Sex-specific differences in emphysema using a murine antisense oligonucleotide model of α-1 antitrypsin deficiency.
Sex-specific differences in emphysema using a murine antisense oligonucleotide model of α-1 antitrypsin deficiency.
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使用α-1抗胰蛋白酶缺乏症的小鼠反义寡核苷酸模型来观察肺气肿的性别特异性差异。
DOI：
10.1152/ajplung.00502.2018
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发表时间：
2019
期刊：
影响因子：
--
通讯作者：
Varisco,BrianM
中科院分区：
文献类型：
--
作者：
Joshi,Rashika;Ojha,Mohit;Lewis,Jana;Fan,Qiang;Monia,Brett;Guo,Shuling;Varisco,BrianM
α-1抗胰蛋白酶（AAT）缺乏是肺气肿的主要遗传原因;然而，直到最近，还没有真正的AAT缺乏的动物模型，阻碍了新疗法的开发。这个缺点现在通过AAT无效和反义寡核苷酸小鼠模型来解决。本研究的目的是更全面地表征反义寡核苷酸模型。在6、12和24周后，抗AAT小鼠的肝脏AAT mRNA和血清AAT水平均低于对照组。6周和12周抗AAT寡核苷酸治疗诱导的肺气肿在雌性小鼠中比雄性小鼠更严重：平均线性截距为73.4 μ m vs 62.5 μm（P= 0.000003）。然而，在给药24周时，对照组接受利格列汀给药的小鼠也出现肺气肿。治疗6周后，抗AAT雄性和雌性小鼠显示出相似的血清AAT水平降低，并且在炎症、丝氨酸蛋白酶或基质金属蛋白酶mRNA中没有性别或治疗特异性改变，除了胰凝乳蛋白酶样弹性蛋白酶1（Cela 1），其在抗AAT中分别比对照雄性和雌性肺高7倍和9倍，并且在雌性与雄性抗AAT处理的肺中高1.6倍（P= 0.04）。虽然肺AAT蛋白水平在抗AAT处理的小鼠中降低，但肺AAT mRNA水平不受影响。这些发现与AAT缺乏的女性患者肺气肿易感性增加一致。AAT缺陷的抗AAT寡核苷酸模型对于AAT缺陷性肺气肿的隔室特异性、体内分子生物学和性别特异性研究是有用的，但在持续时间超过12周的研究中应谨慎使用。
α-1 Antitrypsin (AAT) deficiency is the leading genetic cause of emphysema; however, until recently, no genuine animal models of AAT deficiency existed, hampering the development of new therapies. This shortcoming is now addressed by bothAAT-null and antisense oligonucleotide mouse models. The goal of this study was to more fully characterize the antisense oligonucleotide model. Both liverAATmRNA and serum AAT levels were lower in anti-AAT versus control oligonucleotide-treated mice after 6, 12, and 24 wk. Six and twelve weeks of anti-AAT oligonucleotide therapy induced emphysema that was worse in female than male mice: mean linear intercept 73.4 versus 62.5 μm (P= 0.000003). However, at 24 wk of treatment, control oligonucleotide-treated mice also developed emphysema. After 6 wk of therapy, anti-AAT male and female mice demonstrated a similar reduction serum AAT levels, and there were no sex or treatment-specific alterations in inflammatory, serine protease, or matrix metalloproteinase mRNAs, with the exception ofchymotrypsin-like elastase 1(Cela1), which was 7- and 9-fold higher in anti-AAT versus control male and female lungs, respectively, and 1.6-fold higher in female versus male anti-AAT-treated lungs (P= 0.04). While lung AAT protein levels were reduced in anti-AAT-treated mice, lungAATmRNA levels were unaffected. These findings are consistent with increased emphysema susceptibility of female patients with AAT-deficiency. The anti-AAT oligonucleotide model of AAT deficiency is useful for compartment-specific, in vivo molecular biology, and sex-specific studies of AAT-deficient emphysema, but it should be used with caution in studies longer than 12-wk duration.
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肺泡上皮细胞分泌α1-抗胰蛋白酶
DOI：
--
发表时间：
1994
期刊：
影响因子：
--
作者：
P. Venembre;A. Boutten;N. Seta;M. Dehoux;B. Crestani;M. Aubier;G. Durand
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DOI：
10.15326/jcopdf.3.3.2015.0182
发表时间：
2016-07-01
影响因子：
2.4
作者：
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通讯作者：
Teckman, Jeffrey
影响因子：
10.5
作者：
KOOPMAN, P;POVEY, S;LOVELLBADGE, RH
通讯作者：
LOVELLBADGE, RH
影响因子：
15.9
作者：
MOLMENTI, EP;PERLMUTTER, DH;RUBIN, DC
通讯作者：
RUBIN, DC
使用速率比浊法建立沙特人 α1-抗胰蛋白酶的正常参考范围。
影响因子：
3.1
作者：
S. Sedrani;S. I. El;A. Warsy
通讯作者：
A. Warsy