Sex-specific differences in emphysema using a murine antisense oligonucleotide model of α-1 antitrypsin deficiency

Abstract

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.

Rosa26-LSL-dCas9-VPR: a versatile mouse model for tissue specific and simultaneous activation of multiple genes for drug discovery

“…In accordance with recent studies 29,30,32,34,58 , overexpression of circulating PCSK9 led to reduced LDLR, which was accompanied by increased LDL and cholesterol concentrations in plasma and vice versa. In addition to this, we also observed sex dependent differences in serum/plasma levels of alpa-1-antitrypsin (male > female), LDL (female > male) and PCSK9 in control mice in accordance with the literature [59][60][61][62][63][64] . This distinction was still visible in AAT plasma levels despite a general 1.6-fold increase after overexpression.…”

Androgen and Androgen Receptors as Regulators of Monocyte and Macrophage Biology in the Healthy and Diseased Lung

“…In 2016, Tam et al ( 265 ) reported that smoke-induced COPD is characterized by small airway remodeling in female but not male mice and that ovariectomy before smoke exposure ameliorates the disease. Another study focusing on α-1 antitrypsin deficiency, the leading genetic cause of emphysema, also uncovered a higher susceptibility of female mice for this condition ( 266 ). However, these studies did not determine if androgens mediate resistance to COPD, or if the key to the observed sex differences is ovarian sex hormones.…”

Mass Spectrometry-Based Atlas of Extracellular Matrix Proteins across 25 Mouse Organs

“…Proteins with the highest inter-replicate variability contain primarily metabolic (i.e., CPT1B, SCP2, ECI2, FABP5, BLVRB, and UQCRH) and protease modulating components (i.e., SERPINA1A, SERPINA3K, and SERPINA1D). Of the top 20 most variable proteins, 11 have been previously shown to be sexually dimorphic or regulated by sex hormones, including SCP2, SERPINA1A, , A1BG, SERPINA3K, FHL1, FABP5, LIFR, CDH2, CAND1, UQCRH, and SERPINA1D . Thus, it is likely that some of the inter-replicate variation observed in these proteins is due to sex-based biological differences.…”