SB203580, a p38 inhibitor, improved cardiac function but worsened lung injury and survival during Escherichia coli pneumonia in mice.
SB203580, a p38 inhibitor, improved cardiac function but worsened lung injury and survival during Escherichia coli pneumonia in mice.
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SB203580 是一种 p38 抑制剂，可改善小鼠大肠杆菌肺炎期间的心脏功能，但会恶化肺损伤和生存率。
DOI：
10.1097/ta.0b013e3181bb9cd3
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发表时间：
2010
期刊：
影响因子：
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通讯作者：
Eichacker,PeterQ
中科院分区：
文献类型：
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作者：
Su,Junwu;Cui,Xizhong;Li,Yan;Mani,Haresh;Ferreyra,GabrielaA;Danner,RobertL;Hsu,LewisL;Fitz,Yvonne;Eichacker,PeterQ
背景：p38丝裂原活化蛋白激酶（MAPK）抑制可降低脂多糖刺激下的心肺损伤和致死率，支持其在脓毒症中的治疗应用。然而，只有一项临床前研究报道了p38抑制剂（SB203580, 100 mg/kg）在感染期间的生存效应。因此，我们在气管内感染大肠杆菌并给予抗生素和液体治疗的小鼠（n= 763）中测试了SB203580。方法与结果：与安慰剂相比，高剂量SB203580 （100 mg/kg）预处理增加了死亡危险比（95%置信区间）（3.6 [2.1,6.1],p< 0.0001）。递减剂量（10、1或0.1 mg/kg）从有害到无显著影响（递减剂量效应p< 0.0001）。在大肠杆菌感染后48小时，而不是24小时，高剂量和低剂量SB203580预处理均降低了心脏磷酸化p38 MAPK水平，并改善了心输出量（p≤0.07）。低剂量SB203580没有显著改变肺中性粒细胞，但增加了48小时肺损伤（p= 0.05）。高剂量组24 h时肺中性粒细胞减少（p分别为0.09和0.01），48 h时肺中性粒细胞增加（p均≤0.01）。高剂量组肺损伤大于低剂量组（p= 0.002）。结论：SB203580对大肠杆菌攻毒小鼠的心肺功能有不同程度的影响。此外，高剂量使生存恶化，低剂量没有改善。总之，这些发现表明，在将p38 MAPK抑制剂应用于严重感染或有严重感染风险的患者之前，明确定义这种治疗的风险和益处是很重要的。
Background:Supporting its therapeutic application in sepsis, p38 mitogen-activated protein kinase (MAPK) inhibition decreases cardiopulmonary injury and lethality with lipopolysaccharide challenge. However, only one preclinical study has reported the survival effects of a p38 inhibitor (SB203580, 100 mg/kg) during infection. We therefore tested SB203580 in mice (n= 763) challenged with intratracheal Escherichia coli and treated with antibiotics and fluids.Methods and Results:Compared with placebo, high dose SB203580 (100 mg/kg) pretreatment increased the hazards ratio of death (95% confidence interval)(3.6 [2.1, 6.1], p< 0.0001). Decreasing doses (10, 1, or 0.1 mg/kg) went from being harmful to having no significant effect (p< 0.0001 for the effect of decreasing dose). At 48 hours, but not 24 hours after E. coli, high and low dose SB203580 pretreatment decreased cardiac phosphorylated p38 MAPK levels and improved cardiac output either (p≤ 0.07). Low dose SB203580 did not alter lung neutrophils significantly but increased lung injury at 48 hours (p= 0.05). High dose decreased lung neutrophils and injury at 24 hours (p= 0.09 and 0.01, respectively) but then increased them at 48 hours (both p≤ 0.01). Lung injury was greater with high versus low dose at 48 hours (p= 0.002).Conclusion:Thus, SB203580 had divergent effects on cardiac and lung function in E. coli challenged mice. Furthermore, high dose worsened survival and low dose did not improve it. Altogether, these findings suggest that clearly defining the risks and benefits of p38 MAPK inhibition is important before such treatment is applied in patients with or at risk of serious infection.