PATHOGENESIS OF LUNG INJURY IN LUNG AND PERITONEAL SEPSIS

有问题。这个项目将研究细胞和分子事件 将初级身体空间的局部感染与全身感染联系起来 对远处器官的后果和伤害。主要的假设是一个 三室模型最好地解释了人类对细菌的反应 以及他们的产品。在这个模型中，细菌进入初始隔间 (如肺部或腹腔)，以及细菌之间的局部相互作用 宿主效应系统决定着细菌是否有效地 被淘汰了。当第一隔室反应无效时，反应 发生在第二个“全身”隔室。当第二个车厢 反应严重，反应发生在第三隔间(远处 器官)。在肺部，这些反应包括对上皮细胞的损伤 障碍和持续的功能丧失。我们将调查重要的 与理解此模型相关的问题。重大的长期 目标是了解第二个和第三个隔间的反应 可以最小化，而不会对细菌在 第一个车厢。 明确的目标。1)研究“第一隔室”反应。 肺和腹膜腔，以确定为什么 这两个部位的“间隔”反应不同；2)至 调查第一个隔间之间的关键相互关系 和第二间隔炎性反应；3)研究 第三肺上皮损伤的发生机制 4)研究保护第三方的策略 不会对体内的抗菌反应产生不利影响 第一个车厢。 实验方法。我们将研究肺炎或腹膜炎的兔子 由于感染了大肠杆菌，并在感染后跟踪他们长达24小时。 第一个隔室的反应将与全身反应进行比较 生理和炎症反应变量，以及测量 第三隔室(肺)的功能和解剖完整性。新的 保护第三隔间而不妥协的策略 将对第一隔间的抗菌防御进行调查。 意义重大。这些研究将提供有关 肺局部和全身反应与肺损伤的关系 脓毒症，并将有助于确定预防的最佳方法 而脓毒症并发症的治疗是专注于特定的微生物 (例如，更好的抗生素)，或干扰宿主反应 (例如，更好的抗炎治疗)，或者两者兼而有之。

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.