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.
Lin
Yi-Tseng
YT
Graduate Institute of Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan.
Chen
Yen-Hsu
YH
Yang
Yi-Hsin
YH
Jao
Hsiao-Ching
HC
Abiko
Yoshimitsu
Y
Yokoyama
Kazushige
K
Hsu
Chin
C
D000818:Animals; D000841:Anisomycin / Q000494:pharmacology; D015153:Blotting, Western; D002465:Cell Movement / Q000187:drug effects / Q000235:genetics; D004789:Enzyme Activation / Q000187:drug effects; D051547:Heme Oxygenase-1 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D008099:Liver / Q000187:drug effects / Q000201:enzymology* / Q000378:metabolism*; D008297:Male; D020556:Neutrophil Infiltration / Q000235:genetics / Q000502:physiology*; D009504:Neutrophils / Q000166:cytology* / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D016133:Polymerase Chain Reaction; D011524:Protoporphyrins / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D018805:Sepsis / Q000235:genetics / Q000276:immunology* / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*
D011524:Protoporphyrins; C017803:zinc protoporphyrin; C007095:cobaltiprotoporphyrin; D000841:Anisomycin; D051547:Heme Oxygenase-1; D048051:p38 Mitogen-Activated Protein Kinases