THE INFLUENCE OF SITE AND SEVERITY OF INFECTION

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Selectin adhesion molecules present on both neutrophils and endothelial cells are important in early neutrophil-endothelial interactions during infection and inflammation. Some preclinical studies suggest that inhibiting selectin function may be beneficial during systemic inflammation associated with conditions such as sepsis. However, selectins are important in recruiting neutrophils to sites of bacterial infection and their inhibition could have detrimental effects during sepsis. Furthermore, administration of a selectin directed monoclonal antibody (MAb) to patients with sepsis was not beneficial. Interest continues in the use of anti-adhesion molecule strategies during systemic inflammation however, and an integrin directed monoclonal antibody is presently under study in patients with trauma. In order to further assess the effects of inhibiting selectin molecule function during infection and sepsis, we investigated the influence of two factors, i.e., site and dose of bacterial infection, on the effects of MAbs directed against L-selectin. In this study, site but not dose of bacterial challenge fundamentally altered the effects of L-selectin MAb. With intravascular infection, MAb significantly improved survival. With pneumonia, despite reducing early lung injury, MAb significantly worsened survival and later lung repair. These studies sug-gest that inhibiting selectin function may be beneficial with infection and inflammation occurring primarily in the intravascular space. However, in patients with extravascular infection, this inhibition may worsen host defense and outcome. Additional studies are underway to determine the basis for the variable effects of L-selectin MAb in these stud-ies. In addition, studies are planned which will employ FAB fragments of this MAb.