Comparison Study of Airway Reactivity Outcomes due to a Pharmacologic Challenge Test: Impulse Oscillometry versus Least Mean Squared Analysis Techniques
Abstract:The technique of measuring transpulmonary pressure and respiratory airflow with manometry and pneumotachography using the least mean squared analysis (LMS) has been used broadly in both preclinical and clinical settings for the evaluation of neonatal respiratory function during tidal volume breathing for lung tissue and airway frictional mechanical properties measurements. Whereas the technique of measuring respiratory function using the impulse oscillation technique (IOS) involves the assessment of the relati… Show more
“…When methacholine was co-delivered with a bronchodilator, the airway remodeling was prevented, suggesting that bronchoconstriction, and not the methacholine itself, was responsible for the airway remodeling. In our studies, we delivered a single dose of bethanechol that elicited bronchoconstriction [9]. Although we did not observe airway remodeling in our piglets, our findings are consistent with previous work suggesting that bronchoconstriction contributes to asthma pathology [27].…”
Section: Resultssupporting
confidence: 90%
“…A laryngotracheal atomizer (MADgic) was passed directly beyond the vocal folds to aerosolize either a 500 µl of 0.9% saline control or 8 mg/ml bethanechol chloride (Selleckchem) in 0.9% saline solution to the airway. The dose selected has previously been shown to acutely increase airway resistance in piglets [9]. Of the total 16 piglets that underwent instillation, 6 piglets were simply observed and euthanized.…”
Airway hyperreactivity is a hallmark feature of asthma and can be precipitated by airway insults, such as ozone exposure or viral infection. A proposed mechanism linking airway insults to airway hyperreactivity is augmented cholinergic transmission. In the current study, we tested the hypothesis that acute potentiation of cholinergic transmission is sufficient to induce airway hyperreactivity. We atomized the cholinergic agonist bethanechol to neonatal piglets and forty-eight hours later measured airway resistance. Bethanechol-treated piglets displayed increased airway resistance in response to intravenous methacholine compared to saline-treated controls. In the absence of an airway insult, we expected to find no evidence of airway inflammation; however, transcripts for several asthma-associated cytokines, including IL17A, IL1A, and IL8, were elevated in the tracheas of bethanechol-treated piglets. In the lungs, prior bethanechol treatment increased transcripts for IFNγ and its downstream target CXCL10. These findings suggest that augmented cholinergic transmission is sufficient to induce airway hyperreactivity, and raise the possibility that cholinergic-mediated regulation of pro-inflammatory pathways might contribute.
“…When methacholine was co-delivered with a bronchodilator, the airway remodeling was prevented, suggesting that bronchoconstriction, and not the methacholine itself, was responsible for the airway remodeling. In our studies, we delivered a single dose of bethanechol that elicited bronchoconstriction [9]. Although we did not observe airway remodeling in our piglets, our findings are consistent with previous work suggesting that bronchoconstriction contributes to asthma pathology [27].…”
Section: Resultssupporting
confidence: 90%
“…A laryngotracheal atomizer (MADgic) was passed directly beyond the vocal folds to aerosolize either a 500 µl of 0.9% saline control or 8 mg/ml bethanechol chloride (Selleckchem) in 0.9% saline solution to the airway. The dose selected has previously been shown to acutely increase airway resistance in piglets [9]. Of the total 16 piglets that underwent instillation, 6 piglets were simply observed and euthanized.…”
Airway hyperreactivity is a hallmark feature of asthma and can be precipitated by airway insults, such as ozone exposure or viral infection. A proposed mechanism linking airway insults to airway hyperreactivity is augmented cholinergic transmission. In the current study, we tested the hypothesis that acute potentiation of cholinergic transmission is sufficient to induce airway hyperreactivity. We atomized the cholinergic agonist bethanechol to neonatal piglets and forty-eight hours later measured airway resistance. Bethanechol-treated piglets displayed increased airway resistance in response to intravenous methacholine compared to saline-treated controls. In the absence of an airway insult, we expected to find no evidence of airway inflammation; however, transcripts for several asthma-associated cytokines, including IL17A, IL1A, and IL8, were elevated in the tracheas of bethanechol-treated piglets. In the lungs, prior bethanechol treatment increased transcripts for IFNγ and its downstream target CXCL10. These findings suggest that augmented cholinergic transmission is sufficient to induce airway hyperreactivity, and raise the possibility that cholinergic-mediated regulation of pro-inflammatory pathways might contribute.
“…The airways were accessed with a laryngoscope, and a laryngotracheal atomizer (MADgic, Moutainside Medical Equipment, Marcy, NY, USA) was passed directly beyond the vocal folds to aerosolize either 500 µl of bethanechol chloride in 0.9% saline solution or 0.9% saline solution alone (control) to the airway (Reznikov et al., 2018). The selected dose previously resulted in an acute increase in airway resistance in piglets (Reznikov et al., 2018; Rodriguez, Bullard, Armani, Miller, & Shaffer, 2013). Airway resistance is mediated by smooth muscle in the airways that is located deep to submucosal glands, which are a key target for mucus secretion in the present study.…”
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.
“…Airways were accessed with a laryngoscope and a laryngotracheal atomizer (MADgic) was passed directly beyond the vocal folds to aerosolize either a 500 µl of 0.9% saline solution (control) or bethanechol chloride in 0.9% saline solution to the airway [16]. The dose selected has previously been shown to acutely increase airway resistance in piglets [16,17].…”
Number of Tables: 1Conflict of interest statement: None declared.
AbstractPurpose: Mucus abnormalities are central to the pathophysiology of several chronic airway diseases. Mucus secretion and clearance are regulated, in part, by cholinergic innervation.Prolonged cholinergic stimulation may contribute to mucus abnormalities in disease. Thus, we tested the hypothesis that prolonged cholinergic stimulation gives rise to lasting mucus abnormalities in airways.
Methods:We delivered aerosolized bethanechol, a cholinergic agonist, to pig airways. Fortyeight hours later, we measured mucus secretion and mucociliary transport in tracheal segments ex vivo. Tracheal and bronchoalveolar lavage concentrations of the major secreted mucus glycoproteins, mucin5B (MUC5B) or mucin5AC (MUC5AC), were measured with ELISA and antibody labeling. Pig airway epithelia were cultured at the air-liquid interface and treated with bethanechol for forty-eight hours. Stimulated fluid secretion was measured with reflected microscopy and Ussing chambers were used to measure ion transport.Results: Airways from bethanechol-challenged pigs exhibited sheet-like mucus films, which were not associated with a greater abundance of MUC5AC or MUC5B. Epithelia treated with bethanechol had diminished fluid secretion and decreased Cltransport. However, mucus and fluid alterations were not associated with impaired mucociliary transport.
Conclusions:These data suggest that cholinergic transmission induces sustained alterations in airway mucus properties. Such defects might compound and/or contribute to persistent mucus phenotypes found after the resolution of airway inflammation.
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