PDGF胶原纤维化 PDGF collagen fibrosis - PubMed 文献(第 2 页)
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PDGF胶原纤维化 的 PubMed 搜索结果(第 2 页)
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11. Involvement of PDGF in fibrosis and scleroderma: recent insights from animal models and potential therapeutic opportunities.
11. PDGF在纤维化和硬皮病中的参与：来自动物模型的最新见解及潜在治疗机会PMID:日期:2013-01-12[中文摘要] 纤维化是被称为硬皮病或系统性硬化症（SSc）的自身免疫性疾病的主要特征。近三年发表的研究表明，血小板衍生生长因子（PDGFs）在SSc相关纤维化中发挥核心作用。PDGFs还可能参与SSc相关的自身免疫和血管病变。PDGF信号通路已被充分了解，且PDGF受体表达于分泌胶原的成纤维细胞以及间充质干细胞和/或祖细胞上，这些细胞可能以深远且出人意料的方式影响SSc。尽管要完全理解PDGFs如何参与SSc仍有大量工作要做，但将PDGF抑制剂用作SSc治疗方法已引起广泛关注。
[英文摘要] Fibrosis is the principal characteristic of the autoimmune disease known as scleroderma or systemic sclerosis (SSc). Studies published within the last three years suggest central involvement of platelet-derived growth factors (PDGFs) in SSc-associated fibrosis. PDGFs may also be involved in SSc-associated autoimmunity and vasculopathy. The PDGF signaling pathway is well understood and PDGF receptors are expressed on collagen-secreting fibroblasts and on mesenchymal stem and/or progenitor cells that may affect SSc in profound and unexpected ways. Although much work remains before we fully understand how PDGFs are involved in SSc, there is much interest in using PDGF inhibitors as a therapeutic approach to SSc.
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12. Myofibroblast-specific YY1 promotes liver fibrosis.
12. 肌成纤维细胞特异性YY1促进肝纤维化PMID:日期:2019-05-10[中文摘要] 肝纤维化是多种慢性肝炎和肝损伤的共同结局。肌成纤维细胞通过细胞外基质（ECM）蛋白的积累，与肝纤维化的进展密切相关。然而，肌成纤维细胞中促纤维化基因及ECM蛋白转录调控的分子机制在很大程度上仍不清楚。我们利用他莫昔芬诱导的肌成纤维细胞特异性Cre表达小鼠品系，选择性敲除转录因子阴阳1（YY1），在此表明肌成纤维细胞中YY1的缺失可减轻四氯化碳诱导的肝纤维化。YY1敲除对肝纤维化的保护作用伴随着YY1突变小鼠肝组织中促纤维化基因和ECM蛋白表达的减少，包括TNF-α、TGF-β、PDGF、IL-6、α-SMA和Col1α1。此外，利用人肝星状细胞（HSC）系LX-2，我们发现通过siRNA处理敲低肌成纤维细胞中的YY1可抑制肌成纤维细胞增殖、α-SMA表达和胶原沉积。总之，我们的研究结果揭示了YY1在肝脏肌成纤维细胞中的特定作用，并为肝纤维化相关肝脏疾病提出了一种新的治疗策略。
[英文摘要] Liver fibrosis is a common consequence of various chronic hepatitis and liver injuries. The myofibroblasts, through the accumulation of extracellular matrix (ECM) proteins, are closely associated with the progression of liver fibrosis. However, the molecular mechanisms underlying transcriptional regulation of fibrogenic genes and ECM proteins in myofibroblasts remain largely unknown. Using tamoxifen inducible myofibroblast-specific Cre-expressing mouse lines with selective deletion of the transcription factor Yin Yang 1 (YY1), here we show that YY1 deletion in myofibroblasts mitigates carbon tetrachloride-induced liver fibrosis. This protective effect of YY1 ablation on liver fibrosis was accompanied with reduced expression of profibrogenic genes and ECM proteins, including TNF-α, TGF-β, PDGF, IL-6, α-SMA and Col1α1 in liver tissues from YY1 mutant mice. Moreover, using the human hepatic stellate cell (HSC) line LX-2, we found that knockdown of YY1 in myofibroblasts by siRNA treatment diminished myofibroblast proliferation, α-SMA expression, and collagen deposition. Collectively, our findings reveal a specific role of YY1 in hepatic myofibroblasts and suggest a new therapeutic strategy for hepatic fibrosis-associated liver diseases.
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13. Myofibroblasts. II. Intestinal subepithelial myofibroblasts.
13. 肌成纤维细胞。II. 肠道上皮下肌成纤维细胞PMID:期刊:The American journal of physiology PubMed日期:1999-08[中文摘要] 肠上皮下肌成纤维细胞（ISEMF）和Cajal间质细胞是肠道中已鉴定的两种肌成纤维细胞类型。肠道肌成纤维细胞可被多种生长因子激活并增殖，尤其是血小板衍生生长因子（PDGF）家族，包括PDGF-BB和干细胞因子（SCF），这是通过表达PDGF受体和SCF受体c-kit实现的。ISEMF已被证实在肠道器官发生中发挥重要作用，这些细胞分泌的生长因子和细胞因子可促进上皮修复和增殖，即创伤愈合。其在克罗恩病和胶原性结肠炎纤维化中的作用正在研究中。通过环氧合酶（COX）-1和COX-2的激活，ISEMF在某些促分泌剂刺激下可增强肠道离子分泌。通过形成阻止Na(+)扩散的上皮下屏障，它们创建了一个高渗区室，这可能解释了肠道能够逆不利渗透梯度转运液体的能力。通过旁分泌前列腺素和生长因子（如转化生长因子-β），ISEMF可能在结肠肿瘤发生和转移中发挥作用。息肉ISEMF中的COX-2可能是非甾体抗炎药（NSAIDs）的靶点，这可以解释家族性腺瘤性息肉病中肿瘤的消退以及NSAIDs对散发性结肠肿瘤发生的预防作用。需要更多研究来阐明这些多效性细胞的功能。
[英文摘要] Intestinal subepithelial myofibroblasts (ISEMF) and the interstitial cells of Cajal are the two types of myofibroblasts identified in the intestine. Intestinal myofibroblasts are activated and proliferate in response to various growth factors, particularly the platelet-derived growth factor (PDGF) family, which includes PDGF-BB and stem cell factor (SCF), through expression of PDGF receptors and the SCF receptor c-kit. ISEMF have been shown to play important roles in the organogenesis of the intestine, and growth factors and cytokines secreted by these cells promote epithelial restitution and proliferation, i.e., wound repair. Their role in the fibrosis of Crohn's disease and collagenous colitis is being investigated. Through cyclooxygenase (COX)-1 and COX-2 activation, ISEMF augment intestinal ion secretion in response to certain secretagogues. By forming a subepithelial barrier to Na(+) diffusion, they create a hypertonic compartment that may account for the ability of the gut to transport fluid against an adverse osmotic gradient. Through the paracrine secretion of prostaglandins and growth factors (e.g., transforming growth factor-beta), ISEMF may play a role in colonic tumorigenesis and metastasis. COX-2 in polyp ISEMF may be a target for nonsteroidal anti-inflammatory drugs (NSAIDs), which would account for the regression of the neoplasms in familial adenomatous polyposis and the preventive effect of NSAIDs in the development of sporadic colon neoplasms. More investigation is needed to clarify the functions of these pleiotropic cells.
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14. Thymosinβ4 alleviates cholestatic liver fibrosis in mice through downregulating PDGF/PDGFR and TGFβ/Smad pathways.
14. 胸腺素β4通过下调PDGF/PDGFR和TGFβ/Smad通路减轻小鼠胆汁淤积性肝纤维化PMID:期刊:日期:2019-09-19[中文摘要] 肝纤维化是一个重要的健康问题，缺乏充分且有效的治疗手段。本研究在胆管结扎（BDL）诱导的小鼠胆汁淤积性肝纤维化模型中，探讨了胸腺素β4（Tβ4）对肝纤维生成的影响及其潜在的分子机制。结果显示，外源性Tβ4显著降低了BDL小鼠的死亡率和肝脏/体重比。组织学检查和生化分析表明，BDL诱导了明显的门管区纤维化以及肝脏胶原含量的显著增加。然而，外源性Tβ4显著减轻了这些变化。实时定量PCR检测显示，Tβ4抑制了BDL诱导的多种纤维化基因表达增加，包括α-平滑肌肌动蛋白（α-SMA）、I型和III型胶原、纤连蛋白、TGFβ1、TGFβR II、Smad2、Smad3以及PDGFRβ。免疫组织化学和Western blot结果也显示，Tβ4降低了BDL小鼠肝组织中TGFβ1和PDGFRβ的蛋白水平。使用LX-2细胞的体外研究表明，Tβ4能够降低肝星状细胞中PDGFRβ和TGFβR II的水平。综上所述，本研究的结果提示，外源性Tβ4通过下调PDGF/PDGFR和TGFβ/Smad通路减轻了BDL诱导的胆汁淤积性肝纤维化。
[英文摘要] Liver fibrosis is an important health problem without adequate and effective therapeutics. In this study, effects of thymosinβ4 (Tβ4) on hepatic fibrogenesis and the underlying molecular mechanisms were explored in bile duct ligation (BDL)-induced mice cholestatic liver fibrosis model. Results showed exogenous Tβ4 significantly reduced the mortality and liver/body weight ratio in BDL mice. Histological examinations and biochemical analyses demonstrated that BDL induced evident portal fibrosis and a significant increase in hepatic collagen contents. However, these changes were significantly attenuated by exogenous Tβ4. Quantitative real-time PCR assays showed that Tβ4 suppressed BDL-induced increases in many fibrotic genes expression including α-smooth muscle actin (α-SMA), collagen I, III and fibronectin, TGFβ1, TGFβR II, Smad2, Smad3, and PDGFRβ. Results from immunohistochemistry and Western blots also showed that Tβ4 reduced TGFβ1 and PDGFRβ protein levels in the liver tissues of BDL mice. In vitro studies using LX-2 cells demonstrated that Tβ4 could decrease PDGFRβ and TGFβR II levels in hepatic stellate cells. Taken together, findings in our present studies suggested that exogenous Tβ4 alleviated BDL-induced cholestatic liver fibrosis through downregulating PDGF/PDGFR and TGFβ/Smad pathways.
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15. Evaluation of the flavonol-rich fraction of Rosa damascena in an animal model of liver fibrosis by targeting the expression of fibrotic cytokines, antioxidant/oxidant ratio and collagen cross-linking.
15. 在大鼠肝纤维化动物模型中通过靶向纤维化细胞因子表达、抗氧化/氧化比值及胶原交联来评估富含黄酮醇的大马士革玫瑰提取物PMID:日期:2023-10-03[中文摘要] 富含黄酮的大马士革玫瑰组分（FRFRD）含有抗氧化及活性化合物。因此，本研究旨在探讨富含槲皮素和山柰酚的FRFRD在四氯化碳（CCl4）诱导的肝纤维化中的作用。基于槲皮素和山柰酚的水平，采用高效液相色谱法（HPLC）分离并标准化FRFRD组分。在30只雄性Wistar大鼠中，通过CCl4诱导肝纤维化12周，并在最后4周给予三种浓度的FRFRD。随后，在评估肝脏血清标志物和纤维化参数后，检测转化生长因子-β1（TGF-β）、血小板衍生生长因子（PDGF）和赖氨酰氧化酶同源物2（Loxl2）基因的相对表达量，同时测定赖氨酰氧化酶活性和氧化标志物。与非治疗组相比，治疗组的纤维化标志物显示肝损伤逐步恢复（p < 0.01）。这些结果伴随TGF-β、PDGF和Loxl2基因表达的显著降低，以及赖氨酰氧化酶活性的下降（p < 0.001）。与纤维化组相比，治疗组的抗氧化作用表现为丙二醛（MDA）水平显著降低，过氧化氢酶（CAT）和谷胱甘肽过氧化物酶（GPx）活性升高（p < 0.01）。富含黄酮的大马士革玫瑰组分通过影响胶原交联并降低氧化和炎症水平来改善肝损伤。
[英文摘要] The flavonoid-rich fraction of Rosa damascena (FRFRD) contains antioxidant and active compounds. Therefore, this study aimed to investigate the role of FRFRD, rich in quercetin and kaempferol, in liver fibrosis induced by CCl4. The FRFRD fraction was separated and standardized by High-Performance Liquid Chromatography (HPLC) based on the levels of quercetin and kaempferol. Liver fibrosis was induced over CCl4 over 12 weeks in 30 male Wistar rats, and three concentrations of FRFRD were administered to them during the last four weeks. Subsequently, after evaluation of liver serum markers and fibrotic parameters, the relative expression of transforming growth factor-beta-1 (TGF-β), platelet-derived growth factor (PDGF), and lysyl oxidase homolog 2 (Loxl2) genes were assessed, along with the measurement of lysyl oxidase activity and oxidative markers. Fibrotic markers demonstrated progressive recovery of liver damage in the treated group compared to the non-treatment group (p < 0.01). These results were accompanied by a significant decrease in the expression of TGF-β, PDGF, and Loxl2 genes, as well as, a reduction in lysyl oxidase activity (p < 0.001). The antioxidant effects of the treatment were observed through a significant decrease in malondialdehyde (MDA) levels and an increase in catalase enzyme (CAT) and glutathione peroxidase (GPx) activity in the treatment group compared to the fibrotic group (p < 0.01). The flavonoid-rich fraction of Rosa damascena ameliorates liver damage by affecting collagen cross-linking and lowering oxidative and inflammatory levels.
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16. PDGF-Stimulated Corneal Keratocyte Motility and Migration Patterns on Aligned Collagen Fibrils Are Inhibited by Decorin.
16. PDGF刺激的角膜基质细胞在排列胶原纤维上的运动性和迁移模式被核心蛋白聚糖抑制PMID:日期:2026-07-30[中文摘要] 核心蛋白聚糖（decorin）是一种已被证明可抑制转化生长因子β1（TGF-β1）信号传导的蛋白聚糖，越来越多地被认为是一种潜在的抗纤维化药物，可用于辅助治疗角膜瘢痕和失明。核心蛋白聚糖还已知可与多种其他生长因子相互作用，例如血小板衍生生长因子（PDGF），后者已被证明可刺激角膜细胞迁移，以重新填充受损角膜的脱细胞区域。在其他组织中，核心蛋白聚糖已被证明可抑制PDGF介导的迁移并延长伤口愈合。然而，我们对核心蛋白聚糖在角膜基质环境中对PDGF信号传导影响的理解仍然有限。具体而言，迄今为止，尚无研究在独特组织的纤维状胶原细胞外基质（ECM）背景下探讨核心蛋白聚糖与PDGF之间的相互作用，而该基质提供了在伤口愈合过程中引导细胞迁移的拓扑线索。本研究的目的是使用一种类似于角膜基质ECM的核心蛋白聚糖包被的排列胶原纤维的体外模型来研究这种相互作用。通过该体外模型，我们证明核心蛋白聚糖抑制了PDGF-BB刺激的角膜基质细胞对二维（2D）排列胶原纤维ECM的响应，减少了细胞排列、运动性、PDGF受体β（PDGFRβ）磷酸化以及伤口闭合。我们观察到，当面对脱细胞伤口区域时，核心蛋白聚糖包被基质上的细胞比未包被纤维上的细胞迁移更加随机，且与底层排列胶原纤维的排列一致性更低，导致伤口闭合更慢。此外，核心蛋白聚糖涂层上PDGF-BB刺激的细胞分支增加、实心度降低，表明从PDGF-BB处理通常导致的细长双极形态向星状分支的角膜基质细胞表型转变。虽然核心蛋白聚糖似乎是抗TGF-β1介导纤维化的有效药物，但其与PDGF-BB的相互作用似乎对伤口愈合提出了其他挑战，在开发健康角膜伤口愈合疗法时应予以考虑。
[英文摘要] Decorin, a proteoglycan shown to inhibit transforming growth factor β1 (TGF-β1) signaling, has been increasingly considered as a potential anti-fibrotic agent to aid in therapies addressing corneal scarring and blindness. Decorin is also known to interact with a wide range of other growth factors, such as platelet-derived growth factor (PDGF), which has been shown to stimulate corneal cell migration to repopulate the decellularized region of the wounded cornea. In other tissues, decorin has been shown to inhibit PDGF-mediated migration and prolong wound healing. However, our understanding of the effect of decorin on PDGF signaling in the corneal stroma environment is limited. Specifically, thus far, there have been no studies investigating the interaction between decorin and PDGF in the context of the uniquely organized fibrillar collagen extracellular matrix (ECM), which provides topographic cues that guide cell migration during wound healing. The purpose of this study is to use an in vitro model of decorin-coated aligned collagen fibrils analogous to the corneal stroma ECM to investigate this interaction. With this in vitro model, we demonstrate that decorin inhibits the response of PDGF-BB-stimulated keratocytes to a 2-dimensional (2D) aligned collagen fibril ECM, reducing cell alignment, motility, PDGF receptor β (PDGFRβ) phosphorylation, and wound closure. We observed that when presented with a decellularized wound region, cells on the decorin-coated substrates migrated more randomly and were less aligned with the underlying aligned collagen fibrils than cells on uncoated fibrils, resulting in slower wound closure. Furthermore, PDGF-BB-stimulated cells on the decorin coating had increased branching and reduced solidity, representing a shift from the elongated, bipolar morphology typically resulting from PDGF-BB treatment towards the stellate, branched keratocyte phenotype. While decorin seems to be an effective agent against TGF-β1-mediated fibrosis, its interaction with PDGF-BB appears to present other challenges to wound healing that should be considered in the development of therapies for healthy corneal wound healing.
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17. [Cytokines and pulmonary fibroses].
17. [细胞因子与肺纤维化]PMID:日期:1993[中文摘要] 肺纤维化对应于间质和肺泡中胶原及其他细胞外基质蛋白的积聚。肺纤维化的生化和细胞机制仍知之甚少。肺泡炎细胞（巨噬细胞、淋巴细胞和中性粒细胞）在产生调节成纤维细胞增殖、趋化和分泌活性的因子方面发挥关键作用。在这些因子中，细胞因子（白细胞介素、干扰素和生长因子）发挥着明确但非常复杂的作用。某些细胞因子在体外刺激肺泡炎细胞的募集和活化，以及成纤维细胞的增殖、迁移和分泌活性。涉及的细胞因子如下：肿瘤坏死因子α（TNFα）、白细胞介素1（IL-1）、白细胞介素6（IL-6）、白细胞介素8（IL-8）、转化生长因子β（TGFβ）、血小板衍生生长因子（PDGF）、胰岛素样生长因子1（IGF-1）、纤连蛋白、单核细胞趋化蛋白1（MCP-1）。其他细胞因子，主要是干扰素（α、β或γ型：IFNα、IFNβ、IFNγ），在体外和体内抑制成纤维细胞的增殖和胶原产生。在人类肺纤维化病程中或实验条件下，上述大多数细胞因子在肺内产生过多。毫无疑问，它们在纤维化的发病机制中发挥重要作用，即使目前对其如何相互作用及在体外如何促进纤维化过程尚不十分清楚。某些可能调控纤维化的细胞因子尚待鉴定。未来，细胞因子及其抑制剂的应用或许能为肺纤维化提供新的治疗方法。
[英文摘要] Pulmonary fibrosis corresponds to an accumulation of collagens and other proteins of the extracellular matrix in the interstitium and alveoli. Biochemical and cellular mechanisms of pulmonary fibrogenesis remain poorly understood. The cells of the alveolitis (macrophages, lymphocytes and neutrophils) play a key role in producing the factors which regulate the proliferation, chemotactism and secretory activity of the fibroblasts. Amongst these factors the cytokines (interleukins, interferons and growth factors) play a definite but very complex role. Certain cytokines stimulate in vitro the attraction and activation of cells of the alveolitis, as well as the multiplication, migration and secretory activity of fibroblasts. The following cytokines are involved: tumour necrosis factor alpha: (TNF alpha), interleukin 1 (IL-1), interleukin 6 (IL-6) interleukin 8 (IL-8) transforming growth factor beta (TGF beta), platelet derived growth factor (PDGF), insulin like growth factor 1 (IGF-1), fibronectin, monocyte chemotactic protein 1: (MCP-1). Other cytokines, principally the interferons (of alpha, beta or gamma type: IFN alpha, IFN beta, IFN gamma) inhibit in vitro and in vivo the proliferation and the production of collagen by fibroblasts. During the course of human pulmonary fibrosis or in experimental situations, the majority of the cytokines mentioned above are produced in excess in the lung. Without doubt they play an important role in the pathogenesis of fibrosis, even if it is not yet very well known how they interact and contribute in vitro to the process of fibrogenesis. Certain cytokines potentially regulating in the fibrosis are yet to be identified. In the future the use of cytokines and of their inhibitors will perhaps provide new therapies in pulmonary fibrosis.
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18. Thrombin induces epithelial-mesenchymal transition and collagen production by retinal pigment epithelial cells via autocrine PDGF-receptor signaling.
18. 凝血酶通过自分泌PDGF受体信号通路诱导视网膜色素上皮细胞上皮-间充质转化及胶原产生PMID:日期:2013-12-19[中文摘要] 视网膜色素上皮（RPE）细胞向间充质细胞去分化（即上皮-间充质转化；EMT）及相关的胶原生成促进增生性玻璃体视网膜病变（PVR）的发生。在PVR患者中，眼内凝血级联反应被激活，并可能发挥重要的启动作用。因此，我们研究了凝血蛋白因子Xa和凝血酶对RPE细胞EMT及胶原生成的影响。用因子Xa或凝血酶刺激视网膜色素上皮细胞，并通过实时定量聚合酶链反应（RQ-PCR）、免疫荧光显微镜以及分别对培养上清液中胶原和PDGF-BB进行HPLC和ELISA检测，测定其对闭锁小带（ZO）-1、α-平滑肌肌动蛋白（α-SMA）、胶原及血小板衍生生长因子（PDGF）-B的影响。通过磷酸化分析及使用PDGF受体酪氨酸激酶抑制剂AG1296进行抑制研究，测定PDGF受体的激活情况。凝血酶降低ZO-1基因表达（P < 0.05），并增强编码α-SMA和1型胶原前α1链的基因表达（P < 0.05），提示发生EMT。此外，凝血酶刺激后ZO-1蛋白表达下降，而α-SMA和胶原生成增加。与凝血酶不同，因子Xa几乎不刺激RPE发生EMT。凝血酶明显诱导RPE产生PDGF-BB及PDGF-Rβ链磷酸化。此外，AG1296显著阻断凝血酶对EMT和胶原生成的影响。我们的研究结果表明，凝血酶通过自分泌激活PDGF受体信号通路，是RPE发生EMT的有效诱导因子。凝血级联反应诱导的RPE EMT可能因此促进PVR中纤维化视网膜膜的形成，并应被视为PVR的治疗靶点。
[英文摘要] De-differentiation of RPE cells into mesenchymal cells (epithelial-mesenchymal transition; EMT) and associated collagen production contributes to development of proliferative vitreoretinopathy (PVR). In patients with PVR, intraocular coagulation cascade activation occurs and may play an important initiating role. Therefore, we examined the effect of the coagulation proteins factor Xa and thrombin on EMT and collagen production by RPE cells. Retinal pigment epithelial cells were stimulated with factor Xa or thrombin and the effect on zonula occludens (ZO)-1, α-smooth muscle actin (α-SMA), collagen, and platelet-derived growth factor (PDGF)-B were determined by real-time quantitative-polymerase chain reaction (RQ-PCR), immunofluorescence microscopy, and HPLC and ELISA for collagen and PDGF-BB in culture supernatants, respectively. PDGF-receptor activation was determined by phosphorylation analysis and inhibition studies using the PDGF-receptor tyrosine kinase inhibitor AG1296. Thrombin reduced ZO-1 gene expression (P < 0.05) and enhanced expression of the genes encoding α-SMA and the pro-alpha1 chain of collagen type-1 (P < 0.05), indicating EMT. Also, ZO-1 protein expression declined on thrombin stimulation, whereas production of α-SMA and collagen increased. In contrast to thrombin, factor Xa hardly stimulated EMT by RPE. Thrombin clearly induced PDGF-BB production and PDGF-Rβ chain phosphorylation in RPE. Moreover, AG1296 significantly blocked the effect of thrombin on EMT and collagen production. Our findings demonstrate that thrombin is a potent inducer of EMT by RPE via autocrine activation of PDGF-receptor signaling. Coagulation cascade-induced EMT of RPE may thus contribute to the formation of fibrotic retinal membranes in PVR and should be considered as treatment target in PVR.
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19. Fibrogenesis in Human Mucosa and Muscularis Precision-Cut Intestinal Slices.
19. 人黏膜和肌层精密切割肠道切片中的纤维化发生PMID:日期:2024-06-22[中文摘要] 在克罗恩病（CD）中，肠道纤维化是一种普遍存在但尚未解决的并发症，由慢性和透壁性炎症引起。克罗恩病肠道组织学评估显示，包括黏膜和肌层在内的所有层次均出现组织形态学改变。本研究旨在确定黏膜与肌层之间纤维化发生的差异。从人肠道黏膜和肌层制备人精密切割肠道切片（hPCIS），并用TGF-β1和/或PDGF-BB处理72小时。检测基因和蛋白表达以及基质金属蛋白酶（MMP）活性。与黏膜hPCIS相比，肌层hPCIS中多种纤维化标志物的基础基因表达更高。在孵育过程中，肌层hPCIS中Pro-Collagen-1A1分泌增加，而黏膜hPCIS中未增加。在黏膜和肌层hPCIS中，孵育过程中MMP基因表达增加，但肌层hPCIS中MMP9、MMP12和MMP13除外。用TGF-β1孵育导致黏膜hPCIS中COL1A1表达增加，但肌层hPCIS中未增加。在肌层hPCIS中，TGF-β1处理导致MMP1和CTSK表达降低，而MMP13表达增加。在TGF-β1存在下，蛋白酶抑制剂表达稳定，但SERPINE1除外，其在肌层hPCIS中表达增加。我们得出结论，与黏膜hPCIS相比，肌层hPCIS中纤维化发生更为显著，尤其是在TGF-β1刺激下。
[英文摘要] In Crohn's Disease (CD), intestinal fibrosis is a prevalent yet unresolved complication arising from chronic and transmural inflammation. The histological assessment of CD intestines shows changes in tissue morphology in all the layers, including the mucosa and muscularis. This study aimed to determine the differences in fibrogenesis between mucosa and muscularis. Human precision-cut intestinal slices (hPCIS) were prepared from human intestine mucosa and muscularis and treated with TGF-β1 and/or PDGF-BB for 72 h. Gene and protein expression and matrix metalloproteinase (MMP) activity were determined. The basal gene expression of various fibrosis markers was higher in muscularis compared to mucosa hPCIS. During incubation, Pro-Collagen-1A1 secretion increased in muscularis but not in mucosa hPCIS. MMP gene expression increased during incubation in mucosa and muscularis hPCIS, except for MMP9, MMP12, and MMP13 in muscularis hPCIS. Incubation with TGF-β1 caused increased COL1A1 expression in the mucosa but not in muscularis hPCIS. In muscularis hPCIS, TGF-β1 treatment caused a decrease in MMP1 and CTSK expression, while MMP13 was increased. In the presence of TGF-β1, protease inhibitor expression was stable, except for SERPINE1, which was increased in muscularis hPCIS. We conclude that fibrogenesis is more pronounced in muscularis hPCIS compared to mucosa hPCIS, especially when stimulated with TGF-β1.
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20. Brivanib attenuates hepatic fibrosis in vivo and stellate cell activation in vitro by inhibition of FGF, VEGF and PDGF signaling.
20. Brivanib通过抑制FGF、VEGF和PDGF信号传导在体内减轻肝纤维化并在体外抑制星状细胞活化PMID:日期:2014-04-07[中文摘要] 布里瓦尼是一种选择性血管内皮生长因子受体（VEGFR）和成纤维细胞生长因子受体（FGFR）酪氨酸激酶抑制剂，这两种受体均参与肝纤维化机制。我们假设布里瓦尼通过抑制VEGFR和FGFR可抑制肝纤维化。因此，我们在三种小鼠纤维化模型中检测了布里瓦尼对肝纤维化的影响。在体内，我们通过胆管结扎（BDL）、慢性四氯化碳（CCl4）和慢性硫代乙酰胺（TAA）给药诱导肝纤维化。通过免疫组织化学和Western免疫印迹检测肝纤维化。在体外，我们使用LX-2人肝星状细胞（HSC）评估布里瓦尼对星状细胞增殖和活化的影响。在BDL、CCl4和TAA体内诱导后，接受布里瓦尼治疗的小鼠显示出肝纤维化减轻，肝脏中Iα1胶原和α-平滑肌肌动蛋白表达减少。在体外，布里瓦尼降低了由血小板衍生生长因子（PDGF）、VEGF和FGF诱导的HSC增殖。布里瓦尼还降低了星状细胞活力，并抑制了PDGFBB诱导的其同源受体磷酸化。布里瓦尼可减轻三种不同动物模型中的肝纤维化，并降低人肝星状细胞活化。布里瓦尼可能代表一种治疗肝纤维化和预防肝癌的新方法。
[英文摘要] Brivanib is a selective inhibitor of vascular endothelial growth factor receptor (VEGFR) and fibroblast growth factor receptor (FGFR) tyrosine kinases, which are both involved in mechanisms of liver fibrosis. We hypothesized that inhibition of VEGFR and FGFR by brivanib would inhibit liver fibrosis. We therefore examined the effect of brivanib on liver fibrosis in three mouse models of fibrosis. In vivo, we induced liver fibrosis by bile duct ligation (BDL), chronic carbon tetrachloride (CCl4), and chronic thioacetamide (TAA) administration. Liver fibrosis was examined by immunohistochemistry and Western immunoblotting. In vitro, we used LX-2 human hepatic stellate cells (HSCs) to assess the effect of brivanib on stellate cell proliferation and activation. After in vivo induction with BDL, CCl4, and TAA, mice treated with brivanib showed reduced liver fibrosis and decreased expression of collagen Iα1 and α-smooth muscle actin in the liver. In vitro, brivanib decreased proliferation of HSCs induced by platelet-derived growth factor (PDGF), VEGF, and FGF. Brivanib also decreased stellate cell viability and inhibited PDGFBB-induced phosphorylation of its cognate receptor. Brivanib reduces liver fibrosis in three different animal models and decreases human hepatic stellate cell activation. Brivanib may represent a novel therapeutic approach to treatment of liver fibrosis and prevention of liver cancer.