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

Meng, Xianzhong, Lihua Ao, James M. Brown, Daniel R. Meldrum, Brett C. Sheridan, Brian S. Cain, Anirban Banerjee, and Alden H. Harken. LPS induces late cardiac functional protection against ischemia independent of cardiac and circulating TNF-a. Am. J. Physiol. 273 (Heart Circ. Physiol. 42): H1894–H1902, 1997.—Lipopolysaccharide (LPS) and tumor necrosis factor (TNF)-a independently induce cardioprotection against ischemia in the rat at 24 h after administration, suggesting that endogenously synthesized TNF-a 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-a profile, 2) to examine whether prior protein synthesis inhibition abrogates the protection, and 3) to assess the effects of TNF-a 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-a 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-a 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-a and substantially suppressed circulating TNF-a (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-a precedes the delayed protection, it may not be required for the delayed protection.