MACROPHAGE FUNCTION IN SURGICAL SEPSIS

败血症是主要的非神经系统死亡原因后， 创伤、热损伤和重大择期手术， 死亡率为65%。 外科败血症的死亡通常是 与患者免疫防御系统的崩溃有关，和/或 相关的多器官衰竭（MOF），但这些原因 宿主防御中的异常尚不清楚。 由于主机 早期脓毒症中的抗性取决于抗原的识别（即， 细菌）通过单核细胞-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， 确定异常的性质和时间进程， 巨噬细胞功能，可能导致随后的 免疫抑制 由于内毒素已被证明对 各种脓毒症模型中免疫功能、巨噬细胞抗原 将在内毒素中研究呈递细胞（APC）的功能- 耐药（C3 H/HeJ）和内毒素敏感（C3 H/HeN）小鼠， 盲肠结扎穿孔致腹腔内脓毒症 （CLP）。 抗原识别的连续步骤包括 巨噬细胞白细胞介素1（I1-1）产生，巨噬细胞抗原 将测定巨噬细胞-T细胞相互作用 使用抗原特异性T细胞克隆D10.G4.1。 的作用 创伤作为一种免疫抑制因素， 使用标准后肢骨折进行验证 模型 一些研究已经证实了 创伤后免疫抑制。 这项建议 将消除免疫抑制作用 脓毒症（CLP）单独以及综合影响 对巨噬细胞功能的影响。 这一建议的核心假设是， 巨噬细胞功能障碍的早期阶段 脓毒症是可逆的，而长期脓毒症导致 深层不可逆的免疫抑制， 对所看到的高死亡率负有部分责任的人 外科脓毒症。 如果巨噬细胞中出现可逆性异常 功能可以确定，然后治疗干预， 发病后早期采用的药物操作 脓毒症可能会消除脓毒性损伤及其伴随的 免疫抑制 这样的治疗可能会导致 患者死亡率大幅降低， 脓毒症-一个影响估计15万人的问题 每年在美国的病人。

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.