Targeted Therapy for Idiopathic Pulmonary Fibrosis: Where To Now?

Rangarajan, Sunad; Locy, Morgan L.; Luckhardt, Tracy; Thannickal, Victor J.

doi:10.1007/s40265-015-0523-6

Cited by 47 publications

(39 citation statements)

References 122 publications

(110 reference statements)

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“…It is also possible that metformin exerts antifibrotic properties by ameliorating impaired autophagy (by activating AMPK, which in turn leads to enhanced autophagy and metabolic reprogramming, both of which have potential benefit in the context of aging-associated fibrosis) [27,36,37], and as some studies have linked IPF with impaired autophagic processes [38,39], we might expect metformin to have an effect on IPF outcomes. However, further research is needed to determine the link between autophagy and the molecular mechanisms of fibrogenesis in IPF.…”

Section: Discussionmentioning

confidence: 99%

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Metformin Does Not Affect Clinically Relevant Outcomes in Patients with Idiopathic Pulmonary Fibrosis

et al. 2018

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Background: Diabetes mellitus is a possible risk factor for the development of idiopathic pulmonary fibrosis (IPF), yet the effect of antidiabetic therapy on the course of IPF is unknown. Objectives: This post hoc analysis assessed the effect of metformin on clinically relevant outcomes in patients with IPF. Methods: For the primary analysis, patients randomized to placebo (n = 624) in 3 phase 3, double-blind, controlled trials of pirfenidone (CAPACITY [NCT00287716 and NCT00287729]; ASCEND [NCT01366209]) were categorized by baseline metformin use. The primary outcome was disease progression (forced vital capacity [FVC] decline ≥10%, 6-min walking distance [6MWD] decline ≥50 m, or death). Other outcomes included mortality, hospitalization, FVC decline (≥10 and ≥5%), and 6MWD decline. Outcomes were also assessed in patients with diabetes and/or hyperglycemia (impaired glucose tolerance [IGT] and diabetes population [IGT-diabetes population]) and all patients included in the 3 studies (intention-to-treat [ITT] population). Results: Overall, 71 (11.4%) patients were metformin users and 553 (88.6%) were nonmetformin users. Baseline data were similar between groups, except for a higher percentage of males (84.5 vs. 73.2%) and a history of diabetes (98.6 vs. 11.6%) in metformin users versus nonmetformin users. The unadjusted 1-year analyses demonstrated no significant differences in disease progression or other outcomes. A higher proportion of metformin users compared with nonmetformin users had a relative FVC decline of ≥5% (63.4 vs. 50.6%, p = 0.043). Results were similar for the IGT-diabetes population and for the ITT population. Multivariable analyses yielded similar results. Conclusions: Metformin has no effect on clinically relevant outcomes in patients with IPF.

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Section: Discussionmentioning

confidence: 99%

“…Preclinical studies have suggested that metformin has antifibrotic and anti-inflammatory effects [23][24][25]. Metformin has been found to attenuate lung fibrosis by inhibiting transforming growth factor-beta (TGF-β) via adenosine monophosphate-activated protein kinase (AMPK) activation [26,27].…”

Section: Introductionmentioning

confidence: 99%

Metformin Does Not Affect Clinically Relevant Outcomes in Patients with Idiopathic Pulmonary Fibrosis

et al. 2018

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“…The discreet targets of Pirfenidone still remain unclear, yet it shows efficacy in delaying disease progression (16). Due to the heterogeneity of this disease, multiple targets in the fibrotic pathway lay open for potential intervention (17). …”

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confidence: 99%

Therapeutic targets in fibrotic pathways

Chen

2016

Cytokine

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The pathogenetic heterogeneity of pulmonary fibrosis yields both challenges and opportunities for therapy. Its complexity implicates a variety of cellular processes, signaling pathways, and genetics as drivers of disease. TGF-β stimulation is one avenue, and is central to pro-fibrotic protein expression, leading to decreased pulmonary function. Here we report our recent findings, introducing the E3 ligase Fibrosis Inducing E3 Ligase 1 (FIEL1) as an important regulator of TGF-β signaling through the selective degradation of PIAS4. FIEL1 exacerbates bleomycin-induced murine pulmonary fibrosis, while its silencing attenuates the fibrotic phenotype. Further, we developed a small molecule inhibitor of FIEL1 (BC-1485) that inhibits the degradation of PIAS4, and ameliorates fibrosis in murine models. New understanding of this pathway illustrates the many targeting opportunities among the complexity of pulmonary fibrosis in the continuing search for therapy.

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“…Although affecting fewer people than IPF per se, similar pathological changes are seen in a minority of adult cancer survivors exposed to lung irradiation as part of their treatment, described as RIPF [5]; childhood lung cancer survivors also show a four-fold increased risk of developing pulmonary fibrosis after radiation treatment [6]. Currently, there are no approved treatment options for patients with RIPF, although regimens for IPF, such as Pirfenidone and Nimatinib, slow the progression of the disease [3, 7]. Efforts to halt or reverse the progression of pulmonary fibrotic disease have, to date, ended in failure.…”

Section: Introductionmentioning

confidence: 99%

Radiation induced pulmonary fibrosis as a model of progressive fibrosis: Contributions of DNA damage, inflammatory response and cellular senescence genes

Beach

Johnston

Groves

et al. 2017

Experimental Lung Research

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Purpose of Study: Studies of pulmonary fibrosis (PF) have resulted in DNA damage, inflammatory response, and cellular senescence, being widely hypothesized to play a role in the progression of the disease. Utilizing these aforementioned terms, genomics databases were interrogated along with the term, “pulmonary fibrosis,” to identify genes common among all 4 search terms. Findings were compared to data derived from a model of radiation-induced progressive pulmonary fibrosis (RIPF) to verify that these genes are similarly expressed, supporting the use of radiation as a model for diseases involving PF, such as human idiopathic pulmonary fibrosis (IPF). Materials and Methods: In an established model of RIPF, C57BL/6J mice were exposed to 12.5 Gy thorax irradiation and sacrificed at 24 hours, 1, 4, 12, and 32 weeks following exposure, and lung tissue was compared to age-matched controls by RNA sequencing. Results: Of 176 PF associated gene transcripts identified by database interrogation, 146 (>82%) were present in our experimental model, throughout the progression of RIPF. Analysis revealed that nearly 85% of PF gene transcripts were associated with at least 1 other search term. Furthermore, of 22 genes common to all four terms, 16 were present experimentally in RIPF. Conclusions: This illustrates the validity of RIPF as a model of progressive PF/IPF based on the numbers of transcripts reported in both literature and observed experimentally. Well characterized genes and proteins are implicated in this model, supporting the hypotheses that DNA damage, inflammatory response and cellular senescence are associated with the pathogenesis of PF.

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Targeted Therapy for Idiopathic Pulmonary Fibrosis: Where To Now?

Cited by 47 publications

References 122 publications

Metformin Does Not Affect Clinically Relevant Outcomes in Patients with Idiopathic Pulmonary Fibrosis

Metformin Does Not Affect Clinically Relevant Outcomes in Patients with Idiopathic Pulmonary Fibrosis

Therapeutic targets in fibrotic pathways

Radiation induced pulmonary fibrosis as a model of progressive fibrosis: Contributions of DNA damage, inflammatory response and cellular senescence genes

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