title: Inhibition of Bach1 ameliorates indomethacin-induced intestinal injury in mice.
abstract: BTB and CNC homolog 1 (Bach1) is a transcriptional repressor of heme oxygenase-1 (HO-1). It plays an important role in the feedback regulation of HO-1 expression, which protects cells from various insults including oxidative stress and inflammatory cytokines. However, the role of Bach1 in intestinal inflammation remains unclear. In this study, the role of Bach1 in intestinal mucosal injury was elucidated using 8-week-old female C57BL/6 (wild-type) and homozygous Bach1-deficient C57BL/6 mice. Intestinal mucosal injuries induced by a single subcutaneous administration of indomethacin were evaluated macroscopically, histologically, and biochemically. Mucosal protein content and chemokine mRNA levels were determined by real-time PCR. Our results showed that the indomethacin-induced intestinal injury was remarkably improved in Bach1-deficient mice. Histological examination showed that the area of injured lesion was decreased in Bach1-deficient mice compared to wild-type mice. Administration of indomethacin induced expression of inflammatory chemokines such as KC, MIP1alpha and MCP1, which was suppressed in Bach1-deficient mice. Myeloperoxidase activity in the intestinal mucosa was also significantly decreased in Bach1-deficient mice. Additionally, Bach1 deficiency enhanced immunopositivity of HO-1 in the intestinal mucosa after indomethacin administration. Disruption of the Bach1 gene thus caused inhibition of mucosal injury, indicating that inhibition of Bach1 may be a novel therapeutic strategy for treating indomethacin-induced intestinal injury.
authors.affiliation: Department of Molecular Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan.
authors.forename: A
authors.initials: A
authors.lastname: Harusato
authors.forename: Y
authors.initials: Y
authors.lastname: Naito
authors.forename: T
authors.initials: T
authors.lastname: Takagi
authors.forename: S
authors.initials: S
authors.lastname: Yamada
authors.forename: K
authors.initials: K
authors.lastname: Mizushima
authors.forename: Y
authors.initials: Y
authors.lastname: Hirai
authors.forename: R
authors.initials: R
authors.lastname: Horie
authors.forename: K
authors.initials: K
authors.lastname: Inoue
authors.forename: K
authors.initials: K
authors.lastname: Fukumoto
authors.forename: I
authors.initials: I
authors.lastname: Hirata
authors.forename: T
authors.initials: T
authors.lastname: Omatsu
authors.forename: E
authors.initials: E
authors.lastname: Kishimoto
authors.forename: K
authors.initials: K
authors.lastname: Uchiyama
authors.forename: O
authors.initials: O
authors.lastname: Handa
authors.forename: T
authors.initials: T
authors.lastname: Ishikawa
authors.forename: S
authors.initials: S
authors.lastname: Kokura
authors.forename: H
authors.initials: H
authors.lastname: Ichikawa
authors.forename: A
authors.initials: A
authors.lastname: Muto
authors.forename: K
authors.initials: K
authors.lastname: Igarashi
authors.forename: T
authors.initials: T
authors.lastname: Yoshikawa
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000633:toxicity*; D050976:Basic-Leucine Zipper Transcription Factors / Q000235:genetics / Q000502:physiology*; D018932:Chemokine CCL2 / Q000235:genetics / Q000378:metabolism; D054405:Chemokine CCL3 / Q000235:genetics / Q000378:metabolism; D018925:Chemokines / Q000235:genetics / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D051547:Heme Oxygenase-1 / Q000378:metabolism; D007079:Ileitis / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D007213:Indomethacin / Q000633:toxicity*; D007413:Intestinal Mucosa / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D007579:Jejunal Diseases / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D020556:Neutrophil Infiltration / Q000187:drug effects; D012333:RNA, Messenger / Q000378:metabolism; D011897:Random Allocation; D012720:Severity of Illness Index; D014456:Ulcer / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; C486316:Bach1 protein, mouse; D050976:Basic-Leucine Zipper Transcription Factors; C491768:Ccl2 protein, mouse; C496534:Ccl3 protein, mouse; D018932:Chemokine CCL2; D054405:Chemokine CCL3; D018925:Chemokines; D008565:Membrane Proteins; D012333:RNA, Messenger; C074302:keratinocyte-derived chemokines; D051547:Heme Oxygenase-1; C496542:Hmox1 protein, mouse; D007213:Indomethacin