Critical role of proteostasis-imbalance in pathogenesis of COPD and severe emphysema

Abstract

The environmental, genetic, and/or age-related changes in proteostasis induce inflammation, oxidative stress, and apoptosis. We quantified the correlation of protein expression of critical proteostasis mediators to severity of chronic lung disease using lung tissue samples from control and chronic obstructive pulmonary disease (COPD) subjects (GOLD stage 0–IV) and cigarette smoke (CS)-induced murine model. The human bronchial epithelial cells, HEK-293, and Beas2B cells were used for in vitro experiments to verify the mechanisms. Our data verifies the correlation of higher expression of valosin-containing protein (VCP) retrograde translocation complex (VCP-Rma1-gp78) with severity of emphysema in COPD lung tissues and over-expression of inflammatory, ER stress and apoptotic mediators like NFκB, GADD-153/CHOP, and p-eIF2α. Moreover, subjects with severe emphysema had a higher accumulation of ubiquitinated proteins and deubiquitinating enzyme, UCHL-1, indicating towards the aggregation of misfolded or damaged proteins. The modulation of both protein degradation and synthesis rates by CS-extract substantiates the pathogenetic role of proteostasis-imbalance in emphysema and COPD. We identified that VCP also mediates proteasomal degradation of HDAC2 and Nrf2, as a potential mechanism for increased oxidative stress and corticosteroid resistance in COPD subjects with emphysema. Next, we confirmed that higher VCP expression associates with increased inflammation and apoptosis using in vitro and murine models. Our data clearly shows aberrant proteostasis in COPD subjects with severe emphysema. In addition, we evaluate therapeutic efficacy of salubrinal (ER stress inhibitor) to correct the proteostasis-imbalance based on its ability to control VCP expression and ubiquitin accumulation. Overall, our data demonstrate for the first time the critical role of proteostasis-imbalance in pathogenesis of severe emphysema.

MicroRNA-223 controls the expression of histone deacetylase 2: a novel axis in COPD

“…While previous studies reported that nitration of tyrosine residues affect activity and stability of HDAC2 protein [19] and, moreover, that proteosomal imbalance might be of critical importance for these processes [20], the regulation of HDAC2 gene expression and associated pathways in COPD have not completely been unraveled. miRNAs have emerged as post-transcriptional gene silencers and we thus suggested their involvement in the decreased expression of HDAC2.…”

Oxidative and endoplasmic reticulum stress in respiratory disease

“…There is evidence for ER stress in COPD but it is based on a limited number of validated studies 97, 98, 99. However, there is reasonably clear evidence that exposure of bronchial epithelial cells to cigarette smoke (the environmental driver of COPD) increases ER stress 100, 101…”

“…Salubrinal has been demonstrated to repress cigarette smoke‐induced airway epithelial ER stress which is relevant for COPD therapy 98. 4‐phenylbutyrate (4‐PBA) and tauroursodeoxycholic acid (TUDCA) are chemical chaperones which promote correct folding in the ER that have been used widely in animal models of ER stress.…”

Autophagy: A Crucial Moderator of Redox Balance, Inflammation, and Apoptosis in Lung Disease

“…CS exposure may impair the delivery of bacteria to lysosomes (115), suggesting that defective xenophagy in alveolar macrophages of smokers may contribute to recurrent infections in COPD patients. CS affects oxidative protein folding in the ER (74), and it can induce the UPR in human alveolar epithelial cells (165), which may lead to ER stress and impaired protein homeostasis in the lungs of COPD patients (13,105,111).…”