title: Nrf2 deficiency influences susceptibility to steroid resistance via HDAC2 reduction.
abstract: Abnormal lung inflammation and oxidant burden are associated with a significant reduction in histone deacetylase 2 (HDAC2) abundance and steroid resistance. We hypothesized that Nrf2 regulates steroid sensitivity via HDAC2 in response to inflammation in mouse lung. Furthermore, HDAC2 deficiency leads to steroid resistance in attenuating lung inflammatory response, which may be due to oxidant/antioxidant imbalance. Loss of antioxidant transcription factor Nrf2 resulted in decreased HDAC2 level in lung, and increased inflammatory lung response which was not reversed by steroid. Thus, steroid resistance or inability of steroids to control lung inflammatory response is dependent on Nrf2-HDAC2 axis. These findings have implications in steroid resistance, particularly during the conditions of oxidative stress when the lungs are more susceptible to inflammatory response, which is seen in patients with chronic obstructive pulmonary disease, asthma, rheumatoid arthritis, and inflammatory bowel disease.
authors.affiliation: Department of Environmental Medicine, Lung Biology and Disease Program, University of Rochester Medical Center, Rochester, NY, USA.
authors.forename: David
authors.initials: D
authors.lastname: Adenuga
authors.forename: Samuel
authors.initials: S
authors.lastname: Caito
authors.forename: Hongwei
authors.initials: H
authors.lastname: Yao
authors.forename: Isaac K
authors.initials: IK
authors.lastname: Sundar
authors.forename: Jae-Woong
authors.initials: JW
authors.lastname: Hwang
authors.forename: Sangwoon
authors.initials: S
authors.lastname: Chung
authors.forename: Irfan
authors.initials: I
authors.lastname: Rahman
mesh_terms: D000818:Animals; D019819:Budesonide / Q000627:therapeutic use; D004351:Drug Resistance / Q000235:genetics*; D005938:Glucocorticoids / Q000627:therapeutic use*; D056464:Histone Deacetylase 2 / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D051267:NF-E2-Related Factor 2 / Q000235:genetics*; D011014:Pneumonia / Q000188:drug therapy* / Q000201:enzymology
chemical_list: D005938:Glucocorticoids; D051267:NF-E2-Related Factor 2; C495636:Nfe2l2 protein, mouse; D019819:Budesonide; C533424:Hdac2 protein, mouse; D056464:Histone Deacetylase 2