TUMOR-NECROSIS-FACTOR CAUSES MICROVASCULAR PROTEIN LEAKAGE INDEPENDENTLY OF NEUTROPHILS OR MAST-CELLS

Tumor necrosis factor-alpha (TNP-alpha) has been implicated as an impo rtant mediator in the development of multiple system organ failure aft er either severe injury or infection. Using the rat cremaster muscle, we previously showed that systemically administered TNF-alpha caused h ypotension, tachypnea, and microvascular protein leakage in associatio n with leukocyte-endothelial adherence. In the current study, we hypot hesized that topical administration of TNF-alpha to the cremaster musc le would cause microvascular protein leakage independent of changes in hemodynamic parameters. In addition, histological methods were used t o study the role of neutrophils and mast cells in the TNF-alpha-induce d microvascular protein leakage. Topically applied low-dose (1 ng/ml) TNF-alpha caused microvascular leakage in the cremaster, without chang es in central hemodynamic parameters, but high-dose TNF-alpha (10 ng/m l) did not cause protein leakage. Histological studies did not demonst rate evidence of either neutrophil adhesion or mast cell degranulation in topically applied TNF-alpha-treated cremasters compared to control s. These data suggest that TNF-alpha-induced macromolecular leakage is a dose-dependent phenomenon which can occur independently of neutroph ils or mast cell degranulation.