Prostacyclin analogs as the brakes for pulmonary artery smooth muscle cell proliferation: is it sufficient to treat severe pulmonary hypertension?

The report by Clapp and coworkers in the current issue of the American Journal of Respiratory Cell and Molecular Biology advances our understanding of the antiproliferative effect of prostacyclin analogs on cultured pulmonary artery smooth muscle cells (1). The authors compared the antiproliferative effects and correlated these effects with the elevation of intracellular of cAMP of several prostacyclin analogs, which included Iloprost, Beraprost, Cicaprost, and the novel analog UT-15. The relevance of these studies lays on the importance of prostacyclin as one of the few effective drugs to treat severe pulmonary hypertension (SPH); in particular, the idiopathic form also known as primary pulmonary hypertension (PPH). SPH is characterized by extreme increases of pulmonary artery pressures (usually at levels above 45 mm Hg mean pulmonary pressures), ultimately resulting in patient’s demise due to right heart failure. SPH can be sporadic, familial, or related to a variety of underlying conditions such as collagen vascular disease (the CREST variant of scleroderma or systemic lupus erythematosus), congenital heart malformations, HIV infection, cirrhosis, or anorectic drug use (2). SPH occurs infrequently as compared with pulmonary hypertension associated with chronic lung diseases such as chronic obstructive and interstitial pulmonary diseases. The morphologic alterations of the pulmonary arteries in SPH differ from those seen in lungs with mild pulmonary hypertension. In SPH, the vascular lumen is obliterated because of proliferation of endothelial cells forming plexiform or concentric lesions, myofibroblasts embedded in a mucopolysaccharide matrix, and media vascular thickening (Figure 1) (2). In contrast, in mild pulmonary hypertension, the pulmonary vascular media appears thickened whereas the intima presents with the characteristic monolayer lining of endothelial cells. Excessive vasoconstriction has been the prevailing hypothesis of the pathobiology of SPH. Accordingly, several studies investigated whether a deficiency of vasodilators such as prostacyclin was present in patients with PPH. Patients with SPH were reported to have decreased serum levels of the vasodilator prostacyclin, as assessed by urinary excretion of the 2,3-dinor-6-keto PGF 1 metabolite, whereas the vasoconstrictor thromboxane was increased (3). This report supported the therapeutic supplementation of prostacyclin, as it suggested that lung synthesis of prostacyclin was decreased in patients with SPH. The direct histologic documentation of decreased expression of the enzyme responsible for the production of prostacyclin (prostacyclin synthase) in lungs of patients with SPH was accomplished seven years later (4). Initially introduced as a bridge to transplant, prostacyclin has been shown to improve hemodynamics and exercise tolerance, and to prolong survival in severe PPH (5). Furthermore, prostacyclin has been demonstrated to induce long term reductions in the pulmonary vascular resistance that exceed those of immediate vasodilation (6). To better appreciate the overall impact of the study by Clapp and coworkers, we wish to bring into perspective the current knowledge of prostacyclin receptor signaling (in particular, the signaling in smooth muscle cells), the role of prostacyclin and prostacyclin receptor in experimental models of pulmonary hypertension, and the potential limitations of prostacyclin as an effective therapy for SPH in light of our recent understanding of the pathogenesis of SPH.