This project will investigate the mechanism of experimental septic lung injury with particular emphasis on the contribution of neurophil (PMN) adherence to endothelial cells. Experimental lung injury is used as a model of the adult respiratory distress syndrome in the United States with a mortality greater than 50% when it was first reported. Mortality had remained unchanged over the past 20 years. PMNs and their products in alveolar lavage fluid are hallmarks of ARDS and they have been implicated in causing experimental lung injury. The first specific aim will extensively characterize physiologic changes associated with three known cause of lung injury. The protocol used to produce injury have their origin in events that occur in trauma victims.
In specific aims 2 and 3, rabbits will be treated with the monoclonal antibody (MAb) 60.3 at various times int he protocol developed is specific aim 1. The MAb 60.3 is directed to a functional epitope on the CD11/CD18 glycoprotein adherence complex on the PMNs and blocks CD18 dependent PMN adherence. The hypothesis of this proposal predict that PMNs are responsible for lung injury in models of sepsis. Further, they predict that PMNs form a protected microenvironment and blocking formation of that environment with anti-CD18 monoclonal antibodies will significantly reduce the injury. Treatment with ant-CD18 MAb will be effective in preventing lung injury since CD18 appeared to be in major mechanism of adherence in lung in response to live E. coli bacteria or E.coli endotoxin.
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