Superoxide dismutase prevents the thrombin-induced increase in lung vascular permeability: role of superoxide in mediating the alterations in lung fluid balance.

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Abstract
We investigated the effects of superoxide dismutase (SOD) and SOD linked to Ficoll (mol. wt = 400,000) on the changes in pulmonary transvascular fluid and protein exchange following pulmonary microembolism induced with alpha-thrombin. Studies were made in chronically prepared unanesthetized sheep with lung lymph fistulas. Control thrombin challenged sheep (n = 5) were compared to animals infused with SOD (the SOD-thrombin group, n = 5) or animals infused with SOD linked to high molecular weight Ficoll (the Ficoll-SOD-thrombin group, n = 6). The Ficoll-SOD-thrombin animals were also compared to animals infused with Ficoll alone (the Ficoll-thrombin group, n = 4). In the control-thrombin group, thrombin induced sustained increases in the pulmonary transvascular protein clearance (pulmonary lymph flow X lymph/plasma protein concentration ratio) and pulmonary vascular resistance (PVR). In the SOD-thrombin group, thrombin initially increased both pulmonary transvascular protein clearance and PVR; however, the later increases in protein clearance and PVR were blunted. The pulmonary reflection coefficients for total protein (sigma), a measure of vascular permeability to protein, decreased from a value of 0.70 +/- 0.03 in normal sheep to 0.60 +/- 0.01 following thrombin challenge (p less than 0.05) indicating an increase in lung vascular permeability. The sigma value in the SOD-treated animals was 0.70 +/- 0.02, indicating a protective effect of SOD. The infusion of the Ficoll-SOD complex also attenuated the increases in pulmonary transvascular protein clearance and PVR after thrombin. However, the infusion of Ficoll alone induced a similar protection. The lymph from the SOD-thrombin and Ficoll-SOD-thrombin groups prevented the reduction of ferricytochrome C by xanthine/xanthine oxidase, whereas, the lymph from the Ficoll-thrombin animals did not have this effect, indicating SOD activity was present in the animals receiving the enzyme but not in the group infused with Ficoll alone. Differences in the degree of intravascular coagulation could not explain the response to Ficoll since the decreases in fibrinogen concentration following the thrombin were similar in all the groups. Since Ficoll and related dextrans may modify neutrophil function, in particular neutrophil adherence to the endothelium, we examined the effects of Ficoll on neutrophil adherence. The results indicated that when Ficoll was added to the endothelial medium Ficoll reduced the increase adherence of neutrophils to the endothelial cell monolayer. Therefore, Ficoll as a carrier for SOD may provide a direct protection in models of lung vascular injury that are dependent on neutrophils.(ABSTRACT TRUNCATED AT 400 WORDS)