This review focuses on the role and regulation of mucin glycoproteins (mucins) in airway health and disease. Mucins are highly glycosylated macromolecules (≥50% carbohydrate, wt/wt). MUC protein ba...

Respiratory Tract Mucin Genes and Mucin Glycoproteins in Health and Disease

Mucins, Mucus, and Sputum*

Host cell proteases that cleave the hemagglutinin (HA) of influenza viruses in the human respiratory tract are still not identified. Here we cloned two human type II transmembrane serine proteases with known airway localization, TMPRSS2 and HAT, into mammalian expression vector. Cotransfection of mammalian cells with plasmids encoding HA and either protease resulted in HA cleavage in situ. Transient expression of either protease in MDCK cells enabled multicycle replication of influenza viruses in these cells in the absence of exogenous trypsin. These data suggest that TMPRSS2 and HAT are candidates for proteolytic activation of influenza viruses in vivo.

Proteolytic Activation of Influenza Viruses by Serine Proteases TMPRSS2 and HAT from Human Airway Epithelium

The epithelial cells lining the airways serve protective functions. The "barrier function" of the epithelium protects the individual from damage by inhaled irritants. The epithelium produces mucins which become hydrated and form a viscoelastic gel which spreads over the epithelial surface. In healthy individuals inhaled foreign materials become entrapped in the mucus and are cleared by mucociliary transport and by coughing. In many chronic inflammatory airway diseases, however, excessive mucus is produced and is inadequately cleared, leading to mucous obstruction and infection. At present there is no specific treatment for hypersecretion. However, the discovery that an epidermal growth factor receptor (EGFR) cascade is involved in mucin production by a wide variety of stimuli suggests that blockade may provide specific treatment for hypersecretory diseases. EGFR pathways have also been implicated in the repair of damaged airway epithelium. The roles of EGFR in airway epithelial cell hypersecretion and epithelial damage and repair are reviewed and future potential treatments are suggested.

https://thorax.bmj.com/content/thoraxjnl/59/11/992.full.pdf

Roles of epidermal growth factor receptor activation in epithelial cell repair and mucin production in airway epithelium

In this review, we summarize work over the past 15 years on mucin gene expression and regulation in the lung, as well as how mucin gene expression is altered in chronic lung diseases. This field owes a great debt to Carol Basbaum for her pioneering work in dissecting signaling pathways regulating mucin gene expression and for her tremendous energy in promoting the importance of understanding the basic pathogenic mechanisms that drive mucus overproduction in cystic fibrosis, chronic obstructive pulmonary disease, and asthma.

Regulation of mucin genes in chronic inflammatory airway diseases.

Human airway trypsin-like protease (HAT) is a serine protease found in sputum of patients with chronic airway diseases and is an agonist of protease-activated receptor-2 (PAR-2). Results from this study show that HAT treatment also enhances mucus production by the airway epithelial cell line NCI-H292 in vitro. Histologic examination showed that HAT enhances mucous glycoconjugate synthesis, whereas the PAR-2 agonist peptide (PAR-2 AP) has no such effect. HAT, but not PAR-2 AP, enhances MUC2 and MUC5AC gene expression 23-fold and 32-fold, respectively. The proteolytic activity of HAT is required to enhance MUC5AC gene expression; the addition of the inhibitors of trypsin-like protease activity of HAT, aprotinin and leupeptin, abolishes its enhancing effect. AG1478, anti-epidermal growth factor receptor (anti-EGFR)–neutralizing antibody, and antiamphiregulin (AR)-neutralizing antibody all inhibited the stimulatory effect of HAT. Furthermore, HAT increases AR gene expression and subsequent AR protein release, whereas PAR-2 AP shows no such effects. These results indicate that HAT enhances mucin gene expression through an AR-EGFR pathway, and PAR-2 is not sufficient for or does not directly cause HATinduced mucin gene expression. Thus, HAT might be a possible therapeutic target to prevent excessive mucus production in patients with chronic airway diseases. Human airway trypsin-like protease (HAT) is a novel serine protease that, based on its protease activity, can be purified from the sputum of patients with chronic airway diseases such as chronic bronchitis and bronchial asthma (1). It exists in sputum as a monomer with a molecular size of 27 kD, estimated from gel filtration chromatography results. HAT cDNA has been cloned from a tracheal tissue cDNA library; analysis of this cDNA suggests that HAT is originally translated as a precursor with a molecular size of 48 kD and possesses a hydrophobic transmembrane domain near the N-terminus (2). Based on this derived structure, HAT is thought to be a member of the type-II transmembrane

https://www.atsjournals.org/doi/pdf/10.1165/rcmb.2003-0199OC

Hirofumi Tanabe

Papers

Human airway trypsin-like protease increases mucin gene expression in airway epithelial cells.