Complement-dependent injury and protection in a murine model of acute dextran sulfate sodium-induced colitis.
Complement-dependent injury and protection in a murine model of acute dextran sulfate sodium-induced colitis.
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DOI：
10.4049/jimmunol.1200553
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发表时间：
2012-06-15
期刊：
影响因子：
--
通讯作者：
Tomlinson S
中科院分区：
文献类型：
--
作者：
Schepp-Berglind J;Atkinson C;Elvington M;Qiao F;Mannon P;Tomlinson S
补体在许多炎症性疾病的病理生理学中起着关键作用，在这里，我们研究了补体在炎症性肠病（IBD）发病机制中的作用。与野生型（wt）小鼠相比，C3或因子B（fB）缺陷的小鼠免受急性DSS诱导的结肠炎。然而，C1 q/MBL双缺陷小鼠表现出比野生型小鼠更严重的结肠炎。当小鼠在DSS治疗后恢复时，所有C1 q/MBL-/-小鼠在恢复期第2天死亡，并且令人惊讶的是，所有C3-/-和fB-/-小鼠在第5天死亡。补体缺陷小鼠死亡前血清内毒素水平显著升高，特别是在C1 q/MBL-/-小鼠中，抗生素治疗阻止了DSS在所有补体缺陷小鼠中的致死作用。与补体缺乏相反，用CR2-Crry（阻断C3活化的所有途径）或CR2-fH（阻断旁路途径）靶向补体抑制在治疗已建立的急性结肠炎时具有高度保护性。内毒素水平在补体抑制小鼠中保持较低，并且补体抑制还减少炎性细胞因子、白细胞浸润和组织损伤，同时改善伤口修复和粘膜愈合。CR2-fH比CR2-Crry提供更有效的保护。因此，补体在急性DSS诱导的结肠炎中具有致病和保护作用，而旁路途径似乎在组织炎症和损伤中起关键作用，经典/凝集素途径在宿主防御和伤口修复方面提供重要保护。靶向抑制旁路途径可能代表治疗IBD急性期的治疗方式。
Complement plays a key role in the pathophysiology of many inflammatory diseases, and here we investigated the role of complement in the pathogenesis of inflammatory bowel disease (IBD). Compared to wild type (wt) mice, mice deficient in C3 or factor B (fB) were protected from acute DSS-induced colitis. C1q/MBL double deficient mice, however, exhibited more severe colitis than wt mice. When mice were allowed to recover after DSS treatment, all C1q/MBL-/- mice died by day 2 of recovery period and, surprisingly, all C3-/- and fB-/- mice died by day 5. Serum endotoxin levels were significantly increased in complement deficient mice prior to death, particularly in C1q/MBL-/- mice, and antibiotic treatment prevented the lethal effect of DSS in all complement deficient mice. In contrast to complement deficiency, targeted complement inhibition with either CR2-Crry (blocks all pathways at C3 activation) or CR2-fH (blocks alternative pathway), was highly protective at treating established acute colitis. Endotoxin levels remained low in complement inhibited mice, and complement inhibition also reduced inflammatory cytokines, leuckocyte infiltration and tissue injury, while improving wound repair and mucosal healing. CR2-fH provided more effective protection than CR2-Crry. Thus, complement has both pathogenic and protective roles in acute DSS-induced colitis, and whereas the alternative pathway appears to play a key role in tissue inflammation and injury, the classical/lectin pathway provides important protection in terms of host defense and wound repair. Targeted inhibition of the alternative pathway may represent a therapeutic modality for treating acute phases of IBD.
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DOI：
10.4049/jimmunol.181.11.8068
发表时间：
2008-12-01
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Huang Y;Qiao F;Atkinson C;Holers VM;Tomlinson S
通讯作者：
Tomlinson S
DOI：
10.4049/jimmunol.1002741
发表时间：
2011-03-01
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Dahlke K;Wrann CD;Sommerfeld O;Sossdorf M;Recknagel P;Sachse S;Winter SW;Klos A;Stahl GL;Ma YX;Claus RA;Reinhart K;Bauer M;Riedemann NC
通讯作者：
Riedemann NC
影响因子：
6
作者：
Stahl, GL;Xu, YY;Zhao, H
通讯作者：
Zhao, H
影响因子：
3.2
作者：
Hoffmann, Christina;Hoffmann, Peter;Weimann, Andreas
通讯作者：
Weimann, Andreas
影响因子：
64.8
作者：
Prodeus, AP;Zhou, XN;Carroll, MC
通讯作者：
Carroll, MC