Dynamic role of myofibroblasts in oral lesions

Fibroblasts are the most abundant cellular components of connective tissue. They possess phenotypical heterogenicity and may be present in the form of smooth muscle cells or myofibroblasts(MFs). MFs are spindle-shaped cells with stress fibres and welldeveloped fibronexus,and they display α-smooth muscle actin immunohistochemically and smoothmuscle myofilaments ultrastructurally. MFs play a crucial role in physiological and pathological processes. Derived from various sources,they play pivotal roles not only by synthesizing and producing extracellular matrix components,such as other connective tissue cells,but also are involved in force production. In the tissue remodelling phase of wound closure,integrinmediated interactions between MFs and type I collagen result in scar tissue formation. The tumour stroma in oral cancer actively recruits various cell types into the tumour mass,where they act as different sources of MFs. This article reviews the importance of MFs and its role in pathological processes such as wound healing,odontogenic cysts and tumours,salivary gland tumours,oral preneoplasia,and oral squamous cell carcinoma. Research oriented on blocking the transdifferentiation of fibroblasts into MFs can facilitate the development of noninvasive therapeutic strategies for the treatment of fibrosis and/or cancer.

Effects of Oxidized Low Density Lipoprotein on Transformation of Valvular Myofibroblasts to Osteoblast-like Phenotype

In order to investigate the roles of Wnt signal pathway in transformation of cardiac valvular myofibroblasts to the osteoblast-like phenotype, the primary cultured porcine aortic valve myofibroblasts were incubated with oxidized low density lipoprotein（ox-LDL, 50 mg/L）, and divided into four groups according to the ox-LDL treatment time： control group, ox-LDL 24-h group, ox-LDL 48-h group, and ox-LDL 72-h group. Wnt signal pathway blocker Dickkopf-1（DDK-1, 100 μg/L） was added in ox-LDL 72-h group. The expression of α-smooth muscle actin（α-SMA）, bone morphogenetic protein 2（BMP2）, alkaline phosphatase（ALP）, and osteogenic transcription factor Cbfa-1 was detected by Western blotting, and that of β-catenin, a key mediator of Wnt signal pathway by immunocytochemical staining method. The Wnt/β-catenin was observed and the transformation of myofibroblasts to the osteoblast-like phenotype was examined. The expression of α-SMA, BMP2, ALP and Cbfa-1 proteins in the control group was weaker than in the ox-LDL-treated groups. In ox-LDL-treated groups, the protein expression of α-SMA, BMP2, ALP, and Cbfa-1 was significantly increased in a time-dependent manner as compared with the control group, and there was significant difference among the three ox-LDL-treated groups（P〈0.05 for all）; β-catenin protein was also up-regulated in the ox-LDL-treated groups in a time-dependent manner as compared with the control group（P〈0.05）, and its transfer from cytoplasm to nucleus and accumulation in the nucleus were increased in the same fashion（P〈0.05）. After addition of DKK-1, the expression of α-SMA, bone-related proteins and β-catenin protein was significantly reduced as compared with ox-LDL 72-h group（P〈0.05）. The Wnt/ β-catenin signaling pathway may play an important role in transformation of valvular myofibroblasts to the osteoblast-like phenotype.

A red wine polyphenolic extract reduces the activation phenotype of cultured human liver myofibroblasts

AIM: To test the effect of a standardized red wine polyphenolic extract (RWPE) on the phenotype of human liver myofibroblasts in culture. METHODS: Human myofibroblasts grown from liver explants were used in this study. Cell proliferation was measured with the 3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyltetrazolium bromide (MTT) assay. Signaling events were analyzed by western blot with phosphospecific antibodies. Matrix-metalloproteinase activity was measured with gel zymography. RESULTS: We found that cell proliferation was dose-dependently decreased by up to 90% by RWPE while cell viability was not affected. Exposure to RWPE also greatly decreased the phosphorylation of ERK1/ERK2 and Akt in response to stimulation by the mitogenic factor platelet-derived growth factor BB (PDGF-BB). Finally, RWPE affected extracellular matrix remodeling by decreasing the secretion by myofibroblasts of matrix-metalloproteinase-2 and of tissue inhibitor of matrix- metalloproteinases-1.CONCLUSION: Altogether, RWPE decreases the activation state of liver myofibroblasts. The identification of the active compounds in RWPE could offer new therapeutic strategies against liver fibrosis.

An Improved Assay for Measuring Low Levels of Nitric Oxide in Cultured Pulmonary Myofibroblasts

Quantification of nitric oxide (NO) from cultured cells is a valuable tool for studying cell signaling. Detection of NO in biological fluids can be difficult however, due to its transient half-life and low physiological concentrations. In this study, we have refined an existing amperometric method to determine relative levels of accumulated nitrogen oxides (NOX) in cell culture and have used this method to reproducibly quantify NO from cultured pulmonary myofibroblasts. Basal levels of NO produced by pulmonary myofibroblasts ranged from 0.6 nM to 20 nM and varied due to the growth conditions of the cells, i.e. higher NO concentrations were observed in differentiated cells. The constitutive eNOS isoform is primarily responsible for the observed NO accumulation in these cells since transcript levels of eNOS are 10-fold higher than the inducible iNOS form while nNOS was undetectable. Treatment of myofibroblasts with the inhibitors L-NNA and L-NAME resulted in a concentration dependent decrease in measured NOx. Overall, the improved assay presented here should be applicable to measuring NOX levels from many different cell types and under a wide variety of conditions.

Hydrogen sulfide suppresses transforming growth factor-β1-induced differentiation of human cardiac fibroblasts into myofibroblasts

In heart disease, transforming growth factor-β1 （TGF-β1） converts fibroblasts into myofibroblasts, which synthesize and se- crete fibrillar type I and III collagens. The purpose of the present study was to investigate how hydrogen sulfide （HzS） sup- presses TGF-~l-induced differentiation of human cardiac fibroblasts to myofibroblasts. Human cardiac fibroblasts were se- rum-starved in fibroblast medium for 16 h before exposure to TGF-β1 （10 ng mL-1） for 24 h with or without sodium hydrosul- fide （NariS, 100 μmol L-1, 30 min pretreatment） treatment. NariS, an exogenous HzS donor, potently inhibited the prolifera- tion and migration of TGF-β1-induced human cardiac fibroblasts and regulated their cell cycle progression. Furthermore, NariS treatment led to suppression of fibroblast differentiation into myofibroblasts, and reduced the levels of collagen, TGF-β1, and activated Smad3 in TGF-β1-induced human cardiac fibroblasts in vitro. We therefore conclude that H2S sup- presses TGF-β1-stimulated conversion of fibroblasts to myofibroblasts by inhibiting the TGF-β1/Smad3 signaling pathway, as well as by inhibiting the proliferation, migration, and cell cycle progression of human cardiac myofibroblasts. These effects of H2S may play significant roles in cardiac remodeling associated with heart failure.

Subretinal fibrosis secondary to neovascular age-related macular degeneration:mechanisms and potential therapeutic targets

Subretinal fibrosis is the end-stage sequelae of neovascular age-related macular degeneration.It causes local damage to photoreceptors,retinal pigment epithelium,and choroidal vessels,which leads to permanent central vision loss of patients with neovascular age-related macular degeneration.The pathogenesis of subretinal fibrosis is complex,and the underlying mechanisms are largely unknown.Therefore,there are no effective treatment options.A thorough understanding of the pathogenesis of subretinal fibrosis and its related mechanisms is important to elucidate its complications and explore potential treatments.The current article reviews several aspects of subretinal fibrosis,including the current understanding on the relationship between neovascular age-related macular degeneration and subretinal fibrosis;multimodal imaging techniques for subretinal fibrosis;animal models for studying subretinal fibrosis;cellular and non-cellular constituents of subretinal fibrosis;pathophysiological mechanisms involved in subretinal fibrosis,such as aging,infiltration of macrophages,different sources of mesenchymal transition to myofibroblast,and activation of complement system and immune cells;and several key molecules and signaling pathways participating in the pathogenesis of subretinal fibrosis,such as vascular endothelial growth factor,connective tissue growth factor,fibroblast growth factor 2,platelet-derived growth factor and platelet-derived growth factor receptor-β,transforming growth factor-βsignaling pathway,Wnt signaling pathway,and the axis of heat shock protein 70-Toll-like receptors 2/4-interleukin-10.This review will improve the understanding of the pathogenesis of subretinal fibrosis,allow the discovery of molecular targets,and explore potential treatments for the management of subretinal fibrosis.

Role of oxygen free radicals in the proliferation of myofibroblasts induced by AngII

Previous studies have demonstrated the important role of angiotension II(AngII)in promoting proliferation of myofibroblasts(myoFbs)and myocardial fibrosis.However,the underlying mechanisms and the role of oxygen free radicals in the proliferation of myofibroblasts induced by AngII are unclear.The present study was designed to shed light on this issue through exploration of AngII signaling pathways via in vitro experiments.Primary cultures of neonatal rat myoFbs were divided into five groups which were treated with AngII(10^(-8) to 10^(-6) M),AngII with the antioxidant N-acetyl-L-cysteine(NAC),or normal culture medium.We observed the proliferation of myoFbs as induced by AngII at different concentrations with MTT.Reactive oxygen species(ROS)levels in myoFbs were detected by monitoring the fluorescence of 2',7'-dichlorofluorescein.The contents and levels of oxygen free radicals(OH·)in the three groups were detected by spectrophotometer,immunocytochemical staining,and confocal fluorescence.Western blot and image analysis were used to measure membrane translocation and expression of phospho-protein kinase Ca.MyoFbs incubated with AngII(10^(-8) to 10^(-6) M)for 24 h increased their rate of proliferation,the content of OH·,and expression of ROS(P<0.01 vs.control group),whereas these parameters decreased in the presence of NAC.Immunocytochemistry,confocal fluorescence staining and image analysis showed that AngII could promote the translocation and expression of p-PKCα in membrane,and the antioxidant NAC blocked this increase(P<0.01).Western blot results also showed that NAC could inhibit the expression of p-PKCα.

Pharmacological regulation of tissue fibrosis by targeting the mechanical contraction of myofibroblasts

Fibrosis can occur in almost all tissues and organs and affects normal physiological function,which may have serious consequences,such as organ failure.However,there are currently no effective,broad-spectmm drugs suitable for clinical application.Revealing the process of fibrosis is an important prerequisite for the development of new therapeutic targets and drugs.Studies have shown that the limiting of myofibroblast activation or the promoting of their elimination can ameliorate fibrosis.However,it has not been reported whether a direct decrease in cell contraction can inhibit fibrosis in vivo.Here,we have shown that(-)-blebbistatin(Ble),a non-muscle myosin II inhibitor,displayed significant inhibition of liver fibrosis in different chronic injury mouse models in vivo.We found that Ble reduced the stiffness of fibrotic tissues from the early stage,which reduced the extent of myofibroblast activation induced by a stiffer extracellular matrix(ECM).Moreover,Ble also reduced the activation of myofibroblasts induced by TGF-β1,which is the most potent pro-fibrotic cytokine.Mechanistically,Ble reduced mechanical contraction,which inhibited the assembly of stress fibers,decreased the F/G-actin ratio,and led to the exnucleation of YAPJ and MRTF-A.Finally,we verified its broad-spectrum antifibrotic effect in multiple models of organ fibrosis.Our results highlighted the important role of mechanical contraction in myofibroblast activation and maintenance,rather than just a characteristic of activation,suggesting that it may be a potential target to explore broad-spectrum drugs for the treatment of fibrotic diseases.

TL1A Promotes Fibrogenesis in Colonic Fibroblasts via the TGF-β1/Smad3 Signaling Pathway

Objective Intestinal fibrosis is a refractory complication of inflammatory bowel disease(IBD).Tumor necrosis factor ligand-related molecule-1A(TL1A)is important for IBD-related intestinal fibrosis in a dextran sodium sulfate(DSS)-induced experimental colitis model.This study aimed to explore the effects of TL1A on human colonic fibroblasts.Methods A trinitrobenzene sulfonic acid(TNBS)-induced experimental colitis model of LCK-CD2-TL1A-GFP transgenic(Tg)or wild-type(WT)mice was established to determine the effect and mechanism of TL1A on intestinal fibrosis.The human colonic fibroblast CCD-18Co cell line was treated concurrently with TL1A and human peripheral blood mononuclear cell(PBMC)supernatant.The proliferation and activation of CCD-18Co cells were detected by BrdU assays,flow cytometry,immunocytochemistry and Western blotting.Collagen metabolism was tested by Western blotting and real-time quantitative polymerase chain reaction(RT-qPCR).Results The level of collagen metabolism in the TNBS+ethyl alcohol(EtOH)/Tg group was greater than that in the TNBS+EtOH/WT group.Transforming growth factor-β1(TGF-β1)and p-Smad3 in the TNBS+EtOH/Tg group were upregulated as compared with those in the TNBS+EtOH/WT group.The proliferation of CCD-18Co cells was promoted by the addition of human PBMC supernatant supplemented with 20 ng/mL TL1A,and the addition of human PBMC supernatant and TL1A increased CCD-18Co proliferation by 24.4%at 24 h.TL1A promoted cell activation and increased the levels of COL1A2,COL3A1,and TIMP-1 in CCD-18Co cells.Treatment of CCD-18Co cells with TL1A increased the expression of TGF-β1 and p-Smad3.Conclusion TL1A promotes TGF-β1-mediated intestinal fibroblast activation,proliferation,and collagen deposition and is likely related to an increase in the TGF-β1/Smad3 signaling pathway.

Regression of hepatic fibrosis after pharmacological therapy for nonalcoholic steatohepatitis

The global incidence of nonalcoholic fatty liver disease(NAFLD)is escalating considerably.NAFLD covers a range of liver conditions from simple steatosis to the more severe form known as nonalcoholic steatohepatitis,which involves chronic liver inflammation and the transformation of hepatic stellate cells into myofibroblasts that generate excess extracellular matrix,leading to fibrosis.Hepatocyte ballooning is a key catalyst for fibrosis progression,potentially advancing to cirrhosis and its decompensated state.Fibrosis is a critical prognostic factor for outcomes in patients with NAFLD;therefore,those with substantial fibrosis require timely intervention.Although liver biopsy is the most reliable method for fibrosis detection,it is associated with certain risks and limitations,particularly in routine screening.Consequently,various noninvasive diagnostic techniques have been introduced.This review examines the increasing prevalence of NAFLD,evaluates the noninvasive diagnostic techniques for fibrosis,and assesses their efficacy in staging the disease.In addition,it critically appraises current and emerging antifibrotic therapies,focusing on their mechanisms,efficacy,and potential in reversing fibrosis.This review underscores the urgent need for effective therapeutic strategies,given the dire consequences of advanced fibrosis.

Low-grade myofibrosarcoma of the maxillary sinus:Two case reports

BACKGROUND Low-grade myofibroblastic sarcoma(LGMS)is an extremely rare tumor characterized by the malignant proliferation of myofibroblasts.LGMS most commonly develops in adults,predominantly in males,in the head and neck region,oral cavity,especially on the tongue,mandible,and larynx.This article presents 2 cases of LGMS localized to the maxillary sinus and provides an overview of the available literature.CASE SUMMARY Two patients with LGMS located in the maxillary sinus underwent surgery at the Department of Head and Neck Surgery.Case 1:A 46-year-old patient was admitted to the clinic with suspected LGMS recurrence in the right maxillary sinus(rT4aN0M0),with symptoms of pain in the suborbital area,watering of the right eye,thick discharge from the right nostril,and augmented facial asymmetry.After open biopsy-confirmed LGMS,the patient underwent expanded maxillectomy of the right side with immediate palate reconstruction using a microvascular skin flap harvested surgically from the middle arm.The patient qualified for adjuvant radiotherapy for the postoperative bed,with an additional margin.Currently,the patient is under 1.5 years of observation with no evidence of disease.Case 2:A 45-year-old man was admitted to our clinic with facial asymmetry,strabismus,exophthalmos,and visual impairment in the right eye.Six months earlier,the patient had undergone partial jaw resection at another hospital for fibromatosis.A contrast-enhanced computed tomography scan revealed a tumor mass in the postoperative log after an earlier procedure.An open biopsy confirmed lowgrade fibrosarcoma(rT4aN0M0).The patient qualified for an extended total right maxillectomy with orbital excision and right hemimandibulectomy with immediate microvascular reconstruction using an anterolateral thigh flap.The patient subsequently underwent adjuvant radiotherapy to the postoperative area.After 9 months,recurrence occurred in the right mandibular arch below the irradiated area.The lesion infiltrated the base of the skull,which warranted the withdrawal of radiotherapy and salvage surgery.The patient qualified for palliative chemotherapy with a regimen of doxorubicin+dacarbazine+cyclophosphamide and palliative radiotherapy for bone metastases.The patient died 26 months after surgical treatment.The cases have been assessed and compared with cases in the literature.CONCLUSION No specific diagnostic criteria or treatment strategies have been developed for LGMS.The treatment used for LGMS is the same as that used for sinonasal cancer radical tumor excision;adjuvant radiotherapy or chemoradiotherapy should also be considered.They have low malignant potential but are highly invasive,tend to recur,and metastasize to distant sites.Patients should undergo regular follow-up examinations to detect recurrence or metastasis at an early stage.Patients should be treated and observed at the highest referral centers.

Cellular and molecular mechanisms of intestinal fibrosis

Fibrosis is a chronic and progressive process characterized by an excessive accumulation of extracellular matrix (ECM) leading to stiffening and/or scarring of the involved tissue. Intestinal fibrosis may develop in several different enteropathies, including inflammatory bowel disease. It develops through complex cell, extracellular matrix, cytokine and growth factor interactions. Distinct cell types are involved in intestinal fibrosis, such as resident mesenchymal cells (fibroblasts, myofibroblasts and smooth muscle cells) but also ECM-producing cells derived from epithelial and endothelial cells (through a process termed epithelialand endothelial-mesenchymal transition), stellate cells, pericytes, local or bone marrow-derived stem cells. The most important soluble factors that regulate the activation of these cells include cytokines, chemokines, growth factors, components of the renin-angiotensin system, angiogenic factors, peroxisome proliferator-activated receptors, mammalian target of rapamycin, and products of oxidative stress. It soon becomes clear that although inflammation is responsible for triggering the onset of the fibrotic proc-ess, it only plays a minor role in the progression of this condition, as fibrosis may advance in a self-perpetuating fashion. Definition of the cellular and molecular mechanisms involved in intestinal fibrosis may provide the key to developing new therapeutic approaches.

TGF-β信号通路抑制剂对肾脏纤维化的治疗作用

肾脏纤维化是各种原因引起的慢性肾脏病的重要标志[1]。肌成纤维细胞增殖和细胞外基质积聚是肾脏纤维化的特征性改变。目前认为,肾脏纤维化程度能可靠地反映肾脏病的预后。近几十年来,肌成纤维细胞的来源颇具争议。传统观点认为肌成纤维细胞起源于固有的成纤维细胞,但是,循环中的纤维细胞、肾小管上皮细胞转分化（epithelial to myofibroblast transformation,EMT）和内皮细胞向间充质细胞的分化均被认为是其可能的来源。

Transforming growth factor-β1 induces intestinal myofibroblast differentiation and modulates their migration

AIM： To investigate the effects of transforming growth factor β1 （TGF-β1） on the differentiation of colonic lamina propria fibroblasts （CLPF） into myofibroblasts in vitro.METHODS： Primary CLPF cultures were incubated with TGF-β1 and analyzed for production of m-smooth muscle actin （α-SMA）, fibronectin （FN） and FN isoforms. Migration assays were performed in a modified 48-well Boyden chamber. Levels of total and phosphorylated focal adhesion kinase （FAK） in CLPF were analyzed after induction of migration.did not change α-SMA levels, while TGF-β1 treatment for 6 d significantly increased α-SIVlA production. Short term incubation （6 h） with TGF-β1 enhanced CLPF migration, while long term treatment （6 d） of CLPF with TGF-β1 reduced migration to 15%-37% compared to untreated cells. FN and FN isoform mRNA expression were increased after short term incubation with TGF-β1 （2 d） in contrast to long term incubation with TGF-β1 for 6 d. After induction of migration, TGF-β1-preincubated CLPF showed higher amounts of FN and its isoforms and lower levels of total and phosphorylated FAK than untreated cells.CONCLUSION： Long term incubation of CLPF with TGF-β1 induced differentiation into myofibroblasts with enhanced α-SMA, reduced migratory potential and FAK phosphorylation, and increased FN production. In contrast, short term contact （6 h） of fibroblasts with TGF-β1 induced a dose-dependent increase of cell migration and FAK phosphorylation without induction of α-SMA production.

Thiazolidinedione treatment inhibits bile duct proliferation and fibrosis in a rat model of chronic cholestasis

AIM： To investigate the effects of troglitazone （TGZ）, an anti-diabetic drug which activates peroxisome proliferatoractivated receptor-y （PPAR-y）, for liver tissue repair, and the development of ductular reaction, following common bile duct ligation （BDL） in rats. METHODS： Rats were supplemented with TGZ （0.2% w/w in the pelleted food） for i wk before BDL or sham operation. Animals were killed at 1, 2, or 4 wk after surgery. RESULTS： The development of liver fibrosis was reduced in rats receiving TGZ, as indicated by significant decreases of procollagen type I gene expression and liver hydroxyproline levels. Accumulation of a-smooth-muscle actin （SMA）-expressing cells surrounding newly formed bile ducts following BDL, as well as total hepatic levels of SMA were partially inhibited by TGZ treatment, indicating the presence of a reduced number and/or activation of hepatic stellate cells （HSC） and myofibroblasts. Development of the ductular reaction was inhibited by TGZ, as indicated by histochemical evaluation and hepatic activity of γ-glutamyltransferase （GGT）. CONCLUSION： Treatment with thiazolidinedione reduces ductular proliferation and fibrosis in a model of chronic cholestasis, and suggests that limiting cholangiocyte proliferation may contribute to the lower development of scarring in this system.

Cirrhosis and autoimmune liver disease:Current understanding

Primary biliary cirrhosis(PBC),primary sclerosing cholangitis(PSC) and autoimmune hepatitis(AIH) constitute the classic autoimmune liver diseases(AILDs).While AIH target the hepatocytes,in PBC and PSC the targets of the autoimmune attack are the biliary epithelial cells.Persistent liver injury,associated with chronic AILD,leads to un-resolving inflammation,cell proliferation and the deposition of extracellular matrix proteins by hepatic stellate cells and portal myofibroblasts.Liver cirrhosis,and the resultant loss of normal liver function,inevitably ensues.Patients with cirrhosis have higher risks or morbidity and mortality,and that in the decompensated phase,complications of portal hypertension and/or liver dysfunction lead to rapid deterioration.Accurate diagnosis and monitoring of cirrhosis is,therefore of upmost importance.Liver biopsy is currently the gold standard technique,but highly promising non-invasive methodology is under development.Liver transplantation(LT) is an effective therapeutic option for the management of endstage liver disease secondary to AIH,PBC and PSC.LT is indicated for AILD patients who have progressed to end-stage chronic liver disease or developed intractable symptoms or hepatic malignancy;in addition,LT may also be indicated for patients presenting with acute liver disease due to AIH who do not respond to steroids.

Mitochondria: A critical hub for hepatic stellate cells activation during chronic liver diseases

Background: Upon liver injury, quiescent hepatic stellate cells(q HSCs), reside in the perisinusoidal space, phenotypically transdifferentiate into myofibroblast-like cells(MFBs). The q HSCs in the normal liver are less fibrogenic, migratory, and also have less proliferative potential. However, activated HSCs(a HSCs) are more fibrogenic and have a high migratory and proliferative MFBs phenotype. HSCs activation is a highly energetic process that needs abundant intracellular energy in the form of adenosine triphosphate(ATP) for the synthesis of extracellular matrix(ECM) in the injured liver to substantiate the injury. Data sources: The articles were collected through Pub Med and EMBASE using search terms "mitochondria and hepatic stellate cells", "mitochondria and HSCs", "mitochondria and hepatic fibrosis", "mitochondria and liver diseases", and "mitochondria and chronic liver disease", and relevant publications published before September 31, 2020 were included in this review. Results: Mitochondria homeostasis is affected during HSCs activation. Mitochondria in a HSCs are highly energetic and are in a high metabolically active state exhibiting increased activity such as glycolysis and respiration. a HSCs have high glycolytic enzymes expression and glycolytic activity induced by Hedgehog(Hh) signaling from injured hepatocytes. Increased glycolysis and aerobic glycolysis(Warburg effect) endproducts in a HSCs consequently activate the ECM-related gene expressions. Increased Hh signaling from injured hepatocytes downregulates peroxisome proliferator-activated receptor-γ expression and decreases lipogenesis in a HSCs. Glutaminolysis and tricarboxylic acid cycle liberate ATPs that fuel HSCs to proliferate and produce ECM during their activation. Conclusions: Available studies suggest that mitochondria functions can increase in parallel with HSCs activation. Therefore, mitochondrial modulators should be tested in an elaborate manner to control or prevent the HSCs activation during liver injury to subsequently regress hepatic fibrosis.

Expression of Interleukin-26 is upregulated in inflammatory bowel disease

To investigate interleukin (IL)-26 expression in the inflamed mucosa of patients with inflammatory bowel disease (IBD) and the function of IL-26. METHODSHuman colonic subepithelial myofibroblasts (SEMFs) were isolated from colon tissue surgically resected. The expression of IL-26 protein and its receptor complex was analyzed by immunohistochemistry. The gene expression induced by IL-26 was evaluated by real-time polymerase chain reaction. Intracellular signaling pathways were evaluated by immunoblotting and specific small interfering (si) RNA transfection. RESULTSThe mRNA and protein expression of IL-26 were significantly enhanced in the inflamed mucosa of patients with IBD. IL-26 receptor complex was expressed in colonic SEMFs in vivo and in vitro. IL-26 stimulated the mRNA expression of IL-6 and IL-8 in colonic SEMFs. The inhibitors of mitogen-activated protein kinases and phosphoinositide 3-kinase, and siRNAs for signal transducers and activator of transcription 1/3, nuclear factor-kappa B and activator protein-1 significantly reduced the mRNA expression of IL-6 and IL-8 induced by IL-26. CONCLUSIONThese results suggest that IL-26 plays a role in the pathophysiology of IBD through induction of inflammatory mediators.

Protective Effect of Angiotensin(1-7) on Silicotic Fibrosis in Rats

Objective Silicosis, caused by inhalation of silica dust, is the most serious occupational disease in China and the aim of present study was to explore the protective effect of Ang(1-7) on silicotic fibrosis and myofibroblast differentiation induced by Ang II. Methods HOPE-MED 8050 exposure control apparatus was used to establish the rat silicosis model. Pathological changes and collagen deposition of the lung tissue were examined by H.E. and VG staining, respectively. The localizations of ACE2 and α-smooth muscle actin(α-SMA) in the lung were detected by immunohistochemistry. Expression levels of collagen type I, α-SMA, ACE2, and Mas in the lung tissue and fibroblasts were examined by western blot. Levels of ACE2, Ang(1-7), and Ang II in serum were determined by ELISA. Co-localization of ACE2 and α-SMA in fibroblasts was detected by immunofluorescence. Results Ang(1-7) induced pathological changes and enhanced collagen deposition in vivo. Ang(1-7) decreased the expressions of collagen type I and α-SMA and increased the expressions of ACE2 and Mas in the silicotic rat lung tissue and fibroblasts stimulated by Ang II. Ang(1-7) increased the levels of ACE2 and Ang(1-7) and decreased the level of Ang II in silicotic rat serum. A779 enhanced the protective effect of Ang(1-7) in fibroblasts stimulated by Ang II. Conclusion Ang(1-7) exerted protective effect on silicotic fibrosis and myofibroblast differentiation induced by Ang II by regulating ACE2-Ang(1-7)-Mas axis.

Microstructural and ultrastructural changes in the healing process of bile duct trauma

OBJECTIVE: To explore the mechanism of benign biliary stricture caused by bile duct trauma. METHODS: A model of trauma of the common bile duct was established in 28 dogs and then repaired. The anastomotic tissues were taken on 3 days, 1 week, 3 weeks, 3 months, and 6 months respectively after operation and examined by using light microscopy and electromicroscopy. Macrophage. transforming growth factor beta I (TGF-β1) and α-smooth muscle actin (α-SMA) were studied immunohistochemically. RESULTS: The mucosal epithelium of the common bile duct restored poorly, chronic inflammation lasted for a long time, fibroblasts proliferated actively, extracellular matrix overdeposited, and myofibroblasts functioned actively during the whole healing process. Immunohistochemical test showed a high expression of macrophage, TGF-β1 and α-SMA during the healing process lasting a long duration. Macrophages were found in the lamina propria under mucosa, TGF-β1 in the granular tissue, fibroblasts and endothelial cells of blood vessels, while α-SMA in the myofibroblasts and smooth muscle tissue. CONCLUSIONS: The healing of the bile duct is in the mode of overhealing. Myofibroblast is the main cause for contracture of scar and stricture of the bile duct. The high expression of macrophage, TGF-β1 and α-SMA is closely related to active proliferation of fibroblasts, extracellular matrix overdeposition and scar contracture of the bile duct.