Mucus, mucins, and cystic fibrosis

Abstract

Cystic fibrosis (CF) is both the most common and most lethal genetic disease in the Caucasian population. CF is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene and is characterized by the accumulation of thick, adherent mucus plaques in multiple organs, of which the lungs, gastrointestinal tract and pancreatic ducts are the most commonly affected. A similar pathogenesis cascade is observed in all of these organs: loss of CFTR function leads to altered ion transport, consisting of decreased chloride and bicarbonate secretion via the CFTR channel and increased sodium absorption via epithelial sodium channel upregulation. Mucosa exposed to changes in ionic concentrations sustain severe pathophysiological consequences. Altered mucus biophysical properties and weakened innate defense mechanisms ensue, furthering the progression of the disease. Mucins, the highmolecular-weight glycoproteins responsible for the viscoelastic properties of the mucus, play a key role in the disease but the actual mechanism of mucus accumulation is still undetermined. Multiple hypotheses regarding the impact of CFTR malfunction on mucus have been proposed and are reviewed here. (a) Dehydration increases mucin monomer entanglement, (b) defective Ca 2+ chelation compromises mucin expansion, (c) ionic changes alter mucin interactions, and (d) reactive oxygen species increase mucin crosslinking. Although one biochemical change may dominate, it is likely that all of these mechanisms play some role in the progression of CF disease.This article discusses recent findings on the initial cause(s) of aberrant mucus properties in CF and examines therapeutic approaches aimed at correcting mucus properties.

Slc26a3 deletion alters pH‐microclimate, mucin biosynthesis, microbiome composition and increases the TNFα expression in murine colon

“…The extracellular domains of the membrane bound mucins are also shed into the lumen, and both types of mucin have important protective and regulatory functions. 12 The secretion, release from the membrane, and gel-forming properties of mucins depend on the ambient pH, the HCO 3 − concentration, and the hydration of the adjacent extracellular space, [13][14][15] and in this context SLC26A3 may be an important player for the mucus layer properties in the colon. SLC26A3 expression is decreased in murine and human inflamed intestinal mucosa, [16][17][18] and we previously observed a strong reduction in alkalinisation rates in isolated mid-distal colonic mucosa from both inflamed compared to non-inflamed 18 and in slc26a3 −/− compared to wt mice 19 .…”

“…The extracellular domains of the membrane bound mucins are also shed into the lumen, and both types of mucin have important protective and regulatory functions 12 . The secretion, release from the membrane, and gel‐forming properties of mucins depend on the ambient pH, the HCO 3 − concentration, and the hydration of the adjacent extracellular space, 13‐15 and in this context SLC26A3 may be an important player for the mucus layer properties in the colon.…”

Comparison of respiratory pathogen colonization and antimicrobial susceptibility in people with cystic fibrosis bronchiectasis versus non-cystic fibrosis bronchiectasis: a protocol for a systematic review

“…This gene regulates the activity of sodium and chloride channels across the epithelial cells, thereby facilitating appropriate hydration of mucins and effective muco-ciliary clearance in various organs [ 1 ]. Impaired secretion of chloride and bicarbonate ions due to CFTR mutations leads to the formation of thick mucus, which is difficult to clear [ 2 ]. This predisposes CF patients to pulmonary bacterial infections caused by Staphylococcus aureus , Pseudomonas aeruginosa , Haemophilus influenzae , or Burkholderia cepacia complex (Bcc) [ 3 ].…”

Design and Synthesis of Mucin‐Inspired Glycopolymers

“…Mucins are biopolymers found in all animals, either as membrane‐bound brushes or as secretions from epithelial goblet cells and the mucus cells of submucosal glands [1] . Membrane‐bound mucins are involved in signal transduction and cell protection, [2] while secreted mucins fill several roles including adhesion, lubrication, and protection [3–6] .…”

“…Mucins are biopolymers found in all animals, either as membrane-bound brushes or as secretions from epithelial goblet cells and the mucus cells of submucosal glands. [1] Membrane-bound mucins are involved in signal transduction and cell protection, [2] while secreted mucins fill several roles including adhesion, lubrication, and protection. [3][4][5][6] In the human body, for example, ocular mucus hydrates the eye, [7] nasal mucus lubricates the nose and removes pathogens from the respiratory tract, [8] anti-microbial mucus is present in saliva, [9] gastric mucus protects the stomach lining from harmful gastric juices, [10] and intestinal mucus facilitates bolus passage and acts as a defensive barrier against pathogens.…”