The recruitment of neutrophils to the lung is a pivotal factor in the development and perpetuation of acute lung injury (ALI). A rapid, early influx of mature circulating neutrophils to the injured lung is followed by a slower, sustained recruitment of more immature neutrophils from the bone marrow. Much of the progressive damage to the lung that characterizes ALI is attributable to this second, persistent phase of neutrophilia, and its duration and severity are predictors of mortality. Although many of the signals governing the initial influx of neutrophils to the lung in ALI have been delineated, the mechanisms governing the marrow release and lung recruitment of this subsequent, persistent wave of neutrophils are poorly understood. Previously, we have shown that expression of the CXC chemokine Stromal Derived Factor-1 (SDF-1) in bone marrow is critical for the retention of marrow neutrophils under homeostatic conditions. We now have preliminary evidence that marrow SDF-1 is decreased during ALI, and that its downregulation occurs through a neutrophil elastase-dependent mechanism initiated by Granulocyte-Colony Stimulating Factor (G-CSF). Further, pulmonary expression of SDF-1 is increased during ALI, and is critical for the late influx of neutrophils to the lung during the progression of ALI. We hypothesize that the persistent influx of neutrophils to the lung in ALI is driven by: 1) G-CSF- initiated, elastase-mediated, degradation of marrow SDF-1, leading to release of marrow neutrophils, and, 2) Simultaneous increase of pulmonary SDF-1, which serves to recruit these newly-released cells. Using animal models of ALI, we will test this in the following Specific Aims: 1) To determine whether neutrophil elastase-mediated degradation of marrow SDF-1 is responsible for the release of marrow neutrophils in the persistent phase of ALI;2) To investigate whether G-CSF initiates the loss of marrow SDF-1 during ALI;3) To address the role of lung SDF-1 in the recruitment of circulating marrow neutrophils during the persistent phase of ALI. The diagnosis of clinical ALI is typically delayed until after the best-studied events in its pathogenesis have occurred, and the patient has entered the persistent phase of lung inflammation. The studies we propose are expected to improve our limited understanding of this phase of ALI, and could eventually lead to improved therapies for a condition that continues to be all too often fatal.
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