title: Cigarette smoke-induced autophagy impairment accelerates lung aging, COPD-emphysema exacerbations and pathogenesis.
abstract: Cigarette-smoke (CS) exposure and aging are the leading causes of chronic obstructive pulmonary disease (COPD)-emphysema development, although the molecular mechanism that mediates disease pathogenesis remains poorly understood. Our objective was to investigate the impact of CS exposure and aging on autophagy and the pathophysiological changes associated with lung aging (senescence) and emphysema progression. Beas2b cells, C57BL/6 mice, and human (GOLD 0-IV) lung tissues were used to determine the central mechanism involved in CS/age-related COPD-emphysema pathogenesis. Beas2b cells and murine lungs exposed to cigarette smoke extract (CSE)/CS showed a significant ( P < 0.05) accumulation of poly-ubiquitinated proteins and impaired autophagy marker, p62, in aggresome bodies. Moreover, treatment with the autophagy-inducing antioxidant drug cysteamine significantly ( P < 0.001) decreased CSE/CS-induced aggresome bodies. We also found a significant ( P < 0.001) increase in levels of aggresome bodies in the lungs of smokers and COPD subjects in comparison to nonsmoker controls. Furthermore, the presence and levels of aggresome bodies statistically correlated with severity of emphysema and alveolar senescence. In addition to CS exposure, lungs from old mice also showed accumulation of aggresome bodies, suggesting this as a common mechanism to initiate cellular senescence and emphysema. Additionally, Beas2b cells and murine lungs exposed to CSE/CS showed cellular apoptosis and senescence, which were both controlled by cysteamine treatment. In parallel, we evaluated the impact of CS on pulmonary exacerbation, using mice exposed to CS and/or infected with Pseudomonas aeruginosa ( Pa), and confirmed cysteamine's potential as an autophagy-inducing antibacterial drug, based on its ability to control CS-induced pulmonary exacerbation ( Pa-bacterial counts) and resulting inflammation. CS induced autophagy impairment accelerates lung aging and COPD-emphysema exacerbations and pathogenesis.
authors.affiliation: College of Medicine, Central Michigan University, Mt. Pleasant, Michigan.|Department of Pediatric Respiratory Science, The Johns Hopkins University School of Medicine , Baltimore, Maryland.
authors.forename: Neeraj
authors.initials: N
authors.lastname: Vij
authors.affiliation: College of Medicine, Central Michigan University, Mt. Pleasant, Michigan.
authors.forename: Prashanth
authors.initials: P
authors.lastname: Chandramani-Shivalingappa
authors.affiliation: College of Medicine, Central Michigan University, Mt. Pleasant, Michigan.
authors.forename: Colin
authors.initials: C
authors.lastname: Van Westphal
authors.affiliation: College of Medicine, Central Michigan University, Mt. Pleasant, Michigan.
authors.forename: Rachel
authors.initials: R
authors.lastname: Hole
authors.affiliation: College of Medicine, Central Michigan University, Mt. Pleasant, Michigan.
authors.forename: Manish
authors.initials: M
authors.lastname: Bodas
mesh_terms: D000818:Animals; D001343:Autophagy / Q000187:drug effects; D016022:Case-Control Studies; D002460:Cell Line; D016922:Cellular Senescence / Q000187:drug effects; D000073865:Cigarette Smoking / Q000009:adverse effects*; D003543:Cysteamine / Q000494:pharmacology; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D018450:Disease Progression; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure*; D006801:Humans; D002479:Inclusion Bodies / Q000378:metabolism / Q000648:ultrastructure; D018836:Inflammation Mediators / Q000378:metabolism; D008168:Lung / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure*; D008810:Mice, Inbred C57BL; D029424:Pulmonary Disease, Chronic Obstructive / Q000188:drug therapy / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D011656:Pulmonary Emphysema / Q000188:drug therapy / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D000071456:Sequestosome-1 Protein / Q000378:metabolism; D012720:Severity of Illness Index; D012906:Smoke / Q000009:adverse effects*; D054875:Ubiquitination
chemical_list: D016207:Cytokines; D018836:Inflammation Mediators; C099718:SQSTM1 protein, human; D000071456:Sequestosome-1 Protein; D012906:Smoke; C101343:Sqstm1 protein, mouse; D003543:Cysteamine
keywords: COPD; aging; autophagy; cigarette smoke; cysteamine; emphysema; proteostasis