Design: Retrospective observational clinical study and randomized controlled laboratory experiments.
Setting: Pediatric intensive care units and an animal research facility at an academic children’s hospital.
Patients and Subjects: Patients age ≤10 yrs admitted to the intensive care unit with a diagnosis of septic shock. For laboratory studies, we utilized male mice deficient for matrix metalloproteinase-8 and male wild-type C57BL/6J mice.
Interventions: Blood from children with septic shock was analyzed for matrix metalloproteinase-8 messenger RNA expression and matrix metalloproteinase-8 activity, and correlated with disease severity based on mortality and degree of organ failure. A murine model of sepsis was used to explore the effect of genetic and pharmacologic inhibition of matrix metalloproteinase-8 on the inflammatory response to sepsis. Finally, activation of nuclear factor-κB was assessed both in vitro and in vivo.
Measurements and Main Results: Increased matrix metalloproteinase-8 mRNA expression and activity in septic shock correlates with decreased survival and increased organ failure in pediatric patients. Genetic and pharmacologic inhibition of matrix metalloproteinase-8 leads to improved survival and a blunted inflammatory profile in a murine model of sepsis. We also identify matrix metalloproteinase-8 as a direct in vitro activator of the proinflammatory transcription factor, nuclear factor-κB.
Conclusions: Matrix metalloproteinase-8 is a novel modulator of inflammation during sepsis and a potential therapeutic target.
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