Journal articles on the topic 'Fibrotic and inflammatory conditions'
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1
Binatti, Eleonora, Alessio Gerussi, Donatella Barisani, and Pietro Invernizzi. "The Role of Macrophages in Liver Fibrosis: New Therapeutic Opportunities." International Journal of Molecular Sciences 23, no. 12 (June 14, 2022): 6649. http://dx.doi.org/10.3390/ijms23126649.
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Chronic inflammation is the hallmark of fibrotic disorders and is characterized by the activation of immune cells in the damaged tissues. Macrophages have emerged as central players in the fibrotic process since they initiate, sustain and amplify the inflammatory reaction. As regards the liver, distinct populations of phagocytic cells, like Kupffer cells and monocyte-derived macrophages, are indisputably key cells implicated in the pathogenesis of several chronic liver diseases. In this review, we summarize the current knowledge on the origin, role and functions of macrophages in fibrotic conditions, with a specific focus on liver fibrosis; then, we discuss some innovative therapeutic strategies targeting macrophages in fibrotic liver diseases.
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Sgambellone, Silvia, Silvia Marri, Stefano Catarinicchia, Alessandro Pini, Dilip K. Tosh, Kenneth A. Jacobson, Emanuela Masini, Daniela Salvemini, and Laura Lucarini. "Adenosine A3 Receptor (A3AR) Agonist for the Treatment of Bleomycin-Induced Lung Fibrosis in Mice." International Journal of Molecular Sciences 23, no. 21 (November 1, 2022): 13300. http://dx.doi.org/10.3390/ijms232113300.
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Adenosine receptors (ARs) are involved in the suppression and development of inflammatory and fibrotic conditions. Specifically, AR activation promotes differentiation of lung fibroblasts into myofibroblasts, typical of a fibrotic event. Pulmonary fibrosis is a severe disease characterized by inflammation and fibrosis of unknown etiology and lacking an effective treatment. The present investigation explored the action of MRS5980, a new, highly potent and selective A3AR agonist, in an established murine model of lung fibrosis. The effects of either vehicle or MRS5980 were studied in mice following intratracheal bleomycin administration. We evaluated the role of the A3AR agonist on lung stiffness, studying the airway resistance to inflation, oxidative stress (8-OHdG and MDA), inflammation, pro- and anti-inflammatory marker levels (IL-1β, IL-6, TNF-α, IL-10 and IL-17A) and fibrosis establishment, evaluating transforming growth factor (TGF)-β expression and α-smooth muscle actin (α-SMA) deposition in lungs. Bleomycin administration increased lung stiffness, TGF-β levels, α-SMA deposition, and inflammatory and oxidative stress markers. The treatment with MRS5980 attenuated all the analyzed functional, biochemical and histopathological markers in a dose-dependent manner. Our findings support the therapeutic potential of A3AR agonists in lung fibrosis by demonstrating reduced disease progression, as indicated by decreased inflammation, TGF-β expression and fibrotic remodeling.
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Filidou, Eirini, Leonidas Kandilogiannakis, Gesthimani Tarapatzi, Michail Spathakis, Paschalis Steiropoulos, Dimitrios Mikroulis, Konstantinos Arvanitidis, Vasilis Paspaliaris, and George Kolios. "Anti-Inflammatory and Anti-Fibrotic Effect of Immortalized Mesenchymal-Stem-Cell-Derived Conditioned Medium on Human Lung Myofibroblasts and Epithelial Cells." International Journal of Molecular Sciences 23, no. 9 (April 20, 2022): 4570. http://dx.doi.org/10.3390/ijms23094570.
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Idiopathic pulmonary fibrosis (IPF) is caused by progressive lung tissue impairment due to extended chronic fibrosis, and it has no known effective treatment. The use of conditioned media (CM) from an immortalized human adipose mesenchymal stem cell line could be a promising therapeutic strategy, as it can reduce both fibrotic and inflammatory responses. We aimed to investigate the anti-inflammatory and anti-fibrotic effect of CM on human pulmonary subepithelial myofibroblasts (hPSM) and on A549 pulmonary epithelial cells, treated with pro-inflammatory or pro-fibrotic mediators. CM inhibited the proinflammatory cytokine-induced mRNA and protein production of various chemokines in both hPSMs and A549 cells. It also downregulated the mRNA expression of IL-1α, but upregulated IL-1β and IL-6 mRNA production in both cell types. CM downregulated the pro-fibrotic-induced mRNA expression of collagen Type III and the migration rate of hPSMs, but upregulated fibronectin mRNA production and the total protein collagen secretion. CM’s direct effect on the chemotaxis and cell recruitment of immune-associated cells, and its indirect effect on fibrosis through the significant decrease in the migration capacity of hPSMs, makes it a plausible candidate for further development towards a therapeutic treatment for IPF.
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Zhang, Xiwen, Joseph K. Ritter, and Ningjun Li. "Sphingosine-1-phosphate pathway in renal fibrosis." American Journal of Physiology-Renal Physiology 315, no. 4 (October 1, 2018): F752—F756. http://dx.doi.org/10.1152/ajprenal.00596.2017.
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Renal fibrosis is defined as the excessive deposition and modification of extracellular matrix (ECM) in the renal parenchyma in response to injury and inflammation, resulting in renal function loss. This condition is common to many chronic kidney diseases occurring under diverse pathological conditions, such as diabetic and hypertensive nephropathy. Sphingosine-1-phosphate (S1P) is a bioactive sphingolipid metabolite involved in the regulation of cardiovascular functions and the pathogenesis of various cardiovascular diseases. S1P has also been considered an important regulator of fibrotic diseases, playing significant roles in the differentiation of fibroblasts to myofibroblasts and in the induction of inflammatory responses during the early stages of fibrotic diseases. This minireview summarizes recent research findings regarding the importance of the sphingosine kinase-1-S1P-S1P receptor axis and its interactions with other classic fibrotic signaling pathways and the immune inflammatory response to reveal novel therapeutic targets for the treatment or prevention of renal fibrosis.
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Herbelet, Sandrine, Boel De Paepe, and Jan L. De Bleecker. "Abnormal NFAT5 Physiology in Duchenne Muscular Dystrophy Fibroblasts as a Putative Explanation for the Permanent Fibrosis Formation in Duchenne Muscular Dystrophy." International Journal of Molecular Sciences 21, no. 21 (October 24, 2020): 7888. http://dx.doi.org/10.3390/ijms21217888.
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Duchenne muscular dystrophy (DMD) is characterized by chronic inflammation and fibrotic tissue production by fibroblasts. The promyogenic factor nuclear factor of activated T-cells 5 (NFAT5) is virtually present in all cells, responding to hyperosmolar or pro-inflammatory stress. In embryogenic fibroblasts, absence of NFAT5 results in cell cycle arrest. Here, unaffected skeletal muscle fibroblasts from one healthy donor showed NFAT5 nuclear translocation upon hyperosmolar stress and normal cell viability. Absence of NFAT5 translocation under pro-inflammatory conditions resulted in decreased cell growth (Incucyte ZOOM). In DMD skeletal muscle fibroblasts from one DMD patient, NFAT5 was merely located in the nucleus. Exposure to hyperosmolar conditions or pro-inflammatory cytokines IFN-γ, IL-1β and TNF-α had no influence on NFAT5 physiology (immunofluorescence, western blotting, RT-qPCR). Hyperosmolarity resulted in decreased cell viability and pro-inflammatory stress in unaltered cell growth. These findings suggest that NFAT5 is vital to DMD fibroblast survival. Exposure to pro-inflammatory or hyperosmolar stress in DMD fibroblasts results in an unexpected NFAT5 response, where fibroblasts are not triggered by inflammatory cytokines and do not withstand hyperosmolarity. Chronic inflammation could be viewed as a non-restrictive factor in the formation of fibrosis in DMD. Abnormal NFAT5 physiology could provide a molecular explanation for permanent fibrotic matrix production by DMD fibroblasts.
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Pham, Tho X., Yoojin Lee, Minkyung Bae, Siqi Hu, Hyunju Kang, Mi-Bo Kim, Young-Ki Park, and Ji-Young Lee. "Spirulina supplementation in a mouse model of diet-induced liver fibrosis reduced the pro-inflammatory response of splenocytes." British Journal of Nutrition 121, no. 7 (February 26, 2019): 748–55. http://dx.doi.org/10.1017/s0007114519000126.
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AbstractTreatment of liver fibrosis is very limited as there is currently no effective anti-fibrotic therapy. Spirulina platensis (SP) is a blue-green alga that is widely supplemented in healthy foods. The objective of this study was to determine whether SP supplementation can prevent obesity-induced liver fibrosis in vivo. Male C57BL/6J mice were randomly assigned to a low-fat or a high-fat (HF)/high-sucrose/high-cholesterol diet or an HF diet supplemented with 2·5 % SP (w/w) (HF/SP) for 16 or 20 weeks. There were no significant differences in body weight, activity, energy expenditure, serum lipids or glucose tolerance between mice on HF and HF/SP diets. However, plasma alanine aminotransferase level was significantly reduced by SP at 16 weeks. Expression of fibrotic markers and trichrome stains showed no differences between HF and HF/SP. Splenocytes isolated from HF/SP fed mice had lower inflammatory gene expression and cytokine secretion compared with splenocytes from HF-fed mice. SP supplementation did not attenuate HF-induced liver fibrosis. However, the expression and secretion of inflammatory genes in splenocytes were significantly reduced by SP supplementation, demonstrating the anti-inflammatory effects of SP in vivo. Although SP did not show appreciable effect on the prevention of liver fibrosis in this mouse model, it may be beneficial for other inflammatory conditions.
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Rizzi, Manuela, Stelvio Tonello, Davide D’Onghia, and Pier Paolo Sainaghi. "Gas6/TAM Axis Involvement in Modulating Inflammation and Fibrosis in COVID-19 Patients." International Journal of Molecular Sciences 24, no. 2 (January 4, 2023): 951. http://dx.doi.org/10.3390/ijms24020951.
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Gas6 (growth arrest-specific gene 6) is a widely expressed vitamin K-dependent protein that is involved in many biological processes such as homeostatic regulation, inflammation and repair/fibrotic processes. It is known that it is the main ligand of TAMs, a tyrosine kinase receptor family of three members, namely MerTK, Tyro-3 and Axl, for which it displays the highest affinity. Gas6/TAM axis activation is known to be involved in modulating inflammatory responses as well as fibrotic evolution in many different pathological conditions. Due to the rapidly evolving COVID-19 pandemic, this review will focus on Gas6/TAM axis activation in SARS-CoV-2 infection, where de-regulated inflammatory responses and fibrosis represent a relevant feature of severe disease manifestation. Furthermore, this review will highlight the most recent scientific evidence supporting an unsuspected role of Axl as a SARS-CoV-2 infection driver, and the potential therapeutic advantages of the use of existing Axl inhibitors in COVID-19 management. From a physiological point of view, the Gas6/TAM axis plays a dual role, fostering the tissue repair processes or leading to organ damage and loss of function, depending on the prevalence of its anti-inflammatory or profibrotic properties. This review makes a strong case for further research focusing on the Gas6/TAM axis as a pharmacological target to manage different disease conditions, such as chronic fibrosis or COVID-19.
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Hortobagyi, David, Tanja Grossmann, Magdalena Tschernitz, Magdalena Grill, Andrijana Kirsch, Claus Gerstenberger, and Markus Gugatschka. "In vitro mechanical vibration down-regulates pro-inflammatory and pro-fibrotic signaling in human vocal fold fibroblasts." PLOS ONE 15, no. 11 (November 19, 2020): e0241901. http://dx.doi.org/10.1371/journal.pone.0241901.
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Introduction Voice rest following phonotrauma or phonosurgery has a considerable clinical impact, but clinical recommendations are inconsistent due to inconclusive data. As biopsies of the vocal folds (VF) for molecular biology studies in humans are unethical, we established a new in vitro model to explore the effects of vibration on human vocal fold fibroblasts (hVFF) in an inflammatory and normal state, which is based on previously published models. Methods By using a phonomimetic bioreactor we were able to apply predefined vibrational stress patterns on hVFF cultured under inflammatory or normal conditions. Inflammatory and pro-fibrotic stimuli were induced by interleukin (IL)1β and transforming growth factor (TGF)β1, respectively. Mechanical stimulation was applied four hours daily, over a period of 72 hours. Outcome measurements comprised assessment of extracellular matrix (ECM)-related components, angiogenic factors, and inflammatory and fibrogenic markers on gene expression and protein levels. Results Under inflammatory conditions, the inflammatory cytokine IL11, as well as the myofibroblast marker alpha smooth muscle actin (α-SMA) were significantly reduced when additional vibration was applied. The desirable anti-fibrotic ECM component hyaluronic acid was increased following cytokine treatment, but was not diminished following vibration. Conclusion Our experiments revealed the effect of vibrational stress on hVFF in an inflammatory state. Elevated levels of certain pro-inflammatory/pro-fibrotic factors could be mitigated by additional vibrational excitation in an in vitro setting. These findings corroborate clinical studies which recommend early voice activation following an acute event.
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Hazel, K., N. McGinley, A. O’Toole, and S. Keely. "P087 The role of bile acids in mediating fibrosis in inflammatory bowel disease." Journal of Crohn's and Colitis 15, Supplement_1 (May 1, 2021): S187. http://dx.doi.org/10.1093/ecco-jcc/jjab076.216.
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Abstract Background Crohn’s disease is a chronic inflammatory disorder of the gastrointestinal tract that affects approximately 15,000 people in Ireland. 10% of these patients will develop fibrostenosing disease, usually requiring surgery. There are currently no antifibrotic medications in use for the treatment of fibrostenosing CD. Bile acids (BAs), produced in the liver and classically known for their roles in facilitating fat absorption from the diet, have previously been shown to have the capacity to regulate fibroblast activation and to exert protective effects against both hepatic fibrosis and intestinal inflammation. Therefore, altered mucosal fibroblast function in response to luminal BAs may be an important factor in the pathogenesis of fibrostenosing Crohn’s disease. Our aim is to determine if treatment of fibroblasts under pro-fibrotic conditions with naturally occurring BAs decreases markers associated with fibrosis. Methods NIH/3T3, a murine fibroblast cell line, were treated with TGF-ß (5 ng/ml) to induce their activation and transition to myofibroblasts in the absence or presence of varying concentrations of the naturally-occurring BAs, deoxycholic acid (DCA) and ursodeoxycholic acid (UDCA) over 24 hours. qPCR was employed to determine expression of alpha-smooth muscle actin (aSMA), an important marker for ECM deposition and fibrosis. Results Treatment of fibroblasts with DCA within the range of normal physiological concentrations (50 to 200 µM) induced a significant inhibition of TGF-ß-induced aSMA expression. At a concentration of 100 µM, DCA reduced TGF-ß-induced responses by 50%, compared to cells treated with TGF-ß-alone (RQ=2.17; RQ=4.58, respectively) (n=6) (p=0.0031) (Figure 1). Similarly, treatment with UDCA at supraphysiological concentrations (500 µM) decreased aSMA expression following TGF-ß stimulation (RQ=1.75; RQ=3.69, respectively) (n=5) (Figure 2). Treatment with conjugated BAs TDCA and TUDCA suggest an intracellular mechanism of action by DCA and UDCA. INT-777, the specific agonist of the TGR5 bile acid receptor, also reduced TGF-ß-induced aSMA expression, suggesting this receptor may be involved in mediating the effects of naturally-occurring BAs. Figure 1: Figure 2: Conclusion We have shown that treatment of fibroblasts under pro-fibrotic conditions with the BAs, DCA and UDCA, results in a significant decrease in aSMA expression. These data suggest that BAs represent a promising target for the development of new anti-fibrotic agents to treat/prevent fibrostenosing CD.
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Laaninen, Matias, Merja Bläuer, Juhani Sand, Isto Nordback, and Johanna Laukkarinen. "Difference in Early Activation of NF-κB and MCP-1 in Acinar-Cell-Rich versus Fibrotic Human Pancreas Exposed to Surgical Trauma and Hypoxia." Gastroenterology Research and Practice 2014 (2014): 1–7. http://dx.doi.org/10.1155/2014/460363.
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Objectives.Previously we have shown that a pancreas with over 40% acinar cells is exposed to postoperative pancreatitis and other complications after pancreaticoduodenectomy (PD). Our aim was to analyze the expression of NF-κB and MCP-1 in the cut edge of human pancreas after PD in both acinar-cell-rich and fibrotic pancreata.Methods.Several pancreatic samples from six patients, three with acinar-cell-rich and three with fibrotic pancreata, were exposed to surgical trauma in PD, and thereafter to hypoxemia for 15 minutes, 2–2.5 hours, 4 hours, or 6 hours, to mimic postoperative conditions of the pancreatic remnant in a patient. Immunohistochemical analysis of inflammation markers (NF-κB, MCP-1) was performed.Results.In the acinar-cell-rich pancreata, intra-acinar NF-κB and MCP-1 expression increased from mild at 15 minutes to high during the first 4 hours, whereas in ductal cells MCP-1 staining was highly intense at both time points. Acinar cell NF-κB and MCP-1 expression and ductal cell MCP-1 expression were also observed in the fibrotic pancreata, but the activation remained low throughout the 6 hours.Conclusions.In acinar-cell-rich pancreas, an extensive inflammatory cascade begins almost immediately after surgical trauma. Fibrosis may limit the progression of inflammatory process in pancreas.
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Law, Becker M. P., Ray Wilkinson, Xiangju Wang, Katrina Kildey, Kurt Giuliani, Kenneth W. Beagley, Jacobus Ungerer, Helen Healy, and Andrew J. Kassianos. "Human Tissue-Resident Mucosal-Associated Invariant T (MAIT) Cells in Renal Fibrosis and CKD." Journal of the American Society of Nephrology 30, no. 7 (June 11, 2019): 1322–35. http://dx.doi.org/10.1681/asn.2018101064.
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BackgroundMucosal-associated invariant T (MAIT) cells represent a specialized lymphocyte population associated with chronic inflammatory disorders. Little is known, however, about MAIT cells in diseases of the kidney, including CKD.MethodsTo evaluate MAIT cells in human native kidneys with tubulointerstitial fibrosis, the hallmark of CKD, we used multicolor flow cytometry to identify, enumerate, and phenotype such cells from human kidney tissue biopsy samples, and immunofluorescence microscopy to localize these cells. We cocultured MAIT cells and human primary proximal tubular epithelial cells (PTECs) under hypoxic (1% oxygen) conditions to enable examination of mechanistic tubulointerstitial interactions.ResultsWe identified MAIT cells (CD3+ TCR Vα7.2+ CD161hi) in healthy and diseased kidney tissues, detecting expression of tissue-resident markers (CD103/CD69) on MAIT cells in both states. Tissue samples from kidneys with tubulointerstitial fibrosis had significantly elevated numbers of MAIT cells compared with either nonfibrotic samples from diseased kidneys or tissue samples from healthy kidneys. Furthermore, CD69 expression levels, also an established marker of lymphocyte activation, were significantly increased on MAIT cells from fibrotic tissue samples. Immunofluorescent analyses of fibrotic kidney tissue identified MAIT cells accumulating adjacent to PTECs. Notably, MAIT cells activated in the presence of human PTECs under hypoxic conditions (modeling the fibrotic microenvironment) displayed significantly upregulated expression of CD69 and cytotoxic molecules perforin and granzyme B; we also observed a corresponding significant increase in PTEC necrosis in these cocultures.ConclusionsOur findings indicate that human tissue-resident MAIT cells in the kidney may contribute to the fibrotic process of CKD via complex interactions with PTECs.
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El-Hela, Atef A., Mostafa M. Hegazy, Hatem S. Abbass, Amal H. Ahmed, Marwa S. Abu Bakr, Rawah H. Elkousy, Adel Ehab Ibrahim, Sami El Deeb, Ossama M. Sayed, and Enas S. Gad. "Dinebra retroflexa Herbal Phytotherapy: A Simulation Study Based on Bleomycin-Induced Pulmonary Fibrosis Retraction Potential in Swiss Albino Rats." Medicina 58, no. 12 (November 24, 2022): 1719. http://dx.doi.org/10.3390/medicina58121719.
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Background and Objectives: Fibrotic lung disease is one of the main complications of many medical conditions. Therefore, the use of anti-fibrotic agents may provide a chance to prevent, or at least modify, such complication. The aim of this study was to evaluate the protective pulmonary anti-fibrotic and anti-inflammatory effects of Dinebra retroflexa. Materials and methods: Dinebra retroflexa methanolic extract and its synthesized silver nanoparticles were tested on bleomycin-induced pulmonary fibrosis. Pulmonary fibrosis was induced by intratracheal instillation of bleomycin (5 mg/5 mL/kg-Saline) as a supposed model for induced lung fibrosis. The weed evaluation was performed by intratracheal instillation of Dinebra retroflexa methanolic extract and its silver nanoparticles (35 mg/100 mL/kg-DMSO, single dose). Results: The results showed that both Dinebra retroflexa methanolic extract and its silver nanoparticles had a significant pulmonary fibrosis retraction potential, with Ashcroft scores of three and one, respectively, and degrees of collagen deposition reduction of 33.8 and 46.1%, respectively. High-resolution UHPLC/Q-TOF-MS/MS metabolic profiling and colorimetrically polyphenolic quantification were performed for further confirmation and explanation of the represented effects. Such activity was believed to be due to the tentative identification of twenty-seven flavonoids and one phenolic acid along with a phenolic content of 57.8 mg/gm (gallic acid equivalent) and flavonoid content of 22.5 mg/gm (quercetin equivalent). Conclusion: Dinebra retroflexa may be considered as a promising anti-fibrotic agent for people at high risk of complicated lung fibrosis. The results proved that further clinical trials would be recommended to confirm the proposed findings.
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Wu, Hanghang, Chaobo Chen, Siham Ziani, Leonard J. Nelson, Matías A. Ávila, Yulia A. Nevzorova, and Francisco Javier Cubero. "Fibrotic Events in the Progression of Cholestatic Liver Disease." Cells 10, no. 5 (May 5, 2021): 1107. http://dx.doi.org/10.3390/cells10051107.
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Cholestatic liver diseases including primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC) are associated with active hepatic fibrogenesis, which can ultimately lead to the development of cirrhosis. However, the exact relationship between the development of liver fibrosis and the progression of cholestatic liver disease remains elusive. Periductular fibroblasts located around the bile ducts seem biologically different from hepatic stellate cells (HSCs). The fibrotic events in these clinical conditions appear to be related to complex crosstalk between immune/inflammatory mechanisms, cytokine signalling, and perturbed homeostasis between cholangiocytes and mesenchymal cells. Several animal models including bile duct ligation (BDL) and the Mdr2-knockout mice have improved our understanding of mechanisms underlying chronic cholestasis. In the present review, we aim to elucidate the mechanisms of fibrosis in order to help to identify potential diagnostic and therapeutic targets.
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Carmo-Fernandes, André, Michelle Puschkarow, Karin Peters, Stefanie Gnipp, and Marcus Peters. "The Pathogenic Role of Smooth Muscle Cell-Derived Wnt5a in a Murine Model of Lung Fibrosis." Pharmaceuticals 14, no. 8 (July 31, 2021): 755. http://dx.doi.org/10.3390/ph14080755.
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Idiopathic pulmonary fibrosis (IPF) is a disease characterized by extensive fibrosis of the lung tissue. Wnt5a expression was observed to be upregulated in IPF and suggested to be involved in the progression of the disease. Interestingly, smooth muscle cells (SMC) are a major source of Wnt5a in IPF patients. However, no study has been conducted until now to investigate the precise role of smooth muscle-derived Wnt5a in IPF. Here, we used the bleomycin-induced lung fibrosis model in a conditional gene-deficient mouse, where the Wnt5a gene was excised from SMC. We show here that the excision of the Wnt5a gene in SMC led to significantly improved health conditions with minimized weight loss and improved lung function. This improvement was based on a significantly lower deposition of collagen in the lung with a reduced number of fibrotic foci in lung parenchyma. Furthermore, the bleomycin-induced cellular infiltration into the airways was not altered in the gene-deficient mice compared with wild-type mice. Thus, we demonstrate that the Wnt5a expression of SMC of the airways leads to aggravated fibrosis of the lung with poor clinical conditions. This aggravation was not an influence in the bleomycin-induced inflammatory processes but on the development of fibrotic foci in lung parenchyma and the deposition of collagen.
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Loboda, Agnieszka, Mateusz Sobczak, Alicja Jozkowicz, and Jozef Dulak. "TGF-β1/Smads and miR-21 in Renal Fibrosis and Inflammation." Mediators of Inflammation 2016 (2016): 1–12. http://dx.doi.org/10.1155/2016/8319283.
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Renal fibrosis, irrespective of its etiology, is a final common stage of almost all chronic kidney diseases. Increased apoptosis, epithelial-to-mesenchymal transition, and inflammatory cell infiltration characterize the injured kidney. On the molecular level, transforming growth factor-β1 (TGF-β1)-Smad3 signaling pathway plays a central role in fibrotic kidney disease. Recent findings indicate the prominent role of microRNAs, small noncoding RNA molecules that inhibit gene expression through the posttranscriptional repression of their target mRNAs, in different pathologic conditions, including renal pathophysiology. miR-21 was also shown to play a dynamic role in inflammatory responses and in accelerating injury responses to promote organ failure and fibrosis. Understanding the cellular and molecular bases of miR-21 involvement in the pathogenesis of kidney diseases, including inflammatory reaction, could be crucial for their early diagnosis. Moreover, the possibility of influencing miR-21 level by specific antagomirs may be considered as an approach for treatment of renal diseases.
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Selvarajah, Brintha, Ilan Azuelos, Dimitrios Anastasiou, and Rachel C. Chambers. "Fibrometabolism—An emerging therapeutic frontier in pulmonary fibrosis." Science Signaling 14, no. 697 (August 24, 2021): eaay1027. http://dx.doi.org/10.1126/scisignal.aay1027.
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Fibrosis is the final pathological outcome and major cause of morbidity and mortality in many common and chronic inflammatory, immune-mediated, and metabolic diseases. Despite the growing incidence of fibrotic diseases and extensive research efforts, there remains a lack of effective therapies that improve survival. The application of omics technologies has revolutionized our approach to identifying previously unknown therapeutic targets and potential disease biomarkers. The application of metabolomics, in particular, has improved our understanding of disease pathomechanisms and garnered a wave of scientific interest in the role of metabolism in the biology of myofibroblasts, the key effector cells of the fibrogenic response. Emerging evidence suggests that alterations in metabolism not only are a feature of but also may play an influential role in the pathogenesis of fibrosis, most notably in idiopathic pulmonary fibrosis (IPF), the most rapidly progressive and fatal of all fibrotic conditions. This review will detail the role of key metabolic pathways, their alterations in myofibroblasts, and the potential this new knowledge offers for the development of antifibrotic therapeutic strategies.
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Shahrbaf, Mohammad Amin, Masoumeh Nouri, Morteza Zarrabi, Roberto Gramignoli, and Massoud Vosough. "Extraembryonic Mesenchymal Stromal/Stem Cells in Liver Diseases: A Critical Revision of Promising Advanced Therapy Medicinal Products." Cells 11, no. 7 (March 23, 2022): 1074. http://dx.doi.org/10.3390/cells11071074.
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Liver disorders have been increasing globally in recent years. These diseases are associated with high morbidity and mortality rates and impose high care costs on the health system. Acute liver failure, chronic and congenital liver diseases, as well as hepatocellular carcinoma have been limitedly treated by whole organ transplantation so far. But novel treatments for liver disorders using cell-based approaches have emerged in recent years. Extra-embryonic tissues, including umbilical cord, amnion membrane, and chorion plate, contain multipotent stem cells. The pre-sent manuscript discusses potential application of extraembryonic mesenchymal stromal/stem cells, focusing on the management of liver diseases. Extra-embryonic MSC are characterized by robust and constitutive anti-inflammatory and anti-fibrotic properties, indicating as therapeutic agents for inflammatory conditions such as liver fibrosis or advanced cirrhosis, as well as chronic inflammatory settings or deranged immune responses.
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CHARBENEAU, Ryan P., and Marc PETERS-GOLDEN. "Eicosanoids: mediators and therapeutic targets in fibrotic lung disease." Clinical Science 108, no. 6 (May 24, 2005): 479–91. http://dx.doi.org/10.1042/cs20050012.
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Fibrosis is a common end-stage sequella of a number of acute and chronic lung diseases. Current concepts of pathogenesis implicate dysregulated interactions between epithelial cells and mesenchymal cells. Although investigative efforts have documented important roles for cytokines and growth factors in the pathogenesis of fibrotic lung diseases, these observations have not as yet been translated into efficacious therapies, and there is a pressing need for new pathogenetic insights and therapeutic approaches for these devastating disorders. Eicosanoids are lipid mediators derived from arachidonic acid, the most studied of which are the prostaglandins and leukotrienes. Although they are primarily known for their roles in asthma, pain, fever and vascular responses, present evidence indicates that eicosanoids exert relevant effects on immune/inflammatory, as well as structural, cells pertinent to fibrogenesis. In general, leukotrienes promote, whereas prostaglandin E2 opposes, fibrogenic responses. An imbalance of eicosanoids also exists in pulmonary fibrosis, which favours the production of leukotrienes over prostaglandin E2. This review highlights the role of this imbalance in the evolution of fibrotic lung disease, discusses the mechanisms by which it may arise and considers approaches for therapeutic targeting of eicosanoids in these conditions.
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Rojas, Macarena, Yolanda Prado, Pablo Tapia, Leandro J. Carreño, Claudio Cabello-Verrugio, and Felipe Simon. "Oxidized High-Density Lipoprotein Induces Endothelial Fibrosis Promoting Hyperpermeability, Hypotension, and Increased Mortality." Antioxidants 11, no. 12 (December 15, 2022): 2469. http://dx.doi.org/10.3390/antiox11122469.
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During systemic inflammation, reactive oxygen species (ROS) are generated in the bloodstream, producing large amounts of oxidized HDL (oxHDL). OxHDL loses the vascular protective features of native HDL, acquiring detrimental actions. Systemic inflammation promotes endothelial fibrosis, characterized by adhesion protein downregulation and fibrotic-specific gene upregulation, disrupting endothelial monolayer integrity. Severe systemic inflammatory conditions, as found in critically ill patients in the intensive care unit (ICU), exhibit endothelial hyperpermeability, hypotension, and organ hypoperfusion, promoting organ dysfunction and increased mortality. Because endothelial fibrosis disturbs the endothelium, it is proposed that it is the cellular and molecular origin of endothelial hyperpermeability and the subsequent deleterious consequences. However, whether oxHDL is involved in this process is unknown. The aim of this study was to investigate the fibrotic effect of oxHDL on the endothelium, to elucidate the underlying molecular and cellular mechanism, and to determine its effects on vascular permeability, blood pressure, and mortality. The results showed that oxHDL induces endothelial fibrosis through the LOX-1/NOX-2/ROS/NF-κB pathway, TGF-β secretion, and ALK-5/Smad activation. OxHDL-treated rats showed endothelial hyperpermeability, hypotension, and an enhanced risk of death and mortality, which was prevented using an ALK-5 inhibitor and antioxidant diet consumption. Additionally, the ICU patients showed fibrotic endothelial cells, and the resuscitation fluid volume administered correlated with the plasma oxHDL levels associated with an elevated risk of death and mortality. We conclude that oxHDL generates endothelial fibrosis, impacting blood pressure regulation and survival.
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Simmen, Simona, Max Maane, Sarah Rogler, Katherina Baebler, Silvia Lang, Jesus Cosin-Roger, Kirstin Atrott, et al. "Hypoxia Reduces the Transcription of Fibrotic Markers in the Intestinal Mucosa." Inflammatory Intestinal Diseases 6, no. 2 (2021): 87–100. http://dx.doi.org/10.1159/000513061.
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<b><i>Introduction:</i></b> Intestinal fibrosis, characterized by excessive deposition of extracellular matrix proteins, is a common and severe clinical complication of inflammatory bowel disease (IBD). However, the mechanisms underlying fibrosis remain elusive, and currently, there are limited effective pharmacologic treatments that target the development of fibrosis. Hypoxia is one of the key microenvironmental factors influencing intestinal inflammation and has been linked to fibrosis. <b><i>Objective:</i></b> In the present study, we sought to elucidate the impact of hypoxia on fibrotic gene expression in the intestinal mucosa. <b><i>Methods:</i></b> Human volunteers, IBD patients, and dextran sulphate sodium-treated mice were exposed to hypoxia, and colonic biopsies were collected. The human intestinal epithelial cell line Caco-2, human THP-1 macrophages, and primary human gut fibroblasts were subjected to hypoxia, and changes in fibrotic gene expression were assessed. <b><i>Results:</i></b> Human volunteers subjected to hypoxia presented reduced transcriptional levels of fibrotic and epithelial-mesenchymal transition markers in the intestinal mucosa. IBD patients showed a trend towards a decrease in tissue inhibitor of metalloproteinase 1 protein expression. In mice, hypoxic conditions reduced the colonic expression of several collagens and matrix metalloproteinases. Hypoxic Caco-2 cells, THP-1 cells, and primary gut fibroblasts showed a significant downregulation in the expression of fibrotic and tissue remodelling factors. <b><i>Conclusions:</i></b> Stabilization of hypoxia-inducible factors might represent a novel therapeutic approach for the treatment of IBD-associated fibrosis.
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Golpanian, Samuel, Ariel Wolf, Konstantinos E. Hatzistergos, and Joshua M. Hare. "Rebuilding the Damaged Heart: Mesenchymal Stem Cells, Cell-Based Therapy, and Engineered Heart Tissue." Physiological Reviews 96, no. 3 (July 2016): 1127–68. http://dx.doi.org/10.1152/physrev.00019.2015.
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Mesenchymal stem cells (MSCs) are broadly distributed cells that retain postnatal capacity for self-renewal and multilineage differentiation. MSCs evade immune detection, secrete an array of anti-inflammatory and anti-fibrotic mediators, and very importantly activate resident precursors. These properties form the basis for the strategy of clinical application of cell-based therapeutics for inflammatory and fibrotic conditions. In cardiovascular medicine, administration of autologous or allogeneic MSCs in patients with ischemic and nonischemic cardiomyopathy holds significant promise. Numerous preclinical studies of ischemic and nonischemic cardiomyopathy employing MSC-based therapy have demonstrated that the properties of reducing fibrosis, stimulating angiogenesis, and cardiomyogenesis have led to improvements in the structure and function of remodeled ventricles. Further attempts have been made to augment MSCs' effects through genetic modification and cell preconditioning. Progression of MSC therapy to early clinical trials has supported their role in improving cardiac structure and function, functional capacity, and patient quality of life. Emerging data have supported larger clinical trials that have been either completed or are currently underway. Mechanistically, MSC therapy is thought to benefit the heart by stimulating innate anti-fibrotic and regenerative responses. The mechanisms of action involve paracrine signaling, cell-cell interactions, and fusion with resident cells. Trans-differentiation of MSCs to bona fide cardiomyocytes and coronary vessels is also thought to occur, although at a nonphysiological level. Recently, MSC-based tissue engineering for cardiovascular disease has been examined with quite encouraging results. This review discusses MSCs from their basic biological characteristics to their role as a promising therapeutic strategy for clinical cardiovascular disease.
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Włodarczyk, Marcin, Aleksandra Sobolewska, Aleksandra Lesiak, and Joanna Narbutt. "The role of factor XIII-A in the development of inflammatory skin lesions." Open Life Sciences 9, no. 9 (September 1, 2014): 869–73. http://dx.doi.org/10.2478/s11535-014-0319-9.
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AbstractFactor XIII (FXIII) is a unique clotting factor activated in the last stage of the coagulation cascade, with multiple other plasmatic and cellular functions, outside of the traditional homeostasis. Literature data show that FXIII is expressed in skin lesions in the course of various inflammatory skin disorders. Dermis contains a series of macrophages and dendritic cells, which express different phenotypes including FXIII. Increased levels of FXIII-positive cells are present in specific cutaneous inflammatory and fibrotic conditions. The aim of this review is to provide the relationship between FXIII and the development of the inflammatory skin lesions.
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Bhandari, Rajan, Michael S. Ball, Viktor Martyanov, Dillon Popovich, Evelien Schaafsma, Saemi Han, Mohamed Eltanbouly, et al. "Pro-fibrotic Activation of Human Macrophages in Systemic Sclerosis." Journal of Immunology 204, no. 1_Supplement (May 1, 2020): 224.33. http://dx.doi.org/10.4049/jimmunol.204.supp.224.33.
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Abstract Genome-wide gene expression studies implicate macrophages as mediators of fibrosis in Systemic sclerosis (SSc), and we have shown that macrophages constitute the dominant inflammatory signature in SSc tissue. However, little is known about how these cells contribute to fibrotic activation in SSc. Using a bioinformatics approach, we show that the gene expression profile of blood-derived human SSc macrophages is significantly enriched in SSc patient skin. We characterize the immunophenotype of human SSc macrophages as pro-fibrotic, demonstrating that these cells are activated under basal conditions, expressing elevated levels of surface markers associated with activation and releasing CCL2, IL-6, and TGF-beta. We also show that STAT3 is phosphorylated in macrophage from SSc patient compared to the healthy donor, and the phosphorylation is attenuated after IL-6 blockade, suggesting that increased expression of IL-6 by SSc macrophages accounts, at least in part, for increased signaling. Moreover, our results suggest that activation of SSc macrophages arises from soluble factors, as differentiation of healthy donor monocytes in SSc patient-derived plasma confers the immunophenotype of SSc patient macrophages. For the first time, we show that co-culture of human SSc macrophages with SSc fibroblasts induces fibroblast activation. Collectively, these studies implicate macrophages as likely drivers of fibrosis in SSc and suggest therapeutic targeting of these cells may be beneficial in ameliorating disease in SSc patients.
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Protic, Olga, Md Islam, Stefania Greco, Stefano Giannubilo, Pasquale Lamanna, Felice Petraglia, Andrea Ciavattini, Mario Castellucci, Boris Hinz, and Pasquapina Ciarmela. "Activin A in Inflammation, Tissue Repair, and Fibrosis: Possible Role as Inflammatory and Fibrotic Mediator of Uterine Fibroid Development and Growth." Seminars in Reproductive Medicine 35, no. 06 (November 2017): 499–509. http://dx.doi.org/10.1055/s-0037-1607265.
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AbstractThe growth factor activin A belongs to the transforming growth factor-β superfamily and was initially isolated as an inducer of follicle-stimulating hormone secretion. Activin A was later found to play roles in cell proliferation, differentiation, apoptosis, and metabolism. More recently, activin A has also been recognized as a novel player in mediating inflammation, immunity, wound repair, and fibrosis. Elevated levels of activin A during inflammation are responsible for the increased production of extracellular matrix in different pathological conditions, including fibroids. Our group has demonstrated a profibrotic role of activin A in leiomyoma growth. Uterine leiomyoma can be considered as a fibrotic disorder that initiates from myometrial smooth muscle layer of uterus in reproductive-age women and that is driven by a strong inflammatory component. In fertile women, transient inflammation is a physiological and essential process during menstruation, ovulation, and parturition. However, tissue injury from extravasated menstrual blood and/or an altered response to harmful stimuli, such as pathogens, damaged cells, or irritants, can establish chronic inflammation in the uterus, ultimately leading to dysregulated tissue repair. Myofibroblasts are key cells in normal repair and the chronic tissue remodeling characteristic for fibrosis and uterine leiomyoma. In this review, we discuss the role of activin A in inflammation, tissue repair, and fibrosis and we elaborate the hypothesis that it plays a central role in myofibroblast activation and leiomyoma development and growth.
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Blokland, Kaj E. C., Simon D. Pouwels, Michael Schuliga, Darryl A. Knight, and Janette K. Burgess. "Regulation of cellular senescence by extracellular matrix during chronic fibrotic diseases." Clinical Science 134, no. 20 (October 2020): 2681–706. http://dx.doi.org/10.1042/cs20190893.
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Abstract The extracellular matrix (ECM) is a complex network of macromolecules surrounding cells providing structural support and stability to tissues. The understanding of the ECM and the diverse roles it plays in development, homoeostasis and injury have greatly advanced in the last three decades. The ECM is crucial for maintaining tissue homoeostasis but also many pathological conditions arise from aberrant matrix remodelling during ageing. Ageing is characterised as functional decline of tissue over time ultimately leading to tissue dysfunction, and is a risk factor in many diseases including cardiovascular disease, diabetes, cancer, dementia, glaucoma, chronic obstructive pulmonary disease (COPD) and fibrosis. ECM changes are recognised as a major driver of aberrant cell responses. Mesenchymal cells in aged tissue show signs of growth arrest and resistance to apoptosis, which are indicative of cellular senescence. It was recently postulated that cellular senescence contributes to the pathogenesis of chronic fibrotic diseases in the heart, kidney, liver and lung. Senescent cells negatively impact tissue regeneration while creating a pro-inflammatory environment as part of the senescence-associated secretory phenotype (SASP) favouring disease progression. In this review, we explore and summarise the current knowledge around how aberrant ECM potentially influences the senescent phenotype in chronic fibrotic diseases. Lastly, we will explore the possibility for interventions in the ECM–senescence regulatory pathways for therapeutic potential in chronic fibrotic diseases.
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Shapiro, Haim, and Rafael Bruck. "Therapeutic potential of curcumin in non-alcoholic steatohepatitis." Nutrition Research Reviews 18, no. 2 (December 2005): 212–21. http://dx.doi.org/10.1079/nrr2005106.
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Non-alcoholic steatohepatitis (NASH) may be associated with a number of clinical conditions, but it occurs most commonly in patients with insulin resistance. There is as yet no established disease-modifying treatment, and a safe and broadly available agent that targets hepatic steatosis, insulin resistance, inflammation and fibrosis is necessary. The polyphenolic compound curcumin exhibits antioxidant and anti-inflammatory properties, inhibits NF-κB and activates PPAR-γ. In rodents, curcumin prevents dietary-induced hepatic steatosis, hepatic stellate cell activation and production of fibrotic proteins, and ameliorates steatohepatitis induced by the intake of alcohol or a methionine–choline-deficient diet. Indirect evidence suggests that curcumin may improve insulin sensitivity in diabetes and inflammatory states. The present paper reviews the numerous cellular and animal studies indicating that curcumin attenuates many of the pathophysiological processes involved in the development and progression of NASH. It is suggested that basic and clinical studies on curcumin in the development and progression of NASH are indicated.
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Aungier, Susan, and Kim Midwood. "The extracellular matrix: a new dimension in disease diagnosis and treatment." Biochemist 38, no. 4 (August 1, 2016): 10. http://dx.doi.org/10.1042/bio03804010.
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The extracellular matrix (ECM) forms the complex and dynamic 3D environment that defines tissue structure and function. Matrix molecules provide much of the microenvironmental plasticity that dictates cell behaviour, and their dysregulated expression is associated with a wide range of diseases including cancers, and inflammatory and fibrotic conditions. Here, we describe how these matrix molecules are beginning to be used for disease diagnosis and treatment.
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Ryanto, Gusty Rizky Teguh, Kennosuke Yorifuji, Koji Ikeda, and Noriaki Emoto. "Chondroitin sulfate mediates liver responses to injury induced by dual endothelin receptor inhibition." Canadian Journal of Physiology and Pharmacology 98, no. 9 (September 2020): 618–24. http://dx.doi.org/10.1139/cjpp-2019-0649.
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Although dual endothelin receptor antagonists (ERAs) show great promise for treating various conditions, their propensity to induce liver injury limits their clinical usage. Inflammation and fibrosis are important processes in liver responses to injury and it has been suggested that they and dual ERA-induced liver injury are mediated by the proteoglycan component chondroitin sulfate (CS), which is synthesized by CHST3 and CHST13. In this study, we investigated whether dual ER inhibition in the liver could alter CHST3 and CHST13 expression and thus CS production and whether liver CS content could prevent inflammatory and fibrosis responses after liver injury. We observed increased CHST3 and CHST13 expression after liver injury in bile duct ligated mice and histologically confirmed abundant CS deposition in the injured liver. Moreover, treating Hep3B cells with a dual ERA mimic significantly increased CHST3 and CHST13 expression, inflammatory cytokine levels, and glycosaminoglycan deposition. Furthermore, pro-inflammatory and pro-fibrotic markers were observed after dual ERA treatment, while treatment with CS-degrading chondroitinase ABC was able to successfully reverse these phenotypes. These observations suggest that CHST3- and CHST13-induced CS production can mediate liver injury responses caused by dual ER inhibition and thus could be an alternative pathway for treating ERA-induced liver injury.
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Watanabe, Eri, Kazunori Kato, Takahisa Gono, Emiko Chiba, Chihiro Terai, and Shigeru Kotake. "Serum levels of galectin-3 in idiopathic inflammatory myopathies: a potential biomarker of disease activity." Rheumatology 60, no. 1 (August 8, 2020): 322–32. http://dx.doi.org/10.1093/rheumatology/keaa305.
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Abstract Objectives Galectin-3 is involved in various biological activities, including immune activations and fibrosis. Idiopathic inflammatory myopathies (IIMs) are autoimmune diseases of unknown aetiology, often complicated by interstitial lung disease (ILD). The aim of this study was to evaluate the expression of galectin-3 in sera and tissues of patients with IIM and assess the associations of galectin-3 with patient characteristics and disease activity. Results Serum galectin-3 levels were significantly higher in IIM patients than in healthy controls. The serum galectin-3 levels positively correlated with serum levels of inflammatory markers and proinflammatory cytokines/chemokines and the Myositis Intention-to-Treat Activity Index. Stratification analysis revealed that patients with IIM-associated ILD (IIM-ILD) had significantly higher levels of serum galectin-3 than those without IIM-ILD. In addition, patients with acute/subacute interstitial pneumonia had significantly higher levels of serum galectin-3 than those with chronic interstitial pneumonia. Furthermore, serum galectin-3 levels in IIM-ILD patients correlated with the radiological assessments of parenchymal lung involvement and treatment response. Immunohistochemical analysis revealed that galectin-3 was expressed in inflammatory cells of myositis and dermatitis sections, whereas in ILD sections, galectin-3 was expressed in interstitial fibrosis and inflammatory cells. Conclusion Galectin-3 may be involved in the pathogenesis of inflammatory and fibrotic conditions in IIM and can serve as a potential biomarker of disease activity, especially in patients with IIM-ILD.
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Meyer, Gretchen A., and Richard L. Lieber. "Skeletal muscle fibrosis develops in response to desmin deletion." American Journal of Physiology-Cell Physiology 302, no. 11 (June 1, 2012): C1609—C1620. http://dx.doi.org/10.1152/ajpcell.00441.2011.
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Skeletal muscle is a dynamic composite of proteins that responds to both internal and external cues to facilitate muscle adaptation. In cases of disease or altered use, these messages can be distorted resulting in myopathic conditions such as fibrosis. In this work, we describe a mild and progressive fibrotic adaptation in skeletal muscle lacking the cytoskeletal intermediate filament protein desmin. Muscles lacking desmin become progressively stiffer, accumulate increased collagen, and increase expression of genes involved in extracellular matrix turnover. Additionally, in the absence of desmin, skeletal muscle is in an increased state of inflammation and regeneration as indicated by increased centrally nucleated fibers, elevated inflammation and regeneration related gene expression, and increased numbers of inflammatory cells. These data suggest a potential link between increased cellular damage and the development of fibrosis in muscles lacking the cytoskeletal support of the desmin filament network.
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Dragoni, G., B. Creyns, G. De Hertogh, B. Verstockt, W. J. Wollants, B. J. Ke, L. Marcellis, et al. "P067 Proteins citrullination and Crohn’s disease: PAD4 but not PAD2 is a strong marker of ileal inflammation." Journal of Crohn's and Colitis 14, Supplement_1 (January 2020): S168—S169. http://dx.doi.org/10.1093/ecco-jcc/jjz203.196.
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Abstract Background Citrullination is a post-translational modification of proteins, mediated by enzymes called PAD (peptidylarginine deiminases). The immune system can attack citrullinated proteins, leading to autoimmune diseases such as rheumatoid arthritis, multiple sclerosis and ulcerative colitis, and the activity of PAD2 and PAD4 in innate immune cells has been demonstrated for these disorders. Recently, high levels of PAD2 have been described in activated fibroblasts in the context of liver fibrosis. We therefore investigated the role of PAD2 and PAD4, both in inflammatory and fibrotic contexts of ileal Crohn’s disease (CD). Methods We obtained ileal transmural samples from patients operated for stricturing ileal CD. Three different macroscopic areas within each resection specimen (i.e. proximal normal ileum, inflamed ileum and fibrotic ileum) were selected and histologically confirmed by an expert pathologist. Patients undergoing ileocolic resection for other conditions (e.g. right colon cancer) and with healthy terminal ileum were used as controls. For each region (normal CD, inflamed CD, fibrotic CD and control), immunohistochemistry (IHC), RNA and protein evaluations for PAD2 and PAD4 were performed. Multiplex immunofluorescence (IF) for PAD2, PAD4, myeloperoxidase, neutrophil elastase, CD68, vimentin and α-smooth muscle actin were carried out to investigate the enzymes-expressing cells. Additional IF was performed to study citrullinated histone 3 (H3cit) expression, the product of PAD4 activity in neutrophils and component of neutrophil extracellular traps (NETs). Statistical analysis was carried out with Kruskal–Wallis test and post hoc Mann–Whitney test. Results Resection specimens from 13 CD and 11 controls were included. IHC and IF showed an increased expression of both PAD2 and PAD4 in the neutrophils of inflamed areas, in cytoplasm and nucleus, respectively (Figure 1). Activated fibroblasts (vimentin+ and α-smooth muscle actin+) were negative for both enzymes. PAD4 mRNA expression was increased in inflamed tissue (p = 0.001, p = 0.008 and p = 0.028 vs. normal CD, fibrotic CD and controls, respectively), and confirmed using Western Blot (Figure 2). H3cit was increased in the ileal inflammatory infiltrates too (Figure 3), confirming high PAD4 expression. For PAD2, no significant changes were observed at RNA and protein level, mainly due to its reduced expression in epithelial cells from normal to diseased tissue (Figure 4). Conclusion Both PAD2 and PAD4 are strongly expressed in neutrophils of CD ileal resection specimens, but only PAD4 shows a significantly higher expression in the inflammatory context which translates in the formation of NETs. No direct correlation was observed between PAD enzymes and intestinal fibroblasts.
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Sisto, Margherita, Domenico Ribatti, and Sabrina Lisi. "ADAM 17 and Epithelial-to-Mesenchymal Transition: The Evolving Story and Its Link to Fibrosis and Cancer." Journal of Clinical Medicine 10, no. 15 (July 29, 2021): 3373. http://dx.doi.org/10.3390/jcm10153373.
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For decades, metalloproteinase 17 (ADAM17) has been the goal of wide investigation. Since its discovery as the tumour necrosis factor-α convertase, it has been studied as the main drug target, especially in the context of inflammatory conditions and tumour. In fact, evidence is mounting to support a key role of ADAM17 in the induction of the proliferation, migration and progression of tumour cells and the trigger of the pro-fibrotic process during chronic inflammatory conditions; this occurs, probably, through the activation of epithelial-to-mesenchymal transition (EMT). EMT is a central morphologic conversion that occurs in adults during wound healing, tumour progression and organ fibrosis. EMT is characterised by the disassembly of cell–cell contacts, remodelling of the actin cytoskeleton and separation of cells, and generates fibroblast-like cells that express mesenchymal markers and have migratory properties. This transition is characterised by loss of epithelial proteins such as E-cadherin and the acquisition of new mesenchymal markers, including vimentin and a-smooth muscle actin. The present review discusses the current understanding of molecular mechanisms involved in ADAM17-dependent EMT in order to individuate innovative therapeutic strategies using ADAM17-related pathways.
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Fabre, Thomas, Manuel Flores Molina, Geneviève Soucy, Jean-Philippe Goulet, Bernard Willems, Jean-Pierre Villeneuve, Marc Bilodeau, and Naglaa H. Shoukry. "Type 3 cytokines IL-17A and IL-22 drive TGF-β–dependent liver fibrosis." Science Immunology 3, no. 28 (October 26, 2018): eaar7754. http://dx.doi.org/10.1126/sciimmunol.aar7754.
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Inflammatory immune cells can modulate activation of hepatic stellate cells (HSCs) and progression of liver fibrosis. Type 3 inflammation characterized by production of interleukin-17A (IL-17) and IL-22 by innate and adaptive immune cells is implicated in many inflammatory conditions of the gut and can be counteracted by regulatory T cells (Tregs), but its contribution to liver fibrosis is still poorly understood. Here, we evaluated the contribution of type 3 inflammation in liver fibrosis using clinical liver biopsies, in vitro stimulation of primary HSCs, and in vivo mouse models. We report dysregulated type 3 responses in fibrotic lesions with increased IL-17+CD4+/FOXP3hiCD4+ratio and increased IL-17 and IL-22 production in advanced liver fibrosis. Neutrophils and mast cells were the main sources of IL-17 in situ in humans. In addition, we demonstrate a new profibrotic function of IL-22 through enhancement of transforming growth factor–β signaling in HSCs in a p38 mitogen-activated protein kinase–dependent manner. In vivo, IL-22RA1 knockout mice exhibited reduced fibrosis in response to thioacetamide and carbon tetrachloride. Blocking either IL-22 or IL-17 production using aryl hydrocarbon receptor or RAR-related orphan receptor gamma-t antagonists resulted in reduced fibrosis. Together, these data have identified a pathogenic role for type 3 immune response mediated by IL-22 in driving liver fibrosis during chronic liver injury.
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M D, Milan Gowda, Jayachandra K, Siddesha J M, Noor Mohamed Jameel, and Bannikuppe S. Vishwanath. "Phenolic Rich Extract Of Finger Millet Bran Attenuates Lung Inflammation And Fibrosis In A Mouse Model Of Ovalbumin Induced Asthma." International Journal of Pharma and Bio Sciences 12, no. 1 (February 2, 2022): 238–46. http://dx.doi.org/10.22376/ijpbs/lpr.2022.12.1.l238-246.
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Asthma is a serious global health risk characterized by chronic airway inflammation of lungs with infiltration of inflammatory cells, enhanced mucus secretion and narrowing of airways that leads to poor respiratory functions. The clinical symptoms of asthma includes recurrent episodes of cough, shortness of breath, wheezing and chest tightness. One of the pathophysiology of asthma was mediated by overproduction of pro-inflammatory asthmatic leukotrienes through arachidonic acid pathway catalyzed phospholipase A2 (PLA2) and 5-lipoxygenase (5-LOX) enzymes. The available conventional therapies to treat asthma may induce severe side effects on health and high cost. To overcome the disadvantages to treat asthma and to improve the current therapeutic strategy, we used natural products as an alternative therapy. Finger millet (Eleusine coracana) has been used by folk and traditional medicinal practitioners to treat various inflammatory conditions. Previously, we have found the promising anti-inflammatory phytochemicals in finger millet bran (Fmb). Hence, aim of the present study was to identify and characterize anti-asthmatic phytochemicals from Fmb and the objective was to test its anti-inflammatory activity in ovalbumin induced asthma mouse model. Phytochemical analysis of Fmb revealed the presence of phenolics, saponins and anthraquinone. Among all the extracted fractions, finger millet bran methanol extract (FbMe) possessed strong in vitro anti-inflammatory activity by inhibiting pro-inflammatory PLA2 and 5-LOX enzymes activity. Further, in vivo anti-inflammatory activity of FbMe was evaluated in an ovalbumin induced asthma mouse model. FbMe (50 mg/kg) significantly reduced the infiltration of inflammatory cells, lung fibrosis by reducing the deposition of collagen in the tissue. It also inhibited the PLA2 as well as 5-LOX enzymes activity in collected BAL fluid. This finding concludes the presence of strong anti-inflammatory and anti-fibrotic phenolic compounds in the FbMe, which attenuates the lung inflammation and fibrosis probably via inhibition of PLA2 and 5-LOX enzymes activity.
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Ilieva, Mirolyuba, Henry E. Miller, Arav Agarwal, Gabriela K. Paulus, Jens Hedelund Madsen, Alexander J. R. Bishop, Sakari Kauppinen, and Shizuka Uchida. "FibroDB: Expression Analysis of Protein-Coding and Long Non-Coding RNA Genes in Fibrosis." Non-Coding RNA 8, no. 1 (January 28, 2022): 13. http://dx.doi.org/10.3390/ncrna8010013.
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Most long non-coding RNAs (lncRNAs) are expressed at lower levels than protein-coding genes and their expression is often restricted to specific cell types, certain time points during development, and various stress and disease conditions, respectively. To revisit this long-held concept, we focused on fibroblasts, a common cell type in various organs and tissues. Using fibroblasts and changes in their expression profiles during fibrosis as a model system, we show that the overall expression level of lncRNA genes is significantly lower than that of protein-coding genes. Furthermore, we identified lncRNA genes whose expression is upregulated during fibrosis. Using dermal fibroblasts as a model, we performed loss-of-function experiments and show that the knockdown of the lncRNAs LINC00622 and LINC01711 result in gene expression changes associated with cellular and inflammatory responses, respectively. Since there are no lncRNA databases focused on fibroblasts and fibrosis, we built a web application, FibroDB, to further promote functional and mechanistic studies of fibrotic lncRNAs.
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Ly, Thanh-Diep, Christopher Lindenkamp, Eva Kara, Vanessa Schmidt, Anika Kleine, Bastian Fischer, Doris Hendig, Cornelius Knabbe, and Isabel Faust-Hinse. "The Impact of Inflammatory Stimuli on Xylosyltransferase-I Regulation in Primary Human Dermal Fibroblasts." Biomedicines 10, no. 6 (June 19, 2022): 1451. http://dx.doi.org/10.3390/biomedicines10061451.
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Inflammation plays a vital role in regulating fibrotic processes. Beside their classical role in extracellular matrix synthesis and remodeling, fibroblasts act as immune sentinel cells participating in regulating immune responses. The human xylosyltransferase-I (XT-I) catalyzes the initial step in proteoglycan biosynthesis and was shown to be upregulated in normal human dermal fibroblasts (NHDF) under fibrotic conditions. Regarding inflammation, the regulation of XT-I remains elusive. This study aims to investigate the effect of lipopolysaccharide (LPS), a prototypical pathogen-associated molecular pattern, and the damage-associated molecular pattern adenosine triphosphate (ATP) on the expression of XYLT1 and XT-I activity of NHDF. We used an in vitro cell culture model and mimicked the inflammatory tissue environment by exogenous LPS and ATP supplementation. Combining gene expression analyses, enzyme activity assays, and targeted gene silencing, we found a hitherto unknown mechanism involving the inflammasome pathway components cathepsin B (CTSB) and caspase-1 in XT-I regulation. The suppressive role of CTSB on the expression of XYLT1 was further validated by the quantification of CTSB expression in fibroblasts from patients with the inflammation-associated disease Pseudoxanthoma elasticum. Altogether, this study further improves the mechanistic understanding of inflammatory XT-I regulation and provides evidence for fibroblast-targeted therapies in inflammatory diseases.
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De Coster, L., P. Eloy, L. Ferdinande, J. Taildeman, C. A. Cuvelier, and J. B. Watelet. "Different types of tissue composition in inflammatory or reparative upper airway disorders." Rhinology journal 50, no. 4 (December 1, 2012): 393–401. http://dx.doi.org/10.4193/rhino11.164.
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Background: Composition changes of extracellular matrix (ECM) can lead to functional disorders of the upper airways (UA). The aim of this study was to systematically measure both the association patterns and the correlation degree between tissue composition parameters in UA inflammatory diseases. Methodology: Nasal samples were obtained from patients with chronic rhinosinusitis with (CRS+NP), without nasal polyps (CRS), with post-operative adhesions (S) and normal nasal mucosa (NM). A reproducible semi-quantitative method, which takes epithelial and lamina propria damages into account was applied for haematoxylin and eosin, alpha-smooth muscle actin, reticulin, elastin, laminin and collagen type IV stainings. Results: The most severe cases of epithelial shedding have been found in a significant higher amount in CRS+NP when compared with NM. The most severe cases of inflammatory reaction were mainly found in CRS+NP. CRS+NP had significantly more severe cases of oedema than NM. Excluding elastin, networks in other ECM proteins were found modified in fibrotic fields but to a lesser extend in oedematous regions in all conditions. Conclusion: Although non specific, oedema in the lamina propria is a key-feature of CRS+NP, while fibrosis, massively present in CRS and S, affects profoundly the distribution of ECM proteins in these areas.
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Ivanov, A. M., D. Yu Sosnin, and K. R. Galkovich. "Study of urinary monocytic chemotactic factor." Perm Medical Journal 37, no. 1 (May 3, 2020): 93–101. http://dx.doi.org/10.17816/pmj37193-101.
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The review presents the data on clinical diagnostic value of studying one of the components of urinary proteome - macrophage chemotactic protein -1 (MCP-1). Along with the general characteristics of MCP-1, there are given the data on changes in its concentration regarding various diseases of the urinary system. It was shown that for various diseases and research conditions, the concentration of MCP-1 can be an important diagnostic criterion in assessing inflammatory, metabolic, fibrotic and other renal lesions.
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Burns, Rebecca L., and Sharukh J. Bhavnagri. "Undiagnosed Sjögren’s Syndrome Presenting as Mesenteric Panniculitis." Case Reports in Rheumatology 2016 (2016): 1–4. http://dx.doi.org/10.1155/2016/7207638.
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Mesenteric panniculitis is a rare inflammatory and fibrotic process that affects the small intestine mesentery. It may occur following abdominal surgery or in association with a variety of conditions, including malignancy, infection, and certain autoimmune and inflammatory conditions. Herein, an unusual case of mesenteric panniculitis in a patient with primary Sjögren’s syndrome will be presented. The patient presented with abdominal pain, weight loss, sicca symptoms, fatigue, and arthralgia. An abdominal CT revealed mesenteric fat stranding and prominent lymph nodes of the small intestine mesentery. She was found on laboratory workup to have positive antinuclear and anti-SSa antibodies. Minor salivary gland lip biopsy revealed focal lymphocytic sialadenitis. The patient’s symptoms and CT findings improved with corticosteroids. This case suggests that Sjögren’s syndrome should be considered as an underlying disease process in the evaluation of patients with mesenteric panniculitis.
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Baričić, Mirjana, Olga Cvijanović Peloza, Ana Terezija Jerbić Radetić, Veljko Šantić, Hrvoje Omrčen, and Sanja Zoričić Cvek. "Serum Levels of Inflammatory and Fibrotic Cytokines in Patients with Carpal Tunnel Syndrome and Hip Osteoarthritis." Biomedicines 11, no. 1 (December 21, 2022): 11. http://dx.doi.org/10.3390/biomedicines11010011.
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A certain percentage of carpal tunnel syndrome (CTS) is associated with inflammatory conditions. Osteoarthritis (OA) increases the risk of CTS, and both diseases are common in the general population. Moreover, OA and CTS are often present in the same patients. Since inflammation and fibrosis are found in both conditions, the question is whether circulating inflammatory cytokines and cytokines involved in fibrosis in OA and CTS patients could serve as indicators of coexisting CTS and OA pathology. This investigation was performed on 31 CTS patients, 29 hip OA patients, and 15 healthy volunteers. Blood samples were collected, and serum levels of TGF-β1, BMP-7, IL-1β, and TNFα were measured using the ELISA method. The statistical analysis was performed to reveal the most significant differences in the serum levels of these cytokines. Statistical significance was set at p-values 0.05. The serum level of TGF-β1 was the highest in CTS patients (16.36 pg/mL) and significantly different compared to OA and healthy control. Analysis of the cytokine serum level in the subdivided group revealed that serum levels of TGF-β1 and BMP-7 were significantly higher in CTS+/OA+ patients as well as BMP-7 in the OA+/CTS+ group. There was no significant difference in serum levels of the inflammatory cytokines TNFα and IL-1β among all groups. This study showed that in the end stage of CTS and OA, serum levels of inflammatory cytokines (IL1-β and TNFα) were not altered, while the serum levels of TGF-β1 and BMP-7 were significantly higher, especially in patients with coexisting OA and CTS. These findings suggest the possible values of TGF-β1 and BMP-7 as a predictive factor for the comorbidity of CTS and OA.
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Amamou, Asma, Linda Yaker, Mathilde Leboutte, Christine Bôle-Feysot, Guillaume Savoye, and Rachel Marion-Letellier. "Dietary AhR Ligands Have No Anti-Fibrotic Properties in TGF-β1-Stimulated Human Colonic Fibroblasts." Nutrients 14, no. 16 (August 9, 2022): 3253. http://dx.doi.org/10.3390/nu14163253.
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Background: Intestinal fibrosis is a common complication in inflammatory bowel disease (IBD) patients without specific treatment. Aryl hydrocarbon receptor (AhR) activation is associated with better outcomes in intestinal inflammation. Development of novel therapies targeting fibrogenic pathways is required and we aimed to screen dietary AhR ligands for their anti-fibrotic properties in TGF-β1-stimulated human colonic fibroblast cells. Methods: The study was conducted using TGF-β1-stimulated CCD-18Co, a human colonic fibroblast cell line in response to increased concentrations of dietary ligands of AhR such as FICZ, ITE, L-kynurenine and curcumin. Fibrosis markers such as α-SMA, COL1A1, COL3A1 and CTGF were assessed. AhR and ANRT RNA were evaluated. Results: TGF-β1 at 10 ng/mL significantly induced mRNA levels for ECM-associated proteins such as CTGF, COL1A1 and COL3A1 in CCD-18Co cells. FICZ from 10 to 1000 nM, L-kynurenine from 0.1 to 10 μM, ITE from 1 to 100 μM or curcumin from 5 to 20 μM had no significant effect on fibrosis markers in TGF-β1-induced CCD-18Co. Conclusions: Our data highlight that none of the tested dietary AhR ligands had an effect on fibrosis markers in TGF-β1-stimulated human colonic fibroblast cells in our experimental conditions. Further studies are now required to identify novel potential targets in intestinal fibrosis.
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Geiger, Sabine, Daniela Hirsch, and Felix G. Hermann. "Cell therapy for lung disease." European Respiratory Review 26, no. 144 (June 28, 2017): 170044. http://dx.doi.org/10.1183/16000617.0044-2017.
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Besides cancer and cardiovascular diseases, lung disorders are a leading cause of morbidity and death worldwide. For many disease conditions no effective and curative treatment options are available. Cell therapies offer a novel therapeutic approach due to their inherent anti-inflammatory and anti-fibrotic properties. Mesenchymal stem/stromal cells (MSC) are the most studied cell product. Numerous preclinical studies demonstrate an improvement of disease-associated parameters after MSC administration in several lung disorders, including chronic obstructive pulmonary disease, acute respiratory distress syndrome and idiopathic pulmonary fibrosis. Furthermore, results from clinical studies using MSCs for the treatment of various lung diseases indicate that MSC treatment in these patients is safe. In this review we summarise the results of preclinical and clinical studies that indicate that MSCs are a promising therapeutic approach for the treatment of lung diseases. Nevertheless, further investigations are required.
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Yu, Yonghui, Jinghui Sun, Ru Wang, Jiangang Liu, Peili Wang, and Chenglong Wang. "Curcumin Management of Myocardial Fibrosis and its Mechanisms of Action: A Review." American Journal of Chinese Medicine 47, no. 08 (January 2019): 1675–710. http://dx.doi.org/10.1142/s0192415x19500861.
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Myocardial fibrosis is implicated as a leading risk factor for heart failure, arrhythmia, and sudden death after cardiac injury, as the excessive interstitial extracellular matrix impedes heart contraction and electrical conduction. Complicated mechanisms involving oxidative stress, pro-inflammatory cytokines, chemokine families, NLRP3 inflammasomes, growth factors, and non-coding RNAs participate in cardiac fibrogenesis and make it difficult to designate specific and effective therapies. Oriental herbs have been popular for thousands of years in the health care of Asian residents, due to their multi-targeted, multi-faceted approaches and their multi-functional effects in fighting difficult and complicated diseases, including cardiovascular disorders such as myocardial fibrosis. Curcumin, a natural polyphenol and yellow pigment obtained from the spice turmeric, was found to have strong anti-oxidant and anti-inflammatory properties. Increasing evidence has shown that curcumin can be used to prevent and treat myocardial fibrosis, when the myocardium suffers pathological pro-fibrotic changes in vivo and in vitro. The present review focuses on recent studies elucidating the mechanisms of curcumin in treating different pathologic conditions, including ischemia, hypoxia/reoxygenation, pressure or volume overload, and hyperglycemia or high-fat-induced cardiac fibrosis. Novel analogs such as C66, B2BrBC, Y20, and J17 have been designed to maximize the therapeutic potentials of curcumin. These optimized curcumin analogs with improved bioavailability and pharmacokinetic profiles need to be clinically verified before curcumin could be recommended for the treatment of myocardial fibrosis.
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González Rodríguez, Águeda, Stephania C. Isaza, Patricia Marañón, Esthe Rey, and Carmelo García-Monzón. "Regulation of BMP8A expression during hepatic fibrogenesis process." IBJ Plus 1, s5 (June 3, 2022): 8. http://dx.doi.org/10.24217/2531-0151.22v1s5.00008.
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Introduction: Hepatocellular injury is the main triggering event of wound healing response that leads to liver fibrosis. Hepatic stellate cell (HSC) activation is crucial in the progression of fibrogenic process since they represent the major source of extracellular matrix components and contribute to the inflammatory response by secreting proinflammatory cytokines. Bone morphogenetic proteins (BMPs) are soluble growth factors which exert pleiotropic effects in various tissues regulating different physiological processes of cellular homeostasis. Regarding BMP8A, its implication in liver damage has been poorly investigated. Therefore, the aim of this study was to determine BMP8A expression in different fibrosis-mediated liver damage scenarios. Materials and methods: Histological study of livers was performed and hepatic BMP8A expression levels were determined by RT-qPCR in different experimental models of hepatic fibrosis: carbon tetrachloride injected mice, as a classic hepatic fibrosis model, mice subjected to bile duct ligation, as a model of cholestatic damage-derived hepatic fibrosis, and high fat diet fed mice, reproducing the progression of non-alcoholic fatty liver disease (NAFLD) which curses with variable states of concomitant fibrosis in advanced stages. Likewise, the same analysis was conducted in livers from 11 patients with biopsy proven NAFLD-derived fibrosis and 25 NAFLD patients without fibrosis. To reproduce the experimental conditions of the murine models, BMP8A levels were determined in hepatocytes stimulated with conditioned media derived from TGFbeta-stimulated hepatic stellate cells (LX2). Results: Firstly, murine models were validated through a histological examination of the liver and a molecular analysis of fibrotic specific markers. Next, hepatic BMP8A mRNA expression was significant increased in all studied models of hepatic fibrosis comparing with the respective controls. In fact, there is a positive correlation between hepatic BMP8A levels and fibrosis stage as well as with markers of fibrosis. Accordingly, the clinical study revealed an elevated BMP8A expression in fibrotic livers, in comparison with those without any fibrotic sign. Furthermore, in vitro experiments also showed an increased BMP8A expression in Huh7 cells treated with conditioned media derived from TGFbeta-activated LX2 cells. Conclusions: This study reveals for the first time an increased BMP8A hepatic expression in the context of hepatic fibrosis. Its detection in serum might be useful as a non-invasive tool for the diagnosis/prognosis of patients affected by this liver disease. Moreover, these results suggest that BMP8A is involved in hepatic fibrosis progression, being possibly relevant in its therapeutic manage.
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Pompili, Simona, Roberta Sferra, Eugenio Gaudio, Angelo Viscido, Giuseppe Frieri, Antonella Vetuschi, and Giovanni Latella. "Can Nrf2 Modulate the Development of Intestinal Fibrosis and Cancer in Inflammatory Bowel Disease?" International Journal of Molecular Sciences 20, no. 16 (August 20, 2019): 4061. http://dx.doi.org/10.3390/ijms20164061.
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One of the main mechanisms carried out by the cells to counteract several forms of stress is the activation of the nuclear factor erythroid 2-related factor (Nrf2) signaling. Nrf2 signaling controls the expression of many genes through the binding of a specific cis-acting element known as the antioxidant response element (ARE). Activation of Nrf2/ARE signaling can mitigate several pathologic mechanisms associated with an autoimmune response, digestive and metabolic disorders, as well as respiratory, cardiovascular, and neurodegenerative diseases. Indeed, several studies have demonstrated that Nrf2 pathway plays a key role in inflammation and in cancer development in many organs, including the intestine. Nrf2 appears to be involved in inflammatory bowel disease (IBD), an immune-mediated chronic and disabling disease, with a high risk of developing intestinal fibrotic strictures and cancer. Currently, drugs able to increase cytoprotective Nrf2 function are in clinical trials or already being used in clinical practice to reduce the progression of some degenerative conditions. The role of Nrf2 in cancer development and progression is controversial, and drugs able to inhibit abnormal levels of Nrf2 are also under investigation. The goal of this review is to analyze and discuss Nrf2-dependent signals in the initiation and progression of intestinal fibrosis and cancers occurring in IBD.
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Del Papa, N., M. Lorini, V. Carbonelli, A. Minniti, F. Pignataro, W. Maglione, G. Di Luca, N. Montano, and R. Caporali. "AB0153 ADIPOSE-DERIVED STROMAL/STEM CELLS FROM SYSTEMIC SCLEROSIS PATIENTS SUCCESSFULLY EXERT A PARACRINE ANTI-FIBROTIC ACTIVITY AND INDUCE A PRO-ANGIOGENIC PHENOTYPE OF SCLERODERMA FIBROBLASTS IN VITRO." Annals of the Rheumatic Diseases 79, Suppl 1 (June 2020): 1377.2–1377. http://dx.doi.org/10.1136/annrheumdis-2020-eular.3248.
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Background:Adipose-derived stromal/stem cells (ADSCs) are multipotential non-hematopoietic progenitor cells with anti-inflammatory, immunomodulatory and regenerative effects. They have the advantage of accessibility and potent pro-angiogenic effects when compared with other stem cells, such as bone-marrow derived stem cells. Recent studies have shown that autologous fat grafting may be effective in the treatment of fibrotic and vascular complications in systemic sclerosis (SSc), despite a pro-fibrotic signature.Objectives:Aim of the study was to better characterize the proliferative and secretive profile of ADSCs in normoxic and hypoxic conditions, and to evaluate the mechanisms by which ADSCs exert these observed clinical effects.Methods:Adipose tissue samples were obtained by liposuction from 12 SSc patients and 10 healthy donors (HD). ADSCs were purified according to their adherence to the plastic and characterized to express specific MSC surface antigens by flow cytometry analysis. Proliferation of ADSCs from SSc patients and normal controls was evaluated in normoxic and hypoxic conditions. Fibroblasts and ADSCs derived from SSc patients were co-cultured in direct and indirect culture systems and compared to HD. Fibroblasts proliferation, mRNA expression and protein secretion of VEGF and known fibrotic mediators including TGF β-1, TGFR, CTGF, Collagen type I (Col I) were analyzed in the same conditions.Results:Normoxic and hypoxic culture conditions did not modify the proliferation rate of both normal and SSc ADSCs. Hypoxia significantly increased mRNA expression of VEGF by HD and SSc ADSCs but had no effect on the mRNA expression of pro-fibrotic mediators, ie TGFβ and TGFR. Normal and SSc fibroblast proliferation was significantly reduced in both co-culture systems (p < 0.001) and by treatment with normoxic and hypoxic conditioned medium (CM) (p=0.001 and p=0.002). In the same conditions, mRNA expression and protein secretion of TGF-β1, CTGF and Col I were significantly reduced (p = 0.003, p =0.02, p=0.04). These results were confirmed when normal and SSc fibroblasts were cultured in the presence of ADSCs normoxic and hypoxic CM (p=0.02 and p=0.01). Furthermore, a significant increase in mRNA expression and production of VEGF was observed in SSc fibroblasts cultured in the presence of normoxic and hypoxic CM (p = 0.002 and p< 0.0001, respectively).Conclusion:We found that treatment with the medium from normoxic and hypoxic preconditioned ADSCs has an anti-fibrotic effect through both the inhibition of fibroblast proliferation and key mediators of fibrosis. The increased expression of VEGF by SSc fibroblasts in the presence of normoxic and, even more, hypoxic ADSCs CM, suggests that ADSCs can induce a paracrine pro-angiogenic phenotype, even in fibroblasts with a pro-fibrotic signature. Altogether these data show that ADSCs may exert their anti-fibrotic and pro-angiogenetic effects on SSc fibroblasts by the secretion of paracrine factors, partly explaining the mechanisms underlining beneficial clinical results of fat graft in SSc patients.Disclosure of Interests:Nicoletta Del Papa: None declared, Maurizio Lorini: None declared, Vincenzo Carbonelli: None declared, Antonina Minniti: None declared, Francesca Pignataro: None declared, Wanda Maglione: None declared, Gabriele Di Luca: None declared, Nicola Montano: None declared, Roberto Caporali Consultant of: AbbVie; Gilead Sciences, Inc.; Lilly; Merck Sharp & Dohme; Celgene; Bristol-Myers Squibb; Pfizer; UCB, Speakers bureau: Abbvie; Bristol-Myers Squibb; Celgene; Lilly; Gilead Sciences, Inc; MSD; Pfizer; Roche; UCB
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Nyman, R., G. Forsgren, and B. Glimelius. "Long-Term Follow-up of Residual Mediastinal Masses in Treated Hodgkin's Disease Using MR Imaging." Acta Radiologica 37, no. 1P1 (January 1996): 323–26. http://dx.doi.org/10.1177/02841851960371p168.
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Purpose: Long-term follow-up of residual mediastinal masses in treated Hodgkin's disease using MR imaging. Material and Methods: Ten patients, with substantial residual mediastinal masses of low signal intensity (SI) in the T2-weighted image (T2WI), were reinvestigated with MR 19–79 months after completing treatment of Hodgkin's disease. All patients were in complete remission. Results: During the follow-up period, the masses had decreased in size by 0–95% (median 67%) as compared to their initial post-therapy size. The SI continued to be low in the T2WI and was unaffected by the degree of size reduction. Conclusion: It is speculated that these mainly fibrotic residual masses undergo slow degradation of the fibrotic part and/or resorption of remaining inflammatory tissue. It is important to understand the natural, long-term MR imaging changes of these residual masses in order more easily to recognize tumour recurrence or other pathologic conditions.
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Čaja, Fabián, Dmitry Stakheev, Oleksandr Chernyavskiy, Lucie Kubinová, Jiří Křížan, Jiří Dvořák, Pavel Rossmann, et al. "Local Immune Changes in Early Stages of Inflammation and Carcinogenesis Correlate with the Collagen Scaffold Changes of the Colon Mucosa." Cancers 13, no. 10 (May 18, 2021): 2463. http://dx.doi.org/10.3390/cancers13102463.
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Continuous activation of the immune system inside a tissue can lead to remodelling of the tissue structure and creation of a specific microenvironment, such as during the tumour development. Chronic inflammation is a central player in stimulating changes that alter the tissue stroma and can lead to fibrotic evolution. In the colon mucosa, regulatory mechanisms, including TGF-β1, avoid damaging inflammation in front of the continuous challenge by the intestinal microbiome. Inducing either DSS colitis or AOM colorectal carcinogenesis in AVN-Wistar rats, we evaluated at one month after the end of each treatment whether immunological changes and remodelling of the collagen scaffold were already in development. At this time point, we found in both models a general downregulation of pro-inflammatory cytokines and even of TGF-β1, but not of IL-6. Moreover, we demonstrated by multi-photon microscopy the simultaneously presence of pro-fibrotic remodelling of the collagen scaffold, with measurable changes in comparison to the control mucosa. The scaffold was significantly modified depending on the type of induced stimulation. These results suggest that at one month after the end of the DSS or AOM inductions, a smouldering inflammation is present in both induced conditions, since the pro-inflammatory cytokines still exceed, in proportion, the local homeostatic regulation of which TGF-β1 is a part (inflammatory threshold). Such an inflammation appears sufficient to sustain remodelling of the collagen scaffold that may be taken as a possible pathological marker for revealing pre-neoplastic inflammation.
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Avraham, T., SV Daluvoy, JC Zampell, A. Yan, and E. Kueberuwa. "9: LYMPHEDEMA IS A FIBROPROLIFERATIVE CONDITION ASSOCIATED WITH A PRO-FIBROTIC CHRONIC INFLAMMATORY RESPONSE." Plastic and Reconstructive Surgery 125, Supplement (June 2010): 14. http://dx.doi.org/10.1097/01.prs.0000371745.47053.10.
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Akpulat, Uğur, İlyas Onbaşılar, and Y. Çetin Kocaefe. "Tenotomy immobilization as a model to investigate skeletal muscle fibrosis (with emphasis on Secreted frizzled-related protein 2)." Physiological Genomics 48, no. 6 (June 2016): 397–408. http://dx.doi.org/10.1152/physiolgenomics.00010.2016.
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The pathological endpoint of congenital and senile myopathies is chronic muscle degeneration characterized by the atrophy of contractile elements, accompanied by fibrosis and fatty infiltration of the interstitium. Tenotomy is the release of preload that causes abrupt shortening of the muscle and models atrophy and fibrosis without prominent inflammatory response. Fibrosis in the skeletal muscle is known to be triggered by transforming growth factor (TGF)-β, which is activated by inflammatory events. As these were lacking, tenotomy provided an opportunity to investigate transcriptional events on a background without inflammation. An unbiased look at the transcriptome of tenotomy-immobilized soleus muscle revealed that the majority of the transcriptional changes took place in the first 4 wk. Regarding atrophy, proteasomal and lysosomal pathways were actively involved in accompanying cathepsins and calpains in the breakdown of the macromolecular contractile machinery. The transcriptome provided clear-cut evidence for the upregulation of collagens and several extracellular matrix components that define fibrotic remodeling of the skeletal muscle architecture as well as activation of the fibro-adipogenic precursors. Concomitantly, Sfrp2, a Wnt antagonist as well as a procollagen processor, accompanied fibrosis in skeletal muscle with an expression that was stringently confined to the slow-twitch fibers. An interpreted mechanistic scenario construed the kinetic events initiated through the abnormal shortening of the muscle fibers as enough to trigger the resident latent TGF-β in the extracellular matrix, leading to the activation of fibroadipogenic precursors. As in the heart, Sfrp2 shows itself to be a therapeutic target for the prevention of irreversible fibrosis in degenerative skeletal muscle conditions.