Heme oxygenase-1 suppresses the infiltration of neutrophils in rat liver during sepsis through inactivation of p38 MAPK.

To investigate the molecular mechanism underlying heme oxygenase-1 (HO-1)-modulated infiltration of neutrophils, the sepsis model of cecal ligation and puncture in Sprague-Dawley rats was used. In vivo induction and suppression of HO-1 were performed by pretreatment with cobalt protoporphyrin IX (CoPP) and zinc protoporphyrin IX, respectively. Tricarbonyldichlororuthenium(II) dimer, [Ru(CO)₃Cl₂]₂ (a carbon monoxide [CO] releaser), and hemoglobin (a CO scavenger) were used to examine the participation of HO-1/CO in the effect of CoPP pretreatment on formylated peptide (fMLP)-induced p38 mitogen-activated protein kinase (MAPK) phosphorylation. Anisomycin (a p38 MAPK activator) and SB203580 (a p38 MAPK inhibitor) were used to examine p38 MAPK mediation in the attenuation of fMLP-attracted migration by HO-1. The results demonstrated that zinc protoporphyrin IX and CoPP pretreatment conferred enhancing and inhibitory effects, respectively, on hepatic neutrophil infiltration. Pretreatment with CoPP inhibited fMLP-induced migration and p38 MAPK phosphorylation in neutrophils ex vivo. The [Ru(CO)₃Cl₂]₂ stimulated whereas hemoglobin diminished the suppression of fMLP-induced p38 MAPK phosphorylation by CoPP. Moreover, anisomycin diminished the suppressive effects of CoPP pretreatment on fMLP-induced migration, actin polymerization, polarization, and migration speed of neutrophils. These results suggest that HO-1 in neutrophil attenuates its infiltration during sepsis via the inactivation of p38 MAPK. Understanding the mechanism that diminishes neutrophil infiltration by HO-1 may help prevent hepatic failure during sepsis.