title: Interplay between nuclear factor erythroid 2-related factor 2 and amphiregulin during mechanical ventilation.
abstract: Mechanical ventilation (MV) elicits complex and clinically relevant cellular responses in the lungs. The current study was designed to define the role of the transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2), a major regulator of the cellular antioxidant defense system, in the pulmonary response to MV. Nrf2 activity was quantified in ventilated isolated perfused mouse lungs (IPL). Regulation of amphiregulin (AREG) was investigated in BEAS-2B cells with inactivated Nrf2 or Keap1, the inhibitor of Nrf2, using a luciferase vector with AREG promoter. AREG-dependent Nrf2 activity was examined in BEAS-2B cells, murine precision-cut lung slices (PCLS), and IPL. Finally, Nrf2 knockout and wild-type mice were ventilated to investigate the interplay between Nrf2 and AREG during MV in vivo. Lung functions and inflammatory parameters were measured. Nrf2 was activated in a ventilation-dependent manner. The knockdown of Nrf2 and Keap1 via short hairpin RNA in BEAS-2B cells and an EMSA with lung tissue revealed that AREG is regulated by Nrf2. Conversely, AREG application induced a significant Nrf2 activation in BEAS-2B cells, PCLS, and IPL. The signal transduction of ventilation-induced Nrf2 activation was shown to be p38 MAP kinase-dependent. In vivo ventilation experiments indicated that AREG is regulated by Nrf2 during MV. We conclude that Areg expression is regulated by Nrf2. During high-pressure ventilation, Nrf2 becomes activated and induces AREG, leading to a positive feedback loop between Nrf2 and AREG, which involves the p38 MAPK and results in the expression of cytoprotective genes.
authors.affiliation: 1 Institute of Pharmacology and Toxicology and.
authors.forename: Lucy Kathleen
authors.initials: LK
authors.lastname: Reiss
authors.forename: Athanassios
authors.initials: A
authors.lastname: Fragoulis
authors.forename: Stephanie
authors.initials: S
authors.lastname: Siegl
authors.forename: Christopher
authors.initials: C
authors.lastname: Platen
authors.forename: Yuet Wai
authors.initials: YW
authors.lastname: Kan
authors.forename: Jaya
authors.initials: J
authors.lastname: Nautiyal
authors.forename: Malcom
authors.initials: M
authors.lastname: Parker
authors.forename: Thomas
authors.initials: T
authors.lastname: Pufe
authors.forename: Ulrike
authors.initials: U
authors.lastname: Uhlig
authors.forename: Christian
authors.initials: C
authors.lastname: Martin
authors.forename: Stefan
authors.initials: S
authors.lastname: Uhlig
authors.forename: Christoph Jan
authors.initials: CJ
authors.lastname: Wruck
mesh_terms: D066258:Amphiregulin; D000818:Animals; D061745:Antioxidant Response Elements / Q000502:physiology; D001980:Bronchi / Q000166:cytology / Q000502:physiology*; D002478:Cells, Cultured; D066255:EGF Family of Proteins / Q000378:metabolism*; D025461:Feedback, Physiological / Q000502:physiology; D005786:Gene Expression Regulation / Q000502:physiology; D006801:Humans; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D051267:NF-E2-Related Factor 2 / Q000235:genetics* / Q000378:metabolism; D009924:Organ Culture Techniques; D011401:Promoter Regions, Genetic / Q000502:physiology; D012121:Respiration, Artificial; D020545:Respiratory Mucosa / Q000166:cytology / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: C587848:AREG protein, human; D066258:Amphiregulin; C587849:Areg protein, mouse; D066255:EGF Family of Proteins; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; C495636:Nfe2l2 protein, mouse; D048051:p38 Mitogen-Activated Protein Kinases
keywords: amphiregulin; antioxidant response element; mechanical ventilation; nuclear factor erythroid 2–related factor 2; p38 MAP kinase