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 (40mg/kg, n=6), for 15min prior to the induction of brain death and maintained with ventilatory support for 3h. IL-6 and TNFalpha 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 TNFalpha 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 TNFalpha 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.
Oto
Takahiro
T
Department of Cardiothoracic Surgery, Alfred Hospital, Monash University, Melbourne, Australia.
Calderone
Alicia
A
Li
Zhihe
Z
Rosenfeldt
Franklin L
FL
Pepe
Salvatore
S
D000818:Animals; D001926:Brain Death; D004195:Disease Models, Animal; D016027:Heart Transplantation / Q000592:standards; D007211:Indoles / Q000494:pharmacology* / Q000627:therapeutic use; D007249:Inflammation / Q000517:prevention & control*; D015850:Interleukin-6 / Q000032:analysis / Q000097:blood*; D008168:Lung / Q000737:chemistry; D016040:Lung Transplantation / Q000592:standards; D008297:Male; D009206:Myocardium / Q000737:chemistry; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis / Q000097:blood*; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors*
D007211:Indoles; D015850:Interleukin-6; D014409:Tumor Necrosis Factor-alpha; C514526:indole-5-carboxamide; D048051:p38 Mitogen-Activated Protein Kinases