Leukotriene D4 stimulates collagen production from myofibroblasts transformed by TGF-β

Asakura, Takanori; Ishii, Yoshiki; Chibana, Kazuyuki; Fukuda, Takeshi

doi:10.1016/j.jaci.2004.04.037

Cited by 51 publications

(30 citation statements)

References 46 publications

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“…We believe that our study has provided the fi rst piece of evidence for this question. LTD 4 has been reported to induce proliferation of airway smooth muscle cells [11,20] and collagen production by myofi broblasts in combination with TGF-␤ 1 [12] . In addition to the reported mechanisms by which LTD 4 promotes airway remodeling, it may also exacerbate remodeling through interaction with eosinophils.…”

Section: Resultsmentioning

confidence: 99%

“…In particular, eosinophils have been implicated in the pathogenesis of airway remodeling since anti-IL-5 monoclonal antibody treatment reduced the deposition of extracellular matrix protein in parallel with the reduction in eosinophils expressing transforming growth factor-␤ 1 (TGF-␤ 1) [7] and eosinophil defi ciency in a mouse model of asthmainhibited airway smooth muscle proliferation, extracel- 18 lular matrix deposition [9] , and goblet cell hyperplasia [8] . Cysteinyl leukotrienes (CysLTs), major mediators of acute airway obstruction and airway infl ammation in asthma, have also been suggested to cause remodeling [10][11][12] . These reports prompted us to assume that there may be a close link between eosinophils and CysLTs in the context of remodeling, possibly through production of TGF-␤ 1.…”

Section: Introductionmentioning

confidence: 99%

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Leukotriene D<sub>4</sub> Induces Production of Transforming Growth Factor-β1 by Eosinophils

Kato

Fujisawa²,

Nishimori³

et al. 2005

Int Arch Allergy Immunol

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Eosinophils may play an important role in the pathogenesis of airway remodeling in asthma through the production of various fibrogenic cytokines such as transforming growth factor-β1 (TGF-β1). Cysteinyl leukotrienes are also suggested to be involved in remodeling with their potential to induce proliferation of airway smooth muscle cells. Since massive eosinophil infiltration and the release of cysteinyl leukotrienes in airway secretions are often seen in asthma, we hypothesized that cysteinyl leukotrienes may be involved in airway remodeling through induction of TGF-β1 from eosinophils. Peripheral blood eosinophils were cultured with leukotriene D₄ (LTD₄) and/or interleukin-5 (IL-5) or granulocyte colony-stimulating factor (GM-CSF) for 16 h and gene expression of TGF-β1 was quantified with real-time PCR. A combination of LTD₄ and IL-5 or LTD₄ and GM-CSF synergistically induced TGF-β1 expression in eosinophils although stimulation with single factor, LTD₄, IL-5 or GM-CSF did not induce the gene expression. LTD₄ also induced significant gene expression in eosinophils cultured in an intercellular adhesion molecule-1-coated plate. The results suggested that CysLTs stimulate eosinophils to induce TGF-β1 production in allergic inflammation where IL-5 and GM-CSF are abundant and may be involved in the pathogenesis of airway remodeling.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Leukotriene D<sub>4</sub> Induces Production of Transforming Growth Factor-β1 by Eosinophils

Kato

Fujisawa²,

Nishimori³

et al. 2005

Int Arch Allergy Immunol

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“…The action of TGF-β 1 through the CysLT1 receptor in the regulation of ECM molecules has been previously reported by Asakura et al [33]. However, in that study LTD 4 in combination with TGF-β 1 stimulated the production of collagen in a human fetal lung fibroblasts cell line.…”

Section: Discussionmentioning

confidence: 59%

“…More recently, it has been suggested that LTD 4 has the potential to augment fibroblast chemotaxis, and to contribute to the regulation of the wound healing and remodeling in fibrotic processes of the lung [31,32]. LTD 4 may also increase collagen production in activated myofibroblasts by upregulating CysLT1 receptor induced by TGF-β 1 [33]. This evidence strongly supports the possible role of lipid mediators, and especially cysteinyl leukotrienes, in airway remodeling and in the regulation of MMP production.…”

Section: Discussionmentioning

confidence: 71%

LTD4 and TGF-β1 Induce the Expression of Metalloproteinase-1 in Chronic Rhinosinusitis via a Cysteinyl Leukotriene Receptor 1-Related Mechanism

et al. 2016

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Background: Cysteinyl leukotrienes (CysLTs) play a crucial role in the pathogenesis of airway remodeling. The use of CysLTs receptor antagonists has been included in the management of asthma and rhinitis. However, despite the action of these compounds on leukotriene production has been well documented, their role in airway remodeling remains unclear. Objective: We aimed to investigate the capability of the leukotriene receptor antagonist Montelukast to inhibit MMPs release after CysLTs stimulation in nasal tissue fibroblasts. Methods: Fibroblasts were isolated from sinunasal tissue collected from five patients suffering of chronic rhinosinusitis without nasal polyposis. Cells were cultured and stimulated first with LTC4 and LTD4 (10−10, 10−8, 10−6 M) using as pre-stimulus 10 ng/mL of: IL-4, IL-13, or TGF-beta1 and in presence or absence of Montelukast (10−10, 10−8, 10−6 M). To evaluate the regulation of MMP-1 and TIMP-1 we used enzyme immunoassays and to evaluate CysLT1 receptor we used real time PCR. Results: LTD4 but not LTC4 induced production of mRNA for CysLT1 receptor in a dose dependent manner and with an additive effect when the cells where primed with TGF-β1. TNF-α, IL-4, and IL-13 did not influence the expression of the receptor. Levels of MMP-1 but not of TIMP-1 were statistically enhanced in cells primed with TGF-β1 and stimulated with LTD4. Montelukast significantly decreased Cys-LT1 receptor and MMP-1 concentrations in a dose-dependent way in cells stimulated with LTD4 and TGF-β1 separately and when they were applied together. Conclusion: The leukotriene pathway may play an important role in extra-cellular matrix formation in an inflamed environment, such as chronic sinusitis and, consequently, leukotriene receptor antagonists such as Montelukast may be of great benefit in management of this disease.

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“…This synergy was also caused by uregulation of CysLT1R by TGF-b. 29 These results imply that human airway fibroblasts, like airway smooth muscle cells, have the ability to respond to cys-LTs through upregulation of CysLT1R when coincubated with some cytokines. Although we also show here that bronchial fibroblasts respond to cys-LTs only in the presence of RTK growth factors, it is unlikely that this is caused by the upregulation of CysLT1R or CysLT2R by RTK growth factors based on the failure of the receptor antagonists to inhibit the response.…”

Section: Discussionmentioning

confidence: 72%

Cysteinyl leukotrienes synergize with growth factors to induce proliferation of human bronchial fibroblasts

Yoshisue

Kirkham-Brown

Healy

et al. 2007

Journal of Allergy and Clinical Immunology

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Leukotriene D4 stimulates collagen production from myofibroblasts transformed by TGF-β

Cited by 51 publications

References 46 publications

Leukotriene D<sub>4</sub> Induces Production of Transforming Growth Factor-β1 by Eosinophils

Leukotriene D<sub>4</sub> Induces Production of Transforming Growth Factor-β1 by Eosinophils

LTD4 and TGF-β1 Induce the Expression of Metalloproteinase-1 in Chronic Rhinosinusitis via a Cysteinyl Leukotriene Receptor 1-Related Mechanism

Cysteinyl leukotrienes synergize with growth factors to induce proliferation of human bronchial fibroblasts

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