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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.
Keywords: heparan sulfate; glycosaminoglycan; glycocalyx; proteoglycan
Heparan sulfate (HS) is a linear glycosaminoglycan composed of repeating disaccharide units of glucosamine and a hexuronic acid (glucuronic acid or its epimer, iduronic acid). HS synthesis occurs within the Golgi apparatus, where disaccharide polymerization extends from a protein backbone. Together, this HS-protein complex is known as an HS proteoglycan (HSPG). HS undergoes sequential steps of epimerization and/or sulfation, as governed by a system of epimerases and sulfotransferases targeted to specificsites on component HS disaccharides (Figure 1) (1). This complex process of synthesis and modification dictates the biologic functions of HS, which arise largely from the localized negative charge imparted by clusters of sulfation-enriched domains. These domains enable HS to not only bind positively charged residues of soluble ligands and cell surface receptors (2), but also to sequester water (3)-characteristics that allow HS to function both as a structural component of the lung parenchyma and as a regulator of signaling pathways.
HS in Lung Development
Transgenic animal studies have demonstrated theimportanceofHStoproperorgan development (4). As summarized in Table 1, the most severe pulmonary-relevant phenotypes described (embryonic lethal) arise from null mutants of Glact1, Ext1,and Ext2, which encode enzymes that build the initial unmodified HSPG. In addition, genes involved in the further modification of HS affect lung development. Null allele mutants of Ndst1, which encodes an enzyme that sulfates glucosamine at the N position, suffer from neonatal respiratory distress due to lung hypoplasia (5, 6). Genetic manipulations that result in HS containing less iduronic acid (Glce/Hsepi)or6-O sulfation (H6st1) also produce animals that lack proper alveolar development...