title: Statins and pulmonary fibrosis: the potential role of NLRP3 inflammasome activation.
abstract: BACKGROUND
  The role of 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors (statins) in the development or progression of interstitial lung disease (ILD) is controversial.
  
  
  OBJECTIVE
  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.
  
  
  RESULTS
  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.
  
  
  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).
authors.affiliation: Pulmonary and Critical Care Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: Jin-Fu
authors.initials: JF
authors.lastname: Xu
authors.forename: George R
authors.initials: GR
authors.lastname: Washko
authors.forename: Kiichi
authors.initials: K
authors.lastname: Nakahira
authors.forename: Hiroto
authors.initials: H
authors.lastname: Hatabu
authors.forename: Avignat S
authors.initials: AS
authors.lastname: Patel
authors.forename: Isis E
authors.initials: IE
authors.lastname: Fernandez
authors.forename: Mizuki
authors.initials: M
authors.lastname: Nishino
authors.forename: Yuka
authors.initials: Y
authors.lastname: Okajima
authors.forename: Tsuneo
authors.initials: T
authors.lastname: Yamashiro
authors.forename: James C
authors.initials: JC
authors.lastname: Ross
authors.forename: Raúl San José
authors.initials: RS
authors.lastname: Estépar
authors.forename: Alejandro A
authors.initials: AA
authors.lastname: Diaz
authors.forename: Hui-Ping
authors.initials: HP
authors.lastname: Li
authors.forename: Jie-Ming
authors.initials: JM
authors.lastname: Qu
authors.forename: Blanca E
authors.initials: BE
authors.lastname: Himes
authors.forename: Carolyn E
authors.initials: CE
authors.lastname: Come
authors.forename: Katherine
authors.initials: K
authors.lastname: D'Aco
authors.forename: Fernando J
authors.initials: FJ
authors.lastname: Martinez
authors.forename: MeiLan K
authors.initials: MK
authors.lastname: Han
authors.forename: David A
authors.initials: DA
authors.lastname: Lynch
authors.forename: James D
authors.initials: JD
authors.lastname: Crapo
authors.forename: Danielle
authors.initials: D
authors.lastname: Morse
authors.forename: Stefan W
authors.initials: SW
authors.lastname: Ryter
authors.forename: Edwin K
authors.initials: EK
authors.lastname: Silverman
authors.forename: Ivan O
authors.initials: IO
authors.lastname: Rosas
authors.forename: Augustine M K
authors.initials: AM
authors.lastname: Choi
authors.forename: Gary M
authors.initials: GM
authors.lastname: Hunninghake
mesh_terms: D000818:Animals; D001761:Bleomycin / Q000633:toxicity; D002352:Carrier Proteins / Q000187:drug effects / Q000502:physiology*; D020170:Caspase 1 / Q000502:physiology; D004357:Drug Synergism; D005260:Female; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000009:adverse effects*; D054990:Idiopathic Pulmonary Fibrosis / Q000139:chemically induced* / Q000378:metabolism / Q000473:pathology; D058847:Inflammasomes / Q000187:drug effects* / Q000378:metabolism; D008168:Lung / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D011658:Pulmonary Fibrosis / Q000139:chemically induced; D012044:Regression Analysis; D012907:Smoking / Q000009:adverse effects
chemical_list: D002352:Carrier Proteins; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D058847:Inflammasomes; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C492716:Nlrp3 protein, mouse; D001761:Bleomycin; D020170:Caspase 1