title: Differential modulation of surfactant protein D under acute and persistent hypoxia in acute lung injury.
abstract: Hypoxia contributes to the development of fibrosis with epithelial-mesenchymal transition (EMT) via stimulation of hypoxia-inducible factor 1α (HIF-1α) and de novo twist expression. Although hypoxemia is associated with increasing levels of surfactant protein D (SP-D) in acute lung injury (ALI), the longitudinal effects of hypoxia on SP-D expression in lung tissue injury/fibrosis have not been fully evaluated. Here, the involvement of hypoxia and SP-D modulation was evaluated in a model of bleomycin-induced lung injury. We also investigated the molecular mechanisms by which hypoxia might modulate SP-D expression in alveolar cells, by using a doxycycline (Dox)-dependent HIF-1α expression system. Tissue hypoxia and altered SP-D levels were present in bleomycin-induced fibrotic lesions. Acute hypoxia induced SP-D expression, supported by the finding that Dox-induced expression of HIF-1α increased SP-D expression. In contrast, persistent hypoxia repressed SP-D expression coupled with an EMT phenotype and twist expression. Long-term expression of HIF-1α caused SP-D repression with twist expression. Ectopic twist expression repressed SP-D expression. The longitudinal observation of hypoxia and SP-D levels in ALI in vivo was supported by the finding that HIF-1α expression stabilized by acute hypoxia induced increasing SP-D expression in alveolar cells, whereas persistent hypoxia induced de novo twist expression in these cells, causing repression of SP-D and acquisition of an EMT phenotype. Thus this is the first study to demonstrate the molecular mechanisms, in which SP-D expression under acute and persistent hypoxia in acute lung injury might be differentially modulated by stabilized HIF-1α expression and de novo twist expression.
authors.affiliation: Dept. of Respiratory Medicine, Nagoya Univ. Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550 Japan.
authors.forename: Koji
authors.initials: K
authors.lastname: Sakamoto
authors.forename: Naozumi
authors.initials: N
authors.lastname: Hashimoto
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Kondoh
authors.forename: Kazuyoshi
authors.initials: K
authors.lastname: Imaizumi
authors.forename: Daisuke
authors.initials: D
authors.lastname: Aoyama
authors.forename: Takashi
authors.initials: T
authors.lastname: Kohnoh
authors.forename: Masaaki
authors.initials: M
authors.lastname: Kusunose
authors.forename: Motohiro
authors.initials: M
authors.lastname: Kimura
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Kawabe
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Taniguchi
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Hasegawa
mesh_terms: D055371:Acute Lung Injury / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D001761:Bleomycin / Q000009:adverse effects; D015687:Cell Hypoxia / Q000235:genetics / Q000502:physiology*; D045744:Cell Line, Tumor; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics / Q000502:physiology; D005260:Female; D005355:Fibrosis / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D008137:Longitudinal Studies; D051379:Mice; D008810:Mice, Inbred C57BL; D011650:Pulmonary Alveoli / Q000378:metabolism / Q000473:pathology; D037663:Pulmonary Surfactant-Associated Protein D / Q000235:genetics / Q000378:metabolism*
chemical_list: D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D037663:Pulmonary Surfactant-Associated Protein D; D001761:Bleomycin