Research

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15 pages, 3384 KiB

Open AccessArticle

Chondroitin Sulfate Promotes the Proliferation of Keloid Fibroblasts Through Activation of the Integrin and Protein Kinase B Pathways

by Yasuhiro Katayama, Motoko Naitoh, Hiroshi Kubota, Satoko Yamawaki, Rino Aya, Toshihiro Ishiko and Naoki Morimoto

Int. J. Mol. Sci. 2020, 21(6), 1955; https://doi.org/10.3390/ijms21061955 - 13 Mar 2020

Cited by 9 | Viewed by 2988

Abstract

Keloids are dermal fibroproliferative tumors that arise beyond the boundary of the original wound edges and invades adjacent tissue. Keloids are characterized by the extensive production of extracellular matrix (ECM) and abnormal fibroblast proliferation. Chondroitin sulfate (CS) is one of the major structural [...] Read more.

Keloids are dermal fibroproliferative tumors that arise beyond the boundary of the original wound edges and invades adjacent tissue. Keloids are characterized by the extensive production of extracellular matrix (ECM) and abnormal fibroblast proliferation. Chondroitin sulfate (CS) is one of the major structural components of cartilage and ECM. Recently, we reported the over-accumulation of CS in keloid lesions. Keloid-derived fibroblasts (KFs) and normal dermal fibroblasts (NFs) were incubated with CS. The fibroblast proliferation rate was analyzed using a tetrazolium salt colorimetric assay. The activation of the intracellular signaling pathway was analyzed by Western blotting. Wortmannin, a PI3K inhibitor, and anti-integrin antibodies were tested to investigate the mechanism of the CS-induced cell proliferation. CS strongly stimulated the proliferation of KFs, but not NFs. The analysis of the intracellular signal transduction pathway revealed that the stimulation effect of CS on KF proliferation was due to the activation of the protein kinase B (AKT) pathway and that integrin α1 was responsible for this phenomenon. We revealed that CS probably activates the AKT pathway through integrin to induce KF proliferation. CS may be a novel clinical therapeutic target in keloids. Full article

(This article belongs to the Special Issue Recent Advances in Pathophysiology of Fibrosis and Scarring)

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19 pages, 4829 KiB

Open AccessArticle

Deconvolution of RNA-Seq Analysis of Hyperbaric Oxygen-Treated Mice Lungs Reveals Mesenchymal Cell Subtype Changes

by Yuan Yuan, Yilu Zhou, Yali Li, Charlotte Hill, Rob M. Ewing, Mark G. Jones, Donna E. Davies, Zhenglin Jiang and Yihua Wang

Int. J. Mol. Sci. 2020, 21(4), 1371; https://doi.org/10.3390/ijms21041371 - 18 Feb 2020

Cited by 8 | Viewed by 4232

Abstract

Hyperbaric oxygen (HBO) is widely applied to treat several hypoxia-related diseases. Previous studies have focused on the immediate effect of HBO-exposure induced oxidative stress on the lungs, but knowledge regarding the chronic effects from repetitive HBO exposure is limited, especially at the gene [...] Read more.

Hyperbaric oxygen (HBO) is widely applied to treat several hypoxia-related diseases. Previous studies have focused on the immediate effect of HBO-exposure induced oxidative stress on the lungs, but knowledge regarding the chronic effects from repetitive HBO exposure is limited, especially at the gene expression level. We found that repetitive HBO exposure did not alter the morphology of murine lungs. However, by deconvolution of RNA-seq from those mice lungs using CIBERSORTx and the expression profile matrices of 8 mesenchymal cell subtypes obtained from bleomycin-treated mouse lungs, we identify several mesenchymal cell subtype changes. These include increases in Col13a1 matrix fibroblasts, mesenchymal progenitors and mesothelial cell populations and decreases in lipofibroblasts, endothelial and Pdgfrb high cell populations. Our data suggest that repetitive HBO exposure may affect biological processes in the lungs such as response to wounding, extracellular matrix, vasculature development and immune response. Full article

(This article belongs to the Special Issue Recent Advances in Pathophysiology of Fibrosis and Scarring)

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14 pages, 4619 KiB

Open AccessArticle

Effects of Regorafenib, a Multi-Kinase Inhibitor, on Conjunctival Scarring in a Canine Filtration Surgery Model in Comparison with Mitomycin-C

by Emika Nemoto, Shota Kojima, Tetsuya Sugiyama, Denan Jin, Shinji Takai, Michiko Maeda, Ryohsuke Kohmoto, Mari Ueki, Hidehiro Oku and Tsunehiko Ikeda

Int. J. Mol. Sci. 2020, 21(1), 63; https://doi.org/10.3390/ijms21010063 - 20 Dec 2019

Cited by 3 | Viewed by 2395

Abstract

Regorafenib eye drops were developed for treating age-related macular degeneration. This study aimed to investigate the effects of this multi-kinase inhibitor on intraocular pressure (IOP), bleb formation, and conjunctival changes in a canine filtration surgery model. Glaucoma filtration surgery models were created in [...] Read more.

Regorafenib eye drops were developed for treating age-related macular degeneration. This study aimed to investigate the effects of this multi-kinase inhibitor on intraocular pressure (IOP), bleb formation, and conjunctival changes in a canine filtration surgery model. Glaucoma filtration surgery models were created in 24 eyes of 24 beagles. In experiment 1 (Ex 1), regorafenib eye drops (regorafenib group: n = 6) or a vehicle (control group, n = 6) were instilled twice daily for 4 weeks postoperatively. In experiment 2 (Ex 2), regorafenib eye drops were instilled as in Ex 1 (regorafenib group: n = 6) for 12 weeks while conventional intraoperative mitomycin-C (MMC) was utilized (MMC group: n = 6), In Ex 1, only the regorafenib group showed significant IOP reduction with a significantly higher bleb score. Subconjunctival area, collagen density, vessels, and cells showing proliferation and differentiation were lower in subconjunctival tissue in the regorafenib group. In Ex 2, no significant difference was found in IOP reduction and bleb formation between the regorafenib and MMC groups; bleb walls were significantly thicker and collagen density and vessels were higher in the regorafenib group; and no differences were observed in the above-mentioned cells. Thus, regorafenib might be a better alternative to MMC for creating thicker and less ischemic blebs in glaucoma filtration surgery. Full article

(This article belongs to the Special Issue Recent Advances in Pathophysiology of Fibrosis and Scarring)

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21 pages, 7646 KiB

Open AccessArticle

Thrombin Upregulates PAI-1 and Mesothelial–Mesenchymal Transition Through PAR-1 and Contributes to Tuberculous Pleural Fibrosis

by Cheng-Ying Hsieh, Joen-Rong Sheu, Chih-Hao Yang, Wei-Lin Chen, Jie-Heng Tsai and Chi-Li Chung

Int. J. Mol. Sci. 2019, 20(20), 5076; https://doi.org/10.3390/ijms20205076 - 13 Oct 2019

Cited by 6 | Viewed by 3124

Abstract

Thrombin is an essential procoagulant and profibrotic mediator. However, its implication in tuberculous pleural effusion (TBPE) remains unknown. The effusion thrombin and plasminogen activator inhibitor-1 (PAI-1) levels were measured among transudative pleural effusion (TPE, n = 22) and TBPE (n = 24) [...] Read more.

Thrombin is an essential procoagulant and profibrotic mediator. However, its implication in tuberculous pleural effusion (TBPE) remains unknown. The effusion thrombin and plasminogen activator inhibitor-1 (PAI-1) levels were measured among transudative pleural effusion (TPE, n = 22) and TBPE (n = 24) patients. Pleural fibrosis, identified as radiological residual pleural thickening (RPT) and shadowing, was measured at 12-month follow-up. Moreover, in vivo and in vitro effects of thrombin on PAI-1 expression and mesothelial–mesenchymal transition (MMT) were assessed. We demonstrated the effusion thrombin levels were significantly higher in TBPE than TPE, especially greater in TBPE patients with RPT > 10mm than those without, and correlated positively with PAI-1 and pleural fibrosis area. In carbon black/bleomycin-treated mice, knockdown of protease-activated receptor-1 (PAR-1) markedly downregulated α-smooth muscle actin (α-SMA) and fibronectin, and attenuated pleural fibrosis. In pleural mesothelial cells (PMCs), thrombin concentration-dependently increased PAI-1, α-SMA, and collagen I expression. Specifically, Mycobacterium tuberculosis H37Ra (MTBRa) induced thrombin production by PMCs via upregulating tissue factor and prothrombin, and PAR-1 silencing considerably abrogated MTBRa−stimulated PAI-1 expression and MMT. Consistently, prothrombin/PAR-1 expression was evident in the pleural mesothelium of TBPE patients. Conclusively, thrombin upregulates PAI-1 and MMT and may contribute to tuberculous pleural fibrosis. Thrombin/PAR-1 inhibition may confer potential therapy for pleural fibrosis. Full article

(This article belongs to the Special Issue Recent Advances in Pathophysiology of Fibrosis and Scarring)

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15 pages, 12822 KiB

Open AccessArticle

Antifibrotic Effects of High-Mobility Group Box 1 Protein Inhibitor (Glycyrrhizin) on Keloid Fibroblasts and Keloid Spheroids through Reduction of Autophagy and Induction of Apoptosis

by Yeo Reum Jeon, Hyun Roh, Ji Hyuk Jung, Hyo Min Ahn, Ju Hee Lee, Chae-Ok Yun and Won Jai Lee

Int. J. Mol. Sci. 2019, 20(17), 4134; https://doi.org/10.3390/ijms20174134 - 24 Aug 2019

Cited by 18 | Viewed by 4935

Abstract

Overabundance of extracellular matrix resulting from hyperproliferation of keloid fibroblasts (KFs) and dysregulation of apoptosis represents the main pathophysiology underlying keloids. High-mobility group box 1 (HMGB1) plays important roles in the regulation of cellular death. Suppression of HMGB1 inhibits autophagy while increasing apoptosis. [...] Read more.

Overabundance of extracellular matrix resulting from hyperproliferation of keloid fibroblasts (KFs) and dysregulation of apoptosis represents the main pathophysiology underlying keloids. High-mobility group box 1 (HMGB1) plays important roles in the regulation of cellular death. Suppression of HMGB1 inhibits autophagy while increasing apoptosis. Suppression of HMGB1 with glycyrrhizin has therapeutic benefits in fibrotic diseases. In this study, we explored the possible involvement of autophagy and HMGB1 as a cell death regulator in keloid pathogenesis. We have highlighted the potential utility of glycyrrhizin as an antifibrotic agent via regulation of the aberrant balance between autophagy and apoptosis in keloids. Higher HMGB1 expression and enhanced autophagy were observed in keloids. The proliferation of KFs was decreased following glycyrrhizin treatment. While apoptosis was enhanced in keloids after glycyrrhizin treatment, autophagy was significantly reduced. The expressions of ERK1/2, Akt, and NF-κB, were enhanced in HMGB1-teated fibroblasts, but decreased following glycyrrhizin treatment. The expression of extracellular matrix (ECM) components was reduced in glycyrrhizin-treated keloids. TGF-β, Smad2/3, ERK1/2, and HMGB1 were decreased in glycyrrhizin-treated keloids. Treatment with the autophagy inhibitor 3-MA resulted in a decrease of autophagy markers and collagen in the TGF-β-treated fibroblasts. The results indicated that autophagy plays an important role in the pathogenesis of keloids. Because glycyrrhizin appears to reduce ECM and downregulate autophagy in keloids, its potential use for treatment of keloids is indicated. Full article

(This article belongs to the Special Issue Recent Advances in Pathophysiology of Fibrosis and Scarring)

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12 pages, 2160 KiB

Open AccessArticle

Exogenous Administration of Low-Dose Lipopolysaccharide Potentiates Liver Fibrosis in a Choline-Deficient l-Amino-Acid-Defined Diet-Induced Murine Steatohepatitis Model

by Keisuke Nakanishi, Kosuke Kaji, Mitsuteru Kitade, Takuya Kubo, Masanori Furukawa, Soichiro Saikawa, Naotaka Shimozato, Shinya Sato, Kenichiro Seki, Hideto Kawaratani, Kei Moriya, Tadashi Namisaki and Hitoshi Yoshiji

Int. J. Mol. Sci. 2019, 20(11), 2724; https://doi.org/10.3390/ijms20112724 - 03 Jun 2019

Cited by 18 | Viewed by 4157

Abstract

Various rodent models have been proposed for basic research; however, the pathogenesis of human nonalcoholic steatohepatitis (NASH) is difficult to closely mimic. Lipopolysaccharide (LPS) has been reported to play a pivotal role in fibrosis development during NASH progression via activation of toll-like receptor [...] Read more.

Various rodent models have been proposed for basic research; however, the pathogenesis of human nonalcoholic steatohepatitis (NASH) is difficult to closely mimic. Lipopolysaccharide (LPS) has been reported to play a pivotal role in fibrosis development during NASH progression via activation of toll-like receptor 4 (TLR4) signaling. This study aimed to clarify the impact of low-dose LPS challenge on NASH pathological progression and to establish a novel murine NASH model. C57BL/6J mice were fed a choline-deficient l-amino-acid-defined (CDAA) diet to induce NASH, and low-dose LPS (0.5 mg/kg) was intraperitoneally injected thrice a week. CDAA-fed mice showed hepatic CD14 overexpression, and low-dose LPS challenge enhanced TLR4/NF-κB signaling activation in the liver of CDAA-fed mice. LPS challenge potentiated CDAA-diet-mediated insulin resistance, hepatic steatosis with upregulated lipogenic genes, and F4/80-positive macrophage infiltration with increased proinflammatory cytokines. It is noteworthy that LPS administration extensively boosted pericellular fibrosis with the activation of hepatic stellate cells in CDAA-fed mice. Exogenous LPS administration exacerbated pericellular fibrosis in CDAA-mediated steatohepatitis in mice. These findings suggest a key role for LPS/TLR4 signaling in NASH progression, and the authors therefore propose this as a suitable model to mimic human NASH. Full article

(This article belongs to the Special Issue Recent Advances in Pathophysiology of Fibrosis and Scarring)

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16 pages, 10186 KiB

Open AccessArticle

Effects of Caffeine Treatment on Hepatopulmonary Syndrome in Biliary Cirrhotic Rats

by Ching-Chih Chang, Chiao-Lin Chuang, Ming-Hung Tsai, I.-Fang Hsin, Shao-Jung Hsu, Hui-Chun Huang, Fa-Yauh Lee and Shou-Dong Lee

Int. J. Mol. Sci. 2019, 20(7), 1566; https://doi.org/10.3390/ijms20071566 - 28 Mar 2019

Cited by 6 | Viewed by 3349

Abstract

Hepatopulmonary syndrome (HPS) is a lethal complication of cirrhosis characterized by hypoxia and overt intrapulmonary shunting. In this study, we investigated the effect of caffeine in rats with common bile duct ligation (CBDL)-induced liver cirrhosis and HPS. CBDL rats were randomly allocated to [...] Read more.

Hepatopulmonary syndrome (HPS) is a lethal complication of cirrhosis characterized by hypoxia and overt intrapulmonary shunting. In this study, we investigated the effect of caffeine in rats with common bile duct ligation (CBDL)-induced liver cirrhosis and HPS. CBDL rats were randomly allocated to receive caffeine or vehicle for 14 days. On the 28th day after CBDL, mortality rate, hemodynamics, liver, and renal biochemistry parameters and arterial blood gas analysis were evaluated. Lung and liver were dissected for the evaluation of inflammation, angiogenesis and protein expressions. In another series with parallel groups, the intrapulmonary shunting was determined. Caffeine significantly reduced portal pressure (caffeine vs. control: 10.0 ± 3.7 vs. 17.0 ± 8.1 mmHg, p < 0.05) in CBDL rats. The mortality rate, mean arterial pressure, biochemistry data and hypoxia were similar between caffeine-treated and control groups. Caffeine alleviated liver fibrosis and intrahepatic angiogenesis but intrapulmonary inflammation and angiogenesis were not ameliorated. The hepatic VEGF/Rho-A protein expressions were down-regulated but the pulmonary inflammation- and angiogenesis-related protein expressions were not significantly altered by caffeine. Caffeine did not reduce the intrapulmonary shunting, either. Caffeine has been shown to significantly improve liver fibrosis, intrahepatic angiogenesis and portal hypertension in cirrhotic rats, however, it does not ameliorate HPS. Full article

(This article belongs to the Special Issue Recent Advances in Pathophysiology of Fibrosis and Scarring)

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9 pages, 230 KiB

Open AccessArticle

TM6SF2 and MBOAT7 Gene Variants in Liver Fibrosis and Cirrhosis

by Viktorija Basyte-Bacevice, Jurgita Skieceviciene, Irena Valantiene, Jolanta Sumskiene, Vitalija Petrenkiene, Jurate Kondrackiene, Dalius Petrauskas, Frank Lammert and Juozas Kupcinskas

Int. J. Mol. Sci. 2019, 20(6), 1277; https://doi.org/10.3390/ijms20061277 - 14 Mar 2019

Cited by 32 | Viewed by 3781

Abstract

Previous large-scale genetic studies identified single nucleotide polymorphisms (SNPs) of the TM6SF2 and MBOAT7 genes as risk factors for alcoholic liver cirrhosis and non-alcoholic fatty liver disease. In this study, we tried to evaluate the association between TM6SF2 variant rs58542926 and MBOAT7 variant [...] Read more.

Previous large-scale genetic studies identified single nucleotide polymorphisms (SNPs) of the TM6SF2 and MBOAT7 genes as risk factors for alcoholic liver cirrhosis and non-alcoholic fatty liver disease. In this study, we tried to evaluate the association between TM6SF2 variant rs58542926 and MBOAT7 variant rs641738 and the risk of hepatic fibrosis or liver cirrhosis of different etiology. In parallel, we also aimed to evaluate whether these two SNPs modify the effects of the PNPLA3 rs738409 risk variant for the development of hepatic fibrosis and liver cirrhosis. The study was conducted at the Department of Gastroenterology, Lithuanian University of Health Sciences Hospital, and included 334 patients with liver cirrhosis, 128 patients with liver fibrosis, and 550 controls. SNPs were genotyped by quantitative PCR, using TaqMan allelic discrimination assays. Overall, TM6SF2 rs58542926 as well as MBOAT7 rs641738 were not linked to hepatic fibrosis, alcohol or hepatitis C virus induced liver cirrhosis in an Eastern European population. These genetic variations also did not mediate the effect of PNPLA3 rs738409 SNP for liver developing liver fibrosis or liver cirrhosis. Full article

(This article belongs to the Special Issue Recent Advances in Pathophysiology of Fibrosis and Scarring)

Review

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18 pages, 753 KiB

Open AccessReview

The Vascular Involvement in Soft Tissue Fibrosis—Lessons Learned from Pathological Scarring

by Chenyu Huang and Rei Ogawa

Int. J. Mol. Sci. 2020, 21(7), 2542; https://doi.org/10.3390/ijms21072542 - 06 Apr 2020

Cited by 19 | Viewed by 4123

Abstract

Soft tissue fibrosis in important organs such as the heart, liver, lung, and kidney is a serious pathological process that is characterized by excessive connective tissue deposition. It is the result of chronic but progressive accumulation of fibroblasts and their production of extracellular [...] Read more.

Soft tissue fibrosis in important organs such as the heart, liver, lung, and kidney is a serious pathological process that is characterized by excessive connective tissue deposition. It is the result of chronic but progressive accumulation of fibroblasts and their production of extracellular matrix components such as collagens. Research on pathological scars, namely, hypertrophic scars and keloids, may provide important clues about the mechanisms that drive soft tissue fibrosis, in particular the vascular involvement. This is because these dermal fibrotic lesions bear all of the fibrotic characteristics seen in soft tissue fibrosis. Moreover, their location on the skin surface means they are readily observable and directly treatable and therefore more accessible to research. We will focus here on the roles that blood vessel-associated cells play in cutaneous scar pathology and assess from the literature whether these cells also contribute to other soft tissue fibroses. These cells include endothelial cells, which not only exhibit aberrant functions but also differentiate into mesenchymal cells in pathological scars. They also include pericytes, hepatic stellate cells, fibrocytes, and myofibroblasts. This article will review with broad strokes the roles that these cells play in the pathophysiology of different soft tissue fibroses. We hope that this brief but wide-ranging overview of the vascular involvement in fibrosis pathophysiology will aid research into the mechanisms underlying fibrosis and that this will eventually lead to the development of interventions that can prevent, reduce, or even reverse fibrosis formation and/or progression. Full article

(This article belongs to the Special Issue Recent Advances in Pathophysiology of Fibrosis and Scarring)

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28 pages, 876 KiB

Open AccessReview

Current Approaches Targeting the Wound Healing Phases to Attenuate Fibrosis and Scarring

by Amina El Ayadi, Jayson W. Jay and Anesh Prasai

Int. J. Mol. Sci. 2020, 21(3), 1105; https://doi.org/10.3390/ijms21031105 - 07 Feb 2020

Cited by 109 | Viewed by 12446

Abstract

Cutaneous fibrosis results from suboptimal wound healing following significant tissue injury such as severe burns, trauma, and major surgeries. Pathologic skin fibrosis results in scars that are disfiguring, limit normal movement, and prevent patient recovery and reintegration into society. While various therapeutic strategies [...] Read more.

Cutaneous fibrosis results from suboptimal wound healing following significant tissue injury such as severe burns, trauma, and major surgeries. Pathologic skin fibrosis results in scars that are disfiguring, limit normal movement, and prevent patient recovery and reintegration into society. While various therapeutic strategies have been used to accelerate wound healing and decrease the incidence of scarring, recent studies have targeted the molecular regulators of each phase of wound healing, including the inflammatory, proliferative, and remodeling phases. Here, we reviewed the most recent literature elucidating molecular pathways that can be targeted to reduce fibrosis with a particular focus on post-burn scarring. Current research targeting inflammatory mediators, the epithelial to mesenchymal transition, and regulators of myofibroblast differentiation shows promising results. However, a multimodal approach addressing all three phases of wound healing may provide the best therapeutic outcome. Full article

(This article belongs to the Special Issue Recent Advances in Pathophysiology of Fibrosis and Scarring)

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16 pages, 1230 KiB

Open AccessReview

Scars or Regeneration?—Dermal Fibroblasts as Drivers of Diverse Skin Wound Responses

by Dongsheng Jiang and Yuval Rinkevich

Int. J. Mol. Sci. 2020, 21(2), 617; https://doi.org/10.3390/ijms21020617 - 17 Jan 2020

Cited by 76 | Viewed by 8483

Abstract

Scarring and regeneration are two physiologically opposite endpoints to skin injuries, with mammals, including humans, typically healing wounds with fibrotic scars. We aim to provide an updated review on fibroblast heterogeneity as determinants of the scarring–regeneration continuum. We discuss fibroblast-centric mechanisms that dictate [...] Read more.

Scarring and regeneration are two physiologically opposite endpoints to skin injuries, with mammals, including humans, typically healing wounds with fibrotic scars. We aim to provide an updated review on fibroblast heterogeneity as determinants of the scarring–regeneration continuum. We discuss fibroblast-centric mechanisms that dictate scarring–regeneration continua with a focus on intercellular and cell–matrix adhesion. Improved understanding of fibroblast lineage-specific mechanisms and how they determine scar severity will ultimately allow for the development of antiscarring therapies and the promotion of tissue regeneration. Full article

(This article belongs to the Special Issue Recent Advances in Pathophysiology of Fibrosis and Scarring)

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21 pages, 592 KiB

Open AccessReview

Encapsulating Peritoneal Sclerosis: Pathophysiology and Current Treatment Options

by Rajesh M. Jagirdar, Andreas Bozikas, Sotirios G. Zarogiannis, Maria Bartosova, Claus Peter Schmitt and Vassilios Liakopoulos

Int. J. Mol. Sci. 2019, 20(22), 5765; https://doi.org/10.3390/ijms20225765 - 16 Nov 2019

Cited by 53 | Viewed by 7778

Abstract

Encapsulating peritoneal sclerosis (EPS) is a life-threatening complication of long-term peritoneal dialysis (PD), which may even occur after patients have switched to hemodialysis (HD) or undergone kidney transplantation. The incidence of EPS varies across the globe and increases with PD vintage. Causative factors [...] Read more.

Encapsulating peritoneal sclerosis (EPS) is a life-threatening complication of long-term peritoneal dialysis (PD), which may even occur after patients have switched to hemodialysis (HD) or undergone kidney transplantation. The incidence of EPS varies across the globe and increases with PD vintage. Causative factors are the chronic exposure to bioincompatible PD solutions, which cause long-term modifications of the peritoneum, a high peritoneal transporter status involving high glucose concentrations, peritonitis episodes, and smoldering peritoneal inflammation. Additional potential causes are predisposing genetic factors and some medications. Clinical symptoms comprise signs of intestinal obstruction and a high peritoneal transporter status with incipient ultrafiltration failure. In radiological, macro-, and microscopic studies, a massively fibrotic and calcified peritoneum enclosed the intestine and parietal wall in such cases. Empirical treatments commonly used are corticosteroids and tamoxifen, which has fibrinolytic properties. Immunosuppressants like azathioprine, mycophenolate mofetil, or mTOR inhibitors may also help with reducing inflammation, fibrin deposition, and collagen synthesis and maturation. In animal studies, N-acetylcysteine, colchicine, rosiglitazone, thalidomide, and renin-angiotensin system (RAS) inhibitors yielded promising results. Surgical treatment has mainly been performed in severe cases of intestinal obstruction, with varying results. Mortality rates are still 25–55% in adults and about 14% in children. To reduce the incidence of EPS and improve the outcome of this devastating complication of chronic PD, vigorous consideration of the risk factors, early diagnosis, and timely discontinuation of PD and therapeutic interventions are mandatory, even though these are merely based on empirical evidence. Full article

(This article belongs to the Special Issue Recent Advances in Pathophysiology of Fibrosis and Scarring)

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11 pages, 638 KiB

Open AccessReview

Gas6/TAM System: A Key Modulator of the Interplay between Inflammation and Fibrosis

by Mattia Bellan, Micol Giulia Cittone, Stelvio Tonello, Cristina Rigamonti, Luigi Mario Castello, Francesco Gavelli, Mario Pirisi and Pier Paolo Sainaghi

Int. J. Mol. Sci. 2019, 20(20), 5070; https://doi.org/10.3390/ijms20205070 - 12 Oct 2019

Cited by 41 | Viewed by 5001

Abstract

Fibrosis is the result of an overly abundant deposition of extracellular matrix (ECM) due to the fact of repetitive tissue injuries and/or dysregulation of the repair process. Fibrogenesis is a pathogenetic phenomenon which is involved in different chronic human diseases, accounting for a [...] Read more.

Fibrosis is the result of an overly abundant deposition of extracellular matrix (ECM) due to the fact of repetitive tissue injuries and/or dysregulation of the repair process. Fibrogenesis is a pathogenetic phenomenon which is involved in different chronic human diseases, accounting for a high burden of morbidity and mortality. Despite being triggered by different causative factors, fibrogenesis follows common pathways, the knowledge of which is, however, still unsatisfactory. This represents a significant limit for the development of effective antifibrotic drugs. In the present paper, we aimed to review the current evidence regarding the potential role played in fibrogenesis by growth arrest-specific 6 (Gas6) and its receptors Tyro3 protein tyrosine kinase (Tyro3), Axl receptor tyrosine kinase (Axl), and Mer tyrosine kinase protooncogene (MerTK) (TAM). Moreover, we aimed to review data about the pathogenetic role of this system in the development of different human diseases characterized by fibrosis. Finally, we aimed to explore the potential implications of these findings in diagnosis and treatment. Full article

(This article belongs to the Special Issue Recent Advances in Pathophysiology of Fibrosis and Scarring)

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18 pages, 584 KiB

Open AccessReview

Pathophysiology of Fibrosis in the Vocal Fold: Current Research, Future Treatment Strategies, and Obstacles to Restoring Vocal Fold Pliability

by Yoshihiko Kumai

Int. J. Mol. Sci. 2019, 20(10), 2551; https://doi.org/10.3390/ijms20102551 - 24 May 2019

Cited by 42 | Viewed by 4756

Abstract

Communication by voice depends on symmetrical vibrations within the vocal folds (VFs) and is indispensable for various occupations. VF scarring is one of the main reasons for permanent dysphonia and results from injury to the unique layered structure of the VFs. The increased [...] Read more.

Communication by voice depends on symmetrical vibrations within the vocal folds (VFs) and is indispensable for various occupations. VF scarring is one of the main reasons for permanent dysphonia and results from injury to the unique layered structure of the VFs. The increased collagen and decreased hyaluronic acid within VF scars lead to a loss of pliability of the VFs and significantly decreases their capacity to vibrate. As there is currently no definitive treatment for VF scarring, regenerative medicine and tissue engineering have become increasingly important research areas within otolaryngology. Several recent reviews have described the problem of VF scarring and various possible solutions, including tissue engineered cells and tissues, biomaterial implants, stem cells, growth factors, anti-inflammatory cytokines antifibrotic agents. Despite considerable research progress, these technical advances have not been established as routine clinical procedures. This review focuses on emerging techniques for restoring VF pliability using various approaches. We discuss our studies on interactions among adipose-derived stem/stromal cells, antifibrotic agents, and VF fibroblasts using an in vitro model. We also identify some obstacles to advances in research. Full article

(This article belongs to the Special Issue Recent Advances in Pathophysiology of Fibrosis and Scarring)

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12 pages, 1046 KiB

Open AccessReview

LOXL2—A New Target in Antifibrogenic Therapy?

by Angela Puente, Jose Ignacio Fortea, Joaquin Cabezas, Maria Teresa Arias Loste, Paula Iruzubieta, Susana Llerena, Patricia Huelin, Emilio Fábrega and Javier Crespo

Int. J. Mol. Sci. 2019, 20(7), 1634; https://doi.org/10.3390/ijms20071634 - 02 Apr 2019

Cited by 46 | Viewed by 5489

Abstract

The concept of liver fibrosis and cirrhosis being static and therefore irreversible is outdated. Indeed, both human and animal studies have shown that fibrogenesis is a dynamic and potentially reversible process that can be modulated either by stopping its progression and/or by promoting [...] Read more.

The concept of liver fibrosis and cirrhosis being static and therefore irreversible is outdated. Indeed, both human and animal studies have shown that fibrogenesis is a dynamic and potentially reversible process that can be modulated either by stopping its progression and/or by promoting its resolution. Therefore, the study of the molecular mechanisms involved in the pathogenesis of liver fibrosis is critical for the development of future antifibrotic therapies. The fibrogenesis process, common to all forms of liver injury, is characterized by the increased deposition of extracellular matrix components (EMCs), including collagen, proteoglycans, and glycoproteins (laminin and fibronectin 2). These changes in the composition of the extracellular matrix components alter their interaction with cell adhesion molecules, influencing the modulation of cell functions (growth, migration, and gene expression). Hepatic stellate cells and Kupffer cells (liver macrophages) are the key fibrogenic effectors. The antifibrogenic mechanism starts with the activation of Ly6C^high macrophages, which can differentiate into macrophages with antifibrogenic action. The research of biochemical changes affecting fibrosis irreversibility has identified lysyl oxidase-like 2 (LOXL2), an enzyme that promotes the network of collagen fibers of the extracellular matrix. LOXL2 inhibition can decrease cell numbers, proliferation, colony formations, and cell growth, and it can induce cell cycle arrest and increase apoptosis. The development of a new humanized IgG4 monoclonal antibody against LOXL2 could open the window of a new antifibrogenic treatment. The current therapeutic target in patients with liver cirrhosis should focus (after the eradication of the causal agent) on the development of new antifibrogenic drugs. The development of these drugs must meet three premises: Patient safety, in non-cirrhotic phases, down-staging or at least stabilization and slowing the progression to cirrhosis must be achieved; whereas in the cirrhotic stage, the objective should be to reduce fibrosis and portal pressure. Full article

(This article belongs to the Special Issue Recent Advances in Pathophysiology of Fibrosis and Scarring)

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