title: Vagal innervation is required for pulmonary function phenotype inHtr4-/-mice.
abstract: Human genome-wide association studies have identified over 50 loci associated with pulmonary function and related phenotypes, yet follow-up studies to determine causal genes or variants are rare. Single nucleotide polymorphisms in serotonin receptor 4 (HTR4) are associated with human pulmonary function in genome-wide association studies and follow-up animal work has demonstrated thatHtr4is causally associated with pulmonary function in mice, although the precise mechanisms were not identified. We sought to elucidate the role of neural innervation and pulmonary architecture in the lung phenotype ofHtr4-/-animals. We report here that theHtr4-/-phenotype in mouse is dependent on vagal innervation to the lung. Both ex vivo tracheal ring reactivity and in vivo flexiVent pulmonary functional analyses demonstrate that vagotomy abrogates theHtr4-/-airway hyperresponsiveness phenotype. Hyperpolarized3He gas magnetic resonance imaging and stereological assessment of wild-type andHtr4-/-mice reveal no observable differences in lung volume, inflation characteristics, or pulmonary microarchitecture. Finally, control of breathing experiments reveal substantive differences in baseline breathing characteristics between mice with/without functional HTR4 in breathing frequency, relaxation time, flow rate, minute volume, time of inspiration and expiration and breathing pauses. These results suggest that HTR4's role in pulmonary function likely relates to neural innervation and control of breathing.
authors.affiliation: Immunity, Inflammation, and Disease Laboratory, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina.
authors.forename: John S
authors.identifier: http://orcid.org/0000-0002-8447-7871
authors.initials: JS
authors.lastname: House
authors.affiliation: Immunity, Inflammation, and Disease Laboratory, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina.
authors.forename: Cody E
authors.initials: CE
authors.lastname: Nichols
authors.affiliation: Immunity, Inflammation, and Disease Laboratory, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina.
authors.forename: Huiling
authors.initials: H
authors.lastname: Li
authors.affiliation: Institute of Functional and Applied Anatomy, Hannover Medical School, Hannover, Germany.
authors.forename: Christina
authors.initials: C
authors.lastname: Brandenberger
authors.affiliation: Center for In Vivo Microscopy, Duke University Medical Center, Durham, North Carolina.|Biomedical Engineering, Duke University, Durham, North Carolina.
authors.forename: Rohan S
authors.initials: RS
authors.lastname: Virgincar
authors.affiliation: Immunity, Inflammation, and Disease Laboratory, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina.
authors.forename: Laura M
authors.initials: LM
authors.lastname: DeGraff
authors.affiliation: Center for In Vivo Microscopy, Duke University Medical Center, Durham, North Carolina.|Biomedical Engineering, Duke University, Durham, North Carolina.|Radiology, Duke University Medical Center, Durham, North Carolina; and.
authors.forename: Bastiaan
authors.initials: B
authors.lastname: Driehuys
authors.affiliation: Immunity, Inflammation, and Disease Laboratory, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina.
authors.forename: Darryl C
authors.initials: DC
authors.lastname: Zeldin
authors.affiliation: Immunity, Inflammation, and Disease Laboratory, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina; london2@niehs.nih.gov.|Epidemiology Branch, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina.
authors.forename: Stephanie J
authors.identifier: http://orcid.org/0000-0003-4911-5290
authors.initials: SJ
authors.lastname: London
mesh_terms: D000818:Animals; D005838:Genotype; D066298:In Vitro Techniques; D008168:Lung / Q000294:innervation* / Q000502:physiology*; D008810:Mice, Inbred C57BL; D009119:Muscle Contraction / Q000502:physiology; D010641:Phenotype; D012123:Pulmonary Ventilation / Q000502:physiology; D044422:Receptors, Serotonin, 5-HT4 / Q000172:deficiency* / Q000378:metabolism; D012119:Respiration; D012129:Respiratory Function Tests; D012130:Respiratory Hypersensitivity / Q000503:physiopathology; D014132:Trachea / Q000502:physiology; D014628:Vagotomy; D014630:Vagus Nerve / Q000502:physiology* / Q000601:surgery
chemical_list: D044422:Receptors, Serotonin, 5-HT4
keywords: airway hyperresponsiveness; control of breathing; mouse models; pulmonary function; vagal innervation