Statins and Pulmonary Fibrosis
- 1 March 2012
- journal article
- Published by American Thoracic Society in American Journal of Respiratory and Critical Care Medicine
- Vol. 185 (5), 547-556
- https://doi.org/10.1164/rccm.201108-1574oc
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).This publication has 52 references indexed in Scilit:
- Opposite effects of statins on mitochondria of cardiac and skeletal muscles: a ‘mitohormesis’ mechanism involving reactive oxygen species and PGC-1European Heart Journal, 2011
- Lung Volumes and Emphysema in Smokers with Interstitial Lung AbnormalitiesThe New England Journal of Medicine, 2011
- Autophagy proteins regulate innate immune responses by inhibiting the release of mitochondrial DNA mediated by the NALP3 inflammasomeNature Immunology, 2010
- Bleomycin and IL-1β–mediated pulmonary fibrosis is IL-17A dependentThe Journal of Experimental Medicine, 2010
- Identification of Early Interstitial Lung Disease in Smokers from the COPDGene StudyAcademic Radiology, 2010
- The Nalp3 inflammasome is essential for the development of silicosisProceedings of the National Academy of Sciences of the United States of America, 2008
- Innate Immune Activation Through Nalp3 Inflammasome Sensing of Asbestos and SilicaScience, 2008
- Large-scale chemical dissection of mitochondrial functionNature Biotechnology, 2008
- Caveolin-1: a critical regulator of lung fibrosis in idiopathic pulmonary fibrosisThe Journal of Experimental Medicine, 2006
- Potential therapeutic role for statins in respiratory diseaseThorax, 2006