PMID- 19525388
OWN - NLM
STAT- MEDLINE
DCOM- 20090824
LR  - 20211020
IS  - 1522-1504 (Electronic)
IS  - 1040-0605 (Print)
IS  - 1040-0605 (Linking)
VI  - 297
IP  - 2
DP  - 2009 Aug
TI  - Oxidized alpha1-antitrypsin stimulates the release of monocyte chemotactic 
      protein-1 from lung epithelial cells: potential role in emphysema.
PG  - L388-400
LID - 10.1152/ajplung.90373.2008 [doi]
AB  - 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.
FAU - Li, Zhenjun
AU  - Li Z
AD  - Dept. of Medicine, Univ. of Cambridge, Addenbrookes Hospital, United Kingdom.
FAU - Alam, Sam
AU  - Alam S
FAU - Wang, Jicun
AU  - Wang J
FAU - Sandstrom, Caroline S
AU  - Sandstrom CS
FAU - Janciauskiene, Sabina
AU  - Janciauskiene S
FAU - Mahadeva, Ravi
AU  - Mahadeva R
LA  - eng
GR  - Wellcome Trust/United Kingdom
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20090612
PL  - United States
TA  - Am J Physiol Lung Cell Mol Physiol
JT  - American journal of physiology. Lung cellular and molecular physiology
JID - 100901229
RN  - 0 (Anthracenes)
RN  - 0 (CCL2 protein, human)
RN  - 0 (Chemokine CCL2)
RN  - 0 (Interleukin-8)
RN  - 0 (NF-kappa B p50 Subunit)
RN  - 0 (Oxidants)
RN  - 0 (alpha 1-Antitrypsin)
RN  - 1TW30Y2766 (pyrazolanthrone)
RN  - EC 2.7.11.24 (JNK Mitogen-Activated Protein Kinases)
RN  - EC 2.7.11.24 (p38 Mitogen-Activated Protein Kinases)
SB  - IM
MH  - Animals
MH  - Anthracenes/pharmacology
MH  - Bronchi/*cytology
MH  - Bronchoalveolar Lavage Fluid/cytology
MH  - Carcinoma, Non-Small-Cell Lung
MH  - Cell Line, Tumor
MH  - Chemokine CCL2/immunology/*metabolism
MH  - Emphysema/immunology/*metabolism
MH  - Female
MH  - Humans
MH  - Interleukin-8/immunology/metabolism
MH  - JNK Mitogen-Activated Protein Kinases/antagonists & inhibitors/metabolism
MH  - Lung Neoplasms
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - NF-kappa B p50 Subunit/metabolism
MH  - Oxidants/immunology/metabolism
MH  - Oxidation-Reduction
MH  - Protein Conformation
MH  - Respiratory Mucosa/cytology/*metabolism
MH  - alpha 1-Antitrypsin/chemistry/*metabolism/pharmacology
MH  - p38 Mitogen-Activated Protein Kinases/metabolism
PMC - PMC2742802
EDAT- 2009/06/16 09:00
MHDA- 2009/08/25 09:00
PMCR- 2010/08/01
CRDT- 2009/06/16 09:00
PHST- 2009/06/16 09:00 [entrez]
PHST- 2009/06/16 09:00 [pubmed]
PHST- 2009/08/25 09:00 [medline]
PHST- 2010/08/01 00:00 [pmc-release]
AID - 90373.2008 [pii]
AID - L-90373-2008 [pii]
AID - 10.1152/ajplung.90373.2008 [doi]
PST - ppublish
SO  - Am J Physiol Lung Cell Mol Physiol. 2009 Aug;297(2):L388-400. doi: 
      10.1152/ajplung.90373.2008. Epub 2009 Jun 12.