Emily F. A. van't Wout

Z-AAT production in airway epithelial cells and macrophages from Z-AATD patients: polymer formation

Alpha-1 antitrypsin (AAT) is an important neutrophil elastase inhibitor that protects lung tissue from the destructive effects of neutrophil elastase released by degranulating neutrophils. Although the hepatocyte is considered as the primary source of AAT in the lung, local production by macrophages and epithelial cells may contribute to the formation of an anti-elastase screen in the lung. The Z mutation compromises more than 95% of the mutations leading to AAT deficiency (AATD), and is associated with liver disease and early-onset emphysema. Initially, the protease-antiprotease imbalance resulting from the Z mutation was thought to be the main explanation for the development of emphysema. More recently, it was shown that accumulation and polymerization of the misfolded Z-AAT in the endoplasmic reticulum (ER) makes hepatocytes more susceptible to the so-called ER stress response, resulting in cellular dysfunction, inflammation and cell death. This enhanced sensitivity to ER stress may also contribute to lung disease through induction of ER stress in epithelial cells and macrophages after exposure to a secondary trigger, but to date there is limited evidence for this hypothesis. In 2004, Mulgrew et al.showed that Z-AAT polymers are present in broncho-alveolar lavage fluid (BALF) years after liver transplantation, suggesting local secretion and polymerization of Z-AAT in the lung. Carroll et al. showed intracellular accumulation of Z-AAT together with activation of genes involved in the unfolded protein response (UPR) of the ER stress response in peripheral blood monocytes from patients with Z-AATD. Similar findings were stated in immortalized bronchial epithelial cells that over express the Z-AAT protein. More recently, in vivo cigarette smoke exposure of mice that expressed the Z-AAT human gene was found to increase Z-AAT polymer formation as demonstrated in BALF and lung homogenates.

In collaboration with the research groups of D.A. Lomas and S.J. Marciniak (Cambridge, UK), she will address the following issues:

  1. Are Z-AAT polymers expressed in primary bronchial epithelial cells, alveolar type 2 cells, and monocyte-derived macrophages from patients with Z-AATD?
  2. Does cigarette smoke initiate or increase polymerization of Z-AAT by these cells and is this accompanied by increased IL-8 /IL-6 release compared to cells from patients with COPD and non-COPD patients?
  3. Does Z-AAT modulate the ER-stress response in these cells?
  4. Does ER stress promote Z-AAT induction and polymerization?

Curriculum Vitae of Emily F. A. van 't Wout

Emily received her degree of MSc. of Medicine at Leiden University in 2009.
Since 2009, Emily is working at the University Medical Centre Leiden (LUMC) on a PhD student project entitled; ?Alpha -1 antitrypsin deficiency, respiratory infections and airway inflammation: the role of epithelial cells?. In this project, she investigates the role of ER-stress in primary bronchial epithelial cells and macrophages from patients with alpha-1 antitrypsin deficiency in comparison with COPD patients. Furthermore, she explores the role of potential secondary triggers, like bacterial and viral infections and cigarette smoke exposure, in provoking the ER-stress response.

Her eALTA research project "Z-AAT production in airway epithelial cells and macrophages from Z-AATD patients: polymer formation" focuses on the role of extra-hepatic production of Z-AAT in the development of AATD lung disease using primary bronchial epithelial cells (PBEC) and monocyte-derived macrophages. Alveolar type 2 (ATII) cell cultures from resected lung tissue will also be applied. Furthermore the project will address the role of cigarette smoke in relation to the polymerization of Z-AAT by these cells.


Leiden University Medical Centre
Department of Pulmonology
The Netherlands