Cysteinyl-leukotrienes in the regulation of β<sub>2</sub>-adrenoceptor function: an in vitro model of asthma
<p>Abstract</p> <p>Background</p> <p>The response to β<sub>2</sub>-adrenoceptor agonists is reduced in asthmatic airways. This desensitization may be in part due to inflammatory mediators and may involve cysteinyl-leukotrienes (cysteinyl-LTs). Cysteinyl-LTs...
| Main Authors: | , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
BMC
2006-07-01
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| Series: | Respiratory Research |
| Online Access: | http://respiratory-research.com/content/7/1/103 |
| _version_ | 1818327586275590144 |
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| author | Milanese Manlio Ravasi Saula Brichetto Lorenzo Citro Simona Baroffio Michele Rovati G Enrico Crimi Emanuele Brusasco Vito |
| author_facet | Milanese Manlio Ravasi Saula Brichetto Lorenzo Citro Simona Baroffio Michele Rovati G Enrico Crimi Emanuele Brusasco Vito |
| author_sort | Milanese Manlio |
| collection | DOAJ |
| description | <p>Abstract</p> <p>Background</p> <p>The response to β<sub>2</sub>-adrenoceptor agonists is reduced in asthmatic airways. This desensitization may be in part due to inflammatory mediators and may involve cysteinyl-leukotrienes (cysteinyl-LTs). Cysteinyl-LTs are pivotal inflammatory mediators that play important roles in the pathophysiology of asthma, allergic rhinitis, and other inflammatory conditions. We tested the hypothesis that leukotriene D<sub>4 </sub>(LTD<sub>4</sub>) and allergen challenge cause β<sub>2</sub>-adrenoceptor desensitization through the activation of protein kinase C (PKC).</p> <p>Methods</p> <p>The isoproterenol-induced cAMP accumulation was evaluated in human airway smooth muscle cell cultures challenged with exogenous LTD<sub>4 </sub>or the PKC activator phorbol-12-myristate-13-acetate with or without pretreatments with the PKC inhibitor GF109203X or the CysLT<sub>1</sub>R antagonist montelukast. The relaxant response to salbutamol was studied in passively sensitized human bronchial rings challenged with allergen in physiological salt solution (PSS) alone, or in the presence of either montelukast or GF109203X.</p> <p>Results</p> <p>In cell cultures, both LTD<sub>4 </sub>and phorbol-12-myristate-13-acetate caused significant reductions of maximal isoproterenol-induced cAMP accumulation, which were fully prevented by montelukast and GF109203X, respectively. More importantly, GF109203X also prevented the attenuating effect of LTD<sub>4 </sub>on isoproterenol-induced cAMP accumulation. In bronchial rings, both montelukast and GF109203X prevented the rightward displacement of the concentration-response curves to salbutamol induced by allergen challenge.</p> <p>Conclusion</p> <p>LTD<sub>4 </sub>induces β<sub>2</sub>-adrenoceptor desensitization in human airway smooth muscle cells, which is mediated through the activation of PKC. Allergen exposure of sensitized human bronchi may also cause a β<sub>2</sub>-adrenoceptor desensitization through the involvement of the CysLT<sub>1</sub>R-PKC pathway.</p> |
| first_indexed | 2024-12-13T12:18:37Z |
| format | Article |
| id | doaj.art-420f55f0e7c245f9b3b9685238897ba7 |
| institution | Directory Open Access Journal |
| issn | 1465-9921 |
| language | English |
| last_indexed | 2024-12-13T12:18:37Z |
| publishDate | 2006-07-01 |
| publisher | BMC |
| record_format | Article |
| series | Respiratory Research |
| spelling | doaj.art-420f55f0e7c245f9b3b9685238897ba72022-12-21T23:46:39ZengBMCRespiratory Research1465-99212006-07-017110310.1186/1465-9921-7-103Cysteinyl-leukotrienes in the regulation of β<sub>2</sub>-adrenoceptor function: an in vitro model of asthmaMilanese ManlioRavasi SaulaBrichetto LorenzoCitro SimonaBaroffio MicheleRovati G EnricoCrimi EmanueleBrusasco Vito<p>Abstract</p> <p>Background</p> <p>The response to β<sub>2</sub>-adrenoceptor agonists is reduced in asthmatic airways. This desensitization may be in part due to inflammatory mediators and may involve cysteinyl-leukotrienes (cysteinyl-LTs). Cysteinyl-LTs are pivotal inflammatory mediators that play important roles in the pathophysiology of asthma, allergic rhinitis, and other inflammatory conditions. We tested the hypothesis that leukotriene D<sub>4 </sub>(LTD<sub>4</sub>) and allergen challenge cause β<sub>2</sub>-adrenoceptor desensitization through the activation of protein kinase C (PKC).</p> <p>Methods</p> <p>The isoproterenol-induced cAMP accumulation was evaluated in human airway smooth muscle cell cultures challenged with exogenous LTD<sub>4 </sub>or the PKC activator phorbol-12-myristate-13-acetate with or without pretreatments with the PKC inhibitor GF109203X or the CysLT<sub>1</sub>R antagonist montelukast. The relaxant response to salbutamol was studied in passively sensitized human bronchial rings challenged with allergen in physiological salt solution (PSS) alone, or in the presence of either montelukast or GF109203X.</p> <p>Results</p> <p>In cell cultures, both LTD<sub>4 </sub>and phorbol-12-myristate-13-acetate caused significant reductions of maximal isoproterenol-induced cAMP accumulation, which were fully prevented by montelukast and GF109203X, respectively. More importantly, GF109203X also prevented the attenuating effect of LTD<sub>4 </sub>on isoproterenol-induced cAMP accumulation. In bronchial rings, both montelukast and GF109203X prevented the rightward displacement of the concentration-response curves to salbutamol induced by allergen challenge.</p> <p>Conclusion</p> <p>LTD<sub>4 </sub>induces β<sub>2</sub>-adrenoceptor desensitization in human airway smooth muscle cells, which is mediated through the activation of PKC. Allergen exposure of sensitized human bronchi may also cause a β<sub>2</sub>-adrenoceptor desensitization through the involvement of the CysLT<sub>1</sub>R-PKC pathway.</p>http://respiratory-research.com/content/7/1/103 |
| spellingShingle | Milanese Manlio Ravasi Saula Brichetto Lorenzo Citro Simona Baroffio Michele Rovati G Enrico Crimi Emanuele Brusasco Vito Cysteinyl-leukotrienes in the regulation of β<sub>2</sub>-adrenoceptor function: an in vitro model of asthma Respiratory Research |
| title | Cysteinyl-leukotrienes in the regulation of β<sub>2</sub>-adrenoceptor function: an in vitro model of asthma |
| title_full | Cysteinyl-leukotrienes in the regulation of β<sub>2</sub>-adrenoceptor function: an in vitro model of asthma |
| title_fullStr | Cysteinyl-leukotrienes in the regulation of β<sub>2</sub>-adrenoceptor function: an in vitro model of asthma |
| title_full_unstemmed | Cysteinyl-leukotrienes in the regulation of β<sub>2</sub>-adrenoceptor function: an in vitro model of asthma |
| title_short | Cysteinyl-leukotrienes in the regulation of β<sub>2</sub>-adrenoceptor function: an in vitro model of asthma |
| title_sort | cysteinyl leukotrienes in the regulation of β sub 2 sub adrenoceptor function an in vitro model of asthma |
| url | http://respiratory-research.com/content/7/1/103 |
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