Tropisetron suppresses collagen synthesis in skin fibroblasts via α7 nicotinic acetylcholine receptor and attenuates fibrosis in a scleroderma mouse model

Stegemann, Agatha; Sindrilaru, Anca; Eckes, Beate; Rey, Adriana del; Heinick, Alexander; Schulte, Jan S.; Müller, Frank; Grando, Sergei A.; Fiebich, Bernd L.; Scharffetter‐­Kochanek, Karin; Luger, Thomas A.; Böhm, Markus

doi:10.1002/art.37809

Cited by 38 publications

(45 citation statements)

References 49 publications

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“…HDFs from lesional skin of a total of n=5 SSc patients (two males and three females) were generated as previously reported . The mean age of the patient at time of biopsy was 41.8 years (19‐55).…”

Section: Methodsmentioning

confidence: 99%

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Targeting of NADPH oxidase in vitro and in vivo suppresses fibroblast activation and experimental skin fibrosis

Dosoki

Stegemann

Taha

et al. 2016

Experimental Dermatology

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Although there is increasing evidence that oxidative stress is involved in collagen synthesis and myofibroblast activation, the NADPH oxidase (Nox) system is incompletely investigated in the context of human dermal fibroblasts (HDFs) and skin fibrosis. Using the pan-Nox inhibitor diphenyleneiodonium (DPI) as an initial tool, we show that gene expression of collagen type I, α-smooth muscle actin (α-SMA) and fibronectin 1 is suppressed in HDFs. Detailed expression analysis of all Nox isoforms and adaptors revealed expression of RNA and protein expression of Nox4, p22 and Poldip2 but neither Nox1 nor Nox2. Nox4 could be immunolocalized to the endoplasmic reticulum. Importantly, TGF-β had a dose- and time-dependent upregulating effect on NADH activity and Nox4 gene expression in HDFs. Genetic silencing of Nox4 as demonstrated by siRNA in HDFs as well as in murine fibroblasts established from Nox4 knockout mice confirmed that TGF-β -mediated collagen type I gene, α-SMA and fibronectin 1 gene expressions were Nox4-dependent. This TGF-β effect was mediated by Smad3 as shown by in silico promoter analysis, pharmacological inhibition and gene silencing of Smad3. The relevance of these findings is highlighted in the bleomycin-induced scleroderma mouse model. DPI treatment attenuated skin fibrosis and myofibroblast activation. Moreover, Nox4 knockdown by siRNA reduced skin collagen synthesis, α-SMA and fibronectin 1 expression in vivo. Finally, analyses of HDFs from patients with systemic sclerosis confirmed the expression of Nox4 and its adaptors, whereas Nox1 and Nox2 were not detectable. Our findings indicate that Nox4 targeting is a promising future treatment for fibrotic skin diseases.

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Section: Methodsmentioning

confidence: 99%

“…First‐strand cDNA was synthesized using the Revert Aid ™ cDNA Synthesis Kit (Fermentas Life Sciences, St. Leon‐Rot, Germany). Established PCR protocols were used for quantification of the mRNA levels of human and murine COL(I)α 1 , COL(I)α 2 and α‐SMA . Information for all other PCRs is provided in the Supporting Information.…”

Section: Methodsmentioning

confidence: 99%

Targeting of NADPH oxidase in vitro and in vivo suppresses fibroblast activation and experimental skin fibrosis

Dosoki

Stegemann

Taha

et al. 2016

Experimental Dermatology

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“…We [2] and others [3] have detected a functional receptor α7nAchR in human dermal fibroblasts (HDFs). Interestingly, tropisetron antagonized the effect of transforming growth factor-β 1 (TGF-β 1 ) in these cells.…”

Section: Introductionmentioning

confidence: 95%

The α7 nicotinic acetylcholine receptor agonist tropisetron counteracts ultraviolet A‐mediated oxidative stress in human dermal fibroblasts

Stegemann

Böhm

2016

Experimental Dermatology

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“…These are the primary cells responsible for reconstructing the connective tissue in the process of fetal and postnatal wound healing, and are involved in important regulatory events during wound healing [2][3][4]. Therefore, one of the hallmarks of skin wound healing is the proliferation and migration of fibroblasts [5].…”

Section: Introductionmentioning

confidence: 99%

Phenotypic and functional modulation of 20–30 year old dermal fibroblasts by mid- and late-gestational keratinocytes in vitro

Wang¹,

Liu²,

Zhang³

et al. 2015

Burns

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Tropisetron suppresses collagen synthesis in skin fibroblasts via α7 nicotinic acetylcholine receptor and attenuates fibrosis in a scleroderma mouse model

Cited by 38 publications

References 49 publications

Targeting of NADPH oxidase in vitro and in vivo suppresses fibroblast activation and experimental skin fibrosis

Targeting of NADPH oxidase in vitro and in vivo suppresses fibroblast activation and experimental skin fibrosis

The α7 nicotinic acetylcholine receptor agonist tropisetron counteracts ultraviolet A‐mediated oxidative stress in human dermal fibroblasts

Phenotypic and functional modulation of 20–30 year old dermal fibroblasts by mid- and late-gestational keratinocytes in vitro

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