Differential release of matrix metalloproteinase-9 and nitric oxide following infusion of endotoxin to human volunteers.
BACKGROUND
Roughly 400.000 cases of sepsis occur every year in the United States only and this is associated with a very high mortality. Bacterial lipopolysaccharide (LPS) triggers systemic inflammatory reactions in sepsis. However, down-stream cellular cascade initiated by LPS is still being elucidated. Nitric oxide (NO) and matrix metalloproteinases-2 and -9 (MMP-2 and MMP-9) are known to be induced by LPS. We have investigated the release of NO, MMP-2 and MMP-9 following infusion of LPS to volunteers.


METHODS
IPS (2 ng kg-1) was infused to 10 healthy volunteers. Before the experiments were started the subjects had an intravenous catheters placed. An electrocardiogram was also placed and monitored constantly. Body temperature was measured by ear thermometer every 10 min Venous blood was collected and cell-free plasma assayed for the presence of MMP-2 and MMP-9 using zymography and NO using HPLC assay for NO metabolites, nitrite and nitrate.


RESULTS
The administration of LPS resulted in increased body temperature and tachycardia. Time-dependent release of MMP-9(30 fold increase from the baseline) peaking at 2 h following infusion of LPS was observed. LPS did not significantly modify the activity of MMP-2 (P > 0.05). Infusion of LPS did not significantly change the levels of nitrite and nitrate (from 60 +/- 11 to 67 +/- 10 micro m, P > 0.05).


CONCLUSIONS
The release of MMP-9, but not MMP-2 or NO, is a sensitive index of endotoxaemia in humans. MMP-9 release may contribute to the pathogenesis of sepsis via its pro-inflammatory effects on the vasculature.
Albert
J
J
Departments of Surgical Sciences, Section of Anaesthesiology and Intensive Care, Karolinska Hospital, Stockholm, Sweden.
Radomski
A
A
Soop
A
A
Sollevi
A
A
Frostell
C
C
Radomski
M W
MW
D000328:Adult; D001831:Body Temperature; D019446:Endotoxemia / Q000378:metabolism; D004731:Endotoxins / Q000494:pharmacology*; D006339:Heart Rate; D006801:Humans; D007262:Infusions, Intravenous; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism*; D009569:Nitric Oxide / Q000378:metabolism*
D004731:Endotoxins; D008070:Lipopolysaccharides; D009569:Nitric Oxide; C044101:endotoxin, Escherichia coli; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9