Abstract
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. 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. 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. We demonstrated a novel dual airway immunomodulator/bronchodilator role for N/OFQ and suggest targeting this system as an innovative treatment for asthma.
Highlights
Nociceptin/Orphanin FQ (N/OFQ) is the endogenous peptide activator of the N/OFQ receptor (NOP), classified by IUPHAR as a non-opioid member of the opioid family
PpN/OFQ mRNA transcripts were found in peripheral blood eosinophils (PBE), but not in human airway structural cells, from healthy and asthmatic patients with no statistically significant differences (p
Using a combination of complementary in vitro human and in vivo mouse studies, we showed that airway hyperresponsiveness (AHR), eosinophil and mast cell migration and inflammatory mediator release in the lungs were dramatically inhibited by N/OFQ
Summary
Nociceptin/Orphanin FQ (N/OFQ) is the endogenous peptide activator of the N/OFQ receptor (NOP), classified by IUPHAR as a non-opioid (or non-classical) member of the opioid family. Asthma is a complex heterogeneous and devastating disease characterised by variable degree of airflow obstruction, airway hyper-responsiveness, chronic airway inflammation and airway remodelling [Brightling et al, 2012] These changes are the result of a crosstalk between resident structural airway smooth muscle (ASM) and epithelial cells, progenitors including fibrocytes, infiltrating airway submucosal inflammatory cells (eosinophils and T cells) [Brightling et al, 2002], localised mast cells within ASM bundles [Brightling et al, 2002] and Th2 cells (and their cytokines) [Brightling et al, 2002]. These findings were mirrored in OVA-mice where N/OFQ treatment before or during sensitisation substantially reduced airway constriction and immunocyte trafficking to the lung; in particular eosinophils. Conclusions and Implications: We have demonstrated a novel dual airway immunomodulator/bronchodilator role for N/OFQ and suggest targeting this system as an innovative treatment for asthma
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