title: FPR2/ALX activation reverses LPS-induced vascular hyporeactivity in aorta and increases survival in a pneumosepsis model.
abstract: The formylpeptide receptor 2 (FPR2/ALX) is a very promiscuous receptor, utilized by lipid and protein ligands that trigger pro- or anti-inflammatory responses. FPR2/ALX expression is increased in lung tissues of septic animals and its activation has a beneficial therapeutic effect by controlling exacerbated inflammation. Although FPR2/ALX expression was observed in vascular smooth muscle cells, its role in vascular reactivity in inflammatory conditions has not been studied. In this study, we report that LPS increases FPR2/ALX expression in vascular smooth muscle cells (A7r5 cells) and aorta tissue, and that the selective agonist WKYMVm reverses LPS-induced vascular hyporeactivity in mouse aorta rings. Mice bearing pneumosepsis by Klebsiella pneumoniae and treated with WKYMVm recovered the reactivity to vasoconstrictors and the survival improved by 40%. As for the mechanisms involved, FPR2/ALX activation decreases NO production in LPS-stimulated cells and aorta, but it does not seem involve the regulation of NOS-2 expression. The molecular mechanism by which the peptide inhibits NO production still needs to be elucidated, but our data suggests an important role for NO in the WKYMVm beneficial effect observed in LPS injury and sepsis. In conclusion, our data suggest, for the first time, that a receptor, primarily described as a mediator of immune responses, may have an important role in the vascular dysfunctions observed in sepsis and may be a possible target for new therapeutic interventions.
authors.affiliation: Department of Microbiology, Immunology and Parasitology, Universidade Federal de Santa Catarina, SC, Brazil.
authors.forename: Verônica Vargas
authors.initials: VV
authors.lastname: Horewicz
authors.affiliation: Department of Pharmacology, Universidade Federal de Santa Catarina, SC, Brazil.
authors.forename: Sandra
authors.initials: S
authors.lastname: Crestani
authors.affiliation: Department of Pharmacology, Universidade Federal de Santa Catarina, SC, Brazil.
authors.forename: Regina
authors.initials: R
authors.lastname: de Sordi
authors.affiliation: Department of Pharmacology, Universidade Federal de Santa Catarina, SC, Brazil.
authors.forename: Edir
authors.initials: E
authors.lastname: Rezende
authors.affiliation: Department of Pharmacology, Universidade Federal de Santa Catarina, SC, Brazil. Electronic address: jamil.assreuy@ufsc.br.
authors.forename: Jamil
authors.initials: J
authors.lastname: Assreuy
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology / Q000627:therapeutic use*; D001011:Aorta / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D002460:Cell Line; D004730:Endothelium, Vascular / Q000502:physiology / Q000503:physiopathology; D066298:In Vitro Techniques; D007710:Klebsiella Infections / Q000188:drug therapy* / Q000378:metabolism / Q000382:microbiology / Q000503:physiopathology; D007711:Klebsiella pneumoniae / Q000187:drug effects* / Q000254:growth & development / Q000276:immunology; D008070:Lipopolysaccharides / Q000633:toxicity; D008297:Male; D051379:Mice; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D009569:Nitric Oxide / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism; D009842:Oligopeptides / Q000494:pharmacology / Q000627:therapeutic use*; D051381:Rats; D044042:Receptors, Formyl Peptide / Q000819:agonists* / Q000378:metabolism; D018805:Sepsis / Q000188:drug therapy* / Q000378:metabolism / Q000382:microbiology / Q000503:physiopathology; D016019:Survival Analysis; D014655:Vascular Resistance / Q000187:drug effects; D014657:Vasculitis / Q000209:etiology / Q000276:immunology / Q000517:prevention & control*
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D008070:Lipopolysaccharides; D009842:Oligopeptides; D044042:Receptors, Formyl Peptide; C113617:Trp-Lys-Tyr-Met-Val-Met; C481578:formyl peptide receptor 2, mouse; C440499:lipopolysaccharide, Escherichia coli O111 B4; C509690:tryptophyl-arginyl-tryptophyl-tryptophyl-tryptophyl-tryptophanamide; D009569:Nitric Oxide
keywords: FPR2/ALX; LPS; Pneumosepsis; Vascular dysfunction; WKYMVm; WKYMVm-NH(2) (PubChem CID: 57340528); WRW4 (PubChem CID: 49768328)