Serum MMP-8, -9 and TIMP-1 in sepsis: High serum levels of MMP-8 and TIMP-1 are associated with fatal outcome in a multicentre, prospective cohort study. Hypothetical impact of tetracyclines

doi:10.1016/j.phrs.2011.06.019

Pharmacological Research

Volume 64, Issue 6, December 2011, Pages 590-594

https://doi.org/10.1016/j.phrs.2011.06.019 Get rights and content

Abstract

Recent evidence suggests that matrix metalloproteinases (MMPs) and their endogenous inhibitors are involved in the pathogenesis of sepsis. We studied serum levels of MMP-8, MMP-9 and TIMP-1 (tissue inhibitor of matrix metalloproteinase-1) in a multicentre, prospective cohort study of patients with sepsis treated in Intensive Care Units (ICUs). We analyzed serum samples taken on ICU admission from 248 critically ill sepsis patients. MMP-8, -9 and TIMP-1 serum levels were analyzed by enzyme-linked immunosorbent assays. Serum MMP-8, MMP-9 and TIMP-1 levels were significantly higher in patients with severe sepsis than in healthy controls. Serum MMP-8 levels among non-survivors (n = 33) were significantly (p = 0.006) higher than among survivors (n = 215). Serum TIMP-1 but not MMP-9 levels were significantly higher among non-survivors than survivors (p < 0.0001, p = 0.079, respectively). Systemic MMP-8 is upregulated in sepsis suggesting that MMP-8 may contribute to the host response during sepsis. High serum MMP-8 and TIMP-1 levels at ICU admission were seen among patients with fatal outcome. With this background, clinical studies examining the ability of MMP-inhibitors (such as the non-antimicrobial properties of tetracyclines) to diminish the MMP-mediated inflammatory response are needed to develop novel therapies in order to improve the outcome of sepsis.

Introduction

Septic shock remains a leading cause of death in Intensive Care Units (ICUs) [1]. Despite continuing research, the pathogenesis of tissue injury secondary to sepsis remains unclear [1], [2], [3]. Further evaluation of the pathophysiological mechanisms of sepsis is necessary to develop effective treatment strategies. The mammalian immune system is optimized to cope effectively with the constant threat of pathogens. However, when the immune system overreacts, severe sepsis or septic shock may develop [4]. Recent evidence suggests that matrix metalloproteinases (MMPs) and their physiological inhibitors are involved in the pathogenesis of sepsis and septic shock [2], [4].

Matrix metalloproteinases are a group of genetically distinct but structurally related proteolytic enzymes including collagenases (MMP-1, -8, -13), gelatinases (MMP-2, -9), stromelysins (MMP-3, -10, -11, -19), matrilysins (MMP-7, -26), membrane-type MMPs (MT-MMPs) (MMP-14, -15, -16, -17, -24, -25) and other MMPs [5]. MMPs can collectively degrade almost all extracellular matrix proteins [5] and, additionally, process non-matrix bioactive substances such as growth factors, chemokines, cytokines and apoptotic signaling factors. MMPs modulate immunological responses so that they can be either tissue destructive or defensive [5], [6], [7], [8], [9], [10]. Furthermore, MMP-8 can modify blood pressure by several mechanisms [11], [12]. The expression and activity of MMPs are normally low but increase in many pathophysiological conditions such as infection [5], [13].

Experimental studies using either MMP inhibitors such as doxycycline or knock-out models have shown that MMPs are harmful in sepsis [2], [14], [15], [16], [17], [18], [19]. MMP-inhibitor doxycycline has been shown to exert a protective role against the development of vascular hyporeactivity in endotoxemic animal model studies [2], [12]. However, human data are limited. Hoffmann and co-workers [20] have demonstrated elevated serum MMP-9, TIMP-1 and TIMP-2 levels in patients with severe sepsis. In addition, TIMP-1 may predict mortality [21]. However, only two relatively small studies concerning the role of MMP-8 in sepsis exist. Our previous single-center study showed increased MMP-8 levels in serum and peritoneal fluid in critically ill secondary peritonitis patients [22] and a recent small single-center study showed upregulation of MMP-8 in critically ill sepsis patients [23]. Accordingly, we now studied serum MMP-8, MMP-9 and TIMP-1 levels in a larger multicentre cohort of critically ill patients with severe sepsis and septic shock.

Section snippets

Methodological background

This study is a part of the FINNSEPSIS study, a prospective cohort study of the incidence and outcome of severe sepsis and septic shock in 24 Finnish ICUs [1]. Briefly, for inclusion in the study cohort, consecutive ICU admissions during a 4-month period were screened for presence of severe sepsis and septic shock as defined by The American College of Chest Physicians criteria [24]. The study protocol was approved in the local Ethical Committee. Patients or their next of kin, as well as healthy

Results

The clinical characteristics of the study patients are summarized in Table 1. Characteristics of the patients in this sub-study (n = 248) did not differ significantly from the rest of the FINNSEPSIS cohort (n = 222) without a consent to donate blood samples (Table 1).

On ICU admission the median (range) serum MMP-8 (ng/ml) levels for severe sepsis or septic shock patients (n = 248) were significantly higher than those of healthy controls (n = 10) [71.70 (0–1651) vs. 2.320 (0–16.33) p < 0.0001] (Fig. 1).

Discussion

In this large multicentre cohort study we found that serum MMP-8 levels were significantly increased on ICU admission in patients with severe sepsis or septic shock. In addition high serum MMP-8 levels on admission to ICU were associated with fatal outcome. This strengthens the view that MMP-8 is upregulated in severe sepsis and septic shock and may thus contribute to inflammatory response [22].

MMP-8 has been shown to be a central mediator in acute inflammation in MMP-8 deficient murine models,

Concluding remarks

Our findings showing the upregulation of MMP-8 in patients with severe sepsis or septic shock suggest that MMP-8 contributes to the inflammatory response in sepsis. High serum MMP-8 levels on admission to ICU are associated with fatal outcome. These observations justify a randomized clinical trial to scrutinize the effect of doxycycline on outcome of severe sepsis patients.

Acknowledgements

The following centers and principal investigators contributed patients and blood samples to this sub-study of the FINNSEPSIS study: Dr. Vesa Lund, Satakunta Central Hospital, Dr. Markku Suvela, Savonlinna Central Hospital, Dr. Raili Laru-Sompa, Central Finland Central Hospital, Dr. Heikki Laine, South Savo Central Hospital, Dr. Sari Karlsson, North Karelia Central Hospital, Dr. Kari Saarinen, Seinäjoki Central Hospital, Dr. Seppo Hovilehto, South Karelia Central Hospital, Dr. Pekka Loisa,

References (36)

S. Karlsson et al.
Incidence, treatment and outcome of severe sepsis in ICU-treated adults in Finland, the Finnsepsis study
Intensive Care Med
(2007)
J. Cena et al.
Endothelial dependence of matrix metalloproteinase-mediated vascular hyporeactivity caused by lipopolysaccharide
Eur J Pharmacol
(2008)
E.K. Robinson et al.
Effect of NOS inhibition on rat gastric matrix metalloproteinase production during endotoxemia
Shock
(2006)
I. Vanlaere et al.
Matrix metalloproteinases as drug targets in infections caused by gram-negative bacteria and in septic shock
Clin Microbiol Rev
(2009)
T. Sorsa et al.
Matrix metalloproteinases: contribution to pathogenesis, diagnosis and treatment of periodontal inflammation
Ann Med
(2006)
C.A. Owen et al.
Membrane-bound matrix metalloproteinase-8 on activated polymorphonuclear cells is a potent, tissue inhibitor of metalloproteinase-resistant collagenase and serpinase
J Immunol
(2004)
M.M. Gueders et al.
Matrix metalloproteinase-8 deficiency promotes granulocytic allergen-induced airway inflammation
J Immunol
(2005)
J.T. Korpi et al.
Collagenase-2 (matrix metalloproteinase-8) plays a protective role in tongue cancer
Br J Cancer
(2008)
H. Kuula et al.
Local and systemic responses in matrix metalloproteinase 8-deficient mice during Porphyromonas gingivalis-induced periodontitis
Infect Immun
(2009)
P. Piirilä et al.
Matrix metalloproteinases-7, -8, -9 and TIMP-1 in the follow-up of diisocyanate-induced asthma
Allergy
(2009)

G.A. McQuibban et al.

Inflammation dampened by gelatinase A cleavage of monocyte chemoattractant protein-3

Science

(2000)

J.J. Cena et al.

Inhibition of matrix metalloproteinase activity in vivo protects against vascular hyporeactivity in endotoxemia

Am J Physiol Heart Circ Physiol

(2010)

A. Lauhio et al.

Placebo-controlled study of the effects of three-month lymecycline treatment on serum matrix metalloproteinases in reactive arthritis

Ann NY Acad Sci

(1994)

B. Dubois et al.

Gelatinase B deficiency protects against endotoxin shock

Eur J Immunol

(2002)

S.R. Maitra et al.

Inhibition of matrix metalloproteinases by chemically modified tetracyclines in sepsis

Shock

(2003)

J. Hu et al.

Targeting neutrophil collagenase/matrix metalloproteinase-8 and gelatinase B/matrix metalloproteinase-9 with a peptidomimetic inhibitor protects against endotoxin shock

Biochem Pharmacol

(2005)

J. Hu et al.

Inhibition of lethal endotoxin shock with an l-pyridylalanine containing metalloproteinase inhibitor selected by high-throughput screening of a new peptide library

Comb Chem High Throughput Screen

(2006)

J. Steinberg et al.

Chemically modified tetracycline prevents the development of septic shock and acute respiratory distress syndrome in a clinically applicable porcine model

Shock

(2005)

Cited by (89)

Coagulation factor protein abundance in the pre-septic state predicts coagulopathic activities that arise during late-stage murine sepsis
2022, eBioMedicine
Although sepsis accounts for 1 in 5 deaths globally, few molecular therapies exist for this condition. The development of effective biomarkers and treatments for sepsis requires a more complete understanding of host responses and pathogenic mechanisms at early stages of disease to minimize host-driven pathology.
An alternative to the current symptom-based approach used to diagnose sepsis is a precise assessment of blood proteomic changes during the onset and progression of Salmonella Typhimurium (ST) murine sepsis.
A distinct pattern of coagulation factor protein abundance was identified in the pre-septic state– prior to overt disease symptoms or bacteremia– that was predictive of the dysregulation of fibrinolytic and anti-coagulant activities and resultant consumptive coagulopathy during ST murine sepsis. Moreover, the changes in protein abundance observed generally have the same directionality (increased or decreased abundance) reported for human sepsis. Significant overlap of ST coagulopathic activities was observed in Gram-negative Escherichia coli– but not in Gram-positive staphylococcal or pneumococcal murine sepsis models. Treatment with matrix metalloprotease inhibitors prevented aberrant inflammatory and coagulopathic activities post-ST infection and increased survival. Antibiotic treatment regimens initiated after specific changes arise in the plasma proteome post-ST infection were predictive of an increase in disease relapse and death after cessation of antibiotic treatment.
Altered blood proteomics provides a platform to develop rapid and easy-to-perform tests to predict sepsis for early intervention via biomarker incorporation into existing blood tests prompted by patient presentation with general malaise, and to stratify Gram-negative and Gram-positive infections for appropriate treatment. Antibiotics are less effective in microbial clearance when initiated after the onset of altered blood proteomics as evidenced by increased disease relapse and death after termination of antibiotic therapy. Treatment failure is potentially due to altered bacterial / host-responses and associated increased host-driven pathology, providing insight into why delays in antibiotic administration in human sepsis are associated with increased risk for death. Delayed treatment may thus require prolonged therapy for microbial clearance despite the prevailing notion of antibiotic de-escalation and shortened courses of antibiotics to improve drug stewardship.
National Institutes of Health, U.S. Army.
Heparanase as active player in endothelial glycocalyx remodeling
2022, Matrix Biology Plus
Citation Excerpt :
HPSE also has non-enzymatic activity on endothelial cells through ERK activation and intracellular regulation of SDC-1 expression [86]. HPSE may contribute to MMP-9 and VEGF upregulation and trauma [87,88,89]. It has been established that an altered profile of circulating exosome levels is associated with the onset of critical illness [90,91] and HPSE may sustain secretion of exosomes by activating the syndecan–syntenin–ALIX complex that engages the endosomal-sorting complex required for transport (ESCRT) [92,93].
The surface of all animal cells is coated with a layer of carbohydrates linked in various ways to the outer side of the plasma membrane. These carbohydrates are mainly bound to proteins in the form of glycoproteins and proteoglycans and together with the glycolipids constitute the so-called glycocalyx. In particular, the endothelial glycocalyx that covers the luminal layer of the endothelium is composed of glycosaminoglycans (heparan sulphate -HS and hyaluronic acid -HA), proteoglycans (syndecans and glypicans) and adsorbed plasma proteins. Thanks to its ability to absorb water, this structure contributes to making the surface of the vessels slippery but at the same time acts by modulating the mechano-transduction of the vessels, the vascular permeability and the adhesion of leukocytes in thus regulating several physiological and pathological events. Among the various enzymes involved in the degradation of the glycocalyx, heparanase (HPSE) has been shown to be particularly involved. This enzyme is responsible for the cutting of heparan sulfate (HS) chains at the level of the proteoglycans of the endothelial glycocalyx whose dysfunction appears to have a role in organ fibrosis, sepsis and viral infection.
In this mini-review, we describe the mechanisms by which HPSE contributes to glycocalyx remodeling and then examine the role of glycocalyx degradation in the development of pathological conditions and pharmacological strategies to preserve glycocalyx during disease pathogenesis.
Activated matrix metalloproteinase 8 in serum predicts severity of acute pancreatitis
2021, Pancreatology
Severe acute pancreatitis (SAP) has high morbidity and mortality but there are no widely accepted predictive biomarkers in clinical use. Matrix metalloproteinases (MMPs) are active in tissue destruction and inflammatory responses. We studied whether serum levels of activated MMP-8 (aMMP-8), MMP-9 and their regulators tissue inhibitor of matrix metalloproteinases (TIMP)-1, myeloperoxidase (MPO) and human neutrophil elastase (HNE) could predict the development of SAP.
The study comprised 214 AP patients (revised Atlanta classification: 142 mild, MAP; 54 moderately severe, MSAP; 18 SAP) referred to Helsinki University Hospital. A venous blood sample was taken within 72 h from the onset of symptoms. Serum levels of aMMP-8 were determined using immunofluorometric assay, and those of MMP-9, TIMP-1, MPO and HNE using enzyme-linked immunosorbent assay. AP groups were compared using Jonckheere-Terpstra test and predictive value for SAP was analyzed using receiver operating characteristics (ROC) analysis.
Serum aMMP-8 levels were higher in SAP (median 657 ng/ml, interquartile range 542–738 ng/ml) compared to MSAP (358 ng/ml, 175–564 ng/ml; p < 0.001) and MAP (231 ng/ml, 128–507 ng/ml; p < 0.001). Similar trend was seen with TIMP-1 and MPO. In ROC analysis aMMP-8, MPO and TIMP-1 emerged as potential markers for the development of SAP (areas under ROC curves 0.83, 0.71 and 0.69, respectively).
Serum aMMP-8 measured early in the course of AP (within 72 h of symptom onset) predicted the development of SAP.
Berberine prevents primary peritoneal adhesion and adhesion reformation by directly inhibiting TIMP-1
2020, Acta Pharmaceutica Sinica B
Peritoneal adhesions are fibrous tissues that tether organs to one another or to the peritoneal wall and represent the major cause of postsurgical morbidity. Enterolysis at repeat surgeries induces adhesion reformation that is more difficult to prevent than primary adhesion. Here we studied the preventive effects of different approaches of berberine treatment for primary adhesion, and its effects on adhesion reformation compared to Interceed. We found the primary adhesion was remarkably prevented by berberine through intraperitoneal injection 30 min before abrasive surgery (pre-berberine) or direct addition into injured cecum immediately after the surgery (inter-berberine). Rats with adhesion reformation had a more deteriorative collagen accumulation and tissue injury in abrasive sites than rats with primary adhesion. The dysregulated TIMP-1/MMP balance was observed in patients after surgery, as well as adhesion tissues from primary adhesion or adhesion reformation rats. Inter-berberine treatment had a better effect for adhesion reformation prevention than Interceed. Berberine promoted the activation of MMP-3 and MMP-8 by directly blocking TIMP-1 activation core, which was reversed by TIMP-1 overexpression in fibroblasts. In conclusion, this study suggests berberine as a reasonable approach for preventing primary adhesion formation and adhesion reformation.
Applicability of an active matrix metalloproteinase-8 point-of-care test in an oral and maxillofacial surgery clinic: a pilot study
2024, Odontology
Crosstalk between septic shock and venous thromboembolism: a bioinformatics and immunoassay analysis
2023, Frontiers in Cellular and Infection Microbiology

View all citing articles on Scopus

View full text

Serum MMP-8, -9 and TIMP-1 in sepsis: High serum levels of MMP-8 and TIMP-1 are associated with fatal outcome in a multicentre, prospective cohort study. Hypothetical impact of tetracyclines

Abstract

Introduction

Section snippets

Methodological background

Results

Discussion

Concluding remarks

Acknowledgements

Incidence, treatment and outcome of severe sepsis in ICU-treated adults in Finland, the Finnsepsis study

Intensive Care Med

Endothelial dependence of matrix metalloproteinase-mediated vascular hyporeactivity caused by lipopolysaccharide

Eur J Pharmacol

Effect of NOS inhibition on rat gastric matrix metalloproteinase production during endotoxemia

Shock

Matrix metalloproteinases as drug targets in infections caused by gram-negative bacteria and in septic shock

Clin Microbiol Rev

Matrix metalloproteinases: contribution to pathogenesis, diagnosis and treatment of periodontal inflammation

Ann Med

Membrane-bound matrix metalloproteinase-8 on activated polymorphonuclear cells is a potent, tissue inhibitor of metalloproteinase-resistant collagenase and serpinase

J Immunol

Matrix metalloproteinase-8 deficiency promotes granulocytic allergen-induced airway inflammation

J Immunol

Collagenase-2 (matrix metalloproteinase-8) plays a protective role in tongue cancer

Br J Cancer

Local and systemic responses in matrix metalloproteinase 8-deficient mice during Porphyromonas gingivalis-induced periodontitis

Infect Immun

Matrix metalloproteinases-7, -8, -9 and TIMP-1 in the follow-up of diisocyanate-induced asthma

Allergy

Inflammation dampened by gelatinase A cleavage of monocyte chemoattractant protein-3

Science

Inhibition of matrix metalloproteinase activity in vivo protects against vascular hyporeactivity in endotoxemia

Am J Physiol Heart Circ Physiol

Placebo-controlled study of the effects of three-month lymecycline treatment on serum matrix metalloproteinases in reactive arthritis

Ann NY Acad Sci

Gelatinase B deficiency protects against endotoxin shock

Eur J Immunol

Inhibition of matrix metalloproteinases by chemically modified tetracyclines in sepsis

Shock

Targeting neutrophil collagenase/matrix metalloproteinase-8 and gelatinase B/matrix metalloproteinase-9 with a peptidomimetic inhibitor protects against endotoxin shock

Biochem Pharmacol

Inhibition of lethal endotoxin shock with an l-pyridylalanine containing metalloproteinase inhibitor selected by high-throughput screening of a new peptide library

Comb Chem High Throughput Screen

Chemically modified tetracycline prevents the development of septic shock and acute respiratory distress syndrome in a clinically applicable porcine model

Shock