Bronchoconstriction: a potential missing link in airway remodelling

O’Sullivan, Michael J.; Phung, Thien-Khoi N.; Park, Jin‐Ah

doi:10.1098/rsob.200254

Cited by 11 publications

(14 citation statements)

References 100 publications

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“…By using a network-based approach, we show that these genomic patterns are associated with multiple, coordinated signaling pathways that induce cell shape changes via actin repolymerization processes and increased cell motility via ERK-and JNK-mediated activation of AP-1 transcription factors. This analysis points to possible links at the genomic level between HBECs compression, the UJT, and airway remodeling (31).…”

Section: Discussionmentioning

confidence: 77%

Genomic signatures of the unjamming transition in compressed human bronchial epithelial cells

et al. 2021

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Epithelial tissue can transition from a jammed, solid-like, quiescent phase to an unjammed, fluid-like, migratory phase, but the underlying molecular events of the unjamming transition (UJT) remain largely unexplored. Using primary human bronchial epithelial cells (HBECs) and one well-defined trigger of the UJT, compression mimicking the mechanical effects of bronchoconstriction, here, we combine RNA sequencing data with protein-protein interaction networks to provide the first genome-wide analysis of the UJT. Our results show that compression induces an early transcriptional activation of the membrane and actomyosin network and a delayed activation of the extracellular matrix (ECM) and cell-matrix networks. This response is associated with a signaling cascade that promotes actin polymerization and cellular motility through the coordinated interplay of downstream pathways including ERK, JNK, integrin signaling, and energy metabolism. Moreover, in nonasthmatic versus asthmatic HBECs, common genomic patterns associated with ECM remodeling suggest a molecular connection between airway remodeling, bronchoconstriction, and the UJT.

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Section: Discussionmentioning

confidence: 77%

Genomic signatures of the unjamming transition in compressed human bronchial epithelial cells

et al. 2021

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“…This is documented in the skin [ 32 ], liver [ 33 ], heart [ 34 ] and kidney fibrosis [ 35 ], lung diseases as a chronic obstructive pulmonary disease (COPD) [ 36 ], idiopathic pulmonary fibrosis (IPF) [ 37 ] and also in subepithelial fibrosis in asthma [ 6 ]. Routinely used therapies for asthma primarily affect the inflammatory processes in the airways and the symptoms of asthma but are insufficient or ineffective in case of the development of bronchial subepithelial fibrosis [ 6 ], which can be driven also in an inflammation-independent manner [ 38 , 39 , 40 ]. For this reason, the excessive activity of a large population of myofibroblasts as well as the mechanisms of the bronchial subepithelial fibrosis progression leading to the functional impairment of lung tissue in asthmatics remain a challenge for contemporary medicine and cell biology [ 41 ] and are a very interesting and highly important target for new therapeutic strategies.…”

Section: Discussionmentioning

confidence: 99%

SB203580—A Potent p38 MAPK Inhibitor Reduces the Profibrotic Bronchial Fibroblasts Transition Associated with Asthma

Paw

Wnuk

Nit

et al. 2021

IJMS

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Subepithelial fibrosis is a component of the remodeling observed in the bronchial wall of patients diagnosed with asthma. In this process, human bronchial fibroblasts (HBFs) drive the fibroblast-to-myofibroblast transition (FMT) in response to transforming growth factor-β1 (TGF-β1), which activates the canonical Smad-dependent signaling. However, the pleiotropic properties of TGF-β1 also promote the activation of non-canonical signaling pathways which can affect the FMT. In this study we investigated the effect of p38 mitogen-activated protein kinase (MAPK) inhibition by SB203580 on the FMT potential of HBFs derived from asthmatic patients using immunocytofluorescence, real-time PCR and Western blotting methods. Our results demonstrate for the first time the strong effect of p38 MAPK inhibition on the TGF-β1-induced FMT potential throughout the strong attenuation of myofibroblast-related markers: α-smooth muscle actin (α-SMA), collagen I, fibronectin and connexin 43 in HBFs. We suggest the pleiotropic mechanism of SB203580 on FMT impairment in HBF populations by the diminishing of TGF-β/Smad signaling activation and disturbances in the actin cytoskeleton architecture along with the maturation of focal adhesion sites. These observations justify future research on the role of p38 kinase in FMT efficiency and bronchial wall remodeling in asthma.

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“…While the origin of airway remodeling is not well understood, a growing body of evidence suggests that airway epithelial cells are a causal factor [ 1 , 2 , 3 , 4 ]. In particular, during asthma exacerbations, airway narrowing causes mechanical compression of airway epithelial cells, which then produce pathologic mediators thereby contributing to airway remodeling [ 5 , 6 , 7 ]. Mechanical compression applied to well-differentiated human bronchial epithelial (HBE) cells activates multiple signaling cascades, including epidermal growth factor receptor (EGFR), protein kinase C (PKC), extracellular signal-regulated kinase (ERK), and transforming growth factor-β (TGF-β) receptor, all of which are linked to a variety of pathophysiologic features of airway remodeling and asthma [ 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 ].…”

Section: Introductionmentioning

confidence: 99%

Mechanical Compression of Human Airway Epithelial Cells Induces Release of Extracellular Vesicles Containing Tenascin C

Mwase

Phung

O’Sullivan

et al. 2022

Cells

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Aberrant remodeling of the asthmatic airway is not well understood but is thought to be attributable in part to mechanical compression of airway epithelial cells. Here, we examine compression-induced expression and secretion of the extracellular matrix protein tenascin C (TNC) from well-differentiated primary human bronchial epithelial (HBE) cells grown in an air–liquid interface culture. We measured TNC mRNA expression using RT-qPCR and secreted TNC protein using Western blotting and ELISA. To determine intracellular signaling pathways, we used specific inhibitors for either ERK or TGF-β receptor, and to assess the release of extracellular vesicles (EVs) we used a commercially available kit and Western blotting. At baseline, secreted TNC protein was significantly higher in asthmatic compared to non-asthmatic cells. In response to mechanical compression, both TNC mRNA expression and secreted TNC protein was significantly increased in both non-asthmatic and asthmatic cells. TNC production depended on both the ERK and TGF-β receptor pathways. Moreover, mechanically compressed HBE cells released EVs that contain TNC. These data reveal a novel mechanism by which mechanical compression, as is caused by bronchospasm, is sufficient to induce the production of ECM protein in the airway and potentially contribute to airway remodeling.

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Bronchoconstriction: a potential missing link in airway remodelling

Cited by 11 publications

References 100 publications

Genomic signatures of the unjamming transition in compressed human bronchial epithelial cells

Genomic signatures of the unjamming transition in compressed human bronchial epithelial cells

SB203580—A Potent p38 MAPK Inhibitor Reduces the Profibrotic Bronchial Fibroblasts Transition Associated with Asthma

Mechanical Compression of Human Airway Epithelial Cells Induces Release of Extracellular Vesicles Containing Tenascin C

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