Eicosanoids are biologically active lipid mediators, comprising prostaglandins, leukotrienes, thromboxanes, and lipoxins, involved in several pathophysiological processes relevant to asthma, allergies, and allied diseases. Prostaglandins and leukotrienes are the most studied eicosanoids and established inducers of airway pathophysiology including bronchoconstriction and airway inflammation. Drugs inhibiting the synthesis of lipid mediators or their effects, such as leukotriene synthesis inhibitors, leukotriene receptors antagonists, and more recently prostaglandin D2 receptor antagonists, have been shown to modulate features of asthma and allergic diseases. This review, produced by an European Academy of Allergy and Clinical Immunology (EAACI) task force, highlights our current understanding of eicosanoid biology and its role in mediating human pathology, with a focus on new findings relevant for clinical practice, development of novel therapeutics, and future research opportunities.

• MeSH
• alergie * MeSH
• bronchiální astma * etiologie   MeSH
• ikosanoidy MeSH
• konsensus MeSH
• leukotrieny MeSH
• lidé MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH

• Klíčová slova
• plicní depozice, chybovost v inhalační technice,
• MeSH
• aplikace inhalační * MeSH
• beklomethason aplikace a dávkování   MeSH
• bronchiální astma farmakoterapie   MeSH
• chronická obstrukční plicní nemoc farmakoterapie   MeSH
• formoterol fumarát aplikace a dávkování   MeSH
• hormony kůry nadledvin terapeutické užití   MeSH
• kombinovaná farmakoterapie MeSH
• leukotrieny škodlivé účinky   terapeutické užití   MeSH
• lidé středního věku MeSH
• lidé MeSH
• nebulizátory a vaporizátory statistika a číselné údaje   MeSH
• poruchy spánku a bdění chemicky indukované   MeSH
• práškové inhalátory metody   MeSH
• radioisotopová scintigrafie MeSH
• výsledek terapie MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• ženské pohlaví MeSH
• Publikační typ
• kazuistiky MeSH

• MeSH
• antagonisté leukotrienů MeSH
• bronchiální astma * farmakoterapie   MeSH
• leukotrieny MeSH
• lidé MeSH
• monoklonální protilátky MeSH
• omalizumab MeSH
• theofylin MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• přehledy MeSH

• MeSH
• biochemie MeSH
• leukotrieny MeSH
• lipoxiny MeSH
• nukleotidy cyklické MeSH
• prostaglandiny analýza   MeSH
• Publikační typ
• biografie MeSH

• O autorovi
• Samuelsson, Bengt, 1934- Autorita

Leukotrienes (LTs) are pro-inflammatory lipid mediators derived from arachidonic acid (AA) with roles in inflammatory and allergic diseases. The biosynthesis of LTs is initiated by transfer of AA via the 5-lipoxygenase-activating protein (FLAP) to 5-lipoxygenase (5-LO). FLAP inhibition abolishes LT formation exerting anti-inflammatory effects. The soluble epoxide hydrolase (sEH) converts AA-derived anti-inflammatory epoxyeicosatrienoic acids (EETs) to dihydroxyeicosatetraenoic acids (di-HETEs). Its inhibition consequently also counteracts inflammation. Targeting both LT biosynthesis and the conversion of EETs with a dual inhibitor of FLAP and sEH may represent a novel, powerful anti-inflammatory strategy. We present a pharmacophore-based virtual screening campaign that led to 20 hit compounds of which 4 targeted FLAP and 4 were sEH inhibitors. Among them, the first dual inhibitor for sEH and FLAP was identified, N-[4-(benzothiazol-2-ylmethoxy)-2-methylphenyl]-N'-(3,4-dichlorophenyl)urea with IC50 values of 200 nM in a cell-based FLAP test system and 20 nM for sEH activity in a cell-free assay.

• MeSH
• antiflogistika chemie   farmakologie   MeSH
• bezbuněčný systém MeSH
• epoxid hydrolasy antagonisté a inhibitory   MeSH
• inhibitory enzymů chemie   farmakologie   MeSH
• inhibitory proteinu aktivujícího 5-lipoxygenasu chemie   farmakologie   MeSH
• leukotrieny biosyntéza   MeSH
• lidé MeSH
• molekulární modely MeSH
• molekulární struktura MeSH
• počítačová simulace MeSH
• preklinické hodnocení léčiv MeSH
• proteiny aktivující 5-lipoxygenasu metabolismus   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

CONTEXT: The role of neuroinflammation in methanol-induced toxic brain damage has not been studied. OBJECTIVE: We studied acute concentrations and the dynamics of leukotrienes (LT) in serum in hospitalized patients with acute methanol poisoning and in survivors. METHODS: Series of acute cysteinyl-LT and LTB4 concentration measurements were performed in 28/101 hospitalized patients (mean observation time: 88 ± 20 h). In 36 survivors, control LT measurements were performed 2 years after discharge. RESULTS: The acute maximum (Cmax) LT concentrations were higher than concentrations in survivors: Cmax for LTC4 was 80.7 ± 5.6 versus 47.9 ± 4.5 pg/mL; for LTD4, 51.0 ± 6.6 versus 23.1 ± 2.1 pg/mL; for LTE4, 64.2 ± 6.0 versus 26.2 ± 3.9 pg/mL; for LTB4, 59.8 ± 6.2 versus 27.2 ± 1.4 pg/mL (all p < 0.001). The patients who survived had higher LT concentrations than those who died (all p < 0.01). Among survivors, patients with CNS sequelae had lower LTE4 and LTB4 than did those without sequelae (both p < 0.05). The LT concentrations increased at a rate of 0.4-0.5 pg/mL/h and peaked 4-5 days after admission. The patients with better outcomes had higher cys-LTs (all p < 0.01) and LTB4 (p < 0.05). More severely poisoned patients had lower acute LT concentrations than those with minor acidemia. The follow-up LT concentrations in survivors with and without CNS sequelae did not differ (all p > 0.05). The mean decrease in LT concentration was 30.9 ± 9.0 pg/mL for LTC4, 26.3 ± 8.6 pg/mL for LTD4, 37.3 ± 6.4 pg/mL for LTE4, and 32.0 ± 8.8 pg/mL for LTB4. CONCLUSIONS: Our findings suggest that leukotriene-mediated neuroinflammation may play an important role in the mechanisms of toxic brain damage in acute methanol poisoning in humans. Acute elevation of LT concentrations was moderate, transitory, and was not followed by chronic neuroinflammation in survivors.

• MeSH
• akutní nemoc MeSH
• cystein krev   MeSH
• ethanol krev   MeSH
• formiáty krev   MeSH
• hospitalizace MeSH
• hydrogenuhličitany krev   MeSH
• koncentrace vodíkových iontů MeSH
• kreatinin krev   MeSH
• krevní glukóza metabolismus   MeSH
• laktáty krev   MeSH
• leukotrieny krev   MeSH
• lidé středního věku MeSH
• lidé MeSH
• methanol krev   otrava   MeSH
• mozek účinky léků   patologie   MeSH
• následné studie MeSH
• neurodegenerativní nemoci chemicky indukované   patologie   MeSH
• otrava krev   farmakoterapie   MeSH
• výsledek terapie MeSH
• zánět chemicky indukované   patologie   MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH

Human health data regarding exposure to nanoparticles are extremely scarce and biomonitoring of exposure is lacking in spite of rodent pathological experimental data. Potential markers of the health-effects of engineered nanoparticles were examined in 30 workers exposed to TiO2 aerosol, 22 office employees of the same plant, and 45 unexposed controls. Leukotrienes (LT) B4, C4, E4, and D4 were analysed in the exhaled breath condensate (EBC) and urine via liquid chromatography-electrospray ionization-tandem mass spectrometry (LC-ESI-MS/MS). Fractional exhaled nitric oxide (FeNO) and spirometry was also measured. The median particle number concentration of the aerosol in the production ranged from 1.98 × 10(4) to 2.32 × 10(4) particles cm(-3); about 80% of the particles were <100 nm in diameter. Median total mass concentration varied between 0.4 and 0.65 mg m(-3). All LT levels in workers' EBC were elevated relative to the controls (p < 0.01). LTs in the EBC sample were correlated with titanium levels. Urinary LTs were not elevated in the workers and office employees. Office workers had higher LTB4 in EBC (p < 0.05), and higher levels of FeNO (p < 0.01). FeNO was higher in office employees with allergic diseases and was negatively correlated with smoking (p < 0.01). In spirometry significant impairment in the workers was seen only for %VCIN and %PEF (both p < 0.01). Multiple regression analysis confirmed a significant association between production of TiO2 and all cysteinyl LTs in EBC (p < 0.01) and impaired %VCIN and %PEF (both p < 0.01). LTB4 was also associated with smoking (p < 0.01). LT levels complemented our earlier findings of DNA, protein, and lipid damage in the EBC of workers with nanoTiO2 exposures. Cysteinyl LTs in EBC analysis suggest inflammation and potential fibrotic changes in the lungs; they may be helpful for monitoring the biological effect of (nano)TiO2 on workers. Spirometry was not sensitive enough.

• MeSH
• aerosoly analýza   MeSH
• biologické markery analýza   MeSH
• dechové testy metody   MeSH
• dospělí MeSH
• koncentrace vodíkových iontů MeSH
• leukotrieny analýza   moč   MeSH
• lidé MeSH
• nanočástice škodlivé účinky   MeSH
• oxid dusnatý analýza   MeSH
• pracoviště MeSH
• pracovní expozice analýza   MeSH
• regresní analýza MeSH
• respirační funkční testy MeSH
• studie případů a kontrol MeSH
• tandemová hmotnostní spektrometrie MeSH
• titan škodlivé účinky   MeSH
• vydechnutí * MeSH
• Check Tag
• dospělí MeSH
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Předkládaná práce se zejména zabývá problematikou obtížně léčitelného astmatu (OLA), tedy zvláštního fenotypu, který nereaguje na žádnou formu zatím známé antiastmatické farmakoterapie. Práce je založena na diagnostické metodě, kdy molekulární diagnostika vychází z vysoce specifické matrice – kondenzátu vydechovaného vzduchu (KVV). Metoda pracuje se dvěma skupinami biomarkerů, které jsou známé jako cysteinylované lukotrieny a lipoxiny. Cysteinylované leukotrieny jsou mediátory zánětu, naproti tomu lipoxiny mají funkci protizánětlivou. Kombinace těchto dvou skupin biomarkerů pak velmi zpřesňuje fenotypizaci astmatu a zároveň umožňuje oddělení OLA, což bylo potvrzeno v klinické studii. Zároveň se práce snaží vysvětlit, proč OLA pozitivně reagují na terapii SSRI antidepresivy. Bylo zjiš- těno, že KVV OLA obsahuje zvýšené hladiny 5-HT (v porovnání s kontrolní skupinou a ostatními fenotypy astmatu). Tato skutečnost má mnoho možných vysvětlení. Jedno z nich nabízí hypotézu, že OLA by mohlo být jiným onemocněním, které by se pouze demonstrovalo podobně jako astma. Ovšem tato problematika bude jistě v budoucnu ještě vyžadovat další výzkum.

The present work mainly deals with the issue of severe refractory asthma (SRA), i. e. an asthma phenotype that does not respond to any kind of currently used pharmacotherapy. The work is patterned on a diagnostic method that is based on molecular diagnostics of a highly specific matrix – exhaled breath condensate (EBC). The method works with two groups of biomarkers that are known as cysteinyl leukotrienes and lipoxines. Cysteinyl leukotrienes are mediator of inflammation, however lipoxines have the anti -inflammatory function. The combination of these two groups biomarkers can be used for accuracy of asthma phenotyping and it also allows separation of SRA, which was confirmed in a clinical study. At the same time, the work tries to explain, why SRA positively respond to SSRI antidepressants therapy. It has been detected that EBC of SRA contains increased levels of 5-HT (compered to controls and other asthma phenotypes). This phenomenon has several possible explications. One of them offers a hypothesis that SRA could be a different disease that would be only demonstrated as asthma. But this issue will definitely require further research in the future.

• Klíčová slova
• cysteinylované leukotrieny, obtížně léčitelné astma,
• MeSH
• antidepresiva druhé generace terapeutické užití   MeSH
• biologické markery analýza   metabolismus   MeSH
• bronchiální astma * diagnóza   farmakoterapie   metabolismus   MeSH
• dechové testy MeSH
• dospělí MeSH
• fenotyp MeSH
• hmotnostní spektrometrie MeSH
• leukotrieny * analýza   metabolismus   MeSH
• lidé středního věku MeSH
• lidé MeSH
• lipoxiny * analýza   metabolismus   MeSH
• selektivní inhibitory zpětného vychytávání serotoninu terapeutické užití   MeSH
• serotonin analýza   metabolismus   MeSH
• studie případů a kontrol MeSH
• vydechnutí MeSH
• vysokoúčinná kapalinová chromatografie MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• klinické zkoušky MeSH
• práce podpořená grantem MeSH

Diagnostic methods used in the contemporary medical practice consist of a combination of distressing invasive (bronchial biopsy, bronchoalveolar lavage) and semiinvasive (induced sputum technique) methods. Monitoring of specific molecules produced during pathological processes in biological matrices is a relatively new technique which represents an alternative, entirely non-invasive and comfortable method. The principle is based on the quantification of specific substances – "biomarkers", which are considered to be objectively measurable indicators of a physiological/pathological condition of the organism. In contrast with non-specific matrices such as blood plasma (reflecting the state of the whole organism), the exhaled breath condensate is a specific matrix. Concentration levels of biomarkers in the latter matrix point at pathological processes only in the airways and lungs. Typical molecules to be monitored include hydrogen peroxide, leukotrienes, prostaglandins, lipoxins and prostanoids.

• Klíčová slova
• kondenzát vydechovaného vzduchu,
• MeSH
• biologické markery analýza   MeSH
• chronická obstrukční plicní nemoc diagnóza   MeSH
• diagnostické techniky dýchacího ústrojí MeSH
• ELISA MeSH
• hmotnostní spektrometrie MeSH
• kyseliny prostanové analýza   MeSH
• leukotrieny analýza   MeSH
• lidé MeSH
• lipoxiny analýza   MeSH
• metody pro podporu rozhodování MeSH
• prognóza MeSH
• prostaglandiny analýza   MeSH
• vysokoúčinná kapalinová chromatografie MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• práce podpořená grantem MeSH

Interleukin-3 is a growth and differentiation factor for various hematopoietic cells. IL-3 also enhances stimulus-dependent release of mediators and cytokine production by mature basophils. Function of IL-3 has not been studied in horses because of lack of horse-specific reagents. Our aim was to produce recombinant equine IL-3 and test its effect on sulfidoleukotriene and cytokine production by equine peripheral blood leukocytes (PBL). Equine IL-3 was cloned, expressed in E. coli and purified. PBL of 19 healthy and 20 insect bite hypersensitivity (IBH)-affected horses were stimulated with Culicoides nubeculosus extract with or without IL-3. Sulfidoleukotriene (sLT) production was measured in supernatants by ELISA and mRNA expression of IL-4, IL-13 and thymic stromal lymphopoietin (TSLP) assessed in cell lysate by quantitative real-time PCR. Recombinant equine IL-3 (req-IL-3) had a dose dependent effect on sLT production by stimulated equine PBL and significantly increased IL-4, IL-13 and TSLP expression compared to non-primed cells. IL-3 priming significantly increased Culicoides-induced sLT production in IBH-affected but not in non-affected horses and was particularly effective in young IBH-affected horses (≤ 3 years). A functionally active recombinant equine IL-3 has been produced which will be useful for future immunological studies in horses. It will also allow improving the sensitivity of cellular in vitro tests for allergy diagnosis in horses.

• MeSH
• alergie imunologie   veterinární   MeSH
• Ceratopogonidae MeSH
• cytokiny genetika   metabolismus   MeSH
• interleukin-3 farmakologie   MeSH
• klonování DNA * MeSH
• koně metabolismus   MeSH
• kousnutí a bodnutí hmyzem imunologie   veterinární   MeSH
• leukocyty účinky léků   metabolismus   MeSH
• leukotrieny genetika   metabolismus   MeSH
• regulace genové exprese účinky léků   MeSH
• rekombinantní proteiny MeSH
• stárnutí MeSH
• zvířata MeSH
• Check Tag
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH