Host response to post-operative pneumonia

描述(逐字摘自申请者摘要)：麻醉/手术 通过以下机制使患者容易患上医院内肺炎 没有完全定义。呼吸道病毒感染的存在 麻醉/手术期间的(RTI)进一步使宿主的抗菌药复杂化 回应。我们实验室的证据表明麻醉/手术 诱导细胞因子反应的变化(例如，TNFpha、MIP-2、IFNGamma)， 白细胞募集，以及流感RTI对肺的损伤。这些回应是 对宿主抵抗细菌病原体的天然防御也至关重要。我们的重点是 为了检查在病毒RTI期间使宿主容易患上 手术后细菌性肺炎。我们假设麻醉/手术会 在以下过程中的不同阶段更改主机响应 病毒RTI通过改变促炎和抗炎细胞因子的表达， 从而降低了抗菌防御能力。目标1将评估以下各项的效果 流感期间麻醉/手术对细菌清除、炎性细胞的影响 内流和细胞因子的表达对大肠杆菌的挑战.我们预测 流感期间剖腹手术将促进MCP-1和MCP-1的相对表达 IL-10高于TNFpha、MIP-2和IFNGamma。目标2：将在体外评估 剖腹手术联合流感对内毒素刺激的双核细胞因子的影响 表达和吞噬活性，以及b)体外抗MCP-1的能力， 抗IL-10，或IFNGamma治疗以改善M功能障碍。我们假设 流感期间的剖腹手术将改变双核细胞的调节功能 由于表达的选择性增强而导致效应器功能降低 与促炎细胞因子相比具有抗炎症作用。最后，在目标3中，我们将检查 内源性细胞因子在抗菌药物抑制中的作用 选择性细胞因子在流感剖腹手术中的防御作用 操纵。细菌清除、炎性细胞内流和细胞因子 将对水平进行评估。我们预计IL-10或MCP-1的中和作用， 使用IFNGamma或增加TNFalphamRNA表达将有所改善 开腹手术后体征时的抗菌宿主防御 流行性感冒。这些研究将检验导致改变的机制。 病毒RTI术后细菌清除情况，评估 手术后肺炎的一般发病机制，并建议使用免疫佐剂 预防这种并发症的策略。

DESCRIPTION (Verbatim from the Applicant's Abstract): Anesthesia/surgery predisposes the patient to develop nosocomial pneumonia by mechanisms that are not completely defined. The presence of a viral respiratory tract infection (RTI) during anesthesia/surgery further complicates the host antibacterial response. Evidence from our laboratory has demonstrated anesthesia/surgery induces changes in cytokine response (e.g., TNFalpha, MIP-2, IFNgamma), leukocyte recruitment, and lung injury to influenza RTI. These responses are also critical to innate host defenses against bacterial pathogens. Our focus is to examine cellular mechanisms during a viral RTI that predispose the host to a post-surgical bacterial pneumonia. We hypothesize that anesthesia/surgery will change host responses differently during distinct periods in the course of a viral RTI by altering expression of pro- and antiinflammatory cytokines, thereby decreasing antibacterial defenses. Aim #1 will assess the effects of anesthesia/surgery during influenza on bacterial clearance, inflammatory cell influx, and cytokine expression an Escherichia coli challenge. We predict that laparotomy during influenza will promote the relative expression of MCP-1 and IL-10 over TNFalpha, MIP-2, and IFNgamma. Aim #2: will assess ex vivo the combined effect of laparotomy and influenza on a) LPS stimulated aMphi cytokine expression and phagocytic activity, and b) the ability of in vitro antiMCP-1, antiIL-10, or IFNgamma administration to improve M dysfunction. We postulate that laparotomy during influenza will alter aMphi regulatory functions and decrease effector functions as a result of selective enhancement of expression anti-compared to proinflammatory cytokines. Finally, in Aim #3, we will examine the contribution of endogenous cytokines in the suppression of antibacterial defenses following laparotomy during influenza by selective cytokine manipulations. Bacterial clearance, inflammatory cell influx, and cytokine levels will be assessed. We anticipate that neutralization of IL-10 or MCP-1, administration of IFNgamma, or increased TNFalphaexpression will improve antibacterial host defenses following laparotomy during physical signs of influenza. These studies will examine mechanisms that lead to alterations in bacterial clearance post-surgically following a viral RTI, assess the pathogenesis of post-surgical pneumonia in general, and suggest immune adjuvant strategies to prevent this complication.