TUMOR-NECROSIS-FACTOR-ALPHA BLOCKADE PREVENTS NEUTROPHIL CD18 RECEPTOR UP-REGULATION AND ATTENUATES ACUTE LUNG INJURY IN PORCINE SEPSIS WITHOUT INHIBITION OF NEUTROPHIL OXYGEN RADICAL GENERATION

Tumor necrosis factor (TNFalpha), both by direct action and by trafficking cells of the immune system, is implicated in cardiopulmonary derangements and PMN-mediated microvascular injury associated with gram-negative sepsis. We examined the effects of pretreatment with a monoclonal antibody to TNFalpha on PMN function, hemodynamic derangements, and alveolar capillary membrane damage in a septic porcine model. Anti-TNFalpha profoundly improved hemodynamic consequences in this model. Reduction in PMN CD11/18 receptor expression, lung myeloperoxidase activity, and attenuation of peripheral neutropenia (all P < 0.05) indicate that pretreatment significantly reduced lung sequestration of PMNs seen in septic controls. In contrast, PMN oxygen radical (O2-) generation was not significantly different from unprotected septic animals. Despite the presence of circulating PMNs primed for O2- burst, alveolar capillary membrane damage, assessed by bronchoalveolar lavage protein content and arterial PO2 was markedly attenuated in the treatment group (P < 0.05). We conclude that anti-TNFalpha suppresses systemic hemodynamic actions of TNFalpha. Further, it prevents upregulation of PMN adhesion receptors inhibiting PMN/endothelial cell interaction. This prevents formation of a ''microenvironment,'' protected from circulating oxidant scavengers, into which sepsis-activated PMNs release their toxic products. Pretreatment with anti-TNFalpha monoclonal antibody thus affords global protection in porcine Gram-negative sepsis.