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American journal of physiology.Cell physiology

Am.J.Physiol.Cell.Physiol.

13-Jul

ajpcell.00110.2016

LR: 20160714; CI: Copyright (c) 2016; JID: 100901225; OTO: NOTNLM; 2016/06/29 [accepted]; 2016/04/22 [received]; aheadofprint; SO: Am J Physiol Cell Physiol. 2016 Jul 13:ajpcell.00110.2016. doi: 10.1152/ajpcell.00110.2016.

1522-1563; 0363-6143

PMID: 27413169

ENG

JOURNAL ARTICLE

10.1152/ajpcell.00110.2016 [doi]

Unknown(0)

27413169

RATIONALE: 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. OBJECTIVES: To investigate the impact of CS-exposure and aging on autophagy, and pathophysiological changes associated with lung aging (senescence) and emphysema progression. METHODS: 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. RESULTS: Beas2b cells and murine lungs exposed to CSE/CS showed a significant (p0.05) accumulation of poly-ubiquitinated proteins and impaired-autophagy marker, p62, in aggresome-bodies. Moreover, treatment with autophagy-inducing antioxidant drug, cysteamine significantly (p0.001) decreased CSE/CS-induced aggresome-bodies. We also found a significant (p0.001) increase in levels of aggresome-bodies in the lungs of smokers and COPD-subjects in comparison to non-smoker 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. CONCLUSION: CS induced autophagy-impairment accelerates lung aging, COPD-emphysema exacerbations and pathogenesis.

American Journal of Physiology - Cell Physiology

Vij,N., Chandramani,P., Westphal,C.V., Hole,R., Bodas,M.

Central Michigan University, The Johns Hopkins University School of Medicine nvij1@jhmi.edu.; Central Michigan University.; Central Michigan University.; Central Michigan University.; Central Michigan University.

20160713

http://vp9py7xf3h.search.serialssolutions.com/?charset=utf-8&pmid=27413169

2016