Treating pulmonary arterial hypertension: current treatments and future prospects

Abstract

Pulmonary arterial hypertension (PAH) consists of a group of heterogeneous but distinct disorders characterized by complex proliferation of the pulmonary vascular endothelium and progressive pulmonary vascular remodeling that leads to right ventricular failure and death. Over the past two decades, significant advances in our understanding of the pathobiology of PAH have led to the development of several therapeutic targets in this disease. Besides conservative therapeutic strategies such as anticoagulation and diuretics, the current treatment paradigm for PAH targets the mediators of the three main biologic pathways that are critical for its pathogenesis and progression: endothelin receptor antagonists inhibit the upregulated endothelin pathway by blocking the biologic activity of endothelin-1; phosphodiesterase-5 inhibitors prevent breakdown and increase the endogenous availability of cyclic guanosine monophosphate, which signals the vasorelaxing effects of the downregulated mediator nitric oxide; and prostacyclin derivatives provide an exogenous supply of the deficient mediator prostacyclin. In addition to these established current therapeutic options, a large number of potential therapeutic targets are being investigated. These novel therapeutic targets include soluble guanylyl cyclase, phosphodiesterases, tetrahydrobiopterin, 5-hydroxytryptamine (serotonin) receptor 2B, vasoactive intestinal peptide, receptor tyrosine kinases, adrenomedullin, rho kinase, elastases, endogenous steroids, endothelial progenitor cells, immune cells, bone morphogenetic protein and its receptors, potassium channels, metabolic pathways, and nuclear factor of activated T cells. This review provides an overview of the current therapeutic options and potential therapeutic targets for PAH.

A New Approach for the Study of Lung Smooth Muscle Phenotypes and Its Application in a Murine Model of Allergic Airway Inflammation

“…This is particularly relevant since alterations in smooth muscle phenotype are a prominent and defining feature in diseases of the airway and pulmonary vasculature. In addition, our studies of BSMCs from an asthma model provide proof-of-principle evidence that this methodology, coupled with disease models, provides an invaluable and versatile tool for characterization of the signals and pathways involved in the initiation and maintenance of abnormal smooth muscle phenotypes [5], [8].…”

“…As a consequence, the development of meaningful approaches for isolation and comprehensive analysis of human lung smooth muscle cells has stagnated. From a clinical standpoint, this state-of-affairs is one of the key factors that underlie the lack of treatments aimed at reversing the pathological smooth muscle phenotypes characteristic of diseases such as asthma and pulmonary hypertension [6]–[8].…”

Baicalin attenuates transforming growth factor-β1-induced human pulmonary artery smooth muscle cell proliferation and phenotypic switch by inhibiting hypoxia inducible factor-1α and aryl hydrocarbon receptor expression

“…Current PAH therapeutic measures only enhance pulmonary artery systolic pressures rather than improving vascular remodelling, with minor curative effects and at high cost [24]. Moreover, following diagnosis, affected patients have a mean survival time of just 2.5 years.…”

Inhibition of ENaC by Endothelin-1

“…Sitaxsentan, the most selective ETRA antagonist clinically available, has been approved for use in Europe, Canada, and Australia but not in the USA. It was however recently voluntarily withdrawn by Pfizer driven by a review of evolving safety information from clinical trials regarding concerns about idiosyncratic, fatal hepatic failure (Raja & Raja, 2011). Nevertheless, experimental data and recent clinical studies suggest that, despite limitations connected with side effects and relatively poor antagonist selectivity, the antagonists of ETRA, hold promise in the treatment of hypertension and diabetic nephropathy (Meyers & Sethna, 2013).…”