Collagenase 2/Matrix Metalloproteinase 8 in Critically Ill Patients With Secondary Peritonitis

Abstract

Secondary peritonitis is an important indication for surgical intensive care admissions, and it is associated with high morbidity and mortality. Collagenase 2/matrix metalloproteinase (MMP) 8 is a tissue matrix-degrading enzyme that is released from leukocytes upon inflammatory stimuli and may thus contribute to peritonitis-associated organ damage. We studied the levels and activity of MMP-8 in the peritoneal fluid of 15 critically ill patients with secondary peritonitis. The MMP-8 levels were measured from the patients' peritoneal fluid, serum, and urine, and from the serum and urine of 10 healthy controls by immunofluorometric assay. Median MMP-8 level in peritoneal fluid supernatant was 1,317 microg/L (interquartile range [IQR]) (1,254-1,359 microg/L) being significantly higher than in the sera of the patients (P=0.008). Molecular forms and isoform distribution of MMP-8, MMP-1, and MMP-13 in peritoneal fluid, assessed by Western immunoblotting, revealed that the neutrophil-type MMP-8 was the major collagenase species in peritoneal fluid, and it was partially in an activated form. Catalytically competent, active MMP-8 produced the characteristic cleavage products from intact human type I collagen. The serum levels of MMP-8 were higher in the patients, 49 microg/L (IQR, 23-214 microg/L), than in the controls, 11 microg/L (IQR, 8-24 microg/L) (P<0.01). The MMP-8 levels in the urine were higher in the patients, 0.27 microg/L (IQR, 0.04-1.89 microg/L), than in the controls, 0.03 microg/L (IQR, 0.0-0.05 microg/L) (P=0.013). Our data demonstrate for the first time that MMP-8 levels are remarkably elevated and in an active and catalytically competent form in the peritoneal fluid samples of patients with secondary peritonitis.

Matrix Metalloproteinases as Drug Targets in Infections Caused by Gram-Negative Bacteria and in Septic Shock

“…The researchers concluded that TIMP-1 might serve as a useful laboratory marker for predicting the clinical outcome for patients with severe sepsis (44). High levels of neutrophil MMP-8 also were found in the peritoneal fluid of critically ill patients with secondary peritonitis (43). By analyzing the expression of some MMP and TIMP genes in livers, kidneys, spleens, and brains of mice at various time points after LPS injection, Pagenstecher's group demonstrated organ-specific and time-specific upregulation of several MMP genes and the TIMP-1 gene (113).…”

Targeting matrix metalloproteinases with intravenous doxycycline in severe sepsis – A randomised placebo-controlled pilot trial

“…Use of a higher dose regimen may increase the risk of adverse drug effects and antimicrobial resistance. The IFMA method for measuring MMP-8 concentration in serum, although not being a commercially available product, has been successfully used in dental-and sepsis studies [17,20,22]. In a recent study conducted on burn patients using IFMA the healthy controls showed a median plasma MMP-8 concentration of 22.73 (1.66-59.02) ng/ml, whereas in the critically ill patients median MMP-8 was 92.49 (59.62-159.0) [36].…”

“…The sample size was calculated based on a previous study on admission MMP-8 -levels in ICU-treated peritonitis patients [20]. Our study was designed to have an 80% power to detect a 50% change in the plasma levels of MMP-8 of doxycycline-treated patients, with a p-value of <0.05 to designate statistical significance.…”

“…The activity of MMPs is strictly regulated by naturally occurring tissue inhibitors of MMPs (TIMPs), ␣ 2 -macroglobulin, ␣ 1 -antiprotease, tissue factor pathway inhibitor-2 and numerous other proteins [11,15,16]. Compared to healthy controls, elevated levels of MMP-8, -9 and TIMP-1 in urine, serum, skin blister-and peritoneal fluid have been found in critically ill patients [17][18][19][20] and higher concentrations of MMP-8 and TIMP-1 have been associated with increased ICU mortality in severely septic patients [18]. In addition to TIMP-1 and other endogenously produced molecules, tetracycline antibiotics act as MMP inhibitors.…”

Jack of all trades: Pleiotropy and the application of chemically modified tetracycline-3 in sepsis and the acute respiratory distress syndrome (ARDS)

“…Two recent studies have demonstrated that MMPs are present in the 3rd space fluids of human patients; peritoneal ascites fluid [86] and interstitial fluid collected from cutaneous blisters [87]. Both studies demonstrated that concentration and activity of MMPs in third space fluids correlate directly with the severity of sepsis as well as patient survival.…”