Effects of gabexate mesilate (FOY) on ischemia-reperfusion-induced acute lung injury in dogs

Background. To assess the effects of gabexate mesilate (FOY), a protease in hibitor, on a canine model of pulmonary ischemia-reperfusion injury. FOY ha s been applied clinically to treat acute pancreatitis and disseminated intr avascular coagulation (DIC) and has been found to suppress some leukocyte-m ediated tissue injuries in both in vitro and in vivo studies. Materials and methods. Design: Comparison of four experimental groups: grou p 1 (untreated control, n = 8), unilateral (left) pulmonary ischemia due to perfusion and ventilation obstruction followed by reperfusion, without rec eiving any specific treatment; group 2 (negative control, sham operation, n = 8), left pulmonary hilar dissection without ischemia; group 3 (FOY postt reatment, n = 8), FOY treatment during the reperfusion stage only; and grou p 4 (FOY pretreatment, n = 8), FOY treatment before ischemia and then conti nued during reperfusion. Setting: University animal laboratory. Subjects: H eart-worm-free mongrel dogs (12 to 15 kg body wt) were anesthetized with pe ntobarbital and mechanically ventilated. Investigations: Lung ischemia was made by snaring the left pulmonary artery and veins and clamping the bronch us with peribronchial tissue for 90 min followed by reperfusion for 18 h. A nimals of the two treatment groups received a 1 mg/kg bolus of FOY at the b eginning of reperfusion, with infusion of 2 mg/kg/h of FOY continuously sta rting 30 min before ischemia (group 4) or after reperfusion (group 3). Duri ng this study the following were measured: hemodynamics and aerodynamics, b lood gas, bronchoalveolar lavage (BAL) fluid neutrophil percentage and prot ein concentration, lung wet to dry weight ratio (W/D ratio), myeloperoxidas e (MPO) activity of the lung tissue, alveolar neutrophil infiltration, and degree of injury. Results, This model of lung ischemia-reperfusion induced significant pulmon ary hypertension, increased pulmonary vascular resistance, decreased pulmon ary dynamic compliance and arterial hypoxemia, increased BAL fluid total pr otein amount and neutrophil percentage, and increased alveolar neutrophil i nfiltration, histological injury score, and lung tissue MPO assay (group 1) . Animals of the sham operation (negative control, group 2) showed only min imal changes in the above parameters. Treatment with FOY significantly atte nuated the injury by decreasing the lung W/D ratio, alveolar neutrophil inf iltration, histological injury score, lung tissue MPO assay, BAL fluid neut rophil percentage, and protein amount. Pretreatment with FOY (group 4) atte nuated the injury to a significantly greater degree than it did when admini stered at the reperfusion stage only (group 3), which was reflected by the above-mentioned parameters, and as well significantly improved gas exchange function. FOY treatment was found to have Little effect in altering hemody namics and aerodynamics at most time points in this model of lung injury. Conclusions. FOY can attenuate the ischemia-reperfusion-induced acute lung injury in dogs by ameliorating the degree of alveolar membrane permeability change, neutrophil aggregation and activation. FOY treatment starting befo re ischemia attenuated this injury to a significantly higher degree than it s use after ischemia. However, the effect of FOY may be partial because it cannot alter the hemodynamics or aerodynamics as prominently as other param eters in this type of lung injury. Concomitant use of FOY with other agents will have additive or synergic effects in preventing lung ischemia-reperfu sion injury. (C) 1999 Academic Press