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 interleukin-8 (IL-8) from human lung type epithelial cells (A549) and normal human bronchial epithelial (NHBE) cells. Unoxidized and oxidized cleaved, native and polymeric conformations and oxidized secretory leukoproteinase inhibitor did not have any significant effect on MCP-1 or 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 (BAL) fluid. The effect of Ox-AT was dependent on nuclear factor-kappa B (NF-B) and activator protein-1 (AP-1)/c-Jun N-terminal kinase (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 anti-elastase lung protection, but also converts AT into a pro-inflammatory stimulus. Oxidized 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, anti-proteinases and chemokines rather than act independently are likely to interact to cause emphysema.