ALTERATIONS IN ELASTIN AND COLLAGEN RELATED TO THE MECHANISM OF PROGRESSIVE PULMONARY VENOUS OBSTRUCTION IN A PIGLET MODEL - A HEMODYNAMIC, ULTRASTRUCTURAL, AND BIOCHEMICAL-STUDY

We created an animal model to understand better the pathogenesis and underlying mechanism of progressive central pulmonary venous (PV) obstruction, a condition not amenable to current therapy. Twenty piglets underwent banding of their PVs, 18 had a sham operation, and 12 were nonoperated controls. After 1, 3, and 6 weeks hemodynamic data were obtained and correlated with ventricular weights, PV and pulmonary artery (PA) distensibilities (at 1 week), morphometric structural and ultrastructural analyses, and biochemical assessment of elastin determined gravimetrically (and by desmosine level at 1 week), collagen, and elastase activity. At 1 week, PV banding was associated with increased PV compliance (p < 0.05). At 3 weeks, an increased PA pressure (P(pa)) (p < 0.05) was observed, unaccompanied by a rise in PV pressure (P(cw)). In the PV, however, there was breakdown of the internal elastic lamina with apparent migration of smooth muscle muscle cells from media to subendothelium. At 6 weeks, a rise in P(cw) (p < 0.01), a further rise in P(pa) (p < 0.01), and right ventricular hypertrophy (p < 0.005) were observed. We also observed mild PV intimal thickening (p < 0.01), complete degradation of elastic laminae (p < 0.05), and an increase in collagen assessed morphometrically (p < 0.01). The banding procedure resulted in an overall increase in PV elastin synthesis and in the proportion of elastin determined gravimetrically (p < 0.05 for both) but not by desmosine level, suggesting the possibility of poor cross-linking of elastin, which migh account for the early incresead distensibility of the PV. However, our assay could not detect an increase in elastase activity associated with either the increased distensibility or the ultrastructural changes of elastin degradation. The increased P(pa) was not associated with significant PA biochemical or structural changes. We speculate that in response to distal venous obstruction, early remodeling of the PVs increases distensibility, protecting the lung from venous congestion and blunting a rise in P(cw). PA hypertension precedes the rise in P(cw), likely because of reflex vasoconstriciton. The subsequent modest rise in P(cw) is already associated with extensive fibrosis of the PV, suggesting a reason for unsuccessful current therapy and a need for consideration of earlier assessment and intervention.