Prostacyclin Synthase Expression Is Decreased in Lungs from Patients with Severe Pulmonary Hypertension

TLDR

Prostacyclin is a potent vasodilator that also inhibits platelet adhesion and cell proliferation. The study tests whether reduced pulmonary prostacyclin synthase expression contributes to endothelial dysfunction in severe pulmonary hypertension. Lung tissue was examined by immunohistochemistry, Western blotting, and in situ hybridization to quantify PGI₂‑synthase protein and mRNA levels. PGI₂‑synthase expression was markedly reduced in all pulmonary artery sizes in severe PH, with complete loss in concentric lesions, whereas normal lungs showed size‑dependent expression, indicating a phenotypic endothelial alteration.

Abstract

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.