Bleomycin inhibits adipogenesis and accelerates fibrosis in the subcutaneous adipose layer through <scp>TGF</scp>‐β1

Ohgo, Shiro; Hasegawa, Seiji; Hasebe, Yuichi; Mizutani, Hiroshi; Nakata, Satoshi; Akamatsu, Hirohiko

doi:10.1111/exd.12256

Cited by 34 publications

(25 citation statements)

References 22 publications

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“…We next assessed the dermal thickness of the control mice and Ki16425-treated mice. Compared with findings in bleomycin-oil-treated mice, Ki16425 decreased dermal thickness by 42% in the Ki16425-treated mice dosed with 1 mg/kg and 38% in those dosed with 10 35 lm, **P < 0.01]. However, there was no statistically significant dose dependence of Ki16425-induced inhibition ( Fig.…”

Section: Local Injection Of Lpa 13 Antagonist Ki16425 Inhibits the Dmentioning

confidence: 69%

Antifibrotic effect of lysophosphatidic acid receptors LPA₁ and LPA₃ antagonist on experimental murine scleroderma induced by bleomycin

Ohashi

Yamamoto

2015

Experimental Dermatology

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The study of lysophosphatidic acid (LPA) receptor has recently focused on its involvement in the pathogenesis of systemic sclerosis (SSc). We examined the inhibitory effects of the antagonist for the LPA receptor, a selective LPA1 and LPA3 antagonist (Ki16425), on dermal and lung fibrosis in a mouse model of SSc. Ki16425 was administered intra-dermally after 6 h on the same sites as bleomycin injection. Histopathological examination showed that skin lesions were markedly attenuated by treatment with Ki16425 at doses of 1 and 10 mg/kg, along with reduced dermal thickness. Hydroxyproline contents in the Ki16425-treated skin showed a decrease of 35% (1 mg/kg) and 45% (10 mg/kg) compared with those in the oil-injected skin of the controls. The number of mast cells and phospho-Smad2/3-positive spindle cells of the Ki16425-treated skin was significantly decreased compared with that in the controls. Additionally, RT-PCR analysis showed that the mRNA levels of TGF-β1, CTGF, MIP-1α, IFN-γ and collagen α1(I) were significantly decreased in both the 1-mg/kg and 10-mg/kg groups of the Ki16425-treated mice compared with those in the controls. Furthermore, treatment with bleomycin and Ki16425 showed reduction in lung fibrosis, and the hydroxyproline contents in the lungs of the Ki16425-treated mice showed a decrease of 25% (1 mg/kg) and 32% (10 mg/kg) compared with those in the lungs of the controls. Taken together, Ki16425 was found to improve dermal and lung fibrosis in a mouse model of bleomycin-induced murine scleroderma. These results suggest that Ki16425 has the potential to be an effective new treatment for scleroderma.

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Section: Local Injection Of Lpa 13 Antagonist Ki16425 Inhibits the Dmentioning

confidence: 69%

Antifibrotic effect of lysophosphatidic acid receptors LPA₁ and LPA₃ antagonist on experimental murine scleroderma induced by bleomycin

Ohashi

Yamamoto

2015

Experimental Dermatology

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“…The idea that C57BL/6J-Mc1r e/e mice could be more sensitive to BLM was based on the view that the BLM scleroderma model is regarded as an inflammation-driven fibrosis model (13 (29), the role of MC-expressing adipocytes must further be considered. With regard to the human system, it is of special interest that MC 1 immunoreactivity was recently detected in fibroblasts in situ in burn wounds and hypertrophic scars (30).…”

Section: Resultsmentioning

confidence: 99%

Bleomycin‐induced fibrosis in MC₁ signalling‐deficient C57BL/6J‐Mc1r^e/e mice further supports a modulating role for melanocortins in collagen synthesis of the skin

Böhm

Stegemann

2014

Experimental Dermatology

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The melanocortin-1 receptor (MC 1 ) binds a-melanocytestimulating hormone (a-MSH) with high affinity and has a physiological role in cutaneous melanin pigmentation. Previously, we reported that human dermal fibroblasts also express functional MC 1 . a-MSH suppressed transforming growth factor-b 1 -and bleomycin (BLM)-induced collagen synthesis in vitro and in vivo.e/e mice, we tested as to whether MC 1 has a regulatory role on dermal collagen synthesis in the BLM model of scleroderma. Notably, mice with a C57BL/6J genetic background were previously shown to be BLMnon-susceptible. Interestingly, treatment of C57BL/6J-Mc1r e/e but not of C57BL/6J-wild-type mice with BLM increased cutaneous collagen type I content at RNA and protein level along with development of skin fibrosis. Cutaneous levels of connective tissue growth factor and monocyte chemotactic protein-1 were also increased in BLM-treated C57BL/6J-Mc1r e/e mice. Primary dermal fibroblasts from C57BL/6J-wt mice further expressed MC 1 , suggesting that these cells are directly targeted by melanocortins to affect collagen production of the skin. Our findings support the concept that MC 1 has an endogenous regulatory function in collagen synthesis and controls the extent of fibrotic stress responses of the skin.

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“…In a recent study, bleomycin suppresses adipogenesis via TGF-β expression which further suppresses adipogenesis stimulating fibrosis. Furthermore, inhibition of collagen synthesis by fibroblast in a fibrotic environment by adipocyte-conditioned medium was demonstrated [67].…”

Section: Growth Factorsmentioning

confidence: 99%

Cytokines in the immunopathology of systemic sclerosis

Raja

Denton²

2015

Semin Immunopathol

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Cytokines and growth factors are key regulators of immune activation, vascular alteration and excessive production of extracellular matrix which are hallmark events in the pathogenesis of systemic sclerosis (SSc). They modulate cell-cell and cell-matrix interactions. In particular, cytokines play a central role in the immunopathogenesis of SSc on the basis of molecular pathways which are complex and not completely understood. The majority of cytokines that may be involved in SSc pathogenesis have effect upon or are derived from cells of the immune system, including both the innate and adaptive compartments. Novel therapies that block key mediators that drive the fibrotic response are being developed and appear as potential therapeutic tools in the treatment of SSc, highlighting the importance for an effective therapy targeted towards the molecular and cellular pathways. This article reviews cytokine biology in that context, with particular emphasis on immunopathology of the disease, therapeutic targeting and the way that current or emerging treatments for SSc might impact on cytokine biology.

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Bleomycin inhibits adipogenesis and accelerates fibrosis in the subcutaneous adipose layer through TGF‐β1

Cited by 34 publications

References 22 publications

Antifibrotic effect of lysophosphatidic acid receptors LPA₁ and LPA₃ antagonist on experimental murine scleroderma induced by bleomycin

Antifibrotic effect of lysophosphatidic acid receptors LPA₁ and LPA₃ antagonist on experimental murine scleroderma induced by bleomycin

Bleomycin‐induced fibrosis in MC₁ signalling‐deficient C57BL/6J‐Mc1r^e/e mice further supports a modulating role for melanocortins in collagen synthesis of the skin

Cytokines in the immunopathology of systemic sclerosis

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Bleomycin inhibits adipogenesis and accelerates fibrosis in the subcutaneous adipose layer through TGF‐β1

Cited by 34 publications

References 22 publications

Antifibrotic effect of lysophosphatidic acid receptors LPA1 and LPA3 antagonist on experimental murine scleroderma induced by bleomycin

Antifibrotic effect of lysophosphatidic acid receptors LPA1 and LPA3 antagonist on experimental murine scleroderma induced by bleomycin

Bleomycin‐induced fibrosis in MC1 signalling‐deficient C57BL/6J‐Mc1re/e mice further supports a modulating role for melanocortins in collagen synthesis of the skin

Cytokines in the immunopathology of systemic sclerosis

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Product

Resources

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Antifibrotic effect of lysophosphatidic acid receptors LPA₁ and LPA₃ antagonist on experimental murine scleroderma induced by bleomycin

Antifibrotic effect of lysophosphatidic acid receptors LPA₁ and LPA₃ antagonist on experimental murine scleroderma induced by bleomycin

Bleomycin‐induced fibrosis in MC₁ signalling‐deficient C57BL/6J‐Mc1r^e/e mice further supports a modulating role for melanocortins in collagen synthesis of the skin