Administration of chronic intravenous platelet-activating factor induces pulmonary arterial atrophy and hypertension in rabbits

Abstract

Platelet-activating factor (PAF), a lipid mediator of inflammation, was given by continuous intravenous infusion to rabbits for 2, 4, and 8 weeks, and morphologic and hemodynamic findings were correlated. Pulmonary arterial pressure (PAP), cardiac output, and right atrial pressure were measured, and total pulmonary resistance was calculated. In cross-sections of intraparenchymal pulmonary arteries, internal elastic lamina circumference and intimal and medial areas were measured. The ratio of the weight of the right ventricle to the weight of the left ventricle plus septum, and alveolar/artery ratios were also obtained. In bronchoalveolar lavage fluid, total and differential cell counts were determined. After 2 weeks of PAF treatment, PAP rose by 4 mm Hg. The increase in PAP became significant by 4 weeks and remained so at 8 weeks of treatment. Total pulmonary resistance nearly doubled by 2 weeks and continued to be elevated throughout 8 weeks of PAF treatment. Cardiac output fell significantly to 0.26 liters/minute at 2 weeks of PAF treatment and remained low at 4 weeks. By 8 weeks of treatment, it normalized. The significant rise in total pulmonary resistance at 2 and 4 weeks correlated with the rise in PAP and the fall in cardiac output. The alveolar/artery ratio was increased at 2 weeks of treatment and progressively increased at 4 and 8 weeks, reaching statistical significance at 8 weeks. In intra-acinar arteries, after 2 weeks of treatment, there was a reduction in total cross-sectional area (within the external elastic lamina), medial area, and internal elastic lamina circumference measured by computerized image analysis of 5-microns thick Verhoeff Van Gieson-stained sections. Changes in total area, medial area, and internal elastic lamina circumference persisted after 4 and 8 weeks of treatment. In preacinar arteries, similar changes occurred that were significant only after 8 weeks of treatment. Other findings apparent at 2 weeks of treatment included right ventricular hypertrophy and a marked decline in the number of macrophages and lymphocytes recovered from bronchoalveolar lavage fluid. We conclude that chronic intravenous infusion of PAF in rabbits induces remodeling of pulmonary arteries, specifically reduction of the internal elastic lamina, with consequent narrowing of arterial lumens producing increased pulmonary vascular resistance and pulmonary hypertension. We attribute the increase in alveolar/artery without evident vessel obliteration, to a shortening of arterial length, which is of insufficient magnitude to overcome the effect of vessel narrowing on vascular resistance.