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An Adverse Outcome Pathway for Decreased Lung Function Focusing on Mechanisms of Impaired Mucociliary Clearance Following Inhalation Exposure.

ABSTRACT: Adverse outcome pathways (AOPs) help to organize available mechanistic information related to an adverse outcome into key events (KEs) spanning all organizational levels of a biological system(s). AOPs, therefore, aid in the biological understanding of a particular pathogenesis and also help with linking exposures to eventual toxic effects. In the regulatory context, knowledge of disease mechanisms can help design testing strategies using in vitro methods that can measure or predict KEs relevant to the biological effect of interest. The AOP described here evaluates the major processes known to be involved in regulating efficient mucociliary clearance (MCC) following exposures causing oxidative stress. MCC is a key aspect of the innate immune defense against airborne pathogens and inhaled chemicals and is governed by the concerted action of its functional components, the cilia and airway surface liquid (ASL). The AOP network described here consists of sequences of KEs that culminate in the modulation of ciliary beat frequency and ASL height as well as mucus viscosity and hence, impairment of MCC, which in turn leads to decreased lung function.

SUBMITTER: Luettich K

PROVIDER: S-EPMC8915806 | biostudies-literature | 2021

REPOSITORIES: biostudies-literature

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An Adverse Outcome Pathway for Decreased Lung Function Focusing on Mechanisms of Impaired Mucociliary Clearance Following Inhalation Exposure.

Luettich Karsta K Sharma Monita M Yepiskoposyan Hasmik H Breheny Damien D Lowe Frazer J FJ

Frontiers in toxicology 20211214

Adverse outcome pathways (AOPs) help to organize available mechanistic information related to an adverse outcome into key events (KEs) spanning all organizational levels of a biological system(s). AOPs, therefore, aid in the biological understanding of a particular pathogenesis and also help with linking exposures to eventual toxic effects. In the regulatory context, knowledge of disease mechanisms can help design testing strategies using <i>in vitro</i> methods that can measure or predict KEs r ...[more]

PMID: 35295103

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Project description:BackgroundLittle is known of how mucociliary clearance (MCC) in children with cystic fibrosis (CF) and normal pulmonary function compares with healthy adults, or how an acute inhalation of 7% hypertonic saline (HS) aerosol affects MCC in these same children.MethodsWe compared MCC in 12 children with CF and normal pulmonary function after an acute inhalation of 0.12% saline (placebo), or HS, admixed with the radioisotope 99 mtechnetium sulfur colloid in a double-blind, randomized, cross-over study. Mucociliary clearance on the placebo day in the children was also compared to MCC in 10 healthy, non-CF adults. Mucociliary clearance was quantified over a 90 min period, using gamma scintigraphy, and is reported as MCC at 60 min (MCC60) and 90 min (MCC90).ResultsMedian [interquartile range] MCC60 and MCC90 in the children on the placebo visit were 15.4 [12.4-24.5]% and 19.3 [17.3-27.8%]%, respectively, which were similar to the adults with 17.8 [6.4-28.7]% and 29.6 [16.1-43.5]%, respectively. There was no significant improvement in MCC60 (2.2 [-6.2-11.8]%) or MCC90 (2.3 [-1.2-10.5]%) with HS, compared to placebo. In addition, 5/12 and 4/12 of the children showed a decrease in MCC60 and MCC90, respectively, after inhalation of HS. A post hoc subgroup analysis of the change in MCC90 after HS showed a significantly greater improvement in MCC in children with lower placebo MCC90 compared to those with higher placebo MCC90 (p = 0.045).ConclusionsThese data suggest that percent MCC varies significantly between children with CF lung disease and normal pulmonary functions, with some children demonstrating MCC values within the normal range and others showing MCC values that are below normal values. In addition, although MCC did not improve in all children after inhalation of HS, improvement did occur in children with relatively low MCC values after placebo. This finding suggests that acute inhalation of hypertonic saline may benefit a subset of children with low MCC values.

Project description:Background: Infants undergoing congenital cardiac surgery with cardiopulmonary bypass are at high risk for respiratory complications. As impaired airway mucociliary clearance (MCC) can potentially contribute to pulmonary morbidity, our study objective was to measure airway clearance in infants undergoing congenital cardiac surgery and examine correlation with clinical covariables that may impair airway clearance function. Materials and Methods: Airway clearance in infants was measured over 30 min using inhaled nebulized Technetium 99m sulfur colloid administered either via a nasal cannula or the endotracheal tube in intubated infants. This was conducted bedside with a portable gamma camera. No difficulty was encountered in positioning the gamma camera over the patient, and neither the camera nor the MCC scan interfered with routine medical care or caused any adverse events. Patient and perioperative variables were examined relative to the MCC measurements. Results: We prospectively enrolled 57 infants undergoing congenital cardiac surgery and conducted a single MCC scan per patient. MCC data from 42 patients were analyzable, including five pre-operative, 15 (40.5%) in the immediate post-operative period (days 1-2), and 22 (59.5%) were later post-operative (≥3 days). Pre-operative MCC was inversely proportional to days requiring post-operative mechanical ventilation (p = 0.006) and non-invasive positive pressure ventilation (p = 0.017). MCC was higher at later post-operative days (p = 0.002) with immediate post-operative MCC being lower (3%; 0-13%) than either pre-operative (21%; 4-25%) (p = 0.091) or later post-operative MCC (18%; 0-29%) (p = 0.054). Among the infants with low post-operative MCC, significantly more were pre-mature [5/19 (26%) vs. 0/18 (0%); p = 0.046], were intubated [14/19 (75%) vs. only 7/18 (39%); p = 0.033] and were receiving higher FiO2 (40%, 27-47% vs. 26%, 21-37%; p = 0.015). Conclusions: This is the first study to show that infants undergoing congenital cardiac surgery have impaired MCC. MCC appeared lowest in the immediate post-operative period. Worse MCC was associated with pre-maturity, mechanical ventilation, or receiving higher FiO2. These findings suggest MCC scans should be further explored for informing clinical decision making to improve post-surgical respiratory outcomes. The possible therapeutic benefit of airway clearance maneuvers for infants with poor MCC function should also be investigated.

Dataset Information

An Adverse Outcome Pathway for Decreased Lung Function Focusing on Mechanisms of Impaired Mucociliary Clearance Following Inhalation Exposure.

Publications

An Adverse Outcome Pathway for Decreased Lung Function Focusing on Mechanisms of Impaired Mucociliary Clearance Following Inhalation Exposure.

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