Role and New Insights of Pirfenidone in Fibrotic Diseases

Mora, David A. López-de la; Sanchez-Roque, Cibeles; Montoya‐Buelna, Margarita; Sánchez‐Enríquez, Sergio; Lucano-Landeros, Silvia; Macías-Barragán, José; Armendáriz‐Borunda, Juan

doi:10.7150/ijms.11579

Cited by 112 publications

(85 citation statements)

References 50 publications

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“…This supports the relationship between mTOR signaling and collagen I production in p-hIFs and suggests that pirfenidone, at least in part, acts via mTOR to suppress ECM production and p-hIF proliferation. It is important to note that besides anti-fibrotic activity, pirfenidone has also been shown to act as an anti-inflammatory and an anti-oxidant agent in IPF patients [41,42]. Here, we specifically focused on the potential anti-fibrotic action of p-hIFs, but the anti-inflammatory and anti-oxidant activities of pirfenidone may synergize in its therapeutic effect in patients with IBD.…”

Section: Discussionmentioning

confidence: 99%

Pirfenidone Inhibits Cell Proliferation and Collagen I Production of Primary Human Intestinal Fibroblasts

Cui

Zhang

Leng

et al. 2020

Cells

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Intestinal fibrosis is a common complication of inflammatory bowel disease. So far, there is no safe and effective drug for intestinal fibrosis. Pirfenidone is an anti-fibrotic compound available for the treatment of idiopathic pulmonary fibrosis. Here, we explored the anti-proliferative and anti-fibrotic properties of pirfenidone on primary human intestinal fibroblasts (p-hIFs). p-hIFs were cultured in the absence and presence of pirfenidone. Cell proliferation was measured by a real-time cell analyzer (xCELLigence) and BrdU incorporation. Cell motility was monitored by live cell imaging. Cytotoxicity and cell viability were analyzed by Sytox green, Caspase-3 and Water Soluble Tetrazolium Salt-1 (WST-1) assays. Gene expression of fibrosis markers was determined by quantitative reverse transcription PCR (RT-qPCR). The mammalian target of rapamycin (mTOR) signaling was analyzed by Western blotting and type I collagen protein expression additionally by immunofluorescence microscopy. Pirfenidone dose-dependently inhibited p-hIF proliferation and motility, without inducing cell death. Pirfenidone suppressed mRNA levels of genes that contribute to extracellular matrix production, as well as basal and TGF-β1-induced collagen I protein production, which was associated with inhibition of the rapamycin-sensitive mTOR/p70S6K pathway in p-hIFs. Thus, pirfenidone inhibits the proliferation of intestinal fibroblasts and suppresses collagen I production through the TGF-β1/mTOR/p70S6K signaling pathway, which might be a novel and safe anti-fibrotic strategy to treat intestinal fibrosis.

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Section: Discussionmentioning

confidence: 99%

Pirfenidone Inhibits Cell Proliferation and Collagen I Production of Primary Human Intestinal Fibroblasts

Cui

Zhang

Leng

et al. 2020

Cells

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“…It is clinically characterized by a progressive decline in pulmonary function (Raghu et al, 2008). Increased levels of TNFα have been observed experimentally in the lungs of animals with pulmonary fibrosis and patients with IPF (Altintas et al, 2016; Lopez-de la Mora et al, 2015; Losa Garcia et al, 1999; Lozo Vukovac et al, 2014; Pan et al, 1996; Riha et al, 2004; Schupp et al, 2015; Vaillant et al, 1996; Zhang et al, 1993; Ziegenhagen et al, 1998). Lung tissue and alveolar macrophages isolated from patients with IPF release increased amounts of TNFα and sTNF receptors compared to healthy subjects (Cu et al, 2009; Piguet et al, 1993; Zhang et al, 1993).…”

Section: Role Of Tnfα In Pulmonary Diseasesmentioning

confidence: 99%

Anti-TNFα therapy in inflammatory lung diseases

Malaviya

Laskin

2017

Pharmacology & Therapeutics

186

137

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Increased levels of tumor necrosis factor (TNF) α have been linked to a number of pulmonary inflammatory diseases including asthma, chronic obstructive pulmonary disease (COPD), acute lung injury (ALI)/acute respiratory distress syndrome (ARDS), sarcoidosis, and interstitial pulmonary fibrosis (IPF). TNFα plays multiple roles in disease pathology by inducing an accumulation of inflammatory cells, stimulating the generation of inflammatory mediators, and causing oxidative and nitrosative stress, airway hyperresponsiveness and tissue remodeling. TNF-targeting biologics, therefore, present a potentially highly efficacious treatment option. This review summarizes current knowledge on the role of TNFα in pulmonary disease pathologies, with a focus on the therapeutic potential of TNFα-targeting agents in treating inflammatory lung diseases.

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“…Pirfenidone is a pyridone chemical compound and is approved by the Food and Drug Administration (FDA) for the treatment of idiopathic pulmonary brosis. More importantly, Pirfenidone reduces collagen production related to the TGF-β signaling pathway [44]. On the other hand, SB525334 inhibits the TGF-β receptor I (ALK5) and was shown to restore hepatocellular senescence in acute liver injury [43].…”

Section: Discussionmentioning

confidence: 99%

A Combination of Pirfenidone and Inhibition of TGF-β Mitigates Cystic Echinococcosis–Associated Hepatic Injury

Wang

Liao

Wang

et al. 2020

Preprint

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Background & Aims: TGF-β not only inhibits the function of NK cells, but also promotes liver fibrosis. It is unclear whether the inhibition of TGF-β signaling pathway could relieve the CE-related liver fibrosis.Methods: By using the model of CE infected mouse liver, the effect of the infection of CE exerted on NK cells was identified. In vivo, SB525334 and Pirfenidone were applied to intervene the TGF-β signaling pathway.Results: During the infection of Echinococcus granulosus, the inhibitory receptors on the surface of NK cells increased, while the activated receptors decreased. TGF-β1 secretion was increased in liver tissues and mainly derived from macrophages. At the same time, the combination of drugs could also reduce the expression of TGF-β1 signaling pathway-related proteins and collagen. For the secretion of TGF-β1, only the pirfenidone group had an depressing effect. In addition, the combination of drugs can reduce liver cell damage and restore liver function.Conclusions: During the infection the of Echinococcus granulosus, the dysfunction of NK cells may be caused by increased secretion of TGF-β1 from macrophages. Echinococcus granulosus infection was a process of occupying lesions. This persistent pressure was accompanied by senescent hepatocytes. Senescent hepatocytes induced the secretion of TGF-β1 derived from macrophages, and promoted the activation of hepatic stellate cells and accelerated Echinococcus granulosus-associated liver fibrosis. By combining pirfenidone and SB525334, liver function, senescent hepatocytes, fibrosis associated with Echinococcus granulosus infection could be alleviated. Moreover, the functional status of NK cells also received partially amelioration. In summary, our work offered an experimental basis for clinical treatment.

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Role and New Insights of Pirfenidone in Fibrotic Diseases

Cited by 112 publications

References 50 publications

Pirfenidone Inhibits Cell Proliferation and Collagen I Production of Primary Human Intestinal Fibroblasts

Pirfenidone Inhibits Cell Proliferation and Collagen I Production of Primary Human Intestinal Fibroblasts

Anti-TNFα therapy in inflammatory lung diseases

A Combination of Pirfenidone and Inhibition of TGF-β Mitigates Cystic Echinococcosis–Associated Hepatic Injury

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