title: Matrix metalloproteinase-14 triggers an anti-inflammatory proteolytic cascade in endotoxemia.
abstract: 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.
  
  
  
  • 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.
authors.affiliation: Facultad de Ingeniería y Ciencias Agropecuarias, Universidad de las Américas, Quito, Ecuador.
authors.forename: Alina
authors.initials: A
authors.lastname: Aguirre
authors.affiliation: Departamento de Biología Funcional, Área de Fisiología, Instituto de Oncología del Principado de Asturias (IUOPA), Universidad de Oviedo, Oviedo, Spain.
authors.forename: Jorge
authors.initials: J
authors.lastname: Blázquez-Prieto
authors.affiliation: Departamento de Biología Funcional, Área de Fisiología, Instituto de Oncología del Principado de Asturias (IUOPA), Universidad de Oviedo, Oviedo, Spain.|Unidad de Gestión Clínica de Medicina Intensiva, Hospital Valle del Nalón, Langreo, Spain.
authors.forename: Laura
authors.initials: L
authors.lastname: Amado-Rodriguez
authors.affiliation: Departamento de Biología Funcional, Área de Fisiología, Instituto de Oncología del Principado de Asturias (IUOPA), Universidad de Oviedo, Oviedo, Spain.|Unidad de Cuidados Críticos, Área de Gestión Clínica del Corazón, Hospital Universitario Central de Asturias, Oviedo, Spain.
authors.forename: Inés
authors.initials: I
authors.lastname: López-Alonso
authors.affiliation: Departamento de Biología Funcional, Área de Fisiología, Instituto de Oncología del Principado de Asturias (IUOPA), Universidad de Oviedo, Oviedo, Spain.
authors.forename: Estefanía
authors.initials: E
authors.lastname: Batalla-Solís
authors.affiliation: Department of Anesthesiology and Operative Intensive Care Medicine, Charité Universitätsmedizin, Berlin, Germany.
authors.forename: Adrián
authors.initials: A
authors.lastname: González-López
authors.affiliation: Unidad de Gestión Clínica de Medicina Intensiva, Hospital Valle del Nalón, Langreo, Spain.
authors.forename: Moisés
authors.initials: M
authors.lastname: Sánchez-Pérez
authors.affiliation: Departamento de Biología Funcional, Área de Fisiología, Instituto de Oncología del Principado de Asturias (IUOPA), Universidad de Oviedo, Oviedo, Spain.
authors.forename: Carlos
authors.initials: C
authors.lastname: Mayoral-Garcia
authors.affiliation: Departamento de Bioquímica y Biología Molecular, Instituto de Oncología del Principado de Asturias (IUOPA), Universidad de Oviedo, Oviedo, Spain.
authors.forename: Ana
authors.initials: A
authors.lastname: Gutiérrez-Fernández
authors.affiliation: Departamento de Biología Funcional, Área de Fisiología, Instituto de Oncología del Principado de Asturias (IUOPA), Universidad de Oviedo, Oviedo, Spain. Guillermo.muniz@sespa.es.|Unidad de Cuidados Críticos, Área de Gestión Clínica del Corazón, Hospital Universitario Central de Asturias, Oviedo, Spain. Guillermo.muniz@sespa.es.|Centro de Investigación Biomédica en Red-Enfermedades Respiratorias, Instituto de Salud Carlos III, Madrid, Spain. Guillermo.muniz@sespa.es.
authors.forename: Guillermo M
authors.initials: GM
authors.lastname: Albaiceta
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D019446:Endotoxemia / Q000139:chemically induced / Q000201:enzymology* / Q000378:metabolism*; D005260:Female; D005838:Genotype; D006801:Humans; D008070:Lipopolysaccharides / Q000633:toxicity; D008168:Lung / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D008297:Male; D053509:Matrix Metalloproteinase 13 / Q000235:genetics / Q000378:metabolism; D053511:Matrix Metalloproteinase 14 / Q000235:genetics / Q000378:metabolism*; D020778:Matrix Metalloproteinase 2 / Q000235:genetics / Q000378:metabolism; D020784:Matrix Metalloproteinase 8 / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008817:Mice, Mutant Strains; D008875:Middle Aged; D018805:Sepsis / Q000201:enzymology / Q000378:metabolism
chemical_list: D008070:Lipopolysaccharides; D053509:Matrix Metalloproteinase 13; D020778:Matrix Metalloproteinase 2; D020784:Matrix Metalloproteinase 8; D053511:Matrix Metalloproteinase 14
keywords: Alarmins; Endotoxemia; MMP-14; Matrix metalloproteinases; Sepsis