Sections of lung tissue samples from patients with severe PH demonstrated co-expression of caveolin 1 and HO-1; lesions that lacked caveolin 1 expression also lacked HO-1 expression (Fig 7). In the rat model of severe PH, which is based on the single subcutaneous injection of the VEGF receptor antagonist SU 5416 and subsequent exposure of the animals to 3 weeks of chronic hypoxia, a striking proliferative pulmonary vasculopathy develops. Staining of lung tissue sections obtained from five animals treated with SU 5416 and exposed to 3 weeks of hypoxia showed many complex cellular arterial lesions demonstrating striking reduction or absence of caveolin 1 and 2 staining (Fig 8). Some of the lesions demonstrate a rim of caveolin-positive cells lining the residual lumen, similar to the immu-nohistochemical appearance of the human plexiform lesions. Exuberant endothelial cell growth has been described in the lungs from patients with severe PH.
The elucidation of the mechanisms involved in the control of endothelial cell proliferation is fundamentally important in the pathogenesis of severe PH and has recently received increased attention.- Endothelial cells are a major cell type in the lung tissue and normally express high levels of caveolin 1. Caveolin 1 and 2 null animal lungs are markedly abnormal with thickened alveolar walls and hyper-cellularity due primarily to endothelial cells. We previously demonstrated reduced caveolin-1 gene expression in the lungs from patients with PPH. In the present study, we examine caveolin expression in the lung tissue obtained from patients with severe PH and show that there is a strong caveolin 1 and 2 expression in normal endothelial, smooth muscle, and alveolar septal cells, but markedly decreased expression of caveolin 1 and 2 in the plexiform lesions. canadian family pharmacy
A majority of the cells comprising the plexiform lesions show greatly reduced expression of the caveolins. However, protein expression for caveolin 1 is not clearly diminished in Western blots of whole lung tissue extracts from patients with plexiform arteriopathy, indicating the importance of immuno-localization of proteins in lung tissue. In this study, we also show that a rat model of severe PH, which is characterized by endothelial cell growth and partial lumen obliteration, demonstrates diminished expression of both caveolin 1 and 2 in the vascular lesions.
Figure 7. Top left, A: Normal lung demonstrating expression of HO-1 in endothelial cells of pulmonary arteries (arrow) [original X 400]. Top right, B: Normal lung demonstrating HO-1 expression in the vessel endothelium as well as the lung parenchyma (original X 400). Bottom left, C and bottom right, D: Plexiform lesions from patients with severe PH. Bottom left, C: Absent HO-1 expression in all of the cells of plexiform lesion; bottom right, D: Continued presence of HO-1 in the alveolar septae surrounding the lesion (original X 400). See Figure 4 legend for expansion of abbreviation.
Figure 8. Top, A: Rat model of severe PH showing decreased expression of caveolin 1 (arrows) in the vascular lesions. Many of the cells that comprise these proliferative lesions lack caveolin 1 staining, while residual luminal endothelial cell staining remains (original X 100). Bottom, B: Caveolin 2 immunostaining from the rat model of severe PH. There is a parallel lack of caveolin 2 expression in the lesions (arrow) [original X 200].