Oxidized {alpha}1-antitrypsin stimulates the release of monocyte chemotactic protein-1 from lung epithelial cells: potential role in emphysema.
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.
Li
Zhenjun
Z
Dept. of Medicine, Univ. of Cambridge, Addenbrookes Hospital, United Kingdom.
Alam
Sam
S
Wang
Jicun
J
Sandstrom
Caroline S
CS
Janciauskiene
Sabina
S
Mahadeva
Ravi
R
D000818:Animals; D000873:Anthracenes / Q000494:pharmacology; D001980:Bronchi / Q000166:cytology*; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology; D002289:Carcinoma, Non-Small-Cell Lung; D045744:Cell Line, Tumor; D018932:Chemokine CCL2 / Q000276:immunology / Q000378:metabolism*; D004646:Emphysema / Q000276:immunology / Q000378:metabolism*; D005260:Female; D006801:Humans; D016209:Interleukin-8 / Q000276:immunology / Q000378:metabolism; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D008175:Lung Neoplasms; D051379:Mice; D008810:Mice, Inbred C57BL; D052002:NF-kappa B p50 Subunit / Q000378:metabolism; D016877:Oxidants / Q000276:immunology / Q000378:metabolism; D010084:Oxidation-Reduction; D011487:Protein Conformation; D020545:Respiratory Mucosa / Q000166:cytology / Q000378:metabolism*; D000515:alpha 1-Antitrypsin / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D000873:Anthracenes; C111835:CCL2 protein, human; D018932:Chemokine CCL2; D016209:Interleukin-8; D052002:NF-kappa B p50 Subunit; D016877:Oxidants; D000515:alpha 1-Antitrypsin; C432165:pyrazolanthrone; D048031:JNK Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases