Institute of Clinical and Experimental Trauma-Immunology, Ulm University Medical Center, Helmholtzstrasse 8/1, 89081, Ulm, Germany.
Institute of General Physiology, Ulm University, Albert-Einstein-Allee 11, 89081, Ulm, Germany.
Sci Rep. 2021 Jan 25;11(1):2158. doi: 10.1038/s41598-020-79607-1.
Singular blockade of C5a in experimental models of sepsis is known to confer protection by rescuing lethality and decreasing pro-inflammatory responses. However, the role of inhibiting C5a has not been evaluated in the context of sterile systemic inflammatory responses, like polytrauma and hemorrhagic shock (PT + HS). In our presented study, a novel and highly specific C5a L-aptamer, NoxD21, was used to block C5a activity in an experimental murine model of PT + HS. The aim of the study was to assess early modulation of inflammatory responses and lung damage 4 h after PT + HS induction. NoxD21-treated PT + HS mice displayed greater polymorphonuclear cell recruitment in the lung, increased pro-inflammatory cytokine levels in the bronchoalveolar lavage fluids (BALF) and reduced myeloperoxidase levels within the lung tissue. An in vitro model of the alveolar-capillary barrier was established to confirm these in vivo observations. Treatment with a polytrauma cocktail induced barrier damage only after 16 h, and NoxD21 treatment in vitro did not rescue this effect. Furthermore, to test the exact role of both the cognate receptors of C5a (C5aR1 and C5aR2), experimental PT + HS was induced in C5aR1 knockout (C5aR1 KO) and C5aR2 KO mice. Following 4 h of PT + HS, C5aR2 KO mice had significantly reduced IL-6 and IL-17 levels in the BALF without significant lung damage, and both, C5aR1 KO and C5aR2 KO PT + HS animals displayed reduced MPO levels within the lungs. In conclusion, the C5aR2 could be a putative driver of early local inflammatory responses in the lung after PT + HS.
在败血症的实验模型中，单独阻断 C5a 已被证实通过挽救致死率和减少促炎反应来提供保护。然而，在无菌性全身炎症反应（如多发伤和失血性休克）的背景下，抑制 C5a 的作用尚未得到评估。在我们目前的研究中，一种新型且高度特异的 C5a L-适体 NoxD21 被用于阻断实验性多发伤和失血性休克小鼠模型中的 C5a 活性。该研究的目的是评估在诱导多发伤和失血性休克后 4 小时早期对炎症反应和肺损伤的调节作用。NoxD21 处理的多发伤和失血性休克小鼠显示肺中多形核细胞募集增加，支气管肺泡灌洗液中的促炎细胞因子水平升高，肺组织中的髓过氧化物酶水平降低。建立了肺泡毛细血管屏障的体外模型来验证这些体内观察结果。仅在 16 小时后，多伤鸡尾酒处理诱导了屏障损伤，而 NoxD21 的体外处理未能挽救这种效应。此外，为了测试 C5a 的同源受体（C5aR1 和 C5aR2）的确切作用，在 C5aR1 敲除（C5aR1 KO）和 C5aR2 敲除（C5aR2 KO）小鼠中诱导了实验性多发伤和失血性休克。在 4 小时多发伤和失血性休克后，C5aR2 KO 小鼠的 BALF 中 IL-6 和 IL-17 水平显著降低，而肺损伤不明显，并且 C5aR1 KO 和 C5aR2 KO 多发伤和失血性休克动物的肺组织中的 MPO 水平均降低。总之，在多发伤和失血性休克后，C5aR2 可能是肺部早期局部炎症反应的潜在驱动因素。
