u-62840 and Idiopathic-Pulmonary-Fibrosis

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 (EP

Topics: Epoprostenol; Fibrosis; Humans; Hypertension, Pulmonary; Idiopathic Pulmonary Fibrosis

Idiopathic pulmonary fibrosis (IPF) greatly impacts quality of life and eventually leads to premature death from respiratory failure. Inhaled treprostinil was associated with improvements in forced vital capacity (FVC) and reduced exacerbations of underlying lung disease in post hoc analyses from a phase 3 study in patients with precapillary pulmonary hypertension due to interstitial lung disease. These results, combined with preclinical evidence of treprostinil's antifibrotic activity, support its investigation in the treatment of IPF.. The TETON programme consists of two replicate, 52-week, randomised, double-blind placebo-controlled, phase 3 studies, each enrolling 396 subjects (NCT04708782, NCT05255991). Eligible subjects must have a diagnosis of IPF confirmed by central imaging review, along with an FVC ≥45%. Stable background use of pirfenidone or nintedanib is allowed. The primary endpoint is change in absolute FVC at week 52. Secondary endpoints include time to clinical worsening (first event of death, respiratory hospitalisation or ≥10% decline in % predicted FVC), time to first acute exacerbation of IPF, overall survival, change in % predicted FVC and change in the King's Brief Interstitial Lung Disease Questionnaire at week 52. Safety parameters include adverse events, hospitalisations, oxygenation and laboratory parameters. Patients who complete week 52 will be eligible to enter an open-label extension study.. Studies will be conducted in accordance with the International Conference on Harmonisation Guideline for Good Clinical Practice, Declaration of Helsinki principles, and local regulatory, ethical and legal requirements. Results will be published in a peer-reviewed publication.

Topics: Double-Blind Method; Epoprostenol; Humans; Idiopathic Pulmonary Fibrosis; Quality of Life; Treatment Outcome

Idiopathic pulmonary fibrosis (IPF) presents as an incurable change in the lung tissue and mitochondrial dysfunction of unknown origin. Treprostinil, a prostacyclin analogue, has been suggested for IPF therapy. This study assessed the effect of treprostinil on the cAMP signalling and mitochondrial activity in healthy lung fibroblasts and fibroblast-like cells from IPF patients. Six control fibroblast strains and six fibroblast-like IPF cell strains were isolated and expanded from freshly resected lung tissue. The cells were grown to confluence before being treated with either transforming growth factor (TGF)-β1, treprostinil, their combination, or a vehicle for up to 2 days. Mitochondria-regulating proteins were analysed using Western blotting and immunofluorescence, and the mitochondria were analysed using cytochrome C, mitochondrial cytochrome C oxidase II (MTCO2), and MTCO4. The IPF cells showed an increased rate of damaged mitochondria, which were significantly reduced when the cells were treated with treprostinil over 24 h. In the control cells, treprostinil prevented TGF-β-induced mitochondrial damage. Treatment with treprostinil modified the expression of several mitochondria-regulating proteins. In both cell types, treprostinil upregulated the expression of PTEN, p21(Waf1/Cip1), beclin1, LC3 II, parkin, PINK1, MTCO2, and MTCO4. In contrast, treprostinil downregulated the phosphorylation of mTOR and the expression of p62, mitofusin1, and mtiofusin2 in IPF cells. This might explain the reduced mitochondrial damage observed in treprostinil-treated IPF cells and suggest an improvement in the mitochondrial function in IPF. In this study, treprostinil improved mitochondrial impairment in vitro, which might, in part, explain the beneficial clinical effects documented in patients.

Topics: Epoprostenol; Fibroblasts; Humans; Idiopathic Pulmonary Fibrosis; Lung; Transforming Growth Factor beta; Transforming Growth Factor beta1

Idiopathic pulmonary fibrosis (IPF) is a progressive terminal lung disease, and therapies aim to block fibrosis. Fibroblast proliferation is controlled by C/EBP-β, microRNA cluster 17-92 (miR17-92), and Erk1/2 mitogen-activated protein kinase. This study assessed the role of miR17-92 in IPF-fibroblast proliferation and its modification by treprostinil. Fibroblasts were isolated from eight IPF patients, five interstitial lung fibrosis patients, and seven control lungs. Fibroblasts were stimulated with TGF-β1 over 24 h. The miR17-92 expression was analyzed by RT-qPCR, and protein expression by Western blotting. TGF-β1 upregulated C/EBP-β in all fibroblasts, which was reduced by treprostinil in control-fibroblasts, but not in IPF-fibroblasts. Compared to controls, the guide strands miR-19a-3p, miR-19b-3p, miR-20a-5p, and miR-92a-3p, as well as the passenger strands miR-17-3p, miR-18-3p, miR-19a-1-5p, and miR-92a-5p were significantly increased in IPF-fibroblasts. In controls, TGF-β1 and treprostinil significantly reduced specific miR17-92 members. IPF-fibroblast proliferation was inhibited by treprostinil through increased expression of the Erk1/2 inhibitor DUSP1. These data suggest that proliferation control via miR17-92 and C/EBP-β is disrupted in IPF-fibroblasts. Therefore, the inhibition of early stages of signaling cascades or specific mitogen receptors might be less effective. However, the increased proliferation is sensitive to Erk1/2 inhibition by treprostinil-induced DUSP1.

Topics: Cell Proliferation; Cells, Cultured; Dual Specificity Phosphatase 1; Epoprostenol; Extracellular Signal-Regulated MAP Kinases; Female; Fibroblasts; Gene Expression Regulation; Humans; Idiopathic Pulmonary Fibrosis; Male; Middle Aged; Transforming Growth Factor beta1

Idiopathic pulmonary fibrosis (IPF) is characterized by peripheral lung fibrosis and increased interstitial extracellular matrix (ECM) deposition. In IPF, tumor growth factor (TGF)-β1 which is the major stimulus of ECM deposition, and platelet derived growth factor (PDGF)-BB is a potent stimulus of fibrosis. Thus, the effect of Treprostinil on TGF-ß1 and PDGF-induced fibroblast proliferation and ECM deposition was investigated. Human peripheral lung fibroblasts of seven IPF patients and five lung donors were stimulated by PDGF, or TGF-β1, or the combination. Cells were pre-incubated (30 min) with either Treprostinil, forskolin, di-deoxyadenosine (DDA), or vehicle. Treprostinil time dependently activated cAMP thereby preventing PDGF-BB induced proliferation and TGF-β1 secretion. Cell counts indicated proliferation; α-smooth muscle actin (α-SMA) indicted differentiation, and collagen type-1 or fibronectin deposition remodeling. Myo-fibroblast indicating α-SMA expression was significantly reduced and its formation was altered by Treprostinil. Collagen type-I and fibronectin deposition were also reduced by Treprostinil. The effect of Treprostinil on collagen type-I deposition was cAMP sensitive as it was counteracted by DDA, while the effect on fibronectin was not cAMP mediated. Treprostinil antagonized the pro-fibrotic effects of both PDGF-BB and TGF-β1 in primary human lung fibroblasts. The data presented propose a therapeutic relevant anti-fibrotic effect of Treprostinil in IPF.

Topics: Biomarkers; Cell Proliferation; Cells, Cultured; Cyclic AMP; Epoprostenol; Extracellular Matrix; Fibroblasts; Humans; Idiopathic Pulmonary Fibrosis; Transforming Growth Factor beta1

The available therapies and prognosis of idiopathic pulmonary fibrosis remain relatively poor, and concurrent pulmonary hypertension further increases the risk of death and complications after lung transplantation. Limited data exist for the treatment of pulmonary hypertension associated with idiopathic pulmonary fibrosis. We describe a case where intravenous treprostinil was used to bridge an elderly patient with idiopathic pulmonary fibrosis with severe pulmonary hypertension to successful single-lung transplantation.

Topics: Aged; Antihypertensive Agents; Epoprostenol; Female; Humans; Hypertension, Pulmonary; Idiopathic Pulmonary Fibrosis; Lung Transplantation; Piperazines; Purines; Sildenafil Citrate; Spirometry; Sulfones; Tomography, X-Ray Computed; Treatment Outcome; Vasodilator Agents