| Budget Amount *help |
¥3,300,000 (Direct Cost: ¥3,300,000)
Fiscal Year 2001: ¥1,800,000 (Direct Cost: ¥1,800,000)
Fiscal Year 2000: ¥1,500,000 (Direct Cost: ¥1,500,000)
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| Research Abstract |
Experiment 1
FR167653 is a potent suppressant of tumor necrosis factor (TNF)-α and interleukin-1 (IL-1) production, and attenuated ischemia and reperfusion (I/R) injury of organs in our previous experiment. Since p38 mitogen-activated protein (MAP) kinase has been reported to regulate the production of TNF-α and IL-1, we examined the effects of FR167653 on the rat lung I/R model by the expression and activation of p38 MAP kinase. Methods : Experiment (Exp.) 1 : After 1 hour of ischemia, p38 MAP kinase, phosphorylated p38 MAP kinase (active form), the histologic changes of the lung, and serial levels of TNF-α and IL-1β were examined. Exp. 2 : After 2 hours of reperfusion, the arterial oxygen content (PaO_2) and saturation (SaO_2), serial TNF-α and IL-1β levels, and histologic changes in the lung were examined. Rats were divided into three groups in Exp.1. In the control group, a saline solution was administered, and in the FR group, 0.1 mg/kg/hr of FR167653 was administered, intravenousl
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y 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 Exp. 2. Results : Exp. 1 : One hour of ischemia induced almost no changes in the lung or serial cytokine levels. Meanwhile, FR167653 markedly attenuated the expression of phosphorylated p38 MAP kinase. Exp. 2 : SaO_2 and PaO_2 were improved, serial cytokines were lower, and lung damage was smaller in the FR group than in the control group. Conclusion : FR167653 attenuates I/R injury of the lung by suppressing the activation of p38 MAP kinase.
Experiment 2
The activation of p38 mitogen-activated protein kinase (MAPK) plays an important role in the development of ischemia/reperfusion injury. FR167653 is a novel p38 MAPK inhibitor. This study evaluated the effects of p38 MAPK inhibition during cold ischemia on subsequent reperfusion injury using FR167653 as an additive to Euro-Collins solution in canine lung transplantation. Methods : Canine orthotopic left lung transplantation was performed after 12-hour cold storage using Euro-Collins solution with or without FR167653. Fifteen minutes after reperfusion, the right pulmonary artery and the right stem bronchus were ligated, and the animals were observed for 4 hours after reperfusion. Left pulmonary vascular resistance (L-PVR), cardiac output (CO), arterial oxygen pressure (PaO_2), and alveolar-arterial oxygen pressure difference (A-aDO_2) were measured. Lung specimens were harvested for wet-to-dry lung weight ratio (WDR) measurements, histopathological studies, and polymorphonuclear neutrophil (PMN) counts. The activities of p38 MAPK in lung grafts were evaluated. Results : The addition of FR167653 significantly (p<0.05) improved PaO_2, A-aDO_2, L-PVR, CO and WDR, and suppressed PMN infiltration after transplantation. FR167653 also ameliorated histological damage to the lung graft. During cold storage, p38 MAPK was not activated in the lung graft, whereas it was markedly activated 30 minutes after reperfusion. FR167653 significantly (p<0.05) inhibited p38 MAPK activation 30 minutes after reperfusion. Conclusions : The addition of FR167653 to Euro-Collins solution improved lung graft viability associated with the inhibition of p38 MAPK activation. These results suggest that inhibiting p38 MAPK activation may attenuate ischemia/reperfusion injury in lung transplantation. Less
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