Hyaluronan serves a novel role in airway mucosal host defense

Abstract

Enzymes secreted onto epithelial surfaces play a vital role in innate mucosal defense, but are believed to be steadily removed from the surface by mechanical actions. Thus, the amount and availability of enzymes on the surface are thought to be maintained by secretion. In contrast to this paradigm, we show here that enzymes are retained at the apical surface of the airway epithelium by binding to surface-associated hyaluronan, providing an apical enzyme pool 'ready for use' and protected from ciliary clearance. We have studied lactoperoxidase, which prevents bacterial colonization of the airway, and kallikrein, which mediates allergic bronchoconstriction that limits the inhalation of noxious substances. Binding to hyaluronan inhibits kallikrein, which is needed only in certain situations, whereas lactoperoxidase, useful at all times, does not change its activity. Hyaluronan itself interacts withthe receptor for hyaluronic acid-mediated motility (RHAMM or CD168) that is expressed at the apex of ciliated airway epithelial cells. Functionally, hyaluronan binding to RHAMM stimulates ciliary beating. Thus, hyaluronan plays a previously unrecognized pivotal role in mucosal host defense by stimulating ciliary clearance of foreign material while simultaneously retaining enzymes important for homeostasis at the apical surface so that they cannot be removed by ciliary action.

Hyaluronan and Its Heavy Chain Modification in Asthma Severity and Experimental Asthma Exacerbation

“…Options include direct secretion from the airway epithelium, airway smooth muscle cells, goblet cells, mucus glands, or a combination of these. Among these options, the direct secretion from the airway epithelium and airways smooth muscle cells are the most likely, and several studies have demonstrated the ability of the epithelium and airways smooth muscle cells to secrete HA in vitro (3,37,38). The relatively negative staining of HA in goblet cell and mucous gland cell populations indicates that these cells are less likely to be involved in the secretion of HA into the airway lumen.…”

“…HA is a major component and important constituent of the extracellular matrix (2,3). In asthma, studies have linked HA levels in the bronchoalveolar lavage fluid (BAL) with inflammation and have been shown to increase after histamine challenge (4,5).…”

Upregulation of hyaluronan-mediated motility receptor in hepatocellular carcinoma predicts poor survival

“…RHAMM is not only a modulator of growth factor receptor, but also has major roles in progression and proliferation of various types of cancer (9,11). RHAMM has been found in a variety of mammalian cells, including smooth muscle cells, endothelial cells, nerve cells, macrophages, spermatozoa (12,13), and certain types of tumor cell, including prostate (14), breast (15) and gastric (16) cancer, and B-cell chronic lymphocytic leukemia (17). However, whether the upregulation of RHAMM contributes to hepatocarcinogenesis of HCC remains unclear.…”

Hyaluronan in the Treatment of Chronic Rhinosinusitis with Nasal Polyposis

“…It has been demonstrated that HA plays an important role in the processes of wound healing and repair of mucosal surfaces; the presence of mucosal ulcers increase the expression of HA receptors, which provides a ligand for cell adhesion. HA binds to and interacts with the hyaluronic acid-mediated motility [14]. Patients with chronic bronchitis and recurrent exacerbations treated with HA have seen reduce the number of exacerbations, with less need for antibiotic therapies to control recurrent episodes [15].…”