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|Title:||Nociceptin/OrphaninFQ (N/OFQ) modulates immunopathology and airway hyperresponsiveness representing a novel target for the treatment of asthma|
|Authors:||Lambert, David George|
Brightling, Christopher E
Singh, Shailendra R.
|Citation:||British Journal of Pharmacology, 2016, 173 (8), pp. 1286–1301|
|Abstract:||Background and Purpose There is evidence supporting a role for the nociceptin/orphanin FQ (N/OFQ; NOP) receptor and its endogenous ligand N/OFQ in the modulation of neurogenic inflammation, airway tone and calibre. We hypothesized that NOP receptor activation has beneficial effects upon asthma immunopathology and airway hyperresponsiveness. Therefore, the expression and function of N/OFQ and the NOP receptor were examined in healthy and asthmatic human airway tissues. The concept was further addressed in an animal model of allergic asthma. Experimental Approach NOP receptor expression was investigated by quantitative real-time PCR. Sputum N/OFQ was determined by RIA. N/OFQ function was tested using several assays including proliferation, migration, collagen gel contraction and wound healing. The effects of N/OFQ administration in vivo were studied in ovalbumin (OVA)-sensitized and challenged mice. Key Results NOP receptors were expressed on a wide range of human and mouse immune and airway cells. Eosinophils expressed N/OFQ-precursor mRNA and their number correlated with N/OFQ concentration. N/OFQ was found in human sputum and increased in asthma. Additionally, in asthmatic human lungs N/OFQ immunoreactivity was elevated. NOP receptor activation inhibited migration of immunocytes and increased wound healing in airway structural cells. Furthermore, N/OFQ relaxed spasmogen-stimulated gel contraction. Remarkably, these findings were mirrored in OVA-mice where N/OFQ treatment before or during sensitization substantially reduced airway constriction and immunocyte trafficking to the lung, in particular eosinophils. N/OFQ also reduced inflammatory mediators and mucin production. Conclusions and Implications We demonstrated a novel dual airway immunomodulator/bronchodilator role for N/OFQ and suggest targeting this system as an innovative treatment for asthma.|
|Rights:||Copyright © The British Pharmacological Society, 2016. All rights reserved. This is the peer reviewed version of the following article: Singh, S. R., Sullo, N., Matteis, M., Spaziano, G., McDonald, J., Saunders, R., Woodman, L., Urbanek, K., De Angelis, A., De Palma, R., Berair, R., Pancholi, M., Mistry, V., Rossi, F., Guerrini, R., Calò, G., D'Agostino, B., Brightling, C. E., and Lambert, D. G. (2016) Nociceptin/orphanin FQ (N/OFQ) modulates immunopathology and airway hyperresponsiveness representing a novel target for the treatment of asthma. British Journal of Pharmacology, which has been published in final form at dx.doi.org/10.1111/bph.13416. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Self-Archiving.|
|Description:||The file associated with this record is under a 12-month embargo from publication in accordance with the publisher's self-archiving policy, available at http://olabout.wiley.com/WileyCDA/Section/id-820227.html. The full text may be available through the publisher links provided above.|
|Appears in Collections:||Published Articles, Dept. of Cardiovascular Sciences|
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