Oxidants spontaneously released by alveolar macrophages of cigarette smokers can inactivate the active site of alpha 1-antitrypsin, rendering it ineffective as an inhibitor of neutrophil elastase. Academic Article uri icon

Overview

MeSH

  • Adult
  • Antioxidants
  • Binding Sites
  • Female
  • Humans
  • Hydrogen Peroxide
  • Male
  • Superoxides

MeSH Major

  • Macrophages
  • Neutrophils
  • Oxygen
  • Pancreatic Elastase
  • Pulmonary Alveoli
  • Smoking
  • alpha 1-Antitrypsin

abstract

  • Current concepts relating to the pathogenesis of emphysema associated with cigarette smoking is that an imbalance exists within the lower respiratory tract between neutrophil elastase and the local anti-neutrophil elastase screen, enabling uninhibited neutrophil elastase to destroy the alveolar structures over time. The possible role of alveolar macrophages in contributing to this imbalance was investigated by evaluating the ability of cigarette smokers' alveolar macrophages to inactivate alpha 1-antitrypsin (alpha 1AT), the major anti-neutrophil elastase of the human lower respiratory tract. In vitro, alveolar macrophages of smokers spontaneously released 2.5-fold more superoxide anion and eightfold more H2O2 than macrophages of nonsmokers (P less than 0.01, both comparisons). Using a model system that reproduced the relative amounts of alveolar macrophages and alpha 1AT found in the epithelial lining fluid of the lower respiratory tract, we observed that smokers' macrophages caused a 60 +/- 5% reduction in the ability of alpha 1AT to inhibit neutrophil elastase. In marked contrast, under the same conditions, nonsmokers' macrophages had no effect upon the anti-neutrophil elastase function of alpha 1AT. Addition of superoxide dismutase, catalase, mannitol, and methionine prevented inactivation of alpha 1AT by smokers' macrophages, implying that the release of oxidants mediated the inactivation of alpha 1AT. In addition, by utilizing a recombinant DNA produced modified form of alpha 1AT containing an active site substitution (met358----val), the inactivation of alpha 1AT by smokers' alveolar macrophages was prevented, suggesting that the smokers' macrophages inactivate alpha 1AT by oxidizing the active site of the alpha 1AT molecule. These results suggest that in cigarette smokers, the alveolar macrophage can modulate the activity of alpha 1AT as an inhibitor of neutrophil elastase and thus play a role in the pathogenesis of emphysema associated with cigarette smoking.

publication date

  • November 1987

has subject area

  • Adult
  • Antioxidants
  • Binding Sites
  • Female
  • Humans
  • Hydrogen Peroxide
  • Macrophages
  • Male
  • Neutrophils
  • Oxygen
  • Pancreatic Elastase
  • Pulmonary Alveoli
  • Smoking
  • Superoxides
  • alpha 1-Antitrypsin

Research

keywords

  • Journal Article

Identity

Language

  • eng

PubMed Central ID

  • PMC442382

Digital Object Identifier (DOI)

  • 10.1172/JCI113204

PubMed ID

  • 2824559

Additional Document Info

start page

  • 1289

end page

  • 1295

volume

  • 80

number

  • 5