Mini review: Neural mechanisms underlying airway hyperresponsiveness

Abstract

Neural changes underly hyperresponsiveness in asthma and other airway diseases. Afferent sensory nerves, nerves within the brainstem, and efferent parasympathetic nerves all contribute to airway hyperresponsiveness. Inflammation plays a critical role in these nerve changes. Chronic inflammation and pre-natal exposures lead to increased airway innervation and structural changes. Acute inflammation leads to shifts in neurotransmitter expression of afferent nerves and dysfunction of M₂ muscarinic receptors on efferent nerve endings. Eosinophils and macrophages drive these changes through release of inflammatory mediators. Novel tools, including optogenetics, two photon microscopy, and optical clearing and whole mount microscopy, allow for improved studies of the structure and function of airway nerves and airway hyperresponsiveness.

Keywords: Asthma; Inflammation; Muscarinic; Parasympathetic; Sensory.

Figure 1.. Neural mechanisms of airway hyperresponsiveness.

(A) Optically-cleared whole mouse lung labeled with pan-neuronal marker PGP9.5 (white), showing nerves in the trachea (top), esophagus (bottom middle), and branching through the airways. (B) Parasympathetic ganglion located within the trachea. (C) Sensory nerve endings within the mouse lung surrounding an airway (black oval). (D-E) Computer model of nerves within epithelium of human bronchial biopsies from healthy patients (D) and patients with asthma (E), with nerve model in green and nerve branch points marked with a red dot (Imaris software). (F-G) Quantification of nerve length and branch points, showing increases in patients with asthma. *p < 0.05. (H-K) Eosinophils closely associate with airway nerves in asthma. (H-I) Airways of patients who died from fatal asthma, showing eosinophils (major basic protein antibody, pink) localizing around nerve bundles (PGP9.5 antibody, black) (H) and a parasympathetic ganglion (I). (J) Guinea pig airway stained with hematoxylin and eosin. Cross section of nerve bundle center, eosinophils in pink. (K) House dust mite treated mouse airway showing parasympathetic ganglia (PGP9.5, white) with associated eosinophils (GFP expressed under the eosinophil peroxidase promoter, magenta). Figure A: Reprinted with permission of the American Thoracic Society. Copyright © 2020 American Thoracic Society. Cite: Scott, G. D., Blum, E. D., Fryer, A. D., & Jacoby, D. B. (2014). Tissue optical clearing, three-dimensional imaging, and computer morphometry in whole mouse lungs and human airways. American Journal of Respiratory Cell and Molecular Biology, 51(1), 43–55. The American Journal of Respiratory and Critical Care Medicine is an official journal of the American Thoracic Society. Figure C: Reprinted with permission from Scott, G. D. (2012). Sensory Neuroplasticity in Asthma. Oregon Health & Science University.[95] Figures D-G reprinted with permission from Drake, M. G., Scott, G. D., Blum, E. D., Lebold, K. M., Nie, Z., Lee, J. J., Fryer, A. D., Costello, R. W., & Jacoby, D. B. (2018). Eosinophils increase airway sensory nerve density in mice and in human asthma. Science Translational Medicine, 10(457), eaar8477. Figures H-J: Reprinted with permission from Costello, R. W., Schofield, B. H., Kephart, G. M., Gleich, G. J., Jacoby, D. B., & Fryer, A. D. (1997). Localization of eosinophils to airway nerves and effect on neuronal M2 muscarinic receptor function. American Journal of Physiology - Lung Cellular and Molecular Physiology, 273(1 17–1).