Emphysema due to cigarette smoking is characterized by a loss of alveolar structures. We hypothesize that the disappearance of alveoli involves apoptosis of septal endothelial cells and a decreased expression of lung vascular endothelial growth factor (VEGF) and its receptor 2 (VEGF R2). By terminal transferase dUTP nick end labeling (TUNEL) in combination with immunohistochemistry, we found that the number of TUNEL+ septal epithelial and endothelial cells/lung tissue nucleic acid (microg) was increased in the alveolar septa of emphysema lungs (14.2 +/- 2.0/microg, n = 6) when compared with normal lungs (6.8 +/- 1.3/microg, n = 7) (p < 0.01) and with primary pulmonary hypertensive lungs (2.3 +/- 0.8/microg, n = 5) (p < 0.001). The cell death events were not significantly different between healthy nonsmoker (7.4 +/- 1.9/microg) and smoker (5.7 +/- 0.7/microg) control subjects. The TUNEL results were confirmed by single-stranded DNA and active caspase-3 immunohistochemistry, and by DNA ligation assay. Emphysema lungs (n = 12) had increased levels of oligonucleosomal-length DNA fragmentation when compared with normal lungs (n = 11). VEGF, VEGF R2 protein, and mRNA expression were significantly reduced in emphysema. We propose that epithelial and endothelial alveolar septal death due to a decrease of endothelial cell maintenance factors may be part of the pathogenesis of emphysema.

Prostacyclin is a powerful vasodilator and inhibits platelet adhesion and cell growth. We hypothesized that a decrease in expression of the critical enzyme PGI2 synthase (PGI2-S) in the lung may represent an important manifestation of pulmonary endothelial dysfunction in severe pulmonary hypertension (PH). Immunohistochemistry and Western blot analysis were used to assess lung PGI2-S protein expression, and in situ hybridization was used to assess PGI2-S mRNA expression. In the normal pulmonary circulation (n = 7), PGI2-S was expressed in 48% of small, 67% of medium, and 76% of large pulmonary arteries as assessed by immunohistochemistry. PPH (n = 12), cirrhosis-associated (n = 4) and HIV-associated PH (n = 2) lungs exhibited a marked reduction in PGI2-S expression, involving all size ranges of pulmonary arteries. Vessels with concentric lesions showed complete lack of PGI2-S expression. Congenital heart (n = 4) and CREST (n = 2) cases exhibited a more variable immunohistological pattern of PGI2-S expression. These results were complemented by in situ hybridization and Western blots of representative lung samples. We conclude that the different sizes of the pulmonary arteries express PGI2-S differently and that the loss of expression of PGI2-S represents one of the phenotypic alterations present in the pulmonary endothelial cells in severe PH.

Background-The plexiform lesion is the hallmark of severe pulmonary arterial hypertension. However, its genesis and hemodynamic effects are largely unknown because of the limited availability of lung tissue samples from patients with pulmonary arterial hypertension and the lack of appropriate animal models. This study investigated whether rats with severe progressive pulmonary hypertension developed plexiform lesions. Methods and Results-After a single subcutaneous injection of the vascular endothelial growth factor receptor blocker Sugen 5416, rats were exposed to hypoxia for 3 weeks. They were then returned to normoxia for an additional 10 to 11 weeks. Hemodynamic and histological examinations were performed at 13 to 14 weeks after the Sugen 5416 injection. All rats developed pulmonary hypertension (right ventricular systolic pressure Ϸ100 mm Hg) and severe pulmonary arteriopathy, including concentric neointimal and complex plexiform-like lesions. There were 2 patterns of complex lesion formation: a lesion forming within the vessel lumen (stalk-like) and another that projected outside the vessel (aneurysm-like). Immunohistochemical analyses showed that these structures had cellular and molecular features closely resembling human plexiform lesions. Conclusions-Severe, sustained pulmonary hypertension in a very late stage of the Sugen 5416/hypoxia/normoxiaexposed rat is accompanied by the formation of lesions that are indistinguishable from the pulmonary arteriopathy of human pulmonary arterial hypertension. This unique model provides a new and rigorous approach for investigating the genesis, hemodynamic effects, and reversibility of plexiform and other occlusive lesions in pulmonary arterial hypertension. (Circulation. 2010;121:2747-2754.)

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