Dataset Information

Autophagy protein microtubule-associated protein 1 light chain-3B (LC3B) activates extrinsic apoptosis during cigarette smoke-induced emphysema.

ABSTRACT: Chronic obstructive pulmonary disease (COPD) is a debilitating disease caused by chronic exposure to cigarette smoke (CS), which involves airway obstruction and alveolar loss (i.e., emphysema). The mechanisms of COPD pathogenesis remain unclear. Our previous studies demonstrated elevated autophagy in human COPD lung, and as a cellular and tissue response to CS exposure in an experimental model of emphysema in vivo. We identified the autophagic protein microtubule-associated protein 1 light chain-3B (LC3B) as a positive regulator of CS-induced lung epithelial cell death. We now extend these initial observations to explore the mechanism by which LC3B mediates CS-induced apoptosis and emphysema development in vivo. Here, we observed that LC3B(-/-) mice had significantly decreased levels of apoptosis in the lungs after CS exposure, and displayed resistance to CS-induced airspace enlargement, relative to WT littermate mice. We found that LC3B associated with the extrinsic apoptotic factor Fas in lipid rafts in an interaction mediated by caveolin-1 (Cav-1). The siRNA-dependent knockdown of Cav-1 sensitized epithelial cells to CS-induced apoptosis, as evidenced by enhanced death-inducing signaling complex formation and caspase activation. Furthermore, Cav-1(-/-) mice exhibited higher levels of autophagy and apoptosis in the lung in response to chronic CS exposure in vivo. In conclusion, we demonstrate a pivotal role for the autophagic protein LC3B in CS-induced apoptosis and emphysema, suggestive of novel therapeutic targets for COPD treatment. This study also introduces a mechanism by which LC3B, through interactions with Cav-1 and Fas, can regulate apoptosis.

SUBMITTER: Chen ZH

PROVIDER: S-EPMC2973911 | biostudies-literature | 2010 Nov

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Autophagy protein microtubule-associated protein 1 light chain-3B (LC3B) activates extrinsic apoptosis during cigarette smoke-induced emphysema.

Chen Zhi-Hua ZH Lam Hilaire C HC Jin Yang Y Kim Hong-Pyo HP Cao Jiaofei J Lee Seon-Jin SJ Ifedigbo Emeka E Parameswaran Harikrishnan H Ryter Stefan W SW Choi Augustine M K AM

Proceedings of the National Academy of Sciences of the United States of America 20101018 44

Chronic obstructive pulmonary disease (COPD) is a debilitating disease caused by chronic exposure to cigarette smoke (CS), which involves airway obstruction and alveolar loss (i.e., emphysema). The mechanisms of COPD pathogenesis remain unclear. Our previous studies demonstrated elevated autophagy in human COPD lung, and as a cellular and tissue response to CS exposure in an experimental model of emphysema in vivo. We identified the autophagic protein microtubule-associated protein 1 light chain ...[more]

PMID: 20956295

Similar Datasets

Project description:BackgroundThere is a need for agents that suppress inflammation and progression of chronic obstructive pulmonary disease. p38 mitogen-activated protein kinase (p38 MAPK) has been associated with this disorder, and several inhibitors of this cascade are in clinical trials for its treatment, but their efficacy and utility are unknown. This study evaluated the relationship between p38 MAPK activation and susceptibility to cigarette smoke (CS)-induced emphysema, and whether its inhibition ameliorated the lung inflammation and injury in murine models of cigarette smoke exposure.MethodsIn acute and chronic CS exposure, the activation and expression of p38 MAPK in the lungs, as well as lung inflammation and injury (proteinase production, apoptosis, and oxidative DNA damage), were compared between two mouse strains: C57BL/6 (emphysema-susceptible) and NZW (emphysema-resistant). The selective p38 MAPK inhibitor SB203580 (45 mg/kg) was administrated intra-peritoneally to C57BL/6 mice, to examine whether it ameliorated cigarette smoke-induced lung inflammation and injury.ResultsAcute CS-induced lung inflammation (neutrophil infiltration, mRNA expressions of TNF-? and MIP-2), proteinase expression (MMP-12 mRNA), apoptosis, and oxidative DNA damage were significantly lower in NZW than C57BL/6 mice. p38 MAPK was significantly activated and up-regulated by both acute and chronic CS exposure in C57BL/6 but not NZW mice. mRNA expression of p38 MAPK was also upregulated in C57BL/6 by chronic CS exposure and tended to be constitutively suppressed in NZW mice. SB203580 significantly attenuated lung inflammation (neutrophil infiltration, mRNA expressions of TNF-? and MIP-2, protein levels of KC, MIP-1?, IL-1?, and IL-6), proteinase expression (MMP-12 mRNA), oxidative DNA damage, and apoptosis caused by acute CS exposure.ConclusionsCigarette smoke activated p38 MAPK only in mice that were susceptible to cigarette smoke-induced emphysema. Its selective inhibition ameliorated lung inflammation and injury in a murine model of cigarette smoke exposure. p38 MAPK pathways are a possible molecular target for the treatment of chronic obstructive pulmonary disease.

Dataset Information

Autophagy protein microtubule-associated protein 1 light chain-3B (LC3B) activates extrinsic apoptosis during cigarette smoke-induced emphysema.

Publications

Autophagy protein microtubule-associated protein 1 light chain-3B (LC3B) activates extrinsic apoptosis during cigarette smoke-induced emphysema.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure