ENDOTOXIN-INDUCED PULMONARY LEUKOSTASIS IN THE RAT - ROLE OF PLATELET-ACTIVATING-FACTOR AND TUMOR-NECROSIS-FACTOR

Injection of bacterial lipopolysaccharide (LPS) into experimental animals induces septic shock associated with the release of tumor necrosis factor (TNF) and platelet-activating factor (PAF). Because both TNF and PAF stimulate neutrophil adhesion to endothelial cells in vitro, and because neutrophils are important effector cells in sepsis-induced lung vascular injury, the role of TNF and PAF in LPS-induced lung neutrophil sequestration was investigated. Lung myeloperoxidase (MPG) activity was measured as a quantitative assessment of pulmonary leukostasis. Injection of Salmonella enteritidis LPS into rats caused dose-dependent increases in lung MPO that peaked at 2 hours and persisted for up to 24 hours. Injection of purified human recombinant TNF (2 to 200 mu g/kg IV) mimicked the effect of LPS on lung MPG activity. Injection of synthetic PAF increased lung MPO only at the highest and lethal dose (10 mu g/kg). Lower doses (0.1 and I mu g/kg) of PAF had no effect on lung MPG by itself and did not enhance LPS- or TNF-induced lung neutrophil sequestration. Furthermore, pretreatment of the rats with two different PAF receptor-antagonists, WEB 2086 (10 mg/kg IP) and SRI 63-441 (10 mg/kg IP), failed to block LPS-induced (I mg/kg) increase in lung MPO. These data suggest that TNF, not PAF, mediates LPS-induced pulmonary neutrophil sequestration in the intact rat.