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A novel role for matrix metalloproteinase-8 in sepsis*

Solan, Patrick D. MD; Dunsmore, Katherine E. MS; Denenberg, Alvin G. MS; Odoms, Kelli BS; Zingarelli, Basilia MD, PhD; Wong, Hector R. MD

doi: 10.1097/CCM.0b013e318232e404
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Objectives: Matrix metalloproteinase-8 messenger RNA expression was previously found to be increased in whole blood of children with septic shock. The impact of this finding on the severity and inflammatory response to sepsis is unknown. Here, we investigate the relationship between matrix metalloproteinase-8 and disease severity in children with septic shock. We further corroborate the role of matrix metalloproteinase-8 in sepsis in a murine model.

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.

From the Departments of Surgery (PDS) and Pediatrics (KED, AGD, KO, BZ, HRW), University of Cincinnati College of Medicine, and the Division of Critical Care Medicine (KED, AGD, KO, BZ, HRW), Cincinnati Children's Hospital Medical Center and Cincinnati Children's Research Foundation, Cincinnati, OH.

* See also p. 655.

Supported, in part, by grants from the National Institutes of Health: T32 GM008478 (PDS), R01 GM067202 (BZ), RO1 GM064619 (HRW),1RC1HL100474 (HRW), and R01 GM096994 (HRW).

The authors have not disclosed any potential conflicts of interest.

For information regarding this article, E-mail: hector.wong@cchmc.org

© 2012 by the Society of Critical Care Medicine and Lippincott Williams & Wilkins