Differential modulation of surfactant protein D under acute and persistent hypoxia in acute lung injury

作者：Sakamoto Koji; Hashimoto Naozumi^*; Kondoh Yasuhiro; Imaizumi Kazuyoshi; Aoyama Daisuke; Kohnoh Takashi; Kusunose Masaaki; Kimura Motohiro; Kawabe Tsutomu; Taniguchi Hiroyuki; Hasegawa Yoshinori

来源：American Journal of Physiology - Lung Cellular and Molecular Physiology, 2012, 303(1): L43-L53.

DOI：10.1152/ajplung.00061.2012

• epithelial-mesenchymal transition
• fibrosis
• HIF-1 alpha
• twist
• bleomycin

Sakamoto K, Hashimoto N, Kondoh Y, Imaizumi K, Aoyama D, Kohnoh T, Kusunose M, Kimura M, Kawabe T, Taniguchi H, Hasegawa Y. Differential modulation of surfactant protein D under acute and persistent hypoxia in acute lung injury. Am J Physiol Lung Cell Mol Physiol 303: L43-L53, 2012. First published May 4, 2012; doi:10.1152/ajplung.00061.2012.-Hypoxia contributes to the development of fibrosis with epithelial-mesenchymal transition (EMT) via stimulation of hypoxia-inducible factor 1 alpha (HIF-1 alpha) 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-1 alpha 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-1 alpha 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-1 alpha 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-1 alpha 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-1 alpha expression and de novo twist expression.

• 出版日期2012-7