Association between Nonspecific Bronchial Hyperreactivity and Superoxide Anion Production by Polymorphonuclear Leukocytes in Chronic Air-Flow Obstruction

783

599

Reactive oxygen species, either directly or via the formation of lipid peroxidation products, may play a role in enhancing inflammation through the activation of stress kinases (cJun activated kinase, extracellular signal-regulated kinase, p38) and redox-sensitive transcription factors, such as nuclear factor (NF)-kB and activator protein-1. This results in increased expression of a battery of distinct pro-inflammatory mediators. Oxidative stress activates NF-kBmediated transcription of pro-inflammatory mediators either through activation of its activating inhibitor of kB-a kinase or the enhanced recruitment and activation of transcriptional coactivators. Enhanced NF-kB-co-activator complex formation results in targeted increases in histone modifications, such as acetylation leading to inflammatory gene expression.Emerging evidence suggests the glutathione redox couple may entail dynamic regulation of protein function by reversible disulphide bond formation on kinases, phosphatases and transcription factors. Oxidative stress also inhibits histone deacetylase activity and in doing so further enhances inflammatory gene expression and may attenuate glucocorticoid sensitivity.The antioxidant/anti-inflammatory effects of thiol molecules (glutathione, N-acetyl-L-cysteine and N-acystelyn, erdosteine), dietary polyphenols (curcumin-diferuloylmethane, cathechins/ quercetin and reserveratol), specific spin traps, such as a-phenyl-N-tert-butyl nitrone, a catalytic antioxidant (extracellular superoxide dismutase (SOD) mimetic, SOD mimetic M40419 and SOD, and catalase manganic salen compound, eukarion-8), porphyrins (AEOL 10150 and AEOL 10113) and theophylline have all been shown to play a role in either controlling NF-kB activation or affecting histone modifications with subsequent effects on inflammatory gene expression in lung epithelial cells.Thus, oxidative stress regulates both key signal transduction pathways and histone modifications involved in lung inflammation. Various approaches to enhance lung antioxidant capacity and clinical trials of antioxidant compounds in chronic obstructive pulmonary disease are also discussed.

Section: Oxidative Stress In Bloodsupporting

confidence: 57%

Oxidative stress and redox regulation of lung inflammation in COPD

Rahman

Adcock²

2006

783

599

“…Cross-sectional studies investigating AHR in smokers and exsmokers with chronic bronchitis or COPD are presented in [81,82]. This suggests that AHR to histamine and methacholine does not revert to normal levels after smoking cessation in COPD, which could be due to either ongoing inflammation or irreversible structural changes in the lung.…”

Section: Chronic Bronchitis and Chronic Obstructive Pulmonary Diseasementioning

confidence: 99%

The impact of smoking cessation on respiratory symptoms, lung function, airway hyperresponsiveness and inflammation

Willemse¹,

Postma²,

Timens³

et al. 2004

382

235

Smoking is the main risk factor in the development of chronic obstructive pulmonary disease (COPD), and smoking cessation is the only effective treatment for avoiding or reducing the progression of this disease.Despite the fact that smoking cessation is a very important health issue, information about the underlying mechanisms of the effects of smoking cessation on the lungs is surprisingly scarce. It is likely that the reversibility of smoke-induced changes differs between smokers without chronic symptoms, smokers with nonobstructive chronic bronchitis and smokers with COPD. This review describes how these three groups differ regarding the effects of smoking cessation on respiratory symptoms, lung function (forced expiratory volume in one second), airway hyperresponsiveness, and pathological and inflammatory changes in the lung.Smoking cessation clearly improves respiratory symptoms and bronchial hyperresponsiveness, and prevents excessive decline in lung function in all three groups.Data from well-designed studies are lacking regarding the effects on inflammation and remodelling, and the few available studies show contradictory results. In chronic obstructive pulmonary disease, a few histopathological studies suggest that airway inflammation persists in exsmokers. Nevertheless, many studies have shown that smoking cessation improves the accelerated decline in forced expiratory volume in one second, which strongly indicates that important inflammatory and/or remodelling processes are positively affected.

“…Only a few studies have investigated the effect of smoking on AHR in COPD patients. Two cross-sectional studies showed no differences in AHR to histamine or methacholine between exsmokers and smokers with COPD [12,13]. In contrast, the Lung Health Study showed that AHR to methacholine deteriorated to a smaller extend in quitters than in persistent smokers [14].…”

mentioning

confidence: 98%

Smoking cessation improves both direct and indirect airway hyperresponsiveness in COPD

Willemse¹

2004

Smoking induces chronic obstructive pulmonary disease (COPD) and is associated with airway inflammation and airway hyperresponsiveness (AHR). It has not been studied in COPD whether direct (methacholine) and indirect (adenosine-59-monophosphate (AMP)) stimuli are associated with airway inflammation and neither whether smoking cessation improves these features.The current authors cross-sectionally investigated the relationship of AHR to methacholine and AMP with lung function and inflammatory cells in the sputum of 33 smokers with COPD. In addition, changes in these parameters were prospectively assessed in 14 smokers who successfully quit smoking for 1 yr.The presence of AHR to both methacholine and AMP was associated with lower lung function, but not with sputum inflammation. AHR to methacholine and AMP improved significantly after a 1-yr smoking cessation, yet this was unrelated to changes in sputum cell counts. The numbers of neutrophils and epithelial cells significantly increased with smoking cessation.Both direct and indirect airway hyperresponsiveness are associated with lower lung function, but not with sputum inflammation in chronic obstructive pulmonary disease. Interestingly, 1-yr smoking cessation improved both direct and indirect airway hyperresponsiveness, yet without a significant association with changes in lung function or sputum inflammation. Thus, other factors are likely to induce these improvements, e.g. a reduction in stimulation of irritant receptors, airway wall changes or mucus hypersecretion.