[Specific inhibition of thrombin activity during cardiopulmonary bypass reduces ischemia-reperfusion injury of the lung].
The pathophysiologic role of thrombin in the development of lung injury after the normothermic cardiopulumonary bypass (CPB) was studied in the rabbit model. A control group (group D) was subjected to the pericardiotomy without institution of CPB. Group A rabbits (n = 6) underwent left heart bypass (80 ml/kg/min) for 60 minutes without occlusion of the systemic or pulmonary artery and a succeeding reduced flow (20-30 ml/kg/min) for another 30 minutes, group B rabbits (n = 6) underwent complete CPB (80 ml/kg/min) for 60 minutes in the working mode with occlusion of the pulmonary arterial trunk and a succeeding reduced flow without occlusion of the pulmonary artery for another 30 minutes, group C rabbits (n = 6) underwent the same CPB technique as group B in conjunction with continuous intravenous infusion of argatroban (60 micrograms/kg/min), the specific thrombin inhibitor. In this group, infusion of argatroban was initiated 60 minutes prior to institution of CPB and terminated at the end of the experiment. We sacrificed rabbits four hours after the experiment began, and assessed not only morphometrically thrombus formation, leukocytic infiltration and luminal narrowing of small-sized pulmonary arteries but also immunohistochemically the expression of tissue factor (TF) and IL-1 beta, and physico-functionally respiratory index (RI) and pulmonary vascular resistance (PVR). Rabbits in group A showed multiple occurrence of lung thrombi, luminal narrowing of small arteries, and mild infiltration of macrophages and neutrophils positive for TF, and, in addition, their RI and PVR became mildly worse. In group B, all these morphological and physico-functional parameters became much worse than those observed in group A rabbits (p < .01). In contrast, argatroban treatment could significantly improve these parameters (p < .01). The expression of TF and IL-1 beta, however, was not significantly different in group A, B and C. These findings indicate that thrombin function intimately participates in the development of pulmonary ischemia-reperfusion injury during CPB. In addition, the anti-thrombin treatment would be an effective therapeutical tool for the prevention of not only activation of extrinsic coagulation pathway but also its sequential inflammatory and circulatory disturbance in ischemia-reperfusion injury of lung during CPB.
Division of Cardiovascular Surgery, Research Institute of Angiocardiology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
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Tanaka
D000818:Animals; D000991:Antithrombins / Q000627:therapeutic use*; D001120:Arginine / Q000031:analogs & derivatives; D002315:Cardiopulmonary Bypass; D008171:Lung Diseases / Q000517:prevention & control*; D008297:Male; D010875:Pipecolic Acids / Q000627:therapeutic use*; D011817:Rabbits; D015427:Reperfusion Injury / Q000517:prevention & control*; D013449:Sulfonamides; D013917:Thrombin / Q000502:physiology
D000991:Antithrombins; D010875:Pipecolic Acids; D013449:Sulfonamides; D001120:Arginine; D013917:Thrombin; C031942:argatroban