Laying Siege to the Castle: The Role of Sepsis Related Cytokines and Inflammation in Bringing Down the Barriers

Abstract

Abstract The endothelium plays a critical role in the progression from sepsis to organ failure. The endothelium lines all blood vessels and organs in the body. As such, it provides a protective barrier against pathologic micro-organisms. The endothelium is also responsible for dynamically regulating the passage of small molecules, fluid, and cells between the bloodstream and tissues. In sepsis, many factors play a role in compromising the endothelium. Dysfunctional endothelium often results in development of capillary leak, tissue hypoperfusion, hypoxia, edema, and shock. This study evaluates the individual contributions of sepsis-related immunomodulatory cytokines as well as a potential synergistic effect of cytokine combinations on vascular endothelial permeability. The Electric Cell-substrate Impedance Sensor was employed to evaluate the barrier function (Rb) and cell membrane capacitance (CMC) of endothelial cell monolayers treated with an array of cytokines including TNF-α IFN-γ, TGF-β, IL1-β, IL-6, IL-8, IL-10, and IL-12. The ECIS results revealed significant differences in the Rb of cell monolayers exposed to sepsis related cytokines compared to cytokine-free control samples. Components of intercellular tight junctions and associated cell adhesion molecules also revealed differences in the endothelial cell monolayer under immunofluorescence microscopy. Thus, cytokines as individual entities or in combinations that may be produced during episodes of sepsis significantly alter the endothelial morphology and permeability.