Recipient treatment with trimetazidine improves graft function and protects energy status after lung transplantation.
BACKGROUND
Ischemia-reperfusion injury remains an important obstacle to successful lung transplantation. Trimetazidine is an anti-ischemic drug that restores the ability of ischemic cells to produce energy and reduces the generation of oxygen-derived free radicals. The aim of this study was to assess the protective effect of trimetazidine after prolonged ischemia in lung transplantation.


METHODS
Rat single-lung transplantation was performed in 4 experimental groups (n = 5 each). In all groups, transplantation was performed after 18 hours of cold (4 degrees C) ischemia. All donor lungs were flushed with low-potassium dextran-glucose (LPDG) solution that also contained 500 microg/liter prostaglandin estradiol (E(1)). Groups studied included: Group I: flush solution was administered containing 10(-6) mol/liter trimetazidine (TMZ), neither donor nor recipient treatment given; Group II: donors were treated with 5 mg/kg intravenous TMZ 10 minutes prior to harvest, but the flush solution did not contain TMZ; Group III: recipients treated with 5 mg/kg intravenous TMZ 10 minutes before reperfusion, and flush solution contained 10(-6) mol/liter trimetazidine; Group IV: ischemic control group. After 2 hours of reperfusion, oxygenation was measured and lung tissue was frozen and assessed for adenosine triphosphate (ATP) content, myeloperoxidase (MPO) activity and thiobarbituric acid-reactive substances (TBARS). Peak airway pressure (PawP) was recorded throughout the reperfusion period.


RESULTS
Group III showed significantly higher levels of ATP content (11.1 +/- 5.01 pmol vs Group I, 3.36 +/- 1.8 pmol, p = 0.008; vs Group II, 4.7 +/- 1.9 pmol, p = 0.03; vs Group IV, 0.7 +/- 0.2 pmol, p = 0.008), better oxygenation (442.5 +/- 26.5 mm Hg, vs Group I, 161.06 +/- 54.5 mm Hg; vs Group II, 266.02 +/- 76.9 mm Hg; vs Group IV, 89.4 +/- 14.7 mm Hg, p = 0.008) and reduced lipid peroxidation (TBARS) (0.15 +/- 0.03 nmol/g; vs Group I, 1.04 +/- 0.76 nmol/g; vs Group II, 0.69 +/- 0.4 nmol/g; vs Group IV, 2.29 +/- 0.4 nmol/g, p = 0.008). PawP and MPO activity were comparable in the 4 study groups.


CONCLUSIONS
Recipient treatment with TMZ provided significant protection of energy status, better oxygenation and reduced lipid peroxidation. Our data suggest that TMZ may be an important adjunct in the prevention of post-transplant lung ischemia-reperfusion injury.
Inci
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I
Division of Thoracic Surgery, University Hospital, Zurich, Switzerland.
Dutly
A
A
Inci
D
D
Boehler
A
A
Weder
W
W
D000818:Animals; D004734:Energy Metabolism / Q000187:drug effects; D005609:Free Radicals / Q000037:antagonists & inhibitors; D006085:Graft Survival / Q000187:drug effects; D016040:Lung Transplantation; D008297:Male; D051381:Rats; D011916:Rats, Inbred F344; D015427:Reperfusion Injury / Q000378:metabolism / Q000517:prevention & control*; D012128:Respiratory Distress Syndrome / Q000378:metabolism / Q000517:prevention & control*; D014292:Trimetazidine / Q000494:pharmacology*; D014665:Vasodilator Agents / Q000494:pharmacology*
D005609:Free Radicals; D014665:Vasodilator Agents; D014292:Trimetazidine