Mechanical stress-induced mast cell degranulation activates TGF-β1 signalling pathway in pulmonary fibrosis

Shimbori, Chiko; Upagupta, Chandak; Bellaye, Pierre-Simon; Ayaub, Ehab; Sato, Seidai; Yanagihara, Toyoshi; Zhou, Quan; Ognjanovic, Alexander; Ask, Kjetil; Gauldie, Jack; Forsythe, Paul; Kolb, Martin

doi:10.1136/thoraxjnl-2018-211516

Cited by 77 publications

(64 citation statements)

References 41 publications

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“…In the pathological state of ARDS, different mechanical stretch modes and amplitudes have different molecular biological and cytological effects on lung tissue cells, affecting gene expression and metabolism of cells. Biomechanical signal transduction has a key role in the initiation of mechanical activation of intracellular inflammatory signaling pathways (15). During the mechanical ventilation treatment of ARDS, the connective tissue of the lung continuously withstands and transmits mechanical signals.…”

Section: Discussionmentioning

confidence: 99%

Mechanical stretch and LPS affect the proliferation, extracellular matrix remodeling and viscoelasticity of lung fibroblasts

et al. 2020

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The present study aimed to investigate the effects of mechanical stretch and lipopolysaccharides (LPS) on the expression of transforming growth factor-β1 (TGF-β1) and collagen and viscoelasticity in human embryonic MRC-5 lung fibroblasts cultured in vitro and to assess the mechanisms of ARDS-associated ventilator-induced lung injury using an in vitro model. Human embryonic MRC-5 lung fibroblasts were treated with different concentrations of LPS to establish an acute respiratory distress syndrome (ARDS) cell injury model, followed by further culture under different mechanical stretch amplitudes using the Flexcell system to establish a cellular mechanical damage model. The proliferation of MRC-5 cells and the protein and gene expression levels of TGF-β1 and collagen were detected by flow cytometry, ELISA and reverse transcription-quantitative PCR, respectively. As the concentration of LPS increased, the proliferation activity of MRC-5 cells gradually decreased. Low concentrations of LPS led to upregulation of the secretion levels of TGF-β1 and collagen I and the expression of their mRNA, TGF-β1 mRNA and collagen type 1, α1. Conversely, high concentrations of LPS reduced TGF-β1 and collagen I levels and their gene expression. Mechanical stimulation with a stretch of 5% increased the cell proliferation activity; however, it had no significant effect on the expression levels of TGF-β1 and collagen. Mechanical stimulation with a stretching force of 10% inhibited the cell proliferation but increased the expression levels of TGF-β1 and collagen I. A higher mechanical stimulation (15 and 20%) had a significantly greater effect. Mechanical stretch and LPS stimulation led to changes in the structure and viscoelastic behavior of human embryonic MRC-5 lung fibroblasts. In terms of cell function, mechanical stretch may cause an increase in the expression of TGF-β1 in MRC-5 cells, in turn affecting the transcription and translation of collagen genes. This present study provides provides cell-level evidence for understand the mechanisms of action behind the ARDS ventilator-induced lung injury and lung structural remodeling.

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Section: Discussionmentioning

confidence: 99%

Mechanical stretch and LPS affect the proliferation, extracellular matrix remodeling and viscoelasticity of lung fibroblasts

et al. 2020

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“…20 Andersson and colleagues provide evidence for a switch to the connective tissue MC subtype expressing both chymase and tryptase proteases (MC TC ) in IPF lung, 24 and this increase in MC TC s in IPF has been confirmed recently. 20 In contrast, Cha and colleagues propose a protective role for lung MCs since patients with higher numbers of these cells had less decline in lung function. 16 Stem cell factor (SCF) is a key survival factor for mast cells, acting through the tyrosine kinase receptor ckit (also known as CD117 or SCF receptor).…”

Section: Why Read On?mentioning

confidence: 93%

“…Several studies have shown that MCs and their mediators, such as histamine, are increased in lung tissue and bronchoalveolar lavage from patients with IPF. [14][15][16][17][18][19][20] What is the bottom line?…”

Section: Introductionmentioning

confidence: 99%

Inhibition of mast cells: a novel mechanism by which nintedanib may elicit anti-fibrotic effects

Overed-Sayer

Miranda

Dunmore

et al. 2020

Thorax

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BackgroundIdiopathic pulmonary fibrosis (IPF) is a chronic and progressive lung disease which presents a grave prognosis for diagnosed patients. Nintedanib (a triple tyrosine kinase inhibitor) and pirfenidone (unclear mechanism of action) are the only approved therapies for IPF, but have limited efficacy. The pathogenic mechanisms of this disease are not fully elucidated; however, a role for mast cells (MCs) has been postulated.ObjectivesThe aim of this work was to investigate a role for MCs in IPF and to understand whether nintedanib or pirfenidone could impact MC function.Methods and resultsMCs were significantly elevated in human IPF lung and negatively correlated with baseline lung function (FVC). Importantly, MCs were positively associated with the number of fibroblast foci, which has been linked to increased mortality. Furthermore, MCs were increased in the region immediately surrounding the fibroblast foci, and co-culture studies confirmed a role for MC–fibroblast crosstalk in fibrosis. Nintedanib but not pirfenidone inhibited recombinant stem cell factor (SCF)–induced MC survival. Further evaluation of nintedanib determined that it also inhibited human fibroblast-mediated MC survival. This was likely via a direct effect on ckit (SCF receptor) since nintedanib blocked SCF-stimulated ckit phosphorylation, as well as downstream effects on MC proliferation and cytokine release. In addition, nintedanib ablated the increase in lung MCs and impacted high tissue density frequency (HDFm) in a rat bleomycin model of lung fibrosis.ConclusionNintedanib inhibits MC survival and activation and thus provides a novel additional mechanism by which this drug may exert anti-fibrotic effects in patients with IPF.

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“…The severity of lung fibrosis was scored on a scale from 0 to 8 as already published [ 19 ]. Lung sections were stained with toluidine blue to enumerate mast cells [ 35 ].…”

Section: Methodsmentioning

confidence: 99%

Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Inhibitor as a Novel Therapeutic Tool for Lung Injury

Fusco

Siracusa

D’Amico

et al. 2020

IJMS

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Pulmonary fibrosis is a progressive disease characterized by lung remodeling due to excessive deposition of extracellular matrix. In this study, the bleomycin experimental model of pulmonary fibrosis was employed to investigate the anti-fibrotic and immunomodulatory activity of the inhibition of MALT1 protease activity. Mice received a single intra-tracheal administration of bleomycin (1 mg/kg) in the presence or absence of MI-2, a selective MALT1 inhibitor, (a dose of 30 mg/kg administered intra-peritoneally 1 h after bleomycin and daily until the end of the experiment). Seven days after bleomycin instillation mice were sacrificed and bronchoalveolar lavage fluid analysis, measurement of collagen content in the lung, histology, molecular analysis and immunohistochemistry were performed. To evaluate mortality and body weight gain a subset of mice was administered daily with MI-2 for 21 days. Mice that received MI-2 showed decreased weight loss and mortality, inflammatory cells infiltration, cytokines overexpression and tissue injury. Moreover, biochemical and immunohistochemical analysis displayed that MI-2 was able to modulate the excessive production of reactive oxygen species and the inflammatory mediator upregulation induced by bleomycin instillation. Additionally, MI-2 demonstrated anti-fibrotic activity by reducing transforming growth factor-β (TGF-β), α-smooth muscle actin (α-SMA) and receptor associated factor 6 (TRAF6) expression. The underlying mechanisms for the protective effect of MI-2 bleomycin induced pulmonary fibrosis may be attributed to its inhibition on NF-κB pathway. This is the first report showing the therapeutic role of MALT1 inhibition in a bleomycin model of pulmonary fibrosis, thus supporting further preclinical and clinical studies

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Mechanical stress-induced mast cell degranulation activates TGF-β1 signalling pathway in pulmonary fibrosis

Cited by 77 publications

References 41 publications

Mechanical stretch and LPS affect the proliferation, extracellular matrix remodeling and viscoelasticity of lung fibroblasts

Mechanical stretch and LPS affect the proliferation, extracellular matrix remodeling and viscoelasticity of lung fibroblasts

Inhibition of mast cells: a novel mechanism by which nintedanib may elicit anti-fibrotic effects

Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Inhibitor as a Novel Therapeutic Tool for Lung Injury

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