Ayala A, Chaudry I H
Department of Surgery, Michigan State University, East Lansing 48824, USA.
Shock. 1996;6 Suppl 1:S27-38.
Despite recent advances in antibiotic therapy, aggressive operative intervention and intravenous hyperalimentation, sepsis, and multiple organ failure are still reported to contribute to significant morbidity and mortality in the surgical intensive care unit. In light of this, it is essential to determine the mechanism underlying the pathophysiology of sepsis so that better therapeutic interventions can be designed. Experimental studies indicate that murine polymicrobial sepsis induces a marked suppression in both lymphocytic and macrophage function associated with decreased cellular adenosine triphosphate levels and increased Ca2+. However, such changes are not detectable until approximately 12 h after the onset of sepsis. Alternatively, early (0-4 h) in sepsis, macrophages from the liver and peritoneum exhibit augmented innate secretion of proinflammatory cytokines, tumor necrosis factor, interleukin (IL)-6, and IL-1, associated with the systemic release of these agents. Sustained release of immunosuppressive agents transforming growth factor-beta, IL-4, IL-10, and PGE2, as well as glucocorticoids, are also observed during sepsis. In this regard, many investigators, including us, have suggested that an agent(s) released as a part of this systemic inflammatory response to sepsis may be responsible for the protracted suppression of immune cell function. Studies examining the effects of these mediators in vitro on various immune cells have shown that many of these agents also have the capacity to induce a process referred to as programmed cell death (PCD) or apoptosis (Ao). We have presented evidence of marked changes in the rate of Ao in immune cells after the onset of sepsis. These data suggest the possibility that mediators released in response to septic insult contribute to the observed changes in immune cell function through the induction of Ao. Inasmuch, understanding the contribution of PCD to the pathophysiology of sepsis, should provide a better basis from which to develop more effective therapy for the septic patient.
尽管抗生素治疗、积极的手术干预和静脉高营养治疗最近取得了进展，但据报道，脓毒症和多器官功能衰竭仍然是外科重症监护病房患者发病和死亡的重要原因。鉴于此，确定脓毒症病理生理学的潜在机制至关重要，以便设计出更好的治疗干预措施。实验研究表明，小鼠多微生物脓毒症会导致淋巴细胞和巨噬细胞功能显著抑制，同时细胞三磷酸腺苷水平降低，钙离子浓度升高。然而，这些变化直到脓毒症发作后约12小时才会被检测到。另外，在脓毒症早期（0 - 4小时），肝脏和腹膜中的巨噬细胞会表现出促炎细胞因子、肿瘤坏死因子、白细胞介素（IL）-6和IL -1的先天性分泌增加，这些因子会在全身释放。在脓毒症期间还观察到免疫抑制剂转化生长因子-β、IL -4、IL -10和前列腺素E2以及糖皮质激素的持续释放。在这方面，包括我们在内的许多研究人员都认为，作为对脓毒症全身炎症反应一部分而释放的一种或多种物质可能是免疫细胞功能长期抑制的原因。研究这些介质在体外对各种免疫细胞的影响表明，其中许多物质也有能力诱导一种称为程序性细胞死亡（PCD）或凋亡（Ao）的过程。我们已经提供了脓毒症发作后免疫细胞凋亡率显著变化的证据。这些数据表明，对脓毒症刺激作出反应而释放的介质可能通过诱导凋亡导致观察到的免疫细胞功能变化。因此，如果了解PCD对脓毒症病理生理学的作用，应该能为开发更有效的脓毒症患者治疗方法提供更好的基础。
