Alpha1-antitrypsin is an important neutrophil elastase inhibitor that protects lung tissue from the destructive effects of neutrophil elastase released by degranulating neutrophils. In addition to... Show moreAlpha1-antitrypsin is an important neutrophil elastase inhibitor that protects lung tissue from the destructive effects of neutrophil elastase released by degranulating neutrophils. In addition to the liver, local production by macrophages and airway and alveolar epithelial cells may contribute to the formation of an anti-elastase screen in the lung. The Z mutation (E342K) of _1-antitrypsin, compromising over 95% of the _1-antitrypsin deficiency patients, causes subtle misfolding of the protein that permits polymer formation and accumulation within the endoplasmic reticulum (ER) of hepatocytes leading to plasma deficiency. This causes hepatic cirrhosis and early-onset lung emphysema. The discovery of ZZ polymers in broncho-alveolar lavage fluid and pulmonary tissue and their identification many years after liver transplantation led to the proposal that pulmonary pathology could be induced by polymers. Overexpression of Z _1-antitrypsin is known to induce polymer formation, prime cells for an exaggerated ER stress response upon a second hit and initiate NF-_B signalling. However, whether endogenous expression in primary bronchial epithelial cells and monocyte-derived macrophages has similar consequences remained unclear. This thesis concentrate on these specific questions. In addition, we focused on the ER stress response induced by P.aeruginosa as a possible second hit in _1-antitrypsin deficiency Show less
