Augmenting autophagy for prognosis based intervention of COPD-pathophysiology

Abstract

Chronic obstructive pulmonary disease (COPD) is foremost among the non-reversible fatal ailments where exposure to tobacco/biomass-smoke and aging are the major risk factors for the initiation and progression of the obstructive lung disease. The role of smoke-induced inflammatory-oxidative stress, apoptosis and cellular senescence in driving the alveolar damage that mediates the emphysema progression and severe lung function decline is apparent, although the central mechanism that regulates these processes was unknown. To fill in this gap in knowledge, the central role of proteostasis and autophagy in regulating chronic lung disease causing mechanisms has been recently described. Recent studies demonstrate that cigarette/nicotine exposure induces proteostasis/autophagy-impairment that leads to perinuclear accumulation of polyubiquitinated proteins as aggresome-bodies, indicative of emphysema severity. In support of this concept, autophagy inducing FDA-approved anti-oxidant drugs control tobacco-smoke induced inflammatory-oxidative stress, apoptosis, cellular senescence and COPD-emphysema progression in variety of preclinical models. Hence, we propose that precise and early detection of aggresome-pathology can allow the timely assessment of disease severity in COPD-emphysema subjects for prognosis-based intervention. While intervention with autophagy-inducing drugs is anticipated to reduce alveolar damage and lung function decline, resulting in a decrease in the current mortality rates in COPD-emphysema subjects.

Correlation between autophagy levels in peripheral blood mononuclear cells and clinical parameters in patients with chronic obstructive pulmonary disease

“…The studies of Hussain and Sandri (21) and Plant et al (22) demonstrated that autophagy can affect the bronchial-muscle function of patients with COPD. The pathophysiological mechanisms involved in COPD, including oxidative stress and inflammation, are associated with autophagy (14,(23)(24)(25). Therefore, autophagy serves a role in the pathogenesis of COPD.…”

Cigarette smoke exposure induces ROS-mediated autophagy by regulating sestrin, AMPK, and mTOR level in mice

“…Clinically, alveolar emphysema is a primary cause of COPD and thus its early diagnosis may contribute to controlling this pathological condition. Recent evidence supports an important role for autophagy in the progression of COPD-emphysema [1,3,4]. Autophagy is an intracellular mechanism by which damaged cellular components and proteins are degraded and recycled by the cell itself as a defensive mechanism.…”

Cigarette Smoke Exposure Inhibits Bacterial Killing via TFEB-Mediated Autophagy Impairment and Resulting Phagocytosis Defect

“…Previous publications have shown that fisetin has the ability to induce autophagy [ 15 , 18 , 19 , 22 ]; hence, we decided to investigate its effectiveness in recovering CS-impaired phagocytosis. However, it was first necessary to determine the dose of fisetin to be used for further experimentation; thus, by treating RAW264.7 cells with increasing doses of fisetin (0, 10, 20, and 40 μ M) for 8 hrs, we first selected the appropriate dose.…”

“…Fisetin is an over-the-counter dietary supplement that acts as an antioxidant for brain health [ 15 , 22 , 23 ]. In recent studies from our lab and others, fisetin has been shown to induce TFEB and consequentially autophagy [ 15 , 18 , 19 ].…”