Department of Cardiothoracic Surgery, Alfred Hospital, Monash University, Melbourne, Australia.
Heart Lung Circ. 2009 Dec;18(6):393-400. doi: 10.1016/j.hlc.2009.05.706. Epub 2009 Jul 31.
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.
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.
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.
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.
本研究旨在确定实验性脑死亡后大鼠心脏和肺部 p38 丝裂原活化蛋白激酶（p38 MAPK）的激活程度，并验证 SD-282（一种合成的、选择性的 p38 MAPK 小分子抑制剂）是否能阻断该脑死亡模型引起的 p38 MAPK 激活。
成年雄性 Sprague Dawley 大鼠在脑死亡诱导前 15min 分别接受载体（对照组，n=7）或 SD-282（40mg/kg，n=6）治疗，并接受通气支持 3h。采用 ELISA 法检测血浆、心脏和肺组织中白细胞介素-6（IL-6）和肿瘤坏死因子-α（TNFα），Western blot 法检测 p38 MAPK。
与对照组相比，SD-282 治疗供体的肺组织中 p38 MAPK 活性明显降低（中位数[四分位数范围]：13.6[4.0-19.0]% vs 20.2[14.7-31.5]%，p=0.06），表明 p38 MAPK 抑制。尽管存在个体差异，但在心脏中并未观察到 SD-282 对 p38 MAPK 的显著抑制。与对照组相比，SD-282 显著降低了血浆（64[51-81]pg/ml 比 352[200-755]pg/ml，p=0.003 和 4.3[1.5-9.0]pg/ml 比 21.1[10.5-31.5]pg/ml，p=0.015）和肺组织（0.14[0.12-0.62]比 5.8[3.6-6.0]pg/mg 蛋白，p=0.03 和 0.41[0.33-0.45]比 2.1[1.4-2.7]pg/mg 蛋白，p=0.0027）中的 IL-6 和 TNFα 水平。然而，SD-282 并未显著影响心脏中的细胞因子水平。
SD-282 抑制 p38 MAPK 可降低脑死亡后血浆和肺组织中促炎细胞因子 IL-6 和 TNFα 的水平。然而，尽管心脏中的反应存在个体差异，但在目前的条件下并未观察到显著影响。
