TWEAK/Fn14 axis: The current paradigm of tissue injury-inducible function in the midst of complexities

TNF-like weak inducer of apoptosis (TWEAK), a TNF family ligand, and its only known signaling receptor, FGF-inducible molecule-14 (Fn14), have emerged as a key molecular pathway regulating tissue responses after acute tissue injury and in contexts of chronic injury and disease, including autoimmunity, chronic inflammation, fibrosis, and malignancy. Usually dormant due to the low level of Fn14 expression in healthy tissues, this axis is specifically activated by the upregulation of Fn14 expression locally within injured tissues, thereby triggering a wide range of activities in tissue parenchymal and stromal cells as well as tissue progenitor cells. Current evidence supports that although transient TWEAK/Fn14 pathway activation may be beneficial for tissue repair after acute injury, excessive or sustained TWEAK/Fn14 activation due to repeated injury or chronic disease mediates significant tissue damage and pathological tissue remodeling. This paradigm for the dichotomous function of the TWEAK/Fn14 pathway is discussed, highlighting emerging findings, complexities, and implications for the treatment of tissue damage-associated pathologies and cancer.     

上皮-间质转化在子宫腺肌病中作用的研究进展

子宫腺肌病(ADS)是子宫内膜腺体及间质侵入子宫肌层导致的以子宫局灶或弥漫性增大为主要改变的良性疾病,其具体发病机制尚不清楚。目前多数研究者认为ADS是基底层内膜细胞增生、侵入到肌层间质的结果。在上皮-间质转化(EMT)过程中,上皮细胞失去细胞极性,细胞间紧密连接和黏附连接减弱,获得了浸润性和游走迁移能力,成为具有间质细胞功能和特性的细胞。EMT在肿瘤形成中赋予细胞迁移、浸润的能力,而ADS发生、发展过程中子宫内膜细胞侵入肌层的生物学行为与之非常相似。已有研究表明EMT在ADS形成中具有重要作用。目前ADS的临床治疗面临较多的挑战,因此阐明ADS的发生机制是寻求临床早期预防、治疗ADS有效方法的关键。     

G蛋白偶联受体30的特点及其在纤维化疾病中的作用机制

纤维化是一种组织受到破坏后的修复反应,主要由于炎症因子过度刺激引发实质细胞坏死、细胞外基质(extracellular matrix,ECM)分泌过剩,大量沉积于细胞间质,形成胶原蛋白排列紊乱的病理表现,严重者导致器官结构紊乱和功能障碍,甚至发生器官衰竭[1].     

Immunohistochemical characterization of fibroblast subpopulations in normal peritoneal tissue and in peritoneal dialysis-induced fibrosis

Peritoneal fibrosis is one of the most common morphological changes observed in continuous ambulatory peritoneal dialysis (CAPD) patients. Both resident fibroblasts and new fibroblast-like cells derived from the mesothelium by epithelial-to-mesenchymal transition are the main cells involved fibrogenesis. In order to establish markers of peritoneal impairment and pathogenic clues to explain the fibrogenic process, we conducted an immunohistochemical study focused on peritoneal fibroblasts. Parietal peritoneal biopsies were collected from four patient groups: normal controls (n=15), non-CAPD uremic patients (n=17), uremic patients on CAPD (n=27) and non-renal patients with inguinal hernia (n=12). To study myofibroblastic conversion of mesothelial cells, -smooth muscle actin (SMA), desmin, cytokeratins and E-cadherin were analyzed. The expression of CD34 by fibroblasts was also analyzed. Fibroblasts from controls and non-CAPD uremic patients showed expression of CD34, but no myofibroblastic or mesothelial markers. The opposite pattern was present during CAPD-related fibrosis. Expression of cytokeratins and E-cadherin by fibroblast-like cells and -SMA by mesothelial and stromal cells supports that mesothelial-to-myofibroblast transition occurs during CAPD. Loss of CD34 expression correlated with the degree of peritoneal fibrosis. The immunophenotype of fibroblasts varies during the progression of fibrosis. Myofibroblasts seem to derive from both activation of resident fibroblasts and local conversion of mesothelial cells.Manuel López-Cabrera and Rafael Selgas contributed equally to the article.     

核因子-κB在血管紧张素II介导的大鼠胰腺纤维化发生中的作用

目的 :探讨NF -κB在血管紧张素II介导的大鼠胰腺纤维化发生中的作用。方法 :SD大鼠 (2 0 0 -30 0g)随机分为正常组、对照组、治疗组。大鼠胰管内逆行注射 2 %三硝基苯磺酸 (TNBS)复制胰腺纤维化模型。于造模后第 1d始 ,治疗组给予洛沙坦灌胃 (10mg·kg-1·d-1) ,模型组给予等量的无菌蒸馏水。分别采用免疫印迹、免疫组化和TransAMTM方法检测胰腺组织NF -κB表达、分布和活化情况。采用硫堇蓝 (toluidineblue)染色和透射电镜观察肥大细胞数量、分布和活化脱颗粒现象。RT -PCR研究胰腺组织细胞间粘附分子 (ICAM - 1)mRNA表达。结果 :造模后第 3d大鼠胰腺组织NF -κBp6 5蛋白表达及其活性增加 ,第 7d达峰值 [(0 4 0 6± 0 0 86 )mg/g总蛋白 ]。对照组大鼠胰腺组织中肥大细胞活化 ;ICAM - 1mRNA表达于第 3d和第 7d增加。洛沙坦可抑制NF -κB蛋白表达和肥大细胞活化、下调ICAM - 1mRNA表达。结论 :血管紧张素II在大鼠胰腺纤维化形成早期可能通过受体AT1途径促发炎症反应及纤维化 ,具体机制可能与NFκB表达增加并活化有关     

The effect of beta-blockade on myocardial remodelling in Chagas' cardiomyopathy

OBJECTIVE:

Chagas'' disease has spread throughout Latin America because of the high rate of migration among these countries. Approximately 30% of Chagas'' patients will develop cardiomyopathy, and 10% of these will develop severe cardiac damage leading to heart failure. Beta-blockade improves symptoms and survival in heart failure patients; however, its efficacy has not been well established in Chagas'' disease. We evaluated the role of carvedilol in cardiac remodeling and mortality in a Chagas'' cardiomyopathy animal model.

METHODS:

We studied Trypanosoma cruzi infection in 55 Syrian hamsters that were divided into three groups: control (15), infected (20), and infected + carvedilol (20). Animals underwent echocardiography, electrocardiography, and morphometry for collagen evaluation in ventricles stained with picrosirius red.

RESULTS:

The left ventricular diastolic diameter did not change between groups, although it was slightly larger in infected groups, as was left ventricular systolic diameter. Fractional shortening also did not change between groups, although it was slightly lower in infected groups. Collagen accumulation in the interstitial myocardial space was significantly higher in infected groups and was not attenuated by carvedilol. The same response was observed in the perivascular space. The survival curve showed significantly better survival in the control group compared with the infected groups; but no benefit of carvedilol was observed during the study. However, in the acute phase (up to 100 days of infection), carvedilol did reduce mortality.

CONCLUSION:

Carvedilol did not attenuate cardiac remodeling or mortality in this model of Chagas'' cardiomyopathy. The treatment did improve survival in the acute phase of the disease.     

Fibroageing: An ageing pathological feature driven by dysregulated extracellular matrix-cell mechanobiology

Ageing is a multifactorial biological process leading to a progressive decline of physiological functions. The process of ageing includes numerous changes in the cells and the interactions between cell-cell and cell-microenvironment remaining as a critical risk factor for the development of chronic degenerative diseases. Systemic inflammation, known as inflammageing, increases as a consequence of ageing contributing to age-related morbidities. But also, persistent and uncontrolled activation of fibrotic pathways, with excessive accumulation of extracellular matrix (ECM) and organ dysfunction is markedly more frequent in the elderly. In this context, we introduce here the concept of Fibroageing, that is, the propensity to develop tissue fibrosis associated with ageing, and propose that ECM is a key player underlying this process. During ageing, molecules of the ECM become damaged through many modifications including glycation, crosslinking, and accumulation, leading to matrix stiffness which intensifies ageing-associated alterations. We provide a framework with some mechanistic hypotheses proposing that stiff ECM, in addition to the well-known activation of fibrotic positive feedback loops, affect several of the hallmarks of ageing, such as cell senescence and mitochondrial dysfunction, and in this context, is a key mechanism and a driver thread of Fibroageing.     

TGF-β1联合Wnt3a促进子宫内膜纤维化的机制研究

目的:探讨转化生长因子-β1(TGF-β1)与Wnt3a联合对子宫内膜基质细胞纤维化的促进作用。方法:原代分离培养人子宫内膜基质细胞(hESCs),将hESCs分为正常对照组和实验组(不同浓度TGF-β1),RT-PCR和Western blot法检测纤维化标记物(CollageⅠ、α-SMA、Fibronectin)及Wnt/β-catenin信号通路配体和核心分子的表达。筛选10ng/mL TGF-β1与100ng/mL Wnt3a联合作用hESCs,同法检测上述分子和Wnt/β-catenin核心分子的表达。结果:与正常对照组相比,TGF-β1诱导纤维化标记物(CollageⅠ、α-SMA、Fibronectin)、Wnt/β-catenin信号通路配体(Wnt3a)及核心分子(β-catenin、GSK-3β)和下游靶基因(CyclinD1、MMP-9)表达均升高;Wnt3a和TGF-β1联合诱导组纤维化标记物和Wnt/β-catenin信号通路核心分子表达显著高于对照组、Wnt3a组、TGF-β1组,差异均有统计学意义(P<0.05)。结论:Wnt3a联合TGF-β1激活Wnt/β-catenin信号通路促进子宫内膜基质细胞纤维化。     

Antifibrotic effects of crocetin in scleroderma fibroblasts and in bleomycin-induced sclerotic mice

OBJECTIVE:

To investigate the antifibrotic effects of crocetin in scleroderma fibroblasts and in sclerotic mice.

METHODS:

Skin fibroblasts that were isolated from three systemic scleroderma (SSc) patients and three healthy subjects were treated with crocetin (0.1, 1 or 10 μM). Cell proliferation was measured with an MTT assay. Alpha-smooth muscle actin was detected via an immunohistochemical method. Alpha 1 (I) procollagen (COL1A1), alpha 1 (III) procollagen (COL3A1), matrix metalloproteinase (MMP)-1 and tissue inhibitor of matrix metalloproteinase (TIMP)-1 mRNA levels were measured using real-time PCR. SSc mice were established by the subcutaneous injection of bleomycin. Crocetin (50 mg/kg/d) was injected intraperitoneally for 14 days. Dermal thickness and lung fibrosis were assessed with Masson''s trichrome staining. Plasma ET-1 was detected with an enzyme-linked immunosorbent assay (ELISA). Skin and lung ET-1 and COL1A1 mRNA levels were measured via real-time PCR.

RESULTS:

Crocetin inhibited the proliferation of SSc and normal fibroblasts, an effect that increased with crocetin concentration and incubation time. Crocetin decreased the expression of α-SMA and the levels of mRNA for COL1A1, COL3A1 and matrix metalloproteinase-1, while crocetin increased TIMP-1 mRNA levels in both SSc and normal fibroblasts. Skin and lung fibrosis was induced, and the levels of ET-1 in the plasma, skin and lungs were elevated in bleomycin-injected mice. Crocetin alleviated the thickening of the dermis and lung fibrosis; decreased COL1A1 mRNA levels in the skin and lung; and simultaneously decreased ET-1 concentrations in the plasma and ET-1 mRNA levels in the skin and lungs of the bleomycin-induced sclerotic mice, especially during the early phase (weeks 1-3).

CONCLUSION:

Crocetin inhibits cell proliferation, differentiation and collagen production in SSc fibroblasts. Crocetin alleviates skin and lung fibrosis in a bleomycin-induced SSc mouse model, in part due to a reduction in ET-1.     

CCL5: A Double-Edged Sword in Host Defense Against the Hepatitis C Virus

C-C motif ligand 5 (CCL5) facilitates induction of chemotaxis in immune cells and activation of hepatic stellate cells (HSC) at sites of liver inflammation during chronic hepatitis C virus (HCV) infection. Importantly, CCL5 participates in the establishment of T-helper 1 responses crucial in controlling liver disease and HCV infection outcome and demonstrates distinct gene expression patterns between the blood and the liver, stressing the importance of immunoregulatory networks differentially functioning between these compartments. This review illustrates the significance of CCL5-dependent pathways in HCV-related immunopathogenesis by elaborating on biological mechanisms interconnecting peripheral and tissue immunology, liver pathology, HSC activation, and interferon-α immunotherapy.