Matsuda Akihisa, Jacob Asha, Wu Rongqian, Aziz Monowar, Yang Weng-Lang, Matsutani Takeshi, Suzuki Hideyuki, Furukawa Kiyonori, Uchida Eiji, Wang Ping
Department of Surgery, North Shore University Hospital and Long Island Jewish Medical Center, Manhasset and Laboratory of Surgical Research, the Feinstein Institute for Medical Research, Manhasset, NY 11303, USA.
J Nippon Med Sch. 2012;79(1):4-18. doi: 10.1272/jnms.79.4.
Sepsis is a devastating and complex syndrome and continues to be a major cause of morbidity and mortality among critically ill patients at the surgical intensive care unit setting in the United States. The occurrence of sepsis and septic shock has increased significantly over the past two decades. Despite of highly dedicated basic research and numerous clinical trials, remarkable progress has not been made in the development of novel and effective therapeutics. The sepsis-induced physiologic derangements are due largely to the host responses to the invading microorganism in contrast to the direct effects of the microorganism itself. Sepsis, the systemic inflammatory response to infection, is marked by dysregulated production of pro-inflammatory cytokines. Although pro-inflammatory cytokine production is normally indispensable to protect against pathogens and promote tissue repair, the dysregulated and prolonged production of these cytokines can trigger a systemic inflammatory cascade mediated by chemokines, vasoactive amines, the complement and coagulation system, and reactive oxygen species (ROS), amongst others. These mediators collectively lead to multiple organ failure, and ultimately to death. In this regard, the role of inflammation in the pathophysiology of sepsis, although still incompletely understood, is clearly critical. Recent findings resulting from vigorous investigations have contributed to delineate various novel directions of sepsis therapeutics. Among these, this review article is focused on new promising mechanisms and concepts that could have a key role in anti-inflammatory strategies against sepsis, including 1) "inflammasome": a multiprotein complex that activates caspase-1; 2) "the cholinergic anti-inflammatory pathway": the efferent arm of the vagus nerve-mediated, brain-to-immune reflex; 3) "stem cells": unspecialized and undifferentiated precursor cells with the capacity for self-renewal and potential to change into cells of multiple lineages; 4) "milk fat globule-EGF factor VIII (MFG-E8)": a bridging molecule between apoptotic cells and phagocytes, which promotes phagocytosis of apoptotic cells.
脓毒症是一种严重且复杂的综合征，在美国外科重症监护病房的重症患者中，它仍然是发病和死亡的主要原因。在过去二十年中，脓毒症和脓毒性休克的发生率显著增加。尽管进行了高度专注的基础研究和大量临床试验，但在新型有效治疗方法的开发方面尚未取得显著进展。与微生物本身的直接作用相反，脓毒症引起的生理紊乱很大程度上归因于宿主对入侵微生物的反应。脓毒症是对感染的全身性炎症反应，其特征是促炎细胞因子的产生失调。虽然促炎细胞因子的产生通常对于抵御病原体和促进组织修复是必不可少的，但这些细胞因子失调和长期产生会引发由趋化因子、血管活性胺、补体和凝血系统以及活性氧（ROS）等介导的全身性炎症级联反应。这些介质共同导致多器官功能衰竭，并最终导致死亡。在这方面，炎症在脓毒症病理生理学中的作用虽然仍未完全理解，但显然至关重要。积极研究的最新发现有助于勾勒出脓毒症治疗的各种新方向。其中，本文综述聚焦于可能在抗脓毒症炎症策略中起关键作用的新的有前景的机制和概念，包括1）“炎性小体”：一种激活半胱天冬酶 -1的多蛋白复合物；2）“胆碱能抗炎途径”：迷走神经介导的从脑到免疫的反射的传出臂；3）“干细胞”：具有自我更新能力和分化为多种谱系细胞潜力的未特化和未分化的前体细胞；4）“乳脂肪球表皮生长因子 VIII（MFG-E8）”：凋亡细胞与吞噬细胞之间的桥接分子，可促进凋亡细胞的吞噬作用。
