title: Interstitial pneumonia induced by bleomycin treatment is exacerbated in Angptl2-deficient mice.
abstract: Angiopoietin-like protein 2 (ANGPTL2) is a chronic inflammatory mediator that, when deregulated, is associated with various pathologies. However, little is known about its activity in lung. To assess a possible lung function, we generated a rabbit monoclonal antibody that specifically recognizes mouse ANGPTL2 and then evaluated protein expression in mouse lung tissue. We observed abundant ANGPTL2 expression in both alveolar epithelial type I and type II cells and in resident alveolar macrophages under normal conditions. To assess ANGPTL2 function, we compared lung phenotypes in Angptl2 knockout (KO) and wild-type mice but observed no overt changes. We then generated a bleomycin-induced interstitial pneumonia model using wild-type and Angptl2 KO mice. Bleomycin-treated wild-type mice showed specifically upregulated ANGPTL2 expression in areas of severe fibrosing interstitial pneumonia, while Angptl2 KO mice developed more severe lung fibrosis than did comparably treated wild-type mice. Lung fibrosis seen following bone marrow transplant was comparable in wild-type or Angptl2 KO mice treated with bleomycin, suggesting that Angptl2 loss in myeloid cells does not underlie fibrotic phenotypes. We conclude that Angptl2 deficiency in lung epithelial cells and resident alveolar macrophages causes severe lung fibrosis seen following bleomycin treatment, suggesting that ANGPTL2 derived from these cell types plays a protective role against fibrosis in lung.
authors.affiliation: Department of Molecular Genetics, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan; Department of Pulmonary Medicine, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima, Japan.
authors.forename: Ikuyo
authors.initials: I
authors.lastname: Motokawa
authors.affiliation: Department of Molecular Genetics, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan; enmoto@gpo.kumamoto-u.ac.jp.
authors.forename: Motoyoshi
authors.initials: M
authors.lastname: Endo
authors.affiliation: Department of Molecular Genetics, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.
authors.forename: Kazutoyo
authors.initials: K
authors.lastname: Terada
authors.affiliation: Department of Molecular Genetics, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.
authors.forename: Haruki
authors.initials: H
authors.lastname: Horiguchi
authors.affiliation: Department of Molecular Genetics, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.
authors.forename: Keishi
authors.initials: K
authors.lastname: Miyata
authors.affiliation: Department of Molecular Genetics, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Kadomatsu
authors.affiliation: Department of Molecular Genetics, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.
authors.forename: Jun
authors.initials: J
authors.lastname: Morinaga
authors.affiliation: Department of Molecular Genetics, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.
authors.forename: Taichi
authors.initials: T
authors.lastname: Sugizaki
authors.affiliation: Department of Pathology and Experimental Medicine, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.
authors.forename: Takaaki
authors.initials: T
authors.lastname: Ito
authors.affiliation: Division of Developmental Genetics, Institute of Resource Developmental and Analysis, Kumamoto University, Kumamoto, Japan.
authors.forename: Kimi
authors.initials: K
authors.lastname: Araki
authors.affiliation: Department of Bioinformatics, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: Masaki Suimye
authors.initials: MS
authors.lastname: Morioka
authors.affiliation: Department of Cardiovascular Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan; and.
authors.forename: Ichiro
authors.initials: I
authors.lastname: Manabe
authors.affiliation: Department of Pulmonary Medicine, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima, Japan.
authors.forename: Takuya
authors.initials: T
authors.lastname: Samukawa
authors.affiliation: Department of Pulmonary Medicine, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima, Japan.
authors.forename: Masaki
authors.initials: M
authors.lastname: Watanabe
authors.affiliation: Department of Pulmonary Medicine, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima, Japan.
authors.forename: Hiromasa
authors.initials: H
authors.lastname: Inoue
authors.affiliation: Department of Molecular Genetics, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Oike
mesh_terms: D041721:3T3-L1 Cells; D056809:Alveolar Epithelial Cells / Q000378:metabolism; D000091302:Angiopoietin-Like Protein 2; D000075802:Angiopoietin-like Proteins; D042682:Angiopoietins / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D001761:Bleomycin; D008168:Lung / Q000473:pathology; D017563:Lung Diseases, Interstitial / Q000139:chemically induced / Q000235:genetics* / Q000473:pathology; D016676:Macrophages, Alveolar / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D022423:Myeloid Cells / Q000378:metabolism; D011658:Pulmonary Fibrosis / Q000139:chemically induced / Q000235:genetics* / Q000473:pathology; D019700:Thrombospondin 1 / Q000235:genetics / Q000378:metabolism
chemical_list: D000091302:Angiopoietin-Like Protein 2; D000075802:Angiopoietin-like Proteins; D042682:Angiopoietins; C485793:Angptl2 protein, mouse; D019700:Thrombospondin 1; C585483:Thbs1 protein, mouse; D001761:Bleomycin
keywords: angiopoietin-like protein 2; bleomycin-induced interstitial pneumonia; protecting fibrosis