Glycocalyx in Endotoxemia and Sepsis

Abstract

Along with the recognition of a crucial role played by endothelial dysfunction secondarily igniting cardiovascular, pulmonary, and renal complications, investigational focus has extended toward endothelial glycocalyx. This delicate coating of cells, including the vascular endothelium, regulates permeability, leukocyte traffic, nitric oxide production, and coagulation, and harbors diverse growth and survival factors. In this brief overview, we discuss the metabolic signatures of sepsis as they relate to the loss of glycocalyx integrity and highlight the contribution of several proteases, heparanase, and hyaluronidase to the shedding of glycocalyx. Clinical manifestations of glycocalyx degradation in unraveling acute respiratory distress syndrome and the cardiovascular, microcirculatory, and renal complications of sepsis are concisely presented. Finally, we list therapeutic strategies for preventing the degradation of, and for restoration of, the glycocalyx.

Figure 1

Mechanisms of glycocalyx degradation, pathogenic role of liberated fragments of glycocalyx and pathophysiological consequences of the loss of endothelial glycocalyx. The pathways of enzymatic degradation of components of glycocalyx are presented in the central gray boxed areas. Pathogenic features of released fragments of proteoglycan core proteins, short heparan chains, and low–molecular-weight hyaluronic acid (HA) are depicted as yellow boxed areas. The consequences of endothelial glycocalyx degradation are summarized in the green boxed area. ADAM, a disintegrin and metalloproteinase; DAMP, danger-associated molecular patterns; GPI, glycosylphosphatidylinositol; HS, heparan sulfate; MMP, matrix metalloproteinase; PLC, phospholipase C; TNF, tumor necrosis factor; TLR, Toll-like receptor.

Figure 2

Groups of compounds proposed to prevent degradation and accelerate restoration of glycocalyx. Diverse families of proposed therapeutics are shown (orange boxed areas). Gray boxed areas reiterate mechanisms of glycocalyx degradation. The authors have recently proposed the use of liposomal nanocarriers of preassembled glycocalyx, which in the bloodstream fuse with the plasma membrane of endothelial and circulating cells to expeditiously restore their lost glycocalyx. GAG, glycosaminoglycan; HA, hyaluronic acid; HS, heparan sulfate; MMP, matrix metalloproteinase; NO, nitric oxide.