FR167653 ameliorates pulmonary damage in ischemia-reperfusion injury in a canine lung transplantation model.
BACKGROUND
Interleukin (IL)-1 and tumor necrosis factor-alpha (TNF-alpha) are recognized as important factors in ischemia-reperfusion (I/R) injury. FR167653 has been characterized as a potent suppressant of IL-1 and TNF-alpha production. We previously reported that FR167653 suppressed the expression of IL-1 beta mRNA after reperfusion and ameliorated pulmonary I/R injury following 3-hour left lung warm ischemia in dogs. The aim of this study was to investigate the effects of FR167653 on I/R injury in a canine left, single, lung transplantation model.


METHODS
We used 10 pairs of weight-matched dogs. We assigned 5 pairs to the FR group, in which each animal received FR167653 (1 mg/kg/hr) IV from 30 minutes before ischemia until 2 hours after reperfusion; we treated the transplanted lungs with FR167653 after the onset of reperfusion. The others were assigned to the control group. After 8-hour preservation with 4 degrees C Euro-Collins solution, orthotopic left, single, lung transplantation was performed. During a 5-minute clamping test at the right pulmonary artery of each recipient, the left (transplanted) pulmonary arterial pressure (L-PAP), left (transplanted) pulmonary vascular resistance (L-PVR), arterial oxygen pressure (PaO(2)), and alveolar-arterial oxygen pressure difference (A-aDO(2)) were measured. We harvested transplanted lung specimens for histologic study, and we counted polymorphonuclear neutrophils (PMNs), which were identified by staining with naphthol AS-D cholroacetate esterase. Pulmonary perfusion and ventilation scintigraphy (Tc-99m-MAA and Xe-133) were performed. We observed the animals for 3 days after transplantation.


RESULTS
The PAP, L-PVR, PaO(2), and A-aDO(2) revealed significantly (p < 0.05) better function in the FR group than in the control group. Histologically, lung edema was milder, and PMN infiltration was significantly (p < 0.05) lower in the FR group than in the control group. Xe-133 and Tc-99m-MAA were widely distributed throughout the graft lung in the FR group. Three-day survival rates in FR and control groups were 60% and 20%, respectively.


CONCLUSIONS
FR167653 appears to generate a protective effect on I/R injury in lung transplantation in dogs.
Aiba
M
M
Second Department of Surgery, Gunma University School of Medicine, Maebashi, Gunma, Japan.
Takeyoshi
I
I
Sunose
Y
Y
Iwazaki
S
S
Tsutsumi
H
H
Ohwada
S
S
Tomizawa
N
N
Oriuchi
N
N
Matsumoto
K
K
Morishita
Y
Y
D000818:Animals; D001784:Blood Gas Analysis; D004285:Dogs; D007166:Immunosuppressive Agents / Q000627:therapeutic use*; D008168:Lung / Q000098:blood supply* / Q000473:pathology; D016040:Lung Transplantation / Q000276:immunology*; D011650:Pulmonary Alveoli / Q000473:pathology; D011659:Pulmonary Gas Exchange; D011667:Pulmonary Veins / Q000503:physiopathology; D011720:Pyrazoles / Q000627:therapeutic use*; D011725:Pyridines / Q000627:therapeutic use*; D019275:Radiopharmaceuticals; D011897:Random Allocation; D015427:Reperfusion Injury / Q000517:prevention & control*; D013668:Technetium Tc 99m Aggregated Albumin; D014655:Vascular Resistance
C104334:FR 167653; D007166:Immunosuppressive Agents; D011720:Pyrazoles; D011725:Pyridines; D019275:Radiopharmaceuticals; D013668:Technetium Tc 99m Aggregated Albumin