Decreased proteasomal function accelerates cigarette smoke-induced pulmonary emphysema in mice

Abstract

Chronic obstructive pulmonary disease (COPD) is a disease common in elderly people, characterized by progressive destruction of lung parenchyma and chronic inflammation of the airways. The pathogenesis of COPD remains unclear, but recent studies suggest that oxidative stress-induced apoptosis in alveolar cells contributes to emphysematous lung destruction. The proteasome is a multicatalytic enzyme complex that plays a critical role in proteostasis by rapidly destroying misfolded and modified proteins generated by oxidative and other stresses. Proteasome activity decreases with aging in many organs including lungs, and an age-related decline in proteasomal function has been implicated in various age-related pathologies. However, the role of the proteasome system in the pathogenesis of COPD has not been investigated. Recently, we have established a transgenic (Tg) mouse model with decreased proteasomal chymotrypsin-like activity, showing age-related phenotypes. Using this model, we demonstrate here that decreased proteasomal function accelerates cigarette smoke (CS)-induced pulmonary emphysema. CS-exposed Tg mice showed remarkable airspace enlargement and increased foci of inflammation compared with wild-type controls. Importantly, apoptotic cells were found in the alveolar walls of the affected lungs. Impaired proteasomal activity also enhanced apoptosis in cigarette smoke extract (CSE)-exposed fibroblastic cells derived from mice and humans in vitro. Notably, aggresome formation and prominent nuclear translocation of apoptosis-inducing factor were observed in CSE-exposed fibroblastic cells isolated from Tg mice. Collective evidence suggests that CS exposure and impaired proteasomal activity coordinately enhance apoptotic cell death in the alveolar walls that may be involved in the development and progression of emphysema in susceptible individuals such as the elderly.

Augmenting autophagy for prognosis based intervention of COPD-pathophysiology

“…Exposure to tobacco and/or e-cig/nicotine vapor elevates oxidative-nitrative stress and inflammation that results in autophagy-flux impairment, further hampering the vital cellular homeostatic processes involved in the clearance of misfolded proteins and bacterial/viral pathogens that eventually impact the cell survival [10, 11, 18, 23–25]. Moreover, impaired autophagy flux results in perinuclear aggresome-bodies that are the hallmark of several neurodegenerative and protein-misfolding disorders [26–28].…”

“…The recent exhaustive studies using variety of pre-clinical models that includes human lung structural cells or tissues have clearly demonstrated that tobacco-smoke impaired-autophagy mediates accumulation of aggresome-bodies, which is primarily a cytoplasmic organelle comprised of aggregated (misfolded or damaged) proteins that initiates chronic inflammatory-apoptotic responses leading to senescence and emphysema progression (Fig. 1a) [10, 11, 17, 18, 20, 22, 25, 29, 30]. The pathogenic role of autophagy-impairment in COPD-emphysema is supported by findings from multiple studies demonstrating the accumulation of ubiquitinated proteins and p62 (an impaired-autophagy marker) that accelerates cellular senescence and COPD-emphysema pathogenesis [10, 11, 17, 18, 20, 22, 25, 29, 30].…”

“…1a) [10, 11, 17, 18, 20, 22, 25, 29, 30]. The pathogenic role of autophagy-impairment in COPD-emphysema is supported by findings from multiple studies demonstrating the accumulation of ubiquitinated proteins and p62 (an impaired-autophagy marker) that accelerates cellular senescence and COPD-emphysema pathogenesis [10, 11, 17, 18, 20, 22, 25, 29, 30]. Moreover, even acute exposure to cigarette smoke (CS) leads to elevated inflammatory-oxidative stress-mediated cellular apoptosis that statistically and functionally correlates with an accumulation of misfolded poly-ubiquitinated proteins as aggresome-bodies (insoluble protein fraction) in alveolar epithelial or structural cells and lungs (human and murine) [10, 11, 17, 18, 20, 22, 25, 29, 30].…”

Endoplasmic Reticulum Stress Induces HRD1 to Protect Alveolar Type II Epithelial Cells from Apoptosis Induced by Cigarette Smoke Extract

“…The incidence and mortality rate of COPD keep increasing yearly, with significant impact on the health of people worldwide. Although the pathogenesis of COPD is still not fully understood, a variety of studies have shown that inflammation, oxidative stress, protease/anti-protease imbalance, and apoptosis of lung cells are involved in COPD [1][2][3]. Cigarette smoking is the most important risk factor of COPD.…”

Gene expression profile of human lung in a relatively early stage of COPD with emphysema

“…Impaired proteasome function can result in the accumulation of altered proteins, resulting in cellular dysfunction and cell death. Recently, decreased proteasomal function was shown to accelerate cigarette smoke-induced pulmonary emphysema in a mouse model 40. Impaired proteasomal expression might be important in the pathogenesis of emphysema.…”