Inflammation induced conformational changes in Z alpha-1 antirypsin promotes lung Z-AT cell damage

Severe deficiency of the major anti-elastase α1-antitrypsin (AT) due to the Z (Glu342Lys) variant (Z-AT) is the commonest genetic reason for the development of COPD. There is however, significant variability in disease expression in Z-AT homozygotes. We postulated that Z-AT are prone to exaggerated lung damage compared to normal AT (M-AT) during LPS infection. Lung epithelial (A549 and NHBE) cells transfected with human M-AT or Z-AT (M-AT/Z-AT cells) were treated with LPS(20ng). Plasma native AT (N-AT,0.3mg/ml) was used to probe the effect of LPS. At 24h LPS Z-AT cells was compared to M-AT (unless stated) using ELISA, immunoblot or RT-PCR. Z-AT had significantly increased secretion of TNF-α; (mean±SEM) 87±5pg/ml vs. 28±2, IL-6; 296±52pg/ml vs. 40±10, IL-8; 14215±2857pg/ml vs. 1743±227 and MCP-1; 20769±1769pg/ml vs. 3025±161 and their respective mRNA at 0.5h, P