title: Matrix Metalloproteinase-8 Augments Bacterial Clearance in a Juvenile Sepsis Model.
abstract: Genetic ablation or pharmacologic inhibition of matrix metalloproteinase-8 (MMP8) improves survival in an adult murine sepsis model. Because developmental age influences the host inflammatory response, we hypothesized that developmental age influences the role ofMMP8in sepsis. First, we compared sepsis survival between wild type (WT, C57BL/6) andMMP8null juvenile-aged mice (12-14 days) after intraperitoneal injection of a standardized cecal slurry. Second, peritoneal lavages collected at 6 and 18 hours after cecal slurry injection were analyzed for bacterial burden, leukocyte subsets, and inflammatory cytokines. Third, juvenile WT mice were pretreated with anMMP8inhibitor prior to cecal slurry injection; analysis of their bacterial burden was compared to vehicle-injected animals. Fourth, the phagocytic capacity of WT andMMP8null peritoneal macrophages was compared. Finally, peritoneal neutrophil extracellular traps (NETs) were compared using immunofluorescent imaging and quantitative image analysis. We found that juvenileMMP8null mice had greater mortality and higher bacterial burden than WT mice. Leukocyte counts and cytokine concentrations in the peritoneal fluid were increased in theMMP8null mice, relative to the wild type mice. Peritoneal macrophages fromMMP8null mice had reduced phagocytic capacity compared to WT macrophages. There was no quantitative difference in NET formation, but fewer bacteria were adherent to NETs fromMMP8null animals. In conclusion, in contrast to septic adult mice, genetic ablation ofMMP8increased mortality following bacterial peritonitis in juvenile mice. The increase in mortality inMMP8null juvenile mice was associated with reduced bacterial clearance and reduced NET efficiency. We conclude that developmental age influences the role ofMMP8in sepsis.
authors: Division of Critical Care Medicine, Cincinnati Children's Hospital Medical Center and Cincinnati Children's Research Foundation, Cincinnati, OH.|Department of Surgery, University of Cincinnati College of Medicine, Cincinnati, OH.
authors: Sarah J
authors: SJ
authors: Atkinson
authors: Division of Critical Care Medicine, Cincinnati Children's Hospital Medical Center and Cincinnati Children's Research Foundation, Cincinnati, OH.|Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH.
authors: Brian M
authors: BM
authors: Varisco
authors: Division of Critical Care Medicine, Cincinnati Children's Hospital Medical Center and Cincinnati Children's Research Foundation, Cincinnati, OH.|Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH.
authors: Mary
authors: M
authors: Sandquist
authors: Division of Critical Care Medicine, Cincinnati Children's Hospital Medical Center and Cincinnati Children's Research Foundation, Cincinnati, OH.|Department of Surgery, University of Cincinnati College of Medicine, Cincinnati, OH.
authors: Meghan N
authors: MN
authors: Daly
authors: Division of Critical Care Medicine, Cincinnati Children's Hospital Medical Center and Cincinnati Children's Research Foundation, Cincinnati, OH.|Department of Surgery, University of Cincinnati College of Medicine, Cincinnati, OH.
authors: Lindsey
authors: L
authors: Klingbeil
authors: Department of Surgery, University of Cincinnati College of Medicine, Cincinnati, OH.|Division of Research, Department of Surgery, University of Cincinnati College of Medicine, Cincinnati, OH.
authors: Joshua W
authors: JW
authors: Kuethe
authors: Department of Surgery, University of Cincinnati College of Medicine, Cincinnati, OH.|Division of Research, Department of Surgery, University of Cincinnati College of Medicine, Cincinnati, OH.
authors: Emily F
authors: EF
authors: Midura
authors: Division of Critical Care Medicine, Cincinnati Children's Hospital Medical Center and Cincinnati Children's Research Foundation, Cincinnati, OH.
authors: Kelli
authors: K
authors: Harmon
authors: Division of Critical Care Medicine, Cincinnati Children's Hospital Medical Center and Cincinnati Children's Research Foundation, Cincinnati, OH.
authors: Amy
authors: A
authors: Opaka
authors: Division of Critical Care Medicine, Cincinnati Children's Hospital Medical Center and Cincinnati Children's Research Foundation, Cincinnati, OH.
authors: Patrick
authors: P
authors: Lahni
authors: Division of Critical Care Medicine, Cincinnati Children's Hospital Medical Center and Cincinnati Children's Research Foundation, Cincinnati, OH.
authors: Giovanna
authors: G
authors: Piraino
authors: Division of Critical Care Medicine, Cincinnati Children's Hospital Medical Center and Cincinnati Children's Research Foundation, Cincinnati, OH.
authors: Paul
authors: P
authors: Hake
authors: Division of Critical Care Medicine, Cincinnati Children's Hospital Medical Center and Cincinnati Children's Research Foundation, Cincinnati, OH.|Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH.
authors: Basilia
authors: B
authors: Zingarelli
authors: Department of Pathology and Laboratory Medicine, Cincinnati Children's Hospital Medical Center, Cincinnati, OH.
authors: Joel E
authors: JE
authors: Mortenson
authors: Department of Pediatrics, University of Florida, Gainesville, FL.
authors: James L
authors: JL
authors: Wynn
authors: Division of Critical Care Medicine, Cincinnati Children's Hospital Medical Center and Cincinnati Children's Research Foundation, Cincinnati, OH.|Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH.
authors: Hector R
authors: HR
authors: Wong
keywords: Extracellular traps; Matrix metalloproteinase 8; Sepsis; Septic shock