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Endothelin receptor antagonist SB209670 decreases lung allograft apoptosis and improves lung graft function after
M J Shaw1, H Shennib, L Tayara
1Department of Surgery and Pathology, The Montreal General Hospital, McGill University, Quebec, Canada.
Abstract:
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.
Insights
This study shows that an endothelin receptor antagonist reduces apoptosis in lung transplants after ischemia-reperfusion injury. This treatment may improve graft function by protecting lung tissue from cell death.
Area of Science:
- Transplantation immunology
- Cellular injury mechanisms
- Pharmacology
Background:
- Ischemia-reperfusion injury is a significant cause of lung transplant graft dysfunction.
- Apoptosis, or programmed cell death, is implicated in this injury process.
- Endothelin receptors (ET(A)/ET(B)) play a role in vascular tone and inflammation, potentially influencing transplant outcomes.
Purpose of the Study:
- To investigate the effect of a mixed endothelin-A/endothelin-B (ET(A)/ET(B)) receptor antagonist on apoptosis following lung ischemia-reperfusion injury.
- To determine if blocking ET(A)/ET(B) receptors can mitigate cellular damage in lung allografts.
Main Methods:
- Left lung allotransplantation was performed in eleven dogs.
- Donor lungs were preserved and stored for 18-20 hours.
- Apoptosis was quantified using terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling (TUNEL) assay.
- Animals received either saline (control) or the ET receptor antagonist SB209670 intravenously before and after transplantation.
Main Results:
- The saline control group exhibited significantly higher TUNEL staining in airway epithelium and parenchyma compared to native lungs.
- Treatment with the ET receptor antagonist SB209670 significantly reduced TUNEL staining in the allograft lungs.
- Apoptosis levels in the treated group were substantially lower than in the control group.
Conclusions:
- The mixed ET(A)/ET(B)-receptor antagonist SB209670 effectively reduces apoptosis in lung allografts subjected to ischemia-reperfusion injury.
- This pharmacological intervention shows potential for ameliorating lung injury and improving graft outcomes in transplantation.
- Targeting endothelin receptors may be a viable strategy to protect lung transplants from ischemia-reperfusion damage.
