Serial review: role of reactive oxygen and nitrogen species (ROS/RNS) in lung injury and diseases
ROS in the local and systemic pathogenesis of COPD

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Abstract

An imbalance between oxidants and antioxidants is proposed in the pathogenesis of COPD. Potential alterations responsible for an imbalance in oxidant production and intra- and extracellular antioxidant defense systems are discussed with respect to COPD-related changes in the pulmonary compartment. In line with the current view of COPD as a disease with multiple systemic consequences, there is increasing evidence that imbalances in the redox milieu extend beyond the diseased lung in COPD patients. Skeletal muscle dysfunction is often observed in COPD and may result from imbalances in the redox environment of skeletal muscle. Potential triggers of oxidative stress in the muscle compartment include inflammation and hypoxia, and local sources of reactive oxygen and nitrogen species are discussed, as well the mechanisms by which skeletal muscle trophical state, contractility and fatigability may be affected by oxidative stress, resulting in skeletal muscle dysfunction.

Introduction

Chronic obstructive pulmonary disease (COPD) is a slowly progressive condition characterized by poorly reversible airflow limitation that is usually progressive and associated with an abnormal inflammatory response of the lung [1]. The inflammation is chronic and occurs both in the large and small airways, resulting in a heterogeneous disease consisting of morphological changes in three regions of the lungs: central airways (chronic bronchitis), peripheral airways (small airway disease), and the lung parenchyma (emphysema). Smoking has been implicated as the main etiologic factor for the development of COPD [2], and a smoking history of at least 20 pack years is common. However, it is still unknown why only a small proportion of smokers acquire COPD [3]. An increasing amount of research has focused on the hypothesis that an oxidant/antioxidant imbalance occurs in smokers and in patients with COPD as part of the pathogenesis of this condition.

Cigarette smoke contains over 4700 chemical compounds, and both the tar and gas phases contain numerous free radicals and other oxidants present in high concentrations [4]. Nitric Oxide (NO) is present in cigarette smoke in concentrations of 500–1000 ppm [5]. NO reacts quickly with the superoxide anion (O2) to form peroxynitrite (ONOO−) and with peroxyl radicals to give alkyl peroxynitrites (ROONO). The radicals in the tar phase of cigarettes are more stable and are predominantly organic. Cigarette smoke tar is also an effective metal chelator and can bind iron, which can contribute to the generation of H2O2.

An association between dietary intake of antioxidant vitamins and lung function has been demonstrated in epidemiological studies. Epidemiological findings during the last decade have also indicated potential protective effects of dietary factors in the development and clinical course of COPD. Reasonably consistent evidence indicates an association between dietary intake of the antioxidant vitamin C and pulmonary function, while associations regarding vitamin C and COPD symptoms are not consistent, as a link between dietary vitamin C intake and COPD mortality in middle-aged men could not be demonstrated 6, 7. Intake of fruit and whole grains, which are rich in antioxidant substances, also appears to be protectively associated with pulmonary function 8, 9. High intake of catechins, a flavenoid subclass with anti-inflammatory and antioxidative effects, has beneficial associations with the degree of airflow limitation and with the prevalence of chronic cough, chronic phlegm, and breathlessness [9]. These observed effects of diet and nutrition on COPD are of public health relevance, and causality of the observed effects, particularly of antioxidant factors, is supported by the existence of plausible biological mechanisms of action of these agents in the pathogenesis of COPD.

Studies focusing on “susceptibility polymorphisms” in enzymes involved in the xenobiotic metabolism of antioxidant enzyme genes have stressed the possible role of oxidative stress in the pathogenesis of COPD. Indeed, it is well recognized that only a proportion of cigarette smokers develop the clinical syndrome of COPD. Alterations in enzyme systems designed to detoxify reactive substances may contribute to an increased risk for developing COPD. Microsomal epoxide hydrolase (mEH) is a xenobiotic metabolizing enzyme that converts reactive epoxides into more soluble dihydrodiol derivatives that are more readily exerted from the body. A study of patients who had COPD or emphysema showed that there was a significant increase in homozygosity for the slow-activity mEH allele in both groups, suggesting that low levels of mEH leave the lung vulnerable to damage by epoxides [10]. Glutathione-S-transferases are a family of enzymes that play an important role in detoxifying various aromatic hydrocarbons found in cigarette smoke. Homozygous deficiency for GST-M1 was associated with emphysema in patients who had lung cancer and severe chronic bronchitis in heavy smokers [11]. Homozygotes for the isoleucine allele of the GST-P1 polymorphism were significantly increased in Japanese patients with COPD, suggesting that this isoleucine polymorphism may be less protective against xenobiotics in tobacco smoke [12]. Cytochrome P4501A1 (CYP1A1) is another enzyme involved in the xenobiotic metabolism. It has been demonstrated that the high activity allele (Val 462) was associated with susceptibility to centriacinar emphysema in patients who had lung cancer [13]. Genes coding for inflammatory cytokines could be related to a higher susceptibility to develop chronic inflammation, a key pathogenetic factor in COPD. Previously, a relationship between COPD and TNF-α 308G/A polymorphisms was reported in a Taiwanese [14] and a Japanese population [15]. Recent studies with Caucasian COPD populations did not support these data 16, 17, 18, although it has been suggested that homozygosity for the A allele predisposes for a worse prognosis in COPD [18]. In a recent study the putative involvement of TNF-α gene polymorphisms in relation to COPD was extended by analysis of these polymorphisms at locations −376G/A, −308G/A, −238G/A, and +489G/A. The study was performed in a Caucasian COPD population, stratified for the presence of radiological emphysema based on high resolution computed tomography (HRCT) scanning.

It was found that COPD, and especially a subgroup of COPD patients without radiological emphysema, was associated with TNF-α +489G/A gene polymorphism [19].

Inactivation of alpha1-proteinase inhibitor is traditionally considered as the mechanism by which oxidants contribute to the pathogenesis of COPD. It was hypothesized that this inactivation process contributes to a functional deficiency of alpha1-PI in the airspaces and this was thought critical to the proteinase/antiproteinase imbalance as part of the pathogenesis of emphysema. However, present insights regarding the role and the variety of metalloproteinases (MMPs) and their inhibitors in matrix degradation processes have challenged this hypothesis.

Despite the overwhelming amount of studies demonstrating the presence of increased oxidative stress and oxidative damage in patients with COPD, the precise role of the increased oxidant burden in the pathogenesis of COPD needs to be clarified, as oxidative stress can be related to the process of chronic inflammation in COPD.

Markers of oxidative stress have been demonstrated in different bodily compartments. As muscle wasting is highly related to the morbidity and mortality in these patients and has even been found to be present in a considerable proportion even in mild COPD, an increasing amount of research focuses on the role of oxidant/antioxidant imbalance in skeletal muscles. Present insights regarding the role of oxidative oxidant burden in the pathogenesis of the process of muscle wasting is therefore reviewed in this article.

Section snippets

Oxidative stress and the respiratory compartment

The sources of the increased oxidative stress in the respiratory compartment in patients with COPD derive from the increased burden of oxidants in cigarette smoke, and from the increased amounts of reactive oxygen and nitrogen species (ROS and RNS) released from leukocytes and macrophages involved in the inflammatory process in COPD 2, 20. Although the lungs have a well-developed pulmonary and systemic antioxidant defense system, the increased oxidant burden in COPD creates an

ROS in the pathogenesis of skeletal muscle dysfunction

Recently it has been recognized that skeletal muscle abnormalities are associated with COPD [65]. Skeletal muscle dysfunction is apparent for respiratory muscles, especially the diaphragm [66], as well as for peripheral muscles, and is manifested as reductions in muscle strength and endurance 67, 68, 69. Impaired peripheral muscle function may in part be explained by muscle atrophy, as muscle weakness correlated with a reduction in muscle mass, or fat-free mass in COPD patients 67, 70. However,

Abbreviations

  • AMP—adenosine monophosphate

  • BAL—broncho alveolar lavage

  • CO—carbon monoxide

  • COPD—chronic obstructive pulmonary disease

  • Cu,Zn-SOD—copper, zinc superoxide dismutase

  • CYP1A1—cytochrome P4501A1

  • γ-GCS—gamma-glutamylcysteine synthetase

  • GM-CSF—granulocyte-monocyte colony stimulating factor

  • GPx—glutathione peroxidase

  • GSH—glutathione (reduced)

  • GSSG—glutathione (oxidized)

  • GST—glutathione-S-transferase

  • H2O2—hydrogen peroxide

  • 4-HNE—4-hydroxy-2-nonenal

  • HO-1—heme oxygenase-1

  • HOCL—hypochlorous acid

  • IL-8—interleukin-8

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