title: Assessment of airway response distribution and paradoxical airway dilation in mice during methacholine challenge.
abstract: Detailed information on the distribution of airway diameters during bronchoconstriction in situ is required to understand the regional response of the lungs. Imaging studies using computed tomography (CT) have previously measured airway diameters and changes in response to bronchoconstricting agents, but the manual measurements used have severely limited the number of airways measured per subject. Hence, the detailed distribution and heterogeneity of airway responses are unknown. We have developed and applied dynamic imaging and advanced image-processing methods to quantify and compare hundreds of airways in vivo. The method, based on CT, was applied to house dust-mite-sensitized and control mice during intravenous methacholine (MCh) infusion. Airway diameters were measured pre- and post-MCh challenge, and the results compared demonstrate the distribution of airway response throughout the lungs during mechanical ventilation. Forced oscillation testing was used to measure the global response in lung mechanics. We found marked heterogeneity in the response, with paradoxical dilation of airways present at all airway sizes. The probability of paradoxical dilation decreased with decreasing baseline airway diameter and was not affected by pre-existing inflammation. The results confirm the importance of considering the lung as an entire interconnected system rather than a collection of independent units. It is hoped that the response distribution measurements can help to elucidate the mechanisms that lead to heterogeneous airway response in vivo.NEW & NOTEWORTHYInformation on the distribution of airway diameters during bronchoconstriction in situ is critical for understanding the regional response of the lungs. We have developed an imaging method to quantify and compare the size of hundreds of airways in vivo during bronchoconstriction in mice. The results demonstrate large heterogeneity with both constriction and paradoxical dilation of airways, confirming the importance of considering the lung as an interconnected system rather than a collection of independent units.
authors.affiliation: Department of Mechanical and Aerospace Engineering, Monash University, Melbourne, Victoria, Australia; Stephen.Dubsky@monash.edu.
authors.forename: S
authors.initials: S
authors.lastname: Dubsky
authors.affiliation: School of Medicine, University of Tasmania, Hobart, Tasmania, Australia.
authors.forename: G R
authors.initials: GR
authors.lastname: Zosky
authors.affiliation: Harry Perkins Institute for Medical Research, The University of Western Australia, Nedlands, Western Australia, Australia.
authors.forename: K
authors.initials: K
authors.lastname: Perks
authors.affiliation: Department of Mechanical and Aerospace Engineering, Monash University, Melbourne, Victoria, Australia.|4Dx Limited, Melbourne, Victoria, Australia.
authors.forename: C R
authors.initials: CR
authors.lastname: Samarage
authors.affiliation: Department of Mechanical and Aerospace Engineering, Monash University, Melbourne, Victoria, Australia.|4Dx Limited, Melbourne, Victoria, Australia.
authors.forename: Y
authors.initials: Y
authors.lastname: Henon
authors.affiliation: The Ritchie Centre, Hudson Institute of Medical Research, Melbourne, Victoria, Australia; and.|Department of Obstetrics and Gynaecology, Monash University, Melbourne, Victoria, Australia.
authors.forename: S B
authors.initials: SB
authors.lastname: Hooper
authors.affiliation: Department of Mechanical and Aerospace Engineering, Monash University, Melbourne, Victoria, Australia.|4Dx Limited, Melbourne, Victoria, Australia.
authors.forename: A
authors.initials: A
authors.lastname: Fouras
mesh_terms: D000403:Airway Resistance / Q000187:drug effects*; D000818:Animals; D001980:Bronchi / Q000187:drug effects / Q000473:pathology* / Q000503:physiopathology*; D001985:Bronchial Provocation Tests; D016084:Bronchoconstriction / Q000187:drug effects*; D016085:Bronchoconstrictor Agents / Q000494:pharmacology; D007090:Image Interpretation, Computer-Assisted; D008297:Male; D016210:Methacholine Chloride / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D010363:Pattern Recognition, Automated; D015203:Reproducibility of Results; D012680:Sensitivity and Specificity; D014057:Tomography, X-Ray Computed
chemical_list: D016085:Bronchoconstrictor Agents; D016210:Methacholine Chloride
keywords: airways; methacholine; mice; synchrotron imaging; tomography