Targeting Matrix Metalloproteinases in Acute Inflammatory Shock Syndromes

Zheng      Qiu; Jialiang      Hu; Philippe      E. Van den Steen; Ghislain      Opdenakker

Abstract

The integrity of the vascular wall and its intrinsic basement membrane structures ensure that plasma and the corpuscular elements of the blood remain confined to the intravascular milieu and can enter into the extravascular compartment in a well controlled fashion in cases of tissue infection or inflammation. However, sometimes inflammatory stimuli act on blood leukocytes and on endothelial cells from within the blood vessels and in an overwhelming way, leading to inflammatory shock syndromes. These severe conditions with high mortality rates are characterized by intravascular neutrophil degranulation, permeability changes of endothelia and disintegration of basement membranes and lead to almost uncontrollable edema, coagulation changes and multi-organ failure. Matrix metalloproteinases (MMPs) have been functionally linked with septic and endotoxin shock, with cytokine release syndromes and with acute lung injury (ALI) and acute respiratory distress syndrome (ARDS). Here we review a number of association studies, compare inflammatory shock data from gene knockout studies in mice and provide some insights from recent investigations with inhibitors of MMPs. This evaluation strengthens the expectation that MMP inhibitors, in particular those blocking neutrophil proteases, may become useful in the early phase of acute inflammatory shock syndromes.

Keywords: Inflammation, lipopolysaccharide, matrix metalloproteinase, MMP inhibitor, neutrophil, sepsis, Acute Inflammatory Shock, gene knockout, extracellular matrix, intravascular milieu