Mechanisms of lung disease in AATD

AAT emphysema is caused by "deficient" gene mutations, most frequently the Glu342 to Lys "Z" mutation, causing protein misfolding and defective protein secretion, with ensuing six- to eight-fold reduced serum and even lower pulmonary alveolar levels, or the rare null mutations leading to zero protein expression. Loss of antiprotease protection, chiefly against NE, leads to increased alveolar epithelial and elastic tissue degradation, and macrophage activation with excessive production of neutrophil chemotactic factors, triggering a vicious cycle of neutrophil inflammation in response to the elastase-anti-elastase imbalance. Additionally, lung epithelia and macrophages can express higher AAT levels in response to stressors of environmental and bacterial origin. In Z mutation homozygous subjects, this may generate exaggerated levels of misfolded/polymerised AAT, thereby inducing ER stress, release of proinflammatory cytokines and activation of macrophage proteases, i.e. a proteopathic type of inflammation that could impact disease progression.