Ny forskningsrapport från Kina / Avd hög aktivitetsnivå 2

16 kinesiska Unis och sjukhus har medverkat i en studie som granskats och publicerats hos Journal of Clinical Medicine.

Journal of Clinical Medicine (ISSN 2077-0383; CODEN: JCMOHK) is an international peer-reviewed open access journal published monthly online by MDPI.

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Det handlar om studien betitlad
Translational Medicine in Pulmonary-Renal Crosstalk: Therapeutic Targeting of p-Cresyl Sulfate Triggered Nonspecific ROS and Chemoattractants in Dyspneic Patients with Uremic Lung Injury

 Received: 15 August 2018 / Accepted: 7 September 2018 / Published: 9 September 2018

Abstract:

Molecular mechanisms and pathological features of p-Cresyl sulfate (PCS)-induced uremic lung injury (ULI) in chronic kidney disease (CKD) remain unclear. We analyzed pleural effusions (PE) from CKD and non-CKD patients for uremic toxins, reactive oxygen species (ROS), and chemotactic cytokines. Correlations between PE biomarkers and serum creatinine were also studied. Cell viability and inflammatory signaling pathways were investigated in PCS-treated human alveolar cell model. To mimic human diseases, CKD-ULI mouse model was developed with quantitative comparison of immunostaining and morphometric approach. PE from CKD patients enhance expressions of uremic toxins, hydroxyl radicals, and IL-5/IL-6/IL-8/IL-10/IL-13/ENA-78/GRO α/MDC/thrombopoietin/VEGF. PE concentrations of ENA-78/VEGF/IL-8/MDC/PCS/indoxyl sulphate correlate with serum creatinine concentrations. In vitro, PCS promotes alveolar cell death, cPLA2/COX-2/aquaporin-4 expression, and NADPH oxidase/mitochondria activation-related ROS. Intracellular ROS is abrogated by non-specific ROS scavenger N-acetyl cysteine (NAC), inhibitors of NADPH oxidase and mitochondria-targeted superoxide scavenger. However, only NAC protects against PCS-induced cell death. In vivo, expressions of cPLA2/COX2/8-OHdG, resident alveolar macrophages, recruited leukocytes, alveolar space, interstitial edema and capillary leakage increase in lung tissues of CKD-ULI mice, and NAC pretreatment ameliorates alveolar–capillary injury. PCS causes alveolar–capillary injury through triggering intracellular ROS, downstream prostaglandin pathways, cell death, and activating leukocytes to release multiplex chemoattractants and extracellular ROS. Thus PCS and nonspecific ROS serve as potential therapeutic targets. 

 

Introduction

Respiratory distress due to pulmonary edema is a life-threatening complication in patients with renal failure [1]. Cardiogenic pulmonary edema resulting from elevated capillary hydrostatic pressure can be relieved by fluid removal via ultrafiltration or diuresis immediately [2]. Non-cardiogenic pulmonary exudate is caused by inflammation-related hyperpermeability, yet fluid removal only partially improves oxygenation [3]. Patients with chronic kidney disease (CKD) may fall in the spectrum between cardiogenic and non-cardiogenic pulmonary edema [3]. Emerging evidences demonstrate uremic retention solutes exhibit pro-inflammation and pro-oxidant effects on different cell and organ systems [4]. Myriads of mechanisms are involved in uremic lung injury (ULI), including neutrophil activation, vascular hyperpermeability, dysregulation of salt-water transporters, and cytokine expressions [5,6,7,8,9]. Nonetheless, the majority of experimental designs are animal models of acute kidney injury instead of CKD. Our study elucidates prostaglandin (PG) pathways account for inflammatory lung diseases and leukocyte recruitment [10]. Moreover, aquaporins regulate cell volume and membrane water permeability in alveolar fluid homeostasis [11]. Despite previous documented implications, the potential toxic effects of uremic solutes on ULI remain unclear.

p-Cresyl sulfate (PCS), a protein-bound non-dialyzable uremic toxin, accumulates in CKD patients. PCS derives from secondary metabolism of p-cresol, which is produced from protein fermentation by intestinal bacteria [12]. PCS exerts deleterious effects on diverse cell systems: cardiac dysfunction and cardiomyocyte apoptosis resulting from reactive oxygen species (ROS), renal tubular cell damage via NADPH oxidase, ROS production by leukocytes, and endothelial/mononuclear cell cycle arrest due to ROS generation [13,14,15,16]. Clinical researches demonstrate serum concentrations of PCS serve as a predictor of cardiovascular and all-cause mortality in patients with hemodialysis [17,18]. In light of this, PCS might adversely affect the respiratory and immune system. To test this hypothesis, analyzes of uremic toxins, hydroxyl radicals, chemotactic cytokines, and recruited leukocytes in pleural effusions were compared between CKD patients and non-CKD subjects. From bedside to bench, cell viability and inflammatory signaling pathways with reactive oxygen species (ROS) were investigated in PCS-treated human alveolar cell model. To mimic human diseases, we developed a CKD-ULI mouse model using quantitative comparison of immunohistochemical staining and morphometric approach.

Ur rapporten klipper jag PHI relaterat.

 

3.2. PCS Promotes Alveolar Cell Death in a Time- and Dose-Dependent Manner

To outreach above findings to basic research, cell viability was evaluated by holographic imaging cytometry (HoloMonitor M4) or tetrazolium salt (XTT) assay in PCS-treated human alveolar cell model over a 72-h window. As shown in Figure 2A, quantitative analysis elucidated PCS suppressed A549 cell viability in a time- and concentration-dependent manner. Figure 2B,C illustrated A549 cell death significantly reached maximum at 72 h. As shown in Figure 2D with 3D histogram, A549 cells exposed to 100 μg/mL PCS for 72 h exerted the highest death rate.

 Figure 2. p-Cresyl sulfate (PCS) promotes human pulmonary alveolar cell death in a time- and dose-dependent manner. Serum-starved A549 cells were treated without or with PCS (50 or 100 μg/mL) for (A) 24 h, (B) 48 h, and (C) 72 h. (D) cells were treated with 50 or 100 μg/mL PCS for 0, 24, 48, or 72 h.
At the end of incubation, holographic images were captured at least from five random areas.
Cell number changes were analyzed by HoloStudio software. (E) Cell viability was analyzed by XTT assay according to the direction of manufacturer. Absorbance was measured at 490 nm and 650 nm using a BioTek spectrophotometer. Data are expressed as mean ± SEM of different independent experiments (n > 5). * p < 0.05, ^# p < 0.01 as compared with the groups of Basal or 0 min. 

 Cell viability and cell number were analyzed by XTT assay and Holographic cell analysis.

 

Min kommentar

Denna forskningsartikel berör patienter med njursjukdom som riskerar att avlida på grund av njurarnas reducerade förmåga i sin reningsfunktion.Läkarkåren har till idag inte kunna förklara varför människor med njursjukdom avlider trots dialys.När man obducerat hittar man dödsorsak som lungornas kollaps vilket påverkat hjärtat som då "lagt av". Men kopplingen till varför njursjuka dör pga av detta har man ännu inte klurat ut. Förstår man det sambandet har man möjlighet att sätta in läkemedel i förebyggande syfte. I rapporten har forskare tillsammans med sjukhus därför genomfört en omfattande studie för att få förklaringar och svar på orsakssambandet. Med ambitionen att då kunna presentera en lösning.
Och ja,man har kommit långt i den ambitionen.
Det här har man hittat och kunnat påvisa: ett ämne, p-Cresylsulfat (PCS), som kroppen producerar genom  överjäsning av en bakteriflora passerar njuren utan att filtrereras bort då njuren som sagt har minskad funktion. 
PCS passerar även vid dialys av njurpatienterna. Ämnet ackumuleras då hos patienten och påverkar kroppens cellsystem, då framförallt som hjärtdysfunktion och celldöd i hjärtat som konsekvens av lungornas kollaps och förmåga att transportera syre till hjärtat.
I lungorna ansamlas vätska hos en njurskadad,kommet från ansamlingen av PCS.
PCS i sin tur utlöser då nåt som heter ROS, reaktiva syreföreningar. ROS ingår som funktion i cellernas kedja av utvecklingsmönster.Från Wiki:
-Större mängder av reaktiva syreföreningar (ROS) i kroppen kan orsaka allvarliga skador på viktiga biologiska molekyler som DNA och RNA, och ingår bl.a. i apoptos (programmerad celldöd). 
Forskarna visar här att PCS mest troligt är anledningen till njursjukas plötsliga dödsfall.
Då av 2 anledningar.
1. Ansamling av vätska i lungorna som påverkar syretillförsel till hjärtat (hjärtdysfunktion)
2. Påverkan av cellernas apoptos (den programmerade celldöden)
Utifrån denna nya kunskap har man försökt hitta motmedel som tar ner PCS`s påverkan och negativa effekt.
Och ja,man tror sig ha funnit lösningen på detta.
Genom att tillföra patient ämnet N-acetylcysteine (NAC), ett ämne man funnit som motverkar celldöd och har förmåga att minska lungvävnadsskador.
Genom att studera cellernas utveckling före och efter tillsättning av NAC med hjälp av PHI´s HoloMonitor har man förhoppningsvis hittat ett botemedel som kommer minska dödlighet bland njurskadade.
Man har mest troligt även hittat svaret på gåtan läkarkåren ställt sig,varför njurskadade dör av lungkollaps och hjärtstopp.
Min egna åsikt: Ibland känns det jävligt bra att vara aktieägare i ett Bolag som medverkar till forskarnas framsteg.