scholarly journals Pathophysiological Changes to the Peritoneal Membrane during PD-Related Peritonitis: The Role of Mesothelial Cells

2012 ◽  
Vol 2012 ◽  
pp. 1-21 ◽  
Author(s):  
Susan Yung ◽  
Tak Mao Chan
Keyword(s):  
Inflammatory Responses ◽  
Genetic Manipulation ◽  
Mesothelial Cell ◽  
Major Complication ◽  
Mesothelial Cells ◽  
Peritoneal Membrane ◽  
Peritoneal Fibrosis ◽  
Functional Changes ◽  
Membrane Structure And Function ◽  
And Function

The success of peritoneal dialysis (PD) is dependent on the structural and functional integrity of the peritoneal membrane. The mesothelium lines the peritoneal membrane and is the first line of defense against chemical and/or bacterial insult. Peritonitis remains a major complication of PD and is a predominant cause of technique failure, morbidity and mortality amongst PD patients. With appropriate antibiotic treatment, peritonitis resolves without further complications, but in some PD patients excessive peritoneal inflammatory responses lead to mesothelial cell exfoliation and thickening of the submesothelium, resulting in peritoneal fibrosis and sclerosis. The detrimental changes in the peritoneal membrane structure and function correlate with the number and severity of peritonitis episodes and the need for catheter removal. There is evidence that despite clinical resolution of peritonitis, increased levels of inflammatory and fibrotic mediators may persist in the peritoneal cavity, signifying persistent injury to the mesothelial cells. This review will describe the structural and functional changes that occur in the peritoneal membrane during peritonitis and how mesothelial cells contribute to these changes and respond to infection. The latter part of the review discusses the potential of mesothelial cell transplantation and genetic manipulation in the preservation of the peritoneal membrane.

Lithium preserves peritoneal membrane integrity by suppressing mesothelial cell αB-crystallin

2021 ◽  
Vol 13 (608) ◽  
pp. eaaz9705
Author(s):  
Rebecca Herzog ◽  
Juan Manuel Sacnun ◽  
Guadalupe González-Mateo ◽  
Maria Bartosova ◽  
Katarzyna Bialas ◽  
...  
Keyword(s):  
Cell Injury ◽  
Membrane Integrity ◽  
Mesothelial Cell ◽  
Mesothelial Cells ◽  
Cell Protein ◽  
Dependent Manner ◽  
Peritoneal Membrane ◽  
Peritoneal Fibrosis ◽  
Mesenchymal Transition ◽  
Αb Crystallin

Life-saving renal replacement therapy by peritoneal dialysis (PD) is limited in use and duration by progressive impairment of peritoneal membrane integrity and homeostasis. Preservation of peritoneal membrane integrity during chronic PD remains an urgent but long unmet medical need. PD therapy failure results from peritoneal fibrosis and angiogenesis caused by hypertonic PD fluid (PDF)–induced mesothelial cytotoxicity. However, the pathophysiological mechanisms involved are incompletely understood, limiting identification of therapeutic targets. We report that addition of lithium chloride (LiCl) to PDF is a translatable intervention to counteract PDF-induced mesothelial cell death, peritoneal membrane fibrosis, and angiogenesis. LiCl improved mesothelial cell survival in a dose-dependent manner. Combined transcriptomic and proteomic characterization of icodextrin-based PDF-induced mesothelial cell injury identified αB-crystallin as the mesothelial cell protein most consistently counter-regulated by LiCl. In vitro and in vivo overexpression of αB-crystallin triggered a fibrotic phenotype and PDF-like up-regulation of vascular endothelial growth factor (VEGF), CD31-positive cells, and TGF-β–independent activation of TGF-β–regulated targets. In contrast, αB-crystallin knockdown decreased VEGF expression and early mesothelial-to-mesenchymal transition. LiCl reduced VEGF release and counteracted fibrosis- and angiogenesis-associated processes. αB-crystallin in patient-derived mesothelial cells was specifically up-regulated in response to PDF and increased in peritoneal mesothelial cells from biopsies from pediatric patients undergoing PD, correlating with markers of angiogenesis and fibrosis. LiCl-supplemented PDF promoted morphological preservation of mesothelial cells and the submesothelial zone in a mouse model of chronic PD. Thus, repurposing LiCl as a cytoprotective PDF additive may offer a translatable therapeutic strategy to combat peritoneal membrane deterioration during PD therapy.

scholarly journals FC 105LITHIUM PRESERVES PERITONEAL MEMBRANE INTEGRITY BY REDUCING MESOTHELIAL CELL ΑB-CRYSTALLIN

2021 ◽  
Vol 36 (Supplement_1) ◽  
Author(s):  
Rebecca Herzog ◽  
Guadalupe González ◽  
Maria Bartosova ◽  
Juan Manuel Sacnun ◽  
Lisa Daniel-Fischer ◽  
...  
Keyword(s):  
Cell Injury ◽  
Membrane Integrity ◽  
Mesothelial Cell ◽  
Mesothelial Cells ◽  
Peritoneal Membrane ◽  
Peritoneal Fibrosis ◽  
Peritoneal Mesothelial Cells ◽  
Αb Crystallin

Abstract Background and Aims Renal replacement therapy by peritoneal dialysis (PD) is limited in use and duration by progressive impairment of peritoneal membrane integrity and homeostasis. Preservation of peritoneal membrane integrity during chronic PD remains an urgent but long-unmet medical need. PD therapy failure results from peritoneal fibrosis and angiogenesis caused by hypertonic PD fluid (PDF)-induced mesothelial cytotoxicity. The incompletely defined pathophysiological mechanisms involved confound informed selection of therapeutic targets. Addition of cytoprotective agents to PDF have been shown to counteract pathophysiological mechanisms induced by current PDF. Lithium is a well described inhibitor of glycogen synthase kinase 3β and has recently been shown to also have nephroprotective effects in low doses. Here, we aim to characterize icodextrin-based, PDF-induced cellular injury with a combined omics approach and to investigate the effects of LiCl on the PD-induced observed molecular perturbations. Method To investigate mechanisms of acute cellular damage by PDF we chose an in vitro model of primary omental-derived peritoneal mesothelial cells with direct exposure to icodextrin-based PDF, followed by short-term or extended recovery for detection of short-term and long-term changes in transcriptome, proteome, and cell injury. 0, 2.5 or 10 mM LiCl were added to the PDF. In-vitro findings were validated in peritoneal biopsies (n=41) from pediatric PD and CDK5 patients or healthy controls and peritoneal effluents from adult and pediatric PD patients (n=27) or ascites samples (n=4) as control. For in-vivo experiments, healthy and uremic mice (C57/Bl6, female) were chronically exposed to PD-fluid without or with the addition of 5 mM LiCl via an implanted catheter. In-vivo overexpression of CRYAB was induced by i.p. injection of an adenoviral vector. All animal experiments and use of patient samples were approved by the local ethics committees and performed according to animal protection laws or the Declaration of Helsinki, respectively. Results LiCl significantly improved mesothelial cell survival in a dose-dependent manner. Combined transcriptomic and proteomic characterization of icodextrin-based PDF-induced mesothelial cell injury identified αB-crystallin as the mesothelial cell protein most significantly and consistently counter-regulated by LiCl. In-vitro and in-vivo overexpression of αB-crystallin triggered a fibrotic phenotype and PDF-like upregulation of vascular endothelial growth factor (VEGF), CD31-positive cells, and TGFβ-independent activation of TGFβ-regulated targets. In contrast, αB-crystallin knock-down decreased VEGF expression and early mesothelial-to-mesenchymal transition (MMT). LiCl reduced VEGF release and counteracted fibrosis- and angiogenesis-associated processes. αB-crystallin in patient-derived mesothelial cells was specifically upregulated in response to PDF and increased in peritoneal mesothelial cells from pediatric PD patient biopsies, correlating with markers of angiogenesis and fibrosis. Conclusion The cytoprotective effects of LiCl-supplemented PDF may be explained by counter-regulation of PD-induced angiogenesis via the novel target αB-crystallin. Reduction of mesothelial cell damage, peritoneal fibrosis and VEGF suggests therapeutic potential of this intervention. Repurposing LiCl as a cytoprotective PDF additive may offer a translatable therapeutic strategy to combat peritoneal membrane deterioration during PD therapy. Further study of LiCl-supplemented PDF is merited as a realistic approach to improving treatment longevity and patient outcomes during PD treatment.

Mesothelial Cells

2007 ◽  
Vol 27 (2_suppl) ◽  
pp. 110-115 ◽  
Author(s):  
Susan Yung ◽  
Chan Tak Mao
Keyword(s):  
Mesothelial Cell ◽  
In Vitro Models ◽  
Mesothelial Cells ◽  
Dynamic Membrane ◽  
Peritoneal Mesothelial Cells ◽  
Immunohistochemical Markers ◽  
Vitro Model ◽  
And Function

♦ Background The introduction of peritoneal dialysis (PD) as a modality of renal replacement therapy has provoked much interest in the biology of the peritoneal mesothelial cell. Mesothelial cells isolated from omental tissue have immunohistochemical markers that are identical to those of mesothelial stem cells, and omental mesothelial cells can be cultivated in vitro to study changes to their biologic functions in the setting of PD. ♦ Method The present article describes the structure and function of mesothelial cells in the normal peritoneum and details the morphologic changes that occur after the introduction of PD. Furthermore, this article reviews the literature of mesothelial cell culture and the limitations of in vitro studies. ♦ Results The mesothelium is now considered to be a dynamic membrane that plays a pivotal role in the homeostasis of the peritoneal cavity, contributing to the control of fluid and solute transport, inflammation, and wound healing. These functional properties of the mesothelium are compromised in the setting of PD. Cultures of peritoneal mesothelial cells from omental tissue provide a relevant in vitro model that allows researchers to assess specific molecular pathways of disease in a distinct population of cells. Structural and functional attributes of mesothelial cells are discussed in relation to long-term culture, proliferation potential, age of tissue donor, use of human or animal in vitro models, and how the foregoing factors may influence in vitro data. ♦ Conclusions The ability to propagate mesothelial cells in culture has resulted, over the past two decades, in an explosion of mesothelial cell research pertaining to PD and peritoneal disorders. Independent researchers have highlighted the potential use of mesothelial cells as targets for gene therapy or transplantation in the search to provide therapeutic strategies for the preservation of the mesothelium during chemical or bacterial injury.

scholarly journals Peritoneal Dialysis in the 21st Century: The Potential of Gene Therapy

2002 ◽  
Vol 13 (suppl 1) ◽  
pp. S117-S124
Author(s):  
Catherine M. Hoff ◽  
Ty R. Shockley
Keyword(s):  
Gene Therapy ◽  
Peritoneal Dialysis ◽  
Genetic Engineering ◽  
Genetic Manipulation ◽  
Membrane Damage ◽  
Peritoneal Membrane ◽  
Functional Changes ◽  
Therapy Strategy ◽  
Transfer Strategies ◽  
Gene Therapy Strategy

ABSTRACT. One of the greatest biotechnologic advances of the last 25 yr is genetic engineering—the ability to identify and isolate individual genes and transfer genetic elements between cells. Genetic engineering forms the basis of a unique biotechnology platform called gene therapy: an approach to treating disease through genetic manipulation. It is becoming clear that during peritoneal dialysis, the peritoneal membrane undergoes various structural and functional changes that compromise the dialyzing efficiency of the membrane and eventually lead to membrane failure. A gene therapy strategy based on genetic modification of the peritoneal membrane could improve the practice of peritoneal dialysis through the production of proteins that would be of therapeutic value in preventing membrane damage and preserving its dialyzing capacity. The peritoneal membrane can be genetically modified by either ex vivo or in vivo gene transfer strategies with a variety of potentially therapeutic genes, including those for anti-inflammatory cytokines, fibrinolytic factors, and antifibrotic molecules. These genes could be administered either on an acute basis, such as in response to peritonitis, or on an intermittent basis to maintain physiologic homeostasis and perhaps to prevent the adverse changes in the membrane that occur over time. The anticipated effect of a gene therapy strategy could be measured in maintenance of desired transport characteristics and in patients being able to remain on the therapy for longer periods of time without the negative outcomes. In summary, the use of a gene therapy strategy to enhance peritoneal dialysis is an innovative and exciting concept with the potential to provide new treatment platforms for patients with end-stage renal disease.

The John F. Maher Recipient Lecture 2004: Rage in the Peritoneum

2005 ◽  
Vol 25 (1) ◽  
pp. 8-11 ◽  
Author(s):  
An S. De Vriese
Keyword(s):  
Growth Factor ◽  
Transforming Growth Factor Beta ◽  
High Glucose ◽  
Transforming Growth Factor ◽  
Degradation Products ◽  
Mesothelial Cells ◽  
Cell Surface Receptor ◽  
Peritoneal Membrane ◽  
Peritoneal Fibrosis ◽  
Mesenchymal Transition

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.

Intrinsic Cells: Mesothelial Cells — Central Players in Regulating Inflammation and Resolution

2009 ◽  
Vol 29 (2_suppl) ◽  
pp. 21-27 ◽  
Author(s):  
Susan Yung ◽  
Tak Mao Chan
Keyword(s):  
Mesothelial Cell ◽  
Protective Layer ◽  
Mesothelial Cells ◽  
Matrix Proteins ◽  
Peritoneal Membrane ◽  
Peritoneal Inflammation ◽  
Reparative Process ◽  
Novel Therapeutic Strategies ◽  
Peritoneal Function ◽  
Potential Use

Background Preservation of the structural and functional integrity of the peritoneum is essential to maintain the dialytic efficacy of the peritoneal membrane. Although much improvement has been made to peritoneal dialysis (PD) fluids, they remain bioincompatible, and together with peritonitis, they continue to induce peritoneal inflammation and fibrosis. Method This article reviews the putative factors that mediate mesothelial cell inflammation during PD, and the mechanisms by which mesothelial cells attempt to regulate and resolve peritoneal inflammation. Results The mesothelium is the first line of defense to foreign particles and chemicals in the peritoneal cavity. Constant exposure of the mesothelium to the bioincompatible constituents of PD solutions results in denudation of the mesothelium and loss of the peritoneal cavity's protective layer. Detached mesothelial cells in PD solutions have the capacity to replenish the mesothelial layer through their ability to migrate and attach to areas of denudation. Mesothelial cells synthesize a plethora of growth factors, matrix proteins, and proteoglycans that aid in the reparative process and regulate the formation of chemotactic gradients that are essential for infiltration of leukocytes to sites of injury. Conclusions Far from being bystanders in peritoneal function, mesothelial cells have been shown to play a dynamic role in peritoneal homeostasis and immunoregulation. Studies have highlighted the potential use of mesothelial cells in gene therapy and cell transplantation, both of which may provide novel therapeutic strategies for the preservation of the peritoneum during PD.

Overnight Mesothelial Cell Exfoliation: A Magic Tool for Predicting Future Ultrafiltration Failure in Patients on Continuous Ambulatory Peritoneal Dialysis

2008 ◽  
Vol 28 (3_suppl) ◽  
pp. 107-113
Author(s):  
Talerngsak Kanjanabuch ◽  
Monchai Siribamrungwong ◽  
Rungrote Khunprakant ◽  
Sirigul Kanjanabuch ◽  
Piyathida Jeungsmarn ◽  
...  
Keyword(s):  
Peritoneal Dialysis ◽  
Continuous Ambulatory Peritoneal Dialysis ◽  
Mesothelial Cell ◽  
Mesothelial Cells ◽  
Nutrition Status ◽  
Continuous Exposure ◽  
Peritoneal Membrane ◽  
Dialysis Solution ◽  
Ultrafiltration Failure

⋄ Background Continuous exposure of the peritoneal membrane to dialysis solutions during long-term dialysis results in mesothelial cell loss, peritoneal membrane damage, and thereby, ultrafiltration (UF) failure, a major determinant of mortality in patients on continuous ambulatory peritoneal dialysis (CAPD). Unfortunately, none of tests available today can predict long-term UF decline. Here, we propose a new tool to predict such a change. ⋄ Mesothelial cells from 8-hour overnight effluents (1.36% glucose dialysis solution) were harvested, co-stained with cytokeratin (a mesothelial marker) and TUNEL (an apoptotic marker), and were counted using flow cytometry in 48 patients recently started on CAPD. Adequacy of dialysis, UF, nutrition status, dialysate cancer antigen 125 (CA125), and a peritoneal equilibration test (3.86% glucose peritoneal dialysis solution) were simultaneously assessed and were reevaluated 1 year later. ⋄ Results The numbers of total and apoptotic mesothelial cells were 0.19 ± 0.19 million and 0.08 ± 0.12 million cells per bag, respectively. Both numbers correlated well with the levels of end dialysate–to–initial dialysate (D/D0) glucose, dialysate-to-plasma (D/P) creatinine, and sodium dipping. Notably, the counts of cells of both types in patients with diabetes or with high or high-average transport were significantly greater than the equivalent counts in nondiabetic patients or those with low or low-average transport. A cutoff of 0.06 million total mesothelial cells per bag had sensitivity of 1 and a specificity of 0.75 in predicting a further decline in D/D0 glucose and a sensitivity of 0.86 and a specificity of 0.63 to predict a further decline in UF over a 1-year period. In contrast, dialysate CA125 and other measured parameters had low predictive values. ⋄ Conclusions The greater the loss of exfoliated cells, the worse the expected decline in UF. The ability of a count of mesothelial cells to predict a future decline in UF warrants further investigation in clinical practice.

scholarly journals NFAT5 Contributes to Osmolality-Induced MCP-1 Expression in Mesothelial Cells

2012 ◽  
Vol 2012 ◽  
pp. 1-12 ◽  
Author(s):  
Christoph Küper ◽  
Franz-X. Beck ◽  
Wolfgang Neuhofer
Keyword(s):  
Transcription Factor ◽  
Mesothelial Cell ◽  
Nuclear Factor Κb ◽  
Mesothelial Cells ◽  
Nuclear Factor ◽  
Peritoneal Fibrosis ◽  
Activated T Cells ◽  
Monocyte Chemoattractant Protein 1 ◽  
Monocyte Chemoattractant ◽  
Transcription Factor Nuclear Factor

Increased expression of the C-C chemokine monocyte chemoattractant protein-1 (MCP-1) in mesothelial cells in response to high glucose concentrations and/or high osmolality plays a crucial role in the development of peritoneal fibrosis during continuous ambulatory peritoneal dialysis (CAPD). Recent studies suggest that in kidney cells osmolality-induced MCP-1 upregulation is mediated by the osmosensitive transcription factor, nuclear factor of activated T cells 5 (NFAT5). The present study addressed the question of whether activation of NFAT5 by hyperosmolality, as present in PD fluids, contributes to MCP-1 expression in the mesothelial cell line Met5A. Hyperosmolality, induced by addition of glucose, NaCl, or mannitol to the growth medium, increased NFAT5 activity and stimulated MCP-1 expression in Met5A cells. siRNA-mediated knockdown of NFAT5 attenuated osmolality-induced MCP-1 upregulation substantially. Hyperosmolality also induced activation of nuclear factor-κB (NF-κB). Accordingly, pharmacological inhibition of NF-κB significantly decreased osmolality-induced MCP-1 expression. Taken together, these results indicate that high osmolalities activate the transcription factor NFAT5 in mesothelial cells. NFAT5 in turn upregulates MCP-1, likely in combination with NF-κB, and thus may participate in the development of peritoneal fibrosis during CAPD.

scholarly journals miRNA589 Regulates Epithelial-Mesenchymal Transition in Human Peritoneal Mesothelial Cells

2012 ◽  
Vol 2012 ◽  
pp. 1-6 ◽  
Author(s):  
Ke Zhang ◽  
Hao Zhang ◽  
Xun Zhou ◽  
Wen-bin Tang ◽  
Li Xiao ◽  
...  
Keyword(s):  
Epithelial Mesenchymal Transition ◽  
Mesothelial Cell ◽  
Mesothelial Cells ◽  
Control Group ◽  
Peritoneal Fibrosis ◽  
Mesenchymal Transition ◽  
Peritoneal Mesothelial Cells ◽  
Human Peritoneal Mesothelial Cells ◽  
E Cadherin

Background. microRNA (miRNA, miR) are thought to interact with multiple mRNAs which are involved in the EMT process. But the role of miRNAs in peritoneal fibrosis has remained unknown.Objective. To determine if miRNA589 regulates the EMT induced by TGFβ1 in human peritoneal mesothelial cell line (HMrSV5 cells).Methods. 1. Level of miR589 was detected in both human peritoneal mesothelial cells (HPMCs) isolated from continuous ambulatory peritoneal dialysis (CAPD) patients’ effluent and HMrSV5 cells treated with or without TGFβ1. 2. HMrSV5 cells were divided into three groups: control group, TGFβ1 group, and pre-miR-589+TGFβ1 group. The level of miRNA589 was determined by realtime PCR. The expressions of ZO-1, vimentin, and E-cadherin in HPMCs were detected, respectively.Results. Decreased level of miRNA589 was obtained in either HPMCs of long-term CAPD patients or HMrSV5 cells treated with TGFβ1. In vitro, TGFβ1 led to upregulation of vimentin and downregulation of ZO-1 as well as E-cadherin in HMrSV5 cells, which suggested EMT, was induced. The changes were accompanied with notably decreased level of miRNA589 in HMrSV5 cells treated with TGFβ1. Overexpression of miRNA589 by transfection with pre-miRNA589 partially reversed these EMT changes.Conclusion. miRNA589 mediates TGFβ1 induced EMT in human peritoneal mesothelial cells.

scholarly journals Peritoneal Membrane Injury and Peritoneal Dialysis

2014 ◽  
Vol 2014 ◽  
pp. 1-10 ◽  
Author(s):  
Shaan Chugh ◽  
Sultan Chaudhry ◽  
Timothy Ryan ◽  
Peter J. Margetts
Keyword(s):  
Peritoneal Dialysis ◽  
Patient Outcomes ◽  
Structure And Function ◽  
Peritoneal Membrane ◽  
Membrane Injury ◽  
Common Life ◽  
Membrane Structure And Function ◽  
And Function ◽  
Technique Failure ◽  
Improve Patient

For patients with chronic renal failure, peritoneal dialysis (PD) is a common, life sustaining form of renal replacement therapy that is used worldwide. Exposure to nonbiocompatible dialysate, inflammation, and uremia induces longitudinal changes in the peritoneal membrane. Application of molecular biology techniques has led to advances in our understanding of the mechanism of injury of the peritoneal membrane. This understanding will allow for the development of strategies to preserve the peritoneal membrane structure and function. This may decrease the occurrence of PD technique failure and improve patient outcomes of morbidity and mortality.

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