Polymerized Z-α-1 antitrypsin leads to lung injury in a murine model of emphysema
Maria Magallón Serrano, Nazli Khodayari, William Bowers, Edward P. Manning, Xinran Liu, Jungnam Lee, Tammy O. Flagg, Regina Oshins, Aidan Griffin, Sahil Patel, Jorge E. Lascano, Divay Chandra, Susan M. Majka, Irina Petrache, Mark L. Brantly, Karina A. Serban
Maria Magallón Serrano, Nazli Khodayari, William Bowers, Edward P. Manning, Xinran Liu, Jungnam Lee, Tammy O. Flagg, Regina Oshins, Aidan Griffin, Sahil Patel, Jorge E. Lascano, Divay Chandra, Susan M. Majka, Irina Petrache, Mark L. Brantly, Karina A. Serban
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Research Article Cell biology Genetics Pulmonology

Polymerized Z-α-1 antitrypsin leads to lung injury in a murine model of emphysema

Abstract

In α-1 antitrypsin (AAT) deficiency (AATD), emphysema is classically linked to protease-antiprotease imbalance caused by decreased antiprotease AAT due levels and function. This decrease is secondary to the impaired release of Z-AAT polymers from hepatocytes carrying Pi*Z, E342K mutation in SERPENA1 gene. Whether the accumulation of Z-AAT polymers in distal lungs contributes directly to emphysema pathogenesis has remained unexplored due to the lack of suitable model systems. We characterized lung injury and airspace enlargement in a Z-AAT–overexpressing murine model. We generated Z-AAT Serpina1Null mice overexpressing human (E342K) SERPENA1 in Serpina1Null mice and analyzed pulmonary phenotypes in young and aged animals, complemented by translational studies using primary cells, bronchoalveolar lavage fluid (BALf), and lung tissue from individuals who have never smoked and individuals with AATD. Young Z-AAT Serpina1Null mice accumulated Z-AAT polymers in hepatocytes, plasma, and BALf, exhibited spontaneous neutrophilic lung inflammation, increased alveolo-capillary permeability, and premature airspace enlargement, which was worse in older Z-AAT Serpina1Null mice. Moreover, Z-AAT polymers accumulated in alveolar type-2 epithelial (AT2) cells and lung macrophages, associated with endoplasmic reticulum (ER) stress, mitochondria dysfunction, and incomplete autophago-lysosomal fusion, which we recapitulated in lung samples from individuals with AATD. These findings support the pathogenic role of Z-AAT polymer accumulation in distal lung epithelium as a driver of epithelial, endothelial, and macrophage dysfunction linked to AATD emphysema.

Authors

Maria Magallón Serrano, Nazli Khodayari, William Bowers, Edward P. Manning, Xinran Liu, Jungnam Lee, Tammy O. Flagg, Regina Oshins, Aidan Griffin, Sahil Patel, Jorge E. Lascano, Divay Chandra, Susan M. Majka, Irina Petrache, Mark L. Brantly, Karina A. Serban

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Figure 6

Z-AAT polymers accumulation in alveolar type-2 epithelial cells is associated with ER stress and autophagy in Z-AAT Serpina1Null mice and AATD lungs.

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Z-AAT polymers accumulation in alveolar type-2 epithelial cells is assoc...
(A–E) Expression of indicated genes by RT-qPCR in undifferentiated EpCam+MHCII+ AT2 cells isolated from greater than 7-month-old Z-AAT Serpina1Null, Serpina1Null and WT mouse lungs. Gadd153 (ER stress marker, A), Atf4 (unfolded protein response, B), Pink1 (mitophagy, C), Sesn3 (antioxidant and reactive oxygen species defense, D), and Sqstm1/p62 (autophagy marker, E). (F and G) Representative immunofluorescence images of healthy, never smoker, and AATD lungs stained for CHOP (red, ER stress marker, F), and LC3B (red, autophagy marker, G), Muc1 or HTII-280 (green), and DAPI (nuclei); scale bar: 100 μm. Note colocalization (yellow) between CHOP, and LC3B with AT2 cell markers. Data are presented as mean ± SD, t test, 1-way ANOVA, followed by Tukey’s multiple comparisons, or Mann-Whitney test *P < 0.05 versus age-matched WT mice.