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. 2022 Jul;27(7):493-500.
doi: 10.1111/resp.14240. Epub 2022 Mar 9.

Growth of the airway smooth muscle layer from late gestation to childhood is mediated initially by hypertrophy and subsequently hyperplasia

Kimberley C W Wang  1   2 , Graham M Donovan  3 , Sejal Saglani  4 , Thais Mauad  5 , Alan L James  6   7 , John G Elliot  1   6 , Peter B Noble  1
Affiliations

Growth of the airway smooth muscle layer from late gestation to childhood is mediated initially by hypertrophy and subsequently hyperplasia

Kimberley C W Wang et al. Respirology. 2022 Jul.

Abstract

Background and objective: The airway smooth muscle (ASM) layer thickens during development. Identifying the mechanism(s) for normal structural maturation of the ASM reveals pathways susceptible to disease processes. This study characterized thickening of the ASM layer from foetal life to childhood and elucidated the underlying mechanism in terms of hypertrophy, hyperplasia and extracellular matrix (ECM) deposition.

Methods: Airways from post-mortem cases were examined from seven different age groups: 22-24 weeks gestation, 25-31 weeks gestation, term (37-41 weeks gestation), <0.5 year, 0.5-1 year, 2-5 years and 6-10 years. The ASM layer area (thickness), the number and size of ASM cells and the volume fraction of ECM were assessed by planimetry and stereology.

Results: From late gestation to the first year of life, normalized ASM thickness more than doubled as a result of ASM hypertrophy. Thereafter, until childhood, the ASM layer grew in proportion to airway size, which was mediated by ASM hyperplasia. Hypertrophy and hyperplasia of ASM were accompanied by a proportional change in ECM such that the broad composition of the ASM layer was constant across age groups.

Conclusion: These data suggest that the mechanisms of ASM growth from late gestation to childhood are temporally decoupled, with early hypertrophy and subsequent proliferation. We speculate that the developing airway is highly susceptible to ASM thickening in the first year of life and that the timing of an adverse event will determine structural phenotype.

Keywords: airway smooth muscle; asthma; extracellular matrix; hyperplasia; hypertrophy; ontogeny; remodelling.

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Conflict of interest statement

None declared.

Figures

FIGURE 1
FIGURE 1
Predictive change in P bm (A) and ASM thickness (B) with age and exemplar images (<24 weeks gestational age, C; 6–10 years, D). Arrows indicate ASM. Black circles and line, proximal airways; red circles and line, medial airways; blue circles and line, distal airways. The dashed lines indicate that predictions were based on limited data. ASM, airway smooth muscle; P bm, perimeter of basement membrane; yr, year(s)
FIGURE 2
FIGURE 2
Normalized ASM thickness plotted against continuous age (A) or presented in stratified age groups (B). Normalized total wall thickness presented in stratified age groups (C). Data are median (interquartile range). ASM, airway smooth muscle; GA, gestational age; WAt, total wall thickness; yr, year(s). *Significantly different from term (p < 0.05)
FIGURE 3
FIGURE 3
The ASM cell volume (A) and N L (B) presented in stratified age groups. Data are median (interquartile range). ASM, airway smooth muscle; GA, gestational age; N L, total number of ASM cells per millimetre length of airway; V C, mean ASM cell volume; yr, year(s). *Significantly different from term (p < 0.05). ‘Main effect’ indicates an overall effect of age on NL; there were no differences after post hoc analysis
FIGURE 4
FIGURE 4
Modelled effects of ASM thickening occurring solely due to isotropic growth of ASM cells without hyperplasia (hypertrophy only; dotted lines) compared with predicted ASM growth (outputs are the same as those presented in Figure 1B). Hypertrophy cannot account for ASM growth beyond 0.5 year. Black circles and lines, proximal airways; red circles and lines, medial airways; blue circles and lines, distal airways. ASM, airway smooth muscle; yr, year(s)
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References

    1. Noble PB, Jones RL, Cairncross A, Elliot JG, Mitchell HW, James AL, et al. Airway narrowing and bronchodilation to deep inspiration in bronchial segments from subjects with and without reported asthma. J Appl Physiol (1985). 2013;114:1460–71. - PubMed
    1. James AL, Bai TR, Mauad T, Abramson MJ, Dolhnikoff M, McKay KO, et al. Airway smooth muscle thickness in asthma is related to severity but not duration of asthma. Eur Respir J. 2009;34:1040–5. - PubMed
    1. Regamey N, Ochs M, Hilliard TN, Mühlfeld C, Cornish N, Fleming L, et al. Increased airway smooth muscle mass in children with asthma, cystic fibrosis, and non‐cystic fibrosis bronchiectasis. Am J Respir Crit Care Med. 2008;177:837–43. - PubMed
    1. O'Reilly R, Ullmann N, Irving S, Bossley CJ, Sonnappa S, Zhu J, et al. Increased airway smooth muscle in preschool wheezers who have asthma at school age. J Allergy Clin Immunol. 2013;131:1024–32. - PubMed
    1. Owens L, Laing IA, Zhang G, Le Souëf PN. Infant lung function predicts asthma persistence and remission in young adults. Respirology. 2017;22:289–94. - PubMed

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