Department of Traumatology, Hand-, Plastic-, and Reconstructive Surgery, University Hospital of Ulm, Steinhoevelstr. 9, 89075 Ulm, Germany.
Adv Exp Med Biol. 2012;946:135-46. doi: 10.1007/978-1-4614-0106-3_8.
In response to severe tissue trauma, several "molecular danger" sensing and signaling pathways are activated, especially the complement and the apoptosis cascade. Although possible crossroads between both systems have been proposed, little is known about the underlying molecular interactions. In this study a new interaction interface is presented for C3a and C5a generation by the pro-apoptotic factor granzyme B. In vitro incubation of the central human complement components C3 and C5 with the serine protease granzyme B resulted in a concentration-dependent production of the anaphylatoxins C3a and C5a. The so generated anaphylatoxin C5a was chemotactic active for isolated human neutrophils. In a translational approach, intracellular granzyme B concentration in leukocytes was determined early after severe tissue trauma. In comparison to healthy volunteers, multiple injured patients (less than one hour after trauma, Injury Severity Score > 18, n = 5) presented a significant increase in granzmye B levels in neutrophils and lymphocytes. Thus, tissue trauma is associated with early activation of both, the complement and apoptosis system. The present data suggest a new form of interaction between the complement and the apoptosis system on the level of granzyme B that is capable to generate C3a and C5a independently of the established complement proteases.
针对严重的组织创伤，几种“分子危险”感应和信号通路被激活，特别是补体和细胞凋亡级联。尽管已经提出了这两个系统之间可能的交叉点，但对潜在的分子相互作用知之甚少。在这项研究中，提出了一个新的相互作用界面，用于促凋亡因子颗粒酶 B 生成 C3a 和 C5a。在体外将中心人类补体成分 C3 和 C5 与丝氨酸蛋白酶颗粒酶 B 孵育，导致过敏毒素 C3a 和 C5a 的浓度依赖性产生。如此产生的过敏毒素 C5a 对分离的人中性粒细胞具有趋化活性。在转化方法中，在严重组织创伤后早期测定白细胞中的细胞内颗粒酶 B 浓度。与健康志愿者相比，多发伤患者（创伤后不到 1 小时，损伤严重程度评分>18，n=5）在中性粒细胞和淋巴细胞中的颗粒酶 B 水平显著升高。因此，组织创伤与补体和细胞凋亡系统的早期激活有关。本研究数据表明，在颗粒酶 B 水平上，补体和细胞凋亡系统之间存在一种新的相互作用形式，能够独立于已建立的补体蛋白酶生成 C3a 和 C5a。
