13 research outputs found

    IL-17 in Peritoneal Dialysis-Associated Inflammation and Angiogenesis: Conclusions and Perspectives

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    Long-term peritoneal dialysis (PD) is associated with peritoneal membrane remodeling. This includes changes in peritoneal vasculature, which may ultimately lead to inadequate solute and water removal and treatment failure. The potential cause of such alterations is chronic inflammation induced by repeated episodes of infectious peritonitis and/or exposure to bioincompatible PD fluids. While these factors may jeopardize the peritoneal membrane integrity, it is not clear why adverse peritoneal remodeling develops only in some PD patients. Increasing evidence points to the differences that occur between patients in response to the same invading microorganism and/or the differences in the course of inflammatory reaction triggered by different species. Such differences may be related to the involvement of different inflammatory mediators. Here, we discuss the potential role of IL-17 in these processes with emphasis on its impact on peritoneal mesothelial cells and peritoneal vascularity

    Novel aspects of the immune response involved in the peritoneal damage in chronic Kkdney disease patients under dialysis

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    Chronic kidney disease (CKD) incidence is growing worldwide, with a significant percentage of CKD patients reaching end-stage renal disease (ESRD) and requiring kidney replacement therapies (KRT). Peritoneal dialysis (PD) is a convenient KRT presenting benefices as home therapy. In PD patients, the peritoneum is chronically exposed to PD fluids containing supraphysiologic concentrations of glucose or other osmotic agents, leading to the activation of cellular and molecular processes of damage, including inflammation and fibrosis. Importantly, peritonitis episodes enhance peritoneum inflammation status and accelerate peritoneal injury. Here, we review the role of immune cells in the damage of the peritoneal membrane (PM) by repeated exposure to PD fluids during KRT as well as by bacterial or viral infections. We also discuss the anti-inflammatory properties of current clinical treatments of CKD patients in KRT and their potential effect on preserving PM integrity. Finally, given the current importance of coronavirus disease 2019 (COVID-19) disease, we also analyze here the implications of this disease in CKD and KRTThis research was funded by grants from the Instituto de Salud Carlos III (ISCIII) and Fondos FEDER European Union (PI20/00140, PI19/00815, and DTS20/00083). Red de Investi gación Renal REDINREN: RD16/0009/0003 to M.R-O and RICORS2040; RD21/0005/0002 funded by European Union—NextGenerationEU, Sociedad Española de Nefrología. Innovation programme under the Marie Skłodowska-Curie grant of the European Union’s Horizon 2020 (IMPROVE-PD ID: 812699) to M.R-O. E.K. was supported by the grant from the Narodowe Centrum Nauki (NCN, Polish National Science Centre; 2018/29/N/NZ3/02504). R.S. was supported by Ministry for Health of Italy (Ricerca Corrente). This work was also supported by a grant (PID 2019-110132RB I00/AEI/10.13039/501100011033) from the Spanish Ministry of Science and Innovation/Fondo Europeo de Desarrollo Regional (MICINN/FEDER) to M.L.-C

    Angiogenic Role of Mesothelium-Derived Chemokine CXCL1 During Unfavorable Peritoneal Tissue Remodeling in Patients Receiving Peritoneal Dialysis as Renal Replacement Therapy

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    Peritoneal dialysis (PD) is a valuable 'home treatment' option, even more so during the ongoing Coronavirus pandemic. However, the long-term use of PD is limited by unfavourable tissue remodelling in the peritoneal membrane, which is associated with inflammation-induced angiogenesis. This appears to be driven primarily through vascular endothelial growth factor (VEGF), while the involvement of other angiogenic signaling pathways is still poorly understood. Here, we have identified the crucial contribution of mesothelial cell-derived angiogenic CXC chemokine ligand 1 (CXCL1) to peritoneal angiogenesis in PD. CXCL1 expression and peritoneal microvessel density were analysed in biopsies obtained by the International Peritoneal Biobank (NCT01893710 at www.clinicaltrials.gov), comparing 13 children with end-stage kidney disease before initiating PD to 43 children on chronic PD. The angiogenic potential of mesothelial cell-derived CXCL1 was assessed in vitro by measuring endothelial tube formation of human microvascular endothelial cells (HMECs) treated with conditioned medium from human peritoneal mesothelial cells (HPMCs) stimulated to release CXCL1 by treatment with either recombinant IL-17 or PD effluent. We found that the capillary density in the human peritoneum correlated with local CXCL1 expression. Both CXCL1 expression and microvessel density were higher in PD patients than in the age-matched patients prior to initiation of PD. Exposure of HMECs to recombinant CXCL1 or conditioned medium from IL-17-stimulated HPMCs resulted in increased endothelial tube formation, while selective inhibition of mesothelial CXCL1 production by specific antibodies or through silencing of relevant transcription factors abolished the proangiogenic effect of HPMC-conditioned medium. In conclusion, peritoneal mesothelium-derived CXCL1 promotes endothelial tube formation in vitro and associates with peritoneal microvessel density in uremic patients undergoing PD, thus providing novel targets for therapeutic intervention to prolong PD therapy

    Control of neutrophil influx during peritonitis by transcriptional cross‐regulation of chemokine CXCL1 by IL‐17 and IFN‐γ

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    Neutrophil infiltration is a hallmark of peritoneal inflammation, but mechanisms regulating neutrophil recruitment in patients with peritoneal dialysis (PD)-related peritonitis are not fully defined. We examined 104 samples of PD effluent collected during acute peritonitis for correspondence between a broad range of soluble parameters and neutrophil counts. We observed an association between peritoneal IL-17 and neutrophil levels. This relationship was evident in effluent samples with low but not high IFN-γ levels, suggesting a differential effect of IFN-γ concentration on neutrophil infiltration. Surprisingly, there was no association of neutrophil numbers with the level of CXCL1, a key IL-17-induced neutrophil chemoattractant. We investigated therefore the production of CXCL1 by human peritoneal mesothelial cells (HPMCs) under in vitro conditions mimicking clinical peritonitis. Stimulation of HPMCs with IL-17 increased CXCL1 production through induction of transcription factor SP1 and activation of the SP1-binding region of the CXCL1 promoter. These effects were amplified by TNFα. In contrast, IFN-γ dose-dependently suppressed IL-17-induced SP1 activation and CXCL1 production through a transcriptional mechanism involving STAT1. The SP1-mediated induction of CXCL1 was also observed in HPMCs exposed to PD effluent collected during peritonitis and containing IL-17 and TNFα, but not IFN-γ. Supplementation of the effluent with IFN-γ led to a dose-dependent activation of STAT1 and a resultant inhibition of SP1-induced CXCL1 expression. Transmesothelial migration of neutrophils in vitro increased upon stimulation of HPMCs with IL-17 and was reduced by IFN-γ. In addition, HPMCs were capable of binding CXCL1 at their apical cell surface. These observations indicate that changes in relative peritoneal concentrations of IL-17 and IFN-γ can differently engage SP1–STAT1, impacting on mesothelial cell transcription of CXCL1, whose release and binding to HPMC surface may determine optimal neutrophil recruitment and retention during peritonitis

    Funktionelle Charakterisierung der humanen peritonealen Fibroblasten: Auswirkungen auf die peritoneale Immunität bei mit Peritonealdialyse behandelten Patienten

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    Peritoneal dialysis (PD) is a life-saving renal replacement therapy for patients suffering for kidney failure. Long-term exposure of the peritoneal membrane to bioincompatible peritoneal dialysis fluids (PDFs) and repeated peritonitis episodes may provoke structural alterations that eventually lead to the development of fibrosis and technique failure. Peritoneal fibroblasts are key cellular players involved in these processes. The aim of the present study was to purify, identify and functionally analyze human peritoneal fibroblasts (HPFB) with regard to features relevant to successful PD. Having identified HPFB in cell culture and in peritoneal biopsies on the basis of fibroblast specific protein 1 (FSP-1) expression, I analyzed the capacity of HPFB for producing the chemokine CCL5 and found that HPFB synthesize large quantities of CCL5 upon stimulation with macrophage-derived IL-1β and TNF-α in a process that can be amplified by IFN-γ. Moreover, HPFB exposed to high glucose concentrations (corresponding to those in PDFs) showed increased expression of the transcription factor NFAT5 and the chemokine CCL2; the upregulation of these mediators appeared to be independent of each other. An intriguing feature of fibroblasts is their heterogeneity between different anatomic locations and within the same tissue. I found that HPFB in the peritoneum differed in the expression of Thy-1. Following isolation by magnetic activated cell sorting, Thy-1+ HPFB showed increased expression of α-SMA, collagen 1, and TGF-β in comparison to HPFB not expressing Thy-1. Furthermore, Thy-1+ HPFB displayed greater proliferation and contraction ability, suggesting that they could be more prone to acquire myofibroblastic phenotype and thus contribute to peritoneal fibrosis. Peritoneal biopsies from uremic, non-dialyzed, and PD-treated patients showed that both in the omentum and the parietal peritoneum Thy-1+ HPFB constituted the majority of fibroblasts as identified by the presence of FSP-1. In contrast, in healthy individuals FSP-1+ fibroblasts could not be detected in the parietal peritoneum whilst those present in the omentum contained similar proportions of Thy-1+ and Thy-1- cells. These observations indicate that the number of Thy-1 expressing fibroblasts may increase as a result of both uremia and PD therapy. Taken together, the results presented in this thesis demonstrate the involvement of HPFB in inflammatory responses occurring in the dialyzed peritoneum and show the existence of a subset of HPFB that may expand during PD and contribute to the development of peritoneal fibrosis.Die Peritonealdialyse (PD) ist eine lebensrettende Nierenersatztherapie für Patienten mit Nierenversagen. Die langfristige Exposition der Peritonealmembran gegenüber bioinkompatiblen Peritonealdialyselösungen (PDF), aber auch wiederholte Peritonitisepisoden können strukturelle Veränderungen in Gang setzen, die letztendlich in einer peritonealen Fibrose und damit im Therapieversagen münden können. Wichtige zelluläre Elemente bei diesen Prozessen sind die peritonealen Fibroblasten. Das Ziel der vorliegenden Arbeiten war die Isolation, Identifikation und funktionelle Analyse von humanen peritonealen Fibroblasten (HPFB) speziell im Hinblick auf Eigenschaften, die für die erfolgreiche PD von Bedeutung sind. Im Anschluß an die Identifikation von Fibroblasten in Zellkultur oder Peritonealbiopsien anhand ihrer Expression von Fibroblast-Specific Protein 1 (FSP-1) untersuchte ich die Produktion des Chemokins CCL5 in HPFB und fand, daß sie große Mengen an CCL5 nach Stimulation mit IL-1β und TNF-α und amplifiziert durch IFN-γ synthetisieren. Nach Exposition gegenüber hohen Glukosekonzentrationen (wie sie für PDF typisch sind) zeigten HPFB eine vermehrte, jedoch voneinander unabhängige, Expression des Transkriptionsfaktors NFAT5 und des Chemokins CCL2. Eine besondere Eigenschaft von Fibroblasten ist ihre Heterogeneität zwischen verschiedenen anatomischen Lokalisationen innerhalb desselben Gewebes. Diesbezüglich konnte ich zeigen, daß die HPFBs im Peritoneum Unterschiede bezüglich ihrer Expression von Thy-1 aufweisen. Im Anschluß an ihre Isolation mittels magnetischer Zellsortierung zeigten Thy-1+ HPFB eine vermehrte Expression von α-SMA, Kollagen 1 und TGF-β im Vergleich mit Thy-1- HPFB. Weiterhin wiesen Thy-1+ HPFB eine vermehrte Proliferationskapazität und Kontraktionsfähigkeit auf. Dies legt nahe, daß Thy-1+ HPFB mehr zur Bildung eines myofibroblastoiden Phänotyps neigen und somit eher zur Entwicklung einer Peritonealfibrose beitragen können. Peritoneale Biopsien sowohl von urämischen Prädialysepatienten als auch von Patienten unter PD-Behandlung enthielten in Omentum und parietalem Peritoneum mehrheitlich FSP-1+ Thy-1+ HPFB. Im parietalen Peritoneum von nierengesunden Patienten fanden sich im Gegensatz hierzu keine FSP-1+ Fibroblasten, doch fanden sich im Omentum eine vergleichbare Anzahl Thy-1+ und Thy-1- Zellen. Diese Beobachtungen deuten an, daß die Population Thy-1+ Fibroblasten bei Patienten mit zunehmender Urämie sowie im Verlauf der Peritonealdialysetherapie zunehmen könnte. Insgesamt geben die Ergebnisse dieser Studie Hinweise auf eine Beteiligung von peritonealen Fibroblasten an inflammatorischen Prozessen im dialysierten Peritoneum und demonstrieren die Existenz einer Subpopulation von HPFB, die im Verlauf der Peritonealdialyse expandiert und zur Entwicklung einer peritonealen Fibrose beitragen kann

    New Developments in Peritoneal Fibroblast Biology: Implications for Inflammation and Fibrosis in Peritoneal Dialysis

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    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

    Edukacyjna rola pielęgniarki w zapobieganiu zakażeń rota wirusowych

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    Szerzeniu się zakażeń rota wirusowych u dzieci sprzyja łatwość przenoszenia wirusa, szczególnie drogą feralno-oralną. Do zakażenia może dojść poprzez kontakt z osobą chorą, jak również przez styczność z zanieczyszczoną powierzchnią czy przedmiotami. Przebywanie jednego chorego dziecka w skupisku przedszkolnym czy szkole, skutkuje przeniesieniem wirusa na wiele innych dzieci. Głównym zagrożeniem dla dziecka zakażonego rota wirusami jest ryzyko szybkiego odwodnienia spowodowanego wymiotami i gwałtowną biegunką. Celem edukacji jest wyprzedzenie i zabezpieczenie przed chorobą i uświadomienie opiekunom powagi infekcji rota wirusowych. Pielęgniarka oprócz fachowego przygotowania musi posiadać wiedzę na temat występowania reakcji niepożądanych. Obejmuje to zarówno teorię, jak i działania praktyczne, istotna jest znajomość przebiegu choroby. Pielęgniarka posiadająca wiedzę merytoryczną, dotyczącą zakażeń i umiejętności w zakresie profilaktyki, musi umieć pozyskiwać zaufanie zarówno dzieci jak i rodziców, musi umieć wpływać na zmianę niepokojących postaw rodziców wobec szczepień ochronnych

    Wielodyscyplinarny udział pielęgniarki w profilaktyce i leczeniu gruźlicy

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    Zgodnie z Raportem WHO 2013 gruźlica nadal stanowi globalne zagrożenie, nadal konieczne jest podejmowanie nowych metod systematycznego leczenia, kontroli przyjmowania właściwych dawek leku aby uniknąć przedłużonego prątkowania, remisji choroby i powstania lekooporności na podstawowe leki przeciwprątkowe. Przerwane leczenie sprawia też, że rośnie liczba osób będących źródłem zakażenia dla innych. Wielu pacjentów szybko rezygnuje z leczenia, dlatego bardzo istotna jest ciągła edukacja w zakresie celowości przyjmowania leków przez czas wyznaczony przez lekarza. W świetle powyższych faktów dotyczących trudności procesu leczenia, szczególnie istotna jest rola pielęgniarki. Pielęgniarka pracująca na oddziale, gdzie leczeni są pacjenci z gruźlicą bierze udział w procesie diagnozowania chorego, opiekuje się nim podczas hospitalizacji i odpowiedzialna jest za jego ciągłą edukację i podejmowanie działań profilaktycznych. Pielęgniarka spełnia też kluczową rolę sprawując opiekę nad pacjentem w oparciu o program DOTS, czyli uczestniczy w obserwacjach medycznych, nadzoruje rutynowe badania mikrobiologiczne, wraz lekarzem analizuje wrażliwość wyizolowanych prątków na podawane antybiotyki, towarzyszy pacjentowi podczas zażywania leków i przypomina o terminowości ich przyjmowania, cotygodniowo przelicza tabletki chorego, przeprowadza wywiady, przegląda zażywane przez niego leki, ocenia parametry życiowe pacjenta, prowadzi ustawiczną edukację pacjenta
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