Aims: Our overall objective is to understand receptor-mediated endothelial signaling mechanisms that regulate lung microvascular barrier properties. We identified a new barrier mechanism b which ligation of the a5b3 integrin by vitronectin and vitronectin-containing complement complexes, deteriorates the barrier as evident in increase of the lung capillary hydraulic conductivity (Lp). The Lp increase is blocked by tyrosine kinase inhibitors, and may be tyrosine kinase dependent. We will test these novel hypotheses in the lung capillary using soluble ligands and crosslinking antibodies against the a5b3 integrin.
The specific aims are to: 1 define the time course, mechanism and species differences in the a5b3-induced Lp response, and 2) define a5b3-induced epithelial signaling in lung capillaries with regard to protein tyrosine phosphorylation, cytosolic Ca2+ an phospholipase A2 (cPLA2). Procedures: 1) Lp quantification. We will continue to use our split-drop technique for Lp determinations in single arteriolar and venular capillaries o the isolated blood-perfused lung. Rats and other species will be used. 2) Recovery of fresh lung endothelial cells (FLEC). Isolated blood-perfused lungs will be exposed to experimental conditions then processed for recovery of FLEC by a magnetic beads method. FLEC will be subjected to immunoblotting and immunoprecipitation, specific assays for IP3 (inositol triphosphate) and arachidonate release, and ras-MAPK activation. 3) Lung capillary Ca2+ quantification. Lung capillary endothelial Ca2+ will be determined by the fura 2-ratioing method according to our recently developed methods. Significance: These experiments will provide the first understanding regarding integrin regulation of lung microvascular barrier properties. New understandin will be achieved on several new endothelial signaling mechanisms that remain poorly understood in lung microvessels. Our experiments will strengthen the tyrosine kinase hypothesis of microvascular barrier regulation. Hence, they ma lead to development of new therapies for increased lung microvascular permeability. No previous understanding of the proposed mechanisms exists in lung. The proposed studies are therefore, outstandingly novel and important.
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