Recent evidence indicates that the microvasculature of the canine lung is only partially perfused (recruited) at physiologic blood flow rates and full recruitment is achieved with a four fold increase in flow. In the partially recruited lung it is unclear whether flow is directed toward or away from healthy vessels during injury. If lung injury preferentially directs blood away from healthy vessels, then increasing blood flow may recruit healthy vessels and reduce the manifestations of injury. We propose that, in the partially recruited lung, changes in blood flow rate and distribution may alter the response to lung injury. We will study the contribution of altered perfused microvascular surface area and blood flow distribution to the evidence of lung injury. We will use radiolabeled microspheres to obtain anatomic evidence of changes in blood flow distribution while using measures of vascular permeability (capillary filtration coefficient, Kf, and reflection coefficient, sigma) and endothelial ectoenzyme function (endothelial-bound angiotensin converting enzyme activity and kinetic parameters) to evaluate physiological function of perfused microvessels during changes in blood flow rate with and without injury. We will study the role of eicosanoids as factors partitioning blood flow between injured and non-injured vessels by measuring plasma and bronchoalveolar lavage fluid eicosanoid concentrations and employing specific inhibitors of arachidonic acid pathways. In addition, the role of vasoactivity in redistributing blood flow in the injured lung will be examined by varying vascular tone. Experiments will establish important correlations between flow distribution and manifestations of damage in both the injured and non-injured lung and identify potential mechanisms altering distribution. Studies will be performed in the isolated, ventilated, blood perfused lower left lung lobe of dogs. We will correlate blood flow distribution with endothelial ectoenzyme function and microvascular permeability in the non-injured lung and in the lung injured with phorbol myristate acetate. Our findings will help elucidate how blood flow rate and distribution alter the manifestations of vascular dysfunction in an experimental model of the lung injury associated with Adult Respiratory Distress Syndrome. Findings may aid our understanding and treatment of commonly occurring lung disease.
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