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.

Superoxide Dismutase Mimetic, MnTE-2-PyP, Attenuates Chronic Hypoxia-Induced Pulmonary Hypertension, Pulmonary Vascular Remodeling, and Activation of the NALP3 Inflammasome

“…NF-kB and IL gene expression (30). Our data suggest that hypoxia caused initial degradation of intact HA, while HA synthesis may have begun in response to longer hypoxic exposure.…”

Adenosine A2B Receptor and Hyaluronan Modulate Pulmonary Hypertension Associated with Chronic Obstructive Pulmonary Disease

“…Moreover, the treatment of these mice with GS-6201, an ADORA2B antagonist, was able to halt damage to the lungs, including the development of PH. Our data suggest that the mechanisms leading to vascular remodeling involve ADORA2B-mediated increases in HAS-2 and subsequent elevations of HA, a component of the ECM that is able to promote tissue remodeling (17,36) and is elevated in patients with PAH (15, 16). These observations are consistent with our human Figure 5.…”

“…One such mediator is HA, a multifaceted GAG that can promote or inhibit lung pathology, depending on its molecular weight and its accessibility to HABPs (17). In experimental models of disease, heightened levels of HA have been shown to modulate inflammation and fibrosis (17), where an accumulation of HA and its subsequent degradation to low molecular weight (LMW) fragments contribute to the inflammatory and tissue remodeling process (17). Furthermore, increased HA has been observed in the monocrotaline model of PH (43), further implicating its role in vascular remodeling.…”

“…In patients with idiopathic pulmonary arterial hypertension, the up-regulation of hyaluronan (HA), a major component of the lung ECM, has been associated with vascular remodeling (15,16). These observations are of interest, because HA has been shown to play an important role during inflammation and fibrosis (17). However, it remains unknown whether HA plays a role in the pathogenesis of PH secondary to chronic lung diseases such as COPD or idiopathic pulmonary fibrosis (IPF).…”

Low Molecular Weight Hyaluronan Activates Cytosolic Phospholipase A2α and Eicosanoid Production in Monocytes and Macrophages

“…Increased HA levels and HA degradation products are found in bronchoalveolar lavage and in lung tissue of patients with asthma, allergic alveolitis, chronic obstructive pulmonary disease, idiopathic pulmonary fibrosis, ARDS, and other acute and chronic lung diseases (6,62). LMW HA increases uptake of oxidized low density lipoprotein into monocytes (63), and HA overproduction promotes atherosclerosis development in the aorta of ApoE-deficient mice (64).…”