Oxidized α₁-antitrypsin stimulates the release of monocyte chemotactic protein-1 from lung epithelial cells: potential role in emphysema

Abstract

α1-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-κB 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.

Effect of Cigarette Smoke Exposure and Structural Modifications on the α-1 Antitrypsin Interaction with Caspases

“…It still remains to be determined whether the A1AT from exsmokers with COPD has impaired ability to access intracellular caspases in vivo. We now provide additional information regarding the properties of oxidized A1AT, to include a loss of anticaspase activity, in addition to previously known loss of antielastase action and proinflammatory effects of triggering chemokine release and recruitment of inflammatory cells (23).…”

Acute Phase Proteins: Structure and Function Relationship

“…Moreover, oxidized AAT by itself amplifies and perpetuates the inflammatory processes by directly affecting the functional activities of structural and inflammatory cells or by interacting with other molecules such as IgA and low-density lipoproteins. It has been shown that oxidized AAT significantly induces the production of IL-8 and MCP-1 from a lung epithelial cell line (A549 cells) and in a time-and dosedependent manner and attracts macrophages (Li et al, 2009). Release of oxidants by these inflammatory cells could oxidize newly synthesized AT, which has diffused into the airways and would perpetuate the cycle.…”

Relationships between chronic obstructive pulmonary disease and lung cancer: biological insights

“…In fact, another investigation (34) demonstrated that inhibition of SOD activity reduced tumor burden in mice and promoted cell death in several NSCLC lines of cells. Furthermore, SOD2 was also shown to favor cell migration and invasiveness of tumors in other investigations (117,118). More recently, mRNA and protein levels of SOD2 were also significantly increased in lung tumors and other cancer types in patients (37).…”

“…In fact, proteins such as cofilin (34), vimentin (115), and alpha-1-antitrypsin (116,117) were also shown to be more oxidized in the normal epithelium of the airways distant to the neoplasm in patients with LC (25), and their function was altered as a result of the oxidative posttranslational modifications, which may contribute to lung destruction and emphysema (116,117).…”