Animal Models Of Scleroderma Research Articles

Lead generation from N-[benzyl(4-phenylbutyl)carbamoyl]amino acid as a novel LPA1 antagonist for the treatment of systemic sclerosis

Lysophosphatidic acid (LPA), a bioactive phospholipid, binds to the G protein-coupled LPA1 receptor on the surfaces of immune cells, to promote progression of fibrosis of the skin and organs through inducing infiltration of immune cells into tissues, chemokine production, inflammatory cytokine production, and fibroblast transformation. Anti-fibrotic effects of LPA1 blockade have been reported in animal models of scleroderma and scleroderma patients. In the study reported herein, we identified the novel urea compound 5 as a hit compound with LPA1 antagonist activity from our in-house library and synthesized the lead compound TP0541640 (18) by structural transformation utilizing a structure-based drug design (SBDD) approach. Compound 18 possessed potent in vitro LPA1 antagonist activity and exhibited a dose-dependent inhibitory effect against LPA-induced histamine release in mice. Furthermore, 18 significantly suppressed collagen production and skin thickening in a mouse model of bleomycin-induced skin fibrosis. Herein, we describe the compound design strategies and in vivo studies in greater detail.

The convergence of fibrosis and immune pathways: 5-HT2 and 5-HT2B antagonists attenuate profibrotic phenotype in human pancreatic stellate cells by modulating signal transducer and activator of transcription 3 phosphorylation

Background: Immune mechanisms are believed to play an important role in the pathogenesis of pancreatic inflammation and fibrosis. Transforming growth factor β1-mediated mechanisms are well known; however, an effective treatment option is yet not available. Serotonin (5-HT) is known to induce fibrosis in carcinoid tumors and diseases such as scleroderma and blocking 5-HT has shown promise in the attenuation of fibrosis in animal models of scleroderma. Herein, we evaluated the role of 5-HT in pancreatic fibrosis and its reversal with antagonists of 5-HT. Methodology: Pancreatic stellate cells (PSCs) were cultured from the two patients of pancreatic cancer undergoing pancreaticoduodenectomy. PSCs were cultured in the presence of 5-HT and as per the disease mimicking strategy (PSCs cultured with 5-HT first followed by 5-HT antagonist (terguride) and 5-HT2Bantagonist (SB204741) for 24 h and pretreatment strategy, PSCs treated with 5-HT antagonists first followed by 5-HT. mRNA expression of profibrotic genes (col1A1, Col1A2, ACTA-2, and CTGF) and Western blot analysis of signal transducer and activator of transcription 3 (STAT-3) and Smad-3 proteins was carried out. Results: 5-HT-induced profibrotic genes mRNA expression in PSCs was significantly reversed by 5-HT antagonists, terguride and SB204741, to a large extent. Pretreatment strategy was more effective in the amelioration of profibrotic potential. SB204741, 5-HT2Bantagonist was more effective than terguride. 5-HT antagonists mediated their effect by reducing the phosphorylation of noncanonical pathway mediator pSTAT3 more significantly then canonical pathway mediator pSmad-3. Conclusion: 5-HT induces profibrotic potential in human PSCs and inhibitors of 5-HT receptors, Terguride and SB 204,741 ameliorate it by reducing the phosphorylation of STAT-3 and Smad-3, more so in pretreatment strategy. 5-HT inhibitors may have a potential to ameliorate fibrosis in pancreas.

Sirtuins and Accelerated Aging in Scleroderma.

Premature activation of aging-associated molecular mechanisms is emerging as an important contributor to many diseases, including scleroderma. Among central regulators of the aging process are a group of histone deacetylases called sirtuins (SIRTs). Recent findings implicate these molecules as pathophysiological players in scleroderma skin and lung fibrosis. The goal of this article is to review recent studies on the involvement of SIRTs in scleroderma from the perspective of aging-related molecular mechanisms. Despite a degree of controversy in this rapidly developing field, the majority of data suggest that SIRT levels are decreased in tissues from patients with scleroderma compared to healthy controls as well as in animal models of scleroderma. Molecular studies reveal several mechanisms through which declining SIRT levels contribute to fibrosis, with the most attention given to modulation of the TGF-β signaling pathway. Activation of SIRTs in cell culture and in animal models elicits antifibrotic effects. Declining SIRT levels and activity are emerging as pathophysiological contributors to scleroderma. Restoration of SIRTs may be therapeutic in patients with scleroderma.

The impact of high-dose narrowband ultraviolet A1 on dermal thickness, collagen and matrix-metalloproteinases in animal model of scleroderma

ObjectiveThe main purpose of the present study was to define the impact of high-dose of 365±5nm ultraviolet A1 (UVA1) on dermal fibrosis in the pre-established, bleomycin-induced mouse model of scleroderma. MethodsDBA/2 strain mice with the pre-established, bleomycin-induced scleroderma were irradiated with cumulative UVA1 dose of 1200J/cm2 and in parallel were challenged with prolonged administration of bleomycin. Non-treated groups served as the control. Light source emitting a narrow band UVA1 light of 365±5nm and 21mW/cm2 power density was used in the study. Histological analysis was performed for the evaluation of dermal thickness. The expressions of matrix-metalloproteinase-1 (MMP-1), matrix-metalloproteinase-3 (MMP-3), collagen types I and III were evaluated by immunohistochemical analyses. The Mann - Whitney U test was used for statistical analysis. ResultsDermal thickness in mice injected with bleomycin during all the experiment (8weeks) and irradiated with UVA1 for the last 5weeks was significantly lower than that in mice challenged only with bleomycin for 8weeks (253.96±31.83μm and 497.43±57.83μm, respectively; P=0.002). The dermal thickness after phototherapy was lower as compared with the pre-existing fibrotic changes observed after 3weeks of bleomycin injections (253.96±31.83μm and 443.87±41.76μm, respectively; P=0.002). High-dose of UVA1 induced the 5.8- and 5.2-fold increase in MMP-1 and MMP-3 expressions, respectively, and the 1.2- and 1.4-fold decrease in collagen type I and collagen type III expressions in the pre-established, bleomycin-induced scleroderma model as compared to that in the control non-irradiated mice (P=0.002). ConclusionsOur study has demonstrated that a cumulative 365±5nm UVA1 radiation dosage of 1200J/cm2 not only prevents the progression of dermal fibrosis, but also induces a regression of pre-existing fibrotic changes.

Intradermal Injections of Bleomycin to Model Skin Fibrosis.

Systemic sclerosis (scleroderma) is a fibrotic condition characterized by immunologic abnormalities, vascular injury, and increased accumulation of extracellular matrix proteins in the affected organs. Although the etiology of scleroderma has not yet been fully elucidated, a growing body of evidence suggests that extracellular matrix overproduction by activated fibroblasts results from a complex interaction among endothelial cells, immunocytes, and fibroblasts, involving a number of mediators such as cytokines, chemokines, growth factors, and their receptors. For a better understanding of the pathophysiology of scleroderma, animal models are important tools. They reproduce several histological as well as biochemical aspects resembling human scleroderma, and we can learn lots of new findings through animal studies. On the other hand, it must be emphasized that there are no animal models so far exhibiting all the aspects of human scleroderma, and studying animal models cannot answer all the problems of human scleroderma. This paper introduces current concepts of various animal models for scleroderma and discusses their advantages/disadvantages, contribution to our understanding of the pathogenesis, and therapeutic approach for human scleroderma.

Animal models of scleroderma: recent progress

We discuss recent advances in evaluating and optimizing animal models of systemic sclerosis (SSc). Such models could be of value for illuminating etiopathogenesis using hypothesis-testing experimental approaches, for developing effective disease-modifying therapies, and for uncovering clinically relevant biomarkers. We describe recent advances in previously reported and novel animal models of SSc. The limitations of each animal model and their ability to recapitulate the pathophysiology of recognized molecular subsets of SSc are discussed. We highlight attrition of dermal white adipose tissue as a consistent pathological feature of dermal fibrosis in mouse models, and its relevance to SSc-associated cutaneous fibrosis. Several animal models potentially useful for studying SSc pathogenesis have been described. Recent studies highlight particular strengths and weaknesses of selected models in recapitulating distinct features of the human disease. When used in the appropriate experimental setting, and in combination, these models singly and together provide a powerful set of in-vivo tools to define underlying mechanisms of disease and to develop and evaluate effective antifibrotic therapies.

Animal Models of Scleroderma: Current State and Recent Development

Systemic sclerosis (SSc) is a multisystem connective tissue disease characterized by three cardinal features: immunological abnormalities, vasculopathy, and fibrosis of skin and certain internal organs. Although several animal models recapitulating selected aspects of SSc have been reported, the absence of models fulfilling the full clinical picture of SSc has hindered progress in the development and testing of therapy for this disease. In recent years, three new inducible animal models have revealed the critical importance of reactive oxygen species, angiotensin II, and the combination of DNA topoisomerase I immunization and IL-6 induction in fibrosis of SSc. In addition, two genetic animal models have revealed the potential involvement of transcription factors, Fra-2 and Fli1, in the fibrosis and vasculopathy of SSc. These new animal models provide important insights into specific pathological processes of SSc and novel therapeutic targets that may lead to more effective treatment of this incurable disease.

Collagen Content in Skin and Internal Organs of the Tight Skin Mouse: An Animal Model of Scleroderma

The Tight Skin mouse is a genetically induced animal model of tissue fibrosis caused by a large in-frame mutation in the gene encoding fibrillin-1 (Fbn-1). We examined the influence of gender on the collagen content of tissues in C57BL/6J wild type (+/+) and mutant Tight Skin (Tsk/+) mice employing hydroxyproline assays. Tissue sections were stained with Masson's trichrome to identify collagen in situ. Adult Tsk/+ mice skin contains ~15% more collagen, on average, than skin from +/+ mice of the same gender. The heart of Tsk/+ males had significantly more collagen than that of +/+ males. No significant gender differences were found in lungs and kidney collagen content. Overall, the collagen content of Tsk/+ males and +/+ males was higher than that of their Tsk/+ and +/+ female counterparts, respectively. Our data confirm increased deposition of collagen in skin and hearts of Tsk/+ mice; however, the effects of the Tsk mutation on collagen content are both tissue specific and gender specific. These results indicate that comparative studies of collagen content between normal and Tsk/+ mice skin and internal organs must take into account gender differences caused by expression of the androgen receptor.

Effectiveness of Palosuran in Bleomycin-Induced Experimental Scleroderma

Systemic sclerosis (SSc) is a disease characterized by skin and internal organ involvement. There is progressive accumulation of extracellular matrix components in the skin and involved organs. Tissue fibrosis is the prominent reason for mortality, and still, there is no satisfactory treatment. The aim of this study was to evaluate the effects of urotensin-II (U-II) antagonist palosuran in an animal model of scleroderma. We also planned to measure U-II, endothelin-1 (ET-1), and transforming growth factor-β1 (TGF-β1) levels, as well as the association of these levels with dermal thickness. Twenty-four male mice were included in this study and they were divided into three groups--group 1: control group, group 2: fibrosis group, and group 3: fibrosis + palosuran treatment group. Fibrosis + palosuran treatment in group 3 reduced ET-1, U-II, and TGF-β1 levels. In total, the diminished values were statistically significant in the ET-1 and TGF-β1 levels (p < 0.05). Dermal thickness was higher in the fibrosis group, when compared with the other groups. There was no significant relationship between dermal thickness and ET-1, U-II, or TGF-β1 levels (p > 0.05). It is believed that U-II is an important mediator in SSc, and its antagonism with palosuran could be a new treatment choice in SSc.

Stem cell therapy: resetting autoimmunity or postponing the inevitable?

Autoimmune diseases (ADs) comprise a heterogeneous group of conditions characterized by the presence of autoantibodies and/or T- or B-lymphocyte reactivity against autoantigens. In many conditions the precise relationship between autoimmune responses and clinical features remains to be defined, but the prevailing notion is that failure of central or peripheral immune tolerance leading to autoimmunity precedes clinically overt autoimmune disease which in the case of rheumatic autoimmune conditions is characterized by systemic inflammation, vasculopathy and signs and symptoms of musculoskeletal involvement. Except for rheumatoid arthritis (RA), rheumatic autoimmune diseases are rare, affecting less than 1% of the population. Nevertheless, they account for a high share of public health expenditure, due to their chronic debilitating nature [Gabriel and Michaud, 2009]. It is not therefore surprising that new therapeutic avenues are constantly being explored. While biologicals have resulted in major breakthroughs in the treatment of RA and juvenile idiopathic arthritis (JIA), connective tissue diseases such as systemic lupus erythematosus (SLE) and systemic sclerosis (SSc) still pose major challenges to clinicians seeking effective treatment options. Biologicals which interfere with the immune response such as rituximab (anti-CD20 mAb) and abatacept (CTLA4-Ig) have not been proven more effective than placebo in controlled clinical trials, which contrasts with the positive collective rituximab experience from large case series. Belimumab (anti-BAFF mAb) is the first new drug to be licensed for use in SLE for several decades, but its efficacy is modest, and its place in the treatment paradigm of lupus remains to be established. Imatinib was hailed as a promising drug for the treatment of systemic sclerosis based on its mechanism of action and on studies in animal models of scleroderma, but it is unlikely that its clinical development in systemic sclerosis will be pursued following disappointing results from pilot studies. Conventional immunosuppressive drugs including glucocorticoids, cyclophosphamide, azathioprine, methotrexate and mycophenolate mofetil therefore still remain the cornerstone in the treatment of connective tissue diseases. However, long-term drug-free remissions are rare and adverse drug reactions and clinical sequelae of long-term use contribute to compliance problems.

B-Cell Depletion Therapy in Systemic Sclerosis: Experimental Rationale and Update on Clinical Evidence

Systemic sclerosis (SSc) is a systemic rheumatic disease with poor prognosis since therapeutic options are limited. Recent evidence from animal models suggests that B-cells may be actively involved in the fibrotic process. B-cells from tight skin mice, an animal model of scleroderma, display a “hyperresponsive” phenotype; treatment with rituximab (RTX) significantly attenuates skin fibrosis in this animal model. In humans, B-cell infiltration is a prominent finding in most lung biopsies obtained from patients with SSc-associated interstitial lung disease. Several open label studies have assessed the clinical efficacy of RTX in SSc. In most patients skin fibrosis improved; lung function either improved or remained stable. Definite conclusions regarding the clinical efficacy of RTX in SSc cannot be drawn but further exploration with a multicenter, randomized study is warranted.

Animal models of scleroderma: fresh insights

Recent years have seen the advent and progress in our understanding of fibrosis and vasculopathy in systemic sclerosis, scleroderma (SSc) largely mediated through the development and study of novel animal models. The most well studied animal models of SSc involve the bleomycin model of induced fibrosis and the Tsk/+ model. However, even though these models provide useful insights into the pathogenesis of fibrosis and vasculopathy, they do not mimic the disease accurately. Several mouse models have been developed that have specifically focused on the vasculopathy of SSc and have yielded relevant insights into this disorder further highlighting the novel mechanisms that may be responsible for this pathological feature. Furthermore, the contribution of the innate immune system mediated by the inflammasome in the induction of fibrosis has also demonstrated significant insights, possibly implicating an etiological mechanism of SSc. And recent transgenic or knockout animal models have emphasized the relevance of macrophage chemoattractant protein-1 (MCP-1), alpha-melanocyte stimulating hormone (α-MSH), and peroxisome proliferator-activated receptor-gamma (PPARγ) in fibrosis. Recent advances in animal models of SSc have elucidated the involvement of relevant proteins that appear to mediate vasculopathy and also implicated the involvement of the innate immune system in fibrosis. These models have identified novel therapeutic targets that may lead to more effective treatments for this incurable disease.

Animal models of scleroderma: lessons from transgenic and knockout mice

The underlying pathogenesis of systemic sclerosis (SSc; scleroderma) involves a complex interplay of inflammation, fibrosis and vasculopathy that is incompletely understood. In this article, we highlight the important contributions that recent preclinical research has made to the knowledge base of pathogenesis and therapeutics in SSc, describe some of the newly developed models available for further investigation and discuss future research opportunities in this fascinating area. Several well characterized SSc models are available for the study of fibrosis. However, recent study on transgenic and knockout models has advanced knowledge both in fibrosis research and in vascular disease in SSc. In the present review, we focus on models in which altered signalling, particularly transforming growth factor-beta (TGF-beta), is limited to fibroblasts. We discuss contemporary models of SSc vascular disease, transgenesis in fibrocyte research, the contribution to neurological signalling research and provide examples of how preclinical models have contributed to novel therapeutics development in SSc. We also look at how research from related disciplines impacts on the SSc knowledge base. These new models represent exciting advances. However, none completely recapitulates the vasculopathic and inflammatory components of this disease. These advances help to delineate the relative contributions of specific ligands, receptors, their signalling pathways and feedback mechanisms, in fibrotic and inflammatory processes and this will provide new targets for potential therapies in SSc.

Scleroderma – Pathophysiology

Scleroderma is a fibrotic condition characterized by immunological abnormalities, vascular injury and increased accumulation of extracellular matrix proteins in the skin. Although the etiology of scleroderma has not yet been fully elucidated, a growing body of evidence suggests that extracellular matrix overproduction by activated fibroblasts results from complex interactions among endothelial cells, lymphocytes, macrophages, and fibroblasts via a number of mediators, such as cytokines, chemokines and growth factors. There is also likely to be a genetic susceptibility to the disease. Recent investigations have further suggested that reactive oxygen species (ROS) and apoptosis are involved in scleroderma. Animal models are indispensable tools for understanding the complex pathophysiology of scleroderma. In this review, current findings on the pathophysiology of human, as well as animal models of scleroderma are described, which may strengthen our understanding of the pathogenesis of, and assist in exploring new treatments for, scleroderma.

Radiation-induced skin injury in the animal model of scleroderma: implications for post-radiotherapy fibrosis

BackgroundRadiation therapy is generally contraindicated for cancer patients with collagen vascular diseases (CVD) such as scleroderma due to an increased risk of fibrosis. The tight skin (TSK) mouse has skin which, in some respects, mimics that of patients with scleroderma. The skin radiation response of TSK mice has not been previously reported. If TSK mice are shown to have radiation sensitive skin, they may prove to be a useful model to examine the mechanisms underlying skin radiation injury, protection, mitigation and treatment.MethodsThe hind limbs of TSK and parental control C57BL/6 mice received a radiation exposure sufficient to cause approximately the same level of acute injury. Endpoints included skin damage scored using a non-linear, semi-quantitative scale and tissue fibrosis assessed by measuring passive leg extension. In addition, TGF-β1 cytokine levels were measured monthly in skin tissue.ResultsContrary to our expectations, TSK mice were more resistant (i.e. 20%) to radiation than parental control mice. Although acute skin reactions were similar in both mouse strains, radiation injury in TSK mice continued to decrease with time such that several months after radiation there was significantly less skin damage and leg contraction compared to C57BL/6 mice (p < 0.05). Consistent with the expected association of transforming growth factor beta-1 (TGF-β1) with late tissue injury, levels of the cytokine were significantly higher in the skin of the C57BL/6 mouse compared to TSK mouse at all time points (p < 0.05).ConclusionTSK mice are not recommended as a model of scleroderma involving radiation injury. The genetic and molecular basis for reduced radiation injury observed in TSK mice warrants further investigation particularly to identify mechanisms capable of reducing tissue fibrosis after radiation injury.

Mouse model of dermal fibrosis induced by one-time injection of bleomycin-poly(L-lactic acid) microspheres

Animal models are useful tools to study various aspects of human diseases. Bleomycin (BLM)-induced scleroderma mouse has been widely investigated as an animal model of scleroderma. Repeated injections of BLM, either daily or every other day, for 3-4 weeks are required to induce scleroderma in mice. Poly(L-lactic acid) (PLA) is a biodegradable, biocompatible and bioabsorbable device that has been widely investigated for controlled drug release. In this study, we fabricated BLM-containing PLA microspheres and subcutaneously injected them into C3H mice for only one time. Treated skins were harvested at days 7 and 21. Then, histological examination and collagen content measurement assay were performed. The mRNA expression of alpha1(I) collagen (COL1A1), monocyte chemoattractant protein-1 (MCP-1), TGF-beta(1) and connective tissue growth factor (CTGF) were quantified by real-time PCR. Dermal fibrosis was histologically observed at day 7 after injection and remained present at day 21. Tissue responses against BLM-PLA microspheres alone were mild. Soluble collagen content and expression level of alpha1(I) collagen mRNA were significantly elevated at day 21. Expression levels of MCP-1 mRNA and TGF-beta(1) mRNA at day 7 and CTGF mRNA at day 21 were also elevated. The present study demonstrated for the first time that one-time injection of BLM-PLA microspheres can induce dermal fibrosis in C3H mice. BLM-PLA microspheres thus offer a labour-saving, simple and powerful tool to establish an animal model of BLM-induced dermal fibrosis.

Application advances in animal models for scleroderma

硬皮病是一种自身免疫性结缔组织疾病,严重影响患者的生活质量.该病的病因和发病机制尚未完全明了,临床上也无理想的治疗方法,在进行基础研究时患者依从性相对较差.因此建立硬皮病的动物模型,对于深入研究本病的发病机制和评价治疗方法有重要意义.综述近十年来利用不同品系的鼠科动物建立的各种硬皮病模型,以及利用这些模型从不同的角度阐明硬皮病可能的发病机制,并在新药筛选和新疗法评价方面取得的一些进展。

Transcription factor T-bet regulates skin sclerosis through its function in innate immunity and via IL-13

Tissue remodeling with fibrosis is a predominant pathophysiological mechanism of many human diseases. Systemic sclerosis is a rare, often lethal, disorder of unknown etiology manifested by dermal fibrosis (scleroderma) and excessive connective tissue deposition in internal organs. Currently, there are no available antifibrotic therapeutics, a reflection of our lack of understanding of this process. Animal models of scleroderma are useful tools to dissect the transcription factors and cytokines that govern fibrosis. A disproportionate increase of type 2 cytokines, like TGF-beta and IL-4, more than type 1 cytokines, like IFN-gamma, is thought to underlie the pathogenesis of scleroderma. In this study, we show that mice deficient in the transcription factor T-box expressed in T cells (T-bet), a master regulator of type 1 immunity, display increased sensitivity to bleomycin-induced dermal sclerosis. Despite the well-established role of T-bet in adaptive immunity, we also show that RAG2(-/-) mice, which lack T and B cells, are vulnerable to bleomycin-induced scleroderma and that RAG2/T-bet double-deficient mice maintain the increased sensitivity to bleomycin observed in T-bet(-/-) mice. Furthermore, overexpression of T-bet in T cells does not affect the induction of skin sclerosis in this model. Lastly, we show that IL-13 is the profibrotic cytokine regulated by T-bet in this model. Together, we conclude that T-bet serves as a repressor of dermal sclerosis through an IL-13-dependent pathway in innate immune cells. T-bet, and its transcriptional network, represent an attractive target for the treatment of systemic sclerosis and other fibrosing disorders.

Fibroblast expression of the coactivator p300 governs the intensity of profibrotic response to transforming growth factor β

Transforming growth factor beta (TGFbeta) induces profibrotic responses in normal fibroblasts, and plays a fundamental role in the pathogenesis of fibrosis in scleroderma (systemic sclerosis [SSc]). The intensity of cellular responses elicited by cytokines is modulated by transcriptional coactivators such as the histone acetylase p300. The objective of these studies was to delineate the physiologic role of p300 in Smad-dependent profibrotic responses elicited by TGFbeta. Ectopic p300 was transiently expressed in normal dermal fibroblasts. Cellular p300 levels were suppressed using p300-specific ribozymes. The regulation of gene expression was examined by transient transfection assays, Northern blotting, and immunoblot analysis. The expression of p300 in normal and scleroderma fibroblasts was evaluated by confocal microscopy and immunoblotting, and p300 levels in skin from mice with experimental scleroderma were assessed by immunohistochemistry. In normal fibroblasts, TGFbeta induced an increase in the levels of p300. Forced expression of ectopic p300 in these cells dramatically enhanced the magnitude of TGFbeta responses, whereas selective depletion of p300 using ribozyme resulted in abrogation of TGFbeta-induced collagen synthesis and promoter activity. Furthermore, TGFbeta lost its ability to induce Smad-dependent transcription in p300-depleted fibroblasts. These responses could be fully rescued with ectopic p300. Abrogation of Smad-mediated TGFbeta signaling was not due to alterations in the levels or the ligand-dependent phosphorylation or intracellular trafficking of endogenous Smads. Immunohistochemical analysis demonstrated substantially increased p300 expression in lesional skin from mice with chronic graft-versus-host disease, an animal model of scleroderma. Furthermore, levels of p300 were 2-3-fold higher in cultured fibroblasts derived from SSc patients than in fibroblasts from matched normal controls. These results establish, for the first time, that the coactivator histone acetylase p300, itself a target of TGFbeta regulation, is an essential component of the cellular TGFbeta signal transduction pathways mediating stimulation of collagen synthesis in fibroblasts. Since the cellular abundance of p300 appears to govern the intensity of profibrotic responses elicited by TGFbeta, elevated p300 expression in lesional tissue may contribute to the progression of skin fibrosis in scleroderma.

Characteristics of Animal Models for Scleroderma

Characteristics of Animal Models for Scleroderma