Use of thiols and implications for the use of inhaled corticosteroids in the presence of oxidative stress in COPD.

BACKGROUND: Oxidative stress and persistent airway inflammation are thought to be important contributors to the development of chronic obstructive pulmonary disease (COPD). This review summarizes the evidence for targeting oxidative stress and inflammation in patients with COPD with mucolytic/antioxidant thiols and inhaled corticosteroids (ICS), either alone or in combination. MAIN BODY: Oxidative stress is increased in COPD, particularly during acute exacerbations. It can be triggered by oxidant air pollutants and cigarette smoke and/or by endogenous reactive oxygen species (ROS) released from mitochondria and activated inflammatory, immune and epithelial cells in the airways, together with a reduction in endogenous antioxidants such as glutathione (GSH). Oxidative stress also drives chronic inflammation and disease progression in the airways by activating intracellular signalling pathways and the release of further inflammatory mediators. ICS are anti-inflammatory agents currently recommended for use with long-acting bronchodilators to prevent exacerbations in patients with moderate-to-severe COPD, especially those with eosinophilic airway inflammation. However, corticosteroids can also increase oxidative stress, which may in turn reduce corticosteroid sensitivity in patients by several mechanisms. Thiol-based agents such as erdosteine, N-acetyl L-cysteine (NAC) and S-carboxymethylcysteine (S-CMC) are mucolytic agents that also act as antioxidants. These agents may reduce oxidative stress directly through the free sulfhydryl groups, serving as a source of reducing equivalents and indirectly though intracellular GSH replenishment. Few studies have compared the effects of corticosteroids and thiol agents on oxidative stress, but there is some evidence for greater antioxidant effects when they are administered together. The current Global Initiative for Chronic Obstructive Lung Disease (GOLD) report supports treatment with antioxidants (erdosteine, NAC, S-CMC) in addition to standard-of-care therapy as they have been demonstrated to reduce COPD exacerbations. However, such studies have demonstrated that NAC and S-CMC reduced the exacerbation risk only in patients not treated with ICS, whereas erdosteine reduced COPD exacerbations irrespective of concomitant ICS use suggesting that erdosteine has additional pharmacological actions to ICS. CONCLUSIONS: Further clinical trials of antioxidant agents with and without ICS are needed to better understand the place of thiol-based drugs in the treatment of patients with COPD.