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

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

Missed opportunities for tobacco use screening and brief cessation advice in South African primary health care: a cross-sectional study

BACKGROUND: Primary health care (PHC) settings offer opportunities for tobacco use screening and brief cessation advice, but data on such activities in South Africa are limited. The aim of this study was to determine the extent to which participants were screened for and advised against tobacco use during consultations. METHODS: This cross-sectional study involved 500 participants, 18 years and older, attended by doctors or PHC nurses. Using an exit-interview questionnaire, information was obtained on participants' tobacco use status, reason(s) for seeking medical care, whether participants had been screened for and advised about their tobacco use and patients' level of comfort about being asked about and advised to quit tobacco use. Main outcome measures included patients' self-reports on having been screened and advised about tobacco use during their current clinic visit and/or any other visit within the last year. Data analysis included the use of chi-square statistics, t-tests and multiple logistic regression analysis. RESULTS: Of the 500 participants, 14.9% were current smokers and 12.1% were smokeless tobacco users. Only 12.9% of the participants were screened for tobacco use during their current visit, indicating the vast majority were not screened. Among the 134 tobacco users, 11.9% reported being advised against tobacco use during the current visit and 35.1% during any other visit within the last year. Of the participants not screened, 88% indicated they would be 'very comfortable' with being screened. A pregnancy-related clinic visit was the single most significant predictor for being screened during the current clinic visit (OR = 4.59; 95%CI = 2.13-9.88). CONCLUSION: Opportunities for tobacco use screening and brief cessation advice were largely missed by clinicians. Incorporating tobacco use status into the clinical vital signs as is done for pregnant patients during antenatal care visits in South Africa has the potential to improve tobacco use screening rates and subsequent cessation

Domain of One’s Own Research

Domain of One’s Own is an initiative started at the University of Mary Washington to empower students, faculty, and staff by giving them a piece of the internet. Implemented at St. Norbert through Knight Domains, members of the SNC community are given their own domain (website) to customize using cPanel applications such as WordPress. The objective of the Domain of One’s Own research fellow was to develop a way to showcase the impact of Knight Domains by gathering examples from the SNC community.https://digitalcommons.snc.edu/collaborative_presentations/1025/thumbnail.jp

The modulatory role of the neuropeptide, N/OFQ, on T cell function

The aim of this study was to elucidate the immunoregulatory role of the neuropeptide, nociceptin (N/OFQ). The effects on human peripheral blood mononuclear cells (PBMCs), CD4⁺ T cells, T regulatory (Treg) cells and dendritic cells (DCs) were investigated. N/OFQ (10⁻¹⁴M and 10⁻¹⁰M) suppressed the proliferative response of PBMCs to the superantigen, staphylococcal enterotoxin B (SEB) and 004⁺ T cells stimulated with CHO(DR4/SEB/CD80) (OHO cells transfected with DR4 and MHO class II and pulsed with SEB). N/OFQ-induced decreased proliferation of SEB-activated T cells, could be blocked by the putative N/OFQ antagonist, UFP-101, indicating the response is specific to N/OFQ. Expression of the co-stimulatory receptor, glucocorticoid-!nduced tumour necrosis factor receptor (GITR) decreased In response to N/OFQ (10⁻¹⁰M) and expression of CD80 increased in response to N/OFQ (10⁻¹⁴M). Functional studies revealed an inhibitory role for CD80 in modulating T cell proliferation. Moreover, CD80 and to a lesser extent, CD86 are involved in the suppressive effect mediated by N/OFQ. N/OFQ can therefore modulate T:T cell communication.EThOS - Electronic Theses Online ServiceGBUnited Kingdo

The relationship between antigenic structure and the requirement for thymus-derived cells in the immune response.

Certain antigens such as polymerized flagellin are capable of producing relatively normal antibody levels in thymectomized mice, whereas others, including heterologous erythrocytes require the presence of T cells in a helper capacity. The mechanism of thymus-independent antibody production was investigated by comparing the primary IgM responses of spleen cells from ATXBM, XBM, and normal mice to various physical forms of the flagellar antigens of Salmonella adelaide in vitro. No reduction in antibody-forming cell levels to polymerized flagellin over a wide dose range was observed in ATXBM cultures, although the same spleen cells did not respond to an optimal dose of sheep red cells. In contrast, when flagellar determinants were presented in a monomeric form or as flagellin-coated donkey red cells, a highly significant difference was observed between the antibody responses of spleen cells from ATXBM mice and XBM or normal controls. The results suggested that the requirement for T cells in antibody production is not a property of specific antigenic determinants, but depends on the mode of antigenic presentation. The validity of this conclusion was confirmed by using another antigenic determinant (DNP) coupled either to the thymus-independent carrier, POL, or to the thymus-dependent carrier, DRC. Spleen cells from XBM mice produced comparable AFC levels to both forms of DNP, but the results from ATXBM cultures showed a marked difference. The anti-DNP response to DNP-DRC was greatly reduced compared to controls, whereas that to DNP-POL was normal even after prolonged thoracic duct drainage of the ATXBM donors and pretreatment of their spleen cells with anti-theta-serum and complement. The data presented here imply that the role of T cells in humoral immunity is the presentation of antigen to B cells in such a manner as to initiate optimal antibody synthesis

Nociceptin-induced modulation of human T cell function

There is an accumulating evidence for the immunoregulatory role of the neuropeptide, nociceptin/orphanin FQ (N/OFQ) however its role on T cell function requires elucidation. This study has demonstrated an inhibitory role for N/OFQ on SEB-activated T cell function. N/OFQ decreases T cell proliferation, which is abrogated when the costimulatory receptors CD80 and CD86 are blocked. In addition, evidence suggests that the immunoregulatory cytokines TGF-β, IFN-γ and nitric oxide (NO) are involved in the N/OFQ effect. N/OFQ also, through involvement of IFN and NO, induces the expression of the immunosuppressive modulator indoleamine 2,3-dioxygenase (IDO), suggesting a central role for IDO in the N/OFQ effect on T cell proliferation. The data presented in this report indicate a multi-faceted mechanism of action used by N/OFQ to modulate T cell function. © 2009 Elsevier Inc. All rights reserved