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To investigate the mechanisms of enhanced airway deposition of subepithelial collagen in asthma and its sensitivity to drug therapy with combination of an inhaled glucocorticosteroid (GC) and a long-acting β(2)-agonist (LABA), a cell model system involving bronchial fibroblasts derived from biopsies from patients with stable mild-to-moderate asthma has been used. To mimic unstable conditions and severe asthma, fibroblasts were stimulated ex vivo with TGFβ1. Primary fibroblasts established from central bronchial biopsies from 8 asthmatic patients were incubated for 24 h with 0.4% serum or TGFβ1 (10 ng/ml) with/without the GC budesonide (BUD; 10 nM) and/or the LABA formoterol (FORM; 0.1 nM). Procollagen peptide I (PICP), metalloproteinase (MMP)-1 and tissue inhibitor of MMPs (TIMP-1) were determined in culture media using ELISA while the activity of MMP-2, -3, -9 by zymography. Metabolically labeled proteoglycans, biglycan and decorin, associated with collagen fibrillation/deposition, were separated using chromatography and SDS-PAGE. The levels of PICP and biglycan were increased 2-fold by TGFβ1 (p < 0.05). The BUD and FORM combination reduced the PICP increase by 58% (p < 0.01) and the biglycan by 36% (p < 0.05) while each drug alone had no effect. Decorin levels were reduced by TGFβ1 in fibroblasts of most patients; BUD alone and BUD and FORM completely counteracted this decrease. MMPs and TIMP-1 were not affected by TGFβ1 or the drugs. These results suggest that BUD and FORM combination therapy, without affecting metalloproteolytic balance, has a potential to counteract enhanced collagen production by bronchial fibroblasts in asthma and to normalize the production of small proteoglycans which may affect collagen fibrillation and deposition.  相似文献
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目的 探讨二肾一夹高血压大鼠 ( 2 K1Ca- HR)血管重构中 Ang 、TGFβ1的作用机制。方法 动物分为实验组、对照组、治疗组 ,观察循环、组织 Ang 含量、肠系膜阻力动脉 TGFβ1 表达及对 enalapril的反应。结果 术后 2周实验组血管 Ang 明显增高 ( P<0 .0 1)持续至 12周 ,血浆 Ang 也显著升高并持续至 8周 ,但呈下降趋势 ,术后12周与术后 2周发生显著差异 ( P<0 .0 1)。实验组从 2周开始出现血管重构以后进行性加重。对照组血管组织无TGFβ1 表达 ,实验组各时相点肠系膜阻力动脉中层 VSMCs TGFβ1 表达阳性。 enalapril可降低循环、血管 Ang 至对照组水平 ,治疗组无血管形态改变 TGFβ1 表达阴性。结论  TGFβ1 在 2 K 1C- HR血管重构中发挥作用 ,其表达活化与血管组织 Ang 的升高关系密切。enalapril具防止血管重构的血管保护作用 ,可能与其抑制了 Ang 升高、TGFβ1 表达有关  相似文献
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Elevated glucose level is the main cause of extracellular matrix (ECM) derangement in various tissues in diabetes mellitus. The development of diabetic nephropathy is considered to be dependent on profibrotic cytokine, transforming growth factor-β1 (TGFβ1). Its excessive activation due to the up-regulation of thrombospondin-1 (TSP-1) in mesangial cells exposed to high glucose contributes to ECM accumulation. However, the role of TSP-1–TGFβ1 pathway in the development of glucose-induced imbalance of ECM homeostasis in skin connective tissue is not studied. We investigated the response of human skin fibroblasts to elevated glucose level (11.0 and 30.0 mM) in terms of: (1) the expression and secretion of fibronectin (FN) and plasminogen activator inhibitor-1 (PAI-1); (2) the accumulation of hyaluronic acid (HA) in pericellular matrix and in the conditioned medium; (3) TGFβ1 expression, secretion and activation; (4) TSP-1 expression and secretion. We demonstrated the up-regulation of FN and PAI-1 by elevated glucose and the stimulation of HA accumulation in both cellular compartments. However, we failed to demonstrate the increase of expression, secretion and activation of TGFβ1, and the increase of TSP-1 expression and secretion in fibroblasts exposed to high glucose. These results show that ECM derangement in skin fibroblasts due to high glucose is not determined by TGFβ1 and its activation by TSP-1.  相似文献
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BACKGROUND & AIMS: The mechanisms by which hepatitis C virus (HCV) induces liver fibrosis are unknown. Hepatocytes secrete HCV proteins, which may interact with hepatic stellate cells (HSCs). Our aims were to investigate whether HCV proteins induce fibrogenic effects on HSCs. METHODS & RESULTS: Human-activated HSCs expressed messenger RNA (mRNA) for the putative HCV receptors CD81, LDL receptor, and C1q receptor as assessed by RT-PCR. Incubation of activated but not quiescent human HSCs with recombinant core and NS3 protein increased intracellular calcium concentration and reactive oxygen species production, as well as stimulated intracellular signaling pathways. Adenoviruses encoding core and nonstructural proteins (NS3-NS5) were used to express HCV proteins in HSCs. Expression of core protein increased cell proliferation in a Ras/ERK and PI3K/AKT dependent manner. In contrast, NS3-NS5 protein expression preferentially induced proinflammatory actions, such as increased chemokine secretion and expression of intercellular cell adhesion molecule type 1 (ICAM-1) through the NF-kappa B and c-Jun N-terminal kinase pathways. These effects were attenuated by antioxidants. Infection of freshly isolated rat HSCs with adenovirus-encoding core protein resulted in accelerated cell activation, as assessed by alpha-smooth muscle actin expression. Moreover, adenovirus-encoding core and NS3-NS5 proteins increased the secretion of bioactive TGF beta 1 and the expression of procollagen alpha1(I) in early cultured rat HSCs, as assessed by ELISA and RNase protection assay, respectively. CONCLUSIONS: HCV core and nonstructural proteins regulate distinct biologic functions in HSCs. A direct interaction between HCV proteins and HSCs may contribute to HCV-induced liver fibrosis.  相似文献
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AIM: To investigate the effects of cyclosporine A (CsA) on thioacetamide (TAA)-induced liver injury.METHODS: CsA was co-administrated (7.5 μg/kg body weight per day, i.p.) into rat to investigate the role of CsA on TAA-(200 mg/kg body weight per 3 d for 30 d, i.p.)induced liver injury.RESULTS: The data show that TAA caused liver fibrosis in rat after 30 d of treatment. CsA alleviates the morphological changes of TAA-induced fibrosis in rat liver. The blood glutamyl oxaloacetic transaminase (GOT)/glutamyl pyruvic transaminase (GPT) in the TAA-injury group is elevated compared to that of the normal rat. Compared with the TAA-injury group, the blood GOT/GPT and TGFβ1 (by RT-PCR analysis) are reduced in the CsA plus TAA-treated rat. The level of the transforming growth factor receptor I (TGFβ-R1) in the CsA plus TAA-treated group showsh igher than that in the TAA only group, but shows a lower level of the fibroblast growth factor receptor 4 (FGFR4) in the CsA plus TAA-treated group, when using the Western blot analysis. After immunostaining of the frozen section,TGFβ-R1 and FGFR4 are more concentrated in rat liverafter CsA plus TAA injury.CONCLUSION: This result suggests that CsA has an alleviated effect on TAA-induced liver injury by increasing the multidrug resistance P-glycoprotein and could be through the regulation of TGFβ-R1 and FGFR4.  相似文献
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Objective: This study aimed to elucidate the role of Transforming growth factor (TGF)-β1 signaling in the proliferation of airway smooth muscle cells (ASMCs). Background: TGF-β1 is an important cytokine in airway remodeling in asthma. However, results of studies focusing on the effect of TGFβ1 on proliferation of ASMCs are controversial. Methods: An allergic model that mimics airway remodeling in chronic asthma was established and primary ASMCs were cultured. Cell proliferation was detected by viable cell counting and Cell Counting Kit (CCK)-8 analysis. Expression and phosphorylation of Smad3, type 1 TGFβ receptor (TGFβRI), type 2 TGFβ receptor (TGFβRII), extracellular signal-regulated kinase (ERK)-1/2, p38 mitogen-activated protein kinase (MAPK), C-Jun N-terminal kinase (JNK) and AKT were detected by western blot. siRNAs were used to knock down Smad3 and TGFβRII. Results: Smad3 and TGFβRII were up-regulated in primary ASMCs isolated from ovalbumin (OVA)-sensitized mice as compared with ASMCs isolated from unsensitized control mice, which persisted for at least four passages. TGFβ1 stimulated proliferation of ASMCs isolated from OVA-sensitized mice, which was inhibited by specific siRNA targeting Smad3 or TGFβRII. However ASMCs from control mice showed no proliferative response to TGFβ1. TGFβ1-induced proliferation of ASMCs from OVA-sensitized mice was markedly attenuated by PD-98059, a specific ERK1/2 inhibitor. TGFβ1 induced ERK1/2 phosphorylation within 15 minute, which was partially blocked by specific inhibitor of Smad3 (SIS3). Conclusions: ASMCs isolated from OVA-sensitized mice showed hyper-proliferation upon TGFβ1 stimulation. This might have been associated with up-regulated Smad3 and TGFβRII and mediated by ERK1/2 downstream to Smad3.  相似文献
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目的:研究双氢青蒿素干预肺纤维化的作用机制。方法构建博来霉素诱导的大鼠肺纤维化模型[1],造模后行灌胃治疗。用 HE 染色、Masson 染色法观察大鼠肺组织病理变化,碱水解法检测羟脯氨酸含量,Ellisa 法检测血清中 TGFβ1(转化生长因子β1)含量,荧光定量 PCR 法检测 TGFβ1、SMAD2、SMAD3基因表达,免疫组化法检测大鼠肺组织中 TGFβ1、SMAD2/3、pSMAD2/3蛋白表达。结果双氢青蒿素可减轻肺纤维化模型大鼠肺组织炎症和纤维化程度,抑制 TGFβ1、SMAD2、SMAD3基因表达和 TGFβ1、SMAD2/3、pS-MAD2/3蛋白表达。结论双氢青蒿素可能通过抑制 TGFβ1-SMAD2/3通路干预肺纤维化。  相似文献
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目的:通过收集 TGFβ1刺激过的前体细胞条件培养基,观察其对 HSC 的影响。方法收集 TGFβ1预处理的前体细胞条件培养基,培养 HSC 细胞48 h,观察 HSC 活化程度及细胞外基质相关指标的变化。结果经 TGFβ1刺激后的前体细胞形态明显变大变圆,胞质比例明显增加,核质比减少。去除 TGFβ1刺激后,发现 TGFβ1刺激超过24 h,前体细胞的上皮-间质转换发生逆转,表现为α-平滑肌肌动蛋白(α-smooth muscle actin,α-SMA)蛋白表达量下降,24 h、36 h 及48 h 分别为对照组的1.31倍(P >0.05)、0.97倍(P =0.027)、1.08倍(P =0.058)。与对照组相比,TGFβ1刺激后前体细胞的条件培养基对 HSCs 的细胞形态无明显差别。进一步分析发现,TGFβ1刺激前体细胞6h 后,其条件培养基促使星状细胞α-SMA 及细胞外基质标志物金属蛋白酶组织抑制剂-1(tissue inhibitor of metalloproteinase,TIMP-1)在蛋白及基因水平上(分别为对照组的4.12倍及2.64倍)的表达;然而刺激超过24h 上述作用相反,在蛋白水平表现为α-SMA 表达降低而 TIMP-1的表达无明显变化,在基因水平α-SMA 及 TIMP-1均呈降低趋势(24 h、36 h、48 h 分别为对照组0.81倍及0.98倍、0.96倍及0.61倍、0.63倍及0.76倍)。结论去除 TGFβ1的刺激后,其诱导的上皮-间质转换可发生逆转,并在逆转过程中可影响星状细胞的活化。  相似文献
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