Deficiency of 5-lipoxygenase accelerates renal allograft rejection in mice.
Acute renal allograft rejection is associated with alterations in renal arachidonic acid metabolism, including enhanced synthesis of leukotrienes (LTs). LTs, the products of the 5-lipoxygenase (5-LO) pathway, are potent lipid mediators with a broad range of biologic activities. Previous studies, using pharmacological agents to inhibit LT synthesis or activity, have implicated these eicosanoids in transplant rejection. To further investigate the role of LTs in acute graft rejection, we transplanted kidneys from CByD2F1 mice into fully allogeneic 129 mice that carry a targeted mutation in the 5lo gene. Unexpectedly, allograft rejection was significantly accelerated in 5-LO-deficient mice compared with wild-type animals. Despite the marked reduction in graft survival, the 5lo mutation had no effect on the hemodynamics or morphology of the allografts. Although LTB4 levels were reduced, renal thromboxane B2 production and cytokine expression were not altered in 5-LO-deficient allograft recipients. These findings suggest that, along with their proinflammatory actions, metabolites of 5-LO can act to enhance allograft survival.
Goulet
J L
JL
Division of Nephrology, Department of Medicine, Duke University and Durham Veterans Affairs Medical Centers, Durham, NC 27705, USA.
Griffiths
R C
RC
Ruiz
P
P
Mannon
R B
RB
Flannery
P
P
Platt
J L
JL
Koller
B H
BH
Coffman
T M
TM
D000818:Animals; D001094:Arachidonate 5-Lipoxygenase / Q000172:deficiency* / Q000235:genetics* / Q000378:metabolism; D003433:Crosses, Genetic; D016207:Cytokines / Q000096:biosynthesis / Q000235:genetics; D006084:Graft Rejection / Q000201:enzymology* / Q000235:genetics* / Q000503:physiopathology; D006893:Hydroxyeicosatetraenoic Acids / Q000096:biosynthesis; D007677:Kidney Function Tests; D016030:Kidney Transplantation / Q000276:immunology* / Q000473:pathology; D007975:Leukotriene B4 / Q000096:biosynthesis; D044045:Lipoxins; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008811:Mice, Inbred DBA; D018345:Mice, Knockout; D012333:RNA, Messenger / Q000096:biosynthesis; D013928:Thromboxane A2 / Q000096:biosynthesis; D013929:Thromboxane B2 / Q000096:biosynthesis
D016207:Cytokines; D006893:Hydroxyeicosatetraenoic Acids; D044045:Lipoxins; D012333:RNA, Messenger; C040527:lipoxin A4; D007975:Leukotriene B4; D013929:Thromboxane B2; D013928:Thromboxane A2; D001094:Arachidonate 5-Lipoxygenase