assistance in recruiting subjects and in preparing samples, to Mrs. and Ms. Shigeru Morita, Hiroki Iwashita, Yumiko Uno and Masashi Yamasaki for assistance with RT-PCR and to Mr. Brent Bell for reading the manuscript. MT and HS do not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. AK received a scholarship of $30,000 in 2004 from Pfizer. YK and TA do not have a financial

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Decreased expression of antioxidant enzymes and increased expression of chemokines in COPD lung

Abstract

Introduction

Section snippets

Subjects

mRNA expressions of the 42 studied candidate genes

Discussion

Acknowledgements

Chest

Eur J Pharmacol

Int J Mol Med

Respir Med

Am J Pathol

Evidence-based health policy–lessons from the global burden of disease study

Science

Cellular and structural bases of chronic obstructive pulmonary disease

Am J Respir Crit Care Med

Antioxidant macromolecules in the epithelial lining fluid of the normal human lower respiratory tract

J Clin Invest

Neutrophils and protease/antiprotease imbalance

Am J Respir Crit Care Med

Xanthine oxidase inhibition reduces reactive nitrogen species production in COPD airways

Eur Respir J

Increase in reactive nitrogen species production in chronic obstructive pulmonary disease airways

Am J Respir Crit Care Med

The study of the antioxidant enzymes in erythrocytes in lung diseases

Patol Fiziol Eksp Ter

Erythrocytes from cigarette smokers contain more glutathione and catalase and protect endothelial cells from hydrogen peroxide better than do erythrocytes from nonsmokers

Am Rev Respir Dis

Comprehensive gene expression profiles reveal pathways related to the pathogenesis of chronic obstructive pulmonary disease

Proc Natl Acad Sci USA

Heterogeneous expression and polymorphic genotype of glutathione S-transferases in human lung

Thorax