RESUMO
á : 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.
Assuntos
Endotoxemia/enzimologia , Endotoxemia/metabolismo , Metaloproteinase 14 da Matriz/metabolismo , Idoso , Idoso de 80 Anos ou mais , Animais , Endotoxemia/induzido quimicamente , Feminino , Genótipo , Humanos , Lipopolissacarídeos/toxicidade , Pulmão/efeitos dos fármacos , Pulmão/enzimologia , Pulmão/metabolismo , Masculino , Metaloproteinase 13 da Matriz/genética , Metaloproteinase 13 da Matriz/metabolismo , Metaloproteinase 14 da Matriz/genética , Metaloproteinase 2 da Matriz/genética , Metaloproteinase 2 da Matriz/metabolismo , Metaloproteinase 8 da Matriz/genética , Metaloproteinase 8 da Matriz/metabolismo , Camundongos , Camundongos Mutantes , Pessoa de Meia-Idade , Sepse/enzimologia , Sepse/metabolismoRESUMO
BACKGROUND: Chemokines are central in the activation and direction of leukocyte subsets to target tissues. However, the monocyte chemoattractant protein-3 (MCP-3) has not been associated with chronic periodontitis. Chronic periodontitis is an infection showing episodic supporting tissue destruction. The aim of this study is to determine the levels and expression of MCP-3 in periodontal sites characterized by active periodontal connective tissue destruction. METHODS: The study population consisted of 15 patients with a progression of periodontitis (15 of 56 patients), 18 patients with chronic periodontitis, and 10 healthy subjects without periodontal disease. As determined by the tolerance method, the 15 patients with moderate to advanced chronic periodontitis showed a progression of periodontitis over a 4-month period. Periodontitis was characterized by at least six sites with a probing depth >or=5 mm, clinical attachment level >or=3 mm, and radiographic bone loss. Gingival crevicular fluid was collected using a paper strip. The total protein concentration was determined. An enzyme-linked immunosorbent assay was performed to determine the total amount of MCP-3, and an immunoWestern blot was conducted to assess molecular MCP-3 forms. To determine the MCP-3 expression by immunohistochemistry, gingival biopsies were obtained from patients with chronic periodontitis and healthy subjects during third-molar extraction surgery. Statistical analyses were performed using statistical software. Data were expressed as subject means +/- SD, using the chi(2) and Student t tests. RESULTS: The total amount and concentration of chemokine MCP-3 were significantly higher in patients with chronic periodontitis than in healthy subjects (8.25 pg versus 0.53 pg, P = 0.006 and 2.95 pg/microl versus 0.45 pg/microl, P = 0.04, respectively). Active sites showed a significantly higher total amount and concentration of MCP-3 than inactive sites (11.12 versus 2.88 pg, P value = 0.005 and 3.95 versus 1.02, P value = 0.005, respectively). Western blot and immunohistochemical staining confirmed the presence of MCP-3 in periodontal disease, with observable differences between patients with chronic periodontitis and healthy subjects. CONCLUSIONS: MCP-3 was highly expressed in patients with chronic periodontitis, particularly in those with progressive periodontal lesions. MCP-3 could be involved in the recruitment of inflammatory cells toward periodontal tissues during the progression of the disease.