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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 Z, Alam S, Wang J, Sandstrom CS, Janciauskiene S, Mahadeva R - Am. J. Physiol. Lung Cell Mol. Physiol. (2009)

Bottom Line: 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.The effect of Ox-AT was dependent on NF-kappaB and activator protein-1 (AP-1)/JNK.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.

View Article: PubMed Central - PubMed

Affiliation: Dept. of Medicine, Univ. of Cambridge, Addenbrookes Hospital, United Kingdom.

ABSTRACT
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.

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A: effect of oxidized secretory leukocyte protease inhibitor (SLPI), oxidized cleaved AT, and polymeric AT on production of IL-8 from A549 cells. There was no significant increase in IL-8 production due to treatment with Ox-SLPI, Ox-Cl-AT, or Ox-LP-AT compared with PBS. TNFα (10 ng/ml) and Ox-AT (0.3 mg/ml) were used as positive controls. PBS was the negative control. Data are representative of 3 independent experiments. B: effect of Ox-SLPI, oxidized cleaved, and polymeric AT on production of MCP-1 from A549 cells. There was no significant increase in MCP-1 production due to treatment with Ox-SLPI, Ox-Cl-AT, or Ox-LP-AT compared with PBS. TNFα (10 ng/ml) and Ox-AT (0.3 mg/ml) were used as positive controls. PBS was negative control. Data are representative of 3 independent experiments.
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f3: A: effect of oxidized secretory leukocyte protease inhibitor (SLPI), oxidized cleaved AT, and polymeric AT on production of IL-8 from A549 cells. There was no significant increase in IL-8 production due to treatment with Ox-SLPI, Ox-Cl-AT, or Ox-LP-AT compared with PBS. TNFα (10 ng/ml) and Ox-AT (0.3 mg/ml) were used as positive controls. PBS was the negative control. Data are representative of 3 independent experiments. B: effect of Ox-SLPI, oxidized cleaved, and polymeric AT on production of MCP-1 from A549 cells. There was no significant increase in MCP-1 production due to treatment with Ox-SLPI, Ox-Cl-AT, or Ox-LP-AT compared with PBS. TNFα (10 ng/ml) and Ox-AT (0.3 mg/ml) were used as positive controls. PBS was negative control. Data are representative of 3 independent experiments.

Mentions: To assess whether the effect seen with Ox-AT was specific or a function of oxidized proteins in general, oxidized SLPI, Ox-Cl-AT, and Ox-LP-AT at final concentrations of 0.03, 0.1, or 0.3 mg/ml were added to A549 cells. The supernatant was removed at 4, 10, and 24 h and quantified by ELISA. None of these oxidized proteins had any significant effect on the production of IL-8 or MCP-1 (Fig. 3, A and B).


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

Li Z, Alam S, Wang J, Sandstrom CS, Janciauskiene S, Mahadeva R - Am. J. Physiol. Lung Cell Mol. Physiol. (2009)

A: effect of oxidized secretory leukocyte protease inhibitor (SLPI), oxidized cleaved AT, and polymeric AT on production of IL-8 from A549 cells. There was no significant increase in IL-8 production due to treatment with Ox-SLPI, Ox-Cl-AT, or Ox-LP-AT compared with PBS. TNFα (10 ng/ml) and Ox-AT (0.3 mg/ml) were used as positive controls. PBS was the negative control. Data are representative of 3 independent experiments. B: effect of Ox-SLPI, oxidized cleaved, and polymeric AT on production of MCP-1 from A549 cells. There was no significant increase in MCP-1 production due to treatment with Ox-SLPI, Ox-Cl-AT, or Ox-LP-AT compared with PBS. TNFα (10 ng/ml) and Ox-AT (0.3 mg/ml) were used as positive controls. PBS was negative control. Data are representative of 3 independent experiments.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2742802&req=5

f3: A: effect of oxidized secretory leukocyte protease inhibitor (SLPI), oxidized cleaved AT, and polymeric AT on production of IL-8 from A549 cells. There was no significant increase in IL-8 production due to treatment with Ox-SLPI, Ox-Cl-AT, or Ox-LP-AT compared with PBS. TNFα (10 ng/ml) and Ox-AT (0.3 mg/ml) were used as positive controls. PBS was the negative control. Data are representative of 3 independent experiments. B: effect of Ox-SLPI, oxidized cleaved, and polymeric AT on production of MCP-1 from A549 cells. There was no significant increase in MCP-1 production due to treatment with Ox-SLPI, Ox-Cl-AT, or Ox-LP-AT compared with PBS. TNFα (10 ng/ml) and Ox-AT (0.3 mg/ml) were used as positive controls. PBS was negative control. Data are representative of 3 independent experiments.
Mentions: To assess whether the effect seen with Ox-AT was specific or a function of oxidized proteins in general, oxidized SLPI, Ox-Cl-AT, and Ox-LP-AT at final concentrations of 0.03, 0.1, or 0.3 mg/ml were added to A549 cells. The supernatant was removed at 4, 10, and 24 h and quantified by ELISA. None of these oxidized proteins had any significant effect on the production of IL-8 or MCP-1 (Fig. 3, A and B).

Bottom Line: 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.The effect of Ox-AT was dependent on NF-kappaB and activator protein-1 (AP-1)/JNK.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.

View Article: PubMed Central - PubMed

Affiliation: Dept. of Medicine, Univ. of Cambridge, Addenbrookes Hospital, United Kingdom.

ABSTRACT
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.

Show MeSH
Related in: MedlinePlus