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

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 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: 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, MeiLan K Han, David A Lynch, James D Crapo, Danielle Morse, Stefan W Ryter, Edwin K Silverman, Ivan O Rosas, Augustine M K Choi, Gary M Hunninghake, COPDGene Investigators
• Journal: American journal of respiratory and critical care medicine (Am J Respir Crit Care Med) Vol. 185 Issue 5 Pg. 547-56 (Mar 01 2012) ISSN: 1535-4970 [Electronic] United States
• PMID: 22246178 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Carrier Proteins
• Hydroxymethylglutaryl-CoA Reductase Inhibitors
• Inflammasomes
• NLR Family, Pyrin Domain-Containing 3 Protein
• Nlrp3 protein, mouse
• Bleomycin
• Caspase 1

Topics

• Animals
• Bleomycin (toxicity)
• Carrier Proteins (drug effects, physiology)
• Caspase 1 (physiology)
• Drug Synergism
• Female
• Humans
• Hydroxymethylglutaryl-CoA Reductase Inhibitors (adverse effects)
• Idiopathic Pulmonary Fibrosis (chemically induced, metabolism, pathology)
• Inflammasomes (drug effects, metabolism)
• Lung (drug effects, metabolism, pathology)
• Male
• Mice
• Mice, Inbred C57BL
• NLR Family, Pyrin Domain-Containing 3 Protein
• Pulmonary Fibrosis (chemically induced)
• Regression Analysis
• Smoking (adverse effects)