Lodoxamide Tromethamine Prevents Neutrophil Accumulation in Reexpansion Pulmonary Edema

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Abstract
Reexpansion pulmonary edema (RPE) is an acute, unilateral lung injury initiated by cytotoxic oxygen metabolites and temporally associated with an influx of polymorphonuclear neutrophils (PMNs); these toxic oxygen products appear to result from reoxygenation of chronically collapsed lung. Lodoxamide tromethamine (U-42585E) reduces infarct size after reperfusion of ischemic myocardium. The possible protective effects of lodoxamide in RPE were examined. Right lungs of rabbits were collapsed for 7 days by injection of air into the pleural space. Reexpansion was accomplished by chest tube with negative pressure in spontaneously ventilating rabbits. Twelve pairs of animals received either lodoxamide (20 mg/kg/h intravenously (i.v.) from 30 min before reexpansion until they were killed) or an equivalent volume of sterile saline. After 2 h, animals were killed by i.v. pentobarbital. Right and left lungs of six pairs of animals were lavaged with 25 ml saline each; the remaining six pairs of animals were studied by measurement of lung wet/dry weight ratio. Albumin concentrations in lavage fluid (BAL) of lodoxamide-treated animals were 243 ± 165 μg/ml in right lung and 29 ± 15 μg/ml in left lung (p < 0.03); albumin concentration in right lung BAL of untreated animals was 1,180 ± 319 μg/ml (p < 0.02 vs. lodoxamide-treated animals). PMN percentages in right BAL (3.8 ± 3.1) and left BAL (2.9 ± 2.2) did not differ in lodoxamide-treated animals (p > 0.65); PMN percentage in right BAL of untreated animals was 18.7 ± 2.9 (p < 0.001 vs. lodoxamide-treated animals). Incubation of PMNs with lodoxamide (1, 10, and 100 μg/ml) resulted in a dose-dependent decrease in directed migration (p < 0.005) but did not affect PMN adherence. Wet/dry weight ratio was not affected by lodoxamide administration. Thus, lodoxamide prevents PMN influx and decreases the alveolar-capillary protein leak in RPE, primarily by inhibiting PMN chemotaxis.