The recent World Health Organization (WHO) classification designates PAH as Group I and includes idiopathic PAH (IPAH), formally known as primary pulmonary hypertension (PPH), familial PAH, and PAH associated with various systemic disorders such as collagen vascular diseases, congenital systemic-to-pulmonary shunts, portal hypertension, anorexigen use, and human immunodeficiency virus (HIV) infection.
Whether idiopathic or related to a systemic disorder, the histologic appearance of lung tissue in each of these conditions share common features which include intimal fibrosis, increased medial thickness, pulmonary arteriolar occlusion and formation of plexiform lesions. Left untreated, PAH is associated with poor outcome. Significant advances in understanding the molecular mechanisms in PAH have delivered insight into the key role played by endothelial dysfunction in initiating and propagating the pulmonary vascular remodeling process: specifically, impaired production of vasoactive mediators, such as prostacyclin and nitric oxide, along with chronic overproduction of vasoconstrictors such as endothelin-1 (ET-1).
The Biology of ET-1 and Endothelin Receptors i n PAH
Since its initial discovery by Yanagisawa and co-workers in 1988, ET-1 has been extensively studied and is recognized as a key mediator of pulmonary vascular biology and pathophysiology in PAH. It is a 21-amino peptide predominantly produced by endothelial cells. The effects of ET-1 include vasoconstriction, and it is recognized as the most potent vasoconstrictive agent discovered to date. It also acts as a strong mitogen by stimulating production of several growth factors, and it induces myocardial fibrosis and hypertrophy, as well as vascular fibrosis with extracellular matrix proliferation. Furthermore,ET-1 is also produced in leukocytes where it increases the production of cytokines in the inflammatory response. In PAH, not only is the plasma levels of ET-1 increased, its level is inversely proportional to the magnitude of the pulmonary blood flow and cardiac output, suggesting that these hemodyanmic changes are influenced directly by this vascular effector. ET-1 exerts its vascular effects through activation of the ETA and ETB receptors. ETA receptors are located on smooth muscle cells whereas ETB receptors are found predominantly on vascular endothelial cells and to a lesser extent on smooth muscle cells. Activation of the ETA and ETB receptors on smooth muscle cells induces vasocon-striction and cellular proliferation and hypertrophy. In contrast, stimulation of ETB receptors on endothelial cells results in production of vasodilators nitric oxide and prostacyclin. In addition, ETB receptors are involved in the clearance of ET-1 from the circulatory system, particulary in the lungs and kidneys. In non-diseased state, a regulated balance is maintained between the production and clearance of ET-1 to keep the circulating level low, a process which is mediated by ETB.