DOCK2 contributes to pulmonary fibrosis by promoting lung fibroblast to myofibroblast transition.
Am J Physiol Cell Physiol
; 323(1): C133-C144, 2022 07 01.
Article
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| MEDLINE
| ID: mdl-35584329
ABSTRACT
Idiopathic pulmonary fibrosis (IPF) is the most common chronic interstitial lung disease and is characterized by progressive scarring of the lung. Transforming growth factor-ß (TGF-ß) signaling plays an essential role in IPF and drives fibroblast to myofibroblast transition (FMT). Dedicator of cytokinesis 2 (DOCK2) is known to regulate diverse immune functions by activating Rac and has been recently implicated in pleural fibrosis. We now report a novel role of DOCK2 in pulmonary fibrosis development by mediating FMT. In primary normal and IPF human lung fibroblasts (HLFs), TGF-ß induced DOCK2 expression concurrent with FMT markers, smooth muscle α-actin (α-SMA), collagen-1, and fibronectin. Knockdown of DOCK2 significantly attenuated TGF-ß-induced expression of these FMT markers. In addition, we found that the upregulation of DOCK2 by TGF-ß is dependent on both Smad3 and ERK pathways as their respective inhibitors blocked TGF-ß-mediated induction. TGF-ß also stabilized DOCK2 protein, which contributes to increased DOCK2 expression. In addition, DOCK2 was also dramatically induced in the lungs of patients with IPF and in bleomycin, and TGF-ß induced pulmonary fibrosis in C57BL/6 mice. Furthermore, increased lung DOCK2 expression colocalized with the FMT marker α-SMA in the bleomycin-induced pulmonary fibrosis model, implicating DOCK2 in the regulation of lung fibroblast phenotypic changes. Importantly, DOCK2 deficiency also attenuated bleomycin-induced pulmonary fibrosis and α-SMA expression. Taken together, our study demonstrates a novel role of DOCK2 in pulmonary fibrosis by modulating FMT and suggests that targeting DOCK2 may present a potential therapeutic strategy for the prevention or treatment of IPF.
Palabras clave
Texto completo:
1
Bases de datos:
MEDLINE
Asunto principal:
Proteínas Activadoras de GTPasa
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Factores de Intercambio de Guanina Nucleótido
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Fibrosis Pulmonar Idiopática
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Miofibroblastos
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Fibroblastos
Tipo de estudio:
Prognostic_studies
Límite:
Animals
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Humans
Idioma:
En
Revista:
Am J Physiol Cell Physiol
Asunto de la revista:
FISIOLOGIA
Año:
2022
Tipo del documento:
Article