alpha(1)-Antitrypsin (AT) is a major
elastase inhibitor within the lung. Oxidation of critical
methionine residues in AT generates oxidized AT (Ox-AT), which has a greatly diminished ability to inhibit
neutrophil elastase. This process may contribute to the pathogenesis of
chronic obstructive pulmonary disease (
COPD) by creating a functional deficiency of AT permitting lung destruction. We show here that Ox-AT promotes release of human
monocyte chemoattractant protein-1 (MCP-1) and
IL-8 from human lung type epithelial cells (A549) and normal human bronchial epithelial (NHBE) cells. Native, cleaved, polymeric AT and secretory leukoproteinase inhibitor (SLPI) and oxidized conformations of cleaved, polymeric AT and SLPI did not have any significant effect on MCP-1 and
IL-8 secretion. These findings were supported by the fact that instillation of Ox-AT into murine lungs resulted in an increase in JE (mouse MCP-1) and increased macrophage numbers in the bronchoalveolar lavage fluid. The effect of Ox-AT was dependent on
NF-kappaB and
activator protein-1 (AP-1)/JNK. These findings have important implications. They demonstrate that the oxidation of methionines in AT by
oxidants released by cigarette
smoke or inflammatory cells not only reduces the antielastase lung protection, but also converts AT into a proinflammatory stimulus. Ox-AT generated in the airway interacts directly with epithelial cells to release
chemokines IL-8 and MCP-1, which in turn attracts macrophages and neutrophils into the airways. The release of
oxidants by these inflammatory cells could oxidize AT, perpetuating the cycle and potentially contributing to the pathogenesis of
COPD. Furthermore, these data demonstrate that molecules such as
oxidants, antiproteinases, and
chemokines, rather than act independently, are likely to interact to cause
emphysema.