Altered leukotriene B₄ metabolism in CYP4F18-deficient mice does not impact inflammation following renal ischemia

详细信息    查看全文

• 作者：Valeria Winslow^a ; Rachel Vaivoda^a ; Aleksandr Vasilyev^a ; David Dombkowski^b ; Karim Douaidy^a ; Christopher Stark^a ; Justin Drake^c ; Evin Guilliams^c ; Dharamainder Choudhary^d ; Frederic Preffer^b ; Ivaylo Stoilov^d ; Peter Christmas^a ; ^c ; ^{pchristma2@radford.edu" class="auth_mail}
• 关键词：AA ; arachidonic acid ; BUN ; blood urea nitrogen ; CYP ; cytochrome P450 ; 20-HETE ; 20-hydroxyeicosatetraenoic acid ; HPLC ; high performance liquid chromatography ; IRI ; ischemia&ndash ; reperfusion injury ; LTB4 ; leukotriene B4 ; LC&ndash ; MS ; liquid chromatography&ndash ; mass spectrometry ; MPO ; myeloperoxidase ; RT-PCR ; reverse transcription-polymerase chain reaction
• 刊名：Biochimica et Biophysica Acta (BBA)/Molecular and Cell Biology of Lipids
• 出版年：June, 2014
• 年：2014
• 卷：1841
• 期：6
• 页码：868-879
• 全文大小：2853 K

文摘

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 蠅, 蠅-1, and 蠅-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.