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SHR Neuro Krebs Kardio Lipid

Paw, M; Borek, I; Wnuk, D; Ryszawy, D; Piwowarczyk, K; Kmiotek, K; Wójcik-Pszczoła, KA; Pierzchalska, M; Madeja, Z; Sanak, M; Błyszczuk, P; Michalik, M; Czyż, J.
Connexin43 Controls the Myofibroblastic Differentiation of Bronchial Fibroblasts from Patients with Asthma.
Am J Respir Cell Mol Biol. 2017; 57(1):100-110
Web of Science PubMed FullText FullText_MUG


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Borek Izabela Malgorzata

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Pathologic accumulation of myofibroblasts in asthmatic bronchi is regulated by extrinsic stimuli and by the intrinsic susceptibility of bronchial fibroblasts to transforming growth factor-β (TGF-β). The specific function of gap junctions and connexins in this process has remained unknown. Here, we investigated the role of connexin43 (Cx43) in TGF-β-induced myofibroblastic differentiation of fibroblasts derived from bronchoscopic biopsy specimens of patients with asthma and donors without asthma. Asthmatic fibroblasts expressed considerably higher levels of Cx43 and were more susceptible to TGF-β1-induced myofibroblastic differentiation than were their nonasthmatic counterparts. TGF-β1 efficiently up-regulated Cx43 levels and activated the canonical Smad pathway in asthmatic cells. Ectopic Cx43 expression in nonasthmatic (Cx43low) fibroblasts increased their predilection to TGF-β1-induced Smad2 activation and fibroblast-myofibroblast transition. Transient Cx43 silencing in asthmatic (Cx43high) fibroblasts by Cx43 small interfering RNA attenuated the TGF-β1-triggered Smad2 activation and myofibroblast formation. Direct interactions of Smad2 and Cx43 with β-tubulin were demonstrated by co-immunoprecipitation assay, whereas the sensitivity of these interactions to TGF-β1 signaling was confirmed by Förster Resonance Energy Transfer analyses. Furthermore, inhibition of the TGF-β1/Smad pathway attenuated TGF-β1-triggered Cx43 up-regulation and myofibroblast differentiation of asthmatic fibroblasts. Chemical inhibition of gap junctional intercellular communication with 18 α-glycyrrhetinic acid did not affect the initiation of fibroblast-myofibroblast transition in asthmatic fibroblasts but interfered with the maintenance of their myofibroblastic phenotype. Collectively, our data identified Cx43 as a new player in the feedback mechanism regulating TGF-β1/Smad-dependent differentiation of bronchial fibroblasts. Thus, our observations point to Cx43 as a novel profibrotic factor in asthma progression.
Find related publications in this database (using NLM MeSH Indexing)
Adult -
Asthma - metabolism
Asthma - pathology
Bronchi - pathology
Cell Differentiation - drug effects
Connexin 43 - metabolism
Extracellular Signal-Regulated MAP Kinases - metabolism
Female -
Gap Junctions - drug effects
Gap Junctions - metabolism
Humans -
MAP Kinase Kinase Kinases - metabolism
Male -
Middle Aged -
Myofibroblasts - drug effects
Myofibroblasts - metabolism
Myofibroblasts - pathology
Phenotype -
Signal Transduction - drug effects
Smad2 Protein - metabolism
Transforming Growth Factor beta1 - pharmacology
Up-Regulation - drug effects

Find related publications in this database (Keywords)
bronchial asthma
myofibroblastic differentiation
transforming growth factor-beta
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