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A szerző a folyóirat-referáló rovat „Érendothel-funkciózavar, oxidatív stressz” tárgykörrel való bővítésének fontosságát szakmailag – a téma nagyságára való tekintettel – néhány önkényesen kiemelt kérdéskör kibontásával támasztja alá: Az endothelium a belső környezet állandóságát, integritását vigyázza, azt különböző anyagok termelésével-elválasztásával, azoknak egyensúlyban tartásával biztosítja. Ha az erek belfelületét, intimáját érő mechanikai, fizikai, kémiai, mikrobiológiai, immunológiai, genetikai károsító téyezők – vagy azok valamelyikének kombinációja – ellen foganatosított válaszreakció folyamán megbomlik az egyensúly az endothelium termelte vasoconstrictorok és vasodilatatorok, a növekedési faktorok és azok gátlói, a proinflammátorok és antiinflammátorok, a protrombotikus és fibrinolitikus tényezők között, endothel-működészavarról beszélünk. Az idült érbetegség, az atherosclerosis indító eseménye az erek hatalmas belfelületén, az endothelsejtekben megy végbe, ezt nevezzük endotheldiszfunkciónak . Az érpatogén tényezők, a rizikófaktorok mindegyike endothel-működészavar , endotheldiszfunkció indukálásával vezet idült (cardio)vascularis megbetegedéshez. Az élettani oxidatív metabolizmus során végbemenő fiziológiás szabad gyökös folyamatok – a védekező-kompenzáló endogén antioxidatív faktorok kimerülésekor – oxidatív stresszt , a veszélyeztető tényezők okozta endothel-működészavart okoznak. Nyomatékosan kiemelendő a „kauzális”, intracellulárisan, mitokondriálisan ható antioxidánsok (sztatinok, angiotenzinkonvertálóenzim-gátlók, angiotenzinreceptor-blokkolók, acetilszalicilsav, a harmadik generációs béta-blokkolók) terápiás, preventív terápiás fontossága, a humán érrendszer élettani, kórélettani, terápiás konszubsztancialitásának, egylényegűségének és az endotheldiszfunkció szisztémás jellegének, az érrendszeri eseményláncolat preventív terápiás jelentőségének kulcsfontossága. Az oxidatív stressz, a konszekutív endotheldiszfunkció területén végbement hatalmas fejlődés a klinikai látásmódot alapjaiban átalakító momentum.
Az öregedő szövetekben reaktív szabad gyökök túltermelődése figyelhető meg, ami nitrooxidatív stresszt indukál. Újabb kutatások szerint e folyamat fontos szerepet tölt be a szív- és érrendszeri funkciók időskori hanyatlásában. A toxikus oxidánsok, mint a hidrogén-peroxid vagy a peroxinitrit, a fehérjék károsításán túl megtámadják a DNS-t, és több reakcióutat, köztük a poli(ADP-ribóz)-polimeráz (PARP) utat aktiválva szövetkárosodáshoz vezetnek. Célkitűzés: Megvizsgáltuk, hogy a vascularis oxidatív stressz in vitro modelljében a PARP gátlása képes-e javítani a hidrogén-peroxid által károsított endothelfunkción. Fő célunk viszont az volt, hogy megvizsgáljuk a PARP akut gátlásának, illetve a peroxinitrit katalitikus lebontásának hatásait az időskori szív- és érrendszeri diszfunkcióra. Módszer: In vitro funkcionális mérésekkel izolált patkány-aortagyűrűkön vizsgáltuk az endothelfüggő és nem endothelfüggő vazorelaxációt acetil-kolin, illetve nátrium-nitroprusszid adására. Az endothelkárosodást hidrogén-peroxiddal váltottuk ki. A kezelt csoportban érgyűrűinket előinkubáltuk a PARP gátlószerével. Az időskori cardiovascularis diszfunkció in vivo patkánymodelljében fiatal és öreg patkányokat kezeltünk a PARP-gátló egyszeri dózisával, illetve a peroxinitrit lebontásának katalizátorával, FP15-tel. Nyomás-konduktancia mikrokatéter segítségével bal kamrai nyomás-térfogat analízist végeztünk patkányainkban a cardialis funkció megítélésére, valamint izolált aortagyűrűk vascularis funkcióit vizsgáltuk. A szöveti és sejtszintű változásokat immunhisztokémiai módszerekkel tanulmányoztuk. Eredmények: In vitro modellünkben hidrogén-peroxid hatására az endothelfunkció dózisfüggő károsodását tapasztaltuk, amely jelentős javulást mutatott PARP-gátlás után. Öreg patkányokban a szívműködés gyengülését figyeltük meg, valamint aortagyűrűikben csökkent endothelfüggő relaxációs választ mértünk. Az akut PARP-gátlás és az FP15-kezelés is szignifikáns javulást eredményezett a szív- és endothelfunkcióban. Öreg állatokban immunhisztokémiai méréseink fokozott nitrooxidatív stressz és PARP-aktiváció jeleit mutatták, amelyek jelentősen csökkentek a kezelések hatására. Következtetések: Eredményeink az endogén peroxinitrit-túltermelődés és a PARP reakcióút jelentőségét mutatják a cardiovascularis funkciók időskori hanyatlásában. A peroxinitrit gyors katalitikus lebontása, valamint a PARP gátlása új antioxidáns terápiás lehetőséget jelenthet az időskori szív- és érrendszeri diszfunkció kezelésében.
Abstract
Exposure to risk factors such as diabetes mellitus and hyperlipidemia decrease the bioavailability of endothelium-derived nitric oxide (NO) and impairs endothelium-dependent vasodilation. Circulating concentrations of an endogenous inhibitor of NO synthase, asymmetric dimethyl-L-arginine (ADMA), has been linked to endothelial dysfunction. It appears to be an independent risk factor for future cardiovascular events and total mortality. The purpose of this study is to investigate serum concentrations of ADMA correlate to diabetes mellitus and hyperlipidemia compared with the healthy subjects. A total of 300 subjects were recruited for the present study (100 normal healthy subjects, 52 males and 48 females); (100 diabetic patients, 51 males and 49 females); (100 hyperlipidemic patients, 50 males and 50 females). Serum concentrations of ADMA were measured with the use of ELISA. The concentration of ADMA were significantly higher (p < 0.001) in diabetic and hyperlipidemic patients in both sexes when compared with their matched control subjects. A positive correlation was obtained between ADMA and glucose of diabetic males (r = 0.40, p = 0.01) and females (r = 0.51, p = 0.01). In addition, a positive correlation was also obtained between ADMA and lipid profile of hyperlipidemic males (total cholesterol: r = 0.71, p = 0.01; triacylglycerol: r = 0.70, p = 0.01; low density lipoprotein cholesterol: r = 0.34, p = 0.05) and females (total cholesterol: r = 0.77, p = 0.01; triacylglycerol: r = 0.51, p = 0.01; low density lipoprotein cholesterol: r = 0.46, p = 0.01). The present study reveals that serum ADMA concentrations are elevated in disorders associated with vascular endothelial dysfunction such as diabetes mellitus and hyperlipidemia. However, endothelial dysfunction is considered as early event in the process of atherogenesis.
Summary
Angiogenesis is integral to the development and progression of atherosclerotic disease and solid tumor growth. New microvessels form in atherosclerotic plaque and the presence of new vessels has been associated with carotid plaque instability. Likewise, solid tumor growth depends upon angiogenesis to provide tumor cells with oxygen and nutrients. Recently, Lanza et al. have demonstrated molecular imaging of angiogenesis both in human melanoma xenografts in nude mice and atherosclerotic rabbits by magnetic resonance imaging (MRI) with clinical magnet strengths using ανβ3-targeted nanoparticles developed in their lab. ανβ3-integrin is a selective molecular epitope expressed by angiogenic endothelium and the MRI contrast agent consists of a lipid-encapsulated, liquid perfluorocarbon nanoparticle directly coupled to a selective ανβ3 ligand. The nanoparticle also contains the paramagnetic contrast agent gadolinium linked to the nanoparticle as Gd-DTPA-bis-oleate. In this work we report on the use of neutron activation analysis to confirm the Gd content of the nanoparticle formulations and determine the biodistribution of Gd post injection.
Uniform view of chronic venous diseases has been formed in the last 3 decades. Chronic venous insufficiency (CVI) is a functional disorder of the venous system of the lower limb. The basis of the pathology is always the venous hypertension caused by valvular insufficiency and reflux with or without venous outflow obstruction. Epifascial, subfascial and transfascial forms of CVI can be distinguished. In the practice these forms are almost always combined. The consistent venous hypertension is the initiating factor in alterations in the microcirculation which leads to skin changes and venous ulceration. The precise mechanism of the development of venous leg ulcer is still uncertain. A recent hypothesis suggests that leukocytes are trapped in the capillaries and attaching to the endothel they become activated and release proteolytic enzymes, free radicals which have destructive effects on lipid membranes, proteins as well as on many connective tissue compounds. The endothelium plays active role in the complex mechanism. Increased expression of tissue metalloproteinases has been observed in the periulcer skin. The presence of perivascular leukocyte infiltration and fibrin cuff is a reflexion of an inflammatory process. The clinical stages of CVI are likely to be the results of a systemic inflammatory response to a period of venous hypertension.
It is now well accepted that alterations in kidney function, due either to primary renal disease or to inappropriate hormonal influences on the kidney, are a cardinal characteristic in all forms of hypertension, and lead to a reduced ability of the kidneys to excrete sodium and the consequent development of elevated arterial pressures (1, 2). However, it is also apparent that many extrarenal factors are important contributors to altered kidney function and hypertension. Central to many hypertensinogenic processes is the inappropriate activation of the renin-angiotensin system (RAS) and its downstream consequences by various pathophysiologic mechanisms (3, 4). There may also be derangements in arachidonic acid metabolites, endothelium derived factors such as nitric oxide and carbon monoxide, and various paracrine and neural systems that normally interact with or provide a counteracting balance to the actions of the RAS. Thus, when the capacity of the kidneys to maintain sodium balance and extracellular fluid volume within appropriate ranges is compromised, increases in arterial pressure become necessary to re-establish normal balance (2, 5, 6).
The first 60-min phase of inflammatory ascites formation was studied by intraperitoneally (i.p.) administered macromolecular inducers: yeast cell wall zymosan binds to specific macrophage receptors, polyethyleneimine (PEI) and concanavalin A (ConA), produces non-covalent cross-links on the surface of various cells, while λ-carrageenan may function as a contact activator. Depletion of peritoneal macrophages was performed by overnight pretreatment with diphtheria toxin in transgenic mice, resulting in a significant (p < 0.01) decrease in the induced formation of ascitic fluid. It was shown that induced ascites is mediated partly (PEI, ConA, and carrageenan) or completely (zymosan) by peritoneal macrophages. Inhibition of prostanoid synthesis with indomethacine or of the kallikrein/bradykinin system with aprotinin also produced a significant (p < 0.01) but incomplete inhibition. A slight additivity occurred between the different inhibitory effects. In another series of experiments, the i.p. administration of bradykinin (without a macromolecular inducer) also produced marked ascites, which was not affected by macrophage depletion. The origin of the macrophage-independent part of the induced ascites is best explained by the deformation of the mesothelial cell surface, resulting in signal transfer to the underlying endothelium and the passage of ascitic fluid in the opposite direction. The soluble mediators are represented by prostanoids, bradykinin and other, unidentified agonists.
Histological and electron microscopic examinations of the kidneys of 8 dogs suffering from fatal, naturally acquired Babesia canis infection and nephropathy are presented. Seven animals were treated with imidocarb dipropionate on average 4.5 days prior to death. Severe anaemia was present only in 2 cases. Degenerative histological changes observed mostly in the proximal convoluted tubules included vacuolar-hydropic degeneration, necrosis and detachment of renal tubular epithelial (RTE) cells from the basement membrane. Necrotic debris occasionally formed acidophilic casts within the tubules. In some cases, necrosis of the whole tubule was observed. Haemoglobin casts in the tubules and haemoglobin droplets in RTE cells seldom appeared. No significant histological changes were seen in the glomeruli. Ultrastructural lesions in RTE cells included nuclear membrane hyperchromatosis, karyopyknosis, karyolysis, swelling or collapse of mitochondria with fragmentation of cristae and vacuolar-hydropic degeneration in the endoplasmic reticulum and microvilli. Nuclear oedema was also observed. Many RTE cells exhibiting necrosis collapsed. Vacuolar-hydropic degeneration and necrosis were also observed in the glomerular and interstitial capillary endothelium. The severe acute tubular necrosis described in this study is probably the result of hypoxic renal injury. Systemic hypotension leading to vasoconstriction in the kidneys might be the most important cause of renal hypoxia in B. canis infections, but anaemia may also contribute to inadequate oxygenation. Imidocarb should be applied with caution in patients with possible renal involvement until further data become available on its potential nephrotoxicity in dogs.
Claudin-5 is an endothelium-specific tight junction protein. The aim of the present study was to detect the expression pattern of this molecule in intact pancreatic tissues and in well-differentiated and poorly differentiated pancreatic acinar cell carcinomas from dogs by the use of cross-reactive humanised anticlaudin-5 antibody. The necropsy samples taken from dogs included 10 nonneoplastic pancreatic tissues, 10 well-differentiated pancreatic acinar cell carcinomas, 10 poorly differentiated pancreatic acinar cell carcinomas, 5 intrahepatic metastases of well-differentiated and 5 intrahepatic metastases of poorly differentiated acinar cell carcinomas. A strong lateral membrane claudin-5 positivity was detected in exocrine cells in all intact pancreas samples. The endocrine cells of the islets of Langerhans and the epithelial cells of the ducts were negative for claudin-5. The endothelial cells of vessels and lymphatic channels in the stroma of the intact pancreas showed strong membrane positivity for this claudin. All well-differentiated exocrine pancreas carcinomas and all poorly-differentiated pancreatic acinar cell carcinoma samples showed a diffuse loss of claudin-5 expression. The claudin-5-positive peritumoural vessels and lymphatic channels facilitated the detection of vascular invasion of the claudin-5-negative cancer cells. In liver metastasis samples, the pancreatic carcinomas were negative for claudin-5. It seems that the loss of expression of claudin-5 may lead to carcinogenesis in canine exocrine pancreatic cells.
Autologous vascular patch grafts developed from the internal rectus sheath were implanted onto the bilateral common iliac vein and jugular vein of 4 experimental beagle dogs. During the development and implanting of the grafts no technical difficulties or perioperative complications were encountered. The follow-up lasted 6 months and 3 months in the case of the common iliac vein grafts and the jugular grafts, respectively. In the postoperative period, the morphological and functional characteristics of the implanted venous sections were examined by Doppler ultrasonography and CT angiography. Normal patency was detected, and none of these check-ups showed obturation or stenosis. The histological survey showed no mesothelial cell layer, but the insides of the grafts showed total restructuring and were covered by a normal endothelial layer. No difference could be detected between samples harvested 3 and 6 months after implanting. The immunohistochemical examinations using anti-claudin-5 and anti-CD31 antibodies confirmed the preliminary results of the histological examinations that the luminal surfaces of the implanted grafts developed a differentiated monolayer endothelium which was free of degenerative and inflammatory signs. The control examinations show the suitability of the internal rectus sheath as a venous wall donor.
