Aberrant cell migration contributes to defective airway epithelial repair in childhood wheeze

Iosifidis, Thomas; Sutanto, Erika N.; Buckley, Alysia G.; Coleman, Laura; Gill, Erin E.; Lee, Ahwon; Ling, Kak-Ming; Hillas, Jessica; Looi, Kevin; Garratt, Luke W.; Martinovich, Kelly M.; Shaw, Nicole C.; Montgomery, Samuel T.; Kicic-Starcevich, E.; Karpievitch, Yuliya V.; Souëf, Peter Le; Laing, Ingrid A.; Vijayasekaran, Shyan; Lannigan, Francis J.; Rigby, Paul; Hancock, Robert E. W.; Knight, Darryl A.; Stick, Stephen M.; Kicic, Anthony

doi:10.1172/jci.insight.133125

Cited by 21 publications

(50 citation statements)

References 60 publications

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“…These findings may be consistent with prior observations of epithelial vulnerability and impaired repair responses in childhood wheeze phenotypes independent of atopy. [50][51][52] Moreover, recent work has implicated PI3K/Akt signaling as the potential upstream regulator responsible for epithelial repair versus vulnerability in the airway, 50 and animal models of asthma have shown PI3K/Akt signaling, acting through MTOR activation, is closely linked to T H 17 inflammation in asthma. 53 It is interesting we observe these findings specifically in a low atopy wheeze phenotype and suggest that the PI3K/Akt-MTOR-T H 17 pathway 54,55 could be targeted for treatment or prevention of this phenotype.…”

Section: Discussionmentioning

confidence: 99%

Endotype of allergic asthma with airway obstruction in urban children

Altman

Calatroni

Ramratnam

et al. 2021

Journal of Allergy and Clinical Immunology

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Section: Discussionmentioning

confidence: 99%

Endotype of allergic asthma with airway obstruction in urban children

Altman

Calatroni

Ramratnam

et al. 2021

Journal of Allergy and Clinical Immunology

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“…Although significant Akt activation and its downstream effects were observed in myofibroblasts, Akt activity on other alveolar cells may contribute to the concept of improvement in lung structure after treatment with SC79. In support of this, a recent study demonstrated that AKT activation enhanced migration and repair of airway epithelial cells (54).…”

Section: Discussionmentioning

confidence: 80%

IGF1R controls mechanosignaling in myofibroblasts required for pulmonary alveologenesis

He¹,

Snowball²,

Sun³

et al. 2021

JCI Insight

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Ventilation throughout life is dependent on the formation of pulmonary alveoli, which create an extensive surface area in which the close apposition of respiratory epithelium and endothelial cells of the pulmonary microvascular enables efficient gas exchange. Morphogenesis of the alveoli initiates at late gestation in humans and the early postnatal period in the mouse. Alveolar septation is directed by complex signaling interactions among multiple cell types. Here, we demonstrate that IGF1 receptor gene ( Igf1r ) expression by a subset of pulmonary fibroblasts is required for normal alveologenesis in mice. Postnatal deletion of Igf1r caused alveolar simplification, disrupting alveolar elastin networks and extracellular matrix without altering myofibroblast differentiation or proliferation. Moreover, loss of Igf1r impaired contractile properties of lung myofibroblasts and inhibited myosin light chain (MLC) phosphorylation and mechanotransductive nuclear YAP activity. Activation of p-AKT, p-MLC, and nuclear YAP in myofibroblasts was dependent on Igf1r . Pharmacologic activation of AKT enhanced MLC phosphorylation, increased YAP activation, and ameliorated alveolar simplification in vivo. IGF1R controls mechanosignaling in myofibroblasts required for lung alveologenesis.

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“…Migration of epithelial cells from the wound edges represents a key early restitution event, allowing for quick covering of denuded airway areas (13,14). Dysregulated wound repair capacity and loss of barrier integrity have been observed in patients with pulmonary disorders including asthma (16,17), chronic obstructive pulmonary disorder (2,(18)(19)(20), and cystic fibrosis (21)(22)(23). Furthermore, viral infections such as human rhinoviruses and influenza A virus have been shown to decrease self-repair processes of airway epithelial cells (24,25).…”

Section: Introductionmentioning

confidence: 99%

RSV attenuates epithelial cell restitution by inhibiting actin cytoskeleton-dependent cell migration

Linfield

Gao

Raduka

et al. 2021

American Journal of Physiology-Lung Cellular and Molecular Phys

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The airway epithelium's ability to repair itself after injury, known as epithelial restitution, is an essential mechanism enabling the respiratory tract's normal functions. Respiratory Syncytial Virus (RSV) is the leading cause of lower respiratory tract infections worldwide. We sought to determine whether RSV delays the airway epithelium wound repair process both in vitro and in vivo. We found that RSV infection attenuated epithelial cell migration, a step in wound repair, promoted stress fiber formation, and mediated assembly of large focal adhesions (FA). Inhibition of Rho kinase (ROCK), a master regulator of actin function, reversed these effects. There was increased RhoA and phospho-myosin light chain (pMLC2) following RSV infection. In vivo, mice were intraperitoneally inoculated with naphthalene to induce lung injury, followed by RSV infection. RSV infection delayed re-epithelialization. There were increased concentrations of pMLC2 in day 7 naphthalene plus RSV animals which normalized by day 14. This study suggests a key mechanism by which RSV infection delays wound healing.

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Aberrant cell migration contributes to defective airway epithelial repair in childhood wheeze

Cited by 21 publications

References 60 publications

Endotype of allergic asthma with airway obstruction in urban children

Endotype of allergic asthma with airway obstruction in urban children

IGF1R controls mechanosignaling in myofibroblasts required for pulmonary alveologenesis

RSV attenuates epithelial cell restitution by inhibiting actin cytoskeleton-dependent cell migration

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