scholarly journals Epithelial to Mesenchymal Transition and Peritoneal Membrane Failure in Peritoneal Dialysis Patients: Pathologic Significance and Potential Therapeutic Interventions

2007 ◽  
Vol 18 (7) ◽  
pp. 2004-2013 ◽  
Author(s):  
Luiz S. Aroeira ◽  
Abelardo Aguilera ◽  
José A. Sánchez-Tomero ◽  
M. Auxiliadora Bajo ◽  
Gloria del Peso ◽  
...  
Keyword(s):  
Peritoneal Dialysis ◽  
Epithelial To Mesenchymal Transition ◽  
Therapeutic Interventions ◽  
Peritoneal Membrane ◽  
Dialysis Patients ◽  
Mesenchymal Transition

Long-term Intervention with Heparins in a Rat Model of Peritoneal Dialysis

2009 ◽  
Vol 29 (1) ◽  
pp. 26-35 ◽  
Author(s):  
Margot N. Schilte ◽  
Jesus Loureiro ◽  
Eelco D. Keuning ◽  
Piet M. ter Wee ◽  
Johanna W.A.M. Celie ◽  
...  
Keyword(s):  
Peritoneal Dialysis ◽  
Epithelial To Mesenchymal Transition ◽  
Morphological Changes ◽  
Glucose Absorption ◽  
Peritoneal Membrane ◽  
Access Port ◽  
Mesenchymal Transition ◽  
Chronic Inflammatory Condition ◽  
Peritoneal Leukocytes

Background Peritoneal dialysis (PD) is associated with functional and structural alterations of the peritoneal membrane, particularly new vessel formation and fibrosis. In addition to anticoagulant effects, heparin displays anti-inflammatory and angiostatic properties. Therefore, the effects of administration of heparins on function and morphology of the peritoneal membrane were studied in a rat PD model. Methods Rats received 10 mL conventional PD fluid (PDF) daily, with or without the addition of unfractionated heparin (UFH) or low molecular weight heparin (LMWH) in the PDF (1 mg/10 mL intraperitoneally) via a mini access port. Untreated rats served as controls. After 5 weeks, a 90-minute functional peritoneal transport test was performed and tissues and peritoneal leukocytes were taken. Results PD treatment induced loss of ultrafiltration ( p < 0.01), a twofold increase in glucose absorption ( p < 0.03), increased urea transport ( p < 0.02), and loss of sodium sieving ( p < 0.03), which were also found in the PDF + heparin groups. Increased peritoneal cell influx and hyaluronan production ( p < 0.02) as well as an exchange of mast cells and eosinophils for neutrophils after PD treatment were observed in PD rats; addition of heparin did not affect those changes. Mesothelial regeneration, submesothelial blood vessel and matrix formation, and accumulation of tissue macrophages were seen in PD animals. Spindle-shaped vimentin-positive and cytokeratin-negative cells indicated either partial injury and denudation of mesothelial cells or epithelial-to-mesenchymal transition. Neither UFH nor LMWH affected any of these morphological changes. Conclusion Within 5 weeks, PD treatment induces a chronic inflammatory condition in the peritoneum, evidenced by high transport, leukocyte recruitment, tissue remodeling, and induction of spindle-shaped cells in the mesothelium. Addition of LMWH or UFH to the PDF did not prevent these adverse PDF-induced peritoneal changes.

scholarly journals Molecular Mechanisms Underlying Peritoneal EMT and Fibrosis

2016 ◽  
Vol 2016 ◽  
pp. 1-11 ◽  
Author(s):  
Raffaele Strippoli ◽  
Roberto Moreno-Vicente ◽  
Cecilia Battistelli ◽  
Carla Cicchini ◽  
Valeria Noce ◽  
...  
Keyword(s):  
Peritoneal Dialysis ◽  
Molecular Mechanisms ◽  
Epithelial To Mesenchymal Transition ◽  
Pathological Process ◽  
Main Role ◽  
Peritoneal Membrane ◽  
Mesenchymal Transition ◽  
Permeable Barrier ◽  
Dialysis Solutions ◽  
Functional Deterioration

Peritoneal dialysis is a form of renal replacement alternative to the hemodialysis. During this treatment, the peritoneal membrane acts as a permeable barrier for exchange of solutes and water. Continual exposure to dialysis solutions, as well as episodes of peritonitis and hemoperitoneum, can cause acute/chronic inflammation and injury to the peritoneal membrane, which undergoes progressive fibrosis, angiogenesis, and vasculopathy, eventually leading to discontinuation of the peritoneal dialysis. Among the different events controlling this pathological process, epithelial to mesenchymal transition of mesothelial cells plays a main role in the induction of fibrosis and in subsequent functional deterioration of the peritoneal membrane. Here, the main extracellular inducers and cellular players are described. Moreover, signaling pathways acting during this process are elucidated, with emphasis on signals delivered by TGF-βfamily members and by Toll-like/IL-1βreceptors. The understanding of molecular mechanisms underlying fibrosis of the peritoneal membrane has both a basic and a translational relevance, since it may be useful for setup of therapies aimed at counteracting the deterioration as well as restoring the homeostasis of the peritoneal membrane.

scholarly journals Mesenchymal Conversion of Mesothelial Cells Is a Key Event in the Pathophysiology of the Peritoneum during Peritoneal Dialysis

2014 ◽  
Vol 2014 ◽  
pp. 1-17 ◽  
Author(s):  
Manuel López-Cabrera
Keyword(s):  
Peritoneal Dialysis ◽  
Epithelial To Mesenchymal Transition ◽  
Degradation Products ◽  
Therapeutic Option ◽  
Functional Decline ◽  
Mesothelial Cells ◽  
Peritoneal Membrane ◽  
Pharmacological Agents ◽  
Membrane Function ◽  
Mesenchymal Transition

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.

Ex Vivo Analysis of Dialysis Effluent-Derived Mesothelial Cells as an Approach to Unveiling the Mechanism of Peritoneal Membrane Failure

2006 ◽  
Vol 26 (1) ◽  
pp. 26-34 ◽  
Author(s):  
Manuel López-Cabrera ◽  
Abelardo Aguilera ◽  
Luiz S. Aroeira ◽  
Marta Ramírez-Huesca ◽  
M. Luisa Pérez-Lozano ◽  
...  
Keyword(s):  
Epithelial To Mesenchymal Transition ◽  
Ex Vivo ◽  
Functional Decline ◽  
Mesothelial Cells ◽  
Therapeutic Interventions ◽  
Peritoneal Membrane ◽  
Peritoneal Fibrosis ◽  
Stromal Fibroblasts ◽  
Mesenchymal Transition ◽  
Ultrafiltration Failure

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.

scholarly journals Shorter daily dwelling time in peritoneal dialysis attenuates the epithelial-to-mesenchymal transition of mesothelial cells

2014 ◽  
Vol 15 (1) ◽  
Author(s):  
Yi-Che Lee ◽  
Yau-Sheng Tsai ◽  
Shih-Yuan Hung ◽  
Tsun-Mei Lin ◽  
Sheng-Hsiang Lin ◽  
...  
Keyword(s):  
Peritoneal Dialysis ◽  
Epithelial To Mesenchymal Transition ◽  
Mesothelial Cells ◽  
Mesenchymal Transition ◽  
Dwelling Time

scholarly journals Systemic Endotoxin in Peritoneal Dialysis Patients

2018 ◽  
Vol 38 (5) ◽  
pp. 381-384 ◽  
Author(s):  
Ali M. Shendi ◽  
Nathan Davies ◽  
Andrew Davenport
Keyword(s):  
Peritoneal Dialysis ◽  
Extracellular Volume ◽  
Peritoneal Membrane ◽  
Dialysis Patients ◽  
Fungal Cell ◽  
Membrane Function ◽  
Patient Demographics ◽  
Markers Of Inflammation ◽  
Systemic Endotoxemia

Previous reports linked systemic endotoxemia in dialysis patients to increased markers of inflammation, cardiovascular disease, and mortality. Many peritoneal dialysis (PD) patients use acidic, hypertonic dialysates, which could potentially increase gut permeability, resulting in systemic endotoxemia. However, the results from studies measuring endotoxin in PD patients are discordant. We therefore measured systemic endotoxin in 55 PD outpatients attending for routine assessment of peritoneal membrane function; mean age 58.7 ± 16.4 years, 32 (58.2%) male, 21 (38.2%) diabetic, median duration of PD treatment 19.5 (13 – 31) months, 32 (58.2%) using 22.7 g/L dextrose dialysates, and 47 (85.5%) icodextrin. The median systemic endotoxin concentration was 0.0485 (0.0043 – 0.103) Eu/mL. We found no association between endotoxin levels and patient demographics, markers of inflammation, serum albumin, N-terminal pro-brain natriuretic peptide, extracellular volume measured by bioimpedance, blood pressure, PD prescriptions or peritoneal membrane transporter status, or medications. The measurement of endotoxin can be lowered by failure to effectively release protein-bound endotoxin prior to analysis and increased by contamination when taking blood samples and processing and storing the samples. Additionally, contamination with β–glucan from fungal cell walls and the use of different assays to analyze endotoxin can also give differing results. These factors may help to explain the disparate results reported in different studies. Our study would suggest that exposure to standard peritoneal dialysates does not substantially increase systemic endotoxin. However, until endotoxin assays can measure free and bound endotoxin separately, the role of endotoxin causing inflammation in PD patients remains to be determined.

scholarly journals Targeting AKT/mTOR in Oral Cancer: Mechanisms and Advances in Clinical Trials

2020 ◽  
Vol 21 (9) ◽  
pp. 3285 ◽  
Author(s):  
Choudhary Harsha ◽  
Kishore Banik ◽  
Hui Li Ang ◽  
Sosmitha Girisa ◽  
Rajesh Vikkurthi ◽  
...  
Keyword(s):  
Oral Cancer ◽  
Epithelial To Mesenchymal Transition ◽  
Mammalian Target Of Rapamycin ◽  
Mtor Inhibitors ◽  
Mtor Pathway ◽  
Mtor Signaling ◽  
Therapeutic Interventions ◽  
Treatment Modalities ◽  
Disease Heterogeneity ◽  
Mesenchymal Transition

Oral cancer (OC) is a devastating disease that takes the lives of lots of people globally every year. The current spectrum of treatment modalities does not meet the needs of the patients. The disease heterogeneity demands personalized medicine or targeted therapies. Therefore, there is an urgent need to identify potential targets for the treatment of OC. Abundant evidence has suggested that the components of the protein kinase B (AKT)/ mammalian target of rapamycin (mTOR) pathway are intrinsic factors for carcinogenesis. The AKT protein is central to the proliferation and survival of normal and cancer cells, and its downstream protein, mTOR, also plays an indispensable role in the cellular processes. The wide involvement of the AKT/mTOR pathway has been noted in oral squamous cell carcinoma (OSCC). This axis significantly regulates the various hallmarks of cancer, like proliferation, survival, angiogenesis, invasion, metastasis, autophagy, and epithelial-to-mesenchymal transition (EMT). Activated AKT/mTOR signaling is also associated with circadian signaling, chemoresistance and radio-resistance in OC cells. Several miRNAs, circRNAs and lncRNAs also modulate this pathway. The association of this axis with the process of tumorigenesis has culminated in the identification of its specific inhibitors for the prevention and treatment of OC. In this review, we discussed the significance of AKT/mTOR signaling in OC and its potential as a therapeutic target for the management of OC. This article also provided an update on several AKT/mTOR inhibitors that emerged as promising candidates for therapeutic interventions against OC/head and neck cancer (HNC) in clinical studies.

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