TIME-DEPENDENT CARDIOVASCULAR AND INFLAMMATORY CHANGES IN ACUTE ENDOTOXEMIA

The pathophysiology of experimental acute endotoxemia is a complex pro cess involving both cardiovascular dysfunction and an inflammatory res ponse. We have examined the correlation in hemodynamic changes and the pulmonary inflammatory response after lipopolysaccharide (LPS) admini stration with respect to time. Importantly, we have measured the lung and plasma levels of nitric oxide (NO) over time, as well as rapid gen eration of lung superoxide after LPS administration. In anesthetized r ats given a bolus injection of LPS (10 mg/kg intravenously, from Salmo nella enteritidis), mean arterial blood pressure dropped by 63-70% wit hin 15 min, and cardiac output fell by 57-63% within 20 min compared w ith saline controls. Mean arterial blood pressure recovered slightly b ut was still 51, 30, and 25% less than that of saline controls 45, 105 , and 165 min after LPS administration, respectively. Cardiac output r emained depressed throughout the experimental period and was 35% lower than in saline controls 165 min after LPS treatment. There was a smal l increase in plasma nitrite/nitrate as an index of plasma NO producti on after 45 min and a 10-fold increase 165 min after LPS addition comp ared with controls, strongly suggesting that NO mediates the hypotensi on that occurs 165 min after LPS administration. Lung NO production in creased twofold 105 min after LPS administration and remained higher t han in saline controls. Histological sections showed that there was fl uid accumulation and alveolar collapse in the lung 45 min after LPS, w hereas after 165 min, there was extensive tissue damage and increased leukocyte accumulation compared with controls. These results suggest t hat there was no correlation between early (1 h) tissue damage and NO production. We found an increase in lung superoxide generation 15 min after injection of LPS that coincided with the alterations in cardiova scular function. These results suggest that early lung tissue damage a nd/or hemodynamic changes may be due to superoxide generation from the lung.