Idiopathic pulmonary fibrosis and pulmonary hypertension: Heracles meets the Hydra

Abstract

Idiopathic pulmonary fibrosis (IPF) is a fatal lung disease where the additional presence of pulmonary hypertension (PH) reduces survival. In particular, the presence of coexistent pulmonary vascular disease in patients with advanced lung parenchymal disease results in worse outcomes than either diagnosis alone. This is true with respect to the natural histories of these diseases, outcomes with medical therapies, and even outcomes following lung transplantation. Consequently, there is a striking need for improved treatments for PH in the setting of IPF. In this review, we summarize existing therapies from the perspective of molecular mechanisms underlying lung fibrosis and vasoconstriction/vascular remodelling and discuss potential future targets for pharmacotherapy. LINKED ARTICLES: This article is part of a themed issue on Risk factors, comorbidities, and comedications in cardioprotection. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v178.1/issuetoc.

FIGURE 1

Vascular remodelling and vasoconstriction in Group 3 pulmonary hypertension (PH). Vasoconstriction and vascular remodelling are hallmarks of Group 3 PH. At the level of the endothelial cell, increased endothelin-1 drives vasoconstriction and vascular remodelling through its effect on smooth muscle cells. Further, increased ACE levels lead to increased angiotensin levels that activate the angiotensin type 1 (AT₁) receptor, which is up-regulated in smooth muscle cells in Group 3 PH that promote vasoconstriction and vascular remodelling. Reduced natriuretic peptide levels in the circulation contribute further to vasoconstriction through reduced activation of the natriuretic peptide receptor A (NPRA) receptor. The hypoxic–adenosinergic response also plays a key role in vascular remodelling in Group 3 PH. Here, hypoxia-inducible factor-1α (HIF-1α) stabilization leads to increased extracellular adenosine levels and expression of the adenosine A_2B receptor (ADORA2B) promoting vascular remodelling

FIGURE 2

Inflammatory mechanisms contributing Group 3 pulmonary hypertension (PH). Myeloid-derived (left) and lymphoid-derived (right) mechanisms that modulate Group 3 PH. Mesenchymal stem cells can inhibit fibrosis and smooth muscle proliferation that attenuated PH. Further, mesenchymal stem cells also inhibit pro-remodelling macrophages with reduced cellular bone morphogenetic protein receptor 2 (BMPR2) levels resulting from IL-6 activation. These cells also release hyaluronan through activation of adenosine A_2B receptor (ADORA2B). Myeloid progenitor cells and myeloid-derived suppressor cells also contribute to PH by modulating angiogenesis, vascular remodelling, and vascular tone. Regulatory T cells and NKT cells negatively regulate PH by inhibiting fibrosis or reducing M2 macrophage expression. Conversely, effector T cells promote inflammation and contribute to the pathophysiology of PH

FIGURE 3

Extracellular matrix, oxidative stress, and metabolism in Group 3 pulmonary hypertension (PH). Increased deposition of the extracellular matrix component hyaluronan can be induced by activation of adenosine A_2B receptor (ADORA2B) by adenosine resulting in increased hyaluronan synthase (HAS) 2 and 3 isozymes in both macrophages and pulmonary artery smooth muscle cells (PASMCs). Deficits in SOD not only alter the metabolism of the cell but also result in greater oxidative stress and fragmentation of hyaluronan that can now activate pattern recognition receptors to promote PH. Altered succinate metabolism can also lead to increased stabilization of hypoxia-inducible factor-1α (HIF-1α) that can lead to increased ADORA2B expression and adenosine levels, maintaining a pro-remodelling cycle