Galectin-3 levels are elevated following nintedanib treatment

Shochet, Gali Epstein; Pomerantz, Alon; Shitrit, David; Bardenstein-Wald, Becky; Ask, Kjetil; Surber, Mark W.; Rabinowicz, Noa; Levy, Yair; Benchetrit, Sydney; Edelstein, E. L.; Zitman‐Gal, Tali

doi:10.1177/2040622320968412

Cited by 6 publications

(2 citation statements)

References 44 publications

(58 reference statements)

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“…STAT3 was previously shown to non-canonically activate Smad3 and therefore, possibly, PAI-1. In our recent work we showed that nintedanib can elevate pSTAT3 levels in HLFs [ 45 ].…”

Section: Discussionmentioning

confidence: 99%

Hypoxia Inducible Factor 1A Supports a Pro-Fibrotic Phenotype Loop in Idiopathic Pulmonary Fibrosis

Shochet

Bardenstein-Wald

McElroy

et al. 2021

IJMS

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Idiopathic pulmonary fibrosis (IPF) is a progressive lung disease with poor prognosis. The IPF-conditioned matrix (IPF-CM) system enables the study of matrix–fibroblast interplay. While effective at slowing fibrosis, nintedanib has limitations and the mechanism is not fully elucidated. In the current work, we explored the underlying signaling pathways and characterized nintedanib involvement in the IPF-CM fibrotic process. Results were validated using IPF patient samples and bleomycin-treated animals with/without oral and inhaled nintedanib. IPF-derived primary human lung fibroblasts (HLFs) were cultured on Matrigel and then cleared using NH4OH, creating the IPF-CM. Normal HLF-CM served as control. RNA-sequencing, PCR and western-blots were performed. HIF1α targets were evaluated by immunohistochemistry in bleomycin-treated rats with/without nintedanib and in patient samples with IPF. HLFs cultured on IPF-CM showed over-expression of ‘HIF1α signaling pathway’ (KEGG, p < 0.0001), with emphasis on SERPINE1 (PAI-1), VEGFA and TIMP1. IPF patient samples showed high HIF1α staining, especially in established fibrous tissue. PAI-1 was overexpressed, mainly in alveolar macrophages. Nintedanib completely reduced HIF1α upregulation in the IPF-CM and rat-bleomycin models. IPF-HLFs alter the extracellular matrix, thus creating a matrix that further propagates an IPF-like phenotype in normal HLFs. This pro-fibrotic loop includes the HIF1α pathway, which can be blocked by nintedanib.

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“…STAT3 was previously shown to non-canonically activate Smad3 and therefore, possibly, PAI-1. In our recent work we showed that nintedanib can elevate pSTAT3 levels in HLFs [ 45 ].…”

Section: Discussionmentioning

confidence: 99%

Hypoxia Inducible Factor 1A Supports a Pro-Fibrotic Phenotype Loop in Idiopathic Pulmonary Fibrosis

Shochet

Bardenstein-Wald

McElroy

et al. 2021

IJMS

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“…Subgroup-analyses of the INBUILD and SENSCIS trials by immunomodulator use at baseline have suggested that nintedanib can be used in combination with glucocorticoid [ 58 ] and mycophenolate [ 59 ] without affecting the efficacy of nintedanib on disease progression. The potential of the combination of nintedanib with the novel antifibrotic Td139 (galectin-3 inhibitor) has also been suggested recently [ 60 ].…”

Section: Adoption Of New Drugs In Clinical Practice and Treatment Optimizationmentioning

confidence: 99%

Progressive Fibrosing Interstitial Lung Diseases: A Current Perspective

et al. 2021

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Interstitial lung diseases (ILDs) are a large and diverse group of rare and chronic respiratory disorders, with idiopathic pulmonary fibrosis (IPF) being the most common and best-studied member. Increasing interest in fibrosis as a therapeutic target and the appreciation that fibrotic mechanisms may be a treatable target of IPF prompted the development and subsequent approval of the antifibrotics, pirfenidone and nintedanib. The management of ILDs has changed considerably following an understanding that IPF and some ILDs share similar disease behavior of progressive fibrosis, termed “progressive fibrosing phenotype”. Indeed, antifibrotic treatment has shown to be beneficial in ILDs characterized by the progressive fibrosing phenotype. This narrative review summarizes current knowledge in the field of progressive fibrosing ILDs. Here, we discuss the clinical characteristics and pathogenesis of lung fibrosis and highlight relevant literature concerning the mechanisms underlying progressive fibrosing ILDs. We also summarize current diagnostic approaches and the available treatments of progressive fibrosing ILDs and address the optimization of treating progressive fibrosing ILDs with antifibrotics in clinical practice.

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