MACROPHAGE RECRUITMENT IN ENDOTOXIN-INDUCED LUNG INJURY

革兰氏阴性菌感染导致的脓毒症约占 仅在美国，每年就有10万人死亡。内毒素，主要的 革兰氏阴性细菌的有毒成分，引发一连串事件 最终会导致心血管衰竭，肺部炎症，以及 随后的肺损伤。肺组织中白细胞向肺的迁移 内毒素血症的发生依赖于 白细胞趋化蛋白及肺组织的表达 血管黏附分子促进白细胞从 通向肺间质和空隙的血管间隙。分子 参与白细胞向肺募集的信号并没有 已经被定义了。在本应用程序中，我们将调查 巨噬细胞活化与趋化蛋白巨噬细胞炎症 蛋白-1α(MIP-1α)在介导肺巨噬细胞募集中的作用 内毒素血症。我们选择研究这种细胞因子是因为我们的初步研究 研究表明，巨噬细胞在介导内毒素- 诱导的肺损伤，2)MIP-1α在肺组织中的表达 内毒素血症，以及3)抑制MIP-1α生物活性可以减轻 内毒素攻击后肺巨噬细胞聚集和损伤。 这一提议的假设是，招募的巨噬细胞代表 肺组织炎症和损伤的重要细胞介质 内毒素血症的发生及肺组织中MIP-1α的表达 代表着一个主要的信号，涉及招募和激活 内毒素诱导的肺部炎症/损伤过程中的血源性巨噬细胞。 本实验室建立了一种小鼠内毒素血症模型，以 实现以下具体目标：1)确定 内毒素血症对大鼠肺炎性细胞募集和损伤的影响 中性粒细胞减少和非中性粒细胞减少的小鼠；2)评估器官特异性 MIP-1α在内毒素血症中的表达 内源性细胞因子肿瘤坏死因子-α α)或白介素1β(IL-1β)代表着 免疫和非免疫肺组织中MIP-1α的体内表达 4)确定MIP-1α在体内的调节作用。 内源性细胞因子产生、肺巨噬细胞募集与肺 特异性中和抗MIP-1对内毒素攻击后损伤的影响 1α血清。组织损伤的介导性因素研究进展 内毒素血症将有助于更好地了解 革兰氏阴性败血症的病理生理学，更重要的是，将促进 用于治疗的新策略的发展 患有这种毁灭性疾病的患者。

Sepsis as a result of gram-negative infection accounts for approximately 100,000 deaths annually in the United States alone. Endotoxin, the major toxic component of gram-negative bacteria, triggers a cascade of events that can culminate in cardiovascular collapse, lung inflammation, and subsequent lung injury. The migration of leukocytes to the lung in the setting of endotoxemia is dependent upon the coordinated production of leukocyte chemoattractant proteins, as well as the expression of lung vascular adhesion molecules that promote the migration of leukocytes from the vascular space to the lung interstitium and airspace. The molecular signals involved in the recruitment of leukocytes to the lung have not been defined. In this application, we will investigate the role of the macrophage activating and chemotactic protein macrophage inflammatory protein-1 alpha (MIP-1alpha) in mediating lung macrophage recruitment in endotoxemia. We have chosen to study this cytokine because our preliminary studies indicate that l) macrophages are important in mediating endotoxin- induced lung injury, 2) MIP-1alpha is expressed within the lung in endotoxemia, and 3) inhibition of MIP-1alpha bioactivity can attenuate lung macrophage accumulation and injury after endotoxin challenge. It is the hypothesis of this proposal that recruited macrophages represent important cellular mediators of lung inflammation and injury in the setting of endotoxemia, and that the expression of MIP-1alpha in the lung represents a major signal involved in the recruitment and activation of blood-borne macrophages during endotoxin-induced lung inflammation/injury. A murine model of endotoxemia has been developed in this laboratory to achieve the following specific objectives: 1) to determine the effect of endotoxemia on lung inflammatory cell recruitment and injury in neutropenic and non-neutropenic mice; 2) to assess the organ-specific expression of MIP-1alpha in the setting of endotoxemia; 3) to determine whether endogenously-produced cytokines tumor necrosis factor-alpha (TNF- alpha) or interleukin-l beta (IL-1beta) represent important signals for the in vivo expression of MIP-1alpha by immune and nonimmune pulmonary cells; and 4) to determine the in vivo role of MIP-1alpha in mediating endogenous cytokine production, lung macrophage recruitment, and lung injury after endotoxin challenge by using specific neutralizing anti-MIP- 1alpha serum. Elucidation of factors involved in mediating tissue injury in endotoxemia will allow for a better understanding of the pathophysiology of gram-negative sepsis, and more importantly, will foster the development of novel strategies to be employed in the treatment of patients with this devastating illness.