A key role for NOX4 in epithelial cell death during development of lung fibrosis
| Autor: | Cécile Guichard, Botond Banfi, Karl-Heinz Krause, Olivier Basset, Olivier Preynat-Seauve, Boris Hinz, Jean-Claude Pache, Constance Barazzone-Argiroffo, Christine Deffert, Jack L. Arbiser, Stephanie Carnesecchi, Yves Donati |
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| Rok vydání: | 2011 |
| Předmět: |
Male
Pathology Apoptosis/drug effects/genetics Physiology Pulmonary Alveoli/drug effects/metabolism/pathology Clinical Biochemistry Oxidative Stress/genetics Gene Expression Apoptosis Smad2 Protein ddc:616.07 medicine.disease_cause Biochemistry Idiopathic Pulmonary Fibrosis/genetics/metabolism/pathology Pathogenesis chemistry.chemical_compound Mice 0302 clinical medicine Pulmonary fibrosis RNA Small Interfering Cells Cultured General Environmental Science RNA Small Interfering/genetics 0303 health sciences NADPH oxidase NADPH Oxidase/antagonists & inhibitors/genetics/metabolism Respiratory Mucosa/metabolism/pathology biology NOX4 Smad2 Protein/metabolism respiratory system 3. Good health Original Research Communications medicine.anatomical_structure NADPH Oxidase 4 030220 oncology & carcinogenesis Transforming Growth Factor beta1/metabolism cardiovascular system medicine.symptom medicine.medical_specialty Inflammation Respiratory Mucosa Bleomycin/pharmacology Bleomycin Alveolar cells Transforming Growth Factor beta1 03 medical and health sciences Reactive Oxygen Species/metabolism medicine Animals Molecular Biology 030304 developmental biology urogenital system NADPH Oxidases Cell Biology medicine.disease Idiopathic Pulmonary Fibrosis Pulmonary Alveoli Oxidative Stress chemistry biology.protein General Earth and Planetary Sciences Reactive Oxygen Species Oxidative stress |
| Zdroj: | Antioxidants & redox signaling Antioxidants and Redox Signaling, Vol. 15, No 3 (2011) pp. 607-19 |
| ISSN: | 1523-0864 |
| DOI: | 10.1089/ars.2010.3829 |
| Popis: | The pathogenesis of pulmonary fibrosis is linked to oxidative stress, possibly generated by the reactive oxygen species (ROS) generating NADPH oxidase NOX4. Epithelial cell death is a crucial early step in the development of the disease, followed only later by the fibrotic stage. We demonstrate that in lungs of patients with idiopathic lung fibrosis, there is strong expression of NOX4 in hyperplastic alveolar type II cells. Aim: To study a possible causative role of NOX4 in the death of alveolar cells, we have generated NOX4-deficient mice. Results: Three weeks after administration of bleomycin, wild-type (WT) mice developed massive fibrosis, whereas NOX4-deficient mice displayed almost normal lung histology, and only little Smad2 phosphorylation and accumulation of myofibroblasts. However, the protective effects of NOX4 deficiency preceded the fibrotic stage. Indeed, at day 7 after bleomycin, lungs of WT mice showed massive increase in epithelial cell apoptosis and inflammation. In NOX4-deficient mice, no increase in apoptosis was observed, whereas inflammation was comparable to WT. In vitro, NOX4-deficient primary alveolar epithelial cells exposed to transforming growth factor-β1 did not generate ROS and were protected from apoptosis. Acute treatment with the NOX inhibitors also blunted transforming growth factor-β1–induced apoptosis. Conclusion: ROS generation by NOX4 is a key player in epithelial cell death leading to pulmonary fibrosis. Antioxid. Redox Signal. 15, 607–619. |
| Databáze: | OpenAIRE |
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