服用他汀或促肺纤维化（间质肺病），与NLRP3有关

　美国研究显示，吸烟者服用他汀类药物与其患间质性肺病（ILD）正相关。论文在线发表于《美国呼吸与危重症杂志》（Am J Respir Crit Care Med）。

原始文献：

Xu JF, Washko GR, Nakahira K, Hatabu H, Patel AS, Fernandez IE, Nishino M, Okajima Y, Yamashiro T, Ross JC, Estépar RS, Diaz AA, Li HP, Qu JM, Himes BE, Come CE, D'Aco K, Martinez FJ, Han MK, Lynch DA, Crapo JD, Morse D, Ryter SW, Silverman EK, Rosas IO, Choi AM, Hunninghake GM; the COPDGene Investigators.Statins and Pulmonary Fibrosis: The Potential Role of NLRP3 Inflammasome Activation.Am J Respir Crit Care Med. 2012 Jan 12.

Abstract

RATIONALE:

The role of HMG-CoA reductase inhibitors (statins) in the development and/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.

RESULTS:

In COPDGene, 38% of subjects with ILA were taking statins compared to 27% of subjects without ILA. Statin use was positively associated in ILA (odds ratio [OR] 1.60, 95% confidence interval [CI] 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 (BMDMs) 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.