FR167653 attenuates ischemia and reperfusion injury of the rat lung with suppressing p38 mitogen-activated protein kinase.
BACKGROUND
FR167653 is a potent suppressant of tumor necrosis factor (TNF)-alpha and interleukin-1 (IL-1) production, and was shown to attenuate ischemia and reperfusion (I/R) organ injury in our previous experiment. Because p38 mitogen-activated protein (MAP) kinase has been reported to regulate the production of TNF-alpha and IL-1, we examined the effects of FR167653 in the rat lung I/R model and determined the expression and activation of p38 MAP kinase.


METHODS
Experiment 1: After 1 hour of ischemia, p38 MAP kinase, phosphorylated p38 MAP kinase (active form), histologic changes of the lung, and serum levels of TNF-alpha and IL-1beta were examined. Experiment 2: After 2 hours of reperfusion, arterial oxygen content (PaO(2)) and saturation (SaO(2)), serum TNF-alpha and IL-1beta levels, and histologic changes in the lung were examined. Rats were divided into three groups in Experiment 1. In the control group, a saline solution was administered and, in the FR group, 0.1 mg/kg per hour of FR167653 was administered, intravenously throughout the experiment, beginning 30 minutes before ischemia. In the non-ischemic group, samples were taken soon after thoracotomy. The rats were divided into control and FR groups in Experiment 2.


RESULTS
Experiment 1: One hour of ischemia induced almost no changes in the lung or serum cytokine levels. Meanwhile, FR167653 markedly attenuated the expression of phosphorylated p38 MAP kinase. Experiment 2: SaO(2) and PaO(2) were improved, serum cytokines were lower, and lung damage was less extensive in the FR group than in the control group.


CONCLUSIONS
FR167653 attenuates I/R injury of the lung and this attenuation is associated with suppression of p38 MAP kinase activation.
Kawashima
Y
Y
Second Department of Surgery, Gunma University School of Medicine, Maebashi, Japan. ykawashi@showa.gunma-u.ac.jp
Takeyoshi
I
I
Otani
Y
Y
Koibuchi
Y
Y
Yoshinari
D
D
Koyama
T
T
Kobayashi
M
M
Matsumoto
K
K
Morishita
Y
Y
D000818:Animals; D016207:Cytokines / Q000187:drug effects; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D007375:Interleukin-1 / Q000097:blood; D007511:Ischemia / Q000517:prevention & control*; D008168:Lung / Q000098:blood supply*; D008297:Male; D020928:Mitogen-Activated Protein Kinases / Q000032:analysis* / Q000037:antagonists & inhibitors*; D023421:Models, Animal; D011720:Pyrazoles / Q000494:pharmacology*; D011725:Pyridines / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D015427:Reperfusion Injury / Q000517:prevention & control*; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis / Q000187:drug effects; D048051:p38 Mitogen-Activated Protein Kinases
D016207:Cytokines; C104334:FR 167653; D007166:Immunosuppressive Agents; D007375:Interleukin-1; D011720:Pyrazoles; D011725:Pyridines; D014409:Tumor Necrosis Factor-alpha; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases