title: Exogenous carbon monoxide inhibits neutrophil infiltration in LPS-induced sepsis by interfering with FPR1 via p38 MAPK but not GRK2.
abstract: Excessive neutrophil infiltration in vital organs is life-threatening to patients who suffer from sepsis. We identified a critical role of exogenous carbon monoxide (CO) in the inhibition of neutrophil infiltration during lipopolysaccharide (LPS)-induced sepsis. CO delivered from carbon monoxide-releasing molecule 2 (CORM-2) dramatically increased the survival rate of C57BL/6 mice subjected to LPS in vivo. CORM-2 significantly suppressed neutrophil infiltration in liver and lung as well as markers of inflammatory responses. Affymetrix GeneChip array analysis revealed that the increased expression of chemoattractant receptor formyl peptide receptor 1 (FPR1) may contribute to the excessive neutrophil infiltration. The under agarose migration assay demonstrated that LPS stimulation promoted migration to the ligand of FPR1, N-Formyl-Met-Leu-Phe (fMLP) but that CORM-2 treatment inhibited this promotion. Further studies demonstrated that CORM-2 internalized FPR1 by inhibiting p38 mitogen-activated protein kinase (MAPK) but not G protein-coupled receptor kinase 2 (GRK2), which may explain the inhibitory effect of CORM-2 on LPS-stimulated neutrophils. In summary, our study demonstrates that exogenous CO inhibits sepsis-induced neutrophil infiltration by interfering with FPR1 via p38 MAPK but not GRK2.
authors.affiliation: Department of Burn and Plastic Surgery, Affiliated Hospital, Jiangsu University, Zhenjiang, Jiangsu Province, China.
authors.forename: Xu
authors.initials: X
authors.lastname: Wang
authors.affiliation: Department of Burn and Plastic Surgery, Affiliated Hospital, Jiangsu University, Zhenjiang, Jiangsu Province, China.
authors.forename: Weiting
authors.initials: W
authors.lastname: Qin
authors.affiliation: Department of Burn and Plastic Surgery, Affiliated Hospital, Jiangsu University, Zhenjiang, Jiangsu Province, China.
authors.forename: Mingming
authors.initials: M
authors.lastname: Song
authors.affiliation: Department of Burn and Plastic Surgery, Affiliated Hospital, Jiangsu University, Zhenjiang, Jiangsu Province, China.
authors.forename: Yisen
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Burn and Plastic Surgery, Affiliated Hospital, Jiangsu University, Zhenjiang, Jiangsu Province, China.
authors.forename: Bingwei
authors.initials: B
authors.lastname: Sun
mesh_terms: D000818:Animals; D002248:Carbon Monoxide / Q000494:pharmacology*; D054769:G-Protein-Coupled Receptor Kinase 2 / Q000378:metabolism; D008070:Lipopolysaccharides / Q000633:toxicity; D051379:Mice; D008810:Mice, Inbred C57BL; D020556:Neutrophil Infiltration / Q000187:drug effects*; D044042:Receptors, Formyl Peptide / Q000378:metabolism*; D018805:Sepsis / Q000378:metabolism / Q000473:pathology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
chemical_list: C469988:Fpr1 protein, mouse; D008070:Lipopolysaccharides; D044042:Receptors, Formyl Peptide; D002248:Carbon Monoxide; C496568:GRK2 protein, mouse; D054769:G-Protein-Coupled Receptor Kinase 2; D048051:p38 Mitogen-Activated Protein Kinases
keywords: FPR1; carbon monoxide; microarray genechip; neutrophil; sepsis