The role of tissue inhibitors of metalloproteinases in microvascular endothelial cell barrier dysfunction during sepsis

Abstract

Sepsis is defined as a dysregulated host response to an infection leading to organ dysfunction and failure. During sepsis circulating proinflammatory mediators, such as cyto- kines and bacterial products, as well as activated inflammatory cells cause dysfunction of the microvasculature, specifically the microvascular endothelial cells (MVECs), leading to loss of MVEC barrier function and increased permeability. While multiple mechanisms are known to initiate septic MVEC barrier dysfunction, our understanding of mechanisms that promote MVEC barrier stability, especially under septic conditions, is limited. Formation and mainte- nance of the MVEC barrier requires stability of MVEC cell–cell junctions, which control the passage of fluid and macromolecules across the endothelium, as well as the extracellular matrix (ECM), which provides critical signaling cues to MVECs through MVEC–ECM interactions. Importantly, disruption of either MVEC intercellular junctions or of the ECM surrounding MVECs can lead to barrier dysfunction. Metalloproteinases, including the matrix metallopro- teinases (MMPs) as well as the closely related a disintegrin and metalloproteinases (ADAMs) and ADAMs with thrombospondin repeats (ADAMTSs), are a family of enzymes capable of proteolytically processing the ECM as well as other proteins associated with MVECs, including cell–cell junctional proteins and leukocyte adhesion receptors. Collectively, this suggests that metalloproteinases may be critical mediators of MVEC barrier function. While metallopro- teinases are regulated at multiple levels, the tissue inhibitors of metalloproteinases (TIMPs) are known to be the primary inhibitors of metalloproteinase activity. Moreover, in addition to inhibiting metalloproteinases, TIMPs have also been found to have metalloproteinase- independent functions. Specifically, TIMPs have been found to regulate vascular endothelial growth factor signaling, focal adhesion kinase-dependent cell survival, and leukocyte–MVEC interaction. Thus, TIMPs have the potential to promote MVEC barrier stability and potentially restrict septic MVEC barrier dysfunction through both metalloproteinase-dependent and metalloproteinase-independent mechanisms.