Therapeutic targets in idiopathic pulmonary fibrosis

Kolb, Martin; Bonella, Francesco; Wollin, Lutz

doi:10.1016/j.rmed.2017.07.062

Cited by 104 publications

(81 citation statements)

References 71 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Alternatively, our findings in this study and in [18] provide rationale for the use of GPCR agonists of G αs -coupled receptors as treatments that actively trigger YAP/TAZ inactivation and thus will have an antifibrotic potential. This is supported by reports that activating IP receptor by selexipag, treprostinil and iloprost [18,[83][84][85][86][87][88][89], β2-adrenoreceptors by oladaterol [90], or melatonin receptors by melatonin [91] is antifibrotic in vitro and in animal fibrosis models, and at the same time inhibits YAP/TAZ [18,23,91].…”

Section: Discussionsupporting

confidence: 55%

GPCR-induced YAP activation sensitizes fibroblasts to profibrotic activity of TGFβ1

et al. 2020

View full text Add to dashboard Cite

Tissue fibrosis is a pathological condition characterized by uncontrolled fibroblast activation that ultimately leads to organ failure. The TGFβ1 pathway, one of the major players in establishment of the disease phenotype, is dependent on the transcriptional co-activators YAP/ TAZ. We were interested whether fibroblasts can be sensitized to TGFβ1 by activation of the GPCR/YAP/TAZ axis and whether this mechanism explains the profibrotic properties of diverse GPCR ligands. We found that LPA, S1P and thrombin cooperate in human dermal fibroblasts with TGFβ1 to induce extracellular matrix synthesis, myofibroblast marker expression and cytokine secretion. Whole genome expression profiling identified a YAP/ TAZ signature behind the synergistic profibrotic effects of LPA and TGFβ1. LPA, S1P and thrombin stimulation led to activation of the Rho-YAP axis, an increase of nuclear YAP-Smad2 complexes and enhanced expression of profibrotic YAP/Smad2-target genes. More generally, dermal, cardiac and lung fibroblast responses to TGFβ1 could be enhanced by increasing YAP nuclear levels (with GPCR ligands LPA, S1P, thrombin or Rho activator) and inhibited by decreasing nuclear YAP (with Rho inhibitor, forskolin, latrunculin B or 2deoxy-glucose). Thus, we present here a conceptually interesting finding that fibroblast responses to TGFβ1 can be predicted based on the nuclear levels of YAP and modulated by stimuli/treatments that change YAP nuclear levels. Our study contributes to better understanding of fibrosis as a complex interplay of signalling pathways and proposes YAP/TAZ as promising targets in the treatment of fibrosis.

show abstract

Section: Discussionsupporting

confidence: 55%

GPCR-induced YAP activation sensitizes fibroblasts to profibrotic activity of TGFβ1

et al. 2020

View full text Add to dashboard Cite

show abstract

“…Pirfenidone (5-methyl-1-phenyl-2-[1H]-pyridone), a bioavailable synthetic molecule, is the first drug to be approved for use on IPF patients. It is an anti-inflammatory and anti-fibrotic agent that down-regulates transforming growth factor beta (TGF-β) and tumor necrosis factor alpha (TNF-α), inhibits collagen synthesis and reduce fibroblast proliferation [7,8]. Two largest randomized clinical trials for pirfenidone on IPF patients, the CAPACITY and ASCEND trials, demonstrated a slower decline of the lung function and sufficient drug tolerability [9,10].…”

mentioning

confidence: 99%

Real-world experiences: Efficacy and tolerability of pirfenidone in clinical practice

et al. 2020

View full text Add to dashboard Cite

BackgroundThe safety of pirfenidone on pulmonary fibrosis patients with other kinds of interstitial lung diseases (ILDs) in addition to idiopathic pulmonary fibrosis (IPF) is unknown. Furthermore, its effectiveness-related factors on IPF patients are not quite explored. MethodsA retrospective study, on patients prescribed pirfenidone for pulmonary fibrosis, was conducted to assess effectiveness on IPF patients and tolerability of all patients with lung fibrosis. The effectiveness of pirfenidone was tested on 110 IPF subjects receiving treatment for �3 months by high-resolution computed tomography (HRCT). Response-linked factors and progression-free survival (PFS) were also analyzed. The data about safety outcomes and drug dose adjustments were collected from all included subjects. ResultsA total of 176 subjects were included: 117 were IPF, 19 connective tissue disease-associated interstitial lung disease (CTD-ILD), and 40 unclassifiable ILD. Out of the 110 IPF subjects, 89 subjects were assessed as stable and 21 as progressive, out of which 10 died of acute exacerbation and 11 progressed. The effectiveness was significantly related to their baseline body mass index (BMI). IPF subjects with BMI>25kg/m 2 or diffusion capacity of carbon monoxide (DLco)>30% had higher PFS rate. The most common adverse events were skin-related and gastrointestinal-related. Drug discontinuation owing to adverse events occurred similarly in these three groups.

show abstract

“…This contrasts with other conditions, notably idiopathic pulmonary fibrosis which have experienced a similar renaissance but where positive phase 3 trials have led to the licensing of new drugs and a positive impact on patients outcomes. 11 The repeated failure of trials in bronchiectasis to give positive outcomes necessitates a re-evaluation of our approach 10,[11][12][13][14][15] In this review, we outline novel approaches to the management of bronchiectasis in adults aiming to take us beyond antibiotics and beyond the recommended therapies in recent guidelines. 4 Furthermore, we propose that recent randomized trials have struggled to show clinical benefits because of the unresolved heterogeneity of bronchiectasis, and that a more logical, stratified approach to therapy will be required going forward.…”

Section: Introductionmentioning

confidence: 99%

Bronchiectasis: new therapies and new perspectives

Chalmers

Chotirmall

2018

The Lancet Respiratory Medicine

167

123

View full text Add to dashboard Cite

European Respiratory Society guidelines for the management of adult bronchiectasis highlight the paucity of treatment options available for patients with this disorder. No treatments have been licensed by regulatory agencies worldwide, and most therapies used in clinical practice are based on very little evidence. Development of new treatments is needed urgently. We did a systematic review of scientific literature and clinical trial registries to identify agents in early-to-late clinical development for bronchiectasis in adults. In this Review, we discuss the mechanisms and potential roles of emerging therapies, including drugs that target airway and systemic inflammation, mucociliary clearance, and epithelial dysfunction. To ensure these treatments achieve success in randomised clinical trials-and therefore reach patients-we propose a reassessment of the current approach to bronchiectasis. Although understanding of the pathophysiology of bronchiectasis is at an early stage, we argue that bronchiectasis is a heterogeneous disease with many different biological mechanisms that drive disease progression (endotypes), and therefore the so-called treatable traits approach used in asthma and chronic obstructive pulmonary disease could be applied to bronchiectasis, with future trials targeted at the specific disease subgroups most likely to benefit.

show abstract

Therapeutic targets in idiopathic pulmonary fibrosis

Cited by 104 publications

References 71 publications

GPCR-induced YAP activation sensitizes fibroblasts to profibrotic activity of TGFβ1

GPCR-induced YAP activation sensitizes fibroblasts to profibrotic activity of TGFβ1

Real-world experiences: Efficacy and tolerability of pirfenidone in clinical practice

Bronchiectasis: new therapies and new perspectives

Contact Info

Product

Resources

About