Abstract
Matrix metalloproteinase-8, released mainly from neutrophils, is a critical regulator of the inflammatory response by its ability to cleave multiple mediators. Herein, we report the results of a model of endotoxemia after intraperitoneal LPS injection in mice lacking MMP-8 and their wildtype counterparts. Control, saline-treated animals showed no differences between genotypes. However, there was an increased lung inflammatory response, with a prominent neutrophilic infiltration in mutant animals after LPS treatment. Using a proteomic approach, we identify alarmins S100A8 and S100A9 as two of the main differences between genotypes. Mice lacking MMP-8 showed a significant increase in these two molecules in lung homogenates, but not in spleen and serum. Mice lacking MMP-8 also showed an increase in MIP-1α levels and a marked activation of the non-canonical NF-κB pathway, with no differences in CXC-chemokines such as MIP-2 or LIX. These results show that MMP-8 can modulate the levels of S100A8 and S100A9 and its absence promotes the lung inflammatory response during endotoxemia.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Calgranulin A / metabolism*
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Calgranulin B / metabolism*
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Endotoxemia / complications
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Endotoxemia / enzymology*
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Endotoxemia / immunology
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Endotoxemia / pathology
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Genotype
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Ligands
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Lipopolysaccharides / pharmacology
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Lung / drug effects
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Lung / microbiology
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Lung / pathology
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Matrix Metalloproteinase 2 / metabolism
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Matrix Metalloproteinase 8 / deficiency*
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Matrix Metalloproteinase 8 / metabolism
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Matrix Metalloproteinase 9 / metabolism
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Mice
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Mice, Inbred C57BL
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NF-kappa B / metabolism
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Pneumonia / complications
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Pneumonia / enzymology*
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Pneumonia / immunology
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Pneumonia / pathology
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Proteomics
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Receptor for Advanced Glycation End Products
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Receptors, Immunologic / metabolism*
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Signal Transduction / drug effects
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Toll-Like Receptors / metabolism*
Substances
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Calgranulin A
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Calgranulin B
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Ligands
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Lipopolysaccharides
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NF-kappa B
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Receptor for Advanced Glycation End Products
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Receptors, Immunologic
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S100A9 protein, mouse
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S100a8 protein, mouse
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Toll-Like Receptors
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Matrix Metalloproteinase 2
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MMP8 protein, mouse
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Matrix Metalloproteinase 8
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Matrix Metalloproteinase 9