title: The double knockout of Bach1 and Bach2 in mice reveals shared compensatory mechanisms in regulating alveolar macrophage function and lung surfactant homeostasis.
abstract: Pulmonary alveolar proteinosis (PAP) is a disease resulting from a dysfunction of the alveolar macrophages (AMs) where excess surfactant protein accumulates in the alveolar spaces. We previously reported that Bach2 KO mice developed PAP due to a defect in the handling of lipids by AMs. To investigate the functions of Bach1 and Bach2, which are regulated by oxidative stress, in the AMs and in lung homeostasis, we generated mice that lacked both Bach1 and Bach2 (Bach1/2 DKO mice). The Bach1/2 DKO mice showed more severe PAP phenotype than Bach2 KO mice with abnormal AMs, whereas the Bach1 KO mice did not develop any pulmonary disease. The PAP-like disease in the Bach1/2 DKO and Bach2 KO mice was not ameliorated by antioxidant, suggesting that ROS was not involved in the onset of PAP in the absence of Bach1 and Bach2. A microarray and a chromatin immunoprecipitation sequence analysis revealed that Bach1 and Bach2 directly repress the common set of genes involved in the inflammatory response, and that Bach2 is a major contributor to this repression. These results suggest that Bach1 and Bach2 work in a complementary manner to maintain the normal function of the AMs and surfactant homeostasis in the lung.
authors.affiliation: Department of Biochemistry, Tohoku University Graduate School of Medicine, Sendai 980-8575, Japan.|Division of Respiratory Medicine, Tohoku University Graduate School of Medicine, Sendai 980-8575, Japan.
authors.forename: Risa
authors.initials: R
authors.lastname: Ebina-Shibuya
authors.affiliation: Department of Biochemistry, Tohoku University Graduate School of Medicine, Sendai 980-8575, Japan.
authors.forename: Miki
authors.initials: M
authors.lastname: Watanabe-Matsui
authors.affiliation: Department of Biochemistry, Tohoku University Graduate School of Medicine, Sendai 980-8575, Japan.
authors.forename: Mitsuyo
authors.initials: M
authors.lastname: Matsumoto
authors.affiliation: Department of Biochemistry, Tohoku University Graduate School of Medicine, Sendai 980-8575, Japan.
authors.forename: Ari
authors.initials: A
authors.lastname: Itoh-Nakadai
authors.affiliation: Department of Cell Proliferation, United Center for Advanced Research and Translational Medicine, Tohoku University Graduate School, Sendai 980-8575, Japan.
authors.forename: Ryo
authors.initials: R
authors.lastname: Funayama
authors.affiliation: Department of Cell Proliferation, United Center for Advanced Research and Translational Medicine, Tohoku University Graduate School, Sendai 980-8575, Japan.
authors.forename: Keiko
authors.initials: K
authors.lastname: Nakayama
authors.affiliation: Department of Biochemistry, Tohoku University Graduate School of Medicine, Sendai 980-8575, Japan.
authors.forename: Akihiko
authors.initials: A
authors.lastname: Muto
authors.affiliation: Department of Biochemistry, Tohoku University Graduate School of Medicine, Sendai 980-8575, Japan igarashi@med.tohoku.ac.jp.|Center for Regulatory Epigenome and Diseases, Tohoku University Graduate School of Medicine, Sendai 980-8575, Japan.|AMED-CREST, Japan Agency for Medical Research and Development, Tokyo 100-0004, Japan.
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Igarashi
mesh_terms: D000818:Animals; D050976:Basic-Leucine Zipper Transcription Factors / Q000235:genetics / Q000378:metabolism*; D008168:Lung / Q000378:metabolism*; D016676:Macrophages, Alveolar / Q000166:cytology / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D011663:Pulmonary Surfactants / Q000378:metabolism*
chemical_list: C486316:Bach1 protein, mouse; C102109:Bach2 protein, mouse; D050976:Basic-Leucine Zipper Transcription Factors; D011663:Pulmonary Surfactants
keywords: Bach1; Bach2; oxidative stress; pulmonary alveolar proteinosis; tissue macrophage