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.
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