Elsevier

Drug Discovery Today

Volume 19, Issue 8, August 2014, Pages 1251-1256
Drug Discovery Today

Review
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Inflammation in pulmonary hypertension: what we know and what we could logically and safely target first

https://doi.org/10.1016/j.drudis.2014.04.007Get rights and content

Inflammation is important for the initiation and the maintenance of vascular remodeling in most of the animal models of pulmonary arterial hypertension (PAH), and therapeutic targeting of inflammation in these models blocks PAH development. In humans, pulmonary vascular lesions of PAH are the source of cytokine and chemokine production, related to inflammatory cell recruitment and lymphoid neogenesis. Circulating autoantibodies to endothelial cells and to fibroblasts have been reported in 10–40% of patients with idiopathic PAH, suggesting a possible role for autoimmunity in the pathogenesis of pulmonary vascular lesions. Current specific PAH treatments have immunomodulatory properties, and some studies have demonstrated a correlation between levels of circulating inflammatory mediators and patient survival. New immunopathological approaches to PAH should enable the development of innovative treatments for this severe condition.

Introduction

Pulmonary arterial hypertension (PAH) is a devastating disease in which pulmonary vascular remodeling leads to an increased pulmonary vascular resistance resulting in right-heart failure and early death (Fig. 1). It is understood that inflammation and autoimmunity can contribute to PAH pathobiology (Fig, 1, Box 1). The main expected action of current PAH therapeutics is the decrease in pulmonary vascular resistance through the induction of pulmonary artery vasodilatation (prostacyclin analogs, endothelin receptor antagonists, phosphodiesterase type 5 inhibitors and soluble guanylate cyclase stimulators) 1, 2. These treatments do not however afford a cure, and mainly only relieve symptoms and improve health-related quality of life in PAH patients. Thus, new treatments interfering with different mechanisms of PAH pathobiology are required to block disease progression. The presence of pulmonary vascular inflammation and, more specifically, of an adaptive immune response characterized by pulmonary lymphoid neogenesis in PAH patients [3] indicates that new drugs targeting the immunological component of the disease could be considered. As a proof of concept there is evidence that the current PAH therapeutics could have immunomodulatory properties and case reports have suggested that immunosuppressive agents and several targeted immunotherapeutic approaches could improve PAH. Here, we review and evaluate these three aspects of immunomodulatory approaches in PAH.

Section snippets

Anti-inflammatory therapies in autoimmune-disease-associated PAH

Recent reviews have focused on evidence of inflammation in PAH and highlighted the role of inflammation and autoimmunity into disease pathophysiology 4, 5, 6, 7. These highlight the potential of immunotherapy to control disease outcome, and even the treatment of at-risk patients such as those with connective tissue disease or infectious diseases. Immunosuppressive drugs have been widely tested in experimental models of PAH. Not surprisingly, immunosuppressive agents such as dexamethasone,

Immunomodulatory properties of current specific PAH therapeutics

Currently, three pathological pathways are targeted (the endothelin, nitric oxide and prostacyclin pathways) and four classes of therapeutic drugs specific to PAH are available: prostacyclin (epoprostenol) and its analogs (treprostinil, iloprost, beraprost); endothelin receptor antagonists (bosentan, ambrisentan, macitentan); phosphodiesterase type 5 inhibitors (PDE5i) (sildenafil, tadalafil); and soluble guanylate cyclase stimulators (riociguat). All these treatments act on endothelial

Targeted immunotherapy in idiopathic PAH

Although current PAH treatments possess immunomodulatory properties [6], there is no approved therapeutic specifically targeting the inflammatory processes. However, some case studies demonstrated beneficial effects of such strategies.

Concluding remarks

Considerable progress has been made in demonstrating inflammatory and autoimmune mechanisms in PAH. However, no major autoantigen involved in disease pathogenesis has been clearly defined and the precise mechanisms by which inflammation triggers and sustains vascular remodeling and, as a consequence, heart failure remain to be clarified. Although in the monocrotaline-induced PH rat model kinetics studies have clearly shown that inflammation precedes vascular remodeling [58], there is no chronic

Conflicts of interest

Professor Humbert has served as an advisory board member for Actelion, Aires, Bayer, Novartis and Pfizer, and received consultancy and lecture fees from Actelion, Aires, Bayer, GlaxoSmithKline, Novartis and Pfizer. Dr Perros has a relationship with Bayer. He received an Investigator Sponsored Study (ISS) grant.

Acknowledgments

Sylvia Cohen-Kaminisky received funding from the Fondation pour la Recherche Médicale (FRM) (grant number: DEQ20100318257). Aurélie Hautefort is supported by a PhD grant from Région Ile de France (CORDDIM). Frédéric Perros receives funding from National Funding Agency for Research (ANR) (Grant: ANR-13-JSV1-001).

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