The Experts below are selected from a list of 13023 Experts worldwide ranked by ideXlab platform
Kazuhiko Takehara - One of the best experts on this subject based on the ideXlab platform.
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potential roles of interleukin 17a in the development of Skin Fibrosis in mice
Arthritis & Rheumatism, 2012Co-Authors: Yoshinobu Okamoto, Manabu Fujimoto, Minoru Hasegawa, Yasuhito Hamaguchi, Takashi Matsushita, Yoichiro Iwakura, Kazuhiko TakeharaAbstract:Objective Although transforming growth factor β (TGFβ) and connective tissue growth factor (CTGF) have been considered to play central roles in the pathogenesis of systemic sclerosis (SSc), other cytokines may also be crucial for the development of SSc. The aim of this study was to examine the roles of T helper cytokines in the development of Skin Fibrosis. Methods To compare the roles of Th1, Th2, and Th17 cytokines, we examined bleomycin-induced SSc in mice deficient for interferon-γ (IFNγ), interleukin-4 (IL-4), and IL-17A. The mechanism by which IL-17A contributes to bleomycin-induced Fibrosis was investigated in vivo and in vitro. The outcome of mice lacking IL-17A was also investigated in TSK-1 mice. Results The loss of IL-17A significantly attenuated bleomycin-induced Skin Fibrosis, whereas a deficiency of IFNγ or IL-4 did not. Leukocyte infiltration and the expression of TGFβ and CTGF messenger RNA in bleomycin-injected Skin were significantly reduced in IL-17A–deficient mice compared with wild-type (WT) mice. Daily bleomycin injections induced the expression of IL-17A in the Skin and potent IL-17A producers in splenic CD4+ T cells from WT mice. Furthermore, a Skin fibroblast cell line expressed increased TGFβ, CTGF, and collagen after the addition of recombinant IL-17A. IL-17A deficiency also attenuated Skin thickness in TSK-1 mice. Conclusion This study demonstrates that IL-17A contributes to Skin Fibrosis in 2 mouse models of SSc. These findings suggest that inhibition of IL-17A represents a therapeutic target for antagonizing fibrotic Skin disorders such as SSc.
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inducible costimulator ligand regulates bleomycin induced lung and Skin Fibrosis in a mouse model independently of the inducible costimulator inducible costimulator ligand pathway
Arthritis & Rheumatism, 2010Co-Authors: Chihiro Tanaka, Kazuhiko Takehara, Shinichi Sato, Manabu Fujimoto, Yasuhito Hamaguchi, Minoru HasegawaAbstract:Objective Systemic sclerosis is a connective tissue disease characterized by Fibrosis of the Skin and internal organs, including the lungs. Inducible costimulator (ICOS), which is expressed on activated T cells, and its ligand ICOSL, which is expressed on antigen-presenting cells, have been considered a single receptor–ligand pair. Although the ICOS/ICOSL pathway is known to play various roles in adaptive immunity, its roles in innate immunity and tissue Fibrosis remain unknown. Methods We assessed the roles of ICOS and ICOSL in tissue Fibrosis by administering bleomycin intratracheally or intradermally into mice deficient in ICOS and/or ICOSL. Tissue Fibrosis was evaluated by histologic or biochemical examination. Results ICOS deficiency attenuated the lung and Skin Fibrosis, whereas ICOSL deficiency aggravated it. Mice deficient in both ICOS and ICOSL exhibited accelerated Fibrosis, reflecting a dominant role of ICOSL over ICOS in this model. Interestingly, ICOSL expression on macrophages and B cells derived from bronchoalveolar lavage fluid was significantly elevated in ICOS-deficient mice as compared with wild-type mice during this process. Thus, the levels of ICOSL expression on B cells and macrophages were inversely associated with the severity of tissue Fibrosis. Conclusion Our results indicate that ICOSL expression on antigen-presenting cells plays a previously unknown regulatory role during the development of bleomycin-induced tissue Fibrosis that is independent of the ICOS/ICOSL pathway. Further studies will be needed to clarify the roles of ICOS and ICOSL in the development of systemic sclerosis.
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neutralizing monoclonal antibody to human connective tissue growth factor ameliorates transforming growth factor β induced mouse Fibrosis
Journal of Cellular Physiology, 2008Co-Authors: Yuka Ikawa, Manabu Fujimoto, Pohsing Ng, Koki Endo, Miki Kondo, Sonoko Chujo, Wataru Ishida, Fumiaki Shirasaki, Kazuhiko TakeharaAbstract:Skin fibrotic disorders such as systemic sclerosis (SSc) are characterized by an excessive accumulation of extracellular matrix (ECM) and are understood to develop under the influence of fibrogenic growth factors. To better understand the detailed mechanisms of persistent Fibrosis in SSc, we have previously established an animal model of Skin Fibrosis induced by exogenous application of growth factors. In this model, transforming growth factor-β (TGF-β) transiently induced subcutaneous Fibrosis and serial injections of connective tissue growth factor (CTGF) after TGF-β caused persistent Fibrosis. These results suggest that CTGF plays an important role in the development of persistent Skin Fibrosis and that CTGF may be a potential and specific therapeutic target in Skin Fibrosis. Therefore, the aim of the current study is to develop a neutralizing monoclonal antibody against human CTGF. We also investigated the neutralizing effect of the antibodies in our animal model. Firstly, by using the DNA immunization method, we developed a panel of anti-CTGF antibodies recognizing the native conformation of human CTGF. Next, to examine the anti-fibrosing effects of these antibodies, newborn B6 mice received subcutaneous injections of TGF-β for 3 days with either anti-CTGF neutralizing antibodies or control purified immunoglobulin. Anti-CTGF antibodies significantly reduced Skin Fibrosis and collagen contents compared with the control group. These results suggest that our anti-CTGF antibodies are capable of blocking the development of Skin Fibrosis at least partially and these anti-CTGF neutralizing antibodies may be useful as the feasible strategy to treat Skin fibrotic diseases as SSc. J. Cell. Physiol. 216: 680–687, 2008, © 2008 Wiley-Liss, Inc.
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baff antagonist attenuates the development of Skin Fibrosis in tight Skin mice
Journal of Investigative Dermatology, 2007Co-Authors: Takashi Matsushita, Kazuhiko Takehara, Manabu Fujimoto, Minoru Hasegawa, Kazuhiro Komura, Yukiyo Matsushita, Fumihide Ogawa, Rei Watanabe, Shinichi SatoAbstract:The tight-Skin (TSK/+) mouse, a genetic model for systemic sclerosis (SSc), develops cutaneous Fibrosis and autoimmunity. Although immunological abnormalities have been demonstrated in TSK/+ mice, the roles of B-cell-activating factor belonging to the tumor necrosis factor family (BAFF), a potent B-cell survival factor, have not been investigated. Serum BAFF levels in TSK/+ mice were examined by ELISA. Newborn TSK/+ mice were treated with BAFF antagonist, and then Skin Fibrosis of 8-week-old mice was assessed. Serum BAFF levels were significantly elevated in TSK/+ mice. Remarkably, BAFF antagonist inhibited the development of Skin Fibrosis, hyper-γ-globulinemia, and the autoantibody production in TSK/+ mice. The Skin from TSK/+ mice showed upregulated expressions of fibrogenic cytokines, such as IL-6 and IL-10, while BAFF antagonist significantly suppressed them. Reciprocally, BAFF antagonist augmented antifibrogenic cytokines, such as IFN-γ, in the Skin of TSK/+ mice. Furthermore, TSK/+ B cells with BAFF stimulation had a significantly enhanced ability to produce IL-6. The results suggest that BAFF/BAFF receptor system is critical for the development of Skin Fibrosis in TSK/+ mice and could be a potent therapeutical target.
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CD19-dependent B lymphocyte signaling thresholds influence Skin Fibrosis and autoimmunity in the tight-Skin mouse.
The Journal of clinical investigation, 2002Co-Authors: Eriko Saito, Kazuhiko Takehara, Thomas F. Tedder, Manabu Fujimoto, Minoru Hasegawa, Kazuhiro Komura, Yasuhito Hamaguchi, Yuko Kaburagi, Tetsuya Nagaoka, Shinichi SatoAbstract:The tight-Skin (TSK/+) mouse, a genetic model for human systemic sclerosis (SSc), develops cutaneous Fibrosis and autoantibodies against SSc-specific target autoantigens. Although molecular mechanisms explaining the development of Fibrosis and autoimmunity in SSc patients or TSK/+ mice remain unknown, we recently demonstrated that SSc patients overexpress CD19, an important regulatory molecule expressed by B lymphocytes. B cells from CD19-deficient mice are hyporesponsive to transmembrane signals, while B cells overexpressing CD19 are hyperresponsive and generate autoantibodies. In this study, TSK/+ B cells also exhibited a hyperresponsive phenotype with decreased surface IgM expression, enhanced serum Ig production, and spontaneous autoantibody production. Moreover, CD19 tyrosine phosphorylation was constitutively augmented in TSK/+ B cells. CD19-mediated [Ca2+]i responses, Vav phosphorylation, and Lyn kinase activity were similarly enhanced. Studies of TSK/+ mice deficient in CD19 expression demonstrated that CD19 deficiency significantly decreased Skin Fibrosis in TSK/+ mice. Additionally, CD19 loss in TSK/+ mice upregulated surface IgM expression and completely abrogated hyper-γ-globulinemia and autoantibody production. CD19 deficiency also inhibited IL-6 production by TSK/+ B cells. Thus, chronic B cell activation resulting from augmented CD19 signaling in TSK/+ mice leads to Skin sclerosis possibly through IL-6 overproduction as well as autoimmunity.
Kazunori Inuzuka - One of the best experts on this subject based on the ideXlab platform.
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potential role of transforming growth factor beta 1 smad signaling in secondary lymphedema after cancer surgery
Cancer Science, 2020Co-Authors: Masaki Sano, Satoshi Hirakawa, Minoru Suzuki, Jun-ichi Sakabe, Mikako Ogawa, Seiji Yamamoto, Takanori Hiraide, Takeshi Sasaki, Naoto Yamamoto, Kazunori InuzukaAbstract:Secondary lymphedema often develops after cancer surgery, and over 250 million patients suffer from this complication. A major symptom of secondary lymphedema is swelling with Fibrosis, which lowers the patient's quality of life, even if cancer does not recur. Nonetheless, the pathophysiology of secondary lymphedema remains unclear, with therapeutic approaches limited to physical or surgical therapy. There is no effective pharmacological therapy for secondary lymphedema. Notably, the lack of animal models that accurately mimic human secondary lymphedema has hindered pathophysiological investigations of the disease. Here, we developed a novel rat hindlimb model of secondary lymphedema and showed that our rat model mimics human secondary lymphedema from early to late stages in terms of cell proliferation, lymphatic fluid accumulation, and Skin Fibrosis. Using our animal model, we investigated the disease progression and found that transforming growth factor-beta 1 (TGFB1) was produced by macrophages in the acute phase and by fibroblasts in the chronic phase of the disease. TGFB1 promoted the transition of fibroblasts into myofibroblasts and accelerated collagen synthesis, resulting in Fibrosis, which further indicates that myofibroblasts and TGFB1/Smad signaling play key roles in fibrotic diseases. Furthermore, the presence of myofibroblasts in Skin samples from lymphedema patients after cancer surgery emphasizes the role of these cells in promoting Fibrosis. Suppression of myofibroblast-dependent TGFB1 production may therefore represent an effective pharmacological treatment for inhibiting Skin Fibrosis in human secondary lymphedema after cancer surgery.
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Potential role of transforming growth factor‐beta 1/Smad signaling in secondary lymphedema after cancer surgery
Cancer science, 2020Co-Authors: Masaki Sano, Satoshi Hirakawa, Minoru Suzuki, Jun-ichi Sakabe, Mikako Ogawa, Seiji Yamamoto, Takanori Hiraide, Takeshi Sasaki, Naoto Yamamoto, Kazunori InuzukaAbstract:Secondary lymphedema often develops after cancer surgery, and over 250 million patients suffer from this complication. A major symptom of secondary lymphedema is swelling with Fibrosis, which lowers the patient's quality of life, even if cancer does not recur. Nonetheless, the pathophysiology of secondary lymphedema remains unclear, with therapeutic approaches limited to physical or surgical therapy. There is no effective pharmacological therapy for secondary lymphedema. Notably, the lack of animal models that accurately mimic human secondary lymphedema has hindered pathophysiological investigations of the disease. Here, we developed a novel rat hindlimb model of secondary lymphedema and showed that our rat model mimics human secondary lymphedema from early to late stages in terms of cell proliferation, lymphatic fluid accumulation, and Skin Fibrosis. Using our animal model, we investigated the disease progression and found that transforming growth factor-beta 1 (TGFB1) was produced by macrophages in the acute phase and by fibroblasts in the chronic phase of the disease. TGFB1 promoted the transition of fibroblasts into myofibroblasts and accelerated collagen synthesis, resulting in Fibrosis, which further indicates that myofibroblasts and TGFB1/Smad signaling play key roles in fibrotic diseases. Furthermore, the presence of myofibroblasts in Skin samples from lymphedema patients after cancer surgery emphasizes the role of these cells in promoting Fibrosis. Suppression of myofibroblast-dependent TGFB1 production may therefore represent an effective pharmacological treatment for inhibiting Skin Fibrosis in human secondary lymphedema after cancer surgery.
Jared Jagdeo - One of the best experts on this subject based on the ideXlab platform.
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The IL-4/IL-13 axis in Skin Fibrosis and scarring: mechanistic concepts and therapeutic targets
Archives of Dermatological Research, 2020Co-Authors: Julie K. Nguyen, Andrew Mamalis, Evan Austin, Alisen Huang, Jared JagdeoAbstract:Skin Fibrosis, characterized by excessive fibroblast proliferation and extracellular matrix deposition in the dermis, is the histopathologic hallmark of dermatologic diseases such as systemic sclerosis, hypertrophic scars, and keloids. Effective anti-scarring therapeutics remain an unmet need, underscoring the complex pathophysiologic mechanisms of Skin Fibrosis. The Th2 cytokines interleukin (IL)-4 and IL-13 have been implicated as key mediators in the pathogenesis of fibroproliferative disorders. The goal of this article is to summarize the current understanding of the role of the IL-4/IL-13 axis in wound healing and Skin Fibrosis. We conducted a literature search to identify research studies investigating the roles of IL-4 and IL-13 in fibrotic Skin diseases. While transforming growth factor-beta has long been regarded as the main driver of fibrotic processes, research into the cellular and molecular biology of wound healing has revealed other pathways that promote scar tissue formation. IL-4 and IL-13 are important mediators of Skin Fibrosis, supported by evidence from in vitro data, animal models of Fibrosis, and clinical studies. Overactive signaling of the IL-4/IL-13 axis contributes to the initiation and perpetuation of fibrotic Skin diseases. Further insights into the IL-4/IL-13 axis may reveal potential targets for the development of novel therapies that prevent or treat fibrotic Skin diseases.
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high fluence light emitting diode generated red light modulates characteristics associated with Skin Fibrosis
Journal of Biophotonics, 2016Co-Authors: Andrew Mamalis, Jared Jagdeo, Eugene Koo, Manveer Garcha, William J Murphy, Roslyn Rivkah IsseroffAbstract:Skin Fibrosis, often referred to as Skin scarring, is a significant international health problem with limited treatment options. The hallmarks of Skin Fibrosis are increased fibroblast proliferation, collagen production, and migration speed. Recently published clinical observations indicate that visible red light may improve Skin Fibrosis. In this study we hypothesize that high-fluence light-emitting diode-generated red light (HF-LED-RL) modulates the key cellular features of Skin Fibrosis by decreasing cellular proliferation, collagen production, and migration speed of human Skin fibroblasts. Herein, we demonstrate that HF-LED-RL increases reactive oxygen species (ROS) generation for up to 4 hours, inhibits fibroblast proliferation without increasing apoptosis, inhibits collagen production, and inhibits migration speed through modulation of the phosphoinositide 3-kinase (PI3K)/Akt pathway. We demonstrate that HF-LED-RL is capable of inhibiting the unifying cellular processes involved in Skin Fibrosis including fibroblast proliferation, collagen production, and migration speed. These findings suggest that HF-LED-RL may represent a new approach to treat Skin Fibrosis. LED advantages include low cost, portability, and ease of use. Further characterizing the photobiomodulatory effects of HF-LED-RL on fibroblasts and investigating the anti-fibrotic effects of HF-LED-RL in human subjects may provide new insight into the utility of this therapeutic approach for Skin Fibrosis.
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A single-blind, dose escalation, phase I study of high-fluence light-emitting diode-red light (LED-RL) on human Skin: study protocol for a randomized controlled trial
Trials, 2016Co-Authors: Ekaterina Kraeva, R. Rivkah Isseroff, Ted Wun, Jared JagdeoAbstract:Background Skin Fibrosis is involved in a variety of pathologic conditions ranging from scar formation secondary to surgery or trauma to immune-mediated processes. Skin Fibrosis is a significant international health problem with an estimated incidence of greater than 100 million people affected per year worldwide with few effective treatment options available. Preliminary in vitro data generated by our research group suggests that red light can function as a stand-alone treatment for Skin Fibrosis. To our knowledge, no prior clinical trials have been performed to determine the safety of high-fluence (dose) light-emitting diode-red light (LED-RL) phototherapy. The goal of this study is to evaluate the safety of LED-RL fluences from 160 J/cm^2 up to 640 J/cm^2 in healthy subjects. Methods/design This is a single-blind, dose escalation, randomized controlled, phase I study to evaluate the safety of high-fluence LED-RL on human Skin. The protocol for dose escalation requires subjects be enrolled sequentially in groups of five. Within each group, three subjects will be randomized to LED-RL phototherapy and two subjects randomized to mock therapy. Subjects in group 1 randomized to LED-RL phototherapy will receive the maximum recommended starting dose (160 J/cm^2). LED-RL dose will be escalated in subsequent groups (320 J/cm^2, 480 J/cm^2 and 640 J/cm^2). The maximally tolerated dose (MTD) is defined as the dose level below the dose producing unacceptable but reversible toxicity and is considered to be the upper limit of subject tolerance. After either a MTD has been established, or the study endpoint of 640 J/cm^2 has been achieved, an additional 27 LED-RL phototherapy subjects (for a total of 30) and 18 mock therapy subjects (for a total of 20) (determined randomly) will be enrolled. Each subject will receive a total of nine procedures, three times per week for three consecutive weeks. Discussion This study may provide important safety information on the effects of high-fluence LED-RL phototherapy on human Skin and help facilitate future phase II studies to evaluate the efficacy of high-fluence LED-RL as a potential noninvasive, safe, portable, at-home therapy for treatment of Skin Fibrosis. Trial registration ClinicalTrials.gov NCT02630303 . Registered on 9 December 2015.
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oxidative stress and Skin Fibrosis
Current Pathobiology Reports, 2014Co-Authors: Anjali Shroff, Andrew Mamalis, Jared JagdeoAbstract:Fibrosis is defined as increased fibroblast proliferation and deposition of extracellular matrix components with potential clinical ramifications including organ dysfunction and failure. Fibrosis is a characteristic finding of various Skin diseases which can have life-threatening consequences. These implications call for research into this topic as only a few treatments targeting Fibrosis are available. In this review, we discuss oxidative stress and its role in Skin Fibrosis. Recent studies have implicated the importance of oxidative stress in a variety of cellular pathways directly and indirectly involved in the pathogenesis of Skin Fibrosis. The cellular pathways by which oxidative stress affects specific fibrotic Skin disorders are also reviewed. Finally, we also describe various therapeutic approaches specifically targeting oxidative stress to prevent Skin Fibrosis. We believe oxidative stress is a relevant target, and understanding the role of oxidative stress in Skin Fibrosis will enhance knowledge of fibrotic Skin diseases and potentially produce targeted therapeutic options.
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NADPH oxidase enzymes in Skin Fibrosis: molecular targets and therapeutic agents
Archives of Dermatological Research, 2014Co-Authors: Olubukola Babalola, Andrew Mamalis, Jared JagdeoAbstract:Fibrosis is characterized by the excessive deposition of extracellular matrix components eventually resulting in organ dysfunction and failure. In dermatology, Fibrosis is the hallmark component of many Skin diseases, including systemic sclerosis, graft-versus-host disease, hypertrophic scars, keloids, nephrogenic systemic Fibrosis, porphyria cutanea tarda, restrictive dermopathy and other conditions. Fibrotic Skin disorders may be debilitating and impair quality of life. There are few FDA-approved anti-fibrotic drugs; thus, research in this area is crucial in addressing this deficiency. Recent investigations elucidating the pathogenesis of Skin Fibrosis have implicated endogenous reactive oxygen species produced by the multicomponent nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (Nox) enzyme complex. In this review, we discuss Nox enzymes and their role in Skin Fibrosis. An overview of the Nox enzyme family is presented and their role in the pathogenesis of Skin Fibrosis is discussed. The mechanisms by which Nox enzymes influence specific fibrotic Skin disorders are also reviewed. Finally, we describe the therapeutic approaches to ameliorate Skin Fibrosis by directly targeting Nox enzymes with the use of statins, p47phox subunit modulators, or GKT137831, a competitive inhibitor of Nox enzymes. Nox enzymes can also be targeted indirectly via scavenging ROS with antioxidants. We believe that Nox modulators are worthy of further investigation and have the potential to transform the management of Skin Fibrosis by dermatologists.
Manabu Fujimoto - One of the best experts on this subject based on the ideXlab platform.
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potential roles of interleukin 17a in the development of Skin Fibrosis in mice
Arthritis & Rheumatism, 2012Co-Authors: Yoshinobu Okamoto, Manabu Fujimoto, Minoru Hasegawa, Yasuhito Hamaguchi, Takashi Matsushita, Yoichiro Iwakura, Kazuhiko TakeharaAbstract:Objective Although transforming growth factor β (TGFβ) and connective tissue growth factor (CTGF) have been considered to play central roles in the pathogenesis of systemic sclerosis (SSc), other cytokines may also be crucial for the development of SSc. The aim of this study was to examine the roles of T helper cytokines in the development of Skin Fibrosis. Methods To compare the roles of Th1, Th2, and Th17 cytokines, we examined bleomycin-induced SSc in mice deficient for interferon-γ (IFNγ), interleukin-4 (IL-4), and IL-17A. The mechanism by which IL-17A contributes to bleomycin-induced Fibrosis was investigated in vivo and in vitro. The outcome of mice lacking IL-17A was also investigated in TSK-1 mice. Results The loss of IL-17A significantly attenuated bleomycin-induced Skin Fibrosis, whereas a deficiency of IFNγ or IL-4 did not. Leukocyte infiltration and the expression of TGFβ and CTGF messenger RNA in bleomycin-injected Skin were significantly reduced in IL-17A–deficient mice compared with wild-type (WT) mice. Daily bleomycin injections induced the expression of IL-17A in the Skin and potent IL-17A producers in splenic CD4+ T cells from WT mice. Furthermore, a Skin fibroblast cell line expressed increased TGFβ, CTGF, and collagen after the addition of recombinant IL-17A. IL-17A deficiency also attenuated Skin thickness in TSK-1 mice. Conclusion This study demonstrates that IL-17A contributes to Skin Fibrosis in 2 mouse models of SSc. These findings suggest that inhibition of IL-17A represents a therapeutic target for antagonizing fibrotic Skin disorders such as SSc.
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inducible costimulator ligand regulates bleomycin induced lung and Skin Fibrosis in a mouse model independently of the inducible costimulator inducible costimulator ligand pathway
Arthritis & Rheumatism, 2010Co-Authors: Chihiro Tanaka, Kazuhiko Takehara, Shinichi Sato, Manabu Fujimoto, Yasuhito Hamaguchi, Minoru HasegawaAbstract:Objective Systemic sclerosis is a connective tissue disease characterized by Fibrosis of the Skin and internal organs, including the lungs. Inducible costimulator (ICOS), which is expressed on activated T cells, and its ligand ICOSL, which is expressed on antigen-presenting cells, have been considered a single receptor–ligand pair. Although the ICOS/ICOSL pathway is known to play various roles in adaptive immunity, its roles in innate immunity and tissue Fibrosis remain unknown. Methods We assessed the roles of ICOS and ICOSL in tissue Fibrosis by administering bleomycin intratracheally or intradermally into mice deficient in ICOS and/or ICOSL. Tissue Fibrosis was evaluated by histologic or biochemical examination. Results ICOS deficiency attenuated the lung and Skin Fibrosis, whereas ICOSL deficiency aggravated it. Mice deficient in both ICOS and ICOSL exhibited accelerated Fibrosis, reflecting a dominant role of ICOSL over ICOS in this model. Interestingly, ICOSL expression on macrophages and B cells derived from bronchoalveolar lavage fluid was significantly elevated in ICOS-deficient mice as compared with wild-type mice during this process. Thus, the levels of ICOSL expression on B cells and macrophages were inversely associated with the severity of tissue Fibrosis. Conclusion Our results indicate that ICOSL expression on antigen-presenting cells plays a previously unknown regulatory role during the development of bleomycin-induced tissue Fibrosis that is independent of the ICOS/ICOSL pathway. Further studies will be needed to clarify the roles of ICOS and ICOSL in the development of systemic sclerosis.
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neutralizing monoclonal antibody to human connective tissue growth factor ameliorates transforming growth factor β induced mouse Fibrosis
Journal of Cellular Physiology, 2008Co-Authors: Yuka Ikawa, Manabu Fujimoto, Pohsing Ng, Koki Endo, Miki Kondo, Sonoko Chujo, Wataru Ishida, Fumiaki Shirasaki, Kazuhiko TakeharaAbstract:Skin fibrotic disorders such as systemic sclerosis (SSc) are characterized by an excessive accumulation of extracellular matrix (ECM) and are understood to develop under the influence of fibrogenic growth factors. To better understand the detailed mechanisms of persistent Fibrosis in SSc, we have previously established an animal model of Skin Fibrosis induced by exogenous application of growth factors. In this model, transforming growth factor-β (TGF-β) transiently induced subcutaneous Fibrosis and serial injections of connective tissue growth factor (CTGF) after TGF-β caused persistent Fibrosis. These results suggest that CTGF plays an important role in the development of persistent Skin Fibrosis and that CTGF may be a potential and specific therapeutic target in Skin Fibrosis. Therefore, the aim of the current study is to develop a neutralizing monoclonal antibody against human CTGF. We also investigated the neutralizing effect of the antibodies in our animal model. Firstly, by using the DNA immunization method, we developed a panel of anti-CTGF antibodies recognizing the native conformation of human CTGF. Next, to examine the anti-fibrosing effects of these antibodies, newborn B6 mice received subcutaneous injections of TGF-β for 3 days with either anti-CTGF neutralizing antibodies or control purified immunoglobulin. Anti-CTGF antibodies significantly reduced Skin Fibrosis and collagen contents compared with the control group. These results suggest that our anti-CTGF antibodies are capable of blocking the development of Skin Fibrosis at least partially and these anti-CTGF neutralizing antibodies may be useful as the feasible strategy to treat Skin fibrotic diseases as SSc. J. Cell. Physiol. 216: 680–687, 2008, © 2008 Wiley-Liss, Inc.
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baff antagonist attenuates the development of Skin Fibrosis in tight Skin mice
Journal of Investigative Dermatology, 2007Co-Authors: Takashi Matsushita, Kazuhiko Takehara, Manabu Fujimoto, Minoru Hasegawa, Kazuhiro Komura, Yukiyo Matsushita, Fumihide Ogawa, Rei Watanabe, Shinichi SatoAbstract:The tight-Skin (TSK/+) mouse, a genetic model for systemic sclerosis (SSc), develops cutaneous Fibrosis and autoimmunity. Although immunological abnormalities have been demonstrated in TSK/+ mice, the roles of B-cell-activating factor belonging to the tumor necrosis factor family (BAFF), a potent B-cell survival factor, have not been investigated. Serum BAFF levels in TSK/+ mice were examined by ELISA. Newborn TSK/+ mice were treated with BAFF antagonist, and then Skin Fibrosis of 8-week-old mice was assessed. Serum BAFF levels were significantly elevated in TSK/+ mice. Remarkably, BAFF antagonist inhibited the development of Skin Fibrosis, hyper-γ-globulinemia, and the autoantibody production in TSK/+ mice. The Skin from TSK/+ mice showed upregulated expressions of fibrogenic cytokines, such as IL-6 and IL-10, while BAFF antagonist significantly suppressed them. Reciprocally, BAFF antagonist augmented antifibrogenic cytokines, such as IFN-γ, in the Skin of TSK/+ mice. Furthermore, TSK/+ B cells with BAFF stimulation had a significantly enhanced ability to produce IL-6. The results suggest that BAFF/BAFF receptor system is critical for the development of Skin Fibrosis in TSK/+ mice and could be a potent therapeutical target.
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b lymphocyte depletion reduces Skin Fibrosis and autoimmunity in the tight Skin mouse model for systemic sclerosis
American Journal of Pathology, 2006Co-Authors: Minoru Hasegawa, Manabu Fujimoto, Yasuhito Hamaguchi, Takashi Matsushita, Yukiyo Matsushita, Koichi Yanaba, Jeandavid Ouaziz, Junji Uchida, Mayuka Horikawa, Kazuhiro KomuraAbstract:Systemic sclerosis (scleroderma) is an autoimmune disease characterized by excessive extracellular matrix deposition in the Skin. A direct role for B lymphocytes in disease development or progression has remained controversial, although autoantibody production is a feature of this disease. To address this issue, Skin sclerosis and autoimmunity were assessed in tight-Skin mice, a genetic model of human systemic sclerosis, after circulating and tissue B-cell depletion using an anti-mouse CD20 monoclonal antibody before (day 3 after birth) and after disease development (day 56). CD20 monoclonal antibody treatment (10 to 20 μg) depleted the majority (85 to 99%) of circulating and tissue B cells in newborn and adult tight-Skin mice by days 56 and 112, respectively. B-cell depletion in newborn tight-Skin mice significantly suppressed (∼43%) the development of Skin Fibrosis, autoantibody production, and hypergammaglobulinemia. B-cell depletion also restored a more normal balance between Th1 and Th2 cytokine mRNA expression in the Skin. By contrast, B-cell depletion did not affect Skin Fibrosis, hypergammaglobulinemia, and autoantibody levels in adult mice with established disease. Thereby, B-cell depletion during disease onset suppressed Skin Fibrosis, indicating that B cells contribute to the initiation of systemic sclerosis pathogenesis in tight-Skin mice but are not required for disease maintenance.
Sandeep K Agarwal - One of the best experts on this subject based on the ideXlab platform.
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role of stat3 in Skin Fibrosis and transforming growth factor beta signalling
Rheumatology, 2018Co-Authors: Mesias Pedroza, Shervin Assassi, David J Tweardy, Sandeep K AgarwalAbstract:Objective SSc is an autoimmune disease characterized by progressive Fibrosis of the Skin and internal organs. IL-6 and related cytokines that signal through STAT3 have been implicated in the pathogenesis of SSc and mouse models of Fibrosis. The aim of this study was to investigate the efficacy of inhibiting STAT3 in the development of Fibrosis in two mouse models of Skin Fibrosis. Methods Biopsy samples of Skin from SSc patients and healthy control subjects were used to determine the expression pattern of phosphotyrosyl (pY705)-STAT3. C188-9, a small molecule inhibitor of STAT3, was used to treat Fibrosis in the bleomycin-induced Fibrosis model and Tsk-1 mice. In vitro studies were performed to determine the extent to which STAT3 regulates the fibrotic phenotype of dermal fibroblasts. Results Increased STAT3 and pY705-STAT3 was observed in SSc Skin biopsies and in both mouse models of SSc. STAT3 inhibition with C188-9 resulted in attenuated Skin Fibrosis, myofibroblast accumulation, pro-fibrotic gene expression and collagen deposition in both mouse models of Skin Fibrosis. C188-9 decreased in vitro dermal fibroblast production of fibrotic genes induced by IL-6 trans-signalling and TGF-β. Finally, TGF-β induced phosphotyrosylation of STAT3 in a SMAD3-dependent manner. Conclusion STAT3 inhibition decreases dermal Fibrosis in two models of SSc. STAT3 regulates dermal fibroblasts function in vitro and can be activated by TGF-β. These data suggest that STAT3 is a potential therapeutic target for dermal Fibrosis in diseases such as SSc.
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targeting of cadherin 11 decreases Skin Fibrosis in the tight Skin 1 mouse model
PLOS ONE, 2017Co-Authors: Mesias Pedroza, Robert L Welschhans, Sandeep K AgarwalAbstract:Objective Systemic sclerosis (SSc) is an autoimmune disease clinically manifesting as progressive Fibrosis of the Skin and internal organs. Cadherin-11 (CDH11) expression is increased in fibrotic Skin and lung tissue. Targeting CDH11 may be an effective approach to treating Fibrosis. We hypothesize that targeting CDH11 will decrease Fibrosis in the tight Skin-1 (Tsk-1) mouse model. Methods CDH11 expression was determined in the Tsk-1 mouse model using quantitative real time PCR and immunofluorescence (IF). Inhibitory anti- CDH11 monoclonal antibodies were tested in Tsk-1 mice for their ability to decrease hypodermal Fibrosis. Results Expression of CDH11 was increased in fibrotic Skin from Tsk-1 mice compared to pallid controls. IF staining demonstrated that CDH11 expression localized to fibroblasts within the hypodermis of fibrotic Skin. Treatment with inhibitory anti-CDH11 monoclonal antibodies decreased hypodermal thickness and fibrotic mediators in Tsk-1 mice compared to control antibodies. Conclusions These data demonstrate an important role for CDH11 in the development of Skin Fibrosis in Tsk-1 mice. These data add to the growing evidence for the important role of CDH11 in tissue Fibrosis and fibrotic disease such as systemic sclerosis.
