title: FR167653 ameliorates pulmonary damage in ischemia-reperfusion injury in a canine lung transplantation model.
abstract: 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.
authors.affiliation: Second Department of Surgery, Gunma University School of Medicine, Maebashi, Gunma, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Aiba
authors.forename: I
authors.initials: I
authors.lastname: Takeyoshi
authors.forename: Y
authors.initials: Y
authors.lastname: Sunose
authors.forename: S
authors.initials: S
authors.lastname: Iwazaki
authors.forename: H
authors.initials: H
authors.lastname: Tsutsumi
authors.forename: S
authors.initials: S
authors.lastname: Ohwada
authors.forename: N
authors.initials: N
authors.lastname: Tomizawa
authors.forename: N
authors.initials: N
authors.lastname: Oriuchi
authors.forename: K
authors.initials: K
authors.lastname: Matsumoto
authors.forename: Y
authors.initials: Y
authors.lastname: Morishita
mesh_terms: 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
chemical_list: C104334:FR 167653; D007166:Immunosuppressive Agents; D011720:Pyrazoles; D011725:Pyridines; D019275:Radiopharmaceuticals; D013668:Technetium Tc 99m Aggregated Albumin