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Statins and pulmonary fibrosis: the potential role of NLRP3 inflammasome activation.

ABSTRACT: The role of 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors (statins) in the development or progression of interstitial lung disease (ILD) is controversial.To evaluate the association between statin use and ILD.We used regression analyses to evaluate the association between statin use and interstitial lung abnormalities (ILA) in a large cohort of smokers from COPDGene. Next, we evaluated the effect of statin pretreatment on bleomycin-induced fibrosis in mice and explored the mechanism behind these observations in vitro.In COPDGene, 38% of subjects with ILA were taking statins compared with 27% of subjects without ILA. Statin use was positively associated in ILA (odds ratio, 1.60; 95% confidence interval, 1.03-2.50; P = 0.04) after adjustment for covariates including a history of high cholesterol or coronary artery disease. This association was modified by the hydrophilicity of statin and the age of the subject. Next, we demonstrate that statin administration aggravates lung injury and fibrosis in bleomycin-treated mice. Statin pretreatment enhances caspase-1-mediated immune responses in vivo and in vitro; the latter responses were abolished in bone marrow-derived macrophages isolated from Nlrp3(-/-) and Casp1(-/-) mice. Finally, we provide further insights by demonstrating that statins enhance NLRP3-inflammasome activation by increasing mitochondrial reactive oxygen species generation in macrophages.Statin use is associated with ILA among smokers in the COPDGene study and enhances bleomycin-induced lung inflammation and fibrosis in the mouse through a mechanism involving enhanced NLRP3-inflammasome activation. Our findings suggest that statins may influence the susceptibility to, or progression of, ILD. Clinical trial registered with www.clinicaltrials.gov (NCT 00608764).

SUBMITTER: Xu JF

PROVIDER: S-EPMC3297101 | biostudies-literature | 2012 Mar

REPOSITORIES: biostudies-literature

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Statins and pulmonary fibrosis: the potential role of NLRP3 inflammasome activation.

Xu Jin-Fu JF Washko George R GR Nakahira Kiichi K Hatabu Hiroto H Patel Avignat S AS Fernandez Isis E IE Nishino Mizuki M Okajima Yuka Y Yamashiro Tsuneo T Ross James C JC Estépar Raúl San José RS Diaz Alejandro A AA Li Hui-Ping HP Qu Jie-Ming JM Himes Blanca E BE Come Carolyn E CE D'Aco Katherine K Martinez Fernando J FJ Han MeiLan K MK Lynch David A DA Crapo James D JD Morse Danielle D Ryter Stefan W SW Silverman Edwin K EK Rosas Ivan O IO Choi Augustine M K AM Hunninghake Gary M GM

American journal of respiratory and critical care medicine 20120112 5

<h4>Rationale</h4>The role of 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors (statins) in the development or progression of interstitial lung disease (ILD) is controversial.<h4>Objectives</h4>To evaluate the association between statin use and ILD.<h4>Methods</h4>We used regression analyses to evaluate the association between statin use and interstitial lung abnormalities (ILA) in a large cohort of smokers from COPDGene. Next, we evaluated the effect of statin pretreatment on bleomyci ...[more]

PMID: 22246178

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Statins and pulmonary fibrosis: the potential role of NLRP3 inflammasome activation.

Publications

Statins and pulmonary fibrosis: the potential role of NLRP3 inflammasome activation.

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