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DOCK2 Promotes Pleural Fibrosis by Modulating Mesothelial to Mesenchymal Transition
- Source :
- Am J Respir Cell Mol Biol
- Publication Year :
- 2021
-
Abstract
- Mesothelial to mesenchymal transition (MesoMT) is one of the crucial mechanisms underlying pleural fibrosis, which results in restrictive lung disease. DOCK2 (dedicator of cytokinesis 2) plays important roles in immune functions; however, its role in pleural fibrosis, particularly MesoMT, remains unknown. We found that amounts of DOCK2 and the MesoMT marker α-SMA (α-smooth muscle actin) were significantly elevated and colocalized in the thickened pleura of patients with nonspecific pleuritis, suggesting the involvement of DOCK2 in the pathogenesis of MesoMT and pleural fibrosis. Likewise, data from three different pleural fibrosis models (TGF-β [transforming growth factor-β], carbon black/bleomycin, and streptococcal empyema) consistently demonstrated DOCK2 upregulation and its colocalization with α-SMA in the pleura. In addition, induced DOCK2 colocalized with the mesothelial marker calretinin, implicating DOCK2 in the regulation of MesoMT. Our in vivo data also showed that DOCK2-knockout mice were protected from Streptococcus pneumoniae–induced pleural fibrosis, impaired lung compliance, and collagen deposition. To determine the involvement of DOCK2 in MesoMT, we treated primary human pleural mesothelial cells with the potent MesoMT inducer TGF-β. TGF-β significantly induced DOCK2 expression in a time-dependent manner, together with α-SMA, collagen 1, and fibronectin. Furthermore, DOCK2 knockdown significantly attenuated TGF-β–induced α-SMA, collagen 1, and fibronectin expression, suggesting the importance of DOCK2 in TGF-β–induced MesoMT. DOCK2 knockdown also inhibited TGF-β–induced Snail upregulation, which may account for its role in regulating MesoMT. Taken together, the current study provides evidence that DOCK2 contributes to the pathogenesis of pleural fibrosis by mediating MesoMT and deposition of neomatrix and may represent a novel target for its prevention or treatment.
- Subjects :
- Pulmonary and Respiratory Medicine
Epithelial-Mesenchymal Transition
Clinical Biochemistry
Bleomycin
Epithelium
Pathogenesis
chemistry.chemical_compound
Mice
Downregulation and upregulation
Transforming Growth Factor beta
medicine
Animals
Guanine Nucleotide Exchange Factors
Humans
Molecular Biology
Pleurisy
Original Research
Lung
Antibiotics, Antineoplastic
biology
business.industry
GTPase-Activating Proteins
Cell Biology
respiratory system
Pleural Diseases
medicine.disease
Fibrosis
Empyema
respiratory tract diseases
Fibronectin
Mice, Inbred C57BL
Collagen, type I, alpha 1
Disease Models, Animal
medicine.anatomical_structure
chemistry
biology.protein
Cancer research
Pleura
business
Mesothelial Cell
Signal Transduction
Subjects
Details
- ISSN :
- 15354989
- Volume :
- 66
- Issue :
- 2
- Database :
- OpenAIRE
- Journal :
- American journal of respiratory cell and molecular biology
- Accession number :
- edsair.doi.dedup.....d3c0cd64d6c71f35495e2ea4127f6a7c