Oxidation of Z α1-antitrypsin by cigarette smoke induces polymerization: a novel mechanism of early-onset emphysema

Am J Respir Cell Mol Biol. 2011 Aug;45(2):261-9. doi: 10.1165/rcmb.2010-0328OC. Epub 2010 Oct 22.


The acceleration of chronic obstructive pulmonary disease (COPD) by cigarette smoke (CS) in individuals with severe genetic deficiency of α(1)-antitrypsin (Z-AT [Glu342Lys]) exemplifies the critical importance of gene-environmental interactions to the development of COPD. We investigated the molecular basis for the interaction between Z-AT and CS. Female mice (8-10 wk old) transgenic for normal (M-AT) or Z-AT on CBA background were exposed to four 1R3F cigarettes daily for 5 days. Age and sex matched littermates not exposed to CS were used as controls. Bronchoalveolar lavage fluid and lung homogenates were assessed for inflammatory cells, neutrophil elastase, and AT conformers. Z-AT was purified from plasma, exposed to CS extract, and assessed for the development and temporal relationship between AT conformers. Mice transgenic for Z-AT developed a significant increase in pulmonary polymers after acute CS exposure (P = 0.001). There were also increased neutrophils in CS-Z lungs versus controls (P < 0.001), which were tightly correlated with polymer concentrations (r(2) = 0.93). Oxidation of human plasma Z-AT by CS or N-chlorosuccinimide greatly accelerated polymerization (P = 0.004), which could be abrogated by antioxidants (P = 0.359 versus Z control). Our data show that CS accelerates polymerization of Z-AT by oxidative modification, which, in so doing, further reduces pulmonary defense and increases neutrophil influx into the lungs. These novel findings provide a molecular explanation for the striking observation of premature emphysema in ZZ homozygotes who smoke. Further work is required to assess whether antioxidant therapy may be beneficial in Z-AT-related COPD.

MeSH terms

  • Acetylcysteine / pharmacology
  • Animals
  • Antioxidants / pharmacology
  • Bronchoalveolar Lavage Fluid / chemistry
  • Enzyme-Linked Immunosorbent Assay
  • Female
  • Humans
  • Mice
  • Mice, Inbred CBA
  • Mice, Transgenic
  • Neutrophils / cytology
  • Neutrophils / drug effects
  • Neutrophils / metabolism
  • Polymerization / drug effects*
  • Protein Conformation / drug effects*
  • Pulmonary Emphysema / etiology
  • Pulmonary Emphysema / pathology*
  • Smoking / adverse effects*
  • Succinimides / pharmacology
  • alpha 1-Antitrypsin / chemistry*
  • alpha 1-Antitrypsin / physiology*


  • Antioxidants
  • Succinimides
  • alpha 1-Antitrypsin
  • N-chlorosuccinimide
  • Acetylcysteine