Endothelin receptor antagonist SB209670 decreases lung allograft apoptosis and improves lung graft function after prolonged ischemia.
Apoptosis has been postulated as a contributing factor in ischemia-reperfusion graft dysfunction following lung transplantation. The purpose of this study was to determine whether treatment with an endothelin-A/endothelin-B- (ET(A)/ET(B)) receptor antagonist could reduce the level of apoptosis observed in the lung following ischemia-reperfusion injury. Eleven dogs were subjected to left lung allotransplantation. Heart-lung blocks were harvested from donor dogs and preserved with modified Eurocollins solution and stored at 4 degrees C for 18 to 20 h. We investigated the level of apoptosis by terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling (TUNEL), in the lungs of animals receiving an intravenous infusion of saline (control, n = 5) or the ET receptor antagonist SB209670 (n = 6) (15 microg/kg/min). The infusion began 30 min prior to transplantation and continued for up to 6 h thereafter. The TUNEL staining was significantly higher in the airway epithelium and the parenchyma of the saline (control) group (40.67 +/- 6.16), compared with native right lungs (5.00 +/- 0.56) and the treatment group (14.13 +/- 2.84). We conclude that treatment of lung allografts with the mixed ET(A)/ET(B)-receptor antagonist SB209670 can ameliorate lung injury by reducing the level of apoptosis seen in the allograft following ischemia-reperfusion injury.
Shaw
M J
MJ
Department of Surgery and Pathology, The Montreal General Hospital, McGill University, Quebec, Canada.
Shennib
H
H
Tayara
L
L
Ohlstein
E
E
Giaid
A
A
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D004285:Dogs; D065128:Endothelin Receptor Antagonists; D020287:In Situ Nick-End Labeling; D007189:Indans / Q000494:pharmacology*; D007511:Ischemia / Q000503:physiopathology*; D008168:Lung / Q000098:blood supply* / Q000473:pathology / Q000503:physiopathology; D016040:Lung Transplantation / Q000009:adverse effects*; D014184:Transplantation, Homologous
D065128:Endothelin Receptor Antagonists; D007189:Indans; C087551:1H-Indene-2-carboxylic acid, 1-(1,3-benzodioxol-5-yl)-3-(2- (carboxymethoxy)-4-methoxyphenyl)-2,3-dihydro-5-propoxy-, (1S,2R,3S)-