LPS induces late cardiac functional protection against ischemia independent of cardiac and circulating TNF-α.

Lipopolysaccharide (LPS) and tumor necrosis factor (TNF)-α independently induce cardioprotection against ischemia in the rat at 24 h after administration, suggesting that endogenously synthesized TNF-α 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 circulating TNF-α profile, 2) to examine whether prior protein synthesis inhibition abrogates the protection, and 3) to assess the effects of TNF-α inhibition and neutralization on the protection. Rats were treated with LPS (0.5 mg/kg ip). Cardiac functional resistance to normothermic global ischemia-reperfusion was examined at sequential time points after LPS treatment in isolated hearts by the Langendorff technique. Myocardial and circulating TNF-α was determined by enzyme-linked 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 protection at 3 days was abolished by cycloheximide pretreatment (0.5 mg/kg ip 3 h before LPS treatment). Increases in myocardial and circulating TNF-α preceded the acquisition of protection. Dexamethasone pretreatment (4.0 or 8.0 mg/kg ip 30 min before LPS treatment) abolished peak increase in myocardial TNF-α and substantially suppressed circulating TNF-α (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 μg/kg iv immediately 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. Although LPS-induced increase in myocardial and circulating TNF-α precedes the delayed protection, it may not be required for the delayed protection.