The Antifibrotic Effects of Inhaled Treprostinil: An Emerging Option for ILD

Abstract

Interstitial lung diseases (ILD) encompasses a heterogeneous group of parenchymal lung diseases characterized by variable amounts of inflammation and fibrosis. The targeting of fibroblasts and myofibroblasts with antifibrotic treatments is a potential therapeutic target for these potentially fatal diseases. Treprostinil is unique among the prostacyclin mimetics in that it has distinct actions at additional prostaglandin receptors. Preclinical and clinical evidence suggests that treprostinil has antifibrotic effects through the activation of the prostaglandin E receptor 2 (EP₂), the prostaglandin D receptor 1 (DP₁), and peroxisome proliferator-activated receptors (PPAR). In vivo studies of EP₂ and the DP₁ have found that administration of treprostinil resulted in a reduction in cell proliferation, reduced collagen secretion and synthesis, and reduced lung inflammation and fibrosis. In vitro and in vivo studies of PPARβ and PPARγ demonstrated that treprostinil inhibited fibroblast proliferation in a dose-dependent manner. Clinical data from a post hoc analysis of the INCREASE trial found that inhaled treprostinil improved forced vital capacity in the overall population as well as in idiopathic interstitial pneumonia and idiopathic pulmonary fibrosis subgroups. These preclinical and clinical findings suggest a dual benefit of treprostinil through the amelioration of both lung fibrosis and pulmonary hypertension.

Keywords: Antifibrotic; Idiopathic pulmonary fibrosis; Interstitial lung diseases; Pulmonary fibrosis.

Fig. 1

Schematic depicting the impact of treprostinil on the relationship between vascular remodeling, cytokine overexpression, and the development of fibrosis within the lungs. Treprostinil binds and activates the EP2, IP, and DP1 receptors and activates the PPARβ receptors to produce antifibrotic effects. Activation of the EP2, IP, and DP1 receptors leads to vasodilation. Activation of EP2 additionally inhibits fibroblast to myofibroblast differentiation, suppresses fibroblast proliferation, and suppresses collagen overproduction. Activation of DP1 additionally reduces inflammatory cell recruitment and reduces extracellular matrix synthesis. Activation of the nuclear receptor PPARβ leads to suppressed fibroblast proliferation. Collectively, treprostinil activates EP2, IP, DP1, and PPARβ and causes vasodilation, reduced vascular remodeling, reduced fibroblast activity, proliferation and collagen deposition, and reduced inflammation, thereby promoting antifibrotic activity. Mechanistically, when IP, EP2, and DP1 are activated, G protein-coupled signaling triggers adenylyl cyclase and converts ATP to cAMP, which drives the activation of TGFβ1, PDGFββ, and PKA, leading to therapeutic effects. Treprostinil activation of PPARβ drives therapeutic effects via an anti-inflammatory pathway, leading to activation of retinoid X receptor, suppression of B cell lymphoma 6, and suppression of protein kinase C-α (not shown). IP prostacyclin receptor, EP2 prostaglandin E type 2 receptor, DP1 prostaglandin D type 1 receptor, PPARβ peroxisome proliferator-activated receptor β, ECM extracellular matrix, AC adenylyl cyclase, ATP adenosine triphosphate, cAMP cyclic adenosine monophosphate, TGFβ1 transforming growth factor β1, PDGFββ platelet-derived growth factor ββ, PKA protein kinase A