Department of Anesthesiology, Shanghai Xinhua Hospital, Jiaotong University School of Medicine, Shanghai, China.
Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.
J Leukoc Biol. 2018 Feb;103(2):175-183. doi: 10.1189/jlb.3HI0517-173R. Epub 2017 Dec 28.
Hemorrhagic shock (HS) renders patients susceptible to development of systemic inflammatory response syndrome (SIRS) and multiple organ dysfunction syndrome (MODS) through mechanisms that are, as yet, unclear. Cell necroptosis, a form of regulated inflammatory cell death, is one of the mechanisms that controls cell release of inflammatory mediators from innate immune cells, such as polymorphonuclear neutrophils (PMNs), and critically regulates the progress of inflammation. In this study, we investigated the mechanisms of alveolar macrophage (AMϕ) effects on PMN necroptosis following HS. With the use of in vivo and ex vivo HS models, we reveal a novel function of shock-activated AMϕ in promoting PMN necroptosis. We demonstrate that exosomes released from HS-activated AMϕ induce mainly NADPH oxidase-derived reactive oxygen species (ROS) production inside PMNs and subsequent promotion of necroptosis. These findings explore a previously unidentified pathway of AMϕ-PMN cross-talk, which causes enhanced PMN necroptosis and subsequent exaggerated post-HS lung inflammation. The targeting of this PMN death pathway may serve as a new therapeutic strategy for treatment of post-HS SIRS.
失血性休克（HS）通过尚未明确的机制使患者易发生全身炎症反应综合征（SIRS）和多器官功能障碍综合征（MODS）。细胞坏死性凋亡是一种受调控的炎症细胞死亡形式，它是控制先天免疫细胞（如多形核粒细胞（PMN））中炎症介质释放的机制之一，并严格调控炎症的进展。在这项研究中，我们研究了肺泡巨噬细胞（AMϕ）对 HS 后 PMN 坏死性凋亡的作用机制。通过使用体内和体外 HS 模型，我们揭示了激活的 AMϕ 在促进 PMN 坏死性凋亡中的新功能。我们证明，HS 激活的 AMϕ 释放的外泌体主要诱导 PMN 内 NADPH 氧化酶衍生的活性氧（ROS）产生，随后促进坏死性凋亡。这些发现探索了 AMϕ-PMN 相互作用的一个以前未被识别的途径，导致增强的 PMN 坏死性凋亡和随后的 HS 后肺部炎症过度。针对这种 PMN 死亡途径可能成为治疗 HS 后 SIRS 的新治疗策略。
