服用他汀或促肺纤维化(间质肺病),与NLRP3有关
2012-02-04 MedSci MedSci原创
MedSci评论: 随着科技发展,人们对药物的认识越来越深,不再是一个药物,一种疾病,或一个药物,一种机理。其实,人体象庞大的网络系统一样,相互关联,往往牵一发而动全身,而传统所谓“特异性”抑制剂,其实并不是那么特异!不少药物,随着大范围使用,和长期使用,会逐渐暴露一些潜在的风险,如他汀类能导致不少潜在危害,降糖类药物,长期使用,有
MedSci评论: |
随着科技发展,人们对药物的认识越来越深,不再是一个药物,一种疾病,或一个药物,一种机理。其实,人体象庞大的网络系统一样,相互关联,往往牵一发而动全身,而传统所谓“特异性”抑制剂,其实并不是那么特异!不少药物,随着大范围使用,和长期使用,会逐渐暴露一些潜在的风险,如他汀类能导致不少潜在危害,降糖类药物,长期使用,有可能导致癌症,心脏病等。但是,有些药物,却随着机制研究的深入,应用越来越广,如阿司匹林,不仅用于风湿,感冒,还用于卒中预防,现在还用于肿瘤预防。而免疫抑制剂,如雷帕霉素,发现它是mTOR抑制剂,因此能诱导细胞自噬,未来可能广泛应用于大量疾病,如自身免疫性疾病,多种退行性病变(机理可能是自噬不足),各类纤维化,抗衰老,多种慢性损伤,炎症等等。当然,如果mTOR抑制剂真的一天被广泛应用,我们也会发现它们新的危害,这就是科学,永无止境的发展! |
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.
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