基质金属蛋白酶-12 (MMP-12) SNP 影响 MMP 活性、肺巨噬细胞浸润并防止 COPD 患者出现肺气肿,Thorax

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基质金属蛋白酶-12 (MMP-12) SNP 影响 MMP 活性、肺巨噬细胞浸润并防止 COPD 患者出现肺气肿
Thorax ( IF 9.0 ) Pub Date : 2011-07-05 , DOI: 10.1136/thx.2011.159087
Imran Haq ₁ , Gillian E Lowrey , Noor Kalsheker , Simon R Johnson

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背景最近的遗传和动物研究表明，基质金属蛋白酶 12 (MMP-12) 与慢性阻塞性肺病 (COPD) 的发病机制有关。先前已经表明，MMP-12 中 rs652438 的 A/A 等位基因纯合子个体在严重 COPD 患者中的比例过高（n = 1517）。进行了一项研究以检查这些发现的功能基础。方法 rs652438 A 和 G 变体通过定点诱变产生并转染到 COS7 细胞中表达。酪蛋白酶谱和特定的 FRET 活性测定用于比较等位基因之间的 MMP-12 活性。使用 transwell 测定检查细胞迁移。来自两个 COPD 队列的患者进行了 rs652438 基因分型，并与支气管肺泡灌洗液 (n=10) 和诱导痰 (n=262) 中的炎性细胞数量相关；通过CT扫描评估肺气肿评分（n=1428）。结果 A 等位基因的平均 MMP 活性比 G 等位基因的酶谱法高 2.95 倍 (p=0.0049)，FRET 测定法 (p=0.0001) 的平均 MMP 活性高 3.45 倍。表达 A 等位基因的 COS7 细胞的平均迁移是表达 G 等位基因的细胞的 2.31 倍 (p=0.0001)。与 A/G 杂合子相比，A/A 个体的支气管肺泡灌洗液（增加 1.28 倍，p=0.033）和诱导痰（增加 1.58 倍，p=0.083）中的巨噬细胞数量更多。A 等位基因的存在与肺气肿增加呈剂量依赖性相关 (p=0.016)。结论 rs652438 SNP 改变 MMP-12 活性，A 等位基因更活跃，这与 COPD 患者肺部巨噬细胞浸润和肺气肿增加有关。这些发现进一步表明 MMP-12 和这种 SNP 与 COPD 相关。

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Matrix metalloproteinase-12 (MMP-12) SNP affects MMP activity, lung macrophage infiltration and protects against emphysema in COPD

Background Recent genetic and animal studies have implicated matrix metalloproteinase-12 (MMP-12) in the pathogenesis of chronic obstructive pulmonary disease (COPD). It has previously been shown that individuals homozygous for the A/A allele of rs652438 in MMP-12 are over-represented among patients with severe COPD (n=1517). A study was undertaken to examine the functional basis of these findings. Methods rs652438 A and G variants were generated by site-directed mutagenesis and transfected into COS7 cells where they were expressed. Casein zymography and a specific FRET activity assay were used to compare MMP-12 activity between alleles. Cell migration was examined using a transwell assay. Patients from two COPD cohorts were genotyped for rs652438 and associated with inflammatory cell number in bronchoalveolar lavage fluid (n=10) and induced sputum (n=262); the emphysema score (n=1428) was assessed by CT scanning. Results Mean MMP activity was 2.95-fold higher by zymography (p=0.0049) and 3.45-fold higher by FRET assay (p=0.0001) for the A allele than the G allele. Mean migration of COS7 cells expressing the A allele was 2.31-fold greater than for those expressing the G allele (p=0.0001). Macrophage numbers were greater in bronchoalveolar lavage fluid (1.28-fold increase, p=0.033) and induced sputum (1.58-fold increase, p=0.083) of A/A individuals compared with A/G heterozygotes. The presence of the A allele was dose-dependently associated with increased emphysema (p=0.016). Conclusions The rs652438 SNP alters MMP-12 activity with the A allele being more active, which is associated with increased macrophage infiltration and emphysema in the lungs of patients with COPD. These findings further implicate MMP-12 and this SNP in COPD.

更新日期：2011-07-05

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