The overall goal of this proposal is to determine whether microvascular injury is a major determinant of articular destruction in immune mediated arthritis. We hypothesize that microvascular injury in immune mediated arthritis leads to ischemia and damage to intra-articular structures and subchondral (subarticular) bone. Using an animal model of immune- mediated arthritis, the Dumonde Glynn model of antigen induced arthritis (AIA), we will apply new methods of microperfusions to study microvessel occlusion and proliferation during the development of acute AIA and during the evolution of chronic erosive AIA; Using tissue clearance methods we will measure the changes in articular blood flow in acute and chronic AIA which can be correlated with changes in microvessel morphology; Using radiotracer labeled microsperes, distribution of articular blood flow to the individual intra-articular components and epiphyseal bone will be measured in acute and chronic AIA. The second main focus of this project is to investigate the effects of modulating angiogenesis on the development of articular damage during acute and chronic AIA. We will measure the changes in articular blood flow, blood flow distribution, microvessel morphology and histopathology of acute and chronic AIA in control and three treatment groups of animals; We will measure the effects in these experimental groups: 1) AIA rabbits anticoagulated with oral coumadin to examine the effects of blocking the initial microvascular occlusion in immune mediated synovitis. 2) AIA rabbits treated with oral heparin to enhance angiogenesis; and 3) AIA rabbits treated with oral heparin plus hydrocortisone or the non-glucocorticoid, epicortisol to inhibit angiogenesis. If angiogenesis plays a pathogenic role in the erosive process of antigen induced arthritis, enhancement of angiogenesis will increase the severity of AIA and inhibition of angiogenesis will abrogate or lessen the severity of AIA. Chronic inflammatory arthritis produces non-reversible joint destruction in two to seven million individuals in the USA. Its cause and hence specific treatment are unknown and produces health care costs which are three times the national average health care costs. Demonstration of the microvascular injury hypothesis and demonstration of decreased joint destruction by angiomodulation will lead to novel avenues for therapeutic intervention designed to prevent ultimate joint destruction.
