We have proposed that the endothelial cells present in the plexiform lesions of lungs from patients with severe pulmonary hypertension (PH) to some degree resemble a malignant cell phenotype. Because caveolin may function as a tumor suppressor protein, and because plexiform lesion endothelial cells grow abnormally, we hypothesized that plexiform lesions and remodeled small arteries in severe PH may demonstrate a loss of caveolin expression. This hypothesis is based in part on results of gene expression profiling in randomly sampled lung tissue from patients with severe PH vs that of normal lung tissue. In that study, we found a decreased expression of caveolin 1 messenger RNA in lung tissues from patients with severe PH. In the present study, we demonstrate by immunohisto-chemistry that caveolin 1 and 2 are decreased in the plexiform lesions of patients with severe PH, while the endothelial and smooth-muscle cells of patent, normal-appearing vessels retain their caveolin expression. The caveolins are also decreased in some of the muscularized precapillary arterioles. A decrease in caveolin 1 and 2 expression by immunohistochemistry was also found in two rat models of severe PH.
Jung et al demonstrated the association of caveolin 1 and 2 with heme oxygenase-1 (HO-1) in mouse mesangial cells. More recently, Kim et al report the localization of HO-1 to caveolae in rat pulmonary artery endothelial cells as well as providing evidence that caveolin-1 interacts with and modulates heme oxygenase activity. Because of the growing evidence for an association of HO-1 with caveolin and the fact that enhancement of endogenous HO-1 has been shown to prevent hypoxia-induced PH, we also hypothesized that HO-1 expression would be absent or decreased in plexiform lesions, in parallel to the caveolin 1 and 2 expression pattern.
Lung tissue was obtained from 14 patients with plexiform pulmonary arteriopathy (clinical diagnosis of severe PH [Table 1]). Ten of the lung specimens were obtained at autopsy, 3 at lung transplant, and 1 at open-lung biopsy. One of the specimens was obtained from lung tissue from a patient with severe PH associated with the use of an anorexigen (dexfenfluramine) and one from a patient with AIDS. “Normal” tissue from four patients with no history of PH was used as a control. Lobectomy was the tissue source for these four patients, each with a diagnosis of carcinoma preoperatively. Lung tissue from a rat model of severe PH and liver tissue from a patient with a liver hemangioma (positive control for neoangiogenesis) were also examined.
Table 1—Clinical Data
|Patient No.||Diagnosis||Gender/Age, yr||Systolic/Mean/Diastolic Pulmonary Artery Pressure, mm Hg||Tissue Source|
|1||Primary PH||Male/51||106/38/62||Lung transplant|
|5||Primary PH||Male/69||Not available||Autopsy|
|6||Primary PH||Female/69||Not available||Autopsy|
|8||Primary PH||Male/25||87/57/73||Lung transplant|
|9||Primary PH||Female/49||92/27/53||Lung transplant|
|12||Primary PH||Male/38||59||Open-lung biopsy|