Sex-specific differences in emphysema using a murine antisense oligonucleotide model of α-1 antitrypsin deficiency
| Autor: | Brian M. Varisco, Shuling Guo, Qiang Fan, Mohit Ojha, Jana Lewis, Rashika Joshi, Brett Monia |
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| Rok vydání: | 2019 |
| Předmět: |
Male
Pulmonary and Respiratory Medicine congenital hereditary and neonatal diseases and abnormalities Physiology AAT deficiency Mice alpha 1-Antitrypsin Deficiency Physiology (medical) Animals Medicine Sex Characteristics business.industry α 1 antitrypsin Cell Biology Oligonucleotides Antisense Sex specific Mice Inbred C57BL Disease Models Animal Liver Pulmonary Emphysema Gene Knockdown Techniques alpha 1-Antitrypsin Antisense oligonucleotides Immunology Female business Research Article |
| Zdroj: | Am J Physiol Lung Cell Mol Physiol |
| ISSN: | 1522-1504 1040-0605 |
| Popis: | 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 both AAT-null and antisense oligonucleotide mouse models. The goal of this study was to more fully characterize the antisense oligonucleotide model. Both liver AAT mRNA 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 of chymotrypsin-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, lung AAT mRNA 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. |
| Databáze: | OpenAIRE |
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