期刊
JOURNAL OF EXPERIMENTAL MEDICINE
卷 211, 期 9, 页码 1793-1805出版社
ROCKEFELLER UNIV PRESS
DOI: 10.1084/jem.20131902
关键词
-
资金
- National Institutes of Health [R56 AI095657, R01 HL86576, R01 HL082485]
- National Natural Science Foundation of China [81160066, 31370917]
- Guangxi Natural Science Foundation [2013GXNSFCA019012]
- Science & Technology Planning Project of Guangxi Province [1140003-79]
- Science & Technology Planning Project of Guilin City [20110119-1-8]
Liver resection is commonly performed under ischemic conditions, resulting in two types of insult to the remnant liver: ischemia reperfusion injury (IRI) and loss of liver mass. Complement inhibition is recognized as a potential therapeutic modality for IRI, but early complement activation products are also essential for liver regeneration. We describe a novel site-targeted murine complement inhibitor, CR2-CD59, which specifically inhibits the terminal membrane attack complex (MAC), and we use this protein to investigate the complement-dependent balance between liver injury and regeneration in a clinical setting of pharmacological inhibition. CR2-CD59 did not impact in vivo generation of C3 and C5 activation products but was as effective as the C3 activation inhibitor CR2-Crry at ameliorating hepatic IRI, indicating that the MAC is the principle mediator of hepatic IRI. Furthermore, unlike C3 or C5 inhibition, CR2-CD59 was not only protective but significantly enhanced hepatocyte proliferation after partial hepatectomy, including when combined with ischemia and reperfusion. Remarkably, CR2-CD59 also enhanced regeneration after 90% hepatectomy and improved long-term survival from 0 to 70%. CR2-CD59 functioned by increasing hepatic TNF and IL-6 levels with associated STAT3 and Akt activation, and by preventing mitochondrial depolarization and allowing recovery of ATP stores.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据