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Modulation of TRPV1 in Bronchial Epithelium of Children by Asthma Predisposition and Respiratory Syncytial Virus Infection
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A2866 - Modulation of TRPV1 in Bronchial Epithelium of Children by Asthma Predisposition and Respiratory Syncytial Virus Infection
Author Block: T. J. Harford1, F. Rezaee2, R. G. Scheraga3, M. A. Olman4, G. Piedimonte5; 1Pediatric Research Center, Cleveland Clinic Lerner Research Institute, Cleveland, OH, United States, 2Pediatrics, Center for Pediatric Research, Cleveland, OH, United States, 3Respiratory Institute, Cleveland Clinic, Cleveland, OH, United States, 4Dept of Pathobiology, Cleveland Clinic, Cleveland, OH, United States, 5Pediatrics, The Cleveland Clinic, Cleveland, OH, United States.
Rationale: The transient receptor potential vanilloid 1 (TRPV1) channel is expressed in both adult and pediatric human bronchial epithelium (HBE), where it transduces Ca2+ in response to airborne irritants. TRPV1 activation results in bronchoconstriction, cough, and mucus production, and may therefore contribute to the pathophysiology of viral bronchiolitis and asthma. Since asthmatic children face the greatest risk of developing virus-induced airway obstruction, we hypothesized that TRPV1 expression, localization, and function in the airway epithelium is modulated by asthma predisposition and viral infections. Methods: HBE cells derived from normal and asthmatic pediatric patients were assessed for basal TRPV1 expression and localization. We then compared TRPV1 expression and localization in response to RSV infection. To assess the role of NGF on TRPV1 activation, we exogenously treated cells with recombinant human NGF or utilizing siRNA to transiently knock down NGF expression, we assessed TRPV1 expression, localization and activation. Lastly, we assessed movement of [Ca2+]i in the absence or presence of extracellular calcium. Results: Basal TRPV1 protein expression was higher in HBE from asthmatic vs. non-asthmatic children and primarily localized to plasma membranes (PM). During RSV infection, TRPV1 protein increased more in the cytosol than on the PM of asthmatic HBE, while the opposite trend was noted in infected non-asthmatic cells. Nerve growth factor (NGF) binding to tropomyosin-related kinase A receptor receptor (TrkA) recapitulated the effects of RSV infection on TRPV1 expression and localization. Finally, exogenous application of rhNGF recapitulated RSV induced changes in TRPV1 expression, localization and function. Conclusion: Our data suggest that asthmatic children have intrinsically hyperreactive airways due to higher TRPV1-mediated Ca2+ influx across epithelial membranes, and this abnormality is further exacerbated by NGF overexpression during RSV infection driving additional Ca2+ from intracellular stores.
Author Block: T. J. Harford1, F. Rezaee2, R. G. Scheraga3, M. A. Olman4, G. Piedimonte5; 1Pediatric Research Center, Cleveland Clinic Lerner Research Institute, Cleveland, OH, United States, 2Pediatrics, Center for Pediatric Research, Cleveland, OH, United States, 3Respiratory Institute, Cleveland Clinic, Cleveland, OH, United States, 4Dept of Pathobiology, Cleveland Clinic, Cleveland, OH, United States, 5Pediatrics, The Cleveland Clinic, Cleveland, OH, United States.
Rationale: The transient receptor potential vanilloid 1 (TRPV1) channel is expressed in both adult and pediatric human bronchial epithelium (HBE), where it transduces Ca2+ in response to airborne irritants. TRPV1 activation results in bronchoconstriction, cough, and mucus production, and may therefore contribute to the pathophysiology of viral bronchiolitis and asthma. Since asthmatic children face the greatest risk of developing virus-induced airway obstruction, we hypothesized that TRPV1 expression, localization, and function in the airway epithelium is modulated by asthma predisposition and viral infections. Methods: HBE cells derived from normal and asthmatic pediatric patients were assessed for basal TRPV1 expression and localization. We then compared TRPV1 expression and localization in response to RSV infection. To assess the role of NGF on TRPV1 activation, we exogenously treated cells with recombinant human NGF or utilizing siRNA to transiently knock down NGF expression, we assessed TRPV1 expression, localization and activation. Lastly, we assessed movement of [Ca2+]i in the absence or presence of extracellular calcium. Results: Basal TRPV1 protein expression was higher in HBE from asthmatic vs. non-asthmatic children and primarily localized to plasma membranes (PM). During RSV infection, TRPV1 protein increased more in the cytosol than on the PM of asthmatic HBE, while the opposite trend was noted in infected non-asthmatic cells. Nerve growth factor (NGF) binding to tropomyosin-related kinase A receptor receptor (TrkA) recapitulated the effects of RSV infection on TRPV1 expression and localization. Finally, exogenous application of rhNGF recapitulated RSV induced changes in TRPV1 expression, localization and function. Conclusion: Our data suggest that asthmatic children have intrinsically hyperreactive airways due to higher TRPV1-mediated Ca2+ influx across epithelial membranes, and this abnormality is further exacerbated by NGF overexpression during RSV infection driving additional Ca2+ from intracellular stores.
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