Studies on the effects of pharmacological agents on endotoxin induced pulmonary injury

Yang, Li
Lum, Bert K B
Biomedical Sciences (Pharmacology)
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University of Hawaii at Manoa
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Acute respiratory distress syndrome (ARDS) is a severe form of acute lung injury, characterized by inflammation and increased capillary permeability, associated with a constellation of clinical, radiological and physiological abnormalities. The incidence of ARDS is uncertain but has been estimated to be as high as 75 cases per 100,000 hospitalized patients per year. The overall mortality of patients with ARDS remains at 40 to 60 percent. Many factors predispose to ARDS, with sepsis caused by gram negative bacteria being one of the most important. Experimentally, ARDS can be mimicked by the injection of bacterial endotoxin. Previous studies in our laboratory showed that pretreatment with pentoxifylline (a methylated xanthine), bepafant (a platelet activating factor antagonist) and nicardipine (a calcium channel blocker), 15 minutes before the administration of endotoxin, reduced the mortality and manifestations of disseminated intravascular coagulation caused by endotoxin in rats. The objective of the present study was to determine whether these drugs would also protect the rat lung against the deleterious effects of endotoxin. Anesthetized rats were given endotoxin (10 mg/kg) intravenously. One hour later, the lungs were removed and perfused with a buffered salt solution containing 4% Ficoll and aerated with air and 5% CO2 Pulmonary arterial pressure, capillary pressure, capillary permeability, and arterial and venous segmental resistances were significantly higher in lungs obtained from endotoxin-treated animals than in lungs from saline control rats. Endotoxin also caused an increase in lung weight, lung water content and the outflow of lung filtrate as compared to saline-treated controls. Pretreatment in vivo with nicardipine and bepafant, 15 minutes before the administration of endotoxin, significantly reduced the endotoxin-induced increases in capillary permeability and filtrate outflow but did not significantly affect the other parameters of measurement. Pretreatment with pentoxifylline differed from other two drugs in that the methylated xanthine significantly reduced the endotoxin-induced increases in all of the hemodynamic parameters as well as the increase in capillary permeability and filtrate outflow. Studies were also made on the effect of endotoxin on the pulmonary leukocyte count in rats. In these experiments, lungs were removed for histological examination one hour after the intravenous administration of endotoxin (10 mg/kg). Leukocyte numbers were significantly increased in the endotoxin group as compared to the saline group. Pretreatment with nicardipine and bepafant but not pentoxifylline significantly reduced the endotoxin-induced increase in pulmonary leukocyte count. The present results thus showed that the three drugs can protect against endotoxin-induced lung injury, in addition to preventing disseminated intravascular coagulation and death caused by the lipopolysaccharide. Pulmonary migration/sequestration of leucocytes and production/release of autacoids and cytokines from leucocytes are thought to play important roles in the lung injury caused by endotoxin. The results with nicardipine and bepafant suggest that these agents may act at least in part by inhibiting the pulmonary migration/sequestration of leucocytes.
xiii, 113 leaves
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Theses for the degree of Doctor of Philosophy (University of Hawaii at Manoa). Biomedical Sciences (Pharmacology); no. 4371
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