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. The current therapies for COPD are 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. An imbalance of oxidants/antioxidants 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 intervention in COPD.

Figure 1. Aldehyde/carbonyl stress in COPD

Cigarette smoke contains different carbonyl compounds which can carbonylate proteins through direct amino acid oxidation or an indirect mechanism involving lipids oxidation leading to formation of reactive aldehydes such as acrolein and 4-hydroxy-2-nonenal (4-HNE). These aldehye-protein adducts will alter the function and stability of intracellular (e.g. histone deacetylases, nuclear erythroid-related factor 2, or Keap1) or extracellular [e.g. extracellular matrix (ECM)] proteins or cause a variety of cellular and biochemical effects including immunogenicity thereby inducing lung inflammatatory and autoimmune responses, and injury. DNP: 2,4-dinitrophenyl, denotes protein carbonylation.; DC: dendritic cells.

Figure 2. Inflammatory and immune cells involved in COPD

Exposure to cigarette smoke or other irritants activates macrophage and epithelial cells to release chemokines which attract other inflammatory and immune cells including neutrophils, T-cells, dendrtic cells (DC), and B-cells into the lungs. CXCL1 and CXCL8 chemokines act on CXCR2 to attract netrophils while CXCL9, CXCL10 and CXCL11 chemokines bind to CXCR3 to attract T-cells into lungs. Cigarette smoke-induced recruitment of immature DC fails to induce appropriate T-cells response but instead leads to predominantly CD8⁺ T-cells proliferation in lungs. Furthermore, prolonged exposure to cigarette smoke leads to the accumulation of extracellular matrix fragments which are presented by DC to T-cells activiating specific B-cells. This will result in the production of auto-antibody, such as anti-elastin body leading to abnormal autoimmunity in lungs. These inflammatory and immune cells release proteases, perforin, granzyme, and produce anti-self antibody causing alveolar wall destruction. Neutrophil-derived elastase also causes mucus hypersecretion. Epithelial cells and macrophages also release transforming growth factor-β (TGF-β) leading to small airway remodeling.

Figure 3. Mechanism of cigarette smoke-mediated activation of NF-κB and pro-inflammatory gene transcription

Cigarette smoke-mediated oxidative stress can activate the IKK complex to phosphorylate inhibitory IκB proteins, resulting in their ubiquitination and degradation. This leads to the translocation of RelA/p65 into nucleus which is recruited on the promoter of pro-inflammatory genes. Alternative NF-κB pathway is also activated in response to cigarette smoke exposure through the cooperation of NIK with IKK-α to induce the processing of the p100 C-terminus resulting in the nuclear translocation of p52:RelB. Furthermore, IKKα-activated MSK1 in response to cigarette smoke induces NF-κB activation by phosphorylating RelA/p65 and altering chromatin modification. PKCζ, an atypical family member of PKC, regulates the activation of NF-κB via activating IKK, stabilizing IκB-α, and/or directly phosphorylating RelA/p65 in response to stimuli. NIK, NF-κB inducing kinase; IKK, IκB kinase; PKCζ, protein kinase Cζ.