Measurement of Mucociliary Transport: Novel Application of Positron Emission Tomography

Stewart, Carley G.; Hilkin, Brieanna M.; Gansemer, Nicholas D.; Walsh, Susan A.; Acevado, Michael R.; Akurathi, Vamsidhar; Pandya, Darpan N.; Comellas, Alejandro F.; Wadas, Thaddeus J.; Dick, David; Sunderland, John; Stoltz, David A.; Welsh, Michael J.; Alaiwa, Mahmoud H. Abou

doi:10.1109/isbi52829.2022.9761605

Cited by 3 publications

(2 citation statements)

References 18 publications

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“…To measure MCT in small and large airways, we used a previously described PET based MCT assay (22). Gallium-68 MAA was obtained by eluting a germanium-68/gallium-68 generator and applying a commercial MAA labeling kit (Pulmotech MAA; Curium US, Maryland Heights, MO).…”

Section: Methodsmentioning

confidence: 99%

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Mucociliary Clearance is Impaired in Small Airways of Cystic Fibrosis Pigs

Stewart,

Hilkin,

Gansemer

et al. 2024

Preprint

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Rationale: Cystic fibrosis is a genetic disorder characterized by recurrent airway infections, inflammation, and progressive decline in lung function. Autopsy and spirometry data suggest that cystic fibrosis may start in the small airways which, due to the fractal nature of the airways, account for most of the airway tree surface area. However, they are not easily accessible for testing. Objectives: Here, we tested the hypothesis that mucociliary clearance is abnormal in the small airways of newborn cystic fibrosis pigs. Methods: Current mucociliary clearance assays are limited therefore we developed a dynamic positron emission tomography scan assay with high spatial and temporal resolution. Each study was accompanied by a high-resolution computed tomography scan that helped identify the thin outer region of the lung that contained small airways. Measurements and Main Results: Clearance of aerosolized 68Ga macro aggregated albumin from distal airways occurred within minutes after delivery and followed a two-phase process. In cystic fibrosis pigs, both early and late clearance rates were slower. Stimulation of the cystic fibrosis airways with the purinergic agonist UTP further impaired late clearance. Only 1 cystic fibrosis pig treated with UTP out of 6 cleared more than 20% of the delivered dose. Conclusions: These data indicate that mucociliary transport in the small airways is fast and can easily be missed if the acquisition is not fast enough. The data also indicate that mucociliary transport is impaired in small airways of cystic fibrosis pigs. This defect is exacerbated by stimulation of mucus secretions with purinergic agonists.

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Section: Methodsmentioning

confidence: 99%

“…In addition, the planar nature of these assays allows overlap between the central and peripheral regions of interest. To circumvent these limitations, we developed a novel dynamic positron emission tomography (PET) technique to measure mucus transport with high spatial and temporal resolution in the small airways (22).…”

Section: Introductionmentioning

confidence: 99%

Mucociliary Clearance is Impaired in Small Airways of Cystic Fibrosis Pigs

Stewart,

Hilkin,

Gansemer

et al. 2024

Preprint

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Emerging imaging modalities for functional assessment of donor lungs ex vivo

Hudock

Pinezich

Mir

et al. 2023

Current Opinion in Biomedical Engineering

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Transgenic ferret models define pulmonary ionocyte diversity and function

Yuan,

Gasser,

Lemire

et al. 2023

Nature

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Speciation leads to adaptive changes in organ cellular physiology and creates challenges for studying rare cell-type functions that diverge between humans and mice. Rare cystic fibrosis transmembrane conductance regulator (CFTR)-rich pulmonary ionocytes exist throughout the cartilaginous airways of humans1,2, but limited presence and divergent biology in the proximal trachea of mice has prevented the use of traditional transgenic models to elucidate ionocyte functions in the airway. Here we describe the creation and use of conditional genetic ferret models to dissect pulmonary ionocyte biology and function by enabling ionocyte lineage tracing (FOXI1-CreERT2::ROSA-TG), ionocyte ablation (FOXI1-KO) and ionocyte-specific deletion of CFTR (FOXI1-CreERT2::CFTRL/L). By comparing these models with cystic fibrosis ferrets3,4, we demonstrate that ionocytes control airway surface liquid absorption, secretion, pH and mucus viscosity—leading to reduced airway surface liquid volume and impaired mucociliary clearance in cystic fibrosis, FOXI1-KO and FOXI1-CreERT2::CFTRL/L ferrets. These processes are regulated by CFTR-dependent ionocyte transport of Cl− and HCO3−. Single-cell transcriptomics and in vivo lineage tracing revealed three subtypes of pulmonary ionocytes and a FOXI1-lineage common rare cell progenitor for ionocytes, tuft cells and neuroendocrine cells during airway development. Thus, rare pulmonary ionocytes perform critical CFTR-dependent functions in the proximal airway that are hallmark features of cystic fibrosis airway disease. These studies provide a road map for using conditional genetics in the first non-rodent mammal to address gene function, cell biology and disease processes that have greater evolutionary conservation between humans and ferrets.

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Measurement of Mucociliary Transport: Novel Application of Positron Emission Tomography

Cited by 3 publications

References 18 publications

Mucociliary Clearance is Impaired in Small Airways of Cystic Fibrosis Pigs

Mucociliary Clearance is Impaired in Small Airways of Cystic Fibrosis Pigs

Emerging imaging modalities for functional assessment of donor lungs ex vivo

Transgenic ferret models define pulmonary ionocyte diversity and function

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