INHIBITION OF THE BIOLOGIC ACTIVITY OF TUMOR-NECROSIS-FACTOR MAINTAINS VASCULAR ENDOTHELIAL-CELL FUNCTION DURING HYPERDYNAMIC SEPSIS

Background and Objective: Although vascular endothelial cell function (i,e,, the release of endothelium-derived nitric oxide) decreases and plasma tumor necrosis factor (TNF) increases during sepsis, it is not known whether the elevated TNF is responsible for the depression of en dothelial cell function under such conditions, The aim of this study, therefore, was to determine if inhibition of TNF biologic activity by polyethylene glycol dimerized conjugate of the recombinant human form of the p55 soluble TNF receptor (PEG-(rsTNF-R1)(2)) maintains endothel ial function during sepsis. Design, Materials, and Methods: Rats were subjected to sepsis by cecal ligation and puncture (CLP), Immediately before the onset of sepsis, 600 mu g/rat PEG-(rsTNF-R1)(2) or an equal volume of saline was infused intravenously, At 10 hours after CLP (i, e,, hyperdynamic sepsis), the thoracic aorta was isolated, cut into ri ngs, and placed in organ chambers, Dose responses for an endothelium-d ependent vasodilator, acetylcholine (ACh), and an endothelium-independ ent vasodilator, nitroglycerine (NTG), were determined, Endothelial ce ll structure was examined by transmission electron microscopy. Results : Endothelium-dependent vascular relaxation was depressed at 10 hours after the onset of sepsis, Administration of PEG-(rsTNF-R1)(2) before CLP, however, maintained ACh-induced relaxation, In contrast, no signi ficant difference in NTG-induced relaxation was seen, irrespective of administration of PEG-(rsTNF-R1)(2), Furthermore, the deterioration in endothelial structure during sepsis was prevented by PEG (rsTNF-R1)(2 ) pretreatment. Conclusion: Since administration of PEG-(rsTNF-R1)(2) maintains vascular endothelial cell structure and function, it can be concluded that TNF plays a pivotal role in producing endothelial dysfu nction during sepsis, Thus, pharmacologic agents that inhibit TNF biol ogic activity and/or its production may be useful for protecting endot helial cells during sepsis.