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J Mol Med (Berl) ; 95(5): 487-497, 2017 05.
Artículo en Inglés | MEDLINE | ID: mdl-28120021

RESUMEN

ᅟ: Matrix metalloproteinases can modulate the inflammatory response through processing of cyto- and chemokines. Among them, MMP-14 is a non-dispensable collagenase responsible for the activation of other enzymes, triggering a proteolytic cascade. To identify the role of MMP-14 during the pro-inflammatory response, wildtype and Mmp14 -/- mice were challenged with lipopolysaccharide. MMP-14 levels decreased after endotoxemia. Mutant animals showed 100% mortality, compared to 50% in wildtype mice. The increased mortality was related to a more severe lung injury, an impaired lung MMP-2 activation, and increased levels of the alarmin S100A9. There were no differences in the expression of other mediators including Il6, Cxcl2, Tgfb, Il10, or S100a8. A similar result was observed in lung explants of both genotypes cultured in presence of lipopolysaccharide. In this ex vivo model, exogenous activated MMP-2 ameliorated the observed increase in alarmins. Samples from septic patients showed a decrease in serum MMP-14 and activated MMP-2 compared to non-septic critically ill patients. These results demonstrate that the MMP-14-MMP-2 axis is downregulated during sepsis, leading to a proinflammatory response involving S100A9 and a more severe lung injury. This anti-inflammatory role of MMP-14 could have a therapeutic value in sepsis. KEY MESSAGES: • MMP-14 levels decrease in lungs from endotoxemic mice and serum from septic patients. • Mmp14 -/- mice show increased lung injury and mortality following endotoxemia. • Absence of Mmp14 decreases activated MMP-2 and increases S100A9 levels in lung tissue. • MMP-14 ameliorates inflammation by promoting S100A9 cleavage by activated MMP-2.


Asunto(s)
Endotoxemia/enzimología , Endotoxemia/metabolismo , Metaloproteinasa 14 de la Matriz/metabolismo , Anciano , Anciano de 80 o más Años , Animales , Endotoxemia/inducido químicamente , Femenino , Genotipo , Humanos , Lipopolisacáridos/toxicidad , Pulmón/efectos de los fármacos , Pulmón/enzimología , Pulmón/metabolismo , Masculino , Metaloproteinasa 13 de la Matriz/genética , Metaloproteinasa 13 de la Matriz/metabolismo , Metaloproteinasa 14 de la Matriz/genética , Metaloproteinasa 2 de la Matriz/genética , Metaloproteinasa 2 de la Matriz/metabolismo , Metaloproteinasa 8 de la Matriz/genética , Metaloproteinasa 8 de la Matriz/metabolismo , Ratones , Ratones Mutantes , Persona de Mediana Edad , Sepsis/enzimología , Sepsis/metabolismo
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