Heparan Sulfate in the Developing, Healthy, and Injured Lung

Abstract

Remarkable progress has been achieved in understanding the regulation of gene expression and protein translation, and how aberrancies in these template-driven processes contribute to disease pathogenesis. However, much of cellular physiology is controlled by non-DNA, nonprotein mediators, such as glycans. The focus of this Translational Review is to highlight the importance of a specific glycan polymer-the glycosaminoglycan heparan sulfate (HS)-on lung health and disease. We demonstrate how HS contributes to lung physiology and pathophysiology via its actions as both a structural constituent of the lung parenchyma as well as a regulator of cellular signaling. By highlighting current uncertainties in HS biology, we identify opportunities for future high-impact pulmonary and critical care translational investigations.

Proteoglycans as Immunomodulators of the Innate Immune Response to Lung Infection

“…76 These observations have been extended to lungs where PGs and GAGs in the endothelial cell glycocalyx form a hydrated endothelial surface layer that contributes to the vascular barrier function that excludes proteins and fluid. 8,77,78 The ability of GAGs to provide a barrier to fluids and proteins such as albumin is attributed to their negative charge. Therefore, it is not surprising that loss of HA and HS from the endothelial glycocalyx results in pulmonary edema.…”

Intravital imaging of a pulmonary endothelial surface layer in a murine sepsis model

“…The ESL has been regarded as a barrier protecting the endothelial cell from circulating cells and large molecules, preventing platelet adherence and leukocyte adhesion. While being maintained as a membrane-bound structure in normal physiological condition, the ESL has been suggested to be degraded in systemic inflammatory condition including sepsis [3,4]. Several studies have proposed inflammation-induced shedding of glycocalyx associated with endothelial dysfunction in inflammatory cascade [5][6][7][8].…”

Fibroblast Growth Factor Signaling Mediates Pulmonary Endothelial Glycocalyx Reconstitution

“…In vivo, glycocalyx glycosaminoglycans become highly hydrated, forming a substantial gel-like endothelial surface layer (ESL) that projects 0.5 mm to over 10 mm into the vascular lumen (1). An intact ESL contributes to the endothelial barrier to fluid and protein, regulates leukocyte-endothelial adhesion, and transduces fluid shear stress into endothelial nitric oxide synthesis (2). Accordingly, a number of acute and chronic vascular diseases are characterized by degradation of the glycocalyx/ESL (collectively referred to subsequently here as the "ESL").…”

“…As HS is a critical contributor to ESL structure and function (3), ESL reconstitution likely requires induction of HS biosynthesis. HS is a linear glycosaminoglycan composed of repeating hexuronic acid-glucosamine disaccharides, the polymerization of which is dependent upon glucosyltransferases, such as exostosin (EXT)-1 (2). After polymerization, HS undergoes targeted epimerization and sulfation, yielding highly sulfated regions (at least five saccharides in length) of sufficiently negative charge to interact with positively charged residues of proteins, including growth factor ligands and their cognate receptors.…”

“…After polymerization, HS undergoes targeted epimerization and sulfation, yielding highly sulfated regions (at least five saccharides in length) of sufficiently negative charge to interact with positively charged residues of proteins, including growth factor ligands and their cognate receptors. Through these chargebased interactions, HS can serve as a scaffolding molecule, facilitating growth factor ligand-receptor binding and promoting downstream signaling (2).…”