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1
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Ramos C, Gerakopoulos V, Oehler R. Metastasis-associated fibroblasts in peritoneal surface malignancies. Br J Cancer 2024; 131:407-419. [PMID: 38783165 PMCID: PMC11300623 DOI: 10.1038/s41416-024-02717-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2024] [Revised: 05/06/2024] [Accepted: 05/09/2024] [Indexed: 05/25/2024] Open
Abstract
Over decades, peritoneal surface malignancies (PSMs) have been associated with limited treatment options and poor prognosis. However, advancements in perioperative systemic chemotherapy, cytoreductive surgery (CRS), and hyperthermic intraperitoneal chemotherapy (HIPEC) have significantly improved clinical outcomes. PSMs predominantly result from the spread of intra-abdominal neoplasia, which then form secondary peritoneal metastases. Colorectal, ovarian, and gastric cancers are the most common contributors. Despite diverse primary origins, the uniqueness of the peritoneum microenvironment shapes the common features of PSMs. Peritoneal metastization involves complex interactions between tumour cells and the peritoneal microenvironment. Fibroblasts play a crucial role, contributing to tumour development, progression, and therapy resistance. Peritoneal metastasis-associated fibroblasts (MAFs) in PSMs exhibit high heterogeneity. Single-cell RNA sequencing technology has revealed that immune-regulatory cancer-associated fibroblasts (iCAFs) seem to be the most prevalent subtype in PSMs. In addition, other major subtypes as myofibroblastic CAFs (myCAFs) and matrix CAFs (mCAFs) were frequently observed across PSMs studies. Peritoneal MAFs are suggested to originate from mesothelial cells, submesothelial fibroblasts, pericytes, endothelial cells, and omental-resident cells. This plasticity and heterogeneity of CAFs contribute to the complex microenvironment in PSMs, impacting treatment responses. Understanding these interactions is crucial for developing targeted and local therapies to improve PSMs patient outcomes.
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Affiliation(s)
- Cristiano Ramos
- Department of General Surgery, Division of Visceral Surgery, Medical University of Vienna, Vienna, Austria
| | - Vasileios Gerakopoulos
- Department of General Surgery, Division of Visceral Surgery, Medical University of Vienna, Vienna, Austria
| | - Rudolf Oehler
- Department of General Surgery, Division of Visceral Surgery, Medical University of Vienna, Vienna, Austria.
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2
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Chaturvedi S, Singh H, Agarwal V, Jaiswal A, Prasad N. Unravelling the role of Sildenafil and SB204741 in suppressing fibrotic potential of peritoneal fibroblasts obtained from PD patients. Front Pharmacol 2024; 14:1279330. [PMID: 38322704 PMCID: PMC10844479 DOI: 10.3389/fphar.2023.1279330] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2023] [Accepted: 12/20/2023] [Indexed: 02/08/2024] Open
Abstract
Introduction: Peritoneal fibrosis (PF) results in technique failure in peritoneal dialysis (PD) patients. Peritoneal fibroblasts are characterized by increase in the ACTA2 gene, responsible for alpha smooth muscle actin (α-SΜΑ), extracellular matrix (ECM) production, and inflammatory cytokines production, which are the are key mediators in the pathogenesis of PF. 5-hydroxytryptamine (5-HT; serotonin) induces ECM synthesis in fibroblasts in a transforming growth factor-beta 1 (TGF-β1) dependent manner. The purpose of our study was to identify the potential mechanism and role of sildenafil and 5HT2B receptor inhibitor (SB204741) combination in attenuating PD-associated peritoneal fibrosis. Methods: Studies were performed to determine the effect of TGF-β1, sildenafil, and SB204741 on human peritoneal fibroblasts (HPFBs) isolated from the parietal peritoneum of patients in long-term PD patients (n = 6) and controls (n = 6). HPFBs were incubated with TGF-β1 (10 ng/mL) for 1 h and later with TGF-β1 (10 ng/mL)/[sildenafil (10 µM) or SB204741 (1 µM)] and their combination for 24 h (post-treatment strategy). In the pre-treatment strategy, HPFBs were pre-treated with sildenafil (10 µM) or SB204741 (1 µM) and a combination of the two for 1 h and later with only TGF-β1 (10 ng/mL) for 24 h. Results: The anti-fibrotic effects of the combination of sildenafil and SB204741 were greater than that of each drug alone. In TGF-β1-stimulated HPFBs, pro-fibrotic genes (COL1A1, COL1A2, ACTA2, CTGF, FN1, and TGFB1) exhibited higher expression than in controls, which are crucial targets of sildenafil and SB204741 against peritoneal fibrosis. The synergistic approach played an anti-fibrotic role by regulating the pro- and anti-fibrotic gene responses as well as inflammatory cytokine responses. The combination treatment significantly attenuated peritoneal fibrosis, as evident by the almost complete amelioration of ACTA2 expression, restoration of anti-fibrotic genes (MMP2/TIMP1), and, at least, by reducing the expression of pro-inflammatory cytokines (IFN-γ, IL-4, IL-17, IL-1β, IL-6, TNF-α, and TGF-β1) along with an increase in IL-10 levels. Discussion: Taken together, the above research evidences that the combination of sildenafil and SB204741 may have therapeutic potential in suppressing peritoneal fibrosis due to peritoneal dialysis.
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Affiliation(s)
- Saurabh Chaturvedi
- Department of Clinical Immunology and Rheumatology, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, Uttar Pradesh, India
- Department of Medical Laboratory Technology, School of Allied Health Sciences, Delhi Pharmaceutical Sciences and Research University, New Delhi, India
| | - Harshit Singh
- Department of Clinical Immunology and Rheumatology, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, Uttar Pradesh, India
- Immuno Biology Lab, Translational Health Science and Technology Institute, Faridabad, Haryana, India
| | - Vikas Agarwal
- Department of Clinical Immunology and Rheumatology, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, Uttar Pradesh, India
| | - Akhilesh Jaiswal
- Department of Nephrology and Renal Transplantation, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, Uttar Pradesh, India
| | - Narayan Prasad
- Department of Nephrology and Renal Transplantation, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, Uttar Pradesh, India
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Sharma S, Pande G, Rai MK, Agarwal V. Indigenous Primary Culture Protocols for Human Adult Skin Fibroblast, Pancreatic Stellate Cells, and Peritoneal Fibroblasts. INDIAN JOURNAL OF RHEUMATOLOGY 2021; 16:298-303. [DOI: 10.4103/injr.injr_160_20] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Affiliation(s)
| | - Gaurav Pande
- Departments of Medical Gastroenterology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, Uttar Pradesh, India
| | - Mohit Kumar Rai
- Departments of Clinical Immunology and Rheumatology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, Uttar Pradesh, India
- Both authors contributed equally to this work
| | - Vikas Agarwal
- Departments of Clinical Immunology and Rheumatology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, Uttar Pradesh, India
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Shi Y, Hu Y, Cui B, Zhuang S, Liu N. Vascular endothelial growth factor-mediated peritoneal neoangiogenesis in peritoneal dialysis. Perit Dial Int 2021; 42:25-38. [PMID: 33823711 DOI: 10.1177/08968608211004683] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
Peritoneal dialysis (PD) is an important renal replacement therapy for patients with end-stage renal diseases, which is limited by peritoneal neoangiogenesis leading to ultrafiltration failure (UFF). Vascular endothelial growth factor (VEGF) and its receptors are key angiogenic factors involved in almost every step of peritoneal neoangiogenesis. Impaired mesothelial cells are the major sources of VEGF in the peritoneum. The expression of VEGF will be up-regulated in specific pathological conditions in PD patients, such as with non-biocompatible peritoneal dialysate, uremia and inflammation, and so on. Other working cells (i.e. vascular endothelial cells, macrophages and adipocytes) can also stimulate the secretion of VEGF. Meanwhile, hypoxia and activation of complement system further aggravate peritoneal injury and contribute to neoangiogenesis. There are several signalling pathways participating in VEGF-mediated peritoneal neoangiogenesis including tumour growth factor-β, Wnt/β-catenin, Notch and interleukin-6/signal transducer and activator of transcription 3. Moreover, VEGF is highly expressed in dialysate effluent of long-term PD patients and is associated with peritoneal transport function, which supports its role in the alteration of peritoneal structure and function. In this review, we systematically summarize the angiogenic effect of VEGF and evaluate it as a potential target for the prevention of peritoneal neoangiogenesis and UFF. Preservation of the peritoneal membrane using targeted therapy of VEGF-mediated peritoneal neoangiogenesis may increase the longevity of the PD modality for those who require life-long dialysis.
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Affiliation(s)
- Yingfeng Shi
- Department of Nephrology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China
| | - Yan Hu
- Department of Nephrology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China
| | - Binbin Cui
- Department of Nephrology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China
| | - Shougang Zhuang
- Department of Nephrology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China.,Department of Medicine, Rhode Island Hospital and Alpert Medical School, Brown University, Providence, RI, USA
| | - Na Liu
- Department of Nephrology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China
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5
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Wang J, Wang Y, Lou Y, Cui W, Zhang Y, Dong W, Sun J, Miao L. Effect of aquaporin 1 on mouse peritoneal mesothelial cells after a long-term peritoneal dialysis. Ther Apher Dial 2021; 25:88-96. [PMID: 32311233 DOI: 10.1111/1744-9987.13504] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2019] [Revised: 04/03/2020] [Accepted: 04/16/2020] [Indexed: 12/01/2022]
Abstract
Aquaporin 1 (AQP1) is one member of the aquaporin family, also the deeply studied one. It is widely located on the endothelial cells, but the effect of AQP1 on the peritoneal mesothelial cells (PMCs) after long-term peritoneal dialysis (PD) has not been reported before. We divided normal mice into two groups, control group and dialysis group, to confirm the fibrotic changes and expression of APQ1 on peritoneal mesothelial cells. Then we assigned normal mice and AQP1 knockout mice into four groups: Control group, normal dialysis group, AQP1 knockout control group and AQP1 knockout dialysis group. The two dialysis groups received 4.25% glucose dialysis for 28 days. We found that mice in both dialysis groups showed peritoneal fibrotic changes, which were most severe in the AQP1 knockout dialysis group; the peritoneal thickness in the AQP1 knockout dialysis group was also thicker than that in the dialysis group (P < .05). We used electron microscopy to detect ultrastructural changes and observed changes in microvilli and vacuolar degeneration in mesothelial cells from all groups except the control group. The basement membranes were damaged in the AQP1 knockout dialysis group, and peritoneal mesothelial cells were disrupted and detached in this group. Together our findings indicate that AQP1 plays an important role in maintaining the physiological functions of peritoneal mesothelial cells, and AQP1 can protect mesothelial cells during dialysis.
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Affiliation(s)
- Ji Wang
- Department of Pediatrics, Second Hospital of Jilin University, Changchun, China
| | - Yangwei Wang
- Department of Nephrology, Second Hospital of Jilin University, Changchun, China
| | - Yan Lou
- Department of Nephrology, Second Hospital of Jilin University, Changchun, China
| | - Wenpeng Cui
- Department of Nephrology, Second Hospital of Jilin University, Changchun, China
| | - Yunfeng Zhang
- Department of Pediatrics, Second Hospital of Jilin University, Changchun, China
| | - Wenpeng Dong
- Department of Hemodialysis Center, Daqing Oilfield General Hospital, Daqing, Heilongjiang, China
| | - Jing Sun
- Department of Nephrology, Second Hospital of Jilin University, Changchun, China
| | - Lining Miao
- Department of Nephrology, Second Hospital of Jilin University, Changchun, China
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6
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Miao C, Xue X, Dai L, Zhao R, Zhao Z, Song H, Jin H, Li S, Xue Z. The calcium concentration of peritoneal dialysis solution modifies levels of key mediators of peritoneal fibrosis. Semin Dial 2021; 34:51-56. [PMID: 33029812 PMCID: PMC7891347 DOI: 10.1111/sdi.12916] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
BACKGROUND To explore the effects of different calcium concentrations of peritoneal dialysis solution (PDS) on continuous ambulatory peritoneal dialysis (CAPD) and expression of vimentin (VIM), fibroblast-specific protein (FSP1), and E-cadherin. MATERIALS AND METHODS This was a pilot study (#ChiCTR1900021387) conducted from January 2017 to December 2019 at the Hospital. The patients were randomized to undergo CAPD using PDS with a calcium concentration of 1.25 mmol/L (low concentration group) or 1.75 mmol/L (high concentration group). Changes in biochemistry before dialysis and at 6 and 12 months were analyzed. RESULTS There were 50 and 52 participants in the low and high calcium groups. The blood biochemical indexes were all different between the two groups (all Ptime < .05, Pgroup < .05, Pinteraction < .05), but they remained within their normal ranges. VIM and FSP1 increased over 12 months (Ptime < .05); VIM and FSP1 levels in the high concentration group were higher than in the low concentration group (Pgroup < .05, Pinteraction < .05), while E-cadherin showed the inverse association (Ptime < .001, Pgroup < .001, Pinteraction < .001). There was no difference in complications (P = .973). CONCLUSION The calcium concentration in PDS might be an important factor affecting the progression of peritoneal fibrosis.
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Affiliation(s)
- Chusheng Miao
- Department of NephrologyRui'an People's HospitalRui'an CityZhejiang ProvinceChina
| | | | - Li Dai
- Department of NephrologyRui'an People's HospitalRui'an CityZhejiang ProvinceChina
| | - Ruiyu Zhao
- Department of NephrologyRui'an People's HospitalRui'an CityZhejiang ProvinceChina
| | - Zhangjian Zhao
- Department of NephrologyRui'an People's HospitalRui'an CityZhejiang ProvinceChina
| | - Hanlei Song
- Department of NephrologyRui'an People's HospitalRui'an CityZhejiang ProvinceChina
| | - Huanlin Jin
- Department of NephrologyRui'an People's HospitalRui'an CityZhejiang ProvinceChina
| | - Shanshan Li
- Department of NephrologyRui'an People's HospitalRui'an CityZhejiang ProvinceChina
| | - Zengqi Xue
- Department of NephrologyRui'an People's HospitalRui'an CityZhejiang ProvinceChina
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7
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Stahnke T, Gajda-Deryło B, Jünemann AG, Stachs O, Sterenczak KA, Rejdak R, Beck J, Schütz E, Möller S, Barrantes I, Warsow G, Struckmann S, Fuellen G. Suppression of the TGF-β pathway by a macrolide antibiotic decreases fibrotic responses by ocular fibroblasts in vitro. ROYAL SOCIETY OPEN SCIENCE 2020; 7:200441. [PMID: 33047019 PMCID: PMC7540802 DOI: 10.1098/rsos.200441] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/19/2020] [Accepted: 08/19/2020] [Indexed: 05/12/2023]
Abstract
To elucidate and to inhibit post-surgical fibrotic processes after trabeculectomy in glaucoma therapy, we measured gene expression in a fibrotic cell culture model, based on transforming growth factor TGF-β induction in primary human tenon fibroblasts (hTFs), and used Connectivity Map (CMap) data for drug repositioning. We found that specific molecular mechanisms behind fibrosis are the upregulation of actins, the downregulation of CD34, and the upregulation of inflammatory cytokines such as IL6, IL11 and BMP6. The macrolide antibiotic Josamycin (JM) reverses these molecular mechanisms according to data from the CMap, and we thus tested JM as an inhibitor of fibrosis. JM was first tested for its toxic effects on hTFs, where it showed no influence on cell viability, but inhibited hTF proliferation in a concentration-dependent manner. We then demonstrated that JM suppresses the synthesis of extracellular matrix (ECM) components. In hTFs stimulated with TGF-β1, JM specifically inhibited α-smooth muslce actin expression, suggesting that it inhibits the transformation of fibroblasts into fibrotic myofibroblasts. In addition, a decrease of components of the ECM such as fibronectin, which is involved in in vivo scarring, was observed. We conclude that JM may be a promising candidate for the treatment of fibrosis after glaucoma filtration surgery or drainage device implantation in vivo.
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Affiliation(s)
- Thomas Stahnke
- Department of Ophthalmology, Rostock University Medical Center, Rostock, Germany
| | - Beata Gajda-Deryło
- Institute for Biostatistics and Informatics in Medicine and Ageing Research, Rostock University Medical Center, Rostock, Germany
| | - Anselm G. Jünemann
- Department of Ophthalmology, Rostock University Medical Center, Rostock, Germany
| | - Oliver Stachs
- Department of Ophthalmology, Rostock University Medical Center, Rostock, Germany
| | | | - Robert Rejdak
- Department of General Ophthalmology, Medical University in Lublin, Poland
| | - Julia Beck
- Chronix Biomedical GmbH, Göttingen, Germany
| | | | - Steffen Möller
- Institute for Biostatistics and Informatics in Medicine and Ageing Research, Rostock University Medical Center, Rostock, Germany
| | - Israel Barrantes
- Institute for Biostatistics and Informatics in Medicine and Ageing Research, Rostock University Medical Center, Rostock, Germany
| | - Gregor Warsow
- Institute for Biostatistics and Informatics in Medicine and Ageing Research, Rostock University Medical Center, Rostock, Germany
| | - Stephan Struckmann
- Institute for Biostatistics and Informatics in Medicine and Ageing Research, Rostock University Medical Center, Rostock, Germany
- SHIP-KEF, Institute for Community Medicine, Greifswald University Medical Center, Greifswald, Germany
- Authors for correspondence: Stephan Struckmann e-mail:
| | - Georg Fuellen
- Institute for Biostatistics and Informatics in Medicine and Ageing Research, Rostock University Medical Center, Rostock, Germany
- Authors for correspondence: Georg Fuellen e-mail:
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8
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Kang DH. Loosening of the mesothelial barrier as an early therapeutic target to preserve peritoneal function in peritoneal dialysis. Kidney Res Clin Pract 2020; 39:136-144. [PMID: 32576713 PMCID: PMC7321674 DOI: 10.23876/j.krcp.20.052] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2020] [Revised: 05/08/2020] [Accepted: 05/11/2020] [Indexed: 12/21/2022] Open
Abstract
Phenotype transition of peritoneal mesothelial cells (MCs) including the epithelial-to-mesenchymal transition (EMT) is regarded as an early mechanism of peritoneal dysfunction and fibrosis in peritoneal dialysis (PD), producing proinflammatory and pro-fibrotic milieu in the intra-peritoneal cavity. Loosening of intercellular tight adhesion between adjacent MCs as an initial process of EMT creates the environment where mesothelium and submesothelial tissue are more vulnerable to the composition of bio-incompatible dialysates, reactive oxygen species, and inflammatory cytokines. In addition, down-regulation of epithelial cell markers such as E-cadherin facilitates de novo acquisition of mesenchymal phenotypes in MCs and production of extracellular matrices. Major mechanisms underlying the EMT of MCs include induction of oxidative stress, pro-inflammatory cytokines, endoplasmic reticulum stress and activation of the local renin-angiotensin system. Another mechanism of peritoneal EMT is mitigation of intrinsic defense mechanisms such as the peritoneal antioxidant system and anti-fibrotic peptide production in the peritoneal cavity. In addition to use of less bio-incompatible dialysates and optimum treatment of peritonitis in PD, therapies to prevent or alleviate peritoneal EMT have demonstrated a favorable effect on peritoneal function and structure, suggesting that EMT can be an early interventional target to preserve peritoneal integrity.
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Affiliation(s)
- Duk-Hee Kang
- Division of Nephrology, Department of Internal Medicine, Ewha Womans University School of Medicine, Ewha Medical Research Center, Seoul, Republic of Korea
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Souza MR, Ibelli AMG, Savoldi IR, Cantão ME, Peixoto JDO, Mores MAZ, Lopes JS, Coutinho LL, Ledur MC. Transcriptome analysis identifies genes involved with the development of umbilical hernias in pigs. PLoS One 2020; 15:e0232542. [PMID: 32379844 PMCID: PMC7205231 DOI: 10.1371/journal.pone.0232542] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2019] [Accepted: 04/16/2020] [Indexed: 02/06/2023] Open
Abstract
Umbilical hernia (UH) is one of the most frequent defects affecting pig production, however, it also affects humans and other mammals. UH is characterized as an abnormal protrusion of the abdominal contents to the umbilical region, causing pain, discomfort and reduced performance in pigs. Some genomic regions associated to UH have already been identified, however, no study involving RNA sequencing was performed when umbilical tissue is considered. Therefore, here, we have sequenced the umbilical ring transcriptome of five normal and five UH-affected pigs to uncover genes and pathways involved with UH development. A total of 13,216 transcripts were expressed in the umbilical ring tissue. From those, 230 genes were differentially expressed (DE) between normal and UH-affected pigs (FDR <0.05), being 145 downregulated and 85 upregulated in the affected compared to the normal pigs. A total of 68 significant biological processes were identified and the most relevant were extracellular matrix, immune system, anatomical development, cell adhesion, membrane components, receptor activation, calcium binding and immune synapse. The results pointed out ACAN, MMPs, COLs, EPYC, VIT, CCBE1 and LGALS3 as strong candidates to trigger umbilical hernias in pigs since they act in the extracellular matrix remodeling and in the production, integrity and resistance of the collagen. We have generated the first transcriptome of the pig umbilical ring tissue, which allowed the identification of genes that had not yet been related to umbilical hernias in pigs. Nevertheless, further studies are needed to identify the causal mutations, SNPs and CNVs in these genes to improve our understanding of the mechanisms of gene regulation.
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Affiliation(s)
- Mayla Regina Souza
- Programa de Pós-graduação em Zootecnia, Centro de Educação Superior do Oeste, Universidade do Estado de Santa Catarina, UDESC, Chapecó, Santa Catarina, Brazil
| | | | - Igor Ricardo Savoldi
- Programa de Pós-graduação em Zootecnia, Centro de Educação Superior do Oeste, Universidade do Estado de Santa Catarina, UDESC, Chapecó, Santa Catarina, Brazil
| | | | | | | | | | - Luiz Lehmann Coutinho
- Laboratório de Biotecnologia Animal, Escola Superior de Agricultura “Luiz de Queiroz”, Universidade de São Paulo, Piracicaba, São Paulo, Brazil
| | - Mônica Corrêa Ledur
- Programa de Pós-graduação em Zootecnia, Centro de Educação Superior do Oeste, Universidade do Estado de Santa Catarina, UDESC, Chapecó, Santa Catarina, Brazil
- Embrapa Suínos e Aves, Concórdia, Santa Catarina, Brazil
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10
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Fung WWS, Poon PYK, Ng JKC, Kwong VWK, Pang WF, Kwan BCH, Cheng PMS, Li PKT, Szeto CC. Longitudinal Changes of NF-κB Downstream Mediators and Peritoneal Transport Characteristics in Incident Peritoneal Dialysis Patients. Sci Rep 2020; 10:6440. [PMID: 32296091 PMCID: PMC7160129 DOI: 10.1038/s41598-020-63258-3] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2019] [Accepted: 03/26/2020] [Indexed: 11/09/2022] Open
Abstract
The role of intra-peritoneal mediators in the regulation peritoneal transport is not completely understood. We investigate the relation between longitudinal changes in dialysis effluent level of nuclear factor kappa-B (NF-κB) downstream mediators and the change in peritoneal transport over 1 year. We studied 46 incident PD patients. Their peritoneal transport characteristics were determined after starting PD and then one year later. Concomitant dialysis effluent levels of interleukin-6 (IL-6), cyclo-oxygenase-2 (COX-2) and hepatocyte growth factor (HGF) are determined. There were significant correlations between baseline and one-year dialysis effluent IL-6 and COX-2 levels with the corresponding dialysate-to-plasma creatinine level at 4 hours (D/P4) and mass transfer area coefficient of creatinine (MTAC). After one year, patients who had peritonitis had higher dialysis effluent IL-6 (26.6 ± 17.4 vs 15.1 ± 12.3 pg/ml, p = 0.037) and COX-2 levels (4.97 ± 6.25 vs 1.60 ± 1.53 ng/ml, p = 0.007) than those without peritonitis, and the number of peritonitis episode significantly correlated with the IL-6 and COX-2 levels after one year. In contrast, dialysis effluent HGF level did not correlate with peritoneal transport. There was no difference in any mediator level between patients receiving conventional and low glucose degradation product solutions. Dialysis effluent IL-6 and COX-2 levels correlate with the concomitant D/P4 and MTAC of creatinine. IL-6 and COX-2 may contribute to the short-term regulation of peritoneal transport.
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Affiliation(s)
- Winston Wing-Shing Fung
- Carol and Richard Yu Peritoneal Dialysis Research Centre, Department of Medicine & Therapeutics, Prince of Wales Hospital, The Chinese University of Hong Kong, Shatin, Hong Kong, China
| | - Peter Yam-Kau Poon
- Carol and Richard Yu Peritoneal Dialysis Research Centre, Department of Medicine & Therapeutics, Prince of Wales Hospital, The Chinese University of Hong Kong, Shatin, Hong Kong, China.,Li Ka Shing Institute of Health Sciences (LiHS), Faculty of Medicine, The Chinese University of Hong Kong, Shatin, Hong Kong, China
| | - Jack Kit-Chung Ng
- Carol and Richard Yu Peritoneal Dialysis Research Centre, Department of Medicine & Therapeutics, Prince of Wales Hospital, The Chinese University of Hong Kong, Shatin, Hong Kong, China
| | - Vickie Wai-Ki Kwong
- Carol and Richard Yu Peritoneal Dialysis Research Centre, Department of Medicine & Therapeutics, Prince of Wales Hospital, The Chinese University of Hong Kong, Shatin, Hong Kong, China
| | - Wing-Fai Pang
- Carol and Richard Yu Peritoneal Dialysis Research Centre, Department of Medicine & Therapeutics, Prince of Wales Hospital, The Chinese University of Hong Kong, Shatin, Hong Kong, China
| | - Bonnie Ching-Ha Kwan
- Carol and Richard Yu Peritoneal Dialysis Research Centre, Department of Medicine & Therapeutics, Prince of Wales Hospital, The Chinese University of Hong Kong, Shatin, Hong Kong, China.,Li Ka Shing Institute of Health Sciences (LiHS), Faculty of Medicine, The Chinese University of Hong Kong, Shatin, Hong Kong, China
| | - Phyllis Mei-Shan Cheng
- Carol and Richard Yu Peritoneal Dialysis Research Centre, Department of Medicine & Therapeutics, Prince of Wales Hospital, The Chinese University of Hong Kong, Shatin, Hong Kong, China.,Li Ka Shing Institute of Health Sciences (LiHS), Faculty of Medicine, The Chinese University of Hong Kong, Shatin, Hong Kong, China
| | - Philip Kam-Tao Li
- Carol and Richard Yu Peritoneal Dialysis Research Centre, Department of Medicine & Therapeutics, Prince of Wales Hospital, The Chinese University of Hong Kong, Shatin, Hong Kong, China
| | - Cheuk-Chun Szeto
- Carol and Richard Yu Peritoneal Dialysis Research Centre, Department of Medicine & Therapeutics, Prince of Wales Hospital, The Chinese University of Hong Kong, Shatin, Hong Kong, China. .,Li Ka Shing Institute of Health Sciences (LiHS), Faculty of Medicine, The Chinese University of Hong Kong, Shatin, Hong Kong, China.
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11
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Abstract
Several conditions in the peritoneal membrane of peritoneal dialysis (PD) patients promote the accumulation of advanced glycation end-products (AGEs), that is, the uremic state, exposure to high glucose concentrations, and exposure to glucose degradation products (GDPs). AGEs exert some of their biologic actions through binding with a cell surface receptor, termed RAGE. Interaction of AGEs with RAGE induces sustained cellular activation, including the production of the fibrogenic growth factor, transforming growth factor-beta (TGF-β). TGF-β is pivotal in the process of epithelial-to-mesenchymal transition, through which cells of epithelial origin acquire myofibroblastic characteristics. Myofibroblasts are involved in virtually all conditions of pathological fibrosis. Submesothelial fibrosis is an important feature in peritoneal biopsies of PD patients, especially of those with clinical problems. We therefore examined the role of RAGE in peritoneal fibrosis, in an animal model of uremia, of high glucose exposure, and of peritoneal dialysate exposure. All three models were characterized by accumulation of AGEs, upregulation of RAGE, and fibrosis. Antagonism of RAGE prevented the upregulation of TGF-β and fibrosis in the peritoneal membrane. We further examined the underlying mechanism of peritoneal fibrosis in the uremic model. Prominent myofibroblast transdifferentiation of mesothelial cells was identified by co-localization of cytokeratin and α-smooth muscle actin in submesothelial and interstitial fibrotic tissue. Antagonism of RAGE prevented conversion of mesothelial cells to myofibroblasts in uremia. In conclusion, we hypothesize that accumulation of AGEs in the peritoneal membrane, as a consequence of the uremic environment, chronic exposure to high glucose, and exposure to GDPs, results in an increased expression of RAGE. The interaction of AGEs with RAGE induces peritoneal fibrosis by virtue of upregulation of TGF-β and subsequent conversion of mesothelial cells into myofibroblasts.
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Affiliation(s)
- An S. De Vriese
- Renal Unit, University Hospital Gent, and AZ Sint-Jan AV Brugge, Belgium
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12
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Selgas R, Bajo MA, Cirugeda A, Del Peso G, Valdés J, Castro MJ, Sánchez S, Fernández–Reyes MJ, Hevia C, Gil F, Aguilera A, Ortiz J, Alegre L, Álvarez V, Sánchez–Tomero JA. Ultrafiltration and Small Solute Transport at Initiation of PD: Questioning the Paradigm of Peritoneal Function. Perit Dial Int 2020. [DOI: 10.1177/089686080502500113] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022] Open
Abstract
Background Human peritoneal function on commencing peritoneal dialysis (PD) is not yet adequately understood. The objective of this study was to determine peritoneal functional patterns on commencing PD. Methods 367 end-stage renal disease (ESRD) patients on PD for the first time were studied between their initial second to sixth weeks on PD. Urea and creatinine mass transfer area coefficients (MTAC) and standardized ultrafiltration (UF) capacity were determined. Results Mean parametric values were MTAC urea 22.9 ± 7.04 mL/min, MTAC creatinine 10.31 ± 4.68 mL/min, and UF 896 ± 344 mL. Gender, patient size, and diabetes or kidney disease did not affect these parameters. The relationship between values of MTAC creatinine and UF reached statistical significance, although with a low value for Pearson's coefficient ( r=–0.30, p = 0.001). Age showed a significant inverse linear correlation with UF capacity ( r = –0.15, p = 0.003) and MTAC urea ( r = –0.11, p < 0.05). Logistic regression analysis demonstrated that UF below 400 mL was independently related to a high MTAC creatinine and older age. Diabetes was least frequent in patients with the lowest UF. However, in the analysis of MTAC creatinine quintiles, UF values did not follow the expected inverse pattern. The lack of differences in UF between the second and third to fourth MTAC creatinine quintiles is remarkable; MTAC creatinine ranged from 6.71 to 13.54. Conclusions The functional characteristics of human peritoneum varied markedly and there was a less intense than expected relationship between solute and water transports. This mild inverse relationship is intriguing and suggestive of the necessity of redefining some basic concepts. Age was associated with a lower peritoneal UF capacity, in part independently of small solute transport.
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Affiliation(s)
- Rafael Selgas
- Hospital Universitario La Princesa and Hospital Universitario La Paz, “Grupo de Estudios Peritoneales de Madrid” del Instituto Reina Sofía de Investigación Nefrológica (FRIAT), Madrid, Spain
| | - M. Auxiliadora Bajo
- Hospital Universitario La Princesa and Hospital Universitario La Paz, “Grupo de Estudios Peritoneales de Madrid” del Instituto Reina Sofía de Investigación Nefrológica (FRIAT), Madrid, Spain
| | - Antonio Cirugeda
- Hospital Universitario La Princesa and Hospital Universitario La Paz, “Grupo de Estudios Peritoneales de Madrid” del Instituto Reina Sofía de Investigación Nefrológica (FRIAT), Madrid, Spain
| | - Gloria Del Peso
- Hospital Universitario La Princesa and Hospital Universitario La Paz, “Grupo de Estudios Peritoneales de Madrid” del Instituto Reina Sofía de Investigación Nefrológica (FRIAT), Madrid, Spain
| | - Jorge Valdés
- Hospital Universitario La Princesa and Hospital Universitario La Paz, “Grupo de Estudios Peritoneales de Madrid” del Instituto Reina Sofía de Investigación Nefrológica (FRIAT), Madrid, Spain
| | - M. José Castro
- Hospital Universitario La Princesa and Hospital Universitario La Paz, “Grupo de Estudios Peritoneales de Madrid” del Instituto Reina Sofía de Investigación Nefrológica (FRIAT), Madrid, Spain
| | - Sonia Sánchez
- Hospital Universitario La Princesa and Hospital Universitario La Paz, “Grupo de Estudios Peritoneales de Madrid” del Instituto Reina Sofía de Investigación Nefrológica (FRIAT), Madrid, Spain
| | - M. José Fernández–Reyes
- Hospital Universitario La Princesa and Hospital Universitario La Paz, “Grupo de Estudios Peritoneales de Madrid” del Instituto Reina Sofía de Investigación Nefrológica (FRIAT), Madrid, Spain
| | - Covadonga Hevia
- Hospital Universitario La Princesa and Hospital Universitario La Paz, “Grupo de Estudios Peritoneales de Madrid” del Instituto Reina Sofía de Investigación Nefrológica (FRIAT), Madrid, Spain
| | - Fernando Gil
- Hospital Universitario La Princesa and Hospital Universitario La Paz, “Grupo de Estudios Peritoneales de Madrid” del Instituto Reina Sofía de Investigación Nefrológica (FRIAT), Madrid, Spain
| | - Abelardo Aguilera
- Hospital Universitario La Princesa and Hospital Universitario La Paz, “Grupo de Estudios Peritoneales de Madrid” del Instituto Reina Sofía de Investigación Nefrológica (FRIAT), Madrid, Spain
| | - Javier Ortiz
- Hospital Universitario La Princesa and Hospital Universitario La Paz, “Grupo de Estudios Peritoneales de Madrid” del Instituto Reina Sofía de Investigación Nefrológica (FRIAT), Madrid, Spain
| | - Laura Alegre
- Hospital Universitario La Princesa and Hospital Universitario La Paz, “Grupo de Estudios Peritoneales de Madrid” del Instituto Reina Sofía de Investigación Nefrológica (FRIAT), Madrid, Spain
| | - Vicente Álvarez
- Hospital Universitario La Princesa and Hospital Universitario La Paz, “Grupo de Estudios Peritoneales de Madrid” del Instituto Reina Sofía de Investigación Nefrológica (FRIAT), Madrid, Spain
| | - J. Antonio Sánchez–Tomero
- Hospital Universitario La Princesa and Hospital Universitario La Paz, “Grupo de Estudios Peritoneales de Madrid” del Instituto Reina Sofía de Investigación Nefrológica (FRIAT), Madrid, Spain
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13
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López-Cabrera M, Aguilera A, Aroeira LS, Ramírez-Huesca M, Pérez-Lozano ML, Jiménez-Heffernan JA, Bajo MA, Peso del G, Sánchez-Tomero JA, Selgas R. Ex Vivo Analysis of Dialysis Effluent-Derived Mesothelial Cells as an Approach to Unveiling the Mechanism of Peritoneal Membrane Failure. Perit Dial Int 2020. [DOI: 10.1177/089686080602600103] [Citation(s) in RCA: 50] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
During peritoneal dialysis (PD), the peritoneum is exposed to bioincompatible dialysis fluids, which causes progressive fibrosis and angiogenesis and, ultimately, ultrafiltration failure. In addition, repeated episodes of peritonitis or hemoperitoneum may accelerate all these processes. Fibrosis has been classically considered the main cause of peritoneal membrane functional decline. However, in parallel with fibrosis, the peritoneum also displays increases in capillary number (angiogenesis) and vasculopathy in response to PD. Nowadays, there is emerging evidence pointing to peritoneal microvasculature as the main factor responsible for increased solute transport and ultrafiltration failure. However, the pathophysiologic mechanism(s) involved in starting and maintaining peritoneal fibrosis and angiogenesis remain(s) elusive. Peritoneal stromal fibroblasts have been considered (for many years) the cell type mainly involved in structural and functional alterations of the peritoneum; whereas mesothelial cells have been considered mere victims of peritoneal injury caused by PD. Recently, ex vivo cultures of effluent-derived mesothelial cells, in conjunction with immunohistochemical analysis of peritoneal biopsies from PD patients, have identified mesothelial cells as culprits, at least in part, in peritoneal membrane deterioration. This review discusses recent findings that suggest new peritoneal myofibroblastic cells may arise from local conversion of mesothelial cells by epithelial-to-mesenchymal transition during the repair responses that take place in PD. The transdifferentiated mesothelial cells may retain a permanent mesenchymal state, as long as initiating stimuli persist, and contribute to PD-induced fibrosis and angiogenesis, and hence to membrane failure. Future therapeutic interventions could be designated in order to prevent or reverse epithelial-to-mesenchymal transition of mesothelial cells, or its pernicious effects.
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Affiliation(s)
| | - Abelardo Aguilera
- Unidad de Biología Molecular, Hospital Universitario de la Princesa, Madrid
| | - Luiz S. Aroeira
- Unidad de Biología Molecular, Hospital Universitario de la Princesa, Madrid
| | | | | | | | | | | | | | - Rafael Selgas
- Servicio de Nefrología, Hospital Universitario La Paz
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14
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Li D, Lu Z, Li X, Xu Z, Jiang J, Zheng Z, Jia J, Lin S, Yan T. Human umbilical cord mesenchymal stem cells facilitate the up-regulation of miR-153-3p, whereby attenuating MGO-induced peritoneal fibrosis in rats. J Cell Mol Med 2018; 22:3452-3463. [PMID: 29654659 PMCID: PMC6010808 DOI: 10.1111/jcmm.13622] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2018] [Accepted: 03/03/2018] [Indexed: 12/16/2022] Open
Abstract
MiRNAs contribute greatly to epithelial to mesenchymal transition (EMT) of peritoneal mesothelial cells (PMCs), which is a crucial step in peritoneal fibrosis (PF). In this study, we tried to profile whether miRNA expression differences exist after human umbilical cord mesenchymal stem cells (hUCMSCs) treatment in PF rats and investigate the possible role of miR‐153‐3p involved in anti‐EMT process. We randomly assigned 34 rats into three groups: control group (Group Control), MGO‐induced PF rats (Group MGO) and hUCMSCs‐treated rats (Group MGO + hUCMSCs). MiRNA microarrays and real‐time PCR analyses were conducted in three groups. α‐SMA, Snail1 and E‐cadherin expression were detected by Western blot. Luciferase reporter assays were used to detect the effects of miR‐153‐3p overexpression on Snai1 in rat peritoneal mesothelial cells (RPMCs). We identified differentially expressed miRNAs related to EMT, in which miR‐153‐3p demonstrated the greatest increase in Group MGO + hUCMSCs. Transient cotransfection of miR‐153‐3p mimics with luciferase expression plasmids resulted in a significant repression of Snai1 3′‐untranslated region luciferase activity in RPMCs. These studies suggest that miR‐153‐3p is a critical molecule in anti‐EMT effects of hUCMSCs in MGO‐induced PF rats. MiR‐153‐3p might exert its beneficial effect through directly targeting Snai1.
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Affiliation(s)
- Dong Li
- Department of Nephrology, General Hospital of Tianjin Medical University, Tianjin, China
| | - Zhenyu Lu
- Tianjin Precell Biotechnology Co., Ltd., Huayuan Industrial District, Tianjin, China
| | - Xiyuan Li
- Precision Medical Center, General Hospital of Tianjin Medical University, Tianjin, China
| | - Zhongwei Xu
- Central Laboratory, Logistics University of the Chinese People's Armed Police Force, Tianjin, China
| | - Jianqing Jiang
- Department of Nephrology, General Hospital of Tianjin Medical University, Tianjin, China
| | - Zhenfeng Zheng
- Department of Nephrology, General Hospital of Tianjin Medical University, Tianjin, China
| | - Junya Jia
- Department of Nephrology, General Hospital of Tianjin Medical University, Tianjin, China
| | - Shan Lin
- Department of Nephrology, General Hospital of Tianjin Medical University, Tianjin, China
| | - Tiekun Yan
- Department of Nephrology, General Hospital of Tianjin Medical University, Tianjin, China
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15
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Wang Q, Yang X, Xu Y, Shen Z, Cheng H, Cheng F, Liu X, Wang R. RhoA/Rho-kinase triggers epithelial-mesenchymal transition in mesothelial cells and contributes to the pathogenesis of dialysis-related peritoneal fibrosis. Oncotarget 2018; 9:14397-14412. [PMID: 29581852 PMCID: PMC5865678 DOI: 10.18632/oncotarget.24208] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2017] [Accepted: 12/05/2017] [Indexed: 12/22/2022] Open
Abstract
Peritoneal fibrosis (PF) with associated peritoneal dysfunction is almost invariably observed in long-term peritoneal dialysis (PD) patients. Advanced glycation end products (AGEs) are pro-oxidant compounds produced in excess during the metabolism of glucose and are present in high levels in standard PD solutions. The GTPase RhoA has been implicated in PF, but its specific role remains poorly understood. Here, we studied the effects of RhoA/Rho-kinase signaling in AGEs-induced epithelial-mesenchymal transition (EMT) in human peritoneal mesothelial cells (HPMCs), and evaluated morphological and molecular changes in a rat model of PD-related PF. Activation of RhoA/Rho-kinase and activating protein-1 (AP-1) was assessed in HPMCs using pull-down and electrophoretic mobility shift assays, respectively, while expression of transforming growth factor-β, fibronectin, α-smooth muscle actin, vimentin, N-cadherin, and E-cadherin expression was assessed using immunohistochemistry and western blot. AGEs exposure activated Rho/Rho-kinase in HPMCs and upregulated EMT-related genes via AP-1. These changes were prevented by the Rho-kinase inhibitors fasudil and Y-27632, and by the AP-1 inhibitor curcumin. Importantly, fasudil normalized histopathological and molecular alterations and preserved peritoneal function in rats. These data support the therapeutic potential of Rho-kinase inhibitors in PD-related PF.
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Affiliation(s)
- Qinglian Wang
- Department of Nephrology, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, China
| | - Xiaowei Yang
- Department of Nephrology, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, China
| | - Ying Xu
- Department of Nephrology, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, China
| | - Zhenwei Shen
- Department of Biostatistics, School of Public Health, Shandong University, Jinan, China
| | - Hongxia Cheng
- Department of Pathology, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, China
| | - Fajuan Cheng
- Department of Nephrology, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, China
| | - Xiang Liu
- Department of Nephrology, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, China
| | - Rong Wang
- Department of Nephrology, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, China
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16
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Herrick SE, Mutsaers SE. The Potential of Mesothelial Cells in Tissue Engineering and Regenerative Medicine Applications. Int J Artif Organs 2018; 30:527-40. [PMID: 17628854 DOI: 10.1177/039139880703000611] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
Injury to the serosa through injurious agents such as radiation, surgery, infection and disease results in the loss of the protective surface mesothelium and often leads to fibrous adhesion formation. Mechanisms that increase the rate of mesothialisation are therefore actively being investigated in order to reduce the formation of adhesions. These include intraperitoneal delivery of cultured mesothelial cells as well as administration of factors that are known to increase mesothelial proliferation and migration. An exciting alternative that has only recently received attention, is the possible role of mesothelial progenitor cells in the repair and regeneration of denuded serosal areas. Accumulating evidence suggests that such a population exists and under certain conditions is able to form a number of defined cell types indicating a degree of plasticity. Such properties may explain the extensive use of mesothelial cells in various tissue engineering applications including the development of vascular conduits and peripheral nerve replacements. It is likely that with the rapid explosion in the fields of tissue engineering and regenerative medicine, a greater understanding of the potential of mesothelial progenitor cells to repair, replace and possibly regenerate damaged or defective tissue will be uncovered.
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Affiliation(s)
- S E Herrick
- School of Medicine, Faculty of Medical and Human Sciences, University of Manchester, Oxford Road, Manchester, UK.
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17
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Biomarker research to improve clinical outcomes of peritoneal dialysis: consensus of the European Training and Research in Peritoneal Dialysis (EuTRiPD) network. Kidney Int 2017; 92:824-835. [PMID: 28797473 DOI: 10.1016/j.kint.2017.02.037] [Citation(s) in RCA: 39] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2016] [Revised: 02/16/2017] [Accepted: 02/27/2017] [Indexed: 12/15/2022]
Abstract
Peritoneal dialysis (PD) therapy substantially requires biomarkers as tools to identify patients who are at the highest risk for PD-related complications and to guide personalized interventions that may improve clinical outcome in the individual patient. In this consensus article, members of the European Training and Research in Peritoneal Dialysis Network (EuTRiPD) review the current status of biomarker research in PD and suggest a selection of biomarkers that can be relevant to the care of PD patients and that are directly accessible in PD effluents. Currently used biomarkers such as interleukin-6, interleukin-8, ex vivo-stimulated interleukin-6 release, cancer antigen-125, and advanced oxidation protein products that were collected through a Delphi procedure were first triaged for inclusion as surrogate endpoints in a clinical trial. Next, novel biomarkers were selected as promising candidates for proof-of-concept studies and were differentiated into inflammation signatures (including interleukin-17, M1/M2 macrophages, and regulatory T cell/T helper 17), mesothelial-to-mesenchymal transition signatures (including microRNA-21 and microRNA-31), and signatures for senescence and inadequate cellular stress responses. Finally, the need for defining pathogen-specific immune fingerprints and phenotype-associated molecular signatures utilizing effluents from the clinical cohorts of PD patients and "omics" technologies and bioinformatics-biostatistics in future joint-research efforts was expressed. Biomarker research in PD offers the potential to develop valuable tools for improving patient management. However, for all biomarkers discussed in this consensus article, the association of biological rationales with relevant clinical outcomes remains to be rigorously validated in adequately powered, prospective, independent clinical studies.
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18
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Kawka E, Witowski J, Bartosova M, Catar R, Rudolf A, Philippe A, Rutkowski R, Schäfer B, Schmitt CP, Dragun D, Jörres A. Thy-1 +/- fibroblast subsets in the human peritoneum. Am J Physiol Renal Physiol 2017; 313:F1116-F1123. [PMID: 28724609 DOI: 10.1152/ajprenal.00274.2017] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2017] [Revised: 07/17/2017] [Accepted: 07/17/2017] [Indexed: 01/13/2023] Open
Abstract
Fibrotic thickening of the peritoneum develops in patients receiving peritoneal dialysis (PD) for renal failure. For unknown reasons, however, in some patients it progresses to extensive fibrosis that compromises dialysis capacity of the peritoneum. It is increasingly clear that fibroblasts display large heterogeneity not only between but also within tissues. Differential surface expression of thymocyte differentiation antigen 1 (Thy-1) has been shown to identify functionally distinct fibroblast subsets in several organs. Here, we isolated Thy-1+/- subsets of human peritoneal fibroblasts (HPFB) and analyzed them in terms of profibrotic myofibroblast features. In healthy individuals, Thy-1+ cells constituted ~45% of the HPFB population found in the greater omentum but were not detected in the parietal peritoneum. When propagated in culture and compared with Thy-1- cells, omentum-derived Thy-1+ HPFB consistently displayed an increased expression of α-smooth muscle actin, collagen I, and transforming growth factor-β1. They also showed greater proliferation capacity and enhanced contractile properties. The number of Thy-1+ HPFB increased significantly in PD patients and made up more than 70 and 95% of all HPFB found in the omentum and parietal peritoneum, respectively. These data indicate that the expansion of Thy-1+ fibroblasts may contribute to fibrotic thickening of the peritoneal membrane during PD.
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Affiliation(s)
- Edyta Kawka
- Department of Nephrology and Medical Intensive Care, Charité-Universitätsmedizin Berlin, Campus Virchow-Klinikum, Berlin, Germany
| | - Janusz Witowski
- Department of Nephrology and Medical Intensive Care, Charité-Universitätsmedizin Berlin, Campus Virchow-Klinikum, Berlin, Germany.,Department of Pathophysiology, Poznan University of Medical Sciences, Poznań, Poland
| | - Maria Bartosova
- Division of Pediatric Nephrology, Center for Pediatric and Adolescent Medicine, University Hospital Heidelberg, Heidelberg, Germany; and
| | - Rusan Catar
- Department of Nephrology and Medical Intensive Care, Charité-Universitätsmedizin Berlin, Campus Virchow-Klinikum, Berlin, Germany
| | - András Rudolf
- Department of Pathophysiology, Poznan University of Medical Sciences, Poznań, Poland
| | - Aurelie Philippe
- Division of Pediatric Nephrology, Center for Pediatric and Adolescent Medicine, University Hospital Heidelberg, Heidelberg, Germany; and
| | - Rafał Rutkowski
- Department of Pathophysiology, Poznan University of Medical Sciences, Poznań, Poland
| | - Betti Schäfer
- Division of Pediatric Nephrology, Center for Pediatric and Adolescent Medicine, University Hospital Heidelberg, Heidelberg, Germany; and
| | - Claus Peter Schmitt
- Division of Pediatric Nephrology, Center for Pediatric and Adolescent Medicine, University Hospital Heidelberg, Heidelberg, Germany; and
| | - Duska Dragun
- Department of Nephrology and Medical Intensive Care, Charité-Universitätsmedizin Berlin, Campus Virchow-Klinikum, Berlin, Germany
| | - Achim Jörres
- Department of Nephrology and Medical Intensive Care, Charité-Universitätsmedizin Berlin, Campus Virchow-Klinikum, Berlin, Germany; .,Department of Medicine I-Nephrology, Transplantation and Medical Intensive Care, University Witten/Herdecke, Medical Center Cologne-Merheim, Cologne, Germany
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19
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Yang CY, Chau YP, Chen A, Lee OKS, Tarng DC, Yang AH. Targeting cannabinoid signaling for peritoneal dialysis-induced oxidative stress and fibrosis. World J Nephrol 2017; 6:111-118. [PMID: 28540200 PMCID: PMC5424432 DOI: 10.5527/wjn.v6.i3.111] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/04/2016] [Revised: 01/20/2017] [Accepted: 02/20/2017] [Indexed: 02/06/2023] Open
Abstract
Long-term exposure to bioincompatible peritoneal dialysis (PD) solutions frequently results in peritoneal fibrosis and ultrafiltration failure, which limits the life-long use of and leads to the cessation of PD therapy. Therefore, it is important to elucidate the pathogenesis of peritoneal fibrosis in order to design therapeutic strategies to prevent its occurrence. Peritoneal fibrosis is associated with a chronic inflammatory status as well as an elevated oxidative stress (OS) status. Beyond uremia per se, OS also results from chronic exposure to high glucose load, glucose degradation products, advanced glycation end products, and hypertonic stress. Therapy targeting the cannabinoid (CB) signaling pathway has been reported in several chronic inflammatory diseases with elevated OS. We recently reported that the intra-peritoneal administration of CB receptor ligands, including CB1 receptor antagonists and CB2 receptor agonists, ameliorated dialysis-related peritoneal fibrosis. As targeting the CB signaling pathway has been reported to be beneficial in attenuating the processes of several chronic inflammatory diseases, we reviewed the interaction among the cannabinoid system, inflammation, and OS, through which clinicians ultimately aim to prolong the peritoneal survival of PD patients.
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20
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Genomic reprograming analysis of the Mesothelial to Mesenchymal Transition identifies biomarkers in peritoneal dialysis patients. Sci Rep 2017; 7:44941. [PMID: 28327551 PMCID: PMC5361179 DOI: 10.1038/srep44941] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2016] [Accepted: 02/15/2017] [Indexed: 12/21/2022] Open
Abstract
Peritoneal dialysis (PD) is an effective renal replacement therapy, but a significant proportion of patients suffer PD-related complications, which limit the treatment duration. Mesothelial-to-mesenchymal transition (MMT) contributes to the PD-related peritoneal dysfunction. We analyzed the genetic reprograming of MMT to identify new biomarkers that may be tested in PD-patients. Microarray analysis revealed a partial overlapping between MMT induced in vitro and ex vivo in effluent-derived mesothelial cells, and that MMT is mainly a repression process being higher the number of genes that are down-regulated than those that are induced. Cellular morphology and number of altered genes showed that MMT ex vivo could be subdivided into two stages: early/epithelioid and advanced/non-epithelioid. RT-PCR array analysis demonstrated that a number of genes differentially expressed in effluent-derived non-epithelioid cells also showed significant differential expression when comparing standard versus low-GDP PD fluids. Thrombospondin-1 (TSP1), collagen-13 (COL13), vascular endothelial growth factor A (VEGFA), and gremlin-1 (GREM1) were measured in PD effluents, and except GREM1, showed significant differences between early and advanced stages of MMT, and their expression was associated with a high peritoneal transport status. The results establish a proof of concept about the feasibility of measuring MMT-associated secreted protein levels as potential biomarkers in PD.
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21
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Ji S, Deng H, Jin W, Yan P, Wang R, Pang L, Zhou J, Zhang J, Chen X, Zhao X, Shen J. Beta-catenin participates in dialysate-induced peritoneal fibrosis via enhanced peritoneal cell epithelial-to-mesenchymal transition. FEBS Open Bio 2017; 7:265-273. [PMID: 28174691 PMCID: PMC5292666 DOI: 10.1002/2211-5463.12182] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2016] [Revised: 12/11/2016] [Accepted: 12/12/2016] [Indexed: 12/11/2022] Open
Abstract
Long‐term exposure to peritoneal dialysate with high glucose (HG) leads to peritoneal fibrosis and thus decreases dialysis efficiency. In this study, we explored the role of β‐catenin in this process. C57BL/6 mice received daily intraperitoneal injection with 10% of the body weight of saline (control), 4.25% glucose peritoneal dialysis fluid (PDF), or PDF combined with 5 mg·kg−1 of the β‐catenin inhibitor ICG‐001 (PDF+ICG) for 30 days. Also, mice peritoneal epithelial cells (mPECs) were cultured in 4.25% glucose (HG) or combined with 10 μm ICG‐001 (HG+ICG) for 48 h. We found greater thickness of the parietal peritoneum in the PDF‐treated mice. Additionally, lower expression of E‐cadherin, higher expression of Vimentin, β‐catenin, and Snail, and activation of β‐catenin was observed in the mice and in HG‐treated mPECs, all of which were reversed by ICG‐001. The changes in E‐cadherin and Vimentin indicated occurrence of the epithelial‐to‐mesenchymal transition (EMT). Thus, β‐catenin signaling participates in the process of HG‐induced peritoneal fibrosis, and the EMT of peritoneal epithelial cells is one of the underlying mechanisms of this pathological change.
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Affiliation(s)
- Shuiyu Ji
- Department of Nephrology The People's Hospital of Zhejiang Province Hangzhou China
| | - Hao Deng
- Kidney Disease Center The First Affiliated Hospital Zhejiang University Hangzhou China
| | - Wei Jin
- Department of Nephrology The First People's Hospital of Tongxiang China
| | - Pengpeng Yan
- Kidney Disease Center The First Affiliated Hospital Zhejiang University Hangzhou China
| | - Rending Wang
- Kidney Disease Center The First Affiliated Hospital Zhejiang University Hangzhou China
| | - Lisha Pang
- Kidney Disease Center The First Affiliated Hospital Zhejiang University Hangzhou China
| | - Jingyi Zhou
- Kidney Disease Center The First Affiliated Hospital Zhejiang University Hangzhou China
| | - Jiaming Zhang
- Department of Nephrology The People's Hospital of Zhejiang Province Hangzhou China
| | - Xiaoying Chen
- Kidney Disease Center The First Affiliated Hospital Zhejiang University Hangzhou China
| | - Xiang Zhao
- Department of Nephrology The People's Hospital of Zhejiang Province Hangzhou China
| | - Jia Shen
- Kidney Disease Center The First Affiliated Hospital Zhejiang University Hangzhou China
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22
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Oh SH, Kang JG, Lee JH. Co-micellized Pluronic mixture with thermo-sensitivity and residence stability as an injectable tissue adhesion barrier hydrogel. J Biomed Mater Res B Appl Biomater 2016; 106:172-182. [DOI: 10.1002/jbm.b.33824] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2016] [Revised: 10/20/2016] [Accepted: 11/16/2016] [Indexed: 12/20/2022]
Affiliation(s)
- Se Heang Oh
- Department of Nanobiomedical Science; Dankook University; Cheonan 31116 Republic of Korea
| | - Jun Goo Kang
- Department of Advanced Materials; Hannam University; Daejeon 34054 Republic of Korea
| | - Jin Ho Lee
- Department of Advanced Materials; Hannam University; Daejeon 34054 Republic of Korea
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23
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Nazari B, Rice LM, Stifano G, Barron AMS, Wang YM, Korndorf T, Lee J, Bhawan J, Lafyatis R, Browning JL. Altered Dermal Fibroblasts in Systemic Sclerosis Display Podoplanin and CD90. THE AMERICAN JOURNAL OF PATHOLOGY 2016; 186:2650-64. [PMID: 27565038 DOI: 10.1016/j.ajpath.2016.06.020] [Citation(s) in RCA: 41] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/24/2015] [Revised: 05/02/2016] [Accepted: 06/03/2016] [Indexed: 12/21/2022]
Abstract
Tissue injury triggers the activation and differentiation of multiple cell types to minimize damage and initiate repair processes. In systemic sclerosis, these repair processes appear to run unchecked, leading to aberrant remodeling and fibrosis of the skin and multiple internal organs, yet the fundamental pathological defect remains unknown. We describe herein a transition wherein the abundant CD34(+) dermal fibroblasts present in healthy human skin disappear in the skin of systemic sclerosis patients, and CD34(-), podoplanin(+), and CD90(+) fibroblasts appear. This transition is limited to the upper dermis in several inflammatory skin diseases, yet in systemic sclerosis, it can occur in all regions of the dermis. In vitro, primary dermal fibroblasts readily express podoplanin in response to the inflammatory stimuli tumor necrosis factor and IL-1β. Furthermore, we show that on acute skin injury in both human and murine settings, this transition occurs quickly, consistent with a response to inflammatory signaling. Transitioned fibroblasts partially resemble the cells that form the reticular networks in organized lymphoid tissues, potentially linking two areas of fibroblast research. These results allow for the visualization and quantification of a basic stage of fibroblast differentiation in inflammatory and fibrotic diseases in the skin.
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Affiliation(s)
- Banafsheh Nazari
- Section of Rheumatology, Boston University School of Medicine, Boston, Massachusetts
| | - Lisa M Rice
- Section of Rheumatology, Boston University School of Medicine, Boston, Massachusetts
| | - Giuseppina Stifano
- Section of Rheumatology, Boston University School of Medicine, Boston, Massachusetts
| | - Alexander M S Barron
- Section of Rheumatology, Boston University School of Medicine, Boston, Massachusetts; Department of Microbiology, Boston University School of Medicine, Boston, Massachusetts
| | - Yu Mei Wang
- Section of Rheumatology, Boston University School of Medicine, Boston, Massachusetts
| | - Tess Korndorf
- Section of Rheumatology, Boston University School of Medicine, Boston, Massachusetts
| | - Jungeun Lee
- Department of Dermatology, Boston University School of Medicine, Boston, Massachusetts
| | - Jag Bhawan
- Department of Dermatology, Boston University School of Medicine, Boston, Massachusetts
| | - Robert Lafyatis
- Section of Rheumatology, Boston University School of Medicine, Boston, Massachusetts; Division of Rheumatology and Clinical Immunology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania
| | - Jeffrey L Browning
- Section of Rheumatology, Boston University School of Medicine, Boston, Massachusetts; Department of Microbiology, Boston University School of Medicine, Boston, Massachusetts.
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Abstract
Peritoneal dialysis (PD) is a modality for treatment of patients with end-stage renal disease (ESRD) that depends on the structural and functional integrity of the peritoneal membrane. However, long-term PD can lead to morphological and functional changes in the peritoneum; in particular, peritoneal fibrosis has become one of the most common complications that ultimately results in ultrafiltration failure (UFF) and discontinuation of PD. Several factors and mechanisms such as inflammation and overproduction of transforming growth factor-β1 have been implicated in the development of peritoneal fibrosis, but there is no effective therapy to prevent or delay this process. Recent studies have shown that activation of multiple receptor tyrosine kinases (RTKs) is associated with the development and progression of tissue fibrosis in various organs, and there are also reports indicating the involvement of some RTKs in peritoneal fibrosis. This review will describe the role and mechanisms of RTKs in peritoneal fibrosis and discuss the possibility of using them as therapeutic targets for prevention and treatment of this complication.
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Affiliation(s)
- Li Wang
- Department of Nephrology, Shanghai East Hospital, Tongji University, Shanghai, China
| | - Shougang Zhuang
- Department of Nephrology, Shanghai East Hospital, Tongji University, Shanghai, China Department of Medicine, Rhode Island Hospital and Alpert Medical School, Brown University, Providence, RI, USA
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25
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Protein kinase C α inhibition prevents peritoneal damage in a mouse model of chronic peritoneal exposure to high-glucose dialysate. Kidney Int 2016; 89:1253-67. [DOI: 10.1016/j.kint.2016.01.025] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2015] [Revised: 12/23/2015] [Accepted: 01/07/2016] [Indexed: 12/27/2022]
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26
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Osawa H, Nishimura J, Hiraki M, Takahashi H, Haraguchi N, Hata T, Ikenaga M, Murata K, Yamamoto H, Mizushima T, Doki Y, Mori M. Regeneration of peritoneal mesothelial cells after placement of hyaluronate carboxymethyl-cellulose (Seprafilm ®). Surg Today 2016; 47:130-136. [PMID: 27167879 DOI: 10.1007/s00595-016-1350-4] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2016] [Accepted: 03/29/2016] [Indexed: 01/16/2023]
Abstract
PURPOSE To examine the regeneration of mesothelium under a bioresorbable membrane. METHODS A 1 cm2 piece of peritoneum was resected from both sides of the abdominal wall of retired female mice. A piece of hyaluronate and carboxymethyl-cellulose (Seprafilm®) was placed over the wound on one side and the other side was left uncovered. We evaluated the degree of adhesion and regeneration of mesothelial cells macroscopically and histologically using immunohistochemistry at different times. RESULTS Macroscopically, the degree of postoperative adhesion in the treated site was significantly less than that in the untreated site. The membrane was left in place for 7 postoperative days (PODs). By POD 5, the regenerated peritoneum mesothelial cells covered part of the area and by POD 7, they had regenerated over almost all of that area in the abdominal wall. CONCLUSION The anti-adhesion membrane worked as a physical barrier to prevent postoperative adhesion until the mesothelial cells had regenerated completely. To our knowledge, this is the first study conducted to assess the regeneration of peritoneum mesothelial cells under a bioresorbable membrane using immunohistochemistry.
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Affiliation(s)
- Hideki Osawa
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, E2-2-2 Yamada-oka, Suita, 565-0871, Osaka, Japan
| | - Junichi Nishimura
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, E2-2-2 Yamada-oka, Suita, 565-0871, Osaka, Japan.
| | - Masayuki Hiraki
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, E2-2-2 Yamada-oka, Suita, 565-0871, Osaka, Japan
| | - Hidekazu Takahashi
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, E2-2-2 Yamada-oka, Suita, 565-0871, Osaka, Japan
| | - Naotsugu Haraguchi
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, E2-2-2 Yamada-oka, Suita, 565-0871, Osaka, Japan
| | - Taishi Hata
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, E2-2-2 Yamada-oka, Suita, 565-0871, Osaka, Japan
| | - Masakazu Ikenaga
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, E2-2-2 Yamada-oka, Suita, 565-0871, Osaka, Japan.,Department of Surgery, Higashiosaka City General Hospital, 3-4-5, Nishiiwata, Higashiosaka, 578-8588, Osaka, Japan
| | - Kohei Murata
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, E2-2-2 Yamada-oka, Suita, 565-0871, Osaka, Japan.,Department of Surgery, Suita Municipal Hospital, 2-13-20 Katayama-cho, Suita, 564-0082, Osaka, Japan
| | - Hirofumi Yamamoto
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, E2-2-2 Yamada-oka, Suita, 565-0871, Osaka, Japan
| | - Tsunekazu Mizushima
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, E2-2-2 Yamada-oka, Suita, 565-0871, Osaka, Japan
| | - Yuichiro Doki
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, E2-2-2 Yamada-oka, Suita, 565-0871, Osaka, Japan
| | - Masaki Mori
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, E2-2-2 Yamada-oka, Suita, 565-0871, Osaka, Japan
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Liappas G, González-Mateo GT, Sánchez-Díaz R, Lazcano JJ, Lasarte S, Matesanz-Marín A, Zur R, Ferrantelli E, Ramírez LG, Aguilera A, Fernández-Ruiz E, Beelen RHJ, Selgas R, Sánchez-Madrid F, Martín P, López-Cabrera M. Immune-Regulatory Molecule CD69 Controls Peritoneal Fibrosis. J Am Soc Nephrol 2016; 27:3561-3576. [PMID: 27151919 DOI: 10.1681/asn.2015080909] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2015] [Accepted: 03/07/2016] [Indexed: 01/16/2023] Open
Abstract
Patients with ESRD undergoing peritoneal dialysis develop progressive peritoneal fibrosis, which may lead to technique failure. Recent data point to Th17-mediated inflammation as a key contributor in peritoneal damage. The leukocyte antigen CD69 modulates the setting and progression of autoimmune and inflammatory diseases by controlling the balance between Th17 and regulatory T cells (Tregs). However, the relevance of CD69 in tissue fibrosis remains largely unknown. Thus, we explored the role of CD69 in fibroproliferative responses using a mouse model of peritoneal fibrosis induced by dialysis fluid exposure under either normal or uremic status. We found that cd69-/- mice compared with wild-type (WT) mice showed enhanced fibrosis, mesothelial to mesenchymal transition, IL-17 production, and Th17 cell infiltration in response to dialysis fluid treatment. Uremia contributed partially to peritoneal inflammatory and fibrotic responses. Additionally, antibody-mediated CD69 blockade in WT mice mimicked the fibrotic response of cd69-/- mice. Finally, IL-17 blockade in cd69-/- mice decreased peritoneal fibrosis to the WT levels, and mixed bone marrow from cd69-/- and Rag2-/-γc-/- mice transplanted into WT mice reproduced the severity of the response to dialysis fluid observed in cd69-/- mice, showing that CD69 exerts its regulatory function within the lymphocyte compartment. Overall, our results indicate that CD69 controls tissue fibrosis by regulating Th17-mediated inflammation.
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Affiliation(s)
- Georgios Liappas
- Centro de Biología Molecular Severo Ochoa, Consejo Superior de Investigaciones Científicas Universidad Autónoma de Madrid, Madrid, Spain
| | - Guadalupe Tirma González-Mateo
- Centro de Biología Molecular Severo Ochoa, Consejo Superior de Investigaciones Científicas Universidad Autónoma de Madrid, Madrid, Spain
| | - Raquel Sánchez-Díaz
- Signaling and Inflammation Program, Centro Nacional de Investigaciones Cardiovasculares, Madrid, Spain
| | - Juan José Lazcano
- Signaling and Inflammation Program, Centro Nacional de Investigaciones Cardiovasculares, Madrid, Spain
| | - Sandra Lasarte
- Signaling and Inflammation Program, Centro Nacional de Investigaciones Cardiovasculares, Madrid, Spain
| | - Adela Matesanz-Marín
- Signaling and Inflammation Program, Centro Nacional de Investigaciones Cardiovasculares, Madrid, Spain
| | - Rafal Zur
- Department of Immunology and Oncology, Centro Nacional de Biotecnología Consejo Superior de Investigaciones Científicas, Madrid, Spain
| | - Evelina Ferrantelli
- Department of Molecular Cell Biology and Immunology, Vrije Universiteit University Medical Center Vrije Universiteit Medisch Centrum, Amsterdam, The Netherlands
| | | | | | | | - Robert H J Beelen
- Department of Molecular Cell Biology and Immunology, Vrije Universiteit University Medical Center Vrije Universiteit Medisch Centrum, Amsterdam, The Netherlands
| | - Rafael Selgas
- Nephrology Department, Hospital Universitario La Paz, Instituto de Investigación Sanitaria La Paz, Madrid, Spain
| | - Francisco Sánchez-Madrid
- Signaling and Inflammation Program, Centro Nacional de Investigaciones Cardiovasculares, Madrid, Spain.,Immunology Department, Hospital Universitario de la Princesa, Instituto de Investigación Sanitaria La Princesa, Madrid, Spain; and
| | - Pilar Martín
- Signaling and Inflammation Program, Centro Nacional de Investigaciones Cardiovasculares, Madrid, Spain;
| | - Manuel López-Cabrera
- Centro de Biología Molecular Severo Ochoa, Consejo Superior de Investigaciones Científicas Universidad Autónoma de Madrid, Madrid, Spain;
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28
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Sandoval P, Jiménez-Heffernan JA, Guerra-Azcona G, Pérez-Lozano ML, Rynne-Vidal Á, Albar-Vizcaíno P, Gil-Vera F, Martín P, Coronado MJ, Barcena C, Dotor J, Majano PL, Peralta AA, López-Cabrera M. Mesothelial-to-mesenchymal transition in the pathogenesis of post-surgical peritoneal adhesions. J Pathol 2016; 239:48-59. [DOI: 10.1002/path.4695] [Citation(s) in RCA: 61] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2015] [Revised: 12/30/2015] [Accepted: 01/26/2016] [Indexed: 12/19/2022]
Affiliation(s)
- Pilar Sandoval
- Centro de Biología Molecular-Severo Ochoa; CSIC. Cantoblanco; Madrid Spain
| | - José A Jiménez-Heffernan
- Departamento de Anatomía Patológica; Hospital Universitario La Princesa, Instituto de Investigación Sanitaria Princesa (IP); Madrid Spain
| | | | | | - Ángela Rynne-Vidal
- Centro de Biología Molecular-Severo Ochoa; CSIC. Cantoblanco; Madrid Spain
| | - Patricia Albar-Vizcaíno
- Unidad de Biología Molecular y Servicio de Nefrología, Hospital Universitario La Princesa; Instituto de Investigación Sanitaria Princesa (IP); Madrid Spain
| | | | - Paloma Martín
- Departamento de Anatomía Patológica; Hospital Universitario Puerta de Hierro; Madrid Spain
| | - María José Coronado
- Unidad de Microscopía Confocal, Instituto de Investigación Sanitaria Hospital Puerta de Hierro; Madrid Spain
| | - Carmen Barcena
- Departamento de Anatomía Patológica, Hospital Universitario 12 de Octubre; Madrid Spain
| | | | - Pedro Lorenzo Majano
- Unidad de Biología Molecular y Servicio de Nefrología, Hospital Universitario La Princesa; Instituto de Investigación Sanitaria Princesa (IP); Madrid Spain
| | - Abelardo Aguilera Peralta
- Unidad de Biología Molecular y Servicio de Nefrología, Hospital Universitario La Princesa; Instituto de Investigación Sanitaria Princesa (IP); Madrid Spain
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Liu Y, Dong Z, Liu H, Zhu J, Liu F, Chen G. Transition of mesothelial cell to fibroblast in peritoneal dialysis: EMT, stem cell or bystander? Perit Dial Int 2015; 35:14-25. [PMID: 25700459 DOI: 10.3747/pdi.2014.00188] [Citation(s) in RCA: 53] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023] Open
Abstract
Long-term peritoneal dialysis (PD) can lead to fibrotic changes in the peritoneum, characterized by loss of mesothelial cells (MCs) and thickening of the submesothelial area with an accumulation of collagen and myofibroblasts. The origin of myofibroblasts is a central question in peritoneal fibrosis that remains unanswered at present. Numerous clinical and experimental studies have suggested that MCs, through epithelial-mesenchymal transition (EMT), contribute to the pool of peritoneal myofibroblasts. However, recent work has placed significant doubts on the paradigm of EMT in organ fibrogenesis (in the kidney particularly), highlighting the need to reconsider the role of EMT in the generation of myofibroblasts in peritoneal fibrosis. In particular, selective cell isolation and lineage-tracing experiments have suggested the existence of progenitor cells in the peritoneum, which are able to switch to fibroblast-like cells when stimulated by the local environment. These findings highlight the plastic nature of MCs and its contribution to peritoneal fibrogenesis. In this review, we summarize the key findings and caveats of EMT in organ fibrogenesis, with a focus on PD-related peritoneal fibrosis, and discuss the potential of peritoneal MCs as a source of myofibroblasts.
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Affiliation(s)
- Yu Liu
- Department of Nephrology, the Second Xiangya Hospital, Central South University, Changsha, Hunan, PR China; Department of Cellular Biology and Anatomy, Georgia Regents University and Charlie Norwood Veterans Affairs Medical Center, Augusta, Georgia, USA
| | - Zheng Dong
- Department of Nephrology, the Second Xiangya Hospital, Central South University, Changsha, Hunan, PR China; Department of Cellular Biology and Anatomy, Georgia Regents University and Charlie Norwood Veterans Affairs Medical Center, Augusta, Georgia, USA Department of Nephrology, the Second Xiangya Hospital, Central South University, Changsha, Hunan, PR China; Department of Cellular Biology and Anatomy, Georgia Regents University and Charlie Norwood Veterans Affairs Medical Center, Augusta, Georgia, USA
| | - Hong Liu
- Department of Nephrology, the Second Xiangya Hospital, Central South University, Changsha, Hunan, PR China; Department of Cellular Biology and Anatomy, Georgia Regents University and Charlie Norwood Veterans Affairs Medical Center, Augusta, Georgia, USA
| | - Jiefu Zhu
- Department of Nephrology, the Second Xiangya Hospital, Central South University, Changsha, Hunan, PR China; Department of Cellular Biology and Anatomy, Georgia Regents University and Charlie Norwood Veterans Affairs Medical Center, Augusta, Georgia, USA
| | - Fuyou Liu
- Department of Nephrology, the Second Xiangya Hospital, Central South University, Changsha, Hunan, PR China; Department of Cellular Biology and Anatomy, Georgia Regents University and Charlie Norwood Veterans Affairs Medical Center, Augusta, Georgia, USA
| | - Guochun Chen
- Department of Nephrology, the Second Xiangya Hospital, Central South University, Changsha, Hunan, PR China; Department of Cellular Biology and Anatomy, Georgia Regents University and Charlie Norwood Veterans Affairs Medical Center, Augusta, Georgia, USA
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Rapamycin Protects from Type-I Peritoneal Membrane Failure Inhibiting the Angiogenesis, Lymphangiogenesis, and Endo-MT. BIOMED RESEARCH INTERNATIONAL 2015; 2015:989560. [PMID: 26688823 PMCID: PMC4673327 DOI: 10.1155/2015/989560] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/23/2015] [Revised: 08/27/2015] [Accepted: 10/13/2015] [Indexed: 01/16/2023]
Abstract
Preservation of peritoneal membrane (PM) is essential for long-term survival in peritoneal dialysis (PD). Continuous presence of PD fluids (PDF) in the peritoneal cavity generates chronic inflammation and promotes changes of the PM, such as fibrosis, angiogenesis, and lymphangiogenesis. Mesothelial-to-mesenchymal transition (MMT) and endothelial-to-mesenchymal transition (Endo-MT) seem to play a central role in this pathogenesis. We speculated that Rapamycin, a potent immunosuppressor, could be beneficial by regulating blood and lymphatic vessels proliferation. We demonstrate that mice undergoing a combined PD and Rapamycin treatment (PDF + Rapa group) presented a reduced PM thickness and lower number of submesothelial blood and lymphatic vessels, as well as decreased MMT and Endo-MT, comparing with their counterparts exposed to PD alone (PDF group). Peritoneal water transport in the PDF + Rapa group remained at control level, whereas PD effluent levels of VEGF, TGF-β, and TNF-α were lower than in the PDF group. Moreover, the treatment of mesothelial cells with Rapamycin in vitro significantly decreased VEGF synthesis and selectively inhibited the VEGF-C and VEGF-D release when compared with control cells. Thus, Rapamycin has a protective effect on PM in PD through an antifibrotic and antiproliferative effect on blood and lymphatic vessels. Moreover, it inhibits Endo-MT and, at least partially, MMT.
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31
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Herlihy SE, Starke HE, Lopez-Anton M, Cox N, Keyhanian K, Fraser DJ, Gomer RH. Peritoneal Dialysis Fluid and Some of Its Components Potentiate Fibrocyte Differentiation. Perit Dial Int 2015; 36:367-73. [PMID: 26493752 DOI: 10.3747/pdi.2014.00284] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2014] [Accepted: 05/11/2015] [Indexed: 11/15/2022] Open
Abstract
Long-term peritoneal dialysis (PD) often results in the development of peritoneal fibrosis. In many other fibrosing diseases, monocytes enter the fibrotic lesion and differentiate into fibroblast-like cells called fibrocytes. We find that peritoneal tissue from short-term PD patients contains few fibrocytes, while fibrocytes are readily observed in the peritoneal membrane of long-term PD patients. The PD fluid Dianeal (Baxter Healthcare Corporation, Deerfield, IL, USA) contains dextrose, a number of electrolytes including sodium chloride, and sodium lactate. We find that PD fluid potentiates human fibrocyte differentiation in vitro and implicates sodium lactate in this potentiation. The plasma protein serum amyloid P (SAP) inhibits fibrocyte differentiation. Peritoneal dialysis fluid and sodium chloride decrease the ability of human SAP to inhibit human fibrocyte differentiation in vitro Together, these results suggest that PD fluid contributes to the development of peritoneal fibrosis by potentiating fibrocyte differentiation.
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Affiliation(s)
| | | | | | | | | | - Donald J Fraser
- School of Medicine, Cardiff University, Cardiff, Wales, United Kingdom
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32
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New developments in peritoneal fibroblast biology: implications for inflammation and fibrosis in peritoneal dialysis. BIOMED RESEARCH INTERNATIONAL 2015; 2015:134708. [PMID: 26495280 PMCID: PMC4606153 DOI: 10.1155/2015/134708] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/22/2015] [Revised: 08/11/2015] [Accepted: 08/25/2015] [Indexed: 01/19/2023]
Abstract
Uraemia and long-term peritoneal dialysis (PD) can lead to fibrotic thickening of the peritoneal membrane, which may limit its dialytic function. Peritoneal fibrosis is associated with the appearance of myofibroblasts and expansion of extracellular matrix. The extent of contribution of resident peritoneal fibroblasts to these changes is a matter of debate. Recent studies point to a significant heterogeneity and complexity of the peritoneal fibroblast population. Here, we review recent developments in peritoneal fibroblast biology and summarize the current knowledge on the involvement of peritoneal fibroblasts in peritoneal inflammation and fibrosis.
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The Mesothelial Origin of Carcinoma Associated-Fibroblasts in Peritoneal Metastasis. Cancers (Basel) 2015; 7:1994-2011. [PMID: 26426054 PMCID: PMC4695872 DOI: 10.3390/cancers7040872] [Citation(s) in RCA: 70] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2015] [Revised: 09/14/2015] [Accepted: 09/23/2015] [Indexed: 01/15/2023] Open
Abstract
Solid tumors are complex and unstructured organs that, in addition to cancer cells, also contain other cell types. Carcinoma-associated fibroblasts (CAFs) represent an important population in the tumor microenviroment and participate in several stages of tumor progression, including cancer cell migration/invasion and metastasis. During peritoneal metastasis, cancer cells detach from the primary tumor, such as ovarian or gastrointestinal, disseminate through the peritoneal fluid and colonize the peritoneum. Tumor cells metastasize by attaching to and invading through the mesothelial cell (MC) monolayer that lines the peritoneal cavity, then colonizing the submesothelial compact zone where CAFs accumulate. CAFs may derive from different sources depending on the surrounding metastatic niche. In peritoneal metastasis, a sizeable subpopulation of CAFs originates from MCs through a mesothelial-to-mesenchymal transition (MMT), which promotes adhesion, invasion, vascularization and subsequent tumor growth. The bidirectional communication between cancer cells and MC-derived CAFs via secretion of a wide range of cytokines, growth factors and extracellular matrix components seems to be crucial for the establishment and progression of the metastasis in the peritoneum. This manuscript provides a comprehensive review of novel advances in understanding how peritoneal CAFs provide cancer cells with a supportive microenvironment, as well as the development of future therapeutic approaches by interfering with the MMT in the peritoneum.
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Fierro-Fernández M, Busnadiego Ó, Sandoval P, Espinosa-Díez C, Blanco-Ruiz E, Rodríguez M, Pian H, Ramos R, López-Cabrera M, García-Bermejo ML, Lamas S. miR-9-5p suppresses pro-fibrogenic transformation of fibroblasts and prevents organ fibrosis by targeting NOX4 and TGFBR2. EMBO Rep 2015; 16:1358-77. [PMID: 26315535 DOI: 10.15252/embr.201540750] [Citation(s) in RCA: 80] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2015] [Accepted: 07/20/2015] [Indexed: 02/06/2023] Open
Abstract
Uncontrolled extracellular matrix (ECM) production by fibroblasts in response to injury contributes to fibrotic diseases, including idiopathic pulmonary fibrosis (IPF). Reactive oxygen species (ROS) generation is involved in the pathogenesis of IPF. Transforming growth factor-β1 (TGF-β1) stimulates the production of NADPH oxidase 4 (NOX4)-dependent ROS, promoting lung fibrosis (LF). Dysregulation of microRNAs (miRNAs) has been shown to contribute to LF. To identify miRNAs involved in redox regulation relevant for IPF, we performed arrays in human lung fibroblasts exposed to ROS. miR-9-5p was selected as the best candidate and we demonstrate its inhibitory effect on TGF-β receptor type II (TGFBR2) and NOX4 expression. Increased expression of miR-9-5p abrogates TGF-β1-dependent myofibroblast phenotypic transformation. In the mouse model of bleomycin-induced LF, miR-9-5p dramatically reduces fibrogenesis and inhibition of miR-9-5p and prevents its anti-fibrotic effect both in vitro and in vivo. In lung specimens from patients with IPF, high levels of miR-9-5p are found. In omentum-derived mesothelial cells (MCs) from patients subjected to peritoneal dialysis (PD), miR-9-5p also inhibits mesothelial to myofibroblast transformation. We propose that TGF-β1 induces miR-9-5p expression as a self-limiting homeostatic response.
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Affiliation(s)
- Marta Fierro-Fernández
- Department of Cell Biology and Immunology, Centro de Biología Molecular "Severo Ochoa" (CBMSO), Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid, Madrid, Spain
| | - Óscar Busnadiego
- Department of Cell Biology and Immunology, Centro de Biología Molecular "Severo Ochoa" (CBMSO), Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid, Madrid, Spain
| | - Pilar Sandoval
- Department of Cell Biology and Immunology, Centro de Biología Molecular "Severo Ochoa" (CBMSO), Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid, Madrid, Spain
| | - Cristina Espinosa-Díez
- Department of Cell Biology and Immunology, Centro de Biología Molecular "Severo Ochoa" (CBMSO), Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid, Madrid, Spain
| | - Eva Blanco-Ruiz
- Department of Cell Biology and Immunology, Centro de Biología Molecular "Severo Ochoa" (CBMSO), Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid, Madrid, Spain
| | - Macarena Rodríguez
- Department of Pathology, Hospital Universitario "Ramón y Cajal", IRYCIS, Madrid, Spain
| | - Héctor Pian
- Department of Pathology, Hospital Universitario "Ramón y Cajal", IRYCIS, Madrid, Spain
| | - Ricardo Ramos
- Genomic Facility, Parque Científico de Madrid, Madrid, Spain
| | - Manuel López-Cabrera
- Department of Cell Biology and Immunology, Centro de Biología Molecular "Severo Ochoa" (CBMSO), Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid, Madrid, Spain
| | | | - Santiago Lamas
- Department of Cell Biology and Immunology, Centro de Biología Molecular "Severo Ochoa" (CBMSO), Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid, Madrid, Spain
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Kitterer D, Latus J, Ulmer C, Fritz P, Biegger D, Ott G, Alscher MD, Witowski J, Kawka E, Jörres A, Seeger H, Segerer S, Braun N. Activation of nuclear factor of activated T cells 5 in the peritoneal membrane of uremic patients. Am J Physiol Renal Physiol 2015; 308:F1247-58. [DOI: 10.1152/ajprenal.00617.2014] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2014] [Accepted: 03/25/2015] [Indexed: 11/22/2022] Open
Abstract
Peritoneal inflammation and fibrosis are responses to the uremic milieu and exposure to hyperosmolar dialysis fluids in patients on peritoneal dialysis. Cells respond to high osmolarity via the transcription factor nuclear factor of activated T cells (NFAT5). In the present study, the response of human peritoneal fibroblasts to glucose was analyzed in vitro. Expression levels of NFAT5 and chemokine (C-C motif) ligand (CCL2) mRNA were quantified in peritoneal biopsies of five nonuremic control patients, five uremic patients before PD (pPD), and eight patients on PD (oPD) using real-time PCR. Biopsies from 5 control patients, 25 pPD patients, and 25 oPD patients were investigated using immunohistochemistry to detect the expression of NFAT5, CCL2, NF-κB p50, NF-κB p65, and CD68. High glucose concentrations led to an early, dose-dependent induction of NFAT5 mRNA in human peritoneal fibroblasts. CCL2 mRNA expression was upregulated by high concentrations of glucose after 6 h, but, most notably, a concentration-dependent induction of CCL2 was present after 96 h. In human peritoneal biopsies, NFAT5 mRNA levels were increased in uremic patients compared with nonuremic control patients. No significant difference was found between the pPD group and oPD group. CCL2 mRNA expression was higher in the oPD group. Immunohistochemistry analysis was consistent with the results of mRNA analysis. CD68-positive cells were significantly increased in the oPD group. In conclusion, uremia results in NFAT5 induction, which might promote early changes of the peritoneum. Upregulation of NFAT5 in PD patients is associated with NFκB induction, potentially resulting in the recruitment of macrophages.
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Affiliation(s)
- Daniel Kitterer
- Division of Nephrology, Department of Internal Medicine, Robert-Bosch-Hospital, Stuttgart, Germany
| | - Joerg Latus
- Division of Nephrology, Department of Internal Medicine, Robert-Bosch-Hospital, Stuttgart, Germany
| | - Christoph Ulmer
- Department of General, Visceral, and Trauma Surgery, Robert-Bosch-Hospital, Stuttgart, Germany
| | - Peter Fritz
- Department of Diagnostic Medicine, Division of Pathology, Robert-Bosch Hospital, Stuttgart, Germany
| | - Dagmar Biegger
- Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, University of Tuebingen, Stuttgart, Germany
| | - German Ott
- Department of Diagnostic Medicine, Division of Pathology, Robert-Bosch Hospital, Stuttgart, Germany
| | - M. Dominik Alscher
- Division of Nephrology, Department of Internal Medicine, Robert-Bosch-Hospital, Stuttgart, Germany
| | - Janusz Witowski
- Department of Pathophysiology, University of Medical Sciences, Poznan, Poland
| | - Edyta Kawka
- Department of Nephrology and Medical Intensive Care, Charité-Universitätsmedizin Berlin, Campus Virchow-Klinikum, Berlin, Germany
| | - Achim Jörres
- Department of Nephrology and Medical Intensive Care, Charité-Universitätsmedizin Berlin, Campus Virchow-Klinikum, Berlin, Germany
| | - Harald Seeger
- Division of Nephrology, University Hospital Zurich, Zurich, Switzerland; and
- Institute of Physiology and Zurich Center for Integrative Human Physiology, University of Zurich, Zurich, Switzerland
| | - Stephan Segerer
- Division of Nephrology, University Hospital Zurich, Zurich, Switzerland; and
- Institute of Physiology and Zurich Center for Integrative Human Physiology, University of Zurich, Zurich, Switzerland
| | - Niko Braun
- Division of Nephrology, Department of Internal Medicine, Robert-Bosch-Hospital, Stuttgart, Germany
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Qin F, Ma Y, Li X, Wang X, Wei Y, Hou C, Lin S, Hou L, Wang C. Efficacy and mechanism of tanshinone IIA liquid nanoparticles in preventing experimental postoperative peritoneal adhesions in vivo and in vitro. Int J Nanomedicine 2015; 10:3699-716. [PMID: 26056449 PMCID: PMC4445949 DOI: 10.2147/ijn.s81650] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023] Open
Abstract
Up to 90% of patients develop adhesion following laparotomy. Upregulating fibrinolysis within the peritoneum reduces adhesions. Tanshinone IIA (Tan IIA) promotes fibrinolysis in hepatic fibrosis and the cardiovascular system and may play a role in preventing adhesions. We report preparation and characterization of liquid nanoparticles of Tan IIA for intravenous administration and investigate its feasibility in clinical practice. Tan IIA liquid nanoparticles (Tan IIA-NPs) were prepared using the emulsion/solvent evaporation method. Adhesions were induced in Sprague–Dawley rats by injuring the parietal peritoneum and cecum, followed by intravenous administration of various Tan IIA-NP dosages. The adhesion scores for each group were collected 7 days after the initial laparotomy. The activity of tissue-type plasminogen activator (tPA) was measured from the peritoneal lavage fluid. The messenger RNA and protein expression levels of plasminogen activator inhibitor-1 (PAI-1) were measured by quantitative real-time polymerase chain reaction and enzyme-linked immunosorbent assay. TGF-β1 and collagen I expressions were measured immunohistochemically in the ischemic tissues. The effects of Tan IIA-NPs and free-Tan IIA on tPA and PAI-1 were measured in vitro in TGF-β1-induced HMrSV5 cells. Tan IIA-NPs exhibited small particle size, high encapsulation efficiency, good stability for storage, and safety for intravenous administration. Tan IIA-NPs were effective in preventing adhesion. Tan IIA-NPs increased tPA activity in peritoneal lavage fluid, and tPA mRNA and protein expression, and decreased PAI-1 mRNA and protein expression in the ischemic tissues. Moreover, Tan IIA-NPs decreased TGF-β1 and collagen I expressions in the ischemic tissues. Tan IIA-NPs administered via tail veins upregulated fibrinolysis in the peritoneum. In vitro studies showed that these effects may be mediated by the TGF-β signal pathway.
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Affiliation(s)
- Fei Qin
- Department of Pharmacy, Nanfang Hospital, Southern Medical University, Guangzhou, People's Republic of China
| | - Yun Ma
- Department of Pharmacy, Nanfang Hospital, Southern Medical University, Guangzhou, People's Republic of China
| | - Xiao Li
- Department of Pharmacy, the Affiliated Hospital of Qingdao University, Qingdao, Shandong, People's Republic of China
| | - Xian Wang
- Department of Pharmacy, Nanfang Hospital, Southern Medical University, Guangzhou, People's Republic of China
| | - Yuanyi Wei
- Department of Pharmacy, Nanfang Hospital, Southern Medical University, Guangzhou, People's Republic of China
| | - Chuqi Hou
- Department of Pharmacology, Southern Medical University, Guangzhou, People's Republic of China
| | - Si Lin
- Department of Pharmacy, Nanfang Hospital, Southern Medical University, Guangzhou, People's Republic of China
| | - Lianbing Hou
- Department of Pharmacy, Nanfang Hospital, Southern Medical University, Guangzhou, People's Republic of China
| | - Chengxi Wang
- Department of Pharmacology, Guangdong Pharmaceutical University, Guangzhou, People's Republic of China
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Oh EY, Collins LC. Keratin Expression Patterns in Stromal Cells of Benign Sclerosing Lesions of the Breast: A Potential Diagnostic Pitfall. Arch Pathol Lab Med 2015; 139:1143-8. [DOI: 10.5858/arpa.2014-0496-oa] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Abstract
Context
Metaplastic carcinomas arising in association with benign sclerosing lesions (BSLs) are rare malignancies in which a neoplastic spindle cell proliferation can be recognized extending beyond the boundaries of the complex sclerosing lesion or papilloma. However, in cases in which the metaplastic carcinoma is of the low-grade fibromatosis-like type or is a low-grade adenosquamous carcinoma, distinction from the background BSL can be a significant challenge. Cytokeratin (CK) and/or p63 immunostains are helpful in confirming the diagnosis of metaplastic carcinoma, but the expression patterns of these markers in the stromal cells of BSLs have not been well characterized.
Objective
To characterize the expression patterns of CKs and p63 in BSLs.
Design
We evaluated the spindle cell component of 55 BSLs using CK 5/6, CK 903, CK MNF116, and p63.
Results
A total of 45 cases (81%) showed no staining for CKs or p63 in benign stromal cells. CK 5/6, CK 903, and p63 were positive in one case each. CK MNF116 stained spindle cells within 10 BSLs. No cases showed spindle cell reactivity for all 4 markers. Positive cases demonstrated very focal, weak staining of spindle cells; only 1 case showed focal, moderate CK staining. Spindle cell positivity was not associated with lesion type, growth pattern, spindle cell atypia, or mitoses.
Conclusions
These findings suggest that although the presence or absence of expression of CK 5/6, CK 903, and p63 may be useful to distinguish BSL from metaplastic carcinomas arising in this setting, CK MNF116 positivity may be a diagnostic pitfall.
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Affiliation(s)
| | - Laura C. Collins
- From the Department of Pathology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts
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Moinuddin Z, Summers A, Van Dellen D, Augustine T, Herrick SE. Encapsulating peritoneal sclerosis-a rare but devastating peritoneal disease. Front Physiol 2015; 5:470. [PMID: 25601836 PMCID: PMC4283512 DOI: 10.3389/fphys.2014.00470] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2014] [Accepted: 11/16/2014] [Indexed: 01/08/2023] Open
Abstract
Encapsulating peritoneal sclerosis (EPS) is a devastating but, fortunately, rare complication of long-term peritoneal dialysis. The disease is associated with extensive thickening and fibrosis of the peritoneum resulting in the formation of a fibrous cocoon encapsulating the bowel leading to intestinal obstruction. The incidence of EPS ranges between 0.7 and 3.3% and increases with duration of peritoneal dialysis therapy. Dialysis fluid is hyperosmotic, hyperglycemic, and acidic causing chronic injury and inflammation in the peritoneum with loss of mesothelium and extensive tissue fibrosis. The pathogenesis of EPS, however, still remains uncertain, although a widely accepted hypothesis is the "two-hit theory," where, the first hit is chronic peritoneal membrane injury from long standing peritoneal dialysis followed by a second hit such as an episode of peritonitis, genetic predisposition and/or acute cessation of peritoneal dialysis, leading to EPS. Recently, EPS has been reported in patients shortly after transplantation suggesting that this procedure may also act as a possible second insult. The process of epithelial-mesenchymal transition of mesothelial cells is proposed to play a central role in the development of peritoneal sclerosis, a common characteristic of patients on dialysis, however, its importance in EPS is less clear. There is no established treatment for EPS although evidence from small case studies suggests that corticosteroids and tamoxifen may be beneficial. Nutritional support is essential and surgical intervention (peritonectomy and enterolysis) is recommended in later stages to relieve bowel obstruction.
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Affiliation(s)
- Zia Moinuddin
- Department of Transplantation, Manchester Royal Infirmary Manchester, UK ; Faculty of Medical and Human Sciences, Institute of Inflammation and Repair, University of Manchester, Manchester Academic Health Science Centre Manchester, UK
| | - Angela Summers
- Department of Transplantation, Manchester Royal Infirmary Manchester, UK
| | - David Van Dellen
- Department of Transplantation, Manchester Royal Infirmary Manchester, UK
| | - Titus Augustine
- Department of Transplantation, Manchester Royal Infirmary Manchester, UK
| | - Sarah E Herrick
- Faculty of Medical and Human Sciences, Institute of Inflammation and Repair, University of Manchester, Manchester Academic Health Science Centre Manchester, UK
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De Sousa E, Del Peso G, Alvarez L, Ros S, Mateus A, Aguilar A, Selgas R, Bajo MA. Peritoneal resting with heparinized lavage reverses peritoneal type I membrane failure. A comparative study of the resting effects on normal membranes. Perit Dial Int 2014; 34:698-705. [PMID: 25292401 DOI: 10.3747/pdi.2013.00286] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022] Open
Abstract
BACKGROUND Ultrafiltration failure (UFF) is a serious complication of long-term peritoneal dialysis (PD). Peritoneal rest (PR) has been demonstrated as a valid treatment to reverse the functional changes that occur in UFF. The effects of PR on a normally functioning human peritoneum are unknown but are expected to be neutral. Our hypothesis was that PR positively modifies peritoneal function in patients with UFF, in contrast to the absence of effects when PR is applied under normal conditions. PATIENTS AND METHODS We studied 84 PR periods, comparing 35 patients with UFF and 49 controls (resting for abdominal surgery with temporary discontinuation of PD). We analyzed peritoneal transport pre-PR and post-PR by calculating the mass transfer coefficients of creatinine (Cr-MTAC), the dialysate/plasma creatinine ratio (D/P Cr) and the ultrafiltration (UF). RESULTS Baseline data was similar for the 2 groups, although the UFF group had a longer median time in PD (39 [18 - 60] vs 10 [5 - 23] months; p = 0.00001). Peritoneal rest induced a decrease in D/P Cr, Cr-MTAC and an increase in UF capacity in the UFF group (p = 0.0001, p = 0.004 and p = 0.001, respectively), without causing changes in the control group. Peritoneal rest in patients with more than 6 months of UFF was not able to reduce peritoneal solute transport or improve UF capacity. Response to PR did not differ among UFF patients with or without a previous history of peritonitis. Peritoneal rest enabled patients with UFF to continue on PD for a median time of 23 months (range, 13 - 46 months). CONCLUSIONS Peritoneal rest induces functional changes in patients with UFF but not in those with no functional abnormalities. This demonstrates that PR works only when abnormal but reversible functional conditions are present. However, the effect is highly dependent on how early PR is applied.
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Affiliation(s)
- Erika De Sousa
- Department of Nephrology, University Hospital La Paz, IdiPAZ, Madrid, Spain; and Department of Nephrology, Hospital Carlos Haya, Malaga, Spain
| | - Gloria Del Peso
- Department of Nephrology, University Hospital La Paz, IdiPAZ, Madrid, Spain; and Department of Nephrology, Hospital Carlos Haya, Malaga, Spain
| | - Laura Alvarez
- Department of Nephrology, University Hospital La Paz, IdiPAZ, Madrid, Spain; and Department of Nephrology, Hospital Carlos Haya, Malaga, Spain
| | - Silvia Ros
- Department of Nephrology, University Hospital La Paz, IdiPAZ, Madrid, Spain; and Department of Nephrology, Hospital Carlos Haya, Malaga, Spain
| | - Ana Mateus
- Department of Nephrology, University Hospital La Paz, IdiPAZ, Madrid, Spain; and Department of Nephrology, Hospital Carlos Haya, Malaga, Spain
| | - Ana Aguilar
- Department of Nephrology, University Hospital La Paz, IdiPAZ, Madrid, Spain; and Department of Nephrology, Hospital Carlos Haya, Malaga, Spain
| | - Rafael Selgas
- Department of Nephrology, University Hospital La Paz, IdiPAZ, Madrid, Spain; and Department of Nephrology, Hospital Carlos Haya, Malaga, Spain
| | - María-Auxiliadora Bajo
- Department of Nephrology, University Hospital La Paz, IdiPAZ, Madrid, Spain; and Department of Nephrology, Hospital Carlos Haya, Malaga, Spain
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Busnadiego O, Loureiro-Álvarez J, Sandoval P, Lagares D, Dotor J, Pérez-Lozano ML, López-Armada MJ, Lamas S, López-Cabrera M, Rodríguez-Pascual F. A pathogenetic role for endothelin-1 in peritoneal dialysis-associated fibrosis. J Am Soc Nephrol 2014; 26:173-82. [PMID: 25012164 DOI: 10.1681/asn.2013070799] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/31/2023] Open
Abstract
In patients undergoing peritoneal dialysis (PD), chronic exposure to nonphysiologic PD fluids elicits low-grade peritoneal inflammation, leading to fibrosis and angiogenesis. Phenotype conversion of mesothelial cells into myofibroblasts, the so-called mesothelial-to-mesenchymal transition (MMT), significantly contributes to the peritoneal dysfunction related to PD. A number of factors have been described to induce MMT in vitro and in vivo, of which TGF-β1 is probably the most important. The vasoconstrictor peptide endothelin-1 (ET-1) is a transcriptional target of TGF-β1 and mediates excessive scarring and fibrosis in several tissues. This work studied the contribution of ET-1 to the development of peritoneal damage and failure in a mouse model of PD. ET-1 and its receptors were expressed in the peritoneal membrane and upregulated on PD fluid exposure. Administration of an ET receptor antagonist, either bosentan or macitentan, markedly attenuated PD-induced MMT, fibrosis, angiogenesis, and peritoneal functional decline. Adenovirus-mediated overexpression of ET-1 induced MMT in human mesothelial cells in vitro and promoted the early cellular events associated with peritoneal dysfunction in vivo. Notably, TGF-β1-blocking peptides prevented these actions of ET-1. Furthermore, a positive reciprocal relationship was observed between ET-1 expression and TGF-β1 expression in human mesothelial cells. These results strongly support a role for an ET-1/TGF-β1 axis as an inducer of MMT and subsequent peritoneal damage and fibrosis, and they highlight ET-1 as a potential therapeutic target in the treatment of PD-associated dysfunction.
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Affiliation(s)
- Oscar Busnadiego
- Centro de Biología Molecular Severo Ochoa, Consejo Superior de Investigaciones Científicas, Universidad Autónoma de Madrid, Madrid, Spain
| | - Jesús Loureiro-Álvarez
- Centro de Biología Molecular Severo Ochoa, Consejo Superior de Investigaciones Científicas, Universidad Autónoma de Madrid, Madrid, Spain; Laboratorio de Envejecimiento e Inflamación, Instituto de Investigación Biomédica, A Coruña, A Coruña, Spain; and
| | - Pilar Sandoval
- Centro de Biología Molecular Severo Ochoa, Consejo Superior de Investigaciones Científicas, Universidad Autónoma de Madrid, Madrid, Spain
| | - David Lagares
- Centro de Biología Molecular Severo Ochoa, Consejo Superior de Investigaciones Científicas, Universidad Autónoma de Madrid, Madrid, Spain
| | | | - María Luisa Pérez-Lozano
- Centro de Biología Molecular Severo Ochoa, Consejo Superior de Investigaciones Científicas, Universidad Autónoma de Madrid, Madrid, Spain
| | - María J López-Armada
- Laboratorio de Envejecimiento e Inflamación, Instituto de Investigación Biomédica, A Coruña, A Coruña, Spain; and
| | - Santiago Lamas
- Centro de Biología Molecular Severo Ochoa, Consejo Superior de Investigaciones Científicas, Universidad Autónoma de Madrid, Madrid, Spain
| | - Manuel López-Cabrera
- Centro de Biología Molecular Severo Ochoa, Consejo Superior de Investigaciones Científicas, Universidad Autónoma de Madrid, Madrid, Spain
| | - Fernando Rodríguez-Pascual
- Centro de Biología Molecular Severo Ochoa, Consejo Superior de Investigaciones Científicas, Universidad Autónoma de Madrid, Madrid, Spain;
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Sandoval P, Jiménez-Heffernan JA, Rynne-Vidal Á, Pérez-Lozano ML, Gilsanz Á, Ruiz-Carpio V, Reyes R, García-Bordas J, Stamatakis K, Dotor J, Majano PL, Fresno M, Cabañas C, López-Cabrera M. Carcinoma-associated fibroblasts derive from mesothelial cells via mesothelial-to-mesenchymal transition in peritoneal metastasis. J Pathol 2014; 231:517-31. [PMID: 24114721 DOI: 10.1002/path.4281] [Citation(s) in RCA: 132] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2013] [Revised: 09/20/2013] [Accepted: 09/24/2013] [Indexed: 12/29/2022]
Abstract
Peritoneal dissemination is a frequent metastatic route for cancers of the ovary and gastrointestinal tract. Tumour cells metastasize by attaching to and invading through the mesothelial cell (MC) monolayer that lines the peritoneal cavity. Metastases are influenced by carcinoma-associated fibroblasts (CAFs), a cell population that derives from different sources. Hence, we investigated whether MCs, through mesothelial-mesenchymal transition (MMT), were a source of CAFs during peritoneal carcinomatosis and whether MMT affected the adhesion and invasion of tumour cells. Biopsies from patients with peritoneal dissemination revealed the presence of myofibroblasts expressing mesothelial markers in the proximity of carcinoma implants. Prominent new vessel formation was observed in the peritoneal areas harbouring tumour cells when compared with tumour-free regions. The use of a mouse model of peritoneal dissemination confirmed the myofibroblast conversion of MCs and the increase in angiogenesis at places of tumour implants. Treatment of omentum MCs with conditioned media from carcinoma cell cultures resulted in phenotype changes reminiscent of MMT. Adhesion experiments demonstrated that MMT enhanced the binding of cancer cells to MCs in a β1-integrin-dependent manner. Scanning electron microscopy imaging showed that the enhanced adhesion was mostly due to increased cell-cell interaction and not to a mere matrix exposure. Invasion assays suggested a reciprocal stimulation of the invasive capacity of tumour cells and MCs. Our results demonstrate that CAFs can derive from mesothelial cells during peritoneal metastasis. We suggest that MMT renders the peritoneum more receptive for tumour cell attachment/invasion and contributes to secondary tumour growth by promoting its vascularization.
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Affiliation(s)
- Pilar Sandoval
- Centro de Biología Molecular-Severo Ochoa, CSIC-UAM, Cantoblanco, Madrid, Spain
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Mesenchymal Conversion of Mesothelial Cells Is a Key Event in the Pathophysiology of the Peritoneum during Peritoneal Dialysis. Adv Med 2014; 2014:473134. [PMID: 26556413 PMCID: PMC4590954 DOI: 10.1155/2014/473134] [Citation(s) in RCA: 72] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/12/2013] [Revised: 11/09/2013] [Accepted: 11/18/2013] [Indexed: 12/03/2022] Open
Abstract
Peritoneal dialysis (PD) is a therapeutic option for the treatment of end-stage renal disease and is based on the use of the peritoneum as a semipermeable membrane for the exchange of toxic solutes and water. Long-term exposure of the peritoneal membrane to hyperosmotic PD fluids causes inflammation, loss of the mesothelial cells monolayer, fibrosis, vasculopathy, and angiogenesis, which may lead to peritoneal functional decline. Peritonitis may further exacerbate the injury of the peritoneal membrane. In parallel with these peritoneal alterations, mesothelial cells undergo an epithelial to mesenchymal transition (EMT), which has been associated with peritoneal deterioration. Factors contributing to the bioincompatibility of classical PD fluids include the high content of glucose/glucose degradation products (GDPs) and their acidic pH. New generation low-GDPs-neutral pH fluids have improved biocompatibility resulting in better preservation of the peritoneum. However, standard glucose-based fluids are still needed, as biocompatible solutions are expensive for many potential users. An alternative approach to preserve the peritoneal membrane, complementary to the efforts to improve fluid biocompatibility, is the use of pharmacological agents protecting the mesothelium. This paper provides a comprehensive review of recent advances that point to the EMT of mesothelial cells as a potential therapeutic target to preserve membrane function.
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Zhang L, Liu F, Peng Y, Sun L, Chen G. Changes in expression of four molecular marker proteins and one microRNA in mesothelial cells of the peritoneal dialysate effluent fluid of peritoneal dialysis patients. Exp Ther Med 2013; 6:1189-1193. [PMID: 24223642 PMCID: PMC3820727 DOI: 10.3892/etm_2013.1281] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2013] [Accepted: 08/21/2013] [Indexed: 01/15/2023] Open
Abstract
The aim of this study was to detect the expression of microRNA-200c and epithelial-mesenchymal transition (EMT) in the mesothelial cells of the peritoneal dialysate effluent fluid of peritoneal dialysis (PD) patients, and to investigate the association between microRNA-200c and peritoneal mesothelial cell EMT. Twelve patients who had recently started continuous ambulatory peritoneal dialysis (PD start group) and 16 patients who had been undergoing peritoneal dialysis for >6 months (PD >6 months group) were randomly chosen for the isolation, culture and identification of effluent cells. qPCR and western blot analysis were used to detect the expression levels of microRNA-200c and the levels of four cellular marker proteins, E-cadherin, vimentin, fibronectin (FN) and COL-1, in effluent cells. The results showed that the effluent cells in peritoneal dialysis were peritoneal mesothelial cells. The level of E-cadherin protein expression was significantly lower in the PD >6 months group than in the PD start group, while vimentin, FN and COL-1 protein expression levels were significantly increased in the PD >6 months group. microRNA-200c in the PD >6 months group was significantly downregulated. The E-cadherin protein expression level was significantly decreased and vimentin, FN and COL-1 protein expression levels were significantly increased in the PD >6 months group. The level of microRNA-200c was significantly reduced in the PD > 6 months group, suggesting that microRNA-200c may be associated with EMT.
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Affiliation(s)
- Lin Zhang
- Department of Nephrology, Second Xiangya Hospital, Institute of Nephrology, Central South University, Changsha, Hunan 410011; ; Department of Nephrology, Fourth Changsha Hospital, Changsha, Hunan 410006, P.R. China
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Young VJ, Brown JK, Saunders PT, Horne AW. The role of the peritoneum in the pathogenesis of endometriosis. Hum Reprod Update 2013; 19:558-69. [DOI: 10.1093/humupd/dmt024] [Citation(s) in RCA: 110] [Impact Index Per Article: 9.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
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Zhang F, Liu H, Liu F, Peng Y, Chen M, Liu Y, Chen G. New insights into the pathogenesis and treatment of peritoneal fibrosis: a potential role of Wnt/β-catenin induced epithelial to mesenchymal transition and stem cells for therapy. Med Hypotheses 2013; 81:97-100. [PMID: 23623424 DOI: 10.1016/j.mehy.2013.03.036] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2012] [Accepted: 03/28/2013] [Indexed: 11/18/2022]
Abstract
Peritoneal fibrosis is a chronic, progressive progress, which is associated with ultrafiltration failure. In the development of peritoneal fibrosis, Epithelial to mesenchymal transition is an important cellular process whereby epithelial cells transform into mesenchymal cells under physiology and pathology conditions, along with change of cell morphology and expression of related genes. It plays an important role in embryogenesis and development of tissues and organs, as well as organ fibrosis and tumorigenesis. Several intracellular signal transduction pathways induce the process of Epithelial to mesenchymal transition. In recent researches, Wnt/β-catenin induced epithelial to mesenchymal transition was suggested to be an important reason for tissues and organs fibrosis. The following paper reviews the potential role of Wnt/β-catenin induced epithelial to mesenchymal transition in peritoneal fibrosis. New potential therapeutic interventions of peritoneal fibrosis are discussed.
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Affiliation(s)
- Fan Zhang
- Nephrology Department, Second Xiangya Hospital, Renal Research Institute of Central South University, People's Republic of China
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Yang CY, Chau YP, Lee HT, Kuo HY, Lee OK, Yang AH. Cannabinoid receptors as therapeutic targets for dialysis-induced peritoneal fibrosis. Am J Nephrol 2013; 37:50-8. [PMID: 23296044 DOI: 10.1159/000345726] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2012] [Accepted: 11/07/2012] [Indexed: 12/21/2022]
Abstract
BACKGROUND Long-term exposure to bioincompatible peritoneal dialysis solutions is frequently complicated with peritoneal fibrosis and ultrafiltration failure. As cannabinoid receptor (CBR) ligands have been reported to be beneficial to ameliorate the process of liver fibrosis, we strove to investigate their therapeutic potential to prevent peritoneal fibrosis. METHODS We used the rat model of peritoneal fibrosis induced by intraperitoneal injection of methylglyoxal and in vitro mesothelial cell culture to test the effects of CBR ligands, including the type 1 CBR (CB(1)R) antagonist and the type 2 CBR (CB(2)R) agonist. RESULTS In the methylglyoxal model, both intraperitoneal CB(1)R antagonist (AM281) and CB(2)R agonist (AM1241) treatment significantly ameliorated peritoneal fibrosis. In addition, CB(1)R antagonist was able to alleviate TGF-β(1)-induced dedifferentiation of mesothelial cells and to maintain epithelial integrity in vitro. CONCLUSIONS Intraperitoneal administration of CBR ligands (CB(1)R antagonist and CB(2)R agonist) offers a potential therapeutic strategy to reduce dialysis-induced peritoneal fibrosis and to prolong the peritoneal survival in peritoneal dialysis patients.
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Affiliation(s)
- Chih-Yu Yang
- Division of Nephrology, Taipei Veterans General Hospital, Taipei, Taiwan, ROC
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Sohler F, Sommer A, Wachter DL, Agaimy A, Fischer OM, Renner SP, Burghaus S, Fasching PA, Beckmann MW, Fuhrmann U, Strick R, Strissel PL. Tissue remodeling and nonendometrium-like menstrual cycling are hallmarks of peritoneal endometriosis lesions. Reprod Sci 2012; 20:85-102. [PMID: 22878529 DOI: 10.1177/1933719112451147] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
Abstract
We identified differentially expressed genes comparing peritoneal endometriosis lesions (n = 18), eutopic endometrium (n = 17), and peritoneum (n = 22) from the same patients with complete menstrual cycles using microarrays (54 675 probe sets) and immunohistochemistry. Peritoneal lesions and peritoneum demonstrated 3901 and 4973 significantly differentially expressed genes compared to eutopic endometrium, respectively. Peritoneal lesions significantly revealed no correlation with a specific menstrual cycle phase by gene expression and histopathology, exhibited low expressed proliferation genes, and constant levels of steroid hormone receptor genes. Tissue remodeling genes in cytoskeleton, smooth muscle contraction, cellular adhesion, tight junctions, and O-glycan biosynthesis were the most significant to lesions, including desmin and smooth muscle myosin heavy chain 11. Protein expression and location of desmin, alpha-actin, and h-caldesmon in peritoneal lesions discriminated between smooth muscle hyperplasia and metaplasia. Peritoneal lesions demonstrate no menstrual cycle phasing but constant steroid hormone receptor expression where a slow but steady growth is linked with tissue remodeling. Our study contributes to the molecular pathology of peritoneal endometriosis and will help to identify clinical targets for treatment and management.
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Affiliation(s)
- Florian Sohler
- Global Drug Discovery, Target Discovery, Bayer Healthcare Pharmaceuticals, Berlin, Germany
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Patterns of matrix metalloproteinases and transforming growth factor-beta 1 expression during peritoneal repair in chlorhexidine induced peritoneal fibrosis mice. Int J Organ Transplant Med 2012. [DOI: 10.1016/j.hkjn.2012.01.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2022] Open
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Cho JH, Do JY, Oh EJ, Ryu HM, Park SY, Kim SO, Hyun SH, Seo HJ, Kim GH, Choi JY, Kim CD, Park SH, Kim YL. Are ex vivo mesothelial cells representative of the in vivo transition from epithelial-to-mesenchymal cells in peritoneal membrane? Nephrol Dial Transplant 2011; 27:1768-79. [PMID: 22025117 DOI: 10.1093/ndt/gfr604] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Abstract
BACKGROUND We investigated whether ex vivo mesothelial cells found in peritoneal dialysis (PD) effluents were representative of the in vivo epithelial-to-mesenchymal transition (EMT) in peritoneal membrane. METHODS Thirty-six male Sprague-Dawley rats were equally divided into three groups: Group C (control), no PD; Group D, infused with 4.25% Dianeal and Group P, infused with 4.25% Physioneal. PD infusions (25 mL) were given twice daily for 8 weeks. The in vivo study included morphometric analyses performed on the peritoneal membranes of tissue specimens obtained at the end of the study. The ex vivo study included peritoneal mesothelial cells collected from PD effluent and cultured to confluence. Cells were scored with light microscopy. RESULTS PD for 8 weeks induced significant EMT. The in vivo expression of EMT markers (α-smooth muscle actin:E-cadherin ratio, matrix metalloproteinase-2 and Snail) was higher in Group D than in Group P. However, ex vivo EMT marker expression was similar in cells derived from Groups D and P. A significant correlation was observed among in vivo EMT markers. Moreover, the ex vivo cell score increased with time on PD. However, changes in the ex vivo cell score did not correlated with changes in the in vivo EMT marker expression. Furthermore, we found no correlation between ex vivo and in vivo cells in the expression of EMT markers. CONCLUSIONS In this animal study, ex vivo findings did not reflect the in vivo EMT changes in the peritoneum. It may be necessary to improve the current methodology for ex vivo studies.
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Affiliation(s)
- Ji-Hyung Cho
- Department of Internal Medicine, CHA Gumi Medical Center, CHA University, Gumi-si, Korea
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