Nociceptin/orphanin FQ (N/OFQ) modulates immunopathology and airway hyperresponsiveness representing a novel target for the treatment of asthma

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Abstract

<div class="section"> <a class="named-anchor" id="bph13416-sec-0001">  </a> <h5 class="section-title" id="d6142876e477">Background and Purpose</h5> <p id="d6142876e479">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. </p> </div><div class="section"> <a class="named-anchor" id="bph13416-sec-0002">  </a> <h5 class="section-title" id="d6142876e482">Experimental Approach</h5> <p id="d6142876e484">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 <i>in vivo</i> were studied in ovalbumin (OVA)‐sensitized and challenged mice. </p> </div><div class="section"> <a class="named-anchor" id="bph13416-sec-0003">  </a> <h5 class="section-title" id="d6142876e490">Key Results</h5> <p id="d6142876e492">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. </p> </div><div class="section"> <a class="named-anchor" id="bph13416-sec-0004">  </a> <h5 class="section-title" id="d6142876e495">Conclusions and Implications</h5> <p id="d6142876e497">We demonstrated a novel dual airway immunomodulator/bronchodilator role for N/OFQ and suggest targeting this system as an innovative treatment for asthma. </p> </div>

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Loss of human Greatwall results in G2 arrest and multiple mitotic defects due to deregulation of the cyclin B-Cdc2/PP2A balance.

Andrew Burgess, Suzanne Vigneron, Estelle Brioudes … (2010)

Here we show that the functional human ortholog of Greatwall protein kinase (Gwl) is the microtubule-associated serine/threonine kinase-like protein, MAST-L. This kinase promotes mitotic entry and maintenance in human cells by inhibiting protein phosphatase 2A (PP2A), a phosphatase that dephosphorylates cyclin B-Cdc2 substrates. The complete depletion of Gwl by siRNA arrests human cells in G2. When the levels of this kinase are only partially depleted, however, cells enter into mitosis with multiple defects and fail to inactivate the spindle assembly checkpoint (SAC). The ability of cells to remain arrested in mitosis by the SAC appears to be directly proportional to the amount of Gwl remaining. Thus, when Gwl is only slightly reduced, cells arrest at prometaphase. More complete depletion correlates with the premature dephosphorylation of cyclin B-Cdc2 substrates, inactivation of the SAC, and subsequent exit from mitosis with severe cytokinesis defects. These phenotypes appear to be mediated by PP2A, as they could be rescued by either a double Gwl/PP2A knockdown or by the inhibition of this phosphatase with okadaic acid. These results suggest that the balance between cyclin B-Cdc2 and PP2A must be tightly regulated for correct mitotic entry and exit and that Gwl is crucial for mediating this regulation in somatic human cells.

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Human eotaxin is a specific chemoattractant for eosinophil cells and provides a new mechanism to explain tissue eosinophilia.

Eduardo García-Zepeda, Marc Rothenberg, Robert T. Ownbey … (1996)

Eotaxin is an eosinophil-specific chemoattractant that has been recently identified in rodent models of asthma and host response against tumors. To determine whether a similar molecule might play a role in human inflammatory diseases characterized by eosinophilia, we isolated the human eotaxin gene. We demonstrate that human eotaxin is an early response gene of cytokine-stimulated epithelial and endothelial cells, and is induced in peripheral blood eosinophils by interleukin-3. Eotaxin is directly chemotactic for eosinophils, but not mononuclear cells or neutrophils. Eotaxin messenger RNA accumulates markedly in the lesions of patients with inflammatory bowel disease (ulcerative colitis and Crohn's disease), but not in the lesions of patients with diverticulitis. These results now provide a mechanism involving eotaxin to explain the eosinophil infiltration seen in a variety of human disease; as such, an eotaxin antagonist may be a novel therapy for certain human diseases characterized by tissue eosinophilia.