NOX1 Promotes Mesothelial–Mesenchymal Transition through Modulation of Reactive Oxygen Species–mediated Signaling
| Autor: | Guoqing Qian, Ann Jeffers, Shuzi Owens, Prashant Chauhan, Mitsuo Ikebe, Wenyi Qin, Torry A. Tucker, Steven Idell, Satoshi Komatsu, Xia Guo |
|---|---|
| Rok vydání: | 2021 |
| Předmět: |
Pulmonary and Respiratory Medicine
Pathology medicine.medical_specialty Epithelial-Mesenchymal Transition Clinical Biochemistry Parapneumonic effusion medicine Animals Humans Restrictive lung disease Pleurisy Molecular Biology Cells Cultured Original Research Mice Knockout chemistry.chemical_classification Reactive oxygen species business.industry Mesenchymal stem cell Thrombin food and beverages Cell Biology Pneumonia Pneumococcal respiratory system medicine.disease Fibrosis Empyema respiratory tract diseases Mice Inbred C57BL Disease Models Animal Pneumonia Streptococcus pneumoniae chemistry NADPH Oxidase 4 NOX1 Factor Xa Host-Pathogen Interactions cardiovascular system NADPH Oxidase 1 Pleura Reactive Oxygen Species business Mesothelial Cell Signal Transduction |
| Zdroj: | Am J Respir Cell Mol Biol |
| ISSN: | 1535-4989 1044-1549 |
| Popis: | Pleural organization may occur after empyema or complicated parapneumonic effusion and can result in restrictive lung disease with pleural fibrosis (PF). Pleural mesothelial cells (PMCs) may contribute to PF through acquisition of a profibrotic phenotype, mesothelial–mesenchymal transition (MesoMT), which is characterized by increased expression of α-SMA (α-smooth muscle actin) and other myofibroblast markers. Although MesoMT has been implicated in the pathogenesis of PF, the role of the reactive oxygen species and the NOX (nicotinamide adenine dinucleotide phosphate oxidase) family in pleural remodeling remains unclear. Here, we show that NOX1 expression is enhanced in nonspecific human pleuritis and is induced in PMCs by THB (thrombin). 4-Hydroxy-2-nonenal, an indicator of reactive oxygen species damage, was likewise increased in our mouse model of pleural injury. NOX1 downregulation blocked THB- and Xa (factor Xa)–mediated MesoMT, as did pharmacologic inhibition of NOX1 with ML-171. NOX1 inhibition also reduced phosphorylation of Akt, p65, and tyrosine 216–GSK-3β, signaling molecules previously shown to be implicated in MesoMT. Conversely, ML-171 did not reverse established MesoMT. NOX4 downregulation attenuated TGF-β– and THB-mediated MesoMT. However, NOX1 downregulation did not affect NOX4 expression. NOX1- and NOX4-deficient mice were also protected in our mouse model of Streptococcus pneumoniae–mediated PF. These data show that NOX1 and NOX4 are critical determinants of MesoMT. |
| Databáze: | OpenAIRE |
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