MACROPHAGE FUNCTION IN SURGICAL SEPSIS

脓毒症是严重烧伤后死亡的主要非神经系统原因 创伤、热损伤和大型择期手术，携带 死亡率为65%。外科脓毒症的死亡通常是 与患者的免疫防御系统和/或 相关的多器官衰竭(MOF)，但导致这些的原因 对宿主防御中的异常现象知之甚少。由于主机 早期脓毒症的抵抗力取决于对抗原的识别(即 细菌)由单核-巨噬细胞谱系的细胞，这 该提案旨在检查脓毒症的早期阶段，以 确定异常的性质和时间进程 巨噬细胞功能可能导致后续 免疫抑制。 因为内毒素已经被证明对 巨噬细胞抗原在各种脓毒症模型中的免疫功能 递呈细胞(APC)功能将在内毒素- 耐药(C3H/HeJ)和内毒素敏感(C3H/HEN)小鼠 盲肠结扎穿刺术所致的腹内脓毒症 (中电)。抗原识别的连续步骤包括 巨噬细胞白介素1(I1-1)产生、巨噬细胞抗原 呈现，巨噬细胞-T细胞的相互作用将被检测 使用抗原特异性T细胞克隆D10.G4.1。的作用 创伤作为免疫抑制因素将是 使用标准后肢骨折进行评估 模特。之前的几项研究已经检查了 创伤后免疫抑制。这项建议 将研究其免疫抑制作用 脓毒症(CLP)及其联合作用 脓毒症和创伤对巨噬细胞功能的影响。 这项提议的中心假设是 急性胰腺炎早期巨噬细胞功能障碍 脓毒症是可逆的，而持续的脓毒症会导致 深刻的不可逆转的免疫抑制是 对高死亡率负有部分责任 在外科败血症中。如果巨噬细胞出现可逆性异常 功能可以被识别，然后治疗干预和 发病后早期使用的药物治疗 脓毒症可能会消除败血症的侮辱及其伴随而来的 免疫抑制。这样的治疗可能会导致 患者死亡率的大幅下降 脓毒症--一个影响大约150,000人的问题 在美国每年都有病人。

Sepsis is the major non-neurologic cause of death after major trauma, thermal injury, and major elective surgery, carrying a mortality of 65 percent. Deaths from surgical sepsis are usually related to a breakdown in the patient's immune defenses and/or associated multiple organ failure (MOF), but the reasons for these aberrations in host defense are poorly understood. Since host resistance in early sepsis depends on recognition of antigen (i.e. bacteria) by cells of the monocyte-macrophage lineage, this proposal is designed to examine the early phases of sepsis to ascertain the nature and time course of abnormalities in macrophage function that may lead to subsequent immunosuppression. Since endotoxin has been shown to have profound effects on immune function in various septic models, macrophage antigen presenting cell (APC) function will be studied in endotoxin- resistant (C3H/HeJ) and endotoxin-sensitive (C3H/HeN) mice with intra-abdominal sepsis produced by cecal ligation an puncture (CLP). The successive steps in antigen recognition including macrophage interleukin 1 (I1-1) production, macrophage antigen presentation, and macrophage-T cell interaction will be assayed using the antigen-specific T cell clone D10.G4.1. THE ROLE OF TRAUMA AS AN IMMUNOSUPPRESSIVE FACTOR WILL BE EVALUATED USING A STANDARD HIND LIMB FRACTURE MODEL. SEVERAL STUDIES HAVE PREVIOUSLY EXAMINED POST-TRAUMATIC IMMUNOSUPPRESSION. THIS PROPOSAL WILL EXAMINE THE IMMUNOSUPPRESSIVE EFFECTS OF SEPSIS (CLP) ALONE AS WELL AS THE COMBINED EFFECTS OF SEPSIS AND TRAUMA ON MACROPHAGE FUNCTION. THE CENTRAL HYPOTHESIS OF THIS PROPOSAL IS THAT MACROPHAGE DYSFUNCTION IN THE EARLY PHASES OF SEPSIS IS REVERSIBLE WHILE PROLONGED SEPSIS LEADS TO PROFOUND IRREVERSIBLE IMMUNOSUPPRESSION THAT IS PARTIALLY RESPONSIBLE FOR THE HIGH MORTALITY SEEN IN SURGICAL SEPSIS. If reversible abnormalities in macrophage function can be identified, then therapeutic interventions and pharmacologic manipulations employed early after the onset of sepsis might abrogate the septic insult and its attendant immunosuppression. SUCH THERAPY COULD LEAD TO A MAJOR REDUCTION IN PATIENT MORTALITY FOLLOWING SEPSIS - A PROBLEM THAT AFFECTS AN ESTIMATED 150,000 PATIENTS EACH YEAR IN THE UNITED STATES.