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

Li, Zhenjun; Alam, Sam; Wang, Jicun; Sandström, Caroline LU ; Janciauskiene, Sabina LU and Mahadeva, Ravi (2009) In American Journal of Physiology: Lung Cellular and Molecular Physiology 297(2). p.388-400
Abstract
Li Z, Alam S, Wang J, Sandstrom CS, Janciauskiene S, Mahadeva R. Oxidized alpha(1)-antitrypsin stimulates the release of monocyte chemotactic protein-1 from lung epithelial cells: potential role in emphysema. Am J Physiol Lung Cell Mol Physiol 297: L388-L400, 2009. First published June 12, 2009; doi:10.1152/ajplung.90373.2008.-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... (More)
Li Z, Alam S, Wang J, Sandstrom CS, Janciauskiene S, Mahadeva R. Oxidized alpha(1)-antitrypsin stimulates the release of monocyte chemotactic protein-1 from lung epithelial cells: potential role in emphysema. Am J Physiol Lung Cell Mol Physiol 297: L388-L400, 2009. First published June 12, 2009; doi:10.1152/ajplung.90373.2008.-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-kappa B 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. (Less)
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
oxidants, chronic obstructive pulmonary disease, interleukin-8
in
American Journal of Physiology: Lung Cellular and Molecular Physiology
volume
297
issue
2
pages
388 - 400
publisher
American Physiological Society
external identifiers
  • wos:000268276200020
  • scopus:67651204310
ISSN
1522-1504
DOI
10.1152/ajplung.90373.2008
language
English
LU publication?
yes
id
0c37f611-cdc4-4703-8ef9-66afd33392bc (old id 1460849)
date added to LUP
2009-08-31 10:58:50
date last changed
2017-11-12 03:28:20
@article{0c37f611-cdc4-4703-8ef9-66afd33392bc,
  abstract     = {Li Z, Alam S, Wang J, Sandstrom CS, Janciauskiene S, Mahadeva R. Oxidized alpha(1)-antitrypsin stimulates the release of monocyte chemotactic protein-1 from lung epithelial cells: potential role in emphysema. Am J Physiol Lung Cell Mol Physiol 297: L388-L400, 2009. First published June 12, 2009; doi:10.1152/ajplung.90373.2008.-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-kappa B 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.},
  author       = {Li, Zhenjun and Alam, Sam and Wang, Jicun and Sandström, Caroline and Janciauskiene, Sabina and Mahadeva, Ravi},
  issn         = {1522-1504},
  keyword      = {oxidants,chronic obstructive pulmonary disease,interleukin-8},
  language     = {eng},
  number       = {2},
  pages        = {388--400},
  publisher    = {American Physiological Society},
  series       = {American Journal of Physiology: Lung Cellular and Molecular Physiology},
  title        = {Oxidized alpha(1)-antitrypsin stimulates the release of monocyte chemotactic protein-1 from lung epithelial cells: potential role in emphysema},
  url          = {http://dx.doi.org/10.1152/ajplung.90373.2008},
  volume       = {297},
  year         = {2009},
}