Bile acid profiles are altered in obese individuals with asthma. Thus, we sought to better understand how obesity-related systemic changes contribute to lung pathophysiology. We also test the therapeutic potential of nitro-oleic acid (NO2-OA), a regulator of metabolic and inflammatory signaling pathways, to mitigate allergen and obesity-induced lung function decline in a murine model of asthma. Bile acids were measured in the plasma of healthy subjects and individuals with asthma and serum and lung tissue of mice with and without allergic airway disease (AAD). Lung function, indices of inflammation and hepatic bile acid enzyme expression were measured in obese mice with house dust mite-induced AAD treated with vehicle or NO2-OA. Serum levels of glycocholic acid and glycoursodeoxycholic acid clinically correlate with body mass index and airway hyperreactivity whereas murine levels of β-muricholic acid and tauro-β-muricholic acid were significantly increased and positively correlated with impaired lung function in obese mice with AAD. NO2-OA reduced murine bile acid levels by modulating hepatic expression of bile acid synthesis enzymes, with a concomitant reduction in small airway resistance and tissue elastance. Bile acids correlate to body mass index and lung function decline and the signaling actions of nitroalkenes can limit AAD by modulating bile acid metabolism, revealing a potential pharmacologic approach to improving the current standard of care.

• MeSH
• antiastmatika terapeutické užití   MeSH
• antigeny roztočů domácího prachu toxicita   MeSH
• bronchiální astma farmakoterapie   etiologie   metabolismus   patofyziologie   MeSH
• dieta s vysokým obsahem tuků škodlivé účinky   MeSH
• dospělí MeSH
• dusíkaté sloučeniny terapeutické užití   MeSH
• hubenost MeSH
• játra účinky léků   metabolismus   MeSH
• kyselina glykocholová krev   MeSH
• kyselina ursodeoxycholová analogy a deriváty   krev   MeSH
• kyseliny olejové terapeutické užití   MeSH
• lidé středního věku MeSH
• lidé MeSH
• mastné kyseliny chemie   fyziologie   MeSH
• mladiství MeSH
• mladý dospělý MeSH
• myši inbrední C57BL MeSH
• myši MeSH
• obezita komplikace   metabolismus   patofyziologie   MeSH
• plíce patofyziologie   MeSH
• preklinické hodnocení léčiv MeSH
• respirační alergie chemicky indukované   farmakoterapie   metabolismus   MeSH
• usilovný výdechový objem MeSH
• vitální kapacita MeSH
• žlučové kyseliny a soli metabolismus   MeSH
• zvířata MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• mužské pohlaví MeSH
• myši MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH
• Názvy látek
• antiastmatika MeSH
• antigeny roztočů domácího prachu MeSH
• CXA-10 MeSH Prohlížeč
• dusíkaté sloučeniny MeSH
• glycoursodeoxycholic acid MeSH Prohlížeč
• kyselina glykocholová MeSH
• kyselina ursodeoxycholová MeSH
• kyseliny olejové MeSH
• mastné kyseliny MeSH
• žlučové kyseliny a soli MeSH

Many diseases accompanied by chronic inflammation are connected with dysregulated activation of macrophage subpopulations. Recently, we reported that nitro-fatty acids (NO2-FAs), products of metabolic and inflammatory reactions of nitric oxide and nitrite, modulate macrophage and other immune cell functions. Bone marrow cell suspensions were isolated from mice and supplemented with macrophage colony-stimulating factor (M-CSF) or granulocyte-macrophage colony-stimulating factor (GM-CSF) in combination with NO2-OA for different times. RAW 264.7 macrophages were used for short-term (1-5min) experiments. We discovered that NO2-OA reduces cell numbers, cell colony formation, and proliferation of macrophages differentiated with colony-stimulating factors (CSFs), all in the absence of toxicity. In a case of GM-CSF-induced bone marrow-derived macrophages (BMMs), NO2-OA acts via downregulation of signal transducer and activator of transcription 5 and extracellular signal-regulated kinase (ERK) activation. In the case of M-CSF-induced BMMs, NO2-OA decreases activation of M-CSFR and activation of related PI3K and ERK. Additionally, NO2-OA also attenuates activation of BMMs. In aggregate, we demonstrate that NO2-OA regulates the process of macrophage differentiation and that NO2-FAs represent a promising therapeutic tool in the treatment of inflammatory pathologies linked with increased accumulation of macrophages in inflamed tissues.

• Klíčová slova
• Differentiation, Growth factors, Inflammation, Macrophages, Nitro-fatty acids, Nitro-oleic acid, Signaling pathways,
• MeSH
• buněčná diferenciace účinky léků   MeSH
• buňky kostní dřeně účinky léků   MeSH
• extracelulárním signálem regulované MAP kinasy genetika   MeSH
• faktory stimulující kolonie genetika   MeSH
• fosfatidylinositol-3-kinasy genetika   MeSH
• kyselina olejová aplikace a dávkování   chemie   MeSH
• makrofágy účinky léků   MeSH
• MAP kinasový signální systém účinky léků   MeSH
• myši MeSH
• oxid dusnatý aplikace a dávkování   chemie   MeSH
• RAW 264.7 buňky MeSH
• regulace genové exprese u nádorů účinky léků   MeSH
• transkripční faktor STAT5 genetika   MeSH
• zánět farmakoterapie   genetika   patologie   MeSH
• zvířata MeSH
• Check Tag
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH
• Názvy látek
• extracelulárním signálem regulované MAP kinasy MeSH
• faktory stimulující kolonie MeSH
• fosfatidylinositol-3-kinasy MeSH
• kyselina olejová MeSH
• oxid dusnatý MeSH
• transkripční faktor STAT5 MeSH

BACKGROUND: Inflammatory-mediated pathological processes in the endothelium arise as a consequence of the dysregulation of vascular homeostasis. Of particular importance are mediators produced by stimulated monocytes/macrophages inducing activation of endothelial cells (ECs). This is manifested by excessive soluble pro-inflammatory mediator production and cell surface adhesion molecule expression. Nitro-fatty acids are endogenous products of metabolic and inflammatory reactions that display immuno-regulatory potential and may represent a novel therapeutic strategy to treat inflammatory diseases. The purpose of our study was to characterize the effects of nitro-oleic acid (OA-NO2) on inflammatory responses and the endothelial-mesenchymal transition (EndMT) in ECs that is a consequence of the altered healing phase of the immune response. METHODS: The effect of OA-NO2 on inflammatory responses and EndMT was determined in murine macrophages and murine and human ECs using Western blotting, ELISA, immunostaining, and functional assays. RESULTS: OA-NO2 limited the activation of macrophages and ECs by reducing pro-inflammatory cytokine production and adhesion molecule expression through its modulation of STAT, MAPK and NF-κB-regulated signaling. OA-NO2 also decreased transforming growth factor-β-stimulated EndMT and pro-fibrotic phenotype of ECs. These effects are related to the downregulation of Smad2/3. CONCLUSIONS: The study shows the pleiotropic effect of OA-NO2 on regulating EC-macrophage interactions during the immune response and suggests a role for OA-NO2 in the regulation of vascular endothelial immune and fibrotic responses arising during chronic inflammation. GENERAL SIGNIFICANCE: These findings propose the OA-NO2 may be useful as a novel therapeutic agent for treatment of cardiovascular disorders associated with dysregulation of the endothelial immune response.

• Klíčová slova
• Endothelial cells, Endothelial-mesenchymal transition, Macrophages, Nitro-fatty acids, Nitro-oleic acid, Vascular inflammation,
• MeSH
• cévní endotel cytologie   účinky léků   metabolismus   MeSH
• endoteliální buňky účinky léků   metabolismus   MeSH
• epitelo-mezenchymální tranzice * MeSH
• kyseliny olejové farmakologie   MeSH
• lidé MeSH
• makrofágy účinky léků   metabolismus   MeSH
• MAP kinasový signální systém MeSH
• myši MeSH
• NF-kappa B metabolismus   MeSH
• proteiny Smad metabolismus   MeSH
• transformující růstový faktor beta farmakologie   MeSH
• transkripční faktory STAT metabolismus   MeSH
• zánět metabolismus   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH
• Názvy látek
• 10-nitro-oleic acid MeSH Prohlížeč
• kyseliny olejové MeSH
• NF-kappa B MeSH
• proteiny Smad MeSH
• transformující růstový faktor beta MeSH
• transkripční faktory STAT MeSH