Statins and pulmonary fibrosis the potential role of NLRP3 inflammasome activation

Jin Fu Xu, George R. Washko, Kiichi Nakahira, Hiroto Hatabu, Avignat S. Patel, Isis E. Fernandez, Mizuki Nishino, Yuka Okajima, Tsuneo Yamashiro, James C. Ross, Raúl San José Estépar, Alejandro A. Diaz, Hui Ping Li, Jie Ming Qu, Blanca E. Himes, Carolyn E. Come, Katherine D'Aco, Fernando J. Martinez, Mei Lan K. Han, David A. LynchJames D. Crapo, Danielle Morse, Stefan W. Ryter, Edwin K. Silverman, Ivan O. Rosas, Augustine M.K. Choi, Gary M. Hunninghake

Research output: Contribution to journalArticle

83 Scopus citations

Abstract

Rationale: The role of 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors (statins) in the development or progression of interstitial lung disease (ILD) is controversial. Objectives: To evaluate the association between statin use and ILD. Methods: 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. Measurements and Main Results: In COPDGene, 38%of subjectswith 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 responseswere abolished in bone marrow-derived macrophages isolated from Nlrp3 -/- andCasp1 -/- mice. Finally,we provide further insights by demonstrating that statins enhance NLRP3-inflammasome activation by increasing mitochondrial reactive oxygen species generation in macrophages. Conclusions: 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).

Original languageEnglish (US)
Pages (from-to)547-556
Number of pages10
JournalAmerican journal of respiratory and critical care medicine
Volume185
Issue number5
DOIs
StatePublished - Mar 1 2012

Keywords

  • Inflammasome
  • Interstitial lung disease
  • Mitochondrial reactive oxygen species
  • Pulmonary fibrosis
  • Statins

ASJC Scopus subject areas

  • Pulmonary and Respiratory Medicine
  • Critical Care and Intensive Care Medicine

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