Oxidation of Z α1-antitrypsin by cigarette smoke induces polymerization: a novel mechanism of early-onset emphysema.
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.
Department of Medicine, University of Cambridge, Addenbrookes Hospital, UK. rm232@cam.ac.uk
Sam
S
Alam
Zhenjun
Z
Li
Sabina
S
Janciauskiene
Ravi
R
Mahadeva
D000111:Acetylcysteine / Q000494:pharmacology; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006801:Humans; D051379:Mice; D008808:Mice, Inbred CBA; D008822:Mice, Transgenic; D009504:Neutrophils / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D058105:Polymerization / Q000187:drug effects*; D011487:Protein Conformation / Q000187:drug effects*; D011656:Pulmonary Emphysema / Q000209:etiology / Q000473:pathology*; D012907:Smoking / Q000009:adverse effects*; D013388:Succinimides / Q000494:pharmacology; D000515:alpha 1-Antitrypsin / Q000737:chemistry* / Q000502:physiology*
D000975:Antioxidants; D013388:Succinimides; D000515:alpha 1-Antitrypsin; C015752:N-chlorosuccinimide; D000111:Acetylcysteine