ANTIOXIDANTS ATTENUATE ENDOTOXIN-INDUCED MICROVASCULAR LEAKAGE OF MACROMOLECULES INVIVO

The purpose of this study was to examine whether antioxidants attenuate endotoxin-induced microvascular hyperpermeability for macromolecules in the hamster cheek pouch. Twenty-two adult male Syrian hamsters were anesthetized, and a removable plastic chamber was placed in the cheek pouch to observe and collect suffusate from the microvasculature. Fluorescent-labeled dextran (FITC-D; mol wt 150,000) was injected intravenously, and changes in the number of microvascular leaky sites and microvascular clearance of FITC-D were measured in five groups: saline control (group 1, n = 4), endotoxin (0.1 mg/ml) suffusion for 120 min (group 2, n = 6), endotoxin plus dimethyl sulfoxide (1.0 g/kg iv; group 3, n = 4), endotoxin plus allopurinol (30 mg/kg ip; group 4, n = 4), and endotoxin plus dimethyl sulfoxide and allopurinol (group 5, n = 4). The number of leaky sites and the FITC-D clearance were significantly higher in group 2 [45 +/- 18 (SD) sites/cm2 and 20 +/- 6 x 10-6 ml/min, respectively; P < 0.01] than in group 1 (7 +/- 6 sites/cm2 and 7 +/- 5 X 10(-6) ml/min), group 3 (9 +/- 5 sites/cm2 and 8 +/- 2 X 10(-6) ml/min), group 4 (11 +/- 7 sites/cm2 and 9 +/- 4 X 10(-6) ml/min), and group 5 (11 +/- 6 sites/cm2 and 7 +/- 1 X 10(-6) ml/min). The leaky sites appeared predominantly in postcapillary venules. There was a positive and significant correlation between the number of leaky sites and FITC-D clearance. We conclude that endotoxin-mediated microvascular injury in vivo is associated with an acute increase in the number of leaky sites and microvascular clearance of macromolecules from the systemic circulation and that antioxidants attenuate these effects. We suggest that oxygen free radicals have a major role in the pathogenesis of endotoxin-mediated microvascular injury in vivo.