Tolerance to shock: An exploration of mechanism

Objective To determine if cross-tolerance to septic shock could be induced by a previous insult with sublethal hemorrhage (SLH) and to characterize th e mechanisms involved in this induced protective response. Background Data It is possible to condition animals by prior SLH such that they tolerate an otherwise lethal hemorrhage. It is also possible to condit ion animals with low doses of lipopolysaccharide (LPS) so that they survive a "lethal" septic insult. However, a paucity of information exists on cros s-tolerance between hemorrhage and sepsis. Methods Rats were made tolerant by conditioning SLH or sham operation. Twen ty-four hours later, tolerant and sham rats were exposed to a lethal dose o f LPS. To explore the mechanism of tolerance induction, rats were given the macrophage (M phi) inhibitor CNI-1493 or saline carrier before SLH. Surviv al and pulmonary vascular injury were determined after LPS. Serum tumor nec rosis factor (TNF) levels and splenic M phi TNF gene expression were measur ed at several time points, Results Prior SLH indeed made rats tolerant and imparted a significant surv ival benefit and reduction in pulmonary vascular injury after LPS. The tole rance induced by SLH was reversed by M phi inhibition. Tolerant animals had low serum TNF levels immediately after SLH and reduced circulating TNF lev els after LPS. SLH, however, did not inhibit the augmentation of TNF gene e xpression after LPS. Conclusions Sublethal hemorrhage bestows protection against a lethal LPS ch allenge. Inhibition of the M phi attenuated the benefit of the tolerance in duced by SLH. Circulating TNF but not TNF gene after LPS is lessened by SLH . This implicates changes in M phi intracellular signaling in induction of the tolerant state.