P38 Mitogen-Activated Protein Kinase Inhibition Reduces Inflammatory Cytokines in a Brain-Dead Transplant Donor Animal Model

The aim of this study was to determine the degree of p38 mitogen-activated protein kinase (p38 MAPK) activation in rat heart and lungs after experimentally induced brain death and to test whether SD-282, a synthetic and selective small molecule inhibitor of p38 MAPK, abrogates p38 MAPK activation invoked by this brain death model. Methods: Adult male Sprague Dawley rats were treated with vehicle (control, n= 7) or SD-282 (40. mg/kg, n= 6), for 15. min prior to the induction of brain death and maintained with ventilatory support for 3. h. IL-6 and TNFα were measured in plasma, heart and lungs using ELISA, and p38 MAPK via Western blot assay. Results: p38 MAPK inhibition was demonstrated by lower p38 MAPK activity in lungs from SD-282-treated donors compared to control (Median [inter-quartile range]: 13.6[4.0-19.0]% vs 20.2[14.7-31.5]% activity, p= 0.06). Although levels varied, significant inhibition of p38 MAPK by SD-282 was not observed in the heart. SD-282 significantly lowered IL-6 and TNFα values compared to control in plasma (64[51-81]. pg/ml vs 352[200-755]. pg/ml, p= 0.003 and 4.3[1.5-9.0]. pg/ml vs 21.1[10.5-31.5]. pg/ml, p= 0.015, respectively) and lungs (0.14[0.12-0.62] vs 5.8[3.6-6.0]. pg/mg protein, p= 0.03 and 0.41[0.33-0.45] vs 2.1[1.4-2.7]. pg/mg protein, p= 0.0027, respectively), however SD-282 did not significantly affect cardiac cytokine levels. Conclusions: p38 MAPK inhibition with SD-282 decreases the pro-inflammatory response as represented by lower IL-6 and TNFα in plasma and lungs following brain death. However, although in heart this response was variable, no significant effect could be demonstrated under the present conditions.