Effects of a p38 mitogen-activated protein kinase inhibitor as an additive to Euro-Collins solution on reperfusion injury in canine lung transplantation1.
BACKGROUND
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-hr 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 hr after reperfusion. Left pulmonary vascular resistance (L-PVR), cardiac output (CO), arterial oxygen pressure (Pao2), and alveolar-arterial oxygen pressure difference (A-aDo2) were measured. Lung specimens were harvested for wet-to-dry lung weight ratio (WDR) measurements, histopathologic 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 Pao2, A-aDo2, L-PVR, CO, and WDR and suppressed PMN infiltration after transplantation. FR167653 also ameliorated histologic damage to the lung graft. During cold storage, p38 MAPK was not activated in the lung graft, whereas it was markedly activated 30 min after reperfusion. FR167653 significantly (P<0.05) inhibited p38 MAPK activation 30 min 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.
2Second Department of Surgery, Gunma University School of Medicine, Maebashi, Japan.
Naoki
N
Hashimoto
Izumi
I
Takeyoshi
Daisuke
D
Yoshinari
Hirofumi
H
Tsutsumi
Masahiko
M
Tokumine
Osamu
O
Totsuka
Yutaka
Y
Sunose
Susumu
S
Ohwada
Koshi
K
Matsumoto
Yasuo
Y
Morishita
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D001794:Blood Pressure / Q000187:drug effects / Q000502:physiology; D004285:Dogs; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006982:Hypertonic Solutions / Q000494:pharmacology*; D007958:Leukocyte Count; D008168:Lung / Q000098:blood supply; D016040:Lung Transplantation / Q000502:physiology*; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors*; D009504:Neutrophils / Q000502:physiology*; D009926:Organ Preservation / Q000379:methods; D019188:Organ Preservation Solutions / Q000494:pharmacology*; D010100:Oxygen / Q000097:blood; D010313:Partial Pressure; D010766:Phosphorylation; D011652:Pulmonary Circulation / Q000187:drug effects; D011720:Pyrazoles / Q000494:pharmacology*; D011725:Pyridines / Q000494:pharmacology*; D015427:Reperfusion Injury / Q000517:prevention & control*; D013997:Time Factors; D014184:Transplantation, Homologous / Q000502:physiology*; D014655:Vascular Resistance / Q000187:drug effects; D048051:p38 Mitogen-Activated Protein Kinases
D000894:Anti-Inflammatory Agents, Non-Steroidal; D004791:Enzyme Inhibitors; C037096:Euro-Collins' solution; C104334:FR 167653; D006982:Hypertonic Solutions; D019188:Organ Preservation Solutions; D011720:Pyrazoles; D011725:Pyridines; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D010100:Oxygen