Glutathione in bronchoalveolar lavage fluid from smokers is related to humoral markers of inflammatory cell activity

Linden, Margareta; Håkansson, Lena; Ohlsson, Kjell; Sjödin, Karin; Tegner, Hans; Tunek, Anders; Venge, Per

doi:10.1007/bf00914309

Cited by 58 publications

(34 citation statements)

References 17 publications

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“…These studies suggest that GSH plays a critical role in maintaining epithelial membrane integrity and may protect epithelial cells against the inflammatory response produced by either inhaled or endogenous oxidants/free radicals. Furthermore, LINDEN and coworkers [204,205] demonstrated that airway obstruction, measured by means of the forced expiratory volume in one second (FEV1) in patients with COPD, correlated significantly with the concentration of GSH in BALF; the higher the BALF GSH, the lower the FEV1. It may be that the BALF GSH levels were influenced by the recent smoking history of these patients [24].…”

Section: Antioxidant Protective Genesmentioning

confidence: 99%

Oxidative stress and regulation of glutathione in lung inflammation

Rahman¹,

MacNee²

2000

Eur Respir J

808

555

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Inflammatory lung diseases are characterized by chronic inflammation and oxidant/antioxidant imbalance, a major cause of cell damage. The development of an oxidant/antioxidant imbalance in lung inflammation may activate redox‐sensitive transcription factors such as nuclear factor‐κB, and activator protein‐1 (AP‐1), which regulate the genes for pro‐inflammatory mediators and protective antioxidant genes. Glutathione (GSH), a ubiquitous tripeptide thiol, is a vital intra‐ and extracellular protective antioxidant against oxidative/nitrosative stresses, which plays a key role in the control of pro‐inflammatory processes in the lungs. Recent findings have suggested that GSH is important in immune modulation, remodelling of the extracellular matrix, apoptosis and mitochondrial respiration. The rate‐limiting enzyme in GSH synthesis is γ‐glutamylcysteine synthetase (γ‐GCS). The human γ‐GCS heavy and light subunits are regulated by AP‐1 and antioxidant response elements and are modulated by oxidants, phenolic antioxidants, growth factors, and inflammatory and anti‐inflammatory agents in lung cells. Alterations in alveolar and lung GSH metabolism are widely recognized as a central feature of many inflammatory lung diseases such as idiopathic pulmonary fibrosis, acute respiratory distress syndrome, cystic fibrosis and asthma. The imbalance and/or genetic variation in antioxidant γ‐GCS and pro‐inflammatory versus antioxidant genes in response to oxidative stress and inflammation in some individuals may render them more susceptible to lung inflammation. Knowledge of the mechanisms of GSH regulation and balance between the release and expression of pro‐ and anti‐inflammatory mediators could lead to the development of novel therapies based on the pharmacological manipulation of the production as well as gene transfer of this important antioxidant in lung inflammation and injury. This review describes the redox control and involvement of nuclear factor‐κB and activator protein‐1 in the regulation of cellular glutathione and γ‐glutamylcysteine synthetase under conditions of oxidative stress and inflammation, the role of glutathione in oxidant‐mediated susceptibility/tolerance, γ‐glutamylcysteine synthetase genetic susceptibility and the potential therapeutic role of glutathione and its precursors in protecting against lung oxidant stress, inflammation and injury.

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Section: Antioxidant Protective Genesmentioning

confidence: 99%

Oxidative stress and regulation of glutathione in lung inflammation

Rahman¹,

MacNee²

2000

Eur Respir J

808

555

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“…However, there are adaptive responses in the antioxidant shield to chronic cigarette smoking. Chronic cigarette smokers have increased GSH in BAL fluid (111,112). This may be due to oxidant-mediated activation of the redox-sensitive transcription factor AP-1 (Figure 1), which upregulates expression of ␥-glutamylcysteine synthetase, the rate-limiting enzyme in GSH synthesis (113,114).…”

Section: Evidence Of Increased Oxidative Stress In Copdmentioning

confidence: 99%

Proteinases and Oxidants as Targets in the Treatment of Chronic Obstructive Pulmonary Disease

Owen¹

2005

Proceedings of the American Thoracic Society

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There is now compelling evidence that proteinases and oxidative stress play pathogenetic roles in the following pathologies in chronic obstructive pulmonary disease: airspace enlargement; chronic inflammation in the airways, lung interstitium, and alveolar space; and mucus hypersecretion in the large airways. Proteinases and oxidants may also contribute to remodeling processes in the small airways. In addition, data are emerging that show interactions between classes of proteinases and between proteinases and oxidants, which amplify lung inflammation and injury in chronic obstructive pulmonary disease. This review discusses the biologic roles of proteinases and oxidants, their roles in the pathogenesis of chronic obstructive pulmonary disease, and their potential as targets for therapy.Keywords: antiinflammatory drugs; antioxidants; oxidative stress; proteinase inhibition; proteinases PROTEINASES AND OXIDANTS IN THE PATHOGENESIS OF COPDThe proteinase-antiproteinase hypothesis for the pathogenesis of chronic obstructive pulmonary disease (COPD) was formulated almost 40 yr ago in response to two key observations. First, genetic deficiency of ␣ 1 -antitrypsin (AAT, the major inhibitor of neutrophil elastase [NE] in the lower respiratory tract) is associated with early onset, severe panlobular emphysema (1). Second, instillation of papain (an enzyme with elastase activity) into rat lungs results in progressive airspace enlargement (2). Since then, other elastolytic proteinases have been shown to cause airspace enlargement when instilled into rodent lungs. Consequently, it was thought that an imbalance between proteinases (especially elastases derived from polymorphonuclear neutrophils [PMNs]) and their inhibitors causes pulmonary emphysema. Although excessive activity of PMN-derived elastases is likely to be important in the panlobular pulmonary emphysema associated with AAT deficiency, this is probably an oversimplification of mechanisms underlying common, "garden variety" COPD in cigarette smokers. Other factors have now been implicated in airspace enlargement in COPD, including other classes of proteinases (matrix metalloproteinases [MMPs] and cysteine proteinases), oxidative stress, and apoptosis of lung structural cells. In addition, COPD is clinically and pathologically a heterogeneous disease and includes chronic inflammation in the airways, lung interstitium, and the alveolar space; mucus hypersecretion; and subepithelial fibrosis in the small airways. There is evidence

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“…There is limited information about respiratory epithelial antioxidant defenses in smokers, and even less about those in patients with COPD. Studies have shown that glutathione is elevated in BALF from chronic smokers (64,75). Even so, glutathione may not be present in sufficient quantities to deal with the excessive oxidant burden during acute smoking, as cigarette smoke exposure depletes glutathione in a dose-and time-dependent manner (76).…”

Section: Role Of Oxidants and Antioxidants In Smoking-induced Copdmentioning

confidence: 99%

Pathogenesis of Chronic Obstructive Pulmonary Disease

MacNee¹

2005

Proceedings of the American Thoracic Society

357

220

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The current paradigm for the pathogenesis of chronic obstructive pulmonary disease is that chronic airflow limitation results from an abnormal inflammatory response to inhaled particles and gases in the lung. Airspace inflammation appears to be different in susceptible smokers and involves a predominance of CD8 ؉ T lymphocytes, neutrophils, and macrophages. Studies have characterized inflammation in the peripheral airspaces in different stages of disease severity. Two other processes have received considerable research attention. The first is a protease-antiprotease imbalance, which has been linked to the pathogenesis of emphysema. However, the hypothesis of an increased protease burden associated with functional inhibition of antiproteases has been difficult to prove and is now considered an oversimplification. The second process, oxidative stress, has a role in many of the pathogenic processes of chronic obstructive pulmonary disease and may be one mechanism that enhances the inflammatory response. In addition, it has been proposed that the development of emphysema may involve alveolar cell loss through apoptosis. This mechanism may involve the vascular endothelial growth factor pathway and oxidative stress.Keywords: apoptosis; emphysema; inflammation; oxidative stress; protease-antiprotease imbalance Chronic obstructive pulmonary disease (COPD) is a slowly progressive condition characterized by airflow limitation, which is largely irreversible (1). Cigarette smoking is the main etiologic factor in this condition, far outweighing any of the other risk factors. The pathogenesis of COPD is therefore strongly linked to the effects of cigarette smoke on the lungs. There is a general relationship between the extent of the smoking history and the severity of the airflow limitation; however, there is a huge individual variation. Fletcher and Peto (2), in an 8-yr prospective study of working men in West London, showed that the average decline in FEV 1 in smokers is faster (60 ml/yr) than in nonsmokers (30 ml/yr). However, smokers who develop COPD have an average decline in FEV 1 of greater than 60 ml/yr, and only 15 to 20% of smokers develop clinically significant COPD. It is from these studies that the concept of the susceptible smoker developed. SUBTYPES OF COPD Chronic BronchitisThe cough and sputum production that define chronic bronchitis result from an innate immune response to inhaled toxic particles and gases in cigarette smoke. In chronic bronchitis there is inflammation in the epithelium of the central airways and in the mucus-producing glands (3). This airway inflammation is associ-

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Glutathione in bronchoalveolar lavage fluid from smokers is related to humoral markers of inflammatory cell activity

Cited by 58 publications

References 17 publications

Oxidative stress and regulation of glutathione in lung inflammation

Oxidative stress and regulation of glutathione in lung inflammation

Proteinases and Oxidants as Targets in the Treatment of Chronic Obstructive Pulmonary Disease

Pathogenesis of Chronic Obstructive Pulmonary Disease

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