title: Nociceptin/orphanin FQ (N/OFQ) modulates immunopathology and airway hyperresponsiveness representing a novel target for the treatment of asthma.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  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
  We demonstrated a novel dual airway immunomodulator/bronchodilator role for N/OFQ and suggest targeting this system as an innovative treatment for asthma.
authors.affiliation: Department of Cardiovascular Sciences, University of Leicester, Division of Anaesthesia, Critical Care and Pain Management, Leicester Royal Infirmary, Leicester, LE2 7LX, UK.|Institute for Lung Health, Department of Infection, Immunity and Inflammation and Health Sciences, University of Leicester, Leicester, UK.
authors.forename: Shailendra R
authors.initials: SR
authors.lastname: Singh
authors.affiliation: Department of Cardiovascular Sciences, University of Leicester, Division of Anaesthesia, Critical Care and Pain Management, Leicester Royal Infirmary, Leicester, LE2 7LX, UK.|Department of Experimental Medicine, Section of Pharmacology L Donatelli,, Second University of Naples, Naples, Italy.
authors.forename: Nikol
authors.initials: N
authors.lastname: Sullo
authors.affiliation: Department of Experimental Medicine, Section of Pharmacology L Donatelli,, Second University of Naples, Naples, Italy.
authors.forename: Maria
authors.initials: M
authors.lastname: Matteis
authors.affiliation: Department of Experimental Medicine, Section of Pharmacology L Donatelli,, Second University of Naples, Naples, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Spaziano
authors.affiliation: Department of Cardiovascular Sciences, University of Leicester, Division of Anaesthesia, Critical Care and Pain Management, Leicester Royal Infirmary, Leicester, LE2 7LX, UK.
authors.forename: John
authors.initials: J
authors.lastname: McDonald
authors.affiliation: Institute for Lung Health, Department of Infection, Immunity and Inflammation and Health Sciences, University of Leicester, Leicester, UK.
authors.forename: Ruth
authors.initials: R
authors.lastname: Saunders
authors.affiliation: Institute for Lung Health, Department of Infection, Immunity and Inflammation and Health Sciences, University of Leicester, Leicester, UK.
authors.forename: Lucy
authors.initials: L
authors.lastname: Woodman
authors.affiliation: Department of Experimental Medicine, Section of Pharmacology L Donatelli,, Second University of Naples, Naples, Italy.
authors.forename: Konrad
authors.initials: K
authors.lastname: Urbanek
authors.affiliation: Department of Experimental Medicine, Section of Pharmacology L Donatelli,, Second University of Naples, Naples, Italy.
authors.forename: Antonella
authors.initials: A
authors.lastname: De Angelis
authors.affiliation: Department of Clinical and Experimental Medicine, Division of Immunology, Second University of Naples, Naples, Italy.
authors.forename: Raffaele
authors.initials: R
authors.lastname: De Palma
authors.affiliation: Institute for Lung Health, Department of Infection, Immunity and Inflammation and Health Sciences, University of Leicester, Leicester, UK.
authors.forename: Rachid
authors.initials: R
authors.lastname: Berair
authors.affiliation: Institute for Lung Health, Department of Infection, Immunity and Inflammation and Health Sciences, University of Leicester, Leicester, UK.
authors.forename: Mitesh
authors.initials: M
authors.lastname: Pancholi
authors.affiliation: Institute for Lung Health, Department of Infection, Immunity and Inflammation and Health Sciences, University of Leicester, Leicester, UK.
authors.forename: Vijay
authors.initials: V
authors.lastname: Mistry
authors.affiliation: Department of Experimental Medicine, Section of Pharmacology L Donatelli,, Second University of Naples, Naples, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Rossi
authors.affiliation: Department of Chemical and Pharmaceutical Sciences, University of Ferrara, Ferrara, Italy.
authors.forename: Remo
authors.initials: R
authors.lastname: Guerrini
authors.affiliation: Department of Medical Sciences, Section of Pharmacology, University of Ferrara, Ferrara, Italy.
authors.forename: Girolamo
authors.initials: G
authors.lastname: Calò
authors.affiliation: Department of Experimental Medicine, Section of Pharmacology L Donatelli,, Second University of Naples, Naples, Italy.
authors.forename: Bruno
authors.initials: B
authors.lastname: D'Agostino
authors.affiliation: Institute for Lung Health, Department of Infection, Immunity and Inflammation and Health Sciences, University of Leicester, Leicester, UK.
authors.forename: Christopher E
authors.initials: CE
authors.lastname: Brightling
authors.affiliation: Department of Cardiovascular Sciences, University of Leicester, Division of Anaesthesia, Critical Care and Pain Management, Leicester Royal Infirmary, Leicester, LE2 7LX, UK.
authors.forename: David G
authors.initials: DG
authors.lastname: Lambert
mesh_terms: D000818:Animals; D001249:Asthma / Q000188:drug therapy / Q000276:immunology* / Q000473:pathology; D002478:Cells, Cultured; D005260:Female; D006801:Humans; D007249:Inflammation / Q000276:immunology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008875:Middle Aged; D018847:Opioid Peptides / Q000008:administration & dosage / Q000276:immunology*; D011957:Receptors, Opioid / Q000235:genetics / Q000276:immunology; D012130:Respiratory Hypersensitivity / Q000188:drug therapy / Q000276:immunology* / Q000473:pathology; D000094942:Nociceptin Receptor; D000097629:Nociceptin
chemical_list: D018847:Opioid Peptides; D011957:Receptors, Opioid; D000094942:Nociceptin Receptor; D000097629:Nociceptin