title: Altered leukotriene B4 metabolism in CYP4F18-deficient mice does not impact inflammation following renal ischemia.
abstract: Inflammatory responses to infection and injury must be restrained and negatively regulated to minimize damage to host tissue. One proposed mechanism involves enzymatic inactivation of the pro-inflammatory mediator leukotriene B4, but it is difficult to dissect the roles of various metabolic enzymes and pathways. A primary candidate for a regulatory pathway is omega oxidation of leukotriene B4 in neutrophils, presumptively by CYP4F3A in humans and CYP4F18 in mice. This pathway generates ω, ω-1, and ω-2 hydroxylated products of leukotriene B4, depending on species. We created mouse models targeting exons 8 and 9 of the Cyp4f18 allele that allows both conventional and conditional knockouts of Cyp4f18. Neutrophils from wild-type mice convert leukotriene B4 to 19-hydroxy leukotriene B4, and to a lesser extent 18-hydroxy leukotriene B4, whereas these products were not detected in neutrophils from conventional Cyp4f18 knockouts. A mouse model of renal ischemia-reperfusion injury was used to investigate the consequences of loss of CYP4F18 in vivo. There were no significant changes in infiltration of neutrophils and other leukocytes into kidney tissue as determined by flow cytometry and immunohistochemistry, or renal injury as assessed by histological scoring and measurement of blood urea nitrogen. It is concluded that CYP4F18 is necessary for omega oxidation of leukotriene B4 in neutrophils, and is not compensated by other CYP enzymes, but loss of this metabolic pathway is not sufficient to impact inflammation and injury following renal ischemia-reperfusion in mice.
authors.affiliation: Nephrology Division, Department of Medicine, Massachusetts General Hospital, Charlestown, MA 02129, USA.
authors.forename: Valeria
authors.initials: V
authors.lastname: Winslow
authors.affiliation: Nephrology Division, Department of Medicine, Massachusetts General Hospital, Charlestown, MA 02129, USA.
authors.forename: Rachel
authors.initials: R
authors.lastname: Vaivoda
authors.affiliation: Nephrology Division, Department of Medicine, Massachusetts General Hospital, Charlestown, MA 02129, USA.
authors.forename: Aleksandr
authors.initials: A
authors.lastname: Vasilyev
authors.affiliation: Department of Pathology, Massachusetts General Hospital, Boston, MA 02114, USA.
authors.forename: David
authors.initials: D
authors.lastname: Dombkowski
authors.affiliation: Nephrology Division, Department of Medicine, Massachusetts General Hospital, Charlestown, MA 02129, USA.
authors.forename: Karim
authors.initials: K
authors.lastname: Douaidy
authors.affiliation: Nephrology Division, Department of Medicine, Massachusetts General Hospital, Charlestown, MA 02129, USA.
authors.forename: Christopher
authors.initials: C
authors.lastname: Stark
authors.affiliation: Biology Department, Radford University, Radford, VA 24142, USA.
authors.forename: Justin
authors.initials: J
authors.lastname: Drake
authors.affiliation: Biology Department, Radford University, Radford, VA 24142, USA.
authors.forename: Evin
authors.initials: E
authors.lastname: Guilliams
authors.affiliation: Department of Surgery, University of Connecticut Health Center, Farmington, CT 06030, USA.
authors.forename: Dharamainder
authors.initials: D
authors.lastname: Choudhary
authors.affiliation: Department of Pathology, Massachusetts General Hospital, Boston, MA 02114, USA.
authors.forename: Frederic
authors.initials: F
authors.lastname: Preffer
authors.affiliation: Department of Surgery, University of Connecticut Health Center, Farmington, CT 06030, USA.
authors.forename: Ivaylo
authors.initials: I
authors.lastname: Stoilov
authors.affiliation: Nephrology Division, Department of Medicine, Massachusetts General Hospital, Charlestown, MA 02129, USA; Biology Department, Radford University, Radford, VA 24142, USA. Electronic address: pchristma2@radford.edu.
authors.forename: Peter
authors.initials: P
authors.lastname: Christmas
mesh_terms: D000818:Animals; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics* / Q000378:metabolism; D000072470:Cytochrome P450 Family 4; D004195:Disease Models, Animal; D006801:Humans; D007249:Inflammation / Q000235:genetics* / Q000378:metabolism; D007668:Kidney / Q000378:metabolism* / Q000473:pathology; D007975:Leukotriene B4 / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D009504:Neutrophils / Q000378:metabolism; D015427:Reperfusion Injury / Q000235:genetics / Q000473:pathology
chemical_list: C000588933:CYP4F18 protein, mouse; D007975:Leukotriene B4; D003577:Cytochrome P-450 Enzyme System; D000072470:Cytochrome P450 Family 4; C465349:CYP4F3 protein, human
keywords: Cytochrome P450; Inflammation; Leukotriene B(4); Neutrophil; ω-Hydroxylase