Alpha-1-antitrypsin aerosolised augmentation abrogates neutrophil elastase-induced expression of cathepsin B and matrix metalloprotease 2 in vivo and in vitro
Alpha-1-antitrypsin aerosolised augmentation abrogates neutrophil elastase-induced expression of cathepsin B and matrix metalloprotease 2 in vivo and in vitro
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DOI：
10.1136/thx.2007.088559
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发表时间：
2008-07-01
期刊：
影响因子：
10
通讯作者：
McElvaney, N. G.
中科院分区：
文献类型：
--
作者：
Geraghty, P.;Rogan, M. P.;McElvaney, N. G.
背景：中性粒细胞弹性蛋白酶(NE)活性在α(1)-抗胰蛋白酶(A1AT)缺乏和肺炎等肺部疾病中升高。最近在体外和小鼠模型中，它被证明可以诱导组织蛋白酶B和基质金属蛋白酶2(MMP2)的表达。急、慢性肺部疾病患者肺组织蛋白酶B和基质金属蛋白酶-2的升高可能与细胞外去甲肾上腺素水平升高有关，A1AT增强治疗可抑制这些酶的表达。肺炎患者经A1AT预处理后，将巨噬细胞暴露于富含游离NE的BAL液中。测定A1AT缺陷患者雾化吸入A1AT前后BAL液中MMP2、组织蛋白酶B、分泌型亮氨酸蛋白酶抑制物(SLPI)和乳铁蛋白的水平。结果：肺炎患者和A1AT缺乏症患者BAL液中含有游离NE的BAL液中组织蛋白酶B和MMP2活性均高于健康志愿者BAL液。肺炎患者BAL液中加入A1AT可显著降低NE诱导的巨噬细胞组织蛋白酶B和基质金属蛋白酶-2的表达。对A1AT缺陷个体的A1AT增强治疗也降低了体内BAL液中组织蛋白酶B和基质金属蛋白酶-2的活性。此外，A1AT缺陷患者在A1AT增强治疗后有更高的SLPI和乳铁蛋白水平。结论：这些发现提示了A1AT在体内和体外抑制NE诱导的基质金属蛋白酶和组织蛋白酶表达上调的新作用。
Background: Neutrophil elastase (NE) activity is increased in lung diseases such as alpha(1)-antitrypsin (A1AT) deficiency and pneumonia. It has recently been shown to induce expression of cathepsin B and matrix metalloprotease 2 (MMP-2) in vitro and in a mouse model. It is postulated that increased cathepsin B and MMP-2 in acute and chronic lung diseases result from high levels of extracellular NE and that expression of these proteases could be inhibited by A1AT augmentation therapy.Methods: Cathepsin and MMP activities were assessed in bronchoalveolar lavage (BAL) fluid from patients with A1AT deficiency, pneumonia and control subjects. Macrophages were exposed to BAL fluid rich in free NE from patients with pneumonia following pretreatment with A1AT. MMP-2, cathepsin B, secretory leucoprotease inhibitor (SLPI) and lactoferrin levels were determined in BAL fluid from A1AT-deficient patients before and after aerosolisation of A1AT.Results: BAL fluid from both patients with pneumonia and those with A1AT deficiency containing free NE had increased cathepsin B and MMP-2 activities compared with BAL fluid from healthy volunteers. The addition of A1AT to BAL fluid from patients with pneumonia greatly reduced NE-induced cathepsin B and MMP-2 expression in macrophages in vitro. A1AT augmentation therapy to A1AT-deficient individuals also reduced cathepsin B and MMP-2 activity in BAL fluid in vivo. Furthermore, A1AT-deficient patients had higher levels of SLPI and lactoferrin after A1AT augmentation therapy.Conclusion: These findings suggest a novel role for A1AT inhibition of NE-induced upregulation of MMP and cathepsin expression both in vitro and in vivo.