PATHOGENESIS OF LUNG INJURY IN LUNG AND PERITONEAL SEPSIS

问题.本项目将研究细胞和分子事件 将主要身体空间的局部感染与全身性感染联系起来， 对远处器官的影响和伤害。主要的假设是， 三室模型最能解释人类对细菌的反应 及其产品。在这个模型中，细菌进入一个初始隔室， (e.g.,肺或腹腔），以及细菌之间的局部相互作用 宿主效应系统决定细菌是否有效地 淘汰当第一房室反应无效时， 发生在第二个“系统”隔间。当第二个隔间 反应是严重的，反应发生在第三隔室（远距离） 器官）。在肺中，这些反应包括上皮细胞的损伤， 障碍和持续功能丧失。我们将调查重要的 与理解这个模型有关的问题。主要长期 目的是了解第二和第三部分的反应 而不会不利地影响微生物中的细菌消除 第一个隔间。 具体目标。1)研究“第一室”反应， 肺和腹膜腔，以确定为什么“第一个 在这两个站点中的每一个中，“隔室”响应不同; 2） 研究第一个隔间之间的关键相互关系 和第二隔室炎症反应; 3）研究 在第三次肺损伤中发生肺上皮损伤的机制 （4）研究保护第三层的战略 而不会不利地影响细菌的抗菌反应 第一个隔间。 实验方法。我们将研究患肺炎或腹膜炎的兔子 由于E.大肠杆菌，并在感染后跟踪他们长达24小时。 将第一隔室中的反应与全身反应进行比较。 生理和炎症反应变量，以及 第三室（肺）的功能和解剖完整性。新 保护第三部分的战略， 将研究第一隔室中的抗菌防御。 意义这些研究将提供有关 局部和全身反应与肺损伤的关系 脓毒症，并将有助于确定是否最好的预防方法， 脓毒性并发症的治疗重点是针对特定的生物体 (e.g.,更好的抗生素），或干扰宿主反应 (e.g.,更好的抗炎治疗），或两者。

Problem. This project will investigate the cellular and molecular events that link local infection in a primary body space with systemic consequences and injury to distant organs. The major hypothesis is that a three compartment model best explains the responses of humans to bacteria and their products. In this model, bacteria enter an initial compartment (e.g., lungs or abdominal cavity), and local interactions between bacteria and host effector systems govern whether bacteria are effectively eliminated. When first compartment responses are ineffective, responses occur in the second "systemic" compartment. When the second compartment responses are severe, responses occur in the third compartment (distant organs). In the lungs these responses include injury to the epithelial barrier and sustained loss of function. We will investigate important questions that relate to understanding this model. The major long-term goal is to understand how responses in the second and third compartments can be minimized without adversely affecting bacterial elimination in the first compartment. Specific Aims. 1) to investigate the "first compartment" responses in the lungs and the peritoneal cavity, in order to determine why the "first compartment" responses differ in each of these two sites; 2) to investigate the critical inter-relationships between the first compartment and the second compartment inflammatory responses; 3) to investigate the mechanisms by which injury occurs to the lung epithelium in the third compartment; 4) to investigate strategies that will protect the third compartment without adversely affecting antibacterial responses in the first compartment. Experimental approach. We will study rabbits with pneumonia or peritonitis due to E. coli, and follow them for up to 24 hours after infection. Responses in the first compartment will be compared with systemic physiologic and inflammatory response variables, and measurements of functional and anatomic integrity of the third compartment (lungs). New strategies to protect the third compartment without compromising antibacterial defenses in the first compartment will be investigated. Significance. These studies will provide information about the relationship between local and systemic responses and lung injury in sepsis, and will help to determine whether the best approach to prevention and treatment of septic complications is to focus on the specific organism (e.g., better antibiotics), or on interfering with the host response (e.g., better anti-inflammatory therapy), or both.