Alpha-1 antitrypsin (AAT) polymerization in alveolar macrophages of AAT deficient individuals and in smokers

Background: Alpha-1 antitrypsin (AAT) is a protease inhibitor whose deficiency, due to its polymerization in liver cells, is associated with lung emphysema. Alveolar macrophages (AM) produce AAT, however it is not known if AAT could polymerize in AM, further decreasing lung AAT and its defensive role and promoting lung inflammation. Aims: To investigate if AAT polymerizes in the AM and study the possible relation between polymerization and degree of lung inflammation. Methods: We used the 2C1 monoclonal antibody (mAb) (provided by prof Lomas, UCL, UK), which is specific for polymerized AAT, to perform immunohistochemical analysis of sections from 33 lungs with severe COPD, 9 of which with AAT deficiency (AATD) and 24 with normal AAT levels, and in 24 lungs without COPD, 11 of which smokers and 13 nonsmokers. AM positive for AAT polymerization were counted and expressed as percentage of total AMs in lung sections. Results: Polymerization of AAT was detected in [27(5-55)%] of AMs in AATD patients, but also in AMs of smokers with COPD [24(0-54)%] and in smokers without COPD [24(0-46)%], while in nonsmokers AMs did not show polymerization [0(0-2)%] (p Conclusions: Polymerization of AAT in alveolar macrophages occurs in the lungs of AATD patients but also in smokers with or without COPD and normal AAT levels. This suggests that smoking itself induces conformational changes in the AAT predisposing to polymerization, with consequent loss of the AAT protective effect in the lung.