TRAPS Dotaz Zobrazit nápovědu
Statiny patří mezi nejpoužívanější léky v kardiologii. Jejich význam spočívá nejen ve snížení cholesterolu, a tím ve zlepšení rizikového profilu nemocných, ale především ve snížení mortality na kardiovaskulární nemoci u pacientů v sekundární i primární prevenci. S rostoucím používáním statinů však roste riziko nežádoucích účinků. Mezi nejzávažnější nežádoucí účinky patří rhabdomyolýza. Musíme si být rovněž vědomi možnosti lékových interakcí, především s léky metabolizovanými cytochromem cyp3A4.
Statins belong to the most frequently used medications in cardiology. They are effective not only in lowering cholesterol and improving the patients´ risk profile, but especially in lowering cardiovascular mortality of patients in secondary and primary prevention. However, with increased use of statins, the risk of side-effects and drug interactions increases. The most serious side-effect is rhabdomyolysis. We should be aware also of drug interactions, especially with medications metabolized by cytochrom cyp 3A4.
- MeSH
- hypolipidemika škodlivé účinky terapeutické užití MeSH
- kardiovaskulární nemoci farmakoterapie mortalita prevence a kontrola MeSH
- lékové interakce MeSH
- nemoci jater etiologie MeSH
- nemoci svalů etiologie komplikace MeSH
- rhabdomyolýza etiologie MeSH
- statiny škodlivé účinky terapeutické užití MeSH
- Publikační typ
- přehledy MeSH
Diabetes mellitus 1. typu (DM1) je multifaktorálne autoimunitné ochorenie, ktoré spočíva v napadnutí inzulín produkujúcich beta buniek v pankrease cytotoxickými CD8 lymfocytmi. No nielen T lymfocyty sa podieľajú na tomto ničení beta buniek. Práve kooperáciou rôznych zložiek vrodenej a získanej imunity dochádza k rozvoji zápalu a následnej autoimunitnej reakcii. Dysregulácia vrodenej imunity je zjavná nielen u dlhodobobých pacientov s DM1 a nie je asociovaná so zmenami v metabolizme, z čoho vyplýva, že ide o potenciálne geneticky podmienené faktory. Pretože presymptomatickí pacienti by mali veľký úžitok z včasnej identifikácie nástupu patologických procesov vedúcich k symptomatickému DM1, je dôležité porozumieť tejto dysregulácii čo najdetailnejšie. V tomto prehľade sa budeme venovať neutrofilom a ich produktom, ktoré sa volajú neutrofilné extracelulárne pasce (NET). Skladajú sa najmä z vlastnej DNA a antimikrobiálnych proteínov a sú význačným mechanizmom antiinfekčnej imunity. Avšak v posledných rokoch si NETy získali nemalú pozornosť v oblasti autoimunitných ochorení, pretože sami o sebe predstavujú potenciálny zdroj autoantigénov, na ktoré by imunitný systém mohol prehnane reagovať. Monocyty a dendritické bunky (DC) od DM1 pacientov prehnane reagujú na prítomnosť DNA, mikrobiálnej aj vlastnej DNA. A preto NETy u DM1 sú schopné indukovať IFNγ-produkujúce T lymfocyty skrz aktiváciu DC a tým prispievať k autoimunitnému procesu.
Type 1 diabetes (T1D) is an autoimmune disease with multifactorial aetiology that involves an attack of self-reactive cytotoxic CD8 lymphocytes on insulin-producing beta cells in the pancreas. However, not only T lymphocytes contribute to the T1D pathophysiology. Both innate and adaptive immunity mechanisms cooperate in the development of inflammation leading to autoimmune destruction. Innate immunity dysregulation is apparent not only in long-term treated T1D patients and is not associated with metabolic changes, suggesting that the changes are intrinsic and potentially determined genetically. Since presymptomatic patients would benefit from early identification of the onset of the pathological processes leading to symptomatic T1D, we believe that thorough understanding the underlying mechanisms is crucial. Here, we focus on neutrophils and their products called neutrophil extracellular traps (NETs). NET structures are predominantly composed of neutrophil DNA and antimicrobial proteins and are an important mechanism of antimicrobial defence; however, in recent years, NETs gained considerable attention in the field of autoimmune diseases as a source of potential autoantigens. They are able to induce IFNγ-producing T cells through activation of dendritic cells (DCs), since we show that T1D monocytes and DCs inappropriately react to the presence of DNA regardless of the origin, including microbial or endogenous sources, suggesting that aberrant recognition of DNA contained in NETs also participates in the inflammation associated.
- MeSH
- autoimunitní nemoci genetika imunologie MeSH
- diabetes mellitus 1. typu * genetika imunologie patofyziologie MeSH
- extracelulární pasti imunologie metabolismus MeSH
- lidé MeSH
- neutrofily imunologie metabolismus MeSH
- pankreas imunologie patofyziologie patologie MeSH
- přirozená imunita genetika imunologie MeSH
- Check Tag
- lidé MeSH
- Klíčová slova
- netóza,
- MeSH
- aktivace neutrofilů imunologie MeSH
- autoimunita imunologie MeSH
- buněčná smrt imunologie MeSH
- extracelulární pasti * fyziologie imunologie MeSH
- extracelulární prostor imunologie MeSH
- imunitní systém fyziologie imunologie MeSH
- infekce imunologie MeSH
- lidé MeSH
- nádory imunologie MeSH
- neutrofily * imunologie MeSH
- přirozená imunita imunologie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- práce podpořená grantem MeSH
- přehledy MeSH
Diabetes is associated with dire peripheral sequelae including foot ulcers and amputations. A recent article by Wong et al. demystifies this connection by demonstrating that the neutrophil defense mechanism of extruding decondensed chromatin, termed NETosis, mediates delayed wound healing in diabetes and provides a therapeutic strategy for this indication.
- MeSH
- citrulin metabolismus MeSH
- extracelulární pasti * účinky léků MeSH
- hojení ran * účinky léků MeSH
- hydrolasy genetika metabolismus MeSH
- komplikace diabetu patologie MeSH
- lidé MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
Eye rheum is a physiological discharge, which accumulates at the medial angle of the healthy eye soon after opening in the morning. Microscopic evaluation of eye rheum revealed the presence of viable neutrophils, bacteria, epithelial cells, and particles, aggregated by neutrophil extracellular traps. We observed that in the evening, during eye closure, high C5a recruited neutrophils to the tear film and activated them. In this hypoxic area rich in CO2 , neutrophils fight microbial aggressors by degranulation. Immediately after eye opening, the microenvironment of the ocular surface changes, the milieu gets normoxic, and loss of CO2 induces subtle alkalinization of tear film. These conditions favored the formation of neutrophil extracellular traps (NETs) that initially covers the ocular surface and tend to aggregate by eyelid blinking. These aggregated neutrophil extracellular traps (aggNETs) are known as eye rheum and contain several viable neutrophils, epithelial cells, dust particles, and crystals packed together by NETs. Similar to aggNETs induced by monosodium urate crystals, the eye rheum shows a robust proteolytic activity that degraded inflammatory mediators before clinically overt inflammation occur. Finally, the eye rheum passively floats with the tear flow to the medial angle of the eye for disposal. We conclude that the aggNETs-based eye rheum promotes cleaning of the ocular surface and ameliorates the inflammation on the neutrophil-rich ocular surfaces.
BACKGROUND: Thrombosis is linked to neutrophil release of neutrophil extracellular traps (NETs). NETs are proposed as a mechanism of resistance to thrombolysis. This study intends to analyze the composition of thrombi retrieved after mechanical thrombectomy, estimate the age and organization of thrombi, and evaluate associations with the use of thrombolysis, antiplatelets, and heparin. METHODS: This retrospective observational study involved 72 samples (44 from cerebral and 28 coronary arteries), which were stained with hematoxylin and eosin, anti-NE (neutrophil elastase) antibody, and anti-histone H2B (histone H2B) antibody, representing different components in NET formation, all detectable during the later stages of NETosis, for histochemical and digital quantification of NET content. The histological and morphological evaluations of the specimens were correlated, through univariate and mediation analyses, with clinical information and therapy administered before intervention. RESULTS: The results demonstrated that the composition of cerebral and coronary thrombi differs, and there were significantly more lytic cerebral thrombi than coronary thrombi (66% versus 14%; P=0.005). There was a considerably higher expression of NETs in the cerebral thrombi as testified by the higher expression of H2B (P=0.031). Thrombolysis was remarkably associated with higher NE positivity (average marginal effect, 6.461 [95% CI, 0.7901-12.13]; P=0.02555), regardless of the origin of thrombi. There was no notable association between the administration of antiaggregant therapy/heparin and H2B/NE amount when adjusted for the thrombus location. Importantly, the age of the thrombus was the only independent predictor of NET content without any mediation of the thrombolytic treatment (P=0.014). CONCLUSIONS: The age of the thrombus is the driving force for NET content, which correlates with impaired clinical outcomes. The therapy that is currently administered does not modify NET content. This study supports the need to investigate new pharmacological approaches added to thrombolysis to prevent NET formation or enhance their disruption, such as recombinant human DNase I (deoxyribonuclease I).
Tuberculosis (TB) remains one of the top 10 causes of death worldwide and still poses a serious challenge to public health. Recent attention to neutrophils has uncovered unexplored areas demanding further investigation. Therefore, the aim of this study was to determine neutrophil activation and circulatory neutrophil extracellular trap (NET) formation in various types of TB. Sera from TB patients (n = 91) and healthy controls (NHD; n = 38) were analyzed for NE-DNA and MPO-DNA complexes, cell-free DNA (cfDNA), and protease activity (elastase). We show that these NET parameters were increased in TB sera. Importantly, NET formation and NE activity were elevated in TB patients with extensive tissue damage when compared to those with minor damage and in patients with relapse, compared to new cases. We discuss the importance of balancing NET formation to prevent tissue damage or even relapse and argue to analyze circulating NET parameters to monitor the risk of disease relapse. To investigate the tissues for NETs and to find the source of the circulating NET degradation products, we collected sections of granulomas in lung and lymph node biopsies. Samples from other diseases with granulomas, including sarcoidosis (SARC) and apical periodontitis (AP), served as controls. Whereas NET formation characterizes the caseating granulomas, both caseating and non-caseating granulomas harbor DNA with unusual conformation. As TB is associated with hypercoagulation and thromboembolism, we further imaged the pulmonary vessels of TB patients and detected vascular occlusions with neutrophil aggregates. This highlights the dual role of neutrophils in the pathology of TB.
- MeSH
- aktivace neutrofilů MeSH
- dospělí MeSH
- extracelulární pasti * metabolismus MeSH
- granulom * patologie metabolismus MeSH
- lidé středního věku MeSH
- lidé MeSH
- neutrofily * metabolismus MeSH
- studie případů a kontrol MeSH
- tuberkulóza patologie krev MeSH
- volné cirkulující nukleové kyseliny krev MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
PURPOSE: Obstructive Meibomian gland dysfunction (MGD) is one of the leading causes of evaporative dry eye disease. Meibomian glands at the eyelid secrete lipids that prevent evaporation of the aqueous tear film. The pathogenesis of obstructive MGD is incompletely understood to date. Herein, we aim to investigate the pathogenesis of obstructive MGD using murine and human samples with various forms of ocular surface inflammation. METHOD: The presence of Neutrophil extracellular Traps (NETs) was detected with immunofluorescence analysis of ocular surface discharge and biopsy samples from patients with blepharitis. Tear fluid from patients with MGD and blepharitis were evaluated for the presence of inflammatory mediators using bead based immunoassay. Murine model of allergic eye disease (AED) was performed to investigate the role of NETs in MG occlusion. RESULTS: we show that the ocular discharge from patients with blepharitis contains aggregated neutrophil extracellular traps (aggNETs). Furthermore, the ducts of human Meibomian glands affected by blepharitis were largely congested by aggNETs. Tear fluid from patients with MGD showed elevated neutrophil chemoattractants (C5a, IL6, IL8 and IL18). C5a and IL8 correlated with the degree of deficiency of tear fluid. In the murine model of allergic eye disease (AED), aggNETs accumulated in the MG leading to occlusion of their ducts and the retrograde pent-up of the fluid followed by acinar atrophy. Constraining aggNET formation by genetic or pharmacological inhibition of peptidyl arginine deiminase type 4 (PADI4) effectively reduced MG damage. CONCLUSION: We conclude that aggNETs occlude MG causing MGD after ocular surface inflammation.
- MeSH
- extracelulární pasti * MeSH
- lidé MeSH
- meibomské žlázky MeSH
- myši MeSH
- nemoci očních víček * MeSH
- slzy MeSH
- syndromy suchého oka * MeSH
- zánět MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Papillon-Lefèvre syndrome (PLS) is characterized by nonfunctional neutrophil serine proteases (NSPs) and fulminant periodontal inflammation of unknown cause. Here we investigated neutrophil extracellular trap (NET)-associated aggregation and cytokine/chemokine-release/degradation by normal and NSP-deficient human and mouse granulocytes. Stimulated with solid or soluble NET inducers, normal neutrophils formed aggregates and both released and degraded cytokines/chemokines. With increasing cell density, proteolytic degradation outweighed release. Maximum output of cytokines/chemokines occurred mostly at densities between 2 × 107 and 4 × 107 neutrophils/cm3. Assessment of neutrophil density in vivo showed that these concentrations are surpassed during inflammation. Association with aggregated NETs conferred protection of neutrophil elastase against α1-antitrypsin. In contrast, eosinophils did not influence cytokine/chemokine concentrations. The proteolytic degradation of inflammatory mediators seen in NETs was abrogated in Papillon-Lefèvre syndrome (PLS) neutrophils. In summary, neutrophil-driven proteolysis of inflammatory mediators works as a built-in safeguard for inflammation. The absence of this negative feedback mechanism might be responsible for the nonresolving periodontitis seen in PLS.-Hahn, J., Schauer, C., Czegley, C., Kling, L., Petru, L., Schmid, B., Weidner, D., Reinwald, C., Biermann, M. H. C., Blunder, S., Ernst, J., Lesner, A., Bäuerle, T., Palmisano, R., Christiansen, S., Herrmann, M., Bozec, A., Gruber, R., Schett, G., Hoffmann, M. H. Aggregated neutrophil extracellular traps resolve inflammation by proteolysis of cytokines and chemokines and protection from antiproteases.
- MeSH
- chemokiny metabolismus MeSH
- cytokiny metabolismus MeSH
- dospělí MeSH
- extracelulární pasti metabolismus MeSH
- inhibitory proteas metabolismus MeSH
- ionomycin farmakologie MeSH
- kyselina močová farmakologie MeSH
- lidé MeSH
- mediátory zánětu metabolismus MeSH
- mladiství MeSH
- myši inbrední BALB C MeSH
- myši MeSH
- NADPH-oxidasy genetika MeSH
- neutrofily účinky léků metabolismus MeSH
- parodontitida metabolismus MeSH
- proteolýza MeSH
- tetradekanoylforbolacetát farmakologie MeSH
- zánět prevence a kontrola MeSH
- zvířata MeSH
- Check Tag
- dospělí MeSH
- lidé MeSH
- mladiství MeSH
- mužské pohlaví MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
