Airway cholinergic history modifies mucus secretion properties to subsequent cholinergic challenge in diminished chloride and bicarbonate conditions

Abstract

Viral infections precipitate exacerbations in many airway diseases, including asthma and cystic fibrosis. Although viral infections increase cholinergic transmission, few studies have examined how cholinergic history modifies subsequent cholinergic responses in the airway. In our previous work, we found that airway resistance in response to a second cholinergic challenge was increased in young pigs with a history of airway cholinergic stimulation. Given that mucus secretion is regulated by the cholinergic nervous system and that abnormal airway mucus contributes to exacerbations of airway disease, we hypothesized that prior cholinergic challenge would also modify subsequent mucus responses to a secondary cholinergic challenge. Using our established cholinergic challenge-rechallenge model in pigs, we atomized the cholinergic agonist bethanechol or saline control to pig airways. Forty-eight hours later, we removed tracheas and measured mucus secretion properties in response to a second cholinergic stimulation. The second cholinergic stimulation was conducted in conditions of diminished chloride and bicarbonate transport to mimic a cystic fibrosis-like environment. In pigs previously challenged with bethanechol, a second cholinergic stimulation produced a mild increase in sheet-like mucus films; these films were scarcely observed in animals originally challenged with saline control. The subtle increase in mucus films was not associated with changes in mucociliary transport. These data suggest that prior cholinergic history might modify mucus secretion characteristics with subsequent stimulation in certain environmental conditions or disease states. Such modifications and/or more repetitive stimulation might lead to retention of mucus on the airway surface, thereby potentiating exacerbations of airway disease.

Overexpression of Substance P in pig airways increases MUC5AC through an NF‐kβ pathway

“…Signal intensity in the airway mucosa was quantified using the polygon selection tool in ImageJ. Background fluorescence was subtracted manually as described (Liao, Collins, et al, 2020). For airway cultures, two image fields were captured and mean signal intensity reported using Zeiss ZenPro software.…”

Bronchoconstriction: a potential missing link in airway remodelling

“…For example, in a mouse model of asthma, AHR is not due to increased ASM shortening but can be due to airway closure caused by a thickened mucosa [87]. Furthermore, another study showed that porcine airways secreted more mucus when challenged for a second time with cholinergic stimulation, indicating the importance of repeated airway narrowing in leading to the production of mucus [88]. However, it should be noted that the second challenge in this study was administered in an environment of reduced chloride and bicarbonate transport to mimic cystic fibrosis [88].…”

“…Furthermore, another study showed that porcine airways secreted more mucus when challenged for a second time with cholinergic stimulation, indicating the importance of repeated airway narrowing in leading to the production of mucus [88]. However, it should be noted that the second challenge in this study was administered in an environment of reduced chloride and bicarbonate transport to mimic cystic fibrosis [88]. Future work to unravel how the airway epithelium in constricted airways propagates airway inflammation and remodelling should carefully consider the physiological relevance of species and models to be used.…”