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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 inhibitors of NF-κB, p38 MAPK, and JNK on induction of IL-8 and MCP-1 treated with Ox-AT. Ox-AT (0.3 mg/ml) significantly induced IL-8 production in A549 cells (P < 0.001), but this was significantly reduced by Bay11-7082 (P = 0.023) and SP-600125 (P = 0.027). SB-203580 had no significant effect on IL-8 production. Data are means (SE) from 4 separate experiments, *P < 0.05. B: SP-600125 (10 μM) significantly inhibited MCP-1 production in A549 cells (P = 0.003 vs. Ox-AT). Bay11-7082 (10 μM) also had an inhibitory effect on MCP-1 production (P < 0.05 vs. Ox-AT), but SB-203580 had no significant effect on MCP-1 production. Data are means (SE) from 4 separate experiments, *P < 0.05.
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f6: A: effect of inhibitors of NF-κB, p38 MAPK, and JNK on induction of IL-8 and MCP-1 treated with Ox-AT. Ox-AT (0.3 mg/ml) significantly induced IL-8 production in A549 cells (P < 0.001), but this was significantly reduced by Bay11-7082 (P = 0.023) and SP-600125 (P = 0.027). SB-203580 had no significant effect on IL-8 production. Data are means (SE) from 4 separate experiments, *P < 0.05. B: SP-600125 (10 μM) significantly inhibited MCP-1 production in A549 cells (P = 0.003 vs. Ox-AT). Bay11-7082 (10 μM) also had an inhibitory effect on MCP-1 production (P < 0.05 vs. Ox-AT), but SB-203580 had no significant effect on MCP-1 production. Data are means (SE) from 4 separate experiments, *P < 0.05.

Mentions: Bay11-7082, an inhibitor of NF-κB, SB-203580, an inhibitor of p38 MAPK, and SP-600125, an inhibitor of JNK, were separately added to the cell culture media of A549 cells 20 min before treatment with 0.3 mg/ml Ox-AT. Ox-AT-induced IL-8 production [IL-8 = 1526.133(270.03)] was significantly reduced in the presence of the NF-κB inhibitor [Ox-AT + Bay11-7082, IL-8 = 231(33) pg/ml vs. Ox-AT (P = 0.023)] and the JNK inhibitor [Ox-AT + SP-600125, IL-8 = 311(47) pg/ml vs. Ox-AT (P = 0.027)]. There was no significant reduction in Ox-AT-induced IL-8 production in the presence of the MAPK inhibitor (Ox-AT + SB203580, P = 0.379) (Fig. 6A).


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 inhibitors of NF-κB, p38 MAPK, and JNK on induction of IL-8 and MCP-1 treated with Ox-AT. Ox-AT (0.3 mg/ml) significantly induced IL-8 production in A549 cells (P < 0.001), but this was significantly reduced by Bay11-7082 (P = 0.023) and SP-600125 (P = 0.027). SB-203580 had no significant effect on IL-8 production. Data are means (SE) from 4 separate experiments, *P < 0.05. B: SP-600125 (10 μM) significantly inhibited MCP-1 production in A549 cells (P = 0.003 vs. Ox-AT). Bay11-7082 (10 μM) also had an inhibitory effect on MCP-1 production (P < 0.05 vs. Ox-AT), but SB-203580 had no significant effect on MCP-1 production. Data are means (SE) from 4 separate experiments, *P < 0.05.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

f6: A: effect of inhibitors of NF-κB, p38 MAPK, and JNK on induction of IL-8 and MCP-1 treated with Ox-AT. Ox-AT (0.3 mg/ml) significantly induced IL-8 production in A549 cells (P < 0.001), but this was significantly reduced by Bay11-7082 (P = 0.023) and SP-600125 (P = 0.027). SB-203580 had no significant effect on IL-8 production. Data are means (SE) from 4 separate experiments, *P < 0.05. B: SP-600125 (10 μM) significantly inhibited MCP-1 production in A549 cells (P = 0.003 vs. Ox-AT). Bay11-7082 (10 μM) also had an inhibitory effect on MCP-1 production (P < 0.05 vs. Ox-AT), but SB-203580 had no significant effect on MCP-1 production. Data are means (SE) from 4 separate experiments, *P < 0.05.
Mentions: Bay11-7082, an inhibitor of NF-κB, SB-203580, an inhibitor of p38 MAPK, and SP-600125, an inhibitor of JNK, were separately added to the cell culture media of A549 cells 20 min before treatment with 0.3 mg/ml Ox-AT. Ox-AT-induced IL-8 production [IL-8 = 1526.133(270.03)] was significantly reduced in the presence of the NF-κB inhibitor [Ox-AT + Bay11-7082, IL-8 = 231(33) pg/ml vs. Ox-AT (P = 0.023)] and the JNK inhibitor [Ox-AT + SP-600125, IL-8 = 311(47) pg/ml vs. Ox-AT (P = 0.027)]. There was no significant reduction in Ox-AT-induced IL-8 production in the presence of the MAPK inhibitor (Ox-AT + SB203580, P = 0.379) (Fig. 6A).

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