title: Morphologic Characterization of Nerves in Whole-Mount Airway Biopsies.
abstract: BACKGROUND
  Neuroplasticity of bronchopulmonary afferent neurons that respond to mechanical and chemical stimuli may sensitize the cough reflex. Afferent drive in cough is carried by the vagus nerve, and vagal afferent nerve terminals have been well defined in animals. Yet, both unmyelinated C fibers and particularly the morphologically distinct, myelinated, nodose-derived mechanoreceptors described in animals are poorly characterized in humans. To date there are no distinctive molecular markers or detailed morphologies available for human bronchopulmonary afferent nerves.
  
  
  OBJECTIVE
  Morphologic and neuromolecular characterization of the afferent nerves that are potentially involved in cough in humans.
  
  
  METHODS
  A whole-mount immunofluorescence approach, rarely used in human lung tissue, was used with antibodies specific to protein gene product 9.5 (PGP9.5) and, for the first time in human lung tissue, 200-kD neurofilament subunit.
  
  
  RESULTS
  We have developed a robust technique to visualize fibers consistent with autonomic and C fibers and pulmonary neuroendocrine cells. A group of morphologically distinct, 200-kD neurofilament-immunopositive myelinated afferent fibers, a subpopulation of which did not express PGP9.5, was also identified.
  
  
  CONCLUSIONS
  PGP9.5-immunonegative nerves are strikingly similar to myelinated airway afferents, the cough receptor, and smooth muscle-associated airway receptors described in rodents. These have never been described in humans. Full description of human airway nerves is critical to the translation of animal studies to the clinical setting.
authors.affiliation: 1 Centre for Respiratory Medicine and Allergy, Faculty of Medical and Human Sciences, University of Manchester, Manchester, United Kingdom.
authors.forename: Peter W
authors.initials: PW
authors.lastname: West
authors.affiliation: 2 Division of Allergy and Clinical Immunology, Department of Medicine, Johns Hopkins Asthma and Allergy Center, Baltimore, Maryland; and.
authors.forename: Brendan J
authors.initials: BJ
authors.lastname: Canning
authors.affiliation: 3 Takeda Pharmaceuticals, High Wycombe, United Kingdom.
authors.forename: Emilio
authors.initials: E
authors.lastname: Merlo-Pich
authors.affiliation: 1 Centre for Respiratory Medicine and Allergy, Faculty of Medical and Human Sciences, University of Manchester, Manchester, United Kingdom.
authors.forename: Ashley A
authors.initials: AA
authors.lastname: Woodcock
authors.affiliation: 1 Centre for Respiratory Medicine and Allergy, Faculty of Medical and Human Sciences, University of Manchester, Manchester, United Kingdom.
authors.forename: Jaclyn A
authors.identifier: http://orcid.org/0000-0001-8837-4928
authors.initials: JA
authors.lastname: Smith
mesh_terms: D000328:Adult; D000368:Aged; D015415:Biomarkers / Q000378:metabolism; D001706:Biopsy; D001980:Bronchi / Q000294:innervation* / Q000473:pathology; D001999:Bronchoscopy; D002908:Chronic Disease; D003371:Cough / Q000473:pathology*; D005260:Female; D006801:Humans; D008297:Male; D008465:Mechanoreceptors / Q000378:metabolism / Q000473:pathology; D008856:Microscopy, Fluorescence; D008875:Middle Aged; D009475:Neurons, Afferent / Q000378:metabolism / Q000473:pathology*; D020545:Respiratory Mucosa / Q000294:innervation* / Q000473:pathology; D043222:Ubiquitin Thiolesterase / Q000378:metabolism
chemical_list: D015415:Biomarkers; C482860:UCHL1 protein, human; D043222:Ubiquitin Thiolesterase
keywords: afferent neurons; lung; mechanoreceptors; peripheral nervous system