Effects of ONO-5046, a specific neutrophil elastase inhibitor, on cardiopulmonary bypass-induced lung injury in dog

ONO-5046 is a specific inhibitor of neutrophil elastase (PMN-E). The purpose of this study is to evaluate the protective effect of ONO-5046 to lung injury that has resulted from cardiopulmonary bypass (CPB). Without thoracotomy, partial CPB (mean flow; 800 ml/min) was performed for 1 hour in 12 mongrel dogs. After weaned from CPB, dogs were regulated to maintain hemodynamics and were made observation for five hours. Dogs were divided into two groups: group ONO (n = 6): ONO-5046 was administered continuously (15 mg/kg/h) during study; group CONTROL (n = 6): no drugs were used. Using respiratory index, Aa · DO2, pulmonary wet gain and microscopical findings of lung, post-CPB pulmonary function were assessed. And plasma level of PMN- E and IL-6 were measured before, during, and after CPB respectively. Respiratory index, Aa · DO2, pulmonary wet gain of group CONTROL were higher than those of group ONO. Histologic examination revealed interstitial and intraalveolar edema in group CONTROL, but virtually normal lung architecture in group ONO. However here were no significant differences in neutrophil accumulation on lung between both groups. ONO-5046 inhibited not only PMN-E but also IL-6 activity. These results suggested that ONO-5046 has influence on network of inflammation and has protective effect to CPB-associated pulmonary damage.