BACTERIAL MODULATION OF LUNG INFLAMMATORY RESPONSE

描述（未编辑的申请人摘要）：革兰氏阴性杆菌（GNB）是 能够导致严重的危及生命的肺炎的病原体。更 超过60%的医院内肺炎是由GNB和相关的 死亡率通常超过50%。在过去的10-15年里， 这种感染的结果几乎没有改善。结果这个 综合征继续导致显著的发病率和死亡率， 加重了我们国家医疗保健系统的经济负担。 成功使用免疫干预治疗或调节 感染标志着一个新时代的开始， 传染病在有效和有效之间存在着微妙的平衡。 有害的宿主防御反应。GNB中宿主反应的理解 肺炎以及细菌成分如何影响这种反应，反过来， 快速诊断测试的发展，使临床医生， 有效利用多种生物调节剂。也要 了解细菌成分与宿主因子在 在治疗操作之前调节对肺的损伤， 所知甚少。这些信息将使我们能够欣赏相对 改变宿主反应的风险收益比。此外，更精确的 还需要澄清哪些主机组件被损坏。这 知识可以确定独立的治疗干预措施。 他们的总体假设是GNB的表面成分和/或分泌的 蛋白质差异性地改变宿主的抗菌防御，并且直接改变，和/或 间接（通过炎症机制）促进肺损伤。初步数据 支持这一假设。这些反应将产生重大影响 免疫干预治疗的时候。本提案的目标 确定细菌荚膜和0-特异性 抗原调节中性粒细胞以径向方式募集到肺中 并扩展了我们对细菌因素（例如， 溶血素）和细菌诱导的宿主反应元件直接介导 肺损伤的发病机制。

DESCRIPTION (Unedited Applicant's Abstract): Gram-negative bacilli (GNB) are pathogens that are capable of causing severe, life-threatening pneumonia. More than 60 percent of nosocomial pneumonias are caused by GNB and associated mortality rates are often >50 percent. Over the last 10-15 years, there has been little improvement in outcome from this infection. As a result, this syndrome continues to cause significant morbidity and mortality and strongly contributes to the economic burden of our national health care system. The successful use of immune intervention in the treatment or modulation of infections has marked the beginning of a new era in the management of infectious diseases. There exists a delicate balance between an efficacious and injurious host defense response. An understanding of the host response in GNB pneumonia and how bacterial components affect this response will, in turn, lead to the development of rapid diagnostic tests that will enable the clinician to effectively utilize a variety of biologic modulators. It is also necessary to understand the relative role of bacterial components versus host factors in mediating damage to the lungs prior to therapeutic manipulations on which little is known. This information will enable us to appreciate the relative risk benefit ratio of altering the host response. Further, a more precise clarification of which host components are damaged is also needed. This knowledge may identify independent therapeutic interventions. Their global hypothesis is that surface components of GNB and/or secreted proteins differentially alter host antibacterial defenses and directly, and/or indirectly (by inflammatory mechanisms) promote lung injury. Preliminary data supports this hypothesis. These responses will have significant implications when attempting therapeutic immune interventions. The goals of this proposal are to determine the mechanisms by which the bacterial capsule and 0-specific antigen modulate neutrophil recruitment into the lungs in a diametrical manner and extend our evaluations on the relative roles of bacterial factors (e.g. hemolysin) and bacterially induced host response elements in directly mediating the pathogenesis of lung injury.