The development of inflammatory lung disease following marrow ablative therapy is common but poorly understood. Local infiltration of neutrophils and the appearance of diffuse alveolar damage have implicated neutrophils in its development. Recently, release of functionally immature neutrophils into the circulation during pneumonia and sepsis has been implicated in the pathogenesis of acute lung injury. While these cells show prolonged transit times through the microvasculature and appear to be unable to migrate to the airspace, the trafficking and subsequent removal of such potentially injurious cells is unclear. While previous models of neutrophil kinetics have suggested liver and spleen as the sites of neutrophil clearance, we suggest here that the bone marrow plays a significant role. Hence, we propose that the bone marrow selectively removes functionally immature or defective populations of circulating neutrophils, to avoid non- specific tissue damage caused by these cells. Alterations to neutrophil clearance by the marrow as follow ablative therapy may contribute to systemic inflammatory states by allowing the prolonged circulation of such neutrophils. We have recently developed novel methods of observing neutrophil kinetics in a mouse model using bone marrow derived mature neutrophils, as well as techniques for imaging sequestered neutrophils in the marrow space. Accordingly, we will examine the role of marrow in the permanent removal of neutrophils from circulation, and determine the mechanisms responsible for the sequestration of neutrophils in the bone marrow with particular emphasis on macrophage sialoadhesin. Neutrophil retention will be studied using a combination of antibodies, gene-targeted mice, and chimeric carbohydrate ligands. The role of sialoadhesin and resident bone marrow macrophages in the handling of neutrophils in the marrow will be determined using gene-targeted mice lacking sialoadhesin and three-dimensional histological reconstruction of the marrow stroma. We will also pursue the hypothesis that 9-0-deacetylation of neutrophil surface sialic acid acids, possibly as an effect of cell age, modulates retention by altering binding to sialoadhesin. Finally, we will demonstrate the effects of ablation of the resident bone marrow macrophages on the kinetics of neutrophil circulation and removal, and the resulting systemic inflammatory state that may arise. These studies will address fundamental questions of neutrophil biology as well as provide clues to the mechanisms of lung injury in bone marrow transplantation.
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