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GLP-1 receptor agonist ameliorates experimental lung fibrosis.

ABSTRACT: Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, and fatal lung disease. This disease is characterized by an excessive accumulation of extracellular matrix deposition that modify normal lung physiology. Up to date, there are not efficient therapeutic tools to fight IPF. Glucagon-like peptide-1 receptor (GLP-1R) activation plays an essential role in lung functions in normal and in pathological conditions. The aim of the present study was to study the possible beneficial effects of the administration of the GLP-1R agonist, liraglutide, in the pathogenesis of the fibrotic process in an animal model of pulmonary fibrosis induced by bleomycin. We observed that liraglutide decreased mRNA expression of collagen, hydroxyproline and key enzymes for the synthesis of collagen. In addition, GLP-1R activation restored the ACE2 mRNA levels modulating the activities of the RAS components, increased the production of surfactant proteins (SFTPa1, SFTPb, SFTPc) and promoted an improvement in pulmonary and cardiac functionality, including a partial restoration of lung alveolar structure. Liraglutide effects are shown at both the pro-inflammatory and fibrosis phases of the experimental disease. For these reasons, GLP-1 might be regarded as a promising drug for treating pulmonary fibrosis.

SUBMITTER: Fandino J

PROVIDER: S-EPMC7581713 | biostudies-literature | 2020 Oct

REPOSITORIES: biostudies-literature

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GLP-1 receptor agonist ameliorates experimental lung fibrosis.

Fandiño Juan J Toba Laura L González-Matías Lucas C LC Diz-Chaves Yolanda Y Mallo Federico F

Scientific reports 20201022 1

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, and fatal lung disease. This disease is characterized by an excessive accumulation of extracellular matrix deposition that modify normal lung physiology. Up to date, there are not efficient therapeutic tools to fight IPF. Glucagon-like peptide-1 receptor (GLP-1R) activation plays an essential role in lung functions in normal and in pathological conditions. The aim of the present study was to study the possible beneficial effects of t ...[more]

PMID: 33093510

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Project description:BackgroundPersistent fibroblast activation initiated by transforming growth factor β (TGF-β) is a fundamental event in the pathogenesis of systemic sclerosis, and its pharmacological inhibition represents a potential therapeutic strategy. The nuclear receptor, peroxisome proliferator-activated receptor γ (PPAR-γ), exerts potent fibrotic activity. The synthetic oleanane triterpenoid, 2-cyano-3,12-dioxo-olean-1,9-dien-28-oic acid (CDDO), is a PPAR-γ agonist with potential effects on TGF-β signalling and dermal fibrosis.ObjectiveTo examine the modulation of fibrogenesis by CDDO in explanted fibroblasts, skin organ cultures and murine models of scleroderma.Material and methodsThe effects of CDDO on experimental fibrosis induced by bleomycin injection or by overexpression of constitutively active type I TGF-β receptor (TgfbR1ca) were evaluated. Modulation of fibrotic gene expression was examined in human skin organ cultures. To delineate the mechanisms underlying the antifibrotic effects of CDDO, explanted skin fibroblasts cultured in two-dimensional monolayers or in three-dimensional full-thickness human skin equivalents were studied.ResultsCDDO significantly ameliorated dermal fibrosis in two complementary mouse models of scleroderma, as well as in human skin organ cultures and in three-dimensional human skin equivalents. In two-dimensional monolayer cultures of explanted normal fibroblasts, CDDO abrogated fibrogenic responses induced by TGF-β. These CDDO effects occurred via disruption of Smad-dependent transcription and were associated with inhibition of Akt activation. In scleroderma fibroblasts, CDDO attenuated the elevated synthesis of collagen. Remarkably, the in vitro antifibrotic effects of CDDO were independent of PPAR-γ.ConclusionsThe PPAR-γ agonist triterpenoid CDDO attenuates fibrogenesis by antagonistically targeting canonical TGF-β/Smad and Akt signalling in a PPAR-γ-independent manner. These findings identify this synthetic triterpenoid as a potential new therapy for the control of fibrosis.

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GLP-1 receptor agonist ameliorates experimental lung fibrosis.

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GLP-1 receptor agonist ameliorates experimental lung fibrosis.

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