Morphologic Characterization of Nerves in Whole-Mount Airway Biopsies

Am J Respir Crit Care Med. 2015 Jul 1;192(1):30-9. doi: 10.1164/rccm.201412-2293OC.


Rationale: 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.

Objectives: 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.

Measurements and main 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.

Keywords: afferent neurons; lung; mechanoreceptors; peripheral nervous system.

Publication types

  • Evaluation Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Biomarkers / metabolism
  • Biopsy
  • Bronchi / innervation*
  • Bronchi / pathology
  • Bronchoscopy
  • Chronic Disease
  • Cough / pathology*
  • Female
  • Humans
  • Male
  • Mechanoreceptors / metabolism
  • Mechanoreceptors / pathology
  • Microscopy, Fluorescence
  • Middle Aged
  • Neurons, Afferent / metabolism
  • Neurons, Afferent / pathology*
  • Respiratory Mucosa / innervation*
  • Respiratory Mucosa / pathology
  • Ubiquitin Thiolesterase / metabolism


  • Biomarkers
  • UCHL1 protein, human
  • Ubiquitin Thiolesterase