Overexpression of SERPIN B3 promotes epithelial proliferation and lung fibrosis in mice
Overexpression of SERPIN B3 promotes epithelial proliferation and lung fibrosis in mice
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DOI：
10.1038/labinvest.2011.1
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发表时间：
2011-06-01
影响因子：
5
通讯作者：
Calabrese, Fiorella
中科院分区：
文献类型：
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作者：
Lunardi, Francesca;Villano, Gianmarco;Calabrese, Fiorella
SERPIN B3/B4是SERPIN超家族的成员，是通过不同的蛋白水解酶的已知抑制功能来控制蛋白降解的基础。一些研究已经证明SERPIN B3在炎症、程序性细胞死亡和纤维化的调节中发挥重要作用。为了证实SERPIN B3在肺纤维化中的作用，并全面研究其对上皮功能障碍的影响，对SERPIN B3转基因(TG)和野生型(WT)小鼠进行了随机分配博莱霉素(BLM)治疗的分层对照试验。分别于给药后48h(T48h)和20d(T20d)处死TG和WT动物。通过组织学和羟脯氨酸测定评价肺纤维化程度。对结构重塑、炎症反应、上皮细胞凋亡和增殖进行定量。此外，还对促纤维化细胞因子转化生长因子-β、组织蛋白酶K、L和S进行了检测。T48h组的TG和WT小鼠在各指标上均无显著差异。在T20d组，尽管细胞凋亡指数相似，但治疗组炎症反应减轻，上皮细胞增殖明显增加，从而导致不同的细胞凋亡/增殖失衡，上皮细胞增殖显著增加。此外，转基因小鼠表现出更高的转化生长因子-β表达和更广泛的纤维化。对形态学数据进行的一般线性模型分析表明，SERPIN B3的表达与治疗之间的交互作用在纤维化中具有主要意义。这项研究提供了体内证据，证明SERPIN B3在抑制炎症和促进上皮细胞增殖方面的作用，增加了转化生长因子-β的分泌，从而增加了随后发生纤维化的可能性。实验室调查(2011年)91,945-954；doi：10.1038/Labinvest.2011.1；2011年3月14日在线发布
SERPIN B3/B4, members of the serpin superfamily, are fundamental for the control of proteolysis through a known inhibitory function of different proteases. Several studies have documented an important role of SERPIN B3 in the modulation of inflammation, programmed cell death and fibrosis. To confirm the role of SERPIN B3 in lung fibrosis and overall investigate its influence on epithelial dysfunction, a stratified controlled trial randomly assigning bleomycin (BLM) treatment was performed on both SERPIN B3 transgenic (TG) and wild-type (WT) mice. TG and WT animals were killed 48 h (group T48 h) and 20 days (group T20d) after BLM treatment. Lung fibrosis was assessed by histology and hydroxyproline measurement. Architectural remodeling, inflammation, epithelial apoptosis and proliferation were quantified. Moreover, the profibrogenetic cytokine transforming growth factor (TGF)-beta, cathepsin K, L and S were also investigated. No significant differences were observed between TG and WT mice of group T48 h in any parameters. In group T20d, less inflammation and a significant increase in epithelial proliferation were detected in treated TG than WT mice despite a similar apoptotic index, thus resulting in a different apoptosis/proliferation imbalance with a significant gain of epithelial proliferation. Moreover, TG mice showed higher TGF-beta expression and more extended fibrosis. General linear model analysis, applied on morphological data, showed that interaction between SERPIN B3 expression and treatment was mainly significant for fibrosis. This study provides in vivo evidence for a role of SERPIN B3 in inhibiting inflammation and favoring epithelial proliferation with increased TGF-beta secretion and thus the likelihood of consequent fibrogenesis. Laboratory Investigation (2011) 91, 945-954; doi:10.1038/labinvest.2011.1; published online 14 March 2011