MACROPHAGE RECRUITMENT IN ENDOTOXIN-INDUCED LUNG INJURY

革兰氏阴性菌感染导致的败血症约占 仅在美国每年就有10万人死亡。内毒素，主要 革兰氏阴性菌的有毒成分，引发了一连串的事件 最终导致心血管衰竭，肺部炎症， 随后的肺损伤。白细胞向肺内的迁移 内毒素血症的形成依赖于 白细胞趋化蛋白，以及肺组织表达 血管粘附分子，促进白细胞从 血管间隙至肺动脉和肺动脉间隙。分子 参与白细胞向肺募集的信号 被定义。在本应用程序中，我们将研究 巨噬细胞活化趋化蛋白 蛋白-1 α（MIP-1 α）介导肺巨噬细胞募集 内毒素血症我们之所以选择研究这种细胞因子，是因为我们的初步研究 研究表明：1）巨噬细胞在介导内毒素中是重要的， 诱导的肺损伤，2）MIP-1 α在肺内表达， 内毒素血症，和3）MIP-1 α生物活性的抑制可以减弱 内毒素攻击后肺巨噬细胞积聚和损伤。 这是该提议的假设，募集的巨噬细胞代表了 肺内炎症和损伤的重要细胞介质 MIP-1 α在肺组织中的表达 代表参与募集和激活的主要信号 内毒素诱导的肺部炎症/损伤期间的血源性巨噬细胞。 本实验室已建立了一种内毒素血症小鼠模型， 实现以下具体目标：1）确定效果 内毒素血症对肺炎症细胞募集和损伤的影响 血小板减少和非血小板减少小鼠; 2）评估器官特异性 MIP-1 α在内毒素血症中的表达; 3）确定 是否内源性产生的细胞因子肿瘤坏死因子-α（TNF-α） α）或白细胞介素-1 β（IL-1 β）代表了 免疫和非免疫肺组织MIP-1 α表达 4）确定MIP-1 α在体内介导 内源性细胞因子产生、肺巨噬细胞募集和肺 内毒素攻击后使用特异性中和性抗MIP- 1阿尔法血清。阐明参与介导组织损伤的因素 将有助于更好地了解 革兰氏阴性脓毒症的病理生理学，更重要的是， 开发新的策略，用于治疗 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.