Beneficial effects of bile acid receptor agonists in pulmonary disease models

ABSTRACT

Introduction: Bile acids act as steroid hormones, controlling lipid, glucose and energy metabolism, as well as inflammation and fibrosis. Their actions are implemented through activation of nuclear (FXR, VDR, PXR) and membrane G protein-coupled (TGR5, S1PR2) receptors.

Areas covered: This review discusses the potential of FXR and TGR5 as therapeutic targets in the treatment of pulmonary disorders linked to metabolism and/or inflammation. Obeticholic acid (OCA) is the most clinically advanced bile acid-derived agonist for FXR-mediated anti-inflammatory and anti-fibrotic effects. It therefore represents an attractive pharmacological approach for the treatment of lung conditions characterized by vascular and endothelial dysfunctions.

Expert opinion: Inflammation, vascular remodeling and fibrotic processes characterize the progression of pulmonary arterial hypertension (PAH) and idiopathic pulmonary fibrosis (IPF). These processes are only partially targeted by the available therapeutic options and still represent a relevant medical need. The results hereby summarized demonstrate OCA efficacy in preventing experimental lung disorders, i.e. monocrotaline-induced PAH and bleomycin-induced fibrosis, by abating proinflammatory and vascular remodeling progression. TGR5 is also expressed in the lung, and targeting the TGR5 pathway, using the TGR5 agonist INT-777 or the dual FXR/TGR5 agonist INT-767, could also contribute to the treatment of pulmonary disorders mediated by inflammation and fibrosis.

KEYWORDS:

• Bile acids
• FXR
• TGR5
• obeticholic acid
• pulmonary arterial hypertension
• pulmonary fibrosis

Article highlights

• Pulmonary arterial hypertension (PAH) and idiopathic pulmonary fibrosis (IPF) are chronic progressive diseases, characterized by inflammation, vascular remodeling and fibrotic processes. These pathological mechanisms are only partially targeted by the available therapeutic options, and therefore the potential use of FXR (and possibly also TGR5) agonists in lung pathologies appears clinically relevant.

• Experimental studies with the FXR agonist OCA demonstrated its ability to target the shared pathogenic insults in the development of PAH and IPF. In preclinical models of both diseases, the efficacy of OCA was at least comparable to the FDA-approved treatments, i.e. tadalafil and pirfenidone.

• The efficacy of OCA in PAH and IPF models should be confirmed in preclinical studies assessing pharmacological treatment in established pulmonary inflammation- and fibrosis-mediated disorders, to clarify its therapeutic, rather than preventive role.

• The multiple beneficial effects of FXR agonists in models of lung disorders represent a sound basis for further preclinical and clinical research.

• Targeting the TGR5 pathway using the specific TGR5 agonist (INT-777) or the dual FXR/TGR5 agonist (INT-767) could also represent a potentially useful approach in lung disease.

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Declaration of interest

A. Luciano has served as a consultant for Intercept Phamaceuticals. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Additional information

Funding

This paper was not funded.