SB203580, a p38 inhibitor, improved cardiac function but worsened lung injury and survival during Escherichia coli pneumonia in mice.
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.


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).


CONCLUSIONS
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.
Su
Junwu
J
Department of Critical Care Medicine, Clinical Center, National Institutes of Health, 9000 Rockville Pike, Bethesda, MD 20892, USA.
Cui
Xizhong
X
Li
Yan
Y
Mani
Haresh
H
Ferreyra
Gabriela A
GA
Danner
Robert L
RL
Hsu
Lewis L
LL
Fitz
Yvonne
Y
Eichacker
Peter Q
PQ
D000704:Analysis of Variance; D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology; D002302:Cardiac Output / Q000187:drug effects; D004452:Echocardiography; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D004797:Enzyme-Linked Immunosorbent Assay; D004927:Escherichia coli Infections / Q000188:drug therapy* / Q000503:physiopathology; D005440:Fluid Therapy; D007093:Imidazoles / Q000008:administration & dosage / Q000494:pharmacology*; D008070:Lipopolysaccharides / Q000494:pharmacology; D055370:Lung Injury / Q000503:physiopathology; D051379:Mice; D010919:Placebos; D011014:Pneumonia / Q000188:drug therapy* / Q000503:physiopathology; D016016:Proportional Hazards Models; D011725:Pyridines / Q000008:administration & dosage / Q000494:pharmacology*; D015996:Survival Rate
D000900:Anti-Bacterial Agents; D004791:Enzyme Inhibitors; D007093:Imidazoles; D008070:Lipopolysaccharides; D010919:Placebos; D011725:Pyridines; C093642:SB 203580