Neutrophils and Emerging Targets for Treatment in Chronic Obstructive Pulmonary Disease

Mariska Meijer; Ger T Rijkers; Frans J van Overveld


Expert Rev Clin Immunol. 2013;9(11):1055-1068. 

In This Article

Oxidative Stress

In COPD, oxidative stress is provided by two sources. First of all, CS contains high levels of ROS and secondly, activated immune cells such as neutrophils and macrophages release them as a part of the inflammatory process.[62,104] Especially during exacerbations, a marked oxidant/antioxidant-imbalance can be observed.[105] An increase of oxidative stress can lead to inactivation of antiproteases such as A1AT and activation of several metalloproteases as well as NE. Furthermore, NF-κB is upregulated leading to an increased expression of proinflammatory cytokines and an increased activation of recruited immune cells. Furthermore, high levels of ROS can induce the formation of oxygenated phospholipids, which potently inhibit phagocytic activity of alveolar macrophages.[62,106] The dysfunction of these cells is thought to be the reason COPD patients show stable bacterial colonization, despite the increased infiltration of phagocytic cells in the lungs. Therefore, the oxidant/antioxidant could be one of the causes of the bacterial colonization and thus of the recurrent infections that lead to exacerbations of COPD. However, more research is needed to substantiate this theory.

There is evidence that the increase of ROS in COPD is further enhanced by a dysfunction of some of the protective mechanisms for oxidative stress, such as the glutathione cycle.[107] Current studies are trying to investigate if additional antioxidants, either via medication or via changes in the diet are able to delay the progression of COPD, as reviewed by Biswas et al. and Barnes (Table 2).[21,108,109] One compound that seems very promising was the ROS-scavenger N-acetylcysteine (NAC) that can also act as a precursor for glutathione. Several studies showed promising results in decreasing proinflammatory factors such as IL-8 and TNF-α, leading to a significant yet modest decrease of 22–25% in exacerbation rates, although not always in patients previously treated with corticosteroids.[64,110,111] The exact mechanisms of NAC are not yet known, though it likely decreases the hypersecretion of mucus that has consistently been found to correlate with symptom severity.[111] However, NAC is not yet used to treat COPD outside of research settings.