The complement anaphylatoxin C5a induces apoptosis in adrenomedullary cells during experimental sepsis.
The complement anaphylatoxin C5a induces apoptosis in adrenomedullary cells during experimental sepsis.
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补体过敏毒素C5A在实验性败血症过程中诱导肾上腺囊肿细胞的凋亡。
DOI：
10.1371/journal.pone.0002560
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发表时间：
2008-07-02
期刊：
影响因子：
3.7
通讯作者：
Ward, Peter A.
中科院分区：
文献类型：
--
作者：
Flierl, Michael A.;Rittirsch, Daniel;Chen, Anthony J.;Nadeau, Brian A.;Day, Danielle E.;Sarma, J. Vidya;Huber-Lang, Markus S.;Ward, Peter A.
脓毒症仍然是一个知之甚少，神秘的疾病。补体系统是其发病机制中关键参与的级联反应之一。特别是过敏毒素C5a已被证明在脓毒症期间具有许多有害作用。我们研究了高水平的C5a对盲肠结扎和穿刺（CLP）诱导的脓毒症大鼠肾上腺髓质的影响，以及C5a对嗜铬细胞瘤衍生的PC12细胞的儿茶酚胺产生的作用。TUNEL法检测CLP后24小时大鼠肾上腺髓质细胞凋亡明显。这些作用可以通过C5a受体C5aR和C5L2的双重阻断来逆转。当大鼠进行CLP时，发现C5a和去甲肾上腺素的水平作为时间的函数是相反的。PC12细胞产生的去甲肾上腺素和多巴胺显着钝化后，暴露于重组大鼠C5a的时间依赖性和剂量依赖性的方式。这种受损的生产可能与C5a诱导的细胞凋亡的启动有关，如通过膜联蛋白V和碘化丙啶与PC12细胞的结合所定义的。总的来说，我们描述了一个C5a依赖诱导细胞凋亡事件在肾上腺髓质细胞在体内和嗜铬细胞瘤PC12细胞在体外。这些数据表明，实验性脓毒症诱导肾上腺髓质细胞凋亡，这是负责大量的内源性儿茶酚胺。感染性休克可能与这些事件有关。由于两种C5 a受体的阻断实际上消除了体内肾上腺髓质细胞凋亡，因此C5 aR和C5 L2成为有希望的靶点，对脓毒症临床环境中未来的补体阻断策略具有影响。
Sepsis remains a poorly understood, enigmatic disease. One of the cascades crucially involved in its pathogenesis is the complement system. Especially the anaphylatoxin C5a has been shown to have numerous harmful effects during sepsis. We have investigated the impact of high levels of C5a on the adrenal medulla following cecal ligation and puncture (CLP)-induced sepsis in rats as well as the role of C5a on catecholamine production from pheochromocytoma-derived PC12 cells. There was significant apoptosis of adrenal medulla cells in rats 24 hrs after CLP, as assessed by the TUNEL technique. These effects could be reversed by dual-blockade of the C5a receptors, C5aR and C5L2. When rats were subjected to CLP, levels of C5a and norepinephrine were found to be antipodal as a function of time. PC12 cell production of norepinephrine and dopamine was significantly blunted following exposure to recombinant rat C5a in a time-dependent and dose-dependent manner. This impaired production could be related to C5a-induced initiation of apoptosis as defined by binding of Annexin V and Propidium Iodine to PC12 cells. Collectively, we describe a C5a-dependent induction of apoptotic events in cells of adrenal medulla in vivo and pheochromocytoma PC12 cells in vitro. These data suggest that experimental sepsis induces apoptosis of adrenomedullary cells, which are responsible for the bulk of endogenous catecholamines. Septic shock may be linked to these events. Since blockade of both C5a receptors virtually abolished adrenomedullary apoptosis in vivo, C5aR and C5L2 become promising targets with implications on future complement-blocking strategies in the clinical setting of sepsis.
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影响因子：
15.9
作者：
Guo, RF;Huber-Lang, M;Ward, PA
通讯作者：
Ward, PA
DOI：
10.1073/pnas.96.25.14541
发表时间：
1999-12-07
影响因子：
11.1
作者：
Hotchkiss, RS;Tinsley, KW;Karl, IE
通讯作者：
Karl, IE
影响因子：
4.4
作者：
Huber-Lang, M;Sarma, JV;Ward, PA
通讯作者：
Ward, PA
影响因子：
6
作者：
Laudes, IJ;Chu, JC;Ward, PA
通讯作者：
Ward, PA
DOI：
10.1164/rccm.2201087
发表时间：
2003-07-15
影响因子：
24.7
作者：
Annane, D;Aegerter, P;Guidet, B
通讯作者：
Guidet, B