The effect of FR167653 on pulmonary ischemia-reperfusion injury in rats.
BACKGROUND
A novel synthesized organic compound, FR167653, has been characterized as a potent suppressant of interleukin-1 and tumor necrosis factor-alpha. We designed this experimental study to evaluate the effect of FR167653 on ischemia-reperfusion injury of the rat lung.


METHODS
Following general anesthesia, the left bronchus, pulmonary artery and vein were clamped for 1 hour. FR167653 was administered continuously beginning 30 minutes before the onset of ischemia and extending for 2 hours after reperfusion. Thirty-eight Wistar rats were divided into 4 groups according to the dose of FR167653 at the rate of 0.1, 0.05 and 0.025 mg/kg/hr in each group. After the optimal dose was obtained from the result of 1-week survival rate, the group with the optimal dose was compared with a control group by using such parameters as arterial oxygen saturation (SaO(2)), arterial oxygen tension (PaO(2)), cytokines, the expression of p38 MAP kinase and histologic study.


RESULTS
Survival rate of the group received FR at the rate of 0.1 mg/kg/hr (FR0.1 group) was best among the 4 groups. SaO(2) levels and PaO(2) levels after 2-hour of reperfusion were significantly (p < 0.05, respectively) higher in the FR0.1 group than in the control group. After 2-hour reperfusion, IL-1 beta was lower in the FR0.1 group than in the control group, and the expression of p38 MAP kinase was reduced in the FR0.1 group compared with the control group. In histologic study after 2-hour of reperfusion, alveolar damage with edema and interstitial thickening localized along the alveolar duct were observed in the control group, whereas these findings were remarkably less evident in the FR0.1 group.


CONCLUSIONS
We concluded that FR167653 ameliorates ischemia-reperfusion injury of the lung and may inhibit the production of proinflammatory cytokines by means of the inhibition of p38 MAP kinase.
Otani
Y
Y
the Second Department of Surgery, Gunma University School of Medicine, Maebashi, Japan.
Takeyoshi
I
I
Koibuchi
Y
Y
Matsumoto
K
K
Muramoto
M
M
Morishita
Y
Y
D000818:Animals; D001483:Base Sequence; D016207:Cytokines / Q000032:analysis; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D007262:Infusions, Intravenous; D008168:Lung / Q000098:blood supply* / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D008969:Molecular Sequence Data; D010101:Oxygen Consumption; D016133:Polymerase Chain Reaction; D011720:Pyrazoles / Q000494:pharmacology*; D011725:Pyridines / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D012016:Reference Values; D012039:Regional Blood Flow / Q000187:drug effects; D015427:Reperfusion Injury / Q000188:drug therapy* / Q000378:metabolism / Q000401:mortality; D018709:Statistics, Nonparametric; D015996:Survival Rate
D016207:Cytokines; C104334:FR 167653; D011720:Pyrazoles; D011725:Pyridines