Three adhesion receptor families appear very important in mediating pulmonary leukocyte trafficking. The selectin family of receptors initiate early leukocyte/endothelial interactions, while the integrin and immunoglobulin families interact later. We previously found that monoclonal antibodies (MAbs) directed against the integrin family of adhesion molecules limited pulmonary injury and improved survival related to tumor necrosis function challenge in canines. However, administration of integrin MAbs during bacterial peritonitis in a canine model reduced serum endotoxin clearance and worsened cardiovascular function and survival. During pulmonary infection in rats, similar MAbs were beneficial in limiting pulmonary injury, but still worsened survival. In preliminary studies in this same rat model, it appeared that MAbs directed against an endothelial ligand for the integrins, intracellular adhesion molecule-1 (ICAM-1), improved survival compared with integrin-directed MAbs. In additional studies now completed, however, it has become clear that lCAM-1 directed MAbs were also harmful overall. These studies in combination have emphasized the importance of both integrin and ICAM-1 adhesion receptors in host defense during pneumonia. Negotiations for a cooperative research and development agreement with Dr. Robert Rothlein and Boehringer-Ingelheim are presently under way to study MAbs directed against endothelial selectins in this same rat model. Once these studies are performed, our lab will have evaluated the roles of all three of the primary adhesion molecule families important in the pathogenesis of tissue inflammatory injury and host defense in this rat model of bacterial pneumonia.
