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α1-Antitrypsin: what it tells us about COPD
S61 Cigarette smoke promotes polymerisation of Z α1-antitrypsin
  1. S Alam,
  2. Z Li,
  3. S Janciauskiene,
  4. R Mahadeva
  1. University of Cambridge, Cambridge, UK

Abstract

Alpha-1 antitrypsin (AT) is an important inhibitor of neutrophil elastase (NE). Z antitrypsin (Glu342Lys) (Z-AT) polymerises within the hepatocyte and the subsequent severe plasma deficiency exposes the lungs to uncontrolled elastolysis and premature emphysema. We have shown that polymeric Z-AT (pZ-AT) are found in emphysematous alveolar walls and are co-localised with neutrophils. pZ-AT does not inhibit NE and are also pro-inflammatory and chemotactic to neutrophils, suggesting a novel role for pZ-AT in Z-AT related emphysema. Cigarette smoking (CS) accelerates decline in lung function in Z-AT homozygotes, but the mechanism involved in this is unknown. We investigated whether CS exposure would induce formation of pZ-AT. Female transgenic mice for human M-AT and Z-AT were exposed to four 1R3F research cigarettes daily for 5 days. BALF and perfused lungs were subsequently collected. Concentrations of pAT and oxidised AT were assessed by ELISA and immunoblot. Neutrophil numbers were assessed by quantifying stained cytospins and neutrophil elastase activity of lung homogenates (LH). pAT was undetectable in non-CS Z or CS-M mice. Polymeric AT was markedly increased in BALF and LH in CS-Z mice; BALF CS-Z 141(146–114) ng/ml; p=0.001 and LH, 232.5(241.1–218.6) ng/lung, p=0.001. Immunoblot of BALF demonstrated the classical ladders of pATin CS-Z mice.BALF and LH of CS-Z mice had higher neutrophil numbers compared with CS-M mice; NE LH, CS-Z 49(50–45) ng/lung vs CS-M mice 21(25–18); p<0.001. Neutrophil numbers in the lung were tightly correlated with polymer concentrations; correlation coefficient, r2=0.93; p=<0.001. Incubation of plasma purified Z-AT with CS extract (CSE) demonstrated that CSE oxidises Z-AT leading to an accelerated rate of polymerisation; CSE+Z, 114.4 nM/h, Z control 10.3; p<0.001. This was confirmed by the finding that CS-induced polymerisation could be abolished by the antioxidant N-acetyl cysteine CSE+NAC+Z-AT 13.3; p=0.135 vs control. In conclusion, acute CS exposure directly promotes polymerisation of Z-AT via oxidation. The production of pZ-AT further reduces the anti-proteinase protection and attracts neutrophils potentially hastening lung damage. These novel findings provide a molecular explanation for the striking association of premature emphysema in ZZ homozygotes who smoke.

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