Statins and pulmonary fibrosis: the potential role of NLRP3 inflammasome activation. Academic Article uri icon

Overview

MeSH

  • Animals
  • Bleomycin
  • Caspase 1
  • Drug Synergism
  • Female
  • Humans
  • Lung
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Pulmonary Fibrosis
  • Regression Analysis
  • Smoking

MeSH Major

  • Carrier Proteins
  • Hydroxymethylglutaryl-CoA Reductase Inhibitors
  • Idiopathic Pulmonary Fibrosis
  • Inflammasomes

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).

publication date

  • March 1, 2012

has subject area

  • Animals
  • Bleomycin
  • Carrier Proteins
  • Caspase 1
  • Drug Synergism
  • Female
  • Humans
  • Hydroxymethylglutaryl-CoA Reductase Inhibitors
  • Idiopathic Pulmonary Fibrosis
  • Inflammasomes
  • Lung
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Pulmonary Fibrosis
  • Regression Analysis
  • Smoking

Research

keywords

  • Journal Article

Identity

Language

  • eng

PubMed Central ID

  • PMC3297101

Digital Object Identifier (DOI)

  • 10.1164/rccm.201108-1574OC

PubMed ID

  • 22246178

Additional Document Info

start page

  • 547

end page

  • 556

volume

  • 185

number

  • 5