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Review
. 2009 Apr;22(2):224-39, Table of Contents.
doi: 10.1128/CMR.00047-08.

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

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Free PMC article
Review

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

Ineke Vanlaere et al. Clin Microbiol Rev. .
Free PMC article

Abstract

The mammalian immune system is optimized to cope effectively with the constant threat of pathogens. However, when the immune system overreacts, sepsis, severe sepsis, or septic shock can develop. Despite extensive research, these conditions remain the leading cause of death in intensive care units. The matrix metalloproteinases (MMPs) constitute a family of proteases that are expressed in developmental, physiological, and pathological processes and also in response to infections. Studies using MMP inhibitors and MMP knockout mice indicate that MMPs play essential roles in infection and in the host defense against infection. This review provides a brief introduction to some basic concepts of infections caused by gram-negative bacteria and reviews reports describing MMP expression and inhibition, as well as studies with MMP-deficient mice in models of infection caused by gram-negative bacteria and of septic shock. We discuss whether MMPs should be considered novel drug targets in infection and septic shock.

Figures

FIG. 1.
FIG. 1.
General definitions. Inflammation is the host's response to infection or other insults. Normally, a local inflammatory response leads to resolution of the infection or injury. However, if the inflammation becomes dysregulated, systemic activation of the innate immune system can occur. The complex clinical findings associated with this systemic activation are known as SIRS. SIRS is triggered by sterile inflammatory processes, e.g., pancreatitis, trauma, and burns. SIRS is considered to be present when more than one of the following clinical findings exists: fever, tachycardia, tachypnea, or leukocytosis. Sepsis is defined as a suspected or proven infection plus a SIRS. The infection is caused by bacteria, viruses, or fungi, and if the pathogen enters the circulation, the condition is known as bacteremia, viremia, or fungemia, respectively. SIRS evolves to severe SIRS and sepsis to severe sepsis when there is organ dysfunction (e.g., hypotension, oliguria, and thrombocytopenia). Severe sepsis is called septic shock when it is complicated by serious hypotension despite fluid resuscitation. Analogously, severe SIRS can lead to shock. At each stage of the disease, recovery is possible. However, the patient's survival chances decrease substantially in the later stages of the disease.
FIG. 2.
FIG. 2.
The major pathway and inflammatory mediators of sepsis and its related conditions. LPS and other microbial components (PAMPs) trigger PRRs, such as TLR4. However, TLR4 may also be triggered in the absence of infection, for instance by the enzymatic release of ECM proteins (alarmins). PAMPs and alarmins belong to the larger group of DAMPs. Systemic TLR4 triggering leads to overproduction of inflammatory mediators, which contribute to the massive activation and recruitment of different cell types, as well as to the activation of the coagulation pathways. Neutrophils release large amounts of enzymes (e.g., MMPs) and reactive oxygen species (ROS), and the excessive activation of coagulation factors leads to disseminated intravascular coagulation (DIC). This, together with NO-mediated cardiovascular anomalies, will inevitably cause tissue damage and subsequent organ failure and death.
FIG. 3.
FIG. 3.
MMPs influence the response to LPS or gram-negative bacteria via different mechanisms. (Top left) TLR4 regulation. TLR4 triggering by bacterial products leads to the activation of macrophages, which respond to the LPS by producing many proinflammatory mediators, such as cytokines, chemokines, and MMPs. MMPs can cleave membrane-bound CD14 into its soluble form, which can be used by cells lacking this coreceptor (A). Cleavage of the ECM generates alternative TLR4 triggers (B) and possibly relieves the receptor from the suppressive mechanism that is exerted by the ECM. (Top right) Tissue damage. Macrophages and neutrophils are attracted to the site of infection and eliminate the pathogen by releasing a massive amount of toxic products, such as reactive oxygen species, cytokines, and MMPs. Finally, pathogens are phagocytosed and tissue repair is initialized. The toxic products efficiently kill bacteria, but they can also be very harmful to the host if they are released in large amounts, as is the case in sepsis. Consequently, aberrant cleavage of the ECM by the overzealous production of MMPs leads to epithelial (A) and endothelial (B) damage. (Middle left) Cytokine activity. FasL is expressed at the cell membrane of epithelial cells in response to LPS. By shedding, MMP-7 releases the soluble form of FasL (A), which induces apoptosis after binding its receptor Fas. Activated macrophages produce many cytokines. The mature IL-1β, as well as its pro form, is secreted. MMPs can activate the pro form of this cytokine (B) but can also degrade the mature form (C). The major TNF sheddase is TACE, but MMPs also can solubilize this cytokine (D). (Middle right) Chemotaxis. Activated epithelial cells secrete MMPs and chemokines. Chemokines can be sequestered by proteoglycans of the ECM; by cleaving these proteoglycans, MMPs generate a chemokine gradient (A). Chemokines too can be directly activated (B) or inactivated (C) by MMPs. (Bottom left) Bactericidal activities. Paneth cells, which lie at the base of the crypts between the villi of the small intestine, produce antibacterial products, such as lysozyme and defensins. In the mouse, MMP-7 activates these defensins and thus plays an anti-inflammatory role (A). MMP-12, on the other hand, contains a cathelicidin-like domain with direct bactericidal activities (B).

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