Journal articles: 'Myofibroblast MMP'

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Varro, Andrea, Susan Kenny, Elaine Hemers, Catherine McCaig, Sabine Przemeck, Timothy C. Wang, Keith Bodger, and D. Mark Pritchard. "Increased gastric expression of MMP-7 in hypergastrinemia and significance for epithelial-mesenchymal signaling." American Journal of Physiology-Gastrointestinal and Liver Physiology 292, no. 4 (April 2007): G1133—G1140. http://dx.doi.org/10.1152/ajpgi.00526.2006.

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Chronic hypergastrinemia is associated with enterochromaffin-like (ECL) cell hyperplasia, which may progress to gastric carcinoid tumors. The latter consists of epithelial cells and stroma, and both compartments usually regress after normalization of hypergastrinemia. We previously showed that matrix metalloproteinase (MMP)-7 in gastric epithelial cells was upregulated by Heliobacter pylori and described MMP-7-dependent reciprocal signaling between the epithelium and a key stromal cell type, the myofibroblast. Here, we describe the regulation of gastric MMP-7 by gastrin and the potential significance for recruiting and maintaining myofibroblast populations. Biopsies of the gastric corpus and ECL cell carcinoid tumors were obtained from hypergastrinemic patients. Western blot analysis, ELISA, immunohistochemistry, and promoter-luciferase (luc) reporter assays were used to study MMP-7 expression. Gastric myofibroblasts were identified by α-smooth muscle actin (α-SMA) expression, and the effects of MMP-7 on myofibroblast proliferation were investigated. In hypergastrinemic patients, there was an increased abundance of MMP-7 and α-SMA in gastric corpus biopsies and ECL cell carcinoid tumors. In the latter, MMP-7 was localized to ECL cells but not stromal cells, which were nevertheless well represented. Gastrin stimulated MMP-7-luc expression in both AGS-GR and primary human gastric epithelial cells. Conditioned medium from gastrin-treated human gastric glands stimulated myofibroblast proliferation, which was inhibited by neutralizing antibodies to MMP-7. MMP-7 increased the proliferation of myofibroblasts via the MAPK and phosphatidylinositol 3-kinase (PI3K) pathways. In conclusion, stimulation of gastric MMP-7 by elevated plasma gastrin may activate epithelial-mesenchymal signaling pathways regulating myofibroblast function via MAPK and PI3K pathways and contribute to stromal deposition in ECL cell carcinoid tumors.

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Nareznoi, David, Jenya Konikov-Rozenman, Dmytro Petukhov, Raphael Breuer, and Shulamit B. Wallach-Dayan. "Matrix Metalloproteinases Retain Soluble FasL-mediated Resistance to Cell Death in Fibrotic-Lung Myofibroblasts." Cells 9, no. 2 (February 11, 2020): 411. http://dx.doi.org/10.3390/cells9020411.

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A prominent feature of obstructed tissue regeneration following injury in general, and fibrotic lung tissue in particular, is fibroblast proliferation and accumulation. The Fas/FasL apoptotic pathway has been shown to be involved in human idiopathic pulmonary fibrosis (IPF) and bleomycin-induced lung fibrosis in rodents. We previously showed that in normal injury repair, myofibroblasts’ accumulation is followed by their decline by FasL+ T cell-induced cell death. In pathological lung fibrosis, myofibroblasts resist cell death and accumulate. Like other members of the tumor necrosis factor (TNF) family, membrane-bound FasL can be cleaved from the cell surface to generate a soluble form (sFasL). Metalloproteinases (MMPs) are known to convert the membrane-bound form of FasL to sFasL. MMP-7 knockout (KO) mice were shown to be protected from bleomycin (BLM)-induced lung fibrosis. In this study, we detected increased levels of sFasL in their blood serum, as in the lungs of patients with IPF, and IPF-lung myofibroblast culture medium. In this study, using an MMP-inhibitor, we showed that sFasL is decreased in cultures of IPF-lung myofibroblasts and BLM-treated lung myofibroblasts, and in the blood serum of MMP-7KO mice. Moreover, resistant fibrotic-lung myofibroblasts, from the lungs of humans with IPF and of BLM-treated mice, became susceptible to T-cell induced cell death in a co-culture following MMP-inhibition- vs. control-treatment or BLM-treated MMP-7KO vs. wild-type mice, respectively. sFasL may be an unrecognized mechanism for MMP-7-mediated decreased tissue regeneration following injury and the evolution of lung fibrosis.

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Zhao, Tieqiang, Wenyuan Zhao, Weixin Meng, Chang Liu, Yuanjian Chen, and Yao Sun. "Vascular endothelial growth factor-C: its unrevealed role in fibrogenesis." American Journal of Physiology-Heart and Circulatory Physiology 306, no. 6 (March 15, 2014): H789—H796. http://dx.doi.org/10.1152/ajpheart.00559.2013.

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Vascular endothelial growth factor (VEGF)-C is a key mediator of lymphangiogenesis. Our recent study shows that VEGF-C/VEGF receptors (VEGFR)-3 are significantly increased in the infarcted rat myocardium, where VEGFR-3 is expressed not only in lymph ducts but also in myofibroblasts, indicating that VEGF-C has an unrevealed role in fibrogenesis during cardiac repair. The current study is to explore the regulation and molecular mechanisms of VEGF-C in fibrogenesis. The potential regulation of VEGF-C on myofibroblast differentiation/growth/migration, collagen degradation/synthesis, and transforming growth factor (TGF)-β and ERK pathways was detected in cultured cardiac myofibroblasts. Our results showed that VEGF-C significantly increased myofibroblast proliferation, migration, and type I/III collagen production. Matrix metalloproteinase (MMP)-2 and -9 were significantly elevated in the medium of VEGF-C-treated cells, coincident with increased tissue inhibitor of metalloproteinase (TIMP)-1 and TIMP-2. Furthermore, VEGF-C activated the TGF-β1 pathway and ERK phosphorylation, which was significantly suppressed by TGF-β or ERK blockade. This is the first study indicating that in addition to lymphangiogenesis, VEGF-C is also involved in fibrogenesis through stimulation of myofibroblast proliferation, migration, and collagen synthesis, via activation of the TGF-β1 and ERK pathways.

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Selman, Moises, Victor Ruiz, Sandra Cabrera, Lourdes Segura, Remedios Ramírez, Roberto Barrios, and Annie Pardo. "TIMP-1, -2, -3, and -4 in idiopathic pulmonary fibrosis. A prevailing nondegradative lung microenvironment?" American Journal of Physiology-Lung Cellular and Molecular Physiology 279, no. 3 (September 1, 2000): L562—L574. http://dx.doi.org/10.1152/ajplung.2000.279.3.l562.

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Fibroblast proliferation and extracellular matrix accumulation characterize idiopathic pulmonary fibrosis (IPF). We evaluated the presence of tissue inhibitor of metalloproteinase (TIMP)-1, -2, -3, and -4; collagenase-1, -2, and -3; gelatinases A and B; and membrane type 1 matrix metalloproteinase (MMP) in 12 IPF and 6 control lungs. TIMP-1 was found in interstitial macrophages and TIMP-2 in fibroblast foci. TIMP-3 revealed an intense staining mainly decorating the elastic lamina in vessels. TIMP-4 was expressed in IPF lungs by epithelial and plasma cells. TIMP-2 colocalized with Ki67 in fibroblasts, whereas TIMP-3 colocalized with p27 in inflammatory and epithelial cells. Collagenase-1 was localized in macrophages and alveolar epithelial cells, collagenase-2 was localized in a few neutrophils, and collagenase-3 was not detected. MMP-9 was found in neutrophils and subepithelial myofibroblasts. Myofibroblast expression of MMP-9 was corroborated in vitro by RT-PCR. MMP-2 was noticed in myofibroblasts, some of them close to areas of basement membrane disruption, and membrane type 1 MMP was noticed in interstitial macrophages. These findings suggest that in IPF there is higher expression of TIMPs compared with collagenases, supporting the hypothesis that a nondegrading fibrillar collagen microenvironment is prevailing.

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Chuliá-Peris, Lourdes, Cristina Carreres-Rey, Marta Gabasa, Jordi Alcaraz, Julián Carretero, and Javier Pereda. "Matrix Metalloproteinases and Their Inhibitors in Pulmonary Fibrosis: EMMPRIN/CD147 Comes into Play." International Journal of Molecular Sciences 23, no. 13 (June 21, 2022): 6894. http://dx.doi.org/10.3390/ijms23136894.

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Pulmonary fibrosis (PF) is characterized by aberrant extracellular matrix (ECM) deposition, activation of fibroblasts to myofibroblasts and parenchymal disorganization, which have an impact on the biomechanical traits of the lung. In this context, the balance between matrix metalloproteinases (MMPs) and their tissue inhibitors of metalloproteinases (TIMPs) is lost. Interestingly, several MMPs are overexpressed during PF and exhibit a clear profibrotic role (MMP-2, -3, -8, -11, -12 and -28), but a few are antifibrotic (MMP-19), have both profibrotic and antifibrotic capacity (MMP7), or execute an unclear (MMP-1, -9, -10, -13, -14) or unknown function. TIMPs are also overexpressed in PF; hence, the modulation and function of MMPs and TIMP are more complex than expected. EMMPRIN/CD147 (also known as basigin) is a transmembrane glycoprotein from the immunoglobulin superfamily (IgSF) that was first described to induce MMP activity in fibroblasts. It also interacts with other molecules to execute non-related MMP aactions well-described in cancer progression, migration, and invasion. Emerging evidence strongly suggests that CD147 plays a key role in PF not only by MMP induction but also by stimulating fibroblast myofibroblast transition. In this review, we study the structure and function of MMPs, TIMPs and CD147 in PF and their complex crosstalk between them.

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Shin, Seung-Heon, Mi-Kyung Ye, Dong-Won Lee, and Mi-Hyun Che. "Effect of Acacia Honey on Transforming Growth Factor-Beta-1-Induced Myofibroblast Differentiation and Matrix Metalloproteinase-9 Production in Nasal Polyp Fibroblasts." American Journal of Rhinology & Allergy 33, no. 5 (April 18, 2019): 483–89. http://dx.doi.org/10.1177/1945892419843702.

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BackgroundAcacia honey is known to have antioxidant, immune-modulatory, and antiproliferative properties. Nasal fibroblasts participate in local immune responses that control the recruitment of inflammatory cells and the production of extracellular matrix.ObjectivesThe aim of this study was to determine the effect of acacia honey on myofibroblast differentiation and matrix metalloproteinase-9 (MMP-9) production in nasal polyp fibroblasts.MethodsPrimary nasal fibroblasts were isolated from nasal polyps and treated with transforming growth factor-beta 1 (TGF-β1). Reverse transcription-polymerase chain reaction and Western blot analysis were then performed to determine α-smooth muscle actin (α-SMA), tissue inhibitors of matrix metalloproteinase-1, and MMP-9 mRNA expression and protein production in nasal polyp fibroblasts. Phosphorylated Smad ( pSmad) 2/3 and phosphorylated adenosine monophosphate-activated protein kinase ( pAMPK) were then determined by Western blotting.ResultsTGF-β1 stimulation increased α-SMA and MMP-9 mRNA expression and protein production in nasal polyp fibroblasts. Acacia honey effectively suppressed α-SMA and MMP-9 mRNA expression and protein production. It also prevented phosphorylation of Smad 2/3 and AMPK.ConclusionAcacia honey can inhibit TGF-β1-induced myofibroblast differentiation and MMP-9 production in nasal fibroblasts. These results suggest that acacia honey might be useful for inhibiting nasal polyp formation.

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ALFONSO-JAUME, Maria Alejandra, Rajeev MAHIMKAR, and David H. LOVETT. "Co-operative interactions between NFAT (nuclear factor of activated T cells) c1 and the zinc finger transcription factors Sp1/Sp3 and Egr-1 regulate MT1-MMP (membrane type 1 matrix metalloproteinase) transcription by glomerular mesangial cells." Biochemical Journal 380, no. 3 (June 15, 2004): 735–47. http://dx.doi.org/10.1042/bj20031281.

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The transition of normally quiescent glomerular MCs (mesangial cells) to a highly proliferative phenotype with characteristics of myofibroblasts is a process commonly observed in inflammatory diseases affecting the renal glomerulus, the ultimate result of which is glomerulosclerosis. Generation of proteolytically active MMP (matrix metalloproteinase)-2 by the membrane-associated membrane type 1 (MT1)-MMP is responsible for the transition of mesangial cells to the myofibroblast phenotype [Turck, Pollock, Lee, Marti and Lovett (1996) J. Biol. Chem. 271, 15074–15083]. In the present study, we show that the expression of MT1-MMP within the context of MCs is mediated by three discrete cis-acting elements: a proximal non-canonical Sp1 site that preferentially binds Sp1; an overlapping Sp1/Egr-1-binding site that preferentially binds Egr-1; and a more distal binding site for the NFAT (nuclear factor of activated T cells) that binds the NFAT c1 isoform present in MC nuclear extracts. Transfection with an NFAT c1 expression plasmid, or activation of calcineurin with a calcium ionophore, yielded major increases in NFAT c1 nuclear DNA-binding activity, MT1-MMP transcription and protein synthesis, which were additive with the lower levels of transactivation provided by the proximal Sp1 and the overlapping Sp1/Egr-1 sites. Specific binding of NFAT c1 to the MT1-MMP promoter was confirmed by chromatin immunoprecipitation studies, while MT1-MMP expression was suppressed by treatment with the calcineurin inhibitor, cyclosporin A. These studies are the first demonstration that a specific NFAT isoform enhances transcription of an MMP (MT1-MMP) that plays a major role in the proteolytic events that are a dominant feature of acute glomerular inflammation. Suppression of MT1-MMP by commonly used calcineurin inhibitors may play a role in the development of renal fibrosis following renal transplantation.

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Howard, Eric W., Beverly J. Crider, Dawn L. Updike, Elizabeth C. Bullen, Eileen E. Parks, Carol J. Haaksma, David M. Sherry, and James J. Tomasek. "MMP-2 expression by fibroblasts is suppressed by the myofibroblast phenotype." Experimental Cell Research 318, no. 13 (August 2012): 1542–53. http://dx.doi.org/10.1016/j.yexcr.2012.03.007.

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Jara, Paul, Jazmin Calyeca, Yair Romero, Luis Plácido, Guoying Yu, Naftali Kaminski, Vilma Maldonado, José Cisneros, Moisés Selman, and Annie Pardo. "Matrix metalloproteinase (MMP)-19-deficient fibroblasts display a profibrotic phenotype." American Journal of Physiology-Lung Cellular and Molecular Physiology 308, no. 6 (March 15, 2015): L511—L522. http://dx.doi.org/10.1152/ajplung.00043.2014.

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Idiopathic pulmonary fibrosis (IPF) is a progressive and usually lethal interstitial lung disease of unknown etiology characterized by aberrant activation of epithelial cells that induce the migration, proliferation and activation of fibroblasts. The resulting distinctive fibroblastic/myofibroblastic foci are responsible for the excessive extracellular matrix (ECM) production and abnormal lung remodeling. We have recently found that matrix metalloproteinase 19 (MMP-19)-deficient ( Mmp19−/−) mice develop an exaggerated bleomycin-induced lung fibrosis, but the mechanisms are unclear. In this study, we explored the effect of MMP-19 deficiency on fibroblast gene expression and cell behavior. Microarray analysis of Mmp19−/− lung fibroblasts revealed the dysregulation of several profibrotic pathways, including ECM formation, migration, proliferation, and autophagy. Functional studies confirmed these findings. Compared with wild-type mice, Mmp19−/− lung fibroblasts showed increased α1 (I) collagen gene and collagen protein production at baseline and after transforming growth factor-β treatment and increased smooth muscle-α actin expression ( P < 0.05). Likewise, Mmp19-deficient lung fibroblasts showed a significant increase in proliferation ( P < 0.01) and in transmigration and locomotion over Boyden chambers coated with type I collagen or with Matrigel ( P < 0.05). These findings suggest that, in lung fibroblasts, MMP-19 has strong regulatory effects on the synthesis of key ECM components, on fibroblast to myofibroblast differentiation, and in migration and proliferation.

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Hewitson, Tim D., Wen Yang Ho, and Chrishan S. Samuel. "Antifibrotic Properties of Relaxin: In Vivo Mechanism of Action in Experimental Renal Tubulointerstitial Fibrosis." Endocrinology 151, no. 10 (September 8, 2010): 4938–48. http://dx.doi.org/10.1210/en.2010-0286.

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This study examined the efficacy and in vivo mechanism of action of the antifibrotic hormone, relaxin, in a mouse model of unilateral ureteric obstruction (UUO). Kidney fibrosis was assessed in recombinant human gene-2 relaxin-treated animals maintained for 3 and 9 d after UUO. Results were compared with untreated and unoperated animals (d 0). Total collagen, collagen subtypes (I, IV), TGF-β2 production, mothers against decapentaplegic homolog 2 (Smad2) phosphorylation, myofibroblast differentiation, mitosis, and apoptosis were all progressively increased by UUO (all P < 0.05 vs. d 0 group at d 3 and d 9), whereas TGF-β1 production was increased and vascular endothelial growth factor expression (angiogenesis) decreased at d 9 (both P < 0.05 vs. d 0). A progressive increase in matrix metalloproteinase (MMP)-2 after UUO suggested that it was reactive to the increased fibrogenesis. Conversely, MMP-9 was decreased at d 9, whereas its inhibitor tissue inhibitor of metalloproteinase-1 progressively decreased after UUO. Human gene-2 relaxin pretreatment of animals from 4 d prior to UUO ameliorated the increase in total collagen, collagen IV, Smad2 phosphorylation, and myofibroblasts at both time points (all P < 0.05 vs. untreated groups) and inhibited TGF-β2 production and cell proliferation (both P < 0.05 vs. untreated groups) with a trend toward normalizing vascular endothelial growth factor expression at d 9, with no effect on TGF-β1 production or apoptosis. The relaxin-mediated regulation of MMPs and tissue inhibitor of metalloproteinases in this model was not consistent with its antifibrotic properties. The beneficial effects of relaxin were lost when treatment was stopped. These findings establish that relaxin can inhibit both early and established phases of tubulointerstitial fibrosis, primarily by suppressing cell proliferation, myofibroblast differentiation, and collagen production. Not all of these effects paralleled changes to TGF-β-Smad signaling.

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Romano, E., I. Rosa, B. S. Fioretto, D. Giuggioli, M. Manetti, and M. Matucci-Cerinic. "AB0132 STIMULATION OF SOLUBLE GUANYLATE CYCLASE (sGC) FOSTERS ANGIOGENESIS AND BLUNTS ENDOTHELIAL-TO-MESENCHYMAL TRANSITION (EndoMT) OF SYSTEMIC SCLEROSIS (SSc) DERMAL MICROVASCULAR ENDOTHELIAL CELLS." Annals of the Rheumatic Diseases 81, Suppl 1 (May 23, 2022): 1196.1–1196. http://dx.doi.org/10.1136/annrheumdis-2022-eular.2362.

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BackgroundIn SSc, early abnormalities in microvessel morphology and angiogenic impairment in parallel advance with the development of tissue fibrosis orchestrated by myofibroblasts. Increasing evidence suggests that the EndoMT process, in which endothelial cells transdifferentiate into profibrotic myofibroblasts, may take centre stage in SSc pathogenesis [1,2]. sGC is an enzyme regulating cell growth/proliferation and vascular tone/remodelling by catalysing the production of cyclic guanosine monophosphate. Previous studies reported that sGC stimulation inhibits TGFβ-induced fibroblast-to-myofibroblast differentiation and collagen synthesis by blocking non-canonical ERK-dependent TGFβ signalling, and that sCG stimulators (sGCS) may exert antifibrotic effects in experimental models of fibrotic disorders.ObjectivesTo investigate the possible modulatory effects of sGC stimulation on impaired angiogenesis and EndoMT of SSc dermal microvascular endothelial cells (SSc-MVECs).MethodsTo evaluate the effects of treatment with sGCS on endothelial cell viability/proliferation, 5 lines of SSc-MVECs and 5 lines of healthy dermal MVECs (H-MVECs) were challenged with sGCS (here MK-2947) and assayed with both annexin V/PI flow cytometry and WST-1. To analyse the modulation of angiogenesis by sGCS, SSc-MVECs were challenged with MK-2947 and subsequently tested for wound healing and capillary-like tube formation capabilities. To study the effects of MK-2947 on EndoMT, the same cells were assayed for the expression of endothelial and mesenchymal/myofibroblast markers by quantitative real-time PCR, western blotting and immunofluorescence, as well as for their contractile ability by collagen gel contraction assay. Phosphorylation of ERK1/2 was assessed by western blotting.ResultsTreatment with MK-2947 did not affect viability/proliferation of H-MVECs, while it significantly increased the proliferation of SSc-MVECs (p<0.001 vs. basal). Compared to basal condition, the MK-2947 challenge ameliorated both wound healing capability (p<0.001) and angiogenic performance (number of nodes: p<0.01; segments: p<0.001; meshes: p<0.01; and junctions: p<0.001) of SSc-MVECs. Upon stimulation of sGC, SSc-MVECs exhibited increased gene expression of proangiogenic matrix metalloproteinase (MMP)-9 (p<0.05) and decreased expression of both antiangiogenic MMP-12 (p<0.05) and pentraxin-3 (p<0.001) respect to basal SSc-MVECs. A significant increase in both gene and protein expression of the endothelial markers CD31 and VE-cadherin, and a parallel decrease in the expression of the mesenchymal/myofibroblast markers α-SMA, S100A4, and type I collagen were found in MK-2947-treated SSc-MVECs. MK-2947 also downregulated the EndoMT-driving transcription factor SNAIL1 in SSc-MVECs. Stimulation with MK-2947 was able to significantly counteract the intrinsic ability of myofibroblast-like SSc-MVECs to contract collagen gels (p<0.001) and effectively reduce phosphorylated-ERK1/2 protein levels (p<0.01) respect to basal cells.ConclusionStimulation of sGC effectively ameliorates the angiogenic performance and blunts the pathogenic myofibroblast-like profibrotic phenotype of SSc-MVECs.References[1]Manetti M, et al. Endothelial-to-mesenchymal transition contributes to endothelial dysfunction and dermal fibrosis in systemic sclerosis. Ann Rheum Dis. 2017;76:924–34.[2]Romano E, et al. New insights into profibrotic myofibroblast formation in systemic sclerosis: when the vascular wall becomes the enemy. Life (Basel). 2021;11:610.Disclosure of InterestsEloisa Romano: None declared, Irene Rosa: None declared, Bianca Saveria Fioretto: None declared, Dilia Giuggioli: None declared, Mirko Manetti Speakers bureau: has received consulting fees or honorarium from MSD, Marco Matucci-Cerinic Speakers bureau: has received consulting fees or honorarium from Actelion, Janssen, Inventiva, Bayer, Biogen, Boehringer, CSL Behring, Corbus, Galapagos, Mitsubishi, Samsung, Regeneron, Acceleron, MSD, Chemomab, Lilly, Pfizer, Roche, Grant/research support from: has received consulting fees or honorarium from Actelion, Janssen, Inventiva, Bayer, Biogen, Boehringer, CSL Behring, Corbus, Galapagos, Mitsubishi, Samsung, Regeneron, Acceleron, MSD, Chemomab, Lilly, Pfizer, Roche

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SEOMUN, Young, Jeong-a. KIM, Eunjoo H. LEE, and Choun-Ki JOO. "Overexpression of matrix metalloproteinase-2 mediates phenotypic transformation of lens epithelial cells." Biochemical Journal 358, no. 1 (August 8, 2001): 41–48. http://dx.doi.org/10.1042/bj3580041.

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Transforming growth factor-β (TGF-β) is known to be a causative factor in pathological fibrosis and the metastasis of cancer cells, through effects on molecules of the extracellular matrix (ECM). We evaluated the influence of TGF-β1 on the gene expression of matrix metalloproteinase-2 (MMP-2) in lens epithelial cells (LECs). The results showed that TGF-β1 induced the expression of mRNA for MMP-2 in LECs. Subsequently, in order to examine the role of MMP-2, we overexpressed MMP-2 in LECs by stable transfection. The MMP-2-overexpressing LECs showed typical indicators of a myofibroblast-like cell phenotype, such as multiple layers of cells, elongated morphology, and expression of α-smooth muscle actin. We also showed that an MMP inhibitor blocked the TGF-β1-induced morphological change in LECs. These results demonstrate that MMP-2 plays a role in the transformation of LECs, which has implications for the pathological fibrosis of these cells.

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Wang, Baiqiu, Amer Omar, Tatjana Angelovska, Vanja Drobic, Sunil G. Rattan, Stephen C. Jones, and Ian M. C. Dixon. "Regulation of collagen synthesis by inhibitory Smad7 in cardiac myofibroblasts." American Journal of Physiology-Heart and Circulatory Physiology 293, no. 2 (August 2007): H1282—H1290. http://dx.doi.org/10.1152/ajpheart.00910.2006.

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Transforming growth factor-β1 (TGF-β1) signal and downstream Smads play an important role in tissue fibrosis and matrix remodeling in various etiologies of heart failure. Inhibitory Smad7 (I-Smad7) is an inducible regulatory Smad protein that antagonizes TGF-β1 signal mediated via direct abrogation of R-Smad phosphorylation. The effect of ectopic I-Smad7 on net collagen production was investigated using hydroxyproline assay. Adenovirus-mediated I-Smad7 gene (at 100 multiplicity of infection) transfer was associated with significant decrease of collagen synthesis in the presence and absence of TGF-β1 in primary rat cardiac myofibroblasts. In I-Smad7-infected cells, we also observed the ablation of TGF-β1-induced R-Smad2 phosphorylation vs. LacZ controls. Overdriven I-Smad7 was associated with significantly increased expression of immunoreactive 65-kDa matrix metalloproteinase-2 (MMP-2) protein in culture medium of myofibroblast compared with LacZ-infected cells. Expression of the 72-kDa MMP-2 variant, e.g., the inactive form, was not altered by exogenous I-Smad7 transfection/overexpression. Furthermore, I-Smad7 overexpression was associated with a significant increase and decrease in expression of p27 and phospho-Rb protein, respectively, as well as reduced [3H]thymidine incorporation vs. Ad-LacZ-infected controls. We suggest that negative modulation of R-Smad phosphorylation by ectopic I-Smad7 may contribute to the downregulation of collagen in cardiac myofibroblasts and may suppress the proliferation of these cells. Thus treatments targeting the collagen deposition by overexpression of I-Smad7 may provide a new therapeutic strategy for cardiac fibrosis.

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Wang, Xiaohua, Yang Zhou, Ruoyun Tan, Mingxia Xiong, Weichun He, Li Fang, Ping Wen, Lei Jiang, and Junwei Yang. "Mice lacking the matrix metalloproteinase-9 gene reduce renal interstitial fibrosis in obstructive nephropathy." American Journal of Physiology-Renal Physiology 299, no. 5 (November 2010): F973—F982. http://dx.doi.org/10.1152/ajprenal.00216.2010.

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Matrix metalloproteinase-9 (MMP-9) is one of the major components of the matrix proteolytic network, and its role in the pathogenesis of renal interstitial fibrosis remains largely unknown. Here, we demonstrate that ablation of MMP-9 attenuated renal interstitial fibrotic lesions in obstructive nephropathy. Mice lacking MMP-9 were less likely to develop morphological injury, which was characterized by a reduced disruption of tubular basement membrane (TBM) and expression of fibronectin as well as deposition of total tissue collagen in the kidneys after sustained ureteral obstruction compared with their wild-type counterparts. Deficiency of MMP-9 blocked tubular epithelial-to-myofibroblast transition (EMT) but did not alter the induction of transforming growth factor (TGF)-β1 axis expression in the obstructed kidneys. In vitro, TBM, which was digested by MMP-9 instead of MMP-9 itself, induces EMT and enhances migration of transformed cells. Thus increased MMP-9 is detrimental in renal interstitial fibrogenesis through a cascade of events that leads to TBM destruction and in turn to promotion of EMT. Our findings establish a crucial and definite importance of MMP-9 in the pathogenesis of renal interstitial fibrosis at the whole-animal level.

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Hewitson, T. D., I. A. Darby, T. Bisucci, C. L. Jones, and G. J. Becker. "Evolution of tubulointerstitial fibrosis in experimental renal infection and scarring." Journal of the American Society of Nephrology 9, no. 4 (April 1998): 632–42. http://dx.doi.org/10.1681/asn.v94632.

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Renal tubulointerstitial fibrosis may result from a loss of tubulointerstitial volume, which produces a disproportionate increase in the density of matrix. This study examines the relationship between fibrogenesis and collapse in scar formation after experimental renal infection. Escherichia coli were inoculated into the renal cortex of Sprague Dawley rats, with saline substituted in a control group. Glomerular, tubular, and interstitial profile areas were determined. Density of glomerular profiles was used as a measure of tubulointerstitial collapse. Collagen type I, III, and IV expression was examined by in situ hybridization and immunohistochemistry. Myofibroblasts were identified by alpha smooth muscle actin immunohistochemistry, and matrix metalloproteinase-1 (MMP-1) and MMP-2 were localized with appropriate antisera. Acute interstitial edema was followed by increasing density of glomerular profiles, paralleled by loss of interstitial volume and progressive tubular atrophy. Glomerular profile area remained unchanged. Density of glomerular profiles was not temporally related to myofibroblast accumulation. Procollagen alpha 1(I), alpha 1(III), and alpha 1(IV) transcription was focal, spatially related but temporally ordered. Collagen I, III, and IV immunostaining was increased from days 3, 24, and 100, respectively (P < 0.05 versus day 0 and day 100 saline). However, when corrected for glomerular density, collagen I immunostaining decreased between days 24 and 100, whereas collagen III and IV no longer differed from day 0. MMP staining within the lesion was confined to occasional interstitial and epithelial cells throughout. It is concluded that in this model, contraction and collapse of the tubulointerstitial parenchyma has a greater influence than new collagen production on final fibrotic density.

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Zhao, Na, Bo Liu, Si-Wen Liu, Wei Zhang, Hua-Nan Li, Geng Pang, Xiong-Fei Luo, and Jin-Gui Wang. "The Combination of Electroacupuncture and Massage Therapy Alleviates Myofibroblast Transdifferentiation and Extracellular Matrix Production in Blunt Trauma-Induced Skeletal Muscle Fibrosis." Evidence-Based Complementary and Alternative Medicine 2021 (July 7, 2021): 1–10. http://dx.doi.org/10.1155/2021/5543468.

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Complementary therapies, such as acupuncture and massage, had been previously reported to have therapeutic effects on skeletal muscle contusions. However, the recovery mechanisms on skeletal muscles after blunt trauma via the combination of electroacupuncture (EA) and massage therapy remain unclear. In the present study, a rat model of the skeletal muscle fibrosis following blunt trauma to rat skeletal muscle was established, and the potential molecular mechanisms of EA + massage therapy on the skeletal muscle fibrosis were investigated. The results suggested that EA + massage therapy could significantly decrease inflammatory cells infiltration and collagenous fiber content and ameliorate the disarrangement of sarcomeres within myofibrils compared to the model group. Further analysis revealed that EA + massage therapy could reduce the degree of fibrosis and increase the degree of myofibroblast apoptosis by downregulating the mRNA and protein expression of transforming growth factor- (TGF-) β1 and connective tissue growth factor (CTGF). Furthermore, the fibrosis of injured skeletal muscle was inhibited after treatment through the normalization of balance between matrix metalloproteinase- (MMP-) 1 and tissue inhibitor of matrix metalloproteinase (TIMP). These findings suggested that the combination of electroacupuncture and massage therapy could alleviate the fibrotic process by regulating TGF β1-CTGF-induced myofibroblast transdifferentiation and MMP-1/TIMP-1 balance for extracellular matrix production.

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Shi, Zhong-Dong, Xin-Ying Ji, Henry Qazi, and John M. Tarbell. "Interstitial flow promotes vascular fibroblast, myofibroblast, and smooth muscle cell motility in 3-D collagen I via upregulation of MMP-1." American Journal of Physiology-Heart and Circulatory Physiology 297, no. 4 (October 2009): H1225—H1234. http://dx.doi.org/10.1152/ajpheart.00369.2009.

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Neointima formation often occurs in regions where the endothelium has been damaged and the transmural interstitial flow is elevated. Vascular smooth muscle cells (SMCs) and fibroblasts/myofibroblasts (FBs/MFBs) contribute to intimal thickening by migrating from the media and adventitia into the site of injury. In this study, for the first time, the direct effects of interstitial flow on SMC and FB/MFB migration were investigated in an in vitro three-dimensional system. Collagen I gels were used to mimic three-dimensional extracellular matrix (ECM) for rat aortic SMCs and FBs/MFBs. Exposure to interstitial flow induced by 1 cmH2O pressure differential (shear stress, ∼0.05 dyn/cm2; flow velocity, ∼0.5 μm/s; and Darcy permeability, ∼10−11 cm2) substantially enhanced cell motility. Matrix metalloproteinase (MMP) inhibitor (GM-6001) abolished flow-induced migration augmentation, which suggested that the enhanced motility was MMP dependent. The upregulation of MMP-1 played a critical role for the flow-enhanced motility, which was further confirmed by silencing MMP-1 gene expression. Longer exposures to higher flows suppressed the number of migrated cells, although MMP-1 gene expression remained high. This suppression was a result of both flow-induced tissue inhibitor of metalloproteinase-1 upregulation and increased apoptotic and necrotic cell death. Interstitial flow did not affect MMP-2 gene expression or activity in the collagen I gel for any cell type. Our findings shed light on the mechanism by which vascular SMCs and FBs/MFBs contribute to intimal thickening in regions of vascular injury where interstitial flow is elevated.

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Lee, Hsuan-Shu, Luo-Hwa Miau, Chien-Hung Chen, Ling-Ling Chiou, Guan-Tarn Huang, Pei-Ming Yang, and Jin-Chuan Sheu. "Differential role of p38 in IL-1α induction of MMP-9 and MMP-13 in an established liver myofibroblast cell line." Journal of Biomedical Science 10, no. 6 (October 2003): 757–65. http://dx.doi.org/10.1007/bf02256328.

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Lamb, Cheri L., Giovan N. Cholico, Daniel E. Perkins, Michael T. Fewkes, Julia Thom Oxford, Trevor J. Lujan, Erica E. Morrill, and Kristen A. Mitchell. "Aryl Hydrocarbon Receptor Activation by TCDD Modulates Expression of Extracellular Matrix Remodeling Genes during Experimental Liver Fibrosis." BioMed Research International 2016 (2016): 1–14. http://dx.doi.org/10.1155/2016/5309328.

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The aryl hydrocarbon receptor (AhR) is a soluble, ligand-activated transcription factor that mediates the toxicity of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Increasing evidence implicates the AhR in regulating extracellular matrix (ECM) homeostasis. We recently reported that TCDD increased necroinflammation and myofibroblast activation during liver injury elicited by carbon tetrachloride (CCl4). However, TCDD did not increase collagen deposition or exacerbate fibrosis in CCl4-treated mice, which raises the possibility that TCDD may enhance ECM turnover. The goal of this study was to determine how TCDD impacts ECM remodeling gene expression in the liver. Male C57BL/6 mice were treated for 8 weeks with 0.5 mL/kg CCl4, and TCDD (20 μg/kg) was administered during the last two weeks. Results indicate that TCDD increased mRNA levels of procollagen types I, III, IV, and VI and the collagen processing molecules HSP47 and lysyl oxidase. TCDD also increased gelatinase activity and mRNA levels of matrix metalloproteinase- (MMP-) 3, MMP-8, MMP-9, and MMP-13. Furthermore, TCDD modulated expression of genes in the plasminogen activator/plasmin system, which regulates MMP activation, and it also increased TIMP1 gene expression. These findings support the notion that AhR activation by TCDD dysregulates ECM remodeling gene expression and may facilitate ECM metabolism despite increased liver injury.

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Hou, Tzu-Yu, Shi-Bei Wu, Hui-Chuan Kau, and Chieh-Chih Tsai. "JNK and p38 Inhibitors Prevent Transforming Growth Factor-β1-Induced Myofibroblast Transdifferentiation in Human Graves’ Orbital Fibroblasts." International Journal of Molecular Sciences 22, no. 6 (March 14, 2021): 2952. http://dx.doi.org/10.3390/ijms22062952.

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Transforming growth factor-β1 (TGF-β1)-induced myofibroblast transdifferentiation from orbital fibroblasts is known to dominate tissue remodeling and fibrosis in Graves’ ophthalmopathy (GO). However, the signaling pathways through which TGF-β1 activates Graves’ orbital fibroblasts remain unclear. This study investigated the role of the mitogen-activated protein kinase (MAPK) pathway in TGF-β1-induced myofibroblast transdifferentiation in human Graves’ orbital fibroblasts. The MAPK pathway was assessed by measuring the phosphorylation of p38, c-Jun N-terminal kinase (JNK), and extracellular-signal-regulated kinase (ERK) by Western blots. The expression of connective tissue growth factor (CTGF), α-smooth muscle actin (α-SMA), and fibronectin representing fibrogenesis was estimated. The activities of matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) responsible for extracellular matrix (ECM) metabolism were analyzed. Specific pharmacologic kinase inhibitors were used to confirm the involvement of the MAPK pathway. After treatment with TGF-β1, the phosphorylation levels of p38 and JNK, but not ERK, were increased. CTGF, α-SMA, and fibronectin, as well as TIMP-1 and TIMP-3, were upregulated, whereas the activities of MMP-2/-9 were inhibited. The effects of TGF-β1 on the expression of these factors were eliminated by p38 and JNK inhibitors. The results suggested that TGF-β1 could induce myofibroblast transdifferentiation in human Graves’ orbital fibroblasts through the p38 and JNK pathways.

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Morley, M. E., K. Riches, C. Peers, and K. E. Porter. "Hypoxic inhibition of human cardiac fibroblast invasion and MMP-2 activation may impair adaptive myocardial remodelling." Biochemical Society Transactions 35, no. 5 (October 25, 2007): 905–7. http://dx.doi.org/10.1042/bst0350905.

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Cardiac fibroblasts account for up to two-thirds of the total number of cells in the normal heart and are responsible for extracellular matrix homoeostasis. In vitro, type I collagen, the predominant myocardial collagen, stimulates proteolytic activation of constitutively secreted proMMP-2 (pro-matrix metalloproteinase-2). This occurs at the cell membrane and requires formation of a ternary complex with MT1-MMP (membrane-type-1 MMP) and TIMP-2 (tissue inhibitor of metalloproteinases-2). Following MI (myocardial infarction), normally quiescent fibroblasts initiate a wound healing response by transforming into a proliferative and invasive myofibroblast phenotype. Deprivation of oxygen to the myocardium is an inevitable consequence of MI; therefore this reparative event occurs under chronically hypoxic conditions. However, species and preparation variations can strongly influence fibroblast behaviour, which is an important consideration when selecting experimental models for provision of clinically useful information.

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Sato, M., S. Hirayama, H. Lara-Guerra, M. Anraku, T. K. Waddell, M. Liu, and S. Keshavjee. "MMP-Dependent Migration of Extrapulmonary Myofibroblast Progenitors Contributing to Posttransplant Airway Fibrosis in the Lung." American Journal of Transplantation 9, no. 5 (May 2009): 1027–36. http://dx.doi.org/10.1111/j.1600-6143.2009.02605.x.

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Mizuno, Shinya, Kunio Matsumoto, Ming-Yue Li, and Toshikazu Nakamura. "HGF reduces advancing lung fibrosis in mice: a potential role for MMP‐dependent myofibroblast apoptosis." FASEB Journal 19, no. 6 (January 21, 2005): 1–18. http://dx.doi.org/10.1096/fj.04-1535fje.

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Lee, Hsuan-Shu, Luo-Hwa Miau, Chien-Hung Chen, Ling-Ling Chiou, Guan-Tarn Huang, Pei-Ming Yang, and Jin-Chuan Sheu. "Differential Role of p38 in IL-1α Induction of MMP-9 and MMP-13 in an Established Liver Myofibroblast Cell Line." Journal of Biomedical Science 10, no. 6 (2003): 757–65. http://dx.doi.org/10.1159/000073963.

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Phaosri, Mattareeyapar, Salinee Jantrapirom, Mingkwan Na Takuathung, Noppamas Soonthornchareonnon, Seewaboon Sireeratawong, Pensiri Buacheen, Pornsiri Pitchakarn, Wutigri Nimlamool, and Saranyapin Potikanond. "Salacia chinensis L. Stem Extract Exerts Antifibrotic Effects on Human Hepatic Stellate Cells through the Inhibition of the TGF-β1-Induced SMAD2/3 Signaling Pathway." International Journal of Molecular Sciences 20, no. 24 (December 13, 2019): 6314. http://dx.doi.org/10.3390/ijms20246314.

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Salacia chinensis L. (SC) stems have been used as an ingredient in Thai traditional medicine for treating patients with hepatic fibrosis and liver cirrhosis. However, there is no scientific evidence supporting the antifibrotic effects of SC extract. Therefore, this study aimed to determine the antifibrotic activity of SC stem extract in human hepatic stellate cell-line called LX-2. We found that upon TGF-β1 stimulation, LX-2 cells transformed to a myofibroblast-like phenotype with a noticeable increase in α-SMA and collagen type I production. Interestingly, cells treated with SC extract significantly suppressed α-SMA and collagen type I production and reversed the myofibroblast-like characteristics back to normal. Additionally, TGF-β1 also influenced the development of fibrogenesis by upregulation of MMP-2, TIMP-1, and TIMP-2 and related cellular signaling, such as pSmad2/3, pErk1/2, and pJNK. Surprisingly, SC possesses antifibrotic activity through the suppression of TGF-β1-mediated production of collagen type 1, α-SMA, and the phosphorylation status of Smad2/3, Erk1/2, and JNK. Taken together, the present study provides accumulated information demonstrating the antifibrotic effects of SC stem extract and revealing its potential for development for hepatic fibrosis patients.

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PORTER, K., N. TURNER, D. OREGAN, and S. BALL. "Tumor necrosis factor ? induces human atrial myofibroblast proliferation, invasion and MMP-9 secretion: inhibition by simvastatin." Cardiovascular Research 64, no. 3 (December 1, 2004): 507–15. http://dx.doi.org/10.1016/j.cardiores.2004.07.020.

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Lee, Hyo Yeong, Somi Nam, Mi Jeong Kim, Su Jung Kim, Sung Hoon Back, and Hyun Ju Yoo. "Butyrate Prevents TGF-β1-Induced Alveolar Myofibroblast Differentiation and Modulates Energy Metabolism." Metabolites 11, no. 5 (April 22, 2021): 258. http://dx.doi.org/10.3390/metabo11050258.

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Idiopathic pulmonary fibrosis (IPF) is a serious lung disease characterized by excessive collagen matrix deposition and extracellular remodeling. Signaling pathways mediated by fibrotic cytokine transforming growth factor β1 (TGF-β1) make important contributions to pulmonary fibrosis, but it remains unclear how TGF-β1 alters metabolism and modulates the activation and differentiation of pulmonary fibroblasts. We found that TGF-β1 lowers NADH and NADH/NAD levels, possibly due to changes in the TCA cycle, resulting in reductions in the ATP level and oxidative phosphorylation in pulmonary fibroblasts. In addition, we showed that butyrate (C4), a short chain fatty acid (SCFA), exhibits potent antifibrotic activity by inhibiting expression of fibrosis markers. Butyrate treatment inhibited mitochondrial elongation in TGF-β1-treated lung fibroblasts and increased the mitochondrial membrane potential (MMP). Consistent with the mitochondrial observations, butyrate significantly increased ADP, ATP, NADH, and NADH/NAD levels in TGF-β1-treated pulmonary fibroblasts. Collectively, our findings indicate that TGF-β1 induces changes in mitochondrial dynamics and energy metabolism during myofibroblast differentiation, and that these changes can be modulated by butyrate, which enhances mitochondrial function.

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Namsen, Ratchadaporn, Noppamas Rojanasthien, Seewaboon Sireeratawong, Piyanuch Rojsanga, Wutigri Nimlamool, and Saranyapin Potikanond. "Thunbergia laurifolia Exhibits Antifibrotic Effects in Human Hepatic Stellate Cells." Evidence-Based Complementary and Alternative Medicine 2017 (2017): 1–9. http://dx.doi.org/10.1155/2017/3508569.

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Leaves of Thunbergia laurifolia (TL) have been reported to have antioxidation, anti-inflammatory, detoxifying, and hepatoprotective effects. However, studies relating to antifibrotic activity have not been reported. Currently, there is no standard treatment for hepatic fibrosis. This study aimed to investigate the antifibrotic activity of TL in human hepatic stellate LX-2 cells. Results from cell viability and cell death assays showed that the extract at high concentrations was toxic to LX-2 cells. TL extract reversed the transformation of LX-2 cells to myofibroblast-like characteristics in response to stimulation by transforming growth factor-beta 1. This action may be associated with the effect of TL in suppressing α-SMA and collagen-I production observed by immunofluorescence study and western blot analysis. Additionally, TL extract significantly decreased MMP-9 activity which is consistent with the reduction of MMP-9, MMP-2, and TIMP-1 gene expression. The effect of TL in suppressing fibrosis may be associated with its ability to inhibit the activation of p38 MAPK and Erk1/2 kinases as examined by western blot analysis. Our study provides convincing evidence that TL possesses antifibrotic activity which may be through the suppression of TGF-β1-mediated production of MMPs, collagen-1, and α-SMA in hepatic stellate cells.

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Jiang, Yifang, Fengming You, Jie Zhu, Chuan Zheng, Ran Yan, and Jinhao Zeng. "Cryptotanshinone Ameliorates Radiation-Induced Lung Injury in Rats." Evidence-Based Complementary and Alternative Medicine 2019 (February 20, 2019): 1–14. http://dx.doi.org/10.1155/2019/1908416.

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Cryptotanshinone (CTS) was reported to repress a variety of systemic inflammation and alleviate cardiac fibrosis, but it is still unclear whether CTS could prevent radiation-induced lung injury (RILI). Here, we investigated the effects and underlying mechanisms of CTS on a RILI rat model. Our data revealed that CTS could efficiently preserve pulmonary function in RILI rats and reduce early pulmonary inflammation infiltration elicited, along with marked decreased levels of IL-6 and IL-10. Moreover, we found that CTS is superior to prednisone in attenuating collagen deposition and pulmonary fibrosis, in parallel with a marked drop of HYP (a collagen indicator) and α-SMA (a myofibroblast marker). Mechanistically, CTS inhibited profibrotic signals TGF-β1 and NOX-4 expressions, while enhancing the levels of antifibrotic enzyme MMP-1 in lung tissues. It is noteworthy that CTS treatment, in consistent with trichrome staining analysis, exhibited a clear advantage over PND in enhancing MMP-1 levels. However, CTS exhibited little effect on CTGF activation and on COX-2 suppression. Finally, CTS treatment significantly mitigated the radiation-induced activation of CCL3 and its receptor CCR1. In summary, CTS treatment could attenuate RILI, especially pulmonary fibrosis, in rats. The regulation on production and release of inflammatory or fibrotic factors IL-6, IL-10, TGF-β1, NOX-4, and MMP-1, especially MMP-1 and inhibition on CCL3/CCR1 activation, may partly attribute to its attenuating RILI effect.

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Wu, Shi-Bei, Tzu-Yu Hou, Hui-Chuan Kau, and Chieh-Chih Tsai. "Effect of Pirfenidone on TGF-β1-Induced Myofibroblast Differentiation and Extracellular Matrix Homeostasis of Human Orbital Fibroblasts in Graves’ Ophthalmopathy." Biomolecules 11, no. 10 (September 29, 2021): 1424. http://dx.doi.org/10.3390/biom11101424.

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Pirfenidone is a pyridinone derivative that has been shown to inhibit fibrosis in animal models and in patients with idiopathic pulmonary fibrosis. Its effect on orbital fibroblasts remains poorly understood. We investigated the in vitro effect of pirfenidone in transforming growth factor-β1 (TGF-β1)-induced myofibroblast transdifferentiation and extracellular matrix (ECM) homeostasis in primary cultured orbital fibroblasts from patients with Graves’ ophthalmopathy (GO). The expression of fibrotic proteins, including α-smooth muscle actin (α-SMA), connective tissue growth factor (CTGF), fibronectin, and collagen type I, was determined by Western blots. The activities of matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) responsible for the ECM homeostasis were examined. After pretreating the GO orbital fibroblasts with pirfenidone (250, 500, and 750 μg/mL, respectively) for one hour followed by TGF-β1 for another 24 h, the expression of α-SMA, CTGF, fibronectin, and collagen type I decreased in a dose-dependent manner. Pretreating the GO orbital fibroblasts with pirfenidone not only abolished TGF-β1-induced TIMP-1 expression but recovered the MMP-2/-9 activities. Notably, pirfenidone inhibited TGF-β1-induced phosphorylation of p38 and c-Jun N-terminal kinase (JNK), the critical mediators in the TGF-β1 pathways. These findings suggest that pirfenidone modulates TGF-β1-mediated myofibroblast differentiation and ECM homeostasis by attenuating downstream signaling of TGF-β1.

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Cui, Qingbo, Zhigang Wang, Dapeng Jiang, Lihui Qu, Junbin Guo, and Zhaozhu Li. "HGF inhibits TGF-β1-induced myofibroblast differentiation and ECM deposition via MMP-2 in Achilles tendon in rat." European Journal of Applied Physiology 111, no. 7 (December 17, 2010): 1457–63. http://dx.doi.org/10.1007/s00421-010-1764-4.

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Kamel, Marwa, Mohamed Wagih, Gokhan S. Kilic, Concepcion R. Diaz-Arrastia, Mohamed A. Baraka, and Salama A. Salama. "Overhydroxylation of Lysine of Collagen Increases Uterine Fibroids Proliferation: Roles of Lysyl Hydroxylases, Lysyl Oxidases, and Matrix Metalloproteinases." BioMed Research International 2017 (2017): 1–13. http://dx.doi.org/10.1155/2017/5316845.

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The role of the extracellular matrix (ECM) in uterine fibroids (UF) has recently been appreciated. Overhydroxylation of lysine residues and the subsequent formation of hydroxylysylpyridinoline (HP) and lysylpyridinoline (LP) cross-links underlie the ECM stiffness and profoundly affect tumor progression. The aim of the current study was to investigate the relationship between ECM of UF, collagen and collagen cross-linking enzymes [lysyl hydroxylases (LH) and lysyl oxidases (LOX)], and the development and progression of UF. Our results indicated that hydroxyl lysine (Hyl) and HP cross-links are significantly higher in UF compared to the normal myometrial tissues accompanied by increased expression of LH (LH2b) and LOX. Also, increased resistance to matrix metalloproteinases (MMP) proteolytic degradation activity was observed. Furthermore, the extent of collagen cross-links was positively correlated with the expression of myofibroblast marker (α-SMA), growth-promoting markers (PCNA; pERK1/2;FAKpY397; Ki-67; and Cyclin D1), and the size of UF. In conclusion, our study defines the role of overhydroxylation of collagen and collagen cross-linking enzymes in modulating UF cell proliferation, differentiation, and resistance to MMP. These effects can establish microenvironment conducive for UF progression and thus represent potential target treatment options of UF.

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Saika, Shizuya, Osamu Yamanaka, Yuka Okada, Takeshi Miyamoto, Ai Kitano, Kathleen C. Flanders, Yoshitaka Ohnishi, Yuji Nakajima, Winston W. Y. Kao, and Kazuo Ikeda. "Effect of overexpression of pparγ on the healing process of corneal alkali burn in mice." American Journal of Physiology-Cell Physiology 293, no. 1 (July 2007): C75—C86. http://dx.doi.org/10.1152/ajpcell.00332.2006.

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Wound healing involves both local cells and inflammatory cells. Alkali burn of ocular surface tissue is a serious clinical problem often leading to permanent visual impairment resulting from ulceration, scarring and neovascularization during healing. Behaviors of corneal cells and inflammatory cells are orchestrated by growth factor signaling networks that have not been fully uncovered. Here we showed that adenoviral gene introduction of peroxisome proliferator-activated receptor-γ (PPARγ) inhibits activation of ocular fibroblasts and macrophages in vitro and also induced anti-inflammatory and anti-fibrogenic responses in an alkali-burned mouse cornea. PPARγ overexpression suppressed upregulation of inflammation/scarring-related growth factors and matrix metalloproteinases (MMPs) in macrophages. It also suppressed expression of such growth factors and collagen Iα2 and myofibroblast generation upon exposure to TGFβ1. Exogenous PPARγ did not alter phosphorylation of Smad2, but inhibited its nuclear translocation. PPARγ overexpression enhanced proliferation of corneal epithelial cells, but not of fibroblasts in vitro. Epithelial cell expression of MMP-2/-9 and TGFβ1 and its migration were suppressed by PPARγ overexpression. In vivo experiments showed that PPARγ gene introduction suppressed monocytes/macrophages invasion and suppressed the generation of myofibroblasts, as well as upregulation of cytokines/growth factors and MMPs in a healing cornea. In vivo re-epitheliazation with basement membrane reconstruction in the healing, burned, cornea was accelerated by PPARγ-Ad expression, although PPARγ overexpression was considered to be unfavorable for cell migration. Together, these data suggest that overexpression of PPARγ may represent an effective new strategy for treatment of ocular surface burns.

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Arif, Rawa, Maximilian Franz, Anca Remes, Marcin Zaradzki, Markus Hecker, Matthias Karck, Oliver J. Müller, Klaus Kallenbach, and Andreas H. Wagner. "Reduction of Transplant Vasculopathy by Intraoperative Nucleic Acid-based Therapy in a Mouse Aortic Allograft Model." Thoracic and Cardiovascular Surgeon 67, no. 06 (October 23, 2018): 503–12. http://dx.doi.org/10.1055/s-0038-1673633.

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Abstract Background Transplant vasculopathy (TV) is the main limiting factor for long-term graft survival characterized by fibrosis, myofibroblast, and smooth muscle cell (SMC) proliferation. Decoy oligodeoxynucleotide (dODN) against the transcription factor activator protein-1 (AP-1) might interfere with the expression of AV-related genes that govern neointima formation. Methods Aortic allografts from DBA/2 mice were incubated with control buffer, consensus, or mutated control AP-1 dODN and were transplanted into the infrarenal aorta of C57BL/6 mice. Cyclosporine A (10 mg/kg body weight [BW]) was administered daily. Explantation and histomorphometric and immunohistochemical evaluation was performed after 30 days. Matrix metalloproteinase (MMP) activity was visualized by gelatin in situ zymography. Results Intima-to-media (I/M) ratio and neointima formation were significantly reduced in the consensus AP-1 dODN treatment group by 37% (p < 0.05) and 67% (p < 0.01), respectively. SMC α-actin-2 staining and macrophage marker expression revealed a marked reduction in the neointima. I/M ratio was found to correlate with the number of tissue macrophages (p < 0.05). MMP and fibrosis marker expression were not significantly altered. Conclusion Intraoperative AP-1dODN utilization might be a strategy to preserve graft function after transplantation.

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Kölmel, Sebastian, Lukas Hobohm, Anja Käberich, Valentin J. Krieg, Magdalena L. Bochenek, Philip Wenzel, Christoph B. Wiedenroth, et al. "Potential Involvement of Osteopontin in Inflammatory and Fibrotic Processes in Pulmonary Embolism and Chronic Thromboembolic Pulmonary Hypertension." Thrombosis and Haemostasis 119, no. 08 (June 10, 2019): 1332–46. http://dx.doi.org/10.1055/s-0039-1692174.

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Background Inflammation and incomplete thrombus resolution leading to obstructive fibrotic remodelling are considered critical mechanisms for the development of chronic thromboembolic pulmonary hypertension (CTEPH) after pulmonary embolism (PE). Osteopontin (OPN) is involved in a variety of biological processes including inflammation and tissue fibrosis. Methods OPN plasma concentrations were measured in 70 CTEPH and 119 PE patients. Tissue material from 6 CTEPH patients removed during pulmonary endarterectomy and murine venous thrombi induced by subtotal ligation of the inferior vena cava in C57BL/6 mice were analysed by (immuno)histochemistry. Results CTEPH patients had higher OPN plasma concentrations (median, 106.9 [interquartile range, 75.6–155.9]) compared to PE patients (90.4 [53.3–123.9] ng/mL, p = 0.001). OPN- and matrix metalloproteinase (MMP)-9-positive cells were predominantly present in myofibroblast-rich and profibrotic areas of CTEPH tissue material. Early stages of murine thrombus resolution were characterised by high numbers of OPN- and MMP-2-positive cells while OPN was almost absent in fresh thrombi of CTEPH tissue material. PE patients with OPN plasma concentrations of < 55 ng/mL had a 15.2-fold (95% confidence interval, 1.7–135.5, p = 0.015) increased risk for a diagnosis of CTEPH during follow-up. Conclusion The results of the present observational translational study point to a possible involvement of OPN in the pathogenesis of CTEPH by affecting early inflammatory and late fibrotic processes.

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Chang, Xin, Lei Xing, Yi Wang, Chen-Xi Yang, Yu-Jing He, Tian-Jiao Zhou, Xiang-Dong Gao, Ling Li, Hai-Ping Hao, and Hu-Lin Jiang. "Monocyte-derived multipotent cell delivered programmed therapeutics to reverse idiopathic pulmonary fibrosis." Science Advances 6, no. 22 (May 2020): eaba3167. http://dx.doi.org/10.1126/sciadv.aba3167.

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Idiopathic pulmonary fibrosis (IPF) is a highly heterogeneous and fatal disease. However, IPF treatment has been limited by the low drug delivery efficiency to lungs and dysfunctional “injured” type II alveolar epithelial cell (AEC II). Here, we present surface-engineered nanoparticles (PER NPs) loading astaxanthin (AST) and trametinib (TRA) adhered to monocyte-derived multipotent cell (MOMC) forming programmed therapeutics (MOMC/PER). Specifically, the cell surface is designed to backpack plenty of PER NPs that reach directly to the lungs due to the homing characteristic of the MOMC and released PER NPs retarget injured AEC II after responding to the matrix metalloproteinase-2 (MMP-2) in IPF tissues. Then, released AST can enhance synergetic effect of TRA for inhibiting myofibroblast activation, and MOMC can also repair injured AEC II to promote damaged lung regeneration. Our findings provide proof of concept for developing a strategy for cell-mediated lung-targeted delivery platform carrying dual combined therapies to reverse IPF.

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Denton, Christopher P., Gisela E. Lindahl, Korsa Khan, Xu Shiwen, Voon H. Ong, Nicholas J. Gaspar, Konstantinos Lazaridis, et al. "Activation of Key Profibrotic Mechanisms in Transgenic Fibroblasts Expressing Kinase-deficient Type II Transforming Growth Factor-β Receptor (TβRIIΔk)." Journal of Biological Chemistry 280, no. 16 (February 11, 2005): 16053–65. http://dx.doi.org/10.1074/jbc.m413134200.

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We have generated transgenic mice expressing a kinase-deficient type II transforming growth factor-β (TGFβ) receptor selectively on fibroblasts (TβRIIΔk-fib). These mice develop dermal and pulmonary fibrosis. In the present study we explore activation of TGFβ signaling pathways in this strain and examine the profibrotic properties of explanted transgenic fibroblasts including myofibroblast differentiation and abnormal metalloproteinase production. Gene expression profiles of littermate wild type or transgenic fibroblasts were compared using high-density gene arrays and validated by Taqman reverse transcriptase-PCR, Northern and Western blotting. Using a specific inhibitor (SD-208) we demonstrate that the abnormal phenotype of these cells is dependent upon TβRI kinase (ALK5) activity, and that transgenic fibroblasts show enhanced expression and activation of TGFβ together with increased levels of wild type TβRII. Moreover, we confirm that transgene expression is itself regulated by TGFβ and that expression at low levels facilitates signaling, whereas high level expression is inhibitory. For a subset of TGFβ responsive genes basal up-regulation is normalized or suppressed by exogenous recombinant TGFβ1 at time points coincident with increased transgene expression. These findings explain the profound refractoriness of TβRIIΔk-fib fibroblasts to exogenous TGFβ1, despite their activated phenotype. Thus, transgenic fibroblasts recapitulate many hallmark biochemical properties of fibrotic cells, including high level CTGF (CCN2) expression and type I collagen overproduction, altered MMP production, and myofibroblast differentiation. These cells also show an enhanced ability to contract collagen gel matrices. Our study demonstrates that altered high affinity TGFβ receptor function may lead to ligand-dependent activation of downstream signaling, and provides further evidence of a pivotal role for sustained TGFβ overactivity in fibrosis.

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Gabr, Sami A., and Ahmad H. Alghadir. "Evaluation of the Biological Effects of Lyophilized Hydrophilic Extract of Rhus coriaria on Myeloperoxidase (MPO) Activity, Wound Healing, and Microbial Infections of Skin Wound Tissues." Evidence-Based Complementary and Alternative Medicine 2019 (July 14, 2019): 1–14. http://dx.doi.org/10.1155/2019/5861537.

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Impaired wound healing was mainly associated with severe microbial infections which significantly affect diagnostic and therapeutic strategies. Thus, in this study, the potential wound healing activity, anti-inflammatory, and antimicrobial activity of an aqueous extract of Rhus coriaria extract (AERc) were evaluated by wound contraction, scar formation, period of epithelization, MPO enzyme activity, collagenase-2 (MMP-8), hydroxyproline (HPX), and collagen deposition as markers of wound healing at different days of postwound. Phytoconstituents, microbial activity, and fibrogenic markers were screened by HPLC, disc-diffusion, and colorimetric assays. The animals were treated with Rhus coriaria extract (AERc) concentrations at doses of 5 mg.kg−1and 10 mg.kg−1, respectively. On days 6 and 9, the AERc-treated animals at doses of 5 mg.mL−1 and 10 mg.mL−1 exhibited a significant reduction in the wound area, increased deposition of collagen, HPX, and reduction in MMP-8, and MPO enzyme activity when compared with controls. Scar formation and epithelization were completed in 10 days compared to controls. In addition, in wounds infected separately with Staph. aureus or P. aeruginosa, the AERc extract significantly improved wound contraction, deposition of collagen, and HPx and reduced MMP-8 and MPO concentrations, with complete epithelization of wounds in 10-13 days compared to the saline-treated group. Hydrolyzable tannins, gallic acid, quercetin, and myricetin were the most common active components of AERc. In vitro, the AERc and its components were effective against a set of microbes especially Staph. aureus, P. aeruginosa, and Staph. aureus (MRSA). In conclusion, the results showed that antimicrobial, anti-inflammatory, and antioxidant activity of Rhus coriaria extract suggested its importance as a target for formulation of novel drugs against many microbial infections with minimal side effects and could play a good potential role in accelerating wound healing activity via promoting myofibroblast activity, increase of hydroxyproline and collagen deposition, and regulation of MMP-8 and MPO enzyme activities.

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Zhao, Tieqiang, Wenyuan Zhao, Yuanjian Chen, Victoria S. Li, Weixin Meng, and Yao Sun. "Platelet-derived growth factor-D promotes fibrogenesis of cardiac fibroblasts." American Journal of Physiology-Heart and Circulatory Physiology 304, no. 12 (June 15, 2013): H1719—H1726. http://dx.doi.org/10.1152/ajpheart.00130.2013.

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Platelet-derived growth factor (PDGF)-D is a newly recognized member of the PDGF family with its role just now being understood. Our previous study shows that PDGF-D and its receptors (PDGFR-β) are significantly increased in the infarcted heart, where PDGFR-β is primarily expressed by fibroblasts, indicating the involvement of PDGF-D in the development of cardiac fibrosis. In continuing with these findings, the current study explored the molecular basis of PDGF-D on fibrogenesis. Rat cardiac fibroblasts were isolated and treated with PDGF-D (200 ng/ml medium). The potential regulation of PDGF-D on fibroblast growth, phenotype change, collagen turnover, and the transforming growth factor (TGF)-β pathway were explored. We found: 1) PDGF-D significantly elevated cardiac fibroblast proliferation, myofibroblast (myoFb) differentiation, and type I collagen secretion; 2) matrix metalloproteinase (MMP)-1, MMP-2, and MMP-9 protein levels were significantly elevated in PDGF-D-treated cells, which were coincident with increased expressions of tissue inhibitor of metalloproteinase (TIMP)-1 and TIMP-2; 3) PDGF-D significantly enhanced TGF-β1 synthesis, which was eliminated by TGF-β blockade with small-interfering RNA (siRNA); 4) the stimulatory role of PDGF-D on fibroblast proliferation and collagen synthesis was abolished by TGF-β blockade; and 5) TGF-β siRNA treatment significantly suppressed PDGF-D synthesis in fibroblasts. These observations indicate that PDGF-D promotes fibrogenesis through multiple mechanisms. Coelevations of TIMPs and MMPs counterbalance collagen degradation. The profibrogenic role of PDGF-D is mediated through activation of the TGF-β1 pathway. TGF-β1 exerts positive feedback on PDGF-D synthesis. These findings suggest the potential therapeutic effect of PDGFR blockade on interstitial fibrosis in the infarcted heart.

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Takahra, Terumi, David E. Smart, Fiona Oakley, and Derek A. Mann. "Induction of myofibroblast MMP-9 transcription in three-dimensional collagen I gel cultures: regulation by NF-κB, AP-1 and Sp1." International Journal of Biochemistry & Cell Biology 36, no. 2 (February 2004): 353–63. http://dx.doi.org/10.1016/s1357-2725(03)00260-7.

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Buckley, Stephen T., Carlos Medina, Michael Kasper, and Carsten Ehrhardt. "Interplay between RAGE, CD44, and focal adhesion molecules in epithelial-mesenchymal transition of alveolar epithelial cells." American Journal of Physiology-Lung Cellular and Molecular Physiology 300, no. 4 (April 2011): L548—L559. http://dx.doi.org/10.1152/ajplung.00230.2010.

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Fibrosis of the lung is characterized by the accumulation of myofibroblasts, a key mediator in the fibrogenic reaction. Cumulative evidence indicates that epithelial-mesenchymal transition (EMT), a process whereby epithelial cells become mesenchyme-like, is an important contributing source for the myofibroblast population. Underlying this phenotypical change is a dramatic alteration in cellular structure. The receptor for advanced glycation end-products (RAGE) has been suggested to maintain lung homeostasis by mediating cell adhesion, while the family of ezrin/radixin/moesin (ERM) proteins, on the other hand, serve as an important cross-linker between the plasma membrane and cytoskeleton. In the present investigation, we tested the hypothesis that RAGE and ERM interact and play a key role in regulating EMT-associated structural changes in alveolar epithelial cells. Exposure of A549 cells to inflammatory cytokines resulted in phosphorylation and redistribution of ERM to the cell periphery and localization with EMT-related actin stress fibers. Simultaneously, blockade of Rho kinase (ROCK) signaling attenuated these cytokine-induced structural changes. Additionally, RAGE expression was diminished after cytokine stimulation, with release of its soluble isoform via a matrix metalloproteinase (MMP)-9-dependent mechanism. Immunofluorescence microscopy and coimmunoprecipitation revealed association between ERM and RAGE under basal conditions, which was disrupted when challenged with inflammatory cytokines, as ERM in its activated state complexed with membrane-linked CD44. Dual-fluorescence immunohistochemistry of patient idiopathic pulmonary fibrosis (IPF) tissues highlighted marked diminution of RAGE in fibrotic samples, together with enhanced levels of CD44 and double-positive cells for CD44 and phospho (p)ERM. These data suggest that dysregulation of the ERM-RAGE complex might be an important step in rearrangement of the actin cytoskeleton during proinflammatory cytokine-induced EMT of human alveolar epithelial cells.

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Daniel, Laura L., Stephanie L. C. Scofield, Patsy Thrasher, Suman Dalal, Christopher R. Daniels, Cerrone R. Foster, Mahipal Singh, and Krishna Singh. "Ataxia telangiectasia-mutated kinase deficiency exacerbates left ventricular dysfunction and remodeling late after myocardial infarction." American Journal of Physiology-Heart and Circulatory Physiology 311, no. 2 (August 1, 2016): H445—H452. http://dx.doi.org/10.1152/ajpheart.00338.2016.

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Ataxia telangiectasia-mutated kinase (ATM), a cell cycle checkpoint protein, is activated in response to DNA damage and oxidative stress. We have previously shown that ATM deficiency is associated with increased apoptosis and fibrosis and attenuation of cardiac dysfunction early (1–7 days) following myocardial infarction (MI). Here, we tested the hypothesis that enhanced fibrosis and apoptosis, as observed early post-MI during ATM deficiency, exacerbate cardiac dysfunction and remodeling in ATM-deficient mice late post-MI. MIs were induced in wild-type (WT) and ATM heterozygous knockout (hKO) mice by ligation of the left anterior descending artery. Left ventricular (LV) structural and functional parameters were assessed by echocardiography 14 and 28 days post-MI, whereas biochemical parameters were measured 28 days post-MI. hKO-MI mice exhibited exacerbated LV dysfunction as observed by increased LV end-systolic volume and decreased percent fractional shortening and ejection fraction. Infarct size and thickness were not different between the two genotypes. Myocyte cross-sectional area was greater in hKO-MI group. The hKO-MI group exhibited increased fibrosis in the noninfarct and higher expression of α-smooth muscle actin (myofibroblast marker) in the infarct region. Apoptosis and activation of GSK-3β (proapoptotic kinase) were significantly lower in the infarct region of hKO-MI group. Matrix metalloproteinase 2 (MMP-2) expression was not different between the two genotypes. However, MMP-9 expression was significantly lower in the noninfarct region of hKO-MI group. Thus ATM deficiency exacerbates cardiac remodeling late post-MI with effects on cardiac function, fibrosis, apoptosis, and myocyte hypertrophy.

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Devocelle, Aurore, Lola Lecru, Sophie Ferlicot, Thomas Bessede, Jean-Jacques Candelier, Julien Giron-Michel, and Hélène François. "IL-15 Prevents Renal Fibrosis by Inhibiting Collagen Synthesis: A New Pathway in Chronic Kidney Disease?" International Journal of Molecular Sciences 22, no. 21 (October 28, 2021): 11698. http://dx.doi.org/10.3390/ijms222111698.

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Chronic kidney disease (CKD), secondary to renal fibrogenesis, is a public health burden. The activation of interstitial myofibroblasts and excessive production of extracellular matrix (ECM) proteins are major events leading to end-stage kidney disease. Recently, interleukin-15 (IL-15) has been implicated in fibrosis protection in several organs, with little evidence in the kidney. Since endogenous IL-15 expression decreased in nephrectomized human allografts evolving toward fibrosis and kidneys in the unilateral ureteral obstruction (UUO) model, we explored IL-15’s renoprotective role by pharmologically delivering IL-15 coupled or not with its soluble receptor IL-15Rα. Despite the lack of effects on myofibroblast accumulation, both IL-15 treatments prevented tubulointerstitial fibrosis (TIF) in UUO as characterized by reduced collagen and fibronectin deposition. Moreover, IL-15 treatments inhibited collagen and fibronectin secretion by transforming growth factor-β (TGF-β)-treated primary myofibroblast cultures, demonstrating that the antifibrotic effect of IL-15 in UUO acts, in part, through a direct inhibition of ECM synthesis by myofibroblasts. In addition, IL-15 treatments resulted in decreased expression of monocyte chemoattractant protein 1 (MCP-1) and subsequent macrophage infiltration in UUO. Taken together, our study highlights a major role of IL-15 on myofibroblasts and macrophages, two main effector cells in renal fibrosis, demonstrating that IL-15 may represent a new therapeutic option for CKD.

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Lacerda, Carla M. R., John Kisiday, Brennan Johnson, and E. Christopher Orton. "Local serotonin mediates cyclic strain-induced phenotype transformation, matrix degradation, and glycosaminoglycan synthesis in cultured sheep mitral valves." American Journal of Physiology-Heart and Circulatory Physiology 302, no. 10 (May 15, 2012): H1983—H1990. http://dx.doi.org/10.1152/ajpheart.00987.2011.

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This study addressed the following questions: 1) Does cyclic tensile strain induce protein expression patterns consistent with myxomatous degeneration in mitral valves? 2) Does cyclic strain induce local serotonin synthesis in mitral valves? 3) Are cyclic strain-induced myxomatous protein expression patterns in mitral valves dependent on local serotonin? Cultured sheep mitral valve leaflets were subjected to 0, 10, 20, and 30% cyclic strain for 24 and 72 h. Protein levels of activated myofibroblast phenotype markers, α-smooth muscle actin (α-SMA) and nonmuscle embryonic myosin (SMemb); matrix catabolic enzymes, matrix metalloprotease (MMP) 1 and 13, and cathepsin K; and sulfated glycosaminoglycan (GAG) content in mitral valves increased with increased cyclic strain. Serotonin was present in the serum-free media of cultured mitral valves and concentrations increased with cyclic strain. Expression of the serotonin synthetic enzyme tryptophan hydroxylase 1 (TPH1) increased in strained mitral valves. Pharmacologic inhibition of the serotonin 2B/2C receptor or TPH1 diminished expression of phenotype markers (α-SMA and SMemb) and matrix catabolic enzyme (MMP1, MMP13, and cathepsin K) expression in 10- and 30%-strained mitral valves. These results provide first evidence that mitral valves synthesize serotonin locally. The results further demonstrate that tensile loading modulates local serotonin synthesis, expression of effector proteins associated with mitral valve degeneration, and GAG synthesis. Inhibition of serotonin diminishes strain-mediated protein expression patterns. These findings implicate serotonin and tensile loading in mitral degeneration, functionally link the pathogeneses of serotoninergic (carcinoid, drug-induced) and degenerative mitral valve disease, and have therapeutic implications.

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Lee, Jin A., Mi-Rae Shin, and Seong-Soo Roh. "Corni Fructus Alleviates UUO-Induced Renal Fibrosis via TGF-β/Smad Signaling." BioMed Research International 2022 (May 6, 2022): 1–10. http://dx.doi.org/10.1155/2022/5780964.

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Renal fibrosis is a type of chronic kidney disease (CKD) induced by infiltration of inflammatory cells, myofibroblast accumulation, and ECM production in the kidney. From a long time ago, Corni Fructus (CF) is known to supplement the liver and kidney with its tepid properties. In this study, we investigated the renal protective mechanism of CF, which is known to supplement the kidney, in rat model of unilateral ureteral obstruction (UUO). After inducing UUO through surgery, the group was separated ( n = 8 ) and the drug was administered for 2 weeks; normal rats (normal), water-treated UUO rats (control), CF 100 mg/kg-treated UUO rats (CF100), and CF 200 mg/kg-treated UUO rats (CF200). As a result of histopathological examination of kidney tissue with H&E, MT, and PAS staining, it was confirmed that the infiltration of inflammatory cells and the erosion of collagen were relatively decreased in the kidneys treated with CF. Also, CF significantly reduced the levels of MDA and BUN in serum. As a result of confirming the expression of the factors through western blotting, CF treatment significantly reduced the expression of NADPH oxidase and significantly regulated the AMPK/LKB1/NF-κB pathway associated with inflammation. In addition, it downregulated the expression of major fibrotic signaling factors, such as α-SMA, collagen I, MMP-2, and TIMP-1, and significantly regulated the TGF-β1/Smad pathway, which is known as a major regulator of renal fibrosis. Taken together, these findings indicate that CF can alleviate renal fibrosis by regulating the TGF-β1/Smad pathway through inhibition of oxidative stress in UUO.

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Boswell, Bruce A., Anna Korol, Judith A. West-Mays, and Linda S. Musil. "Dual function of TGFβ in lens epithelial cell fate: implications for secondary cataract." Molecular Biology of the Cell 28, no. 7 (April 2017): 907–21. http://dx.doi.org/10.1091/mbc.e16-12-0865.

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The most common vision-disrupting complication of cataract surgery is posterior capsule opacification (PCO; secondary cataract). PCO is caused by residual lens cells undergoing one of two very different cell fates: either transdifferentiating into myofibroblasts or maturing into lens fiber cells. Although TGFβ has been strongly implicated in lens cell fibrosis, the factors responsible for the latter process have not been identified. We show here for the first time that TGFβ can induce purified primary lens epithelial cells within the same culture to undergo differentiation into either lens fiber cells or myofibroblasts. Marker analysis confirmed that the two cell phenotypes were mutually exclusive. Blocking the p38 kinase pathway, either with direct inhibitors of the p38 MAP kinase or a small-molecule therapeutic that also inhibits the activation of p38, prevented TGFβ from inducing epithelial–myofibroblast transition and cell migration but did not prevent fiber cell differentiation. Rapamycin had the converse effect, linking MTOR signaling to induction of fiber cell differentiation by TGFβ. In addition to providing novel potential therapeutic strategies for PCO, our findings extend the so-called TGFβ paradox, in which TGFβ can induce two disparate cell fates, to a new epithelial disease state.

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Lindroos, Pamela M., Annette B. Rice, Yi-Zhe Wang, and James C. Bonner. "Role of Nuclear Factor-κB and Mitogen-Activated Protein Kinase Signaling Pathways in IL-1β-Mediated Induction of α-PDGF Receptor Expression in Rat Pulmonary Myofibroblasts." Journal of Immunology 161, no. 7 (October 1, 1998): 3464–68. http://dx.doi.org/10.4049/jimmunol.161.7.3464.

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Abstract Induction of the α-platelet-derived growth factor receptor (PDGF-Rα) by IL-1β in lung myofibroblasts enhances mitogenic and chemotactic responses to PDGF, and this could be a mechanism of myofibroblast hyperplasia during lung fibrogenesis. Since the regulation of many genes by IL-1β involves activation of NF-κB and mitogen-activated protein (MAP) kinases, we examined these signaling pathways in the control of PDGF-Rα expression by IL-1β in cultured rat lung myofibroblasts. Treatment of cells with pyrrolidine dithiocarbamate (PDTC), an antioxidant that inhibits NF-κB activation, completely blocked PDGF-Rα up-regulation by IL-1β as assayed by [125I]PDGF-AA binding and PDGF-Rα mRNA expression, suggesting a role for NF-κB. However, while IL-1β and TNF-α both induced nuclear binding of the Rel proteins p50 and p65 to an NF-κB consensus oligonucleotide in gel shift assays and caused transient degradation of inhibitor of NF-κB-α (IκB-α) in the cytoplasm of myofibroblasts, only IL-1β up-regulated PDGF-Rα. These results suggest that NF-κB activation alone is not sufficient for up-regulation of PDGF-Rα. An investigation of MAP kinase signaling pathways revealed that IL-1β or PDTC activated extracellular signal-regulated kinase-2 (ERK-2) and c-jun NH2 terminal kinase-1 (JNK-1) phosphorylation of PHAS-1 and c-Jun substrates, respectively. Pretreatment of cells with the MAP kinase kinase-1 (MEK1) inhibitor PD 98059 blocked IL-1β-induced activation of ERK-2 by more than 90% but enhanced IL-1β-stimulated induction of PDGF-Rα expression fourfold. Taken together, these data suggest that IL-1β activates both positive and negative signaling pathways that control the expression of PDGF-Rα. IL-1β appears to mediate its negative effects on PDGF-Rα expression via MAP kinase activation, while the factor(s) that mediate induction of PDGF-Rα remain to be elucidated.

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El-Helou, Viviane, Cindy Proulx, Hugues Gosselin, Robert Clement, Andrea Mimee, Louis Villeneuve, and Angelino Calderone. "Dexamethasone treatment of post-MI rats attenuates sympathetic innervation of the infarct region." Journal of Applied Physiology 104, no. 1 (January 2008): 150–56. http://dx.doi.org/10.1152/japplphysiol.00663.2007.

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Sympathetic fiber innervation of the damaged region following injury represents a conserved event of wound healing. The present study tested the hypothesis that impaired scar healing in post-myocardial infarction (post-MI) rats was associated with a reduction of sympathetic fibers innervating the infarct region. In 1-wk post-MI rats, neurofilament-M-immunoreactive fibers (1,116 ± 250 μm2/mm2) were detected innervating the infarct region and observed in close proximity to a modest number of endothelial nitric oxide synthase-immunoreactive scar-residing vessels. Dexamethasone (Dex) treatment (6 days) of post-MI rats led to a significant reduction of scar weight (Dex + MI 38 ± 4 mg vs. MI 63 ± 2 mg) and a disproportionate nonsignificant decrease of scar surface area (Dex + MI 0.54 ± 0.06 cm2 vs. MI 0.68 ± 0.06 cm2). In Dex-treated post-MI rats, the density of neurofilament-M-immunoreactive fibers (125 ± 47 μm2/mm2) innervating the infarct region was significantly reduced and associated with a decreased expression of nerve growth factor (NGF) mRNA (Dex + MI 0.80 ± 0.07 vs. MI 1.11 ± 0.08; P < 0.05 vs. MI). Previous studies have demonstrated that scar myofibroblasts synthesize NGF and may represent a cellular target of Dex. The exposure of 1st passage scar myofibroblasts to Dex led to a dose-dependent suppression of [3H]thymidine uptake and a concomitant attenuation of NGF mRNA expression (untreated 3.47 ± 0.35 vs. Dex treated 2.28 ± 0.40; P < 0.05 vs. untreated). Thus the present study has demonstrated that impaired scar healing in Dex-treated post-MI rats was associated with a reduction of neurofilament-M-immunoreactive fibers innervating the infarct region. The attenuation of scar myofibroblast proliferation and NGF mRNA expression may represent underlying mechanisms contributing to the diminished neural response in the infarct region of Dex-treated post-MI rats.

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Ottino, Paulo, Jiucheng He, Thomas W. Axelrad, and Haydee E. P. Bazan. "PAF-Induced Furin and MT1-MMP Expression Is Independent of MMP-2 Activation in Corneal Myofibroblasts." Investigative Opthalmology & Visual Science 46, no. 2 (February 1, 2005): 487. http://dx.doi.org/10.1167/iovs.04-0852.

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Inatomi, Osamu, Akira Andoh, Yuhki Yagi, Atsuhiro Ogawa, Kazunori Hata, Hisanori Shiomi, Tohru Tani, Atsushi Takayanagi, Nobuyoshi Shimizu, and Yoshihide Fujiyama. "Matrix metalloproteinase-3 secretion from human pancreatic periacinar myofibroblasts in response to inflammatory mediators." Suizo 22, no. 4 (2007): 513–15. http://dx.doi.org/10.2958/suizo.22.513.

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Journal articles on the topic 'Myofibroblast MMP'

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