Severe antitrypsin (AT) deficiency due to polymerization of the Z variant is the commonest genetic cause of emphysema. There is variability in the development and progression of emphysema even in Z-AT homozygotes. We postulated that episodes of pulmonary inflammation could induce polymerization of Z-AT protein thereby further reducing the anti-proteinase protection. 8 Transgenic mice for human Z-AT (Z-mice) and M-AT (M-mice) received 10µg of intrapulmonary LPS. BALF and lung homogenates (LH) were assessed for lung injury and inflammation and AT conformations at day 1, d3 and d7. Z-mice had more lung injury than M-mice; Wet:dry lung ratio was higher in Z- than M-mice, d1, 6.5±0.42 vs. 4.5±0.24, p=0.001; d3, 7.1±0.51 vs. 5.7±0.29, p=0.03. Z-mice had more pulmonary PMNs d1, BALF 71±3x104cells (mean(SEM)) vs. 52±4, p=0.004; LH intracellular neutrophil elastase (NE), Z- vs. M-mice, median(IQR): d1, 418(490-391)ng/mg vs. 261(285-220), p<0.001. Z-mice had a higher concentration of 8-isoprostane (8-IP) and free NE in BALF compared with M-mice; 8-IP (Z vs. M), d1, 141±29ng/ml vs. 83±19; d3, 211±27 vs. 108±21, p<0.001; BALF, free NE, d1 (Z vs. M), median(IQR) 346(436-316)ng/ml vs. 213(245-113), p=0.001. ELISA and immunoblot revealed that LPS instillation in Z-AT mice led to the development of oxidized-polymers of Z-AT, which further reduces the anti-elastase protection and nullifies the anti-inflammatory effect of AT. This data suggests a molecular mechanism whereby infective exacerbations could further inactivate Z-AT and contribute to the faster decline in lung function in Pi ZZ individuals. This may explain some of the heterogeneity of the lung disease in these individuals.