Current concepts on oxidative/carbonyl stress, inflammation and epigenetics in pathogenesis of chronic obstructive pulmonary disease

Abstract

Chronic obstructive pulmonary disease (COPD) is a global health problem, and current therapy for COPD is poorly effective and the mainstays of pharmacotherapy are bronchodilators. A better understanding of the pathobiology of COPD is critical for the development of novel therapies. In the present review, we have discussed the roles of oxidative/aldehyde stress, inflammation/immunity, and chromatin remodeling in the pathogenesis of COPD. Imbalance of oxidant/antioxidant balance caused by cigarette smoke and other pollutants/biomass fuels plays an important role in the pathogenesis of COPD by regulating redox-sensitive transcription factors (e.g. NF-κB), autophagy and unfolded protein response leading to chronic lung inflammatory response. Cigarette smoke also activates canonical/alternative NF-κB pathways and their upstream kinases leading to sustained inflammatory response in lungs. Recently, epigenetic regulation has been shown to be critical for the development of COPD because the expression/activity of enzymes that regulate these epigenetic modifications have been reported to be abnormal in airways of COPD patients. Hence, the significant advances made in understanding the pathophysiology of COPD as described herein will identify novel therapeutic targets for intervening COPD.

Ascorbate attenuates pulmonary emphysema by inhibiting tobacco smoke and Rtp801-triggered lung protein modification and proteolysis

“…However, most studies have attributed such CS-induced oxidative damage mainly to the endogenous RNS/ROS generated in the lung during smoking (18-20, 34, 37, 38) without analyzing the comparative role of oxidants furnished by the CS itself in such damage process. Although several mechanisms associating oxidative damage of the lung to the pathogenesis of CS-induced emphysema has emerged over the years, none have conjointly addressed the role of CS oxidants along with the lung-generated oxido-nitrosants in the disease process (23,38,39). Indeed, our present work reveals the thus far unanalyzed diverse share and comparative role of the CS oxidants and cellular oxido-nitrosants in emphysematous lung damage inflicted by CS.…”

Oxidative Stress and Chromatin Remodeling in Chronic Obstructive Pulmonary Disease and Smoking-Related Diseases

“…It is shown that NF-jB-induced acetylation of histone H3, but not histone H2A, H2B, or H3, occurs in epithelial cells on specific lysine residues (Lys8 and Lys12) at NF-jB-responsive regulatory elements on proinflammatory genes (57). Oxidative stress and CS activate NF-jB, HAT, CBP/p300 leading to specific histone acetylation in macrophages and lung cells (60,93,178,179,187). Therefore, development of small molecules that target for inhibition of HATs (e.g., CBP/p300, PCAF, and GCN) may be useful for therapeutic intervention in COPD and other chronic inflammatory lung diseases associated with smoking mediated oxidative stress (8,99).…”

Нозоспецифічні Особливості Редокс-Процесів При Бронхіальній Астмі Та Хронічній Обструктивній Хворобі Легень

“…Повышение концентрации NO в выдыхаемом воздухе характерно только для периода обострения ХОБЛ [63]. У больных ХОБЛ (особенно куриль-щиков) характерно наличие высоких уровней кон-центрации пероксинитрита (ONOO -), нитрованых белков (фибриноген, трансферрин, плазминоген, церулоплазмин) [49].…”