Intestine-Derived Matrix Metalloproteinase-8 Is a Critical Mediator of Polymicrobial Peritonitis.
OBJECTIVE
Inhibition of matrix metalloproteinase-8 improves survival following cecal ligation and puncture in mice, making it a potential therapeutic target. In the current study, we expand our understanding of the role of matrix metalloproteinase-8 in sepsis by using an adoptive transfer approach and alternative sepsis models.


METHODS
We used three different sepsis models: cecal ligation and puncture, cecal slurry, and intestinal implantation. In our first model, adoptive transfer experiments were followed by cecal ligation and puncture to test the hypothesis that matrix metalloproteinase-8-containing myeloid cells are a critical factor in sepsis following cecal ligation and puncture. Our second model, cecal slurry, used intraperitoneal injections of cecal contents to induce polymicrobial peritonitis without tissue compromise in the recipient. Our third model, intestinal implantation, involved ligating and puncturing a cecum from a donor, and then removing the cecum and placing it into the recipient's peritoneal cavity. Clinically, blood samples were drawn from pediatric patients within 24 hours of meeting criteria for septic shock.


METHODS
Basic science laboratory.


METHODS
Wild type and genetically modified mice.


METHODS
Experimental models of sepsis.


RESULTS
In our adoptive transfer experiments, matrix metalloproteinase-8 null mice receiving wild-type marrow had a survival advantage when compared with wild-type mice receiving matrix metalloproteinase-8 null marrow, suggesting that matrix metalloproteinase-8-containing myeloid cells are not a critical factor in sepsis following cecal ligation and puncture. In our cecal slurry model, no survival advantage was seen among matrix metalloproteinase-8 null mice. Our third model, intestinal implantation, found that mice receiving matrix metalloproteinase-8 null intestine had a survival advantage when compared with mice receiving wild-type intestine, regardless of recipient genotype. Clinically, median matrix metalloproteinase-8 serum concentrations were higher in patients with sepsis and primary intestinal pathology than in septic patients without primary intestinal pathology.


CONCLUSIONS
Intestine-derived matrix metalloproteinase-8 is a critical component of septic peritonitis secondary to intestinal compromise.
1Division of Critical Care Medicine, Cincinnati Children's Hospital Medical Center and Cincinnati Children's Research Foundation, Cincinnati, OH. 2Department of Surgery, University of Cincinnati College of Medicine, Cincinnati, OH. 3Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH.
Sarah J
SJ
Atkinson
Meghan
M
Nolan
Lindsey
L
Klingbeil
Kelli
K
Harmon
Patrick
P
Lahni
Basilia
B
Zingarelli
Hector R
HR
Wong
D000818:Animals; D002432:Cecum; D004195:Disease Models, Animal; D007413:Intestinal Mucosa / Q000378:metabolism; D008026:Ligation; D008297:Male; D020784:Matrix Metalloproteinase 8 / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D010538:Peritonitis / Q000209:etiology* / Q000378:metabolism / Q000382:microbiology; D011677:Punctures; D018805:Sepsis / Q000209:etiology / Q000378:metabolism; D012772:Shock, Septic / Q000628:therapy
D020784:Matrix Metalloproteinase 8