Role of N-methyl-D-aspartate receptors in the regulation of human airway smooth muscle function and airway responsiveness

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dc.contributor.supervisor Halayko, Andrew John (Immunology) en_US
dc.contributor.author Anaparti, Vidyanand
dc.date.accessioned 2015-08-06T16:46:35Z
dc.date.available 2015-08-06T16:46:35Z
dc.date.issued 2015-06-15 en_US
dc.identifier.citation Non-superscripted number en_US
dc.identifier.uri http://hdl.handle.net/1993/30657
dc.description.abstract Increased airway smooth muscle (ASM) mass contributes to airway hyperresponsiveness (AHR) in asthma and is orchestrated by growth factors, cytokines and chemokines. Airway contractile responses are influenced by neuromediators, such as acetylcholine, and glutamate released by parasympathetic and sympathetic airway nerves. Hyperactivity of these neural elements, termed neurogenic inflammation, is linked with hypercontractility and AHR. Glutamate is a non-essential amino acid derivative, and its physiological role is traditionally considered with respect to its being the primary excitatory neurotransmitter in brain, and regulation of neuronal development and memory. In allergic inflammation, immune cells including dendritic cells, neutrophils and eosinophils, constitutively synthesize and release glutamate, which signals through activation of glutamate receptors, most important among which are ionotrophic N-methyl D-aspartate receptors (NMDA-R). We hypothesized that glutamatergic signaling mediated through NMDA-Rs plays an important role in inducing functional Ca2+ responses in human (H) ASM cells that can underpin airway hypercontractility. We investigated the expression and function of NMDA-Rs in HASM cells, and assessed the effects of pro-inflammatory cytokines on NMDA-R expression and functional responses. Moreover, we measured airway responses to NMDA in mice, murine thin cut lung slice preparations, and floating collagen gels seeded with HASMs. Our data reveal that airway myocytes express multi-subunit NMDA-R complexes that function as receptor-operated calcium channels (ROCCs), mobilizing intracellular Ca2+ in ASM in vitro and airway contraction ex vivo. Individual airway myocytes treated with NMDA-R agonist exhibit disparate temporal patterns of intercellular Ca2+ flux that can be partitioned into four discrete function sub-groups. Further we show that tumor necrosis factor (TNF) exposure modulates NMDA-R subunit expression, and these changes are associated with a shift in the distribution of myocytes in individual Ca2+-mobilization sub-groups in vitro. Further, post-TNF exposure, NMDA-R agonists’ treatment induced Ca2+-dependent airway dilation in murine lung slice preparations, an effect that was prevented by co-treatment with inhibitors of nitric oxide synthase (NOS) or cyclooxygenase (COX). Taken together, we conclude that NMDA-R regulate HASM-mediated airway contraction and their role can be affected upon exposure to asthma-associated inflammatory mediators. Thus, NMDA-Rs are of relevance to mechanisms that determine airway narrowing and AHR associated with chronic respiratory diseases. en_US
dc.publisher American Physiological Society en_US
dc.rights info:eu-repo/semantics/openAccess
dc.subject NMDA receptors en_US
dc.subject Calcium en_US
dc.subject Human airway smooth muscle en_US
dc.subject Glutamate en_US
dc.subject Airway responsiveness en_US
dc.subject Airway smooth muscle contraction en_US
dc.subject Thin cut murine lung slice en_US
dc.subject Asthma en_US
dc.subject Tumor necrosis factor en_US
dc.title Role of N-methyl-D-aspartate receptors in the regulation of human airway smooth muscle function and airway responsiveness en_US
dc.type info:eu-repo/semantics/doctoralThesis
dc.type doctoral thesis en_US
dc.degree.discipline Immunology en_US
dc.contributor.examiningcommittee Anderson, Chris (Pharmacology & Therapeutics) Soussi-Gounni, Abdelilah (Immunology) Kung, Sam (Immunology) Sieck, Gary (Physiology & Biomedical Engineering, Mayo Clinic, USA) en_US
dc.degree.level Doctor of Philosophy (Ph.D.) en_US
dc.description.note October 2015 en_US

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