超氧化物歧化酶3，细胞外超氧化物歧化酶（SOD3）的变异型与肺功能
2009/05/27
研究发现，超氧化物歧化酶3（SOD3）的多态性与成人肺功能下降和易感慢性阻塞性肺疾病有关。我们的前期研究发现，SOD3是导致小鼠通气效率（死腔气量/肺总量）变化的因素之一。由于SOD3能保护肺细胞外基质，我们认为SOD3的变异也能影响出生后肺功能的发育。本研究在不同通气效率的不同种属小鼠（C3H/HeJ [高], JF1/Msf [低]）出生后肺功能发育过程中，检测SOD3的转录体和蛋白定位。与C3H/HeJ 小鼠相比，JF1/Msf 小鼠的Sod3启动子SNPs能影响转录因子的结合位点，发育过程中肺总SOD3 mRNA下降。成年JF1/Msf 小鼠呼吸道上皮细胞和肺泡II型细胞总的SOD3活性和SOD3转录体和蛋白以及相关细胞外基质下降。儿童（n=1555; 年龄 9～11岁）中，SOD3有两个常见的SNPs，一个位于启动子区（C/T影响AhR-XRE结合模序），一个位于外显子2（Thr/Ala错义突变），都与第1秒用力呼气量（FEV1）下降有关，启动子SNP与25％最大呼气流量（MEF25）下降相关。体外实验显示，SOD3启动子区来源的含C变异的寡核苷酸与含T变异的寡核苷酸相比，在与标记探针竞争结合核蛋白上具有优势。结合前期关于慢性阻塞性肺疾病（COPD）肺功能下降相关风险的研究，结果均显示，儿童SOD3变异在肺功能上具有决定性作用。
（苏楠 审校）
Ganguly K, et al. Physiol Genomics. 2009 Mar 24. [Epub ahead of print]
Superoxide dismutase 3, extracellular (SOD3) variants and lung function.
Polymorphisms in Superoxide dismutase 3, extracellular (SOD3) have been associated with reduced lung function and susceptibility to chronic obstructive pulmonary disease (COPD) in adults. Previously, we identified SOD3 as a contributing factor to altered ventilation efficiency (dead space volume/total lung capacity) in mice. Because SOD3 protects the extracellular matrix of the lung, we hypothesized that SOD3 variants also may influence postnatal lung function development. In this study, SOD3 transcript and protein localization were examined in mouse strains with differing ventilation efficiency [C3H/HeJ (high), JF1/Msf (low)] during postnatal lung development. Compared to C3H/HeJ mice, JF1/Msf mice had Sod3 promoter SNPs that could affect transcription factor binding sites and a decline in total lung SOD3 mRNA during postnatal development. In adult JF1/Msf mice, total lung SOD3 activity as well as SOD3 transcript and protein in airway epithelial and alveolar type II cells and the associated matrix decreased. In children (n=1555; age 9-11), two common SOD3 SNPs, one located in the promoter region (C/T affecting a predicted AhR-XRE binding motif) and the other in exon 2 (Thr/Ala missense mutation) were associated with decreased forced expiratory volume in one second (FEV1) and the promoter SNP was associated with decreased maximal expiratory flow at 25% volume (MEF25). In vitro, a SOD3 promoter region-derived oligonucleotide containing the C variant was more effective in competing with the nuclear protein-binding capacity of a labelled probe than that containing the T variant. Along with the previous associated risk of lung function decline in COPD, these findings support a possible role of SOD3 variants in determining lung function in children. Key words: Complex trait, COPD, Asthma, Sod3.
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