Pathogens and noxious agents that access the alveoli initiate an inflammatory response that is characterized by neutrophil recruitment out of the circulation and into the ainways. Neutrophils initially transmigrate across capillary endothelium to access the alveoli, and hence, these microvascular endothelial cells possess a gatekeeper function. Whereas under normal, un-lnflamed conditions capillary endothelium does not Impair neutrophil movement through capillaries, in response to inflammation capillary endothelium promptly induces the surface expression of P- selectin, which interacts with neutrophils and initiates their transmigration into alveoli. An increase in endothelial cell cytosolic calcium promotes the translocation of vesicles containing P-selectin from the cytosol to the plasma membrane. Our recent evidence indicates the QIG T-type calcium channel provides the cytosolic calcium source that is needed for such P-selectin surface expression;as this calcium channel Is only expressed in capillary endothelium, and not in either pulmonary artery or vein endothelium, it appears to fulfill a highly specialized role in the lung microcirculation. Indeed, our preliminary data reveal that Pseudomonas aeruginosa causes profound neutrophil recruitment to the ainways, an effect that is abolished in QIG and P-selectin knockout mice. At present, the calcium responsive events that modulate P-selectin surface expression and neutrophil transmigration remain poorly understood. Notably, our preliminary data demonstrate that the QIG T type calcium channel interacts with endothelial cell nitric oxide synthase (N0S3). Calcium permeation through the QIG channel activates N0S3, which produces nitric oxide that opposes P selectin surface expression, characteristic of feedback regulation. Hence, the Specific Aims of this project will test the hypotheses that in alveolar capillary endothelium:  QIG associates with N0S3 and controls its activation; N0S3-derived nitric oxide inhibits P-selectin exocytosis;and  QIG induced N0S3 activation limits the endothelial transition to a proinflammatory phenotype Collectively, this project will determine whether the QIG T-type calcium channel and N0S3 represent novel therapeutic targets for the regulation of neutrophil trafficking in acute lung injury.
Neutrophils are white blood cells that are needed to fight infection. When pathogens, like bacteria, access the ainways, neutrophils migrate out of the blood and into the ainways. This neutrophil response is highly regulated, to ensure that neither too many nor too few cells are recruited Mechanisms responsible for neutrophil airway recruitment are poorly understood, and are the focus of our studies.
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