Vollmar B
Institut für Experimentelle Chirurgie, Medizinische Fakultät, Universität Rostock, Schillingallee 69a, Rostock, Germany.
Chirurg. 2011 Mar;82(3):199-207. doi: 10.1007/s00104-010-2010-7.
Infection or injury, including surgical procedures, induces an inflammatory response of the host organism. This immune response must be finely tuned and precisely regulated, because deficiencies or excesses of the inflammatory response cause morbidity and shorten the lifespan. Activated receptors of the innate immune system (pattern recognition receptors, PRRs), which recognize pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs) including injured tissue-associated intracellular proteins (alarmins), lead to an exaggerated immune response. This is characterized by a complex interplay of cytokines, chemokines, complement and coagulation factors as well as inflammatory and immune regulatory cells. There is increasing recognition that the major pathophysiologic event in sepsis is the progression from the initial hyperinflammatory state to an immunosuppressive state in which the host is unable to eradicate invading pathogens and particularly prone to develop secondary nosocomial infections and organ damage. Surgical trauma-associated immune dysfunction per se predisposes the host to surgery-related sepsis. Immune suppression is mediated by massive apoptosis-induced depletion of lymphocytes and dendritic cells, decreased expression of the cell surface antigen complex HLA-DR and increased expression of negative costimulatory molecules. Besides increased numbers of regulatory T cells there is a shift from a phenotype of inflammatory Th1 cells to an antiinflammatory phenotype of Th2 cells characterized by the production of interleukin-10. Key mediators of sepsis are HMGB1, MIF and complement factor C5a. With the identification of central pathomechanistic events, e.g. amplification of the coagulation, complement and inflammation cascades, immune dysbalance and neuroimmunomodulation via the cholinergic anti-inflammatory reflex, the opportunity now exists to apply these insights to the development of new and novel therapeutics aimed at modulating rather than inhibiting the systemic host response to infection.
感染或损伤，包括外科手术，会诱发宿主机体的炎症反应。这种免疫反应必须得到精确调节，因为炎症反应的不足或过度都会导致发病并缩短寿命。先天免疫系统的活化受体（模式识别受体，PRRs）可识别病原体相关分子模式（PAMPs）和损伤相关分子模式（DAMPs），包括与受损组织相关的细胞内蛋白质（警报素），会导致免疫反应过度。其特征是细胞因子、趋化因子、补体和凝血因子以及炎症和免疫调节细胞之间存在复杂的相互作用。人们越来越认识到，脓毒症的主要病理生理事件是从最初的高炎症状态发展到免疫抑制状态，在此状态下宿主无法根除入侵的病原体，尤其容易发生继发性医院感染和器官损伤。手术创伤相关的免疫功能障碍本身使宿主易患与手术相关的脓毒症。免疫抑制是由大量凋亡导致的淋巴细胞和树突状细胞耗竭、细胞表面抗原复合物HLA-DR表达降低以及负性共刺激分子表达增加介导的。除了调节性T细胞数量增加外，还存在从炎症性Th1细胞表型向以白细胞介素-10产生为特征的抗炎性Th2细胞表型的转变。脓毒症的关键介质是高迁移率族蛋白B1（HMGB1）、巨噬细胞移动抑制因子（MIF）和补体因子C5a。随着对中心病理机制事件的识别，例如凝血、补体和炎症级联反应的放大、免疫失衡以及通过胆碱能抗炎反射的神经免疫调节，现在有机会将这些见解应用于开发旨在调节而非抑制宿主对感染的全身反应的新型治疗方法。
