You Zerong, Yang Jinsheng, Takahashi Kazue, Yager Phoebe H, Kim Hyung-Hwan, Qin Tao, Stahl Gregory L, Ezekowitz R Alan B, Carroll Michael C, Whalen Michael J
Neuroscience Center, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts 02129, USA.
J Cereb Blood Flow Metab. 2007 Dec;27(12):1954-64. doi: 10.1038/sj.jcbfm.9600497. Epub 2007 Apr 25.
Complement component C4 mediates C3-dependent tissue damage after systemic ischemia-reperfusion injury. Activation of C3 also contributes to the pathogenesis of experimental and human traumatic brain injury (TBI); however, few data exist regarding the specific pathways (classic, alternative, and lectin) involved. Using complement knockout mice and a controlled cortical impact (CCI) model, we tested the hypothesis that the classic pathway mediates secondary damage after TBI. After CCI, C4c and C3d immunostaining were detected in cortical vascular endothelial cells in wild-type (WT) mice; however, C4c and C3d immunostaining were also detected in C1q(-/-) mice, and C3d immunostaining was detected in C4(-/-) mice. After CCI, WT and C1q(-/-) mice had similar motor deficits, Morris water maze performance, and brain lesion size. Naive C4(-/-) and WT mice did not differ in baseline motor performance, but C4(-/-) mice had reduced postinjury motor deficits (days 1 to 7, P<0.05) and decreased brain tissue damage (days 14 and 35, P<0.05) versus WT. Reconstitution of C4(-/-) mice with human C4 (hC4) reversed their protection against postinjury motor deficits (P<0.05 versus vehicle), but administration of hC4 did not impair postinjury motor performance (versus vehicle) in WT mice. The protective effects of C4(-/-) were functionally distinct from the classic pathway and terminal complement, as C1q(-/-) and C3(-/-) mice had postinjury tissue damage and motor dysfunction similar to WT. Thus, C4 contributes to motor deficits and brain tissue damage after CCI by mechanism(s) fundamentally different from those involved in experimental systemic ischemia-reperfusion injury.
补体成分C4介导全身缺血再灌注损伤后依赖C3的组织损伤。C3的激活也参与实验性和人类创伤性脑损伤（TBI）的发病机制；然而，关于所涉及的特定途径（经典途径、替代途径和凝集素途径）的数据很少。我们使用补体基因敲除小鼠和控制性皮质撞击（CCI）模型，检验了经典途径介导TBI后继发性损伤的假说。CCI后，在野生型（WT）小鼠的皮质血管内皮细胞中检测到C4c和C3d免疫染色；然而，在C1q基因敲除（-/-）小鼠中也检测到C4c和C3d免疫染色，在C4基因敲除（-/-）小鼠中检测到C3d免疫染色。CCI后，WT和C1q基因敲除（-/-）小鼠具有相似的运动功能缺陷、莫里斯水迷宫表现和脑损伤大小。未受伤的C4基因敲除（-/-）小鼠和WT小鼠在基线运动性能上没有差异，但与WT小鼠相比，C4基因敲除（-/-）小鼠损伤后的运动功能缺陷减轻（第1至7天，P<0.05），脑组织损伤减少（第14天和35天，P<0.05）。用人C4（hC4）重建C4基因敲除（-/-）小鼠可逆转其对损伤后运动功能缺陷的保护作用（与载体相比，P<0.05），但给予hC4不会损害WT小鼠损伤后的运动性能（与载体相比）。C4基因敲除（-/-）的保护作用在功能上与经典途径和末端补体不同，因为C1q基因敲除（-/-）和C3基因敲除（-/-）小鼠损伤后的组织损伤和运动功能障碍与WT小鼠相似。因此，C4通过与实验性全身缺血再灌注损伤所涉及的机制根本不同的机制，导致CCI后的运动功能缺陷和脑组织损伤。
