FR167653 attenuates ischemia and reperfusion injury of the rat lung with suppressing p38 mitogen-activated protein kinase.

Abstract

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.

CONCLUSION:

FR167653 attenuates I/R injury of the lung and this attenuation is associated with suppression of p38 MAP kinase activation.

• Authors: Y Kawashima, I Takeyoshi, Y Otani, Y Koibuchi, D Yoshinari, T Koyama, M Kobayashi, K Matsumoto, Y Morishita
• Journal: The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation (J Heart Lung Transplant) Vol. 20 Issue 5 Pg. 568-74 (May 2001) ISSN: 1053-2498 [Print] United States
• PMID: 11343984 (Publication Type: Journal Article)

Chemical References

• Cytokines
• FR 167653
• Immunosuppressive Agents
• Interleukin-1
• Pyrazoles
• Pyridines
• Tumor Necrosis Factor-alpha
• Mitogen-Activated Protein Kinases
• p38 Mitogen-Activated Protein Kinases

Topics

• Animals
• Cytokines (drug effects)
• Immunosuppressive Agents (pharmacology)
• Interleukin-1 (blood)
• Ischemia (prevention & control)
• Lung (blood supply)
• Male
• Mitogen-Activated Protein Kinases (analysis, antagonists & inhibitors)
• Models, Animal
• Pyrazoles (pharmacology)
• Pyridines (pharmacology)
• Rats
• Rats, Wistar
• Reperfusion Injury (prevention & control)
• Tumor Necrosis Factor-alpha (analysis, drug effects)
• p38 Mitogen-Activated Protein Kinases