Cellular alterations of the distal bovine pulmonary arteries in hypoxia-induced pulmonary hypertension were studied. These lesions were related to pulmonary hemodynamic changes and contrasted to the cellular response observed in hyperkinetic pulmonary and systemic hypertension as well as other forms of vascular injury. Medial thickening and mild adventitial proliferation with an absence of intimal proliferative lesions related to a progressive increase in mean pulmonary arterial pressure and pulmonary vascular resistance were observed. Smooth muscle and endothelial cells exhibited distinct degenerative alterations in response to the maintained hypertensive state resulting from the lowered alveolar oxygen tension.
The expression of activin A, one of the transforming growth factor-beta supergene family, was studied in various pulmonary conditions associated with interstitial pulmonary fibrosis (3 cases with diffuse alveolar damage, 6 cases with idiopathic pulmonary fibrosis, and 1 case with pulmonary fibrosis associated with rheumatoid arthritis) using immunohistochemical techniques on paraffin-embedded sections. Controls consisted of 10 cases with normal pulmonary parenchyma, and 2 cases with primary pulmonary hypertension and 1 case with secondary pulmonary hypertension were also studied. The lung specimens from normal parenchyma weakly expressed immunoreactive activin A on the bronchiolar epithelium. In marked contrast, all of the specimens from cases with diffuse alveolar damage and interstitial pulmonary fibrosis demonstrated strong expression of activin A on metaplastic epithelium, hyperplastic smooth muscle cells, desquamated cells, and alveolar macrophages. Pulmonary arteries from patients with primary or secondary pulmonary hypertension showed abundant immunoreactive activin A on smooth muscle cells. These findings suggest a potential role for this growth factor, activin A, in the pathogenesis of pulmonary tissue remodeling associated with interstitial pulmonary fibrosis.
Immunohistochemistry was performed on lung tissue obtained from patients with severe unexplained pulmonary hypertension using an antibody to the amino-terminal end of the procollagen type I propeptide. This antibody identifies newly synthesized alpha I(I) procollagen before cleavage of the amino-terminal propeptide following secretion and, therefore, can identify sites of active collagen deposition. Procollagen was detected in the media, media and neointima, or neointima alone of a large number of small muscular arteries from hypertensive lungs. Normal adult lungs were negative. Neointimal cells in remodeled small muscular arteries stained positively for alpha-smooth muscle actin and desmin consistent with a smooth muscle lineage. These data suggest smooth muscle-like cells in small muscular arteries are actively synthesizing collagen in patients with severe unexplained pulmonary hypertension.
Chronic hypoxia causes more severe pulmonary hypertension in the Hilltop colony of Sprague-Dawley rats than in the Madison colony and also greater polycythemia and vasoconstriction. This study examines the structural features of the pulmonary artery bed, another contributing factor to hypoxic hypertension. After 14 days of hypobaric hypoxia, in Hilltop rats, more of the intraacinar arteries became muscular, and the medial thickness of intraacinar and preacinar arteries was greater. In Hilltop control rats, muscle was found in more intraacinar arteries, but, paradoxically, acute hypoxic vasoconstriction was less. Thus, while in chronic hypoxia increased muscle correlates with pulmonary hypertension, in control rats the reserve seems to be true. The increased muscle in control Hilltop rats could, however, predispose to the greater muscularization seen after chronic hypoxia.