Repeated Escherichia coli endotoxin-induced pulmonary inflammation causes chronic pulmonary hypertension in sheep....

Chronic pulmonary hypertension occurs in several human diseases in which there is evidence of chronic or repeated bouts of pulmonary inflammation. To determine whether prolonged lung inflammation causes persistent pulmonary hypertension Escherichia coli endotoxin was given to seven chronically instrumented awake sheep three times a week for 10 to 14 weeks. Pulmonary artery, left atrial and systemic arterial pressures, cardiac output, arterial blood gases and pH were monitored before starting endotoxin treatment and twice weekly, immediately before endotoxin infusion. Three sheep receiving saline over a similar time period served as controls. Pulmonary vasoreactivity to breathing 12% oxygen and a bolus infusion of an analog of prostaglandin H2 was also assessed. Peripheral lung biopsy tissue was taken at baseline and at periods throughout the experiment to assess pulmonary inflammation. Repeated endotoxin infusions resulted in a significant increase in mean pulmonary artery pressure from the 8th week of treatment and more than a 50% increase from week 10 (baseline = 18.4 cm H2O +/- 1.0 (mean +/- SE); 10 weeks endotoxin = 27.8 +/- 4.3; p less than 0.05). Pulmonary vasoreactivity to both an analog of prostaglandin H2 and 12% oxygen decreased in the period from 4 to 8 weeks of endotoxin treatment. Light microscopic assessment of lung biopsy tissue showed a persistent four-fold increase above baseline in number of peripheral lung granulocytes. Electron microscopy revealed that granulocytes, lymphocytes, and monocytes sequestered in the lungs of these animals, and that structural damage to the endothelium was minimal. Morphometry of lungs obtained at autopsy in which the pulmonary arteries had been distended with barium-gelatin showed extension of muscle into the walls of smaller intra-acinar arteries (than normal) and a reduction in number of filled peripheral arteries. We conclude that repeated infusions of endotoxin into sheep cause persistent lung inflammation, altered pulmonary vasoreactivity, sustained pulmonary hypertension, and some of the structural changes characteristic of this disease. Chronic inflammation may play a role in the pathogenesis of chronic pulmonary hypertension.