Remember Me
Or use your Academic/Social account:


Or use your Academic/Social account:


You have just completed your registration at OpenAire.

Before you can login to the site, you will need to activate your account. An e-mail will be sent to you with the proper instructions.


Please note that this site is currently undergoing Beta testing.
Any new content you create is not guaranteed to be present to the final version of the site upon release.

Thank you for your patience,
OpenAire Dev Team.

Close This Message


Verify Password:
Verify E-mail:
*All Fields Are Required.
Please Verify You Are Human:
fbtwitterlinkedinvimeoflicker grey 14rssslideshare1
Binnion, Amy Margaret (2010)
Languages: English
Types: Unknown

Classified by OpenAIRE into

mesheuropmc: respiratory tract diseases
Asthma is an inflammatory disease of the airways characterised by airway remodelling and hyperresponsiveness. New treatments are needed for patients with severe asthma whose disease is not controlled with currently available therapies. Asthma pathophysiology is complex, however, accumulating evidence suggests multiple inflammatory pathways in asthma converge onto a relatively small number of downstream targets that may be of therapeutic interest. These include mitogen activated protein kinases (MAPKs), the pro-inflammatory transcription factors nuclear factor-kappaB (NF-kappaB) and activator protein-1 (AP-1) and transcriptional regulators such as histone acetyl transferases (HATs) and histone deacetylases (HDACs). Chemokines are molecules secreted at sties of inflammation, attracting inflammatory cells and perpetuating the inflammatory response. Here we studied the mechanisms by which the pro-inflammatory mediator endothelin-1 (ET-1) and the cytokine tumour necrosis factor-alpha (TNF-alpha) promoted expression by primary human airway smooth muscle cells (HASMC) of two important chemokines, monocyte chemotactic protein-1 (MCP-1) and eotaxin. Further, we studied the mechanisms by which existing asthma therapies (long acting beta agonists (LABA) and glucocorticoids) modulated TNF-alpha-stimulated eotaxin expression. Endothelin-1 stimulated MCP-1 release through a transcriptional mechanism involving NF-kappaB and AP-1; the upstream signalling pathway involved p38 and p44/p42 MAPKs. Previously, this lab showed that TNF-alpha-induced eotaxin release is also NF-kappaB-dependent, involving histone H4 acetylation at the eotaxin promoter. Here we found that TNF-alpha-induced eotaxin release does not involve histone H3 acetylation, and that TNF-alpha-dependent histone H4 acetylation does not occur through alterations in total histone activity or levels of the key HDACs -1 and -2. Similarly, modulation of TNF-alpha effects on eotaxin expression by glucocorticoids and LABA is independent of total HDAC activity and HDAC-1 and -2 levels. These studies support the body of evidence suggesting that multiple inflammatory pathways in asthma converge onto a small number of downstream targets, and are relevant to the understanding and treatment of asthma.
  • The results below are discovered through our pilot algorithms. Let us know how we are doing!

    • 164 Thompson, C., A. Cloutier, Y. Bosse, C. Poisson, P. Larivee, P. P.
    • McDonald, J. Stankova, and M. Rola-Pleszczynski. 2008. Signaling by the cysteinyl-leukotriene receptor 2. Involvement in chemokine gene transcription. J Biol Chem 283:1974-1984.
    • Newton. 2007. Potentiation of NF-kappaB-dependent transcription and inflammatory mediator release by histamine in human airway epithelial cells. Br J Pharmacol 152:891-902.
    • Yu, L., W. K. Wu, Z. J. Li, H. P. Wong, E. K. Tai, H. T. Li, Y. C. Wu, and C. H. Cho. 2008. E series of prostaglandin receptor 2-mediated activation of extracellular signal-regulated kinase/activator protein-1 signaling is required for the mitogenic action of prostaglandin E2 in esophageal squamous-cell carcinoma. J Pharmacol Exp Ther 327:258- 267.
    • Liu, Q., K. A. Merkler, X. Zhang, and M. P. McLean. 2007.
    • Prostaglandin F2alpha suppresses rat steroidogenic acute regulatory protein expression via induction of Yin Yang 1 protein and recruitment of histone deacetylase 1 protein. Endocrinology 148:5209-5219.
    • Dannenberg. 2008. EP2 and EP4 receptors regulate aromatase expression in human adipocytes and breast cancer cells. Evidence of a BRCA1 and p300 exchange. J Biol Chem 283:3433-3444.
    • Bradbury, D. A., L. Corbett, and A. J. Knox. 2004. PI 3-kinase and MAP kinase regulate bradykinin induced prostaglandin E(2) release in human pulmonary artery by modulating COX-2 activity. FEBS Lett 560:30-34.
    • Dashwood, G. Bou-Gharios, C. P. Denton, R. M. du Bois, C. M. Black, A. Leask, and D. J. Abraham. 2004. Endothelin-1 induces expression of matrix-associated genes in lung fibroblasts through MEK/ERK. J Biol Chem 279:23098-23103.
    • Clerk, A., and P. H. Sugden. 1999. Activation of protein kinase cascades in the heart by hypertrophic G protein-coupled receptor agonists. Am J Cardiol 83:64H-69H.
    • Billington, C. K., and R. B. Penn. 2003. Signaling and regulation of G protein-coupled receptors in airway smooth muscle. Respir Res 4:2.
    • 2008. British Guideline on the Management of Asthma. Thorax 63 Suppl 4:iv1-121.
    • Jacobsen, L. B., S. A. Calvin, K. E. Colvin, and M. Wright. 2004.
    • FuGENE 6 Transfection Reagent: the gentle power. Methods 33:104- 112.
    • 2002. Protein kinase C-epsilon mediates bradykinin-induced cyclooxygenase-2 expression in human airway smooth muscle cells.
    • Faseb J 16:1435-1437.
  • No related research data.
  • No similar publications.

Share - Bookmark

Cite this article