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.
Highlights
The inflammatory response consists in local inflammation
Neutrophil count in the bronchoalveolar lavage fluid (BALF) was higher in Mmp82/2 animals than in their wildtype counterparts (Figure 1E)
As gelatinases MMP-2 and -9 have been involved in processing of S100A8 and S100A9, we studied their levels by gelatin zymography (n = 7/group, Figure 4)
Summary
The inflammatory response consists in local inflammation In severe cases, this response spreads from the site of onset and evolves into a systemic injury [1]. This response spreads from the site of onset and evolves into a systemic injury [1] In this setting, the lungs are amongst the most commonly involved organs. Neutrophils are recruited from the circulation [2], and a fullblown immune response takes place in both the interstitium and the alveolar spaces. This syndrome has been termed acute lung injury and may result in a severe lung dysfunction by altering gas exchange and respiratory mechanics. In patients with the systemic inflammatory response syndrome, lung injury is related to a high mortality rate [3]
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