The synthetic pentasaccharide fondaparinux reduces coagulation, inflammation and neutrophil accumulation in kidney ischemia-reperfusion injury.
Ischemia-reperfusion (I/R) injury is associated with activation of coagulation and inflammation. Interestingly, various anticoagulants have been shown to reduce both coagulation and inflammation in animal models of kidney I/R injury. Fondaparinux is a synthetic pentasaccharide that selectively inhibits factor Xa (FXa) in the coagulation cascade. The aim of this study was to investigate the effect of fondaparinux in a lethal murine model of kidney I/R injury. A murine model of kidney I/R was established. In this model, we measured activation of the coagulation cascade and induction of inflammation. Administration of fondaparinux to I/R-injured mice reduced fibrin deposition in the kidney, reduced serum creatinine levels and increased survival from 0 to 44% compared with saline-treated control mice. Fondaparinux also reduced interleukin-6 and macrophage inflammatory protein-2 expression and decreased neutrophil accumulation in the injured kidneys. Finally, we showed that fondaparinux reduced thioglycollate-induced recruitment of neutrophils into the peritoneum and inhibited the binding of U937 cells to P-selectin in vitro. Our data suggest that fondaparinux reduces kidney I/R injury primarily by inhibiting the recruitment of neutrophils.
Frank
R D
RD
Department of Immunology, The Scripps Research Institute, La Jolla, CA 92037, USA.
Schabbauer
G
G
Holscher
T
T
Sato
Y
Y
Tencati
M
M
Pawlinski
R
R
Mackman
N
N
D000818:Animals; D001777:Blood Coagulation / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D054426:Chemokine CXCL2; D003401:Creatine / Q000097:blood; D004353:Drug Evaluation, Preclinical; D005337:Fibrin / Q000378:metabolism; D000077425:Fondaparinux; D007249:Inflammation / Q000188:drug therapy; D015850:Interleukin-6 / Q000097:blood; D007668:Kidney / Q000098:blood supply / Q000473:pathology*; D051379:Mice; D023421:Models, Animal; D015846:Monokines / Q000097:blood; D009504:Neutrophils / Q000187:drug effects*; D011134:Polysaccharides / Q000008:administration & dosage / Q000494:pharmacology*; D015427:Reperfusion Injury / Q000188:drug therapy*; D015996:Survival Rate
D054426:Chemokine CXCL2; D015850:Interleukin-6; D015846:Monokines; D011134:Polysaccharides; D005337:Fibrin; D000077425:Fondaparinux; D003401:Creatine