LPS INDUCES LATE CARDIAC FUNCTIONAL PROTECTION AGAINST ISCHEMIA INDEPENDENT OF CARDIAC AND CIRCULATING TNF-ALPHA

Lipopolysaccharide (LPS) and tumor necrosis factor (TNF)-alpha indepen dently induce cardioprotection against ischemia in the rat at 24 h aft er administration, suggesting that endogenously synthesized TNF-alpha may play a role in LPS-induced protection. The purposes of this study were 1) to delineate the time course of LPS-induced cardiac functional protection against ischemia and its relation with myocardial and circ ulating TNF-alpha profile, 2) to examine whether prior protein synthes is inhibition abrogates the protection, and 3) to assess the effects o f TNF-alpha inhibition and neutralization on the protection. Rats were treated with LPS (0.5 mg/kg ip). Cardiac functional resistance to nor mothermic global ischemia-reperfusion was examined at sequential time points after LPS treatment in isolated hearts by the Langendorff techn ique. Myocardial and circulating TNF-alpha was determined by enzyme-li nked immunosorbent assay at 1-24 h after LPS treatment. Protection was apparent at 24 h, 3 days, and 7 days but not at 2 or 12 h. Maximal pr otection at 3 days was abolished by cycloheximide pretreatment; (0.5 m g/kg ip 3 h before LPS treatment). Increases in myocardial and circula ting TNF-alpha preceded the acquisition of protection. Dexamethasone p retreatment (4.0 or 8.0 mg/kg ip 30 min before LPS treatment) abolishe d peak increase in myocardial TNF-alpha and substantially suppressed c irculating TNF-alpha (54.3 and 85.9% inhibition, respectively) without an influence on the maximal protection. Similarly, maximal protection was not affected by TNF binding protein (40 or 80 mu g/kg iv immediat ely after LPS treatment). The results suggest that LPS-induced cardiac functional protection against ischemia is a delayed and long-lasting protective response that may involve de novo protein synthesis. Althou gh LPS-induced increase in myocardial and circulating TNF-alpha preced es the delayed protection, it may not be required for the delayed prot ection.