Kyselina hyaluronová: známá již téměř století, ale stále aktuální

Hyaluronic acid (HA) has a special position among glycosaminoglycans. As a major component of the extracellular matrix (ECM). This simple, unbranched polysaccharide is involved in the regulation of various biological cell processes, whether under physiological conditions or in cases of cell damage. This review summarizes the history of this molecule's study, its distinctive metabolic pathway in the body, its unique properties, and current information regarding its interaction partners. Our main goal, however, is to intensively investigate whether this relatively simple polymer may find applications in protecting against ionizing radiation (IR) or for therapy in cases of radiation-induced damage. After exposure to IR, acute and belated damage develops in each tissue depending upon the dose received and the cellular composition of a given organ. A common feature of all organ damage is a distinct change in composition and structure of the ECM. In particular, the important role of HA was shown in lung tissue and the variability of this flexible molecule in the complex mechanism of radiation-induced lung injuries. Moreover, HA is also involved in intermediating cell behavior during morphogenesis and in tissue repair during inflammation, injury, and would healing. The possibility of using the HA polymer to affect or treat radiation tissue damage may point to the missing gaps in the responsible mechanisms in the onset of this disease. Therefore, in this article, we will also focus on obtaining answers from current knowledge and the results of studies as to whether hyaluronic acid can also find application in radiation science.Kyselina hyaluronová (HA) má mezi glykosaminoglykany zvláštní postavení. Jako hlavní složka extracelulární matrix (ECM). Tento jednoduchý, nerozvětvený polysacharid se podílí na regulaci různých buněčných procesů, ať už za fyziologických podmínek nebo v případech poškození buněk. Toto review shrnuje historii studia této molekuly, její charakteristickou metabolickou dráhu v těle, její jedinečné vlastnosti a aktuální informace týkající se jejích interakčních partnerů. Naším hlavním cílem je však ověřit, zda tento relativně jednoduchý polymer nachází uplatnění v ochraně před ionizujícím zářením (IR) nebo jako terapeutikum v případech poškození způsobeného zářením. Po expozici IR se v každé tkáni vyvine akutní a post-akutní poškození v závislosti na přijaté dávce a buněčném složení daného orgánu. Společným rysem všech orgánových poškození je zřetelná změna ve složení a struktuře ECM. Zejména byla prokázána důležitá role HA v plicní tkáni a variabilita této flexibilní molekuly v komplexním mechanismu radiačně indukovaných poškození plic. Kromě toho se HA také podílí na zprostředkování interakce buněk během morfogeneze a při reparaci tkáně během zánětu, poranění a hojení. Možnost použití vysokomolekulární HA pro ovlivnění nebo léčbu tkáně poškozené zářením může poukazovat na chybějící mezery v odpovědných mechanismech při nástupu tohoto onemocnění. V tomto článku se proto zaměříme i na získání odpovědí ze současných poznatků a výsledků studií, zda může kyselina hyaluronová najít uplatnění i v radiační vědě

Útlum poranění plic vyvolaných radiací nanočásticemi kyseliny hyaluronové

Purpose Therapeutic thorax irradiation as an intervention in lung cancer has its limitations due to toxic effects leading to pneumonitis and/or pulmonary fibrosis. It has already been confirmed that hyaluronic acid (HA), an extracellular matrix glycosaminoglycan, is involved in inflammation disorders and wound healing in lung tissue. We examined the effects after gamma irradiation of hyaluronic acid nanoparticles (HANPs) applied into lung prior to that irradiation in a dose causing radiation-induced pulmonary injuries (RIPI). Materials and Methods Biocompatible HANPs were first used for viability assay conducted on the J774.2 cell line. Forin vivoexperiments, HANPs were administered intratracheally to C57Bl/6 mice 30 min before thoracic irradiation by 17 Gy. Molecular, cellular, and histopathological parameters were measured in lung and peripheral blood at days 113, 155, and 190, corresponding to periods of significant morphological and/or biochemical alterations of RIPI. Results Modification of linear hyaluronic acid molecule into nanoparticles structure significantly affected the physiological properties and caused long-term stability against ionizing radiation. The HANPs treatments had significant effects on the expression of the cytokines and particularly on the pro-fibrotic signaling pathway in the lung tissue. The radiation fibrosis phase was altered significantly in comparison with a solely irradiated group. Conclusions The present study provides evidence that application of HANPs caused significant changes in molecular and cellular patterns associated with RIPI. These findings suggest that HANPs could diminish detrimental radiation-induced processes in lung tissue, thereby potentially decreasing the extracellular matrix degradation leading to lung fibrosis.Účel: Terapeutické ozařování hrudníku jako intervence u rakoviny plic má svá omezení kvůli toxickým účinkům vedoucím k pneumonitidě a / nebo plicní fibróze. Již bylo potvrzeno, že kyselina hyaluronová (HA), extracelulární matrix glykosaminoglykan, se podílí na zánětlivých poruchách a hojení ran v plicní tkáni. Zkoumali jsme účinky po záření gama nanočástic kyseliny hyaluronové (HANP) aplikovaných do plic před tímto ozářením v dávce způsobující radiační poškození plic (RIPI). Materiály a metody: Biokompatibilní HANP byly nejprve použity pro stanovení životaschopnosti prováděné na buněčné linii J774.2. Pro experimenty in vivo byly HANP podávány intratracheálně myším C57Bl / 6 30 minut před ozařováním hrudníku 17 Gy. Molekulární, buněčné a histopatologické parametry byly měřeny v plicích a periferní krvi ve dnech 113, 155 a 190, což odpovídá obdobím významných morfologických a / nebo biochemických změn RIPI. Výsledky: Modifikace lineární molekuly kyseliny hyaluronové do struktury nanočástic významně ovlivnila fyziologické vlastnosti a způsobila dlouhodobou stabilitu proti ionizujícímu záření. Léčba HANPs měla významné účinky na expresi cytokinů a zejména na profibrotickou signální cestu v plicní tkáni. Fáze radiační fibrózy byla významně změněna ve srovnání s pouze ozářenou skupinou. Závěry: Tato studie poskytuje důkazy, že aplikace HANP způsobila významné změny v molekulárních a buněčných vzorcích spojených s RIPI. Tato zjištění naznačují, že HANP by mohly snížit škodlivé radiačně indukované procesy v plicní tkáni, a tím potenciálně snížit degradaci extracelulární matrice vedoucí k plicní fibróze

The first in vivo multiparametric comparison of different radiation exposure biomarkers in human blood.

The increasing risk of acute large-scale radiological/nuclear exposures of population underlines the necessity of developing new, rapid and high throughput biodosimetric tools for estimation of received dose and initial triage. We aimed to compare the induction and persistence of different radiation exposure biomarkers in human peripheral blood in vivo. Blood samples of patients with indicated radiotherapy (RT) undergoing partial body irradiation (PBI) were obtained soon before the first treatment and then after 24 h, 48 h, and 5 weeks; i.e. after 1, 2, and 25 fractionated RT procedures. We collected circulating peripheral blood from ten patients with tumor of endometrium (1.8 Gy per fraction) and eight patients with tumor of head and neck (2.0-2.121 Gy per fraction). Incidence of dicentrics and micronuclei was monitored as well as determination of apoptosis and the transcription level of selected radiation-responsive genes. Since mitochondrial DNA (mtDNA) has been reported to be a potential indicator of radiation damage in vitro, we also assessed mtDNA content and deletions by novel multiplex quantitative PCR. Cytogenetic data confirmed linear dose-dependent increase in dicentrics (p < 0.01) and micronuclei (p < 0.001) in peripheral blood mononuclear cells after PBI. Significant up-regulations of five previously identified transcriptional biomarkers of radiation exposure (PHPT1, CCNG1, CDKN1A, GADD45, and SESN1) were also found (p < 0.01). No statistical change in mtDNA deletion levels was detected; however, our data indicate that the total mtDNA content decreased with increasing number of RT fractions. Interestingly, the number of micronuclei appears to correlate with late radiation toxicity (r2 = 0.9025) in endometrial patients suggesting the possibility of predicting the severity of RT-related toxicity by monitoring this parameter. Overall, these data represent, to our best knowledge, the first study providing a multiparametric comparison of radiation biomarkers in human blood in vivo, which have potential for improving biological dosimetry

Incidence of micronuclei in PBMCs of endometrial patients (A) and their relation to late radiotoxicity (B).

<p>Number of MN increased with the number of RT fractions. BN, binucleated cells; *, statistically significant difference of the 2^nd and 25^th RT fraction versus Control group (p < 0.001); #, statistically significant difference of the 25^th RT fraction versus 2^nd RT fraction (p < 0.001).</p

Chromosomal changes in PBMCs of head and neck patients.

<p>Number of dicentric chromosomes (A) and structurally aberrant cells (B) was determined and both parameters increase with the number of RT fractions. *, statistically significant difference versus Control group (p < 0.01). Representative figures of dicentric chromosome (C) and structurally aberant cells—ring chromosome (D), double fragment (E) and break (F) are shown.</p

The first <i>in vivo</i> multiparametric comparison of different radiation exposure biomarkers in human blood

<div><p>The increasing risk of acute large-scale radiological/nuclear exposures of population underlines the necessity of developing new, rapid and high throughput biodosimetric tools for estimation of received dose and initial triage. We aimed to compare the induction and persistence of different radiation exposure biomarkers in human peripheral blood <i>in vivo</i>. Blood samples of patients with indicated radiotherapy (RT) undergoing partial body irradiation (PBI) were obtained soon before the first treatment and then after 24 h, 48 h, and 5 weeks; i.e. after 1, 2, and 25 fractionated RT procedures. We collected circulating peripheral blood from ten patients with tumor of endometrium (1.8 Gy per fraction) and eight patients with tumor of head and neck (2.0–2.121 Gy per fraction). Incidence of dicentrics and micronuclei was monitored as well as determination of apoptosis and the transcription level of selected radiation-responsive genes. Since mitochondrial DNA (mtDNA) has been reported to be a potential indicator of radiation damage <i>in vitro</i>, we also assessed mtDNA content and deletions by novel multiplex quantitative PCR. Cytogenetic data confirmed linear dose-dependent increase in dicentrics (p < 0.01) and micronuclei (p < 0.001) in peripheral blood mononuclear cells after PBI. Significant up-regulations of five previously identified transcriptional biomarkers of radiation exposure (<i>PHPT1</i>, <i>CCNG1</i>, <i>CDKN1A</i>, <i>GADD45</i>, and <i>SESN1</i>) were also found (p < 0.01). No statistical change in mtDNA deletion levels was detected; however, our data indicate that the total mtDNA content decreased with increasing number of RT fractions. Interestingly, the number of micronuclei appears to correlate with late radiation toxicity (r² = 0.9025) in endometrial patients suggesting the possibility of predicting the severity of RT-related toxicity by monitoring this parameter. Overall, these data represent, to our best knowledge, the first study providing a multiparametric comparison of radiation biomarkers in human blood <i>in vivo</i>, which have potential for improving biological dosimetry.</p></div