The effective dose of FR167653 in pulmonary ischemia-reperfusion injury.
BACKGROUND
Ischemia-reperfusion injury may result in the local release of proinflammatory cytokines. FR167653 is a potent suppressant of interleukin-1 and tumor necrosis factor-alpha. In a previous study, we reported the efficacy of FR167653 in canine ischemia-reperfusion models. In this report we investigated the dose of FR167653 effective in pulmonary ischemia-reperfusion injury in a canine model.


METHODS
Adult mongrel dogs, weighing 9 to 13 kg, were allocated into five groups. FR167653 was continuously infused (FR-A (n = 7): 1 mg/kg/hr; FR-B (n = 6): 0.5 mg/kg/hr; FR-C (n = 6): 0.1 mg/kg/hr; FR-D (n = 5): 0.05 mg/kg/hr) from 30 minutes prior to ischemia to 2 hours after reperfusion. In the control group (n = 7), a vehicle was given continuously. Warm ischemia was induced for 3 hours. Arterial oxygen saturation (SaO2), left pulmonary vascular resistance (L-PVR), and cardiac output (CO) were measured. The lung was harvested for histologic study.


RESULTS
SaO2 levels after 2 hours of reperfusion were significantly (p < 0.05) higher in groups FR-A, B, C, and D than in the control group. Just after reperfusion, CO deterioration was significantly (p < 0.05) greater in the control group than in the FR-treated groups, and the L-PVR level was significantly (p < 0.05) lower in groups FR-A, B, and C than in the control group. There were statistically significant differences (p < 0.05) in the survival rates of groups FR-A and B and the control group. Histological damage was more severe in the control group than in the FR-treated groups.


CONCLUSIONS
FR 167653 seems to ameliorate ischemia-reperfusion injury of the lung dose-dependently.
Ishikawa
H
H
Second Department of Surgery, Gunma University School of Medicine, 3-39-15 Showa-Machi, Maebashi, Gunma 371-8511, Japan.
Takeyoshi
I
I
Aiba
M
M
Kamoshita
N
N
Ohwada
S
S
Matsumoto
K
K
Morishita
Y
Y
D000818:Animals; D001784:Blood Gas Analysis; D004195:Disease Models, Animal; D004285:Dogs; D007166:Immunosuppressive Agents / Q000008:administration & dosage* / Q000627:therapeutic use; D008168:Lung / Q000473:pathology*; D016040:Lung Transplantation; D011720:Pyrazoles / Q000008:administration & dosage* / Q000627:therapeutic use; D011725:Pyridines / Q000008:administration & dosage* / Q000627:therapeutic use; D015427:Reperfusion Injury / Q000517:prevention & control*; D016019:Survival Analysis
C104334:FR 167653; D007166:Immunosuppressive Agents; D011720:Pyrazoles; D011725:Pyridines