Inactivation of fatty acid amide hydrolase exacerbates experimental fibrosis by enhanced endocannabinoid-mediated activation of CB1
Inactivation of fatty acid amide hydrolase exacerbates experimental fibrosis by enhanced endocannabinoid-mediated activation of CB1
复制标题
脂肪酸酰胺水解酶失活通过增强内源性大麻素介导的 CB1 激活加剧实验性纤维化
DOI：
10.1136/annrheumdis-2012-201823
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发表时间：
2012
影响因子：
27.4
通讯作者：
Distler JH
中科院分区：
文献类型：
--
作者：
Palumbo-Zerr K;Horn A;Distler A;Zerr P;Dees C;Beyer C;Selvi C;Cravatt BF;Distler O;Schett G;Distler JH
合成化合物选择性靶向大麻素受体CB1和CB2，揭示了这两种受体在纤维化中的相反作用。目的探讨内源性大麻素（内源性大麻素）及其主要受体在纤维化中的作用。方法通过脂肪酸酰胺水解酶（FAAH）的药理失活或遗传失活来调节小鼠内源性大麻素水平。内源性大麻素的主要受体是通过选择性抑制CB1或CB2来确定的。通过定量测定真皮厚度、羟脯氨酸含量和肌成纤维细胞计数来测定博来霉素刺激后的纤维化程度。结果FAAH在系统性硬化症成纤维细胞中表达降低。faah缺陷小鼠内源性大麻素水平显著升高，对博莱霉素更敏感。与此一致的是，FAAH的药理抑制显著加重了博莱霉素诱导的纤维化。抑制CB1完全消除FAAH失活的促纤维化作用。相比之下，抑制CB2仅适度增强纤维化，表明CB1是实验性纤维化中内源性大麻素的主要受体。结论FAAH失活诱导的内源性大麻素水平升高通过激活CB1加重实验性纤维化。这些发现强调了内源性大麻素的促纤维化作用，并表明CB1可能比CB2更有希望用于纤维化疾病的靶向治疗。
BackgroundSelective targeting of the cannabinoid receptors CB1 and CB2 by synthetic compounds has revealed opposing roles of both receptors in fibrosis.ObjectivesTo characterise the role of endogenous cannabinoids (endocannabinoids) and their predominant receptor in fibrosis.MethodsThe levels of endocannabinoids in mice were modulated by pharmacological or genetic inactivation of the enzyme fatty acid amide hydrolase (FAAH). The predominant receptor for endocannabinoids was determined by selective inhibition of either CB1 or CB2. The extent of fibrosis upon challenge with bleomycin was determined by quantification of dermal thickness, hydroxyproline content and myofibroblast counts.ResultsThe expression of FAAH is decreased in systemic sclerosis fibroblasts. FAAH-deficient mice with strongly increased levels of endocannabinoids were more sensitive to bleomycin. Consistently, pharmacological inhibition of FAAH significantly exacerbated bleomycin-induced fibrosis. Inhibition of CB1 completely abrogated the profibrotic effects of FAAH inactivation. In contrast, inhibition of CB2 only modestly enhanced fibrosis, indicating that CB1 is the predominant receptor for endocannabinoids in experimental fibrosis.ConclusionsIncreased levels of endocannabinoids induced by inactivation of FAAH worsen experimental fibrosis via activation of CB1. These findings highlight the profibrotic effects of endocannabinoids and suggest that CB1 maybe a more promising candidate for targeted treatments in fibrotic diseases than CB2.
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影响因子：
27.4
作者：
Gonzalez, Estrella Garcia;Selvi, Enrico;Distler, Joerg H. W.
通讯作者：
Distler, Joerg H. W.
影响因子：
27.4
作者：
Beyer, Christian;Reich, Nicole;Distler, Joerg H. W.
通讯作者：
Distler, Joerg H. W.
影响因子：
27.4
作者：
Bergmann, Christina;Akhmetshina, Alfiya;Distler, Joerg H. W.
通讯作者：
Distler, Joerg H. W.
影响因子：
13.5
作者：
Hézode, C;Roudot-Thoraval, F;Mallat, A
通讯作者：
Mallat, A
影响因子：
5.5
作者：
Garcia-Gonzalez, Estrella;Selvi, Enrico;Galeazzi, Mauro
通讯作者：
Galeazzi, Mauro