title: Syndecan 4 Mediates Nrf2-dependent Expansion of Bronchiolar Progenitors That Protect Against Lung Inflammation.
abstract: The use of lung progenitors for regenerative medicine appears promising, but their biology is not fully understood. Here, we found anti-inflammatory attributes in bronchiolar progenitors that were sorted as a multipotent subset of mouse club cells and found to express secretory leukocyte protease inhibitor (SLPI). Notably, the impaired expression of SLPI in mice increased the number of bronchiolar progenitors and decreased the lung inflammation. We determined a transcriptional profile for the bronchiolar progenitors of Slpi-deficient mice and identified syndecan 4, whose expression was markedly elevated as compared to that of wild-type mice. Systemic administration of recombinant syndecan 4 protein caused a substantial increase in the number of bronchiolar progenitors with concomitant attenuation of both airway and alveolar inflammation. The syndecan 4 administration also resulted in activation of the Keap1-Nrf2 antioxidant pathway in lung cells, which is critically involved in the therapeutic responses to the syndecan 4 treatment. Moreover, in 3D culture, the presence of syndecan 4 induced differentiated club cells to undergo Nrf2-dependent transition into bronchiolar progenitors. Our observations reveal that differentiative switches between bronchiolar progenitors and club cells are under the Nrf2-mediated control of SLPI and syndecan 4, suggesting the possibility of new therapeutic approaches in inflammatory lung diseases.
authors: Department of Respiratory Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan.
authors: Arif
authors: A
authors: Santoso
authors: Department of Respiratory Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan.|Department of Respiratory Medicine and Infectious Diseases, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan.
authors: Toshiaki
authors: T
authors: Kikuchi
authors: Department of Respiratory Medicine, Tohoku University Hospital, Sendai, Japan.
authors: Naoki
authors: N
authors: Tode
authors: Department of Respiratory Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan.
authors: Taizou
authors: T
authors: Hirano
authors: Department of Respiratory Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan.
authors: Riyo
authors: R
authors: Komatsu
authors: Department of Respiratory Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan.
authors: Triya
authors: T
authors: Damayanti
authors: Department of Gene Expression Regulation, Institute of Development, Aging and Cancer, Tohoku University, Sendai, Japan.
authors: Hozumi
authors: H
authors: Motohashi
authors: Department of Medical Biochemistry, Tohoku University Graduate School of Medicine, Sendai, Japan.
authors: Masayuki
authors: M
authors: Yamamoto
authors: Department of Pathophysiological Laboratory Sciences, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors: Tetsuhito
authors: T
authors: Kojima
authors: Division of Molecular Immunology, Institute for Genetic Medicine, Hokkaido University, Sapporo, Japan.
authors: Toshimitsu
authors: T
authors: Uede
authors: Department of Respiratory Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan.
authors: Toshihiro
authors: T
authors: Nukiwa
authors: Department of Respiratory Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan.|Department of Respiratory Medicine, Tohoku University Hospital, Sendai, Japan.
authors: Masakazu
authors: M
authors: Ichinose
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics; D000818:Animals; D001761:Bleomycin / Q000009:adverse effects; D055745:Bronchioles / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D054337:Cell Dedifferentiation / Q000187:drug effects; D003598:Cytoskeletal Proteins / Q000235:genetics; D005786:Gene Expression Regulation; D000072019:Kelch-Like ECH-Associated Protein 1; D051379:Mice; D051267:NF-E2-Related Factor 2 / Q000235:genetics*; D009281:Naphthalenes / Q000009:adverse effects; D011014:Pneumonia / Q000139:chemically induced / Q000235:genetics* / Q000517:prevention & control*; D011994:Recombinant Proteins / Q000008:administration & dosage; D053481:Secretory Leukocyte Peptidase Inhibitor / Q000172:deficiency*; D015398:Signal Transduction / Q000187:drug effects; D013234:Stem Cells / Q000166:cytology / Q000187:drug effects; D053671:Syndecan-4 / Q000008:administration & dosage / Q000235:genetics*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D003598:Cytoskeletal Proteins; C117301:Keap1 protein, mouse; D000072019:Kelch-Like ECH-Associated Protein 1; D051267:NF-E2-Related Factor 2; D009281:Naphthalenes; C495636:Nfe2l2 protein, mouse; D011994:Recombinant Proteins; C508306:Sdc4 protein, mouse; D053481:Secretory Leukocyte Peptidase Inhibitor; C506815:Slpi protein, mouse; D053671:Syndecan-4; D001761:Bleomycin; C031721:naphthalene