Figure 1.

Pathogenesis of AAT (alpha-1 antitrypsin) deficiency–associated lung disease. (A) Null mutations and the Pi*ZZ allele in the serine protein inhibitor encoding the SERPINA1 locus leads to absent or misfolded AAT (Z-AAT) that creates a predisposition for liver and lung disease. Z-AAT aggregates in the endoplasmic reticulum (ER) of hepatocytes, leading to ER stress and potentially liver disease. Polymers of Z-AAT fail to reach the lung in sufficient levels, putting the lung parenchyma (alveoli, alveolar ducts, and bronchioles) at risk of injury because of unopposed NE (neutrophil elastase) activity. The alveolar endothelial and epithelial cell junctions restrict the diffusion of AAT (molecular weight, 52 kD) to the alveolar space, such that the AAT level in the epithelial lining fluid (ELF) is often bellow detection (<1–2%). Z polymers of AAT colocalize with neutrophils in alveoli and regulate neutrophil chemotaxis. Thus, in case of AAT deficiency, there is an increased neutrophil pool in the interstitium and in the alveolar airspace, which might be further activated by alveolar macrophages through secreted cytokines and ILs. The protease/antiprotease imbalance compromises the alveolar integrity and accelerates the pathogenesis of emphysema (24, 83–85). (B) Current AAT gene-therapy strategies advanced to human clinical trials (phase I/II) apply intravenous/intrapleural/intramuscular injection of rAAV vectors to provide sufficient amounts of AAT in the lung and the serum. hAAT = human AAT; Pi*ZZ = homozygous Z variant; rAAV = recombinant adeno-associated virus; rAAVrh-10-hAAT = hAAT–expressing rAAV, rhesus macaque serotype 10; rAAV1/2-hAAT = hAAT–expressing rAAV, human serotype 1 or 2. The illustrations were created with BioRender.com.