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 <or= 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 <or= 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.