A novel role for matrix metalloproteinase-8 in sepsis.
OBJECTIVE
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.


METHODS
Retrospective observational clinical study and randomized controlled laboratory experiments.


METHODS
Pediatric intensive care units and an animal research facility at an academic children's hospital.


METHODS
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.


METHODS
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.


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.
Department of Surgery, University of Cincinnati College of Medicine, Cincinnati Children's Hospital Medical Center and Cincinnati Children's Research Foundation, Cincinnati, OH, USA.
Patrick D
PD
Solan
Katherine E
KE
Dunsmore
Alvin G
AG
Denenberg
Kelli
K
Odoms
Basilia
B
Zingarelli
Hector R
HR
Wong
D000818:Animals; D002478:Cells, Cultured; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D004195:Disease Models, Animal; D018450:Disease Progression; D005260:Female; D006801:Humans; D018836:Inflammation Mediators / Q000097:blood* / Q000378:metabolism; D015278:Intensive Care Units, Pediatric; D007963:Leukocytes, Mononuclear / Q000378:metabolism; D017737:Macrophages, Peritoneal / Q000378:metabolism; D008297:Male; D020784:Matrix Metalloproteinase 8 / Q000097:blood* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009102:Multiple Organ Failure / Q000097:blood* / Q000401:mortality; D011379:Prognosis; D012189:Retrospective Studies; D018805:Sepsis / Q000097:blood / Q000188:drug therapy / Q000503:physiopathology; D012720:Severity of Illness Index; D012772:Shock, Septic / Q000097:blood* / Q000401:mortality* / Q000503:physiopathology; D016019:Survival Analysis; D016896:Treatment Outcome
D018836:Inflammation Mediators; D020784:Matrix Metalloproteinase 8