Protective role of selectin ligand inhibition in a large animal model of kidney ischemia-reperfusion injury.
Experiments in rodents have demonstrated an important role for selectins in kidney ischemia-reperfusion injury (IRI). However, the relevance of this in larger mammals, as well as the impact on long-term structure and function is unknown. We tested the hypothesis that small molecule selectin ligand inhibition attenuates IRI, cellular inflammation, and long-term effects on renal interstitial fibrosis. We used a porcine model of kidney IRI and used Texas Biotechnology Corporation (TBC)-1269, a selectin ligand inhibitor. Renal function, tissue inflammation, and tubulointerstitial fibrosis development were evaluated up to 16 weeks. Both warm and cold ischemia models were studied for relevance to native and transplant kidney injury. Pigs treated with TBC-1269 during 45 min of warm ischemia (WI) showed significantly increased glomerular filtration rate compared to control animals. In pigs with severe IRI (WI for 60 min), TBC-1269 treatment during IRI significantly increased renal recovery. Cellular inflammation was strongly reduced, particularly influx of CD4 cells. Quantitative measurement of fibrosis by picrosirius red staining showed strong reduction in TBC-1269-treated groups. TBC-1269 also reduced cold IRI, inflammation, and fibrosis in kidneys preserved for 24 h at 4 degrees C and autotransplanted. The selectin ligand inhibitor TBC-1269 provides a novel and effective approach to attenuate IRI in both warm and cold ischemia in large mammals, in both short and long terms. Selectin ligand inhibition is an attractive strategy for evaluation in human kidney IRI.
Jayle
C
C
INSERM E0324, Centre Hospitalier et Universitaire and Faculte de Medecine, Poitiers, France.
Milinkevitch
S
S
Favreau
F
F
Doucet
C
C
Richer
J P
JP
Deretz
S
S
Mauco
G
G
Rabb
H
H
Hauet
T
T
D000818:Animals; D001713:Biphenyl Compounds / Q000737:chemistry / Q000494:pharmacology; D004195:Disease Models, Animal; D005355:Fibrosis / Q000473:pathology / Q000503:physiopathology; D007150:Immunohistochemistry; D007668:Kidney / Q000473:pathology; D008024:Ligands; D008297:Male; D008358:Mannose / Q000031:analogs & derivatives; D008362:Mannosides / Q000737:chemistry / Q000494:pharmacology; D015394:Molecular Structure; D009395:Nephritis, Interstitial / Q000139:chemically induced / Q000473:pathology; D020011:Protective Agents / Q000627:therapeutic use*; D015427:Reperfusion Injury / Q000473:pathology / Q000517:prevention & control*; D019087:Selectins / Q000187:drug effects / Q000502:physiology*; D013552:Swine; D013601:T-Lymphocytes / Q000378:metabolism
D001713:Biphenyl Compounds; D008024:Ligands; D008362:Mannosides; D020011:Protective Agents; D019087:Selectins; C108700:bimosiamose disodium; D008358:Mannose