Role of hyaluronan and hyaluronan-binding proteins in lung pathobiology

Abstract

Hyaluronan (HA) has diverse functions in normal lung homeostasis and pulmonary disease. HA constitutes the major glycosaminoglycan in lung tissue, with HA degradation products, produced by hyaluronidase enzymes and reactive oxygen species, being implicated in several lung diseases, including acute lung injury, asthma, chronic obstructive pulmonary disease, and pulmonary hypertension. The differential activities of HA and its degradation products are due, in part, to regulation of multiple HA-binding proteins, including cluster of differentiation 44 (CD44), Toll-like receptor 4 (TLR4), HA-binding protein 2 (HABP2), and receptor for HA-mediated motility (RHAMM). Recent research indicates that exogenous administration of high-molecular-weight HA can serve as a novel therapeutic intervention for lung diseases, including lipopolysaccharide (LPS)-induced acute lung injury, sepsis/ventilator-induced lung injury, and airway hyperreactivity. This review focuses on the regulatory role of HA and HA-binding proteins in lung pathology and discusses the capacity of HA to augment and inhibit various lung diseases.

Fig. 1.

Structure of hyaluronan (HA). HA is composed of a linear repeat of disaccharide units consisting of d-glucuronic acid and N-acetylglucosamine. Molecular weight of HA is >1 × 10⁶ in vivo (140, 141).

Fig. 2.

HA regulation of pulmonary vascular function. High-molecular-weight HA (HMW-HA) can be degraded to low-molecular-weight fragments (LMW-HA) by hyaluronidases and/or reactive oxygen species (ROS) production with lung disease (–132). HMW-HA activates the standard form of cluster of differentiation 44 (CD44s) signaling in pulmonary endothelial cells and inhibits HA-binding protein 2 (HABP2) protease activity (81, 124). These events promote increased pulmonary vascular integrity. LMW-HA activates cluster of differentiation 44 variant (CD44v) signaling and induces HABP2 protease activity (81, 124), events that lead to pulmonary vascular leakiness, which is a prominent feature of acute lung injury.

Fig. 3.

HMW-HA protects against ventilator-induced lung injury. Male C57BL/6J wild-type mice (8–10 wk old; Jackson Laboratories, Bar Harbor, ME) were anesthetized with an intraperitoneal injection of ketamine (150 mg/kg) and acetylpromazine (15 mg/kg); then the right internal jugular vein was exposed via neck incision. Mice were allowed to spontaneously breathe or were ventilated (40 ml/kg tidal volume) for 4 h. After 1 h of ventilation, mice received HMW-HA (1.5 mg/kg) or saline control through the internal jugular vein. Mice were killed after 4 h of ventilator-induced lung injury (VILI), and bronchoalveolar lavage protein was analyzed (n = 5 mice per group). *Statistically significant difference (P < 0.05) from spontaneously breathing (SB) group. There is also a statistically significant difference (P < 0.05) between VILI alone and HMW-HA + VILI.

Fig. 4.

Schematic diagram of factors that regulate HA-mediated lung pathobiology. HA mainly exists as HMW-HA in normal lung. Total HMW-HA levels can change in lung pathology due, in part, to the levels and activity of HA synthases. In several lung diseases, HMW-HA is degraded to lower-molecular-weight HA by hyaluronidase enzymes and ROS. HMW-HA and LMW-HA can differentially bind to and have opposing effects on various HA-binding proteins that exist extracellularly (HABP2) on the cell surface (CD44 and Toll-like receptor 4), as well as in other cellular locales (receptor for HA-mediated motility). Therefore, the type of HA-binding protein(s) upregulated in various lung diseases can often determine the functional effects of HA. Furthermore, cell types (e.g., epithelial, endothelial, immune, smooth muscle, fibroblast) targeted by HMW-HA and LWM-HA will have a distinct impact on lung disease progression.