Effects of tolerizing sublethal hemorrhage on p44/42 and SAPK/JNK Map-kinase activation.

Exposure to sublethal hemorrhage (SLH) makes rats tolerant to subsequent hemorrhagic or septic shock. We have shown that this tolerance leads to alterations in cytokine production, macrophage NF-kappaB activation and p38 MAP-kinase activity. The purpose of this study was to explore whether changes in p44/42 and SAPK/JNK MAP kinase activity also occur after the induction of tolerance by SLH. Rats were made tolerant by SLH (mean arterial pressure = 30 mmHg for 15 min with shed blood returned). Shams had anesthesia and instrumentation only. Twenty-four hours after SLH or sham operation, LPS was given (40 mg/kg intraperitoneal). Lung, liver, and splenic tissues were harvested 15, 30, and 45 min following sham, SLH, or LPS. Protein was isolated from tissues for determination of p44/42 and SAPK/JNK phosphorylation by Western blot analysis. Phosphorylation of p44/42 and SAPK/JNK was detected in all tissues following both sham and SLH, and this effect was significantly more pronounced following SLH (P < 0.05). However, activation of both p44/42 and SAPK/JNK in response to LPS, was significantly lower in the SLH rats when compared to shams. Peak activation was seen 30 min after SLH and peak attenuation, 30 min after LPS. The amount of nonphosphorylated protein was comparable in all groups. The induction of tolerance by SLH leads to phosphorylation of both p44/42 and SAPK/JNK MAP-kinases. However, the activation of these same kinases is attenuated in response to LPS in animals made tolerant by SLH.