Epithelial Mucus-Hypersecretion and Respiratory Disease

Abstract

Mucus production, secretion and clearance are considered to play a critical role in maintenance of airway health, however in diseases such as COPD, epidemiological and pathological studies suggest that excess mucus contributes to airway plugging and decline in lung health. The airway surface epithelium is composed of a heterogeneous mix of cell types one of which, the goblet cell, is dedicated to the production of secretory gel-forming mucins. Changes in epithelial cellular composition and function in response to irritants and microbes generally leads to enhanced co-ordinated functioning of the major facets of the mucociliary clearance (MCC) system i.e. mucus secretion, ion/fluid transport and ciliary function. The presence of mucus plugs in the airways of COPD patients demonstrates that facets of the MCC system have become compromised i.e. normally co-ordinated epithelial functions have become uncoupled. Almost nothing is known about the processes leading to such uncoupling. Understanding these processes may provide insights into mechanisms involved in regulation of epithelial integrity and the genesis of respiratory diseases such as COPD. In this review we will discuss regulation of airway epithelial cellular composition and function primarily with respect to goblet cell formation, mucus secretion, airway surface liquid (ASL) homeostasis, hydration of secreted mucus and ciliary clearance. We will discuss the functional overlap between cell populations, the potential impact of derivation from different progenitors and the implications of generating high goblet cell densities in the surface epithelium. The aim of this review is to stimulate discussion and develop hypotheses that could help to determine the mechanisms behind epithelial dysfunction in respiratory disease.

17β-Estradiol inhibits Ca2+-dependent homeostasis of airway surface liquid volume in human cystic fibrosis airway epithelia

“…Following activation of G q , PLC is activated and forms IP 3 , which in turn stimulates Ca 2+ release from the endoplasmic reticulum. However, we failed to observe any difference in IP formation after ATP exposure, suggesting that G q /PLC are unaffected by E2 Figure E2 inhibits Ca 2+ influx in airway epithelia.…”

“…The rate of mucus clearance is set by the volume of airway surface liquid (ASL) on airway surfaces (2). The ASL is composed of a periciliary liquid layer (PCL) that lubricates the cell surface and a mucus layer that traps airborne particles and pathogens (3). Adenosine (ADO) and ATP act as physiological ligands that stimulate P1 and P2 subtypes of purinergic receptors to raise cAMP and Ca 2+ levels, respectively, so that Cl -secretion is activated (4)(5)(6).…”

A New Era of Pulmonary Delivery of Nano-antimicrobial Therapeutics to Treat Chronic Pulmonary Infections

“…Antibiotics delivered for treating bacterial infections associated with these diseases needs to penetrate the sputum and distribute evenly. Drugs such as ion-channel modulators or gene therapeutics which need to reach the epithelial layer must first traverse the thick mucus layer to achieve their desired activity [100,101].…”

“…The increased presence of mucin glycoproteins in the sputum of patients immobilizes P. aeruginosa by surface interactions, which has increased tolerance to antibiotics resisting clearance from these hypoxic mucopurulent masses in the airway [98,105]. The CF sputum is the reason for failure of drug delivery and hence treatment [100,101]. Moreover, antibodies and fragments along with other soluble factors act as molecular traps for viral gene delivery, as demonstrated for adenoviral gene delivery due to the presence of adenoviral antibodies [100].…”

Cordyceps Extracts and the Major Ingredient, Cordycepin: Possible Cellular Mechanisms of Their Therapeutic Effects on Respiratory Disease

“…Mucus clearance is an important component of the innate defense of the lungs against disease. Abnormal ASL volume, salt content, or mucus clearance can compromise airway immunity and predispose the airway to various respiratory diseases and infection (Danahay and Jackson, 2005).…”