PMID- 24921206 OWN - NLM STAT- MEDLINE DCOM- 20150102 LR - 20161125 IS - 1535-4989 (Electronic) IS - 1044-1549 (Linking) VI - 51 IP - 5 DP - 2014 Nov TI - Interplay between nuclear factor erythroid 2-related factor 2 and amphiregulin during mechanical ventilation. PG - 668-77 LID - 10.1165/rcmb.2013-0279OC [doi] AB - 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. FAU - Reiss, Lucy Kathleen AU - Reiss LK AD - 1 Institute of Pharmacology and Toxicology and. FAU - Fragoulis, Athanassios AU - Fragoulis A FAU - Siegl, Stephanie AU - Siegl S FAU - Platen, Christopher AU - Platen C FAU - Kan, Yuet Wai AU - Kan YW FAU - Nautiyal, Jaya AU - Nautiyal J FAU - Parker, Malcom AU - Parker M FAU - Pufe, Thomas AU - Pufe T FAU - Uhlig, Ulrike AU - Uhlig U FAU - Martin, Christian AU - Martin C FAU - Uhlig, Stefan AU - Uhlig S FAU - Wruck, Christoph Jan AU - Wruck CJ LA - eng PT - Journal Article PL - United States TA - Am J Respir Cell Mol Biol JT - American journal of respiratory cell and molecular biology JID - 8917225 RN - 0 (AREG protein, human) RN - 0 (Amphiregulin) RN - 0 (Areg protein, mouse) RN - 0 (EGF Family of Proteins) RN - 0 (NF-E2-Related Factor 2) RN - 0 (NFE2L2 protein, human) RN - 0 (Nfe2l2 protein, mouse) RN - EC 2.7.11.24 (p38 Mitogen-Activated Protein Kinases) SB - IM MH - Amphiregulin MH - Animals MH - Antioxidant Response Elements/physiology MH - Bronchi/cytology/*physiology MH - Cells, Cultured MH - EGF Family of Proteins/*metabolism MH - Feedback, Physiological/physiology MH - Gene Expression Regulation/physiology MH - Humans MH - Mice, Inbred C57BL MH - Mice, Knockout MH - NF-E2-Related Factor 2/*genetics/metabolism MH - Organ Culture Techniques MH - Promoter Regions, Genetic/physiology MH - *Respiration, Artificial MH - Respiratory Mucosa/cytology/physiology MH - Signal Transduction/physiology MH - p38 Mitogen-Activated Protein Kinases/metabolism OTO - NOTNLM OT - amphiregulin OT - antioxidant response element OT - mechanical ventilation OT - nuclear factor erythroid 2-related factor 2 OT - p38 MAP kinase EDAT- 2014/06/13 06:00 MHDA- 2015/01/03 06:00 CRDT- 2014/06/13 06:00 PHST- 2014/06/13 06:00 [entrez] PHST- 2014/06/13 06:00 [pubmed] PHST- 2015/01/03 06:00 [medline] AID - 10.1165/rcmb.2013-0279OC [doi] PST - ppublish SO - Am J Respir Cell Mol Biol. 2014 Nov;51(5):668-77. doi: 10.1165/rcmb.2013-0279OC.