Transgenically-expressed secretoglobin 3A2 accelerates resolution of bleomycin-induced pulmonary fibrosis in mice.
Transgenically-expressed secretoglobin 3A2 accelerates resolution of bleomycin-induced pulmonary fibrosis in mice.
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DOI：
10.1186/s12890-015-0065-4
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发表时间：
2015-07-16
影响因子：
3.1
通讯作者：
Kimura S
中科院分区：
文献类型：
--
作者：
Cai Y;Yoneda M;Tomita T;Kurotani R;Okamoto M;Kido T;Abe H;Mitzner W;Guha A;Kimura S
分泌型珠蛋白(SCGB)3A2是一种小分子细胞因子样分泌蛋白，主要表达于呼吸道上皮细胞。虽然已知SCGB3A2具有抗炎、生长因子和抗纤维化活性，但SCGB3A2是否具有其他作用，特别是在肺内稳态和疾病方面，尚未在体内得到证实。这项研究的目的是在小鼠身上解决这些问题。建立了利用人表面活性蛋白C启动子在肺中表达SCGB3A2的转基因小鼠系。对转Scgb3a2基因小鼠肺进行了详细的组织学、免疫组织化学、生理学和分子鉴定。以Scgb3a2转基因小鼠和野生型小鼠建立博莱霉素肺纤维化模型，在博莱霉素治疗9周后的不同时间点采集肺和支气管肺泡灌洗液进行分析。肺组织的Western blotting显示，与野生型小鼠相比，成年Scgb3a2转基因小鼠肺组织表达的SCGB3A2蛋白水平大约高出五倍。免疫组织化学显示除呼吸道上皮细胞外，肺泡II型细胞也有表达，从而准确地反映了肺表面活性蛋白-C的表达部位。Scgb3a2转基因小鼠肺发育和组织学正常，没有明显的大体表型。然而，当受到博莱霉素诱导的肺纤维化模型时，它们在博莱霉素注射后3周开始表现出加重的纤维化，根据肺组织学、Masson三色染色和羟脯氨酸含量、炎症细胞数量、胶原基因表达和促炎细胞因子水平的测定，这种加重在6周后比野生型小鼠更快地消失。在Scgb3a2转基因肺中，纤维化的减轻与SCGB3A2表达的增加是一致的。这些结果表明SCGB3A2是一种抗纤维化药物，提示重组SCGB3A2有可能用于肺纤维化的治疗。本文的在线版本(doi：10.1186/s12890-0150065-4)包含补充材料，授权用户可以使用。
Secretoglobin (SCGB) 3A2, a cytokine-like secretory protein of small molecular weight, is predominantly expressed in airway epithelial cells. While SCGB3A2 is known to have anti-inflammatory, growth factor, and anti-fibrotic activities, whether SCGB3A2 has any other roles, particularly in lung homeostasis and disease has not been demonstrated in vivo. The aim of this study was to address these questions in mice. A transgenic mouse line that expresses SCGB3A2 in the lung using the human surfactant protein-C promoter was established. Detailed histological, immunohistochemical, physiological, and molecular characterization of the Scgb3a2-transgenic mouse lungs were carried out. Scgb3a2-transgenic and wild-type mice were subjected to bleomycin-induced pulmonary fibrosis model, and their lungs and bronchoalveolar lavage fluids were collected at various time points during 9 weeks post-bleomycin treatment for further analysis. Adult Scgb3a2-transgenic mouse lungs expressed approximately five-fold higher levels of SCGB3A2 protein in comparison to wild-type mice as determined by western blotting of lung tissues. Immunohistochemistry showed that expression was localized to alveolar type II cells in addition to airway epithelial cells, thus accurately reflecting the site of surfactant protein-C expression. Scgb3a2-transgenic mice showed normal lung development and histology, and no overt gross phenotypes. However, when subjected to a bleomycin-induced pulmonary fibrosis model, they initially exhibited exacerbated fibrosis at 3 weeks post-bleomycin administration that was more rapidly resolved by 6 weeks as compared with wild-type mice, as determined by lung histology, Masson Trichrome staining and hydroxyproline content, inflammatory cell numbers, expression of collagen genes, and proinflammatory cytokine levels. The decrease of fibrosis coincided with the increased expression of SCGB3A2 in Scgb3a2-transgenic lungs. These results demonstrate that SCGB3A2 is an anti-fibrotic agent, and suggest a possible therapeutic use of recombinant SCGB3A2 in the treatment of pulmonary fibrosis. The online version of this article (doi:10.1186/s12890-015-0065-4) contains supplementary material, which is available to authorized users.