Therapeutic Strategies to Correct Proteostasis-Imbalance in Chronic Obstructive Lung Diseases

M.      Bodas; I.      Tran; N.      Vij

Abstract

Proteostasis is a critical cellular homeostasis mechanism that regulates the concentration of all cellular proteins by controlling protein- synthesis, processing and degradation. This includes proteinconformation, binding interactions and sub-cellular localization. Environmental, genetic or age-related pathogenetic factors can modulate the proteostasis (proteostasis-imbalance) through transcriptional, translational and post-translational changes that trigger the development of several complex diseases. Although these factors are known to be involved in pathogenesis of chronic obstructive pulmonary disease (COPD), the role of proteostasis mechanisms in COPD is scarcely investigated. As a proof of concept, our recent data reveals a novel role of proteostasis-imbalance in COPD pathogenesis. Briefly, cigarette- and biomass- smoke induced proteostasis-imbalance may aggravate chronic inflammatory-oxidative stress and/or protease-anti-protease imbalance resulting in pathogenesis of severe emphysema. In contrast, pathogenesis of other chronic lung diseases like ΔF508-cystic fibrosis (CF), α1-anti-trypsin-deficiency (α-1 ATD) and pulmonary fibrosis (PF) is regulated by other proteostatic mechanisms, involving the degradation of misfolded proteins (ΔF508-CFTR/α1-AT- Z variant) or regulating the concentration of signaling proteins (such as TGF-β1) by the ubiquitin-proteasome system (UPS). The therapeutic strategies to correct proteostasis-imbalance in misfolded protein disorders such as ΔF508-CF have been relatively well studied and involve strategies that rescue functional CFTR protein to treat the underlying cause of the disease. While in the case of COPDemphysema and/or PF, identification of novel proteostasis-regulators that can control inflammatory-oxidative stress and/or protease-anti-protease balance is warranted.

Keywords: Autophagy, chronic obstructive pulmonary disease (COPD), cigarette smoke (CS), emphysema, proteostasis-imbalance, proteostasis-regulators, respiratory system, environmental pollutants, chronic bronchitis, inflammation, infections, oxidative stress, apoptosis, homeostasis, misfolded polyubiquitinated proteins