Granger Jill, Remick Daniel
Department of Pathology, University of Michigan, Ann Arbor, MI 48109-0602, USA.
Shock. 2005 Dec;24 Suppl 1:45-51. doi: 10.1097/01.shk.0000191413.94461.b0.
Acute pancreatitis has an incidence of approximately 40 cases per year per 100,000 adults. Although usually self-limiting, 10% to 20% of afflicted patients will progress to severe pancreatitis. The mortality rate among patients with severe pancreatitis may approach 30% when they progress to multisystem organ failure. The development of acute pancreatitis illustrates the requirement for understanding the basic mechanisms of disease progression to drive the exploration of therapeutic options. The pathogenesis of acute pancreatitis involves the interplay of local and systemic immune responses that are often difficult to characterize, particularly when results from animal models are used as a foundation for human trials. Experimental studies suggest that the prognosis for acute pancreatitis depends upon the degree of pancreatic necrosis and the intensity of multisystem organ failure generated by the systemic inflammatory response. This suggests an intricate balance between localized tissue damage with proinflammatory cytokine production and a systemic, anti-inflammatory response that restricts the inappropriate movement of proinflammatory agents into the circulation. The critical players of this interaction include the proinflammatory cytokines IL-1beta, TNF-alpha, IL-6, IL-8, and platelet activating factor (PAF). The anti-inflammatory cytokines IL-10, as well as TNF-soluble receptors and IL-1 receptor antagonist, have also been shown to be intimately involved in the inflammatory response to acute pancreatitis. Other compounds implicated in disease pathogenesis in experimental models include complement, bradykinin, nitric oxide, reactive oxygen intermediates, substance P, and higher polyamines. Several of these mediators have been documented to be present at increased concentrations in the plasma of patients with severe, acute pancreatitis. Preclinical work has shown that some of these mediators are markers for disease activity, whereas other inflammatory components may actually drive the disease process as important mediators. Implication of such mediators suggests that interruption or blunting of an inappropriate immune response has the potential to improve outcome. Although the manipulations of specific mediators in animal models may be promising, they may not transition well to the human clinical setting. However, continued reliance on experimental animal models of acute pancreatitis may be necessary to determine the underlying causes of disease. Full understanding of these basic mechanisms involves determining not only which mediators are present, but also closely documenting the kinetics of their appearance. Measurement of the inflammatory response may also serve to identify diagnostic markers for the presence of acute pancreatitis and provide insight into prognosis. Understanding the models, documenting the markers, and deciphering the mediators have the potential to improve treatment of acute pancreatitis.
急性胰腺炎的发病率约为每10万名成年人每年40例。虽然通常为自限性疾病，但10%至20%的患病患者会进展为重症胰腺炎。重症胰腺炎患者进展为多系统器官衰竭时，死亡率可能接近30%。急性胰腺炎的发展表明，需要了解疾病进展的基本机制，以推动治疗方案的探索。急性胰腺炎的发病机制涉及局部和全身免疫反应的相互作用，这种相互作用往往难以描述，特别是当动物模型的结果被用作人体试验的基础时。实验研究表明，急性胰腺炎的预后取决于胰腺坏死的程度和全身炎症反应所产生的多系统器官衰竭的强度。这表明在局部组织损伤与促炎细胞因子产生之间以及限制促炎因子不适当进入循环的全身抗炎反应之间存在着复杂的平衡。这种相互作用的关键参与者包括促炎细胞因子白细胞介素-1β、肿瘤坏死因子-α、白细胞介素-6、白细胞介素-8和血小板活化因子（PAF）。抗炎细胞因子白细胞介素-10，以及肿瘤坏死因子可溶性受体和白细胞介素-1受体拮抗剂，也已被证明与急性胰腺炎的炎症反应密切相关。实验模型中涉及疾病发病机制的其他化合物包括补体、缓激肽、一氧化氮、活性氧中间体、P物质和高级多胺。已证明其中几种介质在重症急性胰腺炎患者的血浆中浓度升高。临床前研究表明，其中一些介质是疾病活动的标志物，而其他炎症成分实际上可能作为重要介质推动疾病进程。这些介质的作用表明，中断或减弱不适当的免疫反应有可能改善预后。虽然在动物模型中对特定介质的操控可能很有前景，但它们可能无法很好地转化到人类临床环境中。然而，可能有必要继续依赖急性胰腺炎的实验动物模型来确定疾病的根本原因。对这些基本机制的全面理解不仅涉及确定存在哪些介质，还涉及密切记录它们出现的动力学。炎症反应的测量也可能有助于识别急性胰腺炎存在的诊断标志物，并提供预后信息。了解模型、记录标志物和解密介质有可能改善急性胰腺炎的治疗。
