Alterations in Leukocyte-Endothelial Adherence Following Burn Injury William J. Mileski MD, Charles L. Rice MD< peter Lipsky MD, and Charles R. Baxter MD. Thermal injury creates profound local and systemic derangements, both of which contribute to acute and chronic morbidity or death. At the local level, thermal injury produces regions of irreversible tissue destruction surrounded by a marginal zone of injury with reduced blood flow. In the post-burn period, ongoing inflammation and microvascular injury in the """"""""zone of stasis"""""""" may result in extension of the area of tissue loss. Leukocytes (WBCs), are central mediators of injury in many acute pathologic processes. WBC-mediated injury is dependent in part of WBC adherence to the vascular endothelial cell (EC) surface. Investigation of the processes involved in leukocyte adherence have identified three main families of receptor/ligand molecules: Integrins (CD11/CD18, VLA-4), Selections(E-selectin, P-selectin, L-selectin) and immunoglobulin supergene families (ICAM-1, VCAM-1). In preliminary studies of local and systemic thermal injury and we have used specific monoclonal antibodies to CD18 and ICAM-1 and observed improvements in microvascular perfusion on the local level and improved generalized organ function ont he systemic level. We propose to explore the role of leukocytes in the pathogenesis of the local and systemic response to burn injury by testing three hypotheses 1) Thermal injury initiates activation of leukocyte dependent local and systemic inflammatory mechanisms which lead to progressive loss of microcirculation in the marginal zones bordering thermal injury and extension in burn size/depth, and distant organ injury. 2) Alterations of WBC-EC adherence contribute to the pathogenesis of both local and systemic inflammatory responses to thermal injury. 3) Blockade of adhesion molecule interaction will prevent some of the local and systemic effects following burn injury. The test these hypotheses we will perform animal and clinical studies. New Zealand white rabbits will be used in models of local injury (<5% TBSA) and major burn injury (30% TBSA). Measurements of microvascular perfusion, WBC accumulation, lipid peroxidation, tissue edema (water content), capillary permeability, physiologic parameters along FACS analysis of isolated leukocytes and immunohistochemical study of tissues for endothelial adhesion markers will be used to assess the role of WBC- endothelial adherence in the pathogenesis of local and systemic tissue injury and. Specific monoclonal antibodies to components of the adherence mechanism will be administered to determine if the inhibition of leukocyte adherence can alter the local and systemic effects. Clinical correlation will come from a study of changes in the levels of shed adherence markers (ICAM-1, E-selection, P-selection, VCAM-1) and the resting and stimulated expression of leukocyte adherence molecules on circulating leukocytes isolated from burn patients.
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