title: NOX1 is responsible for cell death through STAT3 activation in hyperoxia and is associated with the pathogenesis of acute respiratory distress syndrome.
abstract: Reactive oxygen species (ROS) contribute to alveolar cell death in acute respiratory distress syndrome (ARDS) and we previously demonstrated that NOX1-derived ROS contributed to hyperoxia-induced alveolar cell death in mice. The study investigates whether NOX1 expression is modulated in epithelial cells concomitantly to cell death and associated to STAT3 signaling in the exudative phase of ARDS. In addition, the role of STAT3 activation in NOX1-dependent epithelial cell death was confirmed by using a lung epithelial cell line and in mice exposed to hyperoxia. NOX1 expression, cell death and STAT3 staining were evaluated in the lungs of control and ARDS patients by immunohistochemistry. In parallel, a stable NOX1-silenced murine epithelial cell line (MLE12) and NOX1-deficient mice were used to characterize signalling pathways. In the present study, we show that NOX1 is detected in alveolar epithelial cells of ARDS patients in the exudative stage. In addition, increased alveolar epithelial cell death and phosphorylated STAT3 are observed in ARDS patients and associated with NOX1 expression. Phosphorylated STAT3 is also correlated with TUNEL staining. We also confirmed that NOX1-dependent STAT3 activation participates to alveolar epithelial cell death. Silencing and acute inhibition of NOX1 in MLE12 led to decreased cell death and cleaved-caspase 3 induced by hyperoxia. Additionally, hyperoxia-induced STAT3 phosphorylation is dependent on NOX1 expression and associated with cell death in MLE12 and mice. This study demonstrates that NOX1 is involved in human ARDS pathophysiology and is responsible for the damage occurring in alveolar epithelial cells at least in part via STAT3 signalling pathways.
authors.affiliation: Department of Pediatrics Geneva, Switzerland ; Department of Pathology and Immunology, Medical School, University of Geneva Switzerland.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Carnesecchi
authors.affiliation: Department of Pathology and Immunology, Medical School, University of Geneva Switzerland.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Dunand-Sauthier
authors.affiliation: Department of Pediatrics Geneva, Switzerland ; Department of Pathology and Immunology, Medical School, University of Geneva Switzerland.
authors.forename: Filippo
authors.initials: F
authors.lastname: Zanetti
authors.affiliation: Department of Pediatrics Geneva, Switzerland ; Department of Pathology and Immunology, Medical School, University of Geneva Switzerland.
authors.forename: Grigory
authors.initials: G
authors.lastname: Singovski
authors.affiliation: Department of Pathology and Immunology, Medical School, University of Geneva Switzerland.
authors.forename: Christine
authors.initials: C
authors.lastname: Deffert
authors.affiliation: Department of Pediatrics Geneva, Switzerland ; Department of Pathology and Immunology, Medical School, University of Geneva Switzerland.
authors.forename: Yves
authors.initials: Y
authors.lastname: Donati
authors.affiliation: Department of Pediatrics Geneva, Switzerland ; Department of Pathology and Immunology, Medical School, University of Geneva Switzerland.
authors.forename: Thomas
authors.initials: T
authors.lastname: Cagarelli
authors.affiliation: Department of Pathology and Immunology, Medical School, University of Geneva Switzerland.
authors.forename: Jean-Claude
authors.initials: JC
authors.lastname: Pache
authors.affiliation: Department of Pathology and Immunology, Medical School, University of Geneva Switzerland.
authors.forename: Karl-Heinz
authors.initials: KH
authors.lastname: Krause
authors.affiliation: Department of Pathology and Immunology, Medical School, University of Geneva Switzerland.
authors.forename: Walter
authors.initials: W
authors.lastname: Reith
authors.affiliation: Department of Pediatrics Geneva, Switzerland ; Department of Pathology and Immunology, Medical School, University of Geneva Switzerland.
authors.forename: Constance
authors.initials: C
authors.lastname: Barazzone-Argiroffo
mesh_terms: D000818:Animals; D016022:Case-Control Studies; D053148:Caspase 3 / Q000378:metabolism; D016923:Cell Death; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004847:Epithelial Cells / Q000201:enzymology* / Q000473:pathology; D005260:Female; D006801:Humans; D018496:Hyperoxia / Q000201:enzymology* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009247:NADH, NADPH Oxidoreductases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D000074624:NADPH Oxidase 1; D019255:NADPH Oxidases / Q000378:metabolism*; D010766:Phosphorylation; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D011650:Pulmonary Alveoli / Q000201:enzymology* / Q000473:pathology; D034622:RNA Interference; D017382:Reactive Oxygen Species / Q000378:metabolism; D012128:Respiratory Distress Syndrome / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction; D013997:Time Factors; D014162:Transfection
chemical_list: D017382:Reactive Oxygen Species; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; C494087:Stat3 protein, mouse; D009247:NADH, NADPH Oxidoreductases; D000074624:NADPH Oxidase 1; D019255:NADPH Oxidases; C402799:NOX1 protein, human; C000614711:NOX1 protein, mouse; C499321:Parp1 protein, mouse; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases; C505409:Casp3 protein, mouse; D053148:Caspase 3
keywords: ARDS; NOX1; ROS; STAT3; cell death; hyperoxia