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Symposia of the Society For... 1989Although it has generally been accepted that the main structural component of mucus secretions is the high molecular weight glycoprotein it has now been established that... (Review)
Review
Although it has generally been accepted that the main structural component of mucus secretions is the high molecular weight glycoprotein it has now been established that other macromolecules are co-secreted. For example, lysozyme, lactoferrin and albumin are known to be secreted by the serous cells within the sub-mucosal respiratory glands: significantly the albumin is synthesised within the cell and is not derived from serum. The various cells within the gland respond differently to agonists and since goblet cells, apart from when they are in the crypts within the gastro-intestinal tract, do not appear to be innervated, they cannot respond to any agonist as yet identified. It is therefore probable that the changes which occur during disease may result from changes in the sensitivity of a particular cell type to an agonist as this can markedly affect the type of secretion that is produced. Since the products of the serous cell form part of the natural defence system then the reduction in their number which is observed in chronic obstructive airways disease could also be significant in the disease process. Within the gastro-intestinal tract, it has now been established that substances which reduce the mucus structure can produce damage to the underlying membrane. The endogenous surfactants produced in bile are good examples and co-secretion of phosphatidylcholine provides a defence against self-digestion within the gut by the formation of mixed micelles. The importance of the mucus layer in the access of drug molecules to the absorbing epithelium has also been identified. The diffusion of water molecules is hindered even at concentrations below the gelling point (approximately 10-20 mg ml-1) and above this concentration a precipitate fall in diffusion coefficient is followed by a levelling off. This pattern is followed by low molecular weight drug molecules and a reasonable correlation between drug absorption and binding to mucus glycoproteins can be demonstrated. The agents which have been claimed to affect the quality and quantity of mucus secreted by the respiratory epithelium during conditions like chronic obstructive airways disease have been poorly understood. Recent studies have shown that compounds like bromhexine and S-carboxymethylcysteine can block the activity of mucus secretagogues in the rat. Furthermore, it has also been demonstrated that such compounds can prevent the inflammatory response to cigarette smoke. However, their activity is not restricted to the respiratory epithelium and the cervical mucus barrier has also been shown to be compromised following systemic administration.
Topics: Animals; Diffusion; Gels; Humans; Molecular Structure; Mucus; Xenobiotics
PubMed: 2701476
DOI: No ID Found -
Advanced Drug Delivery Reviews Jan 2018Mucus is a highly hydrated viscoelastic gel present on various moist surfaces in our body including the eyes, nasal cavity, mouth, gastrointestinal, respiratory and... (Review)
Review
Mucus is a highly hydrated viscoelastic gel present on various moist surfaces in our body including the eyes, nasal cavity, mouth, gastrointestinal, respiratory and reproductive tracts. It serves as a very efficient barrier that prevents harmful particles, viruses and bacteria from entering the human body. However, the protective function of the mucus also hampers the diffusion of drugs and nanomedicines, which dramatically reduces their efficiency. Functionalisation of nanoparticles with low molecular weight poly(ethylene glycol) (PEGylation) is one of the strategies to enhance their penetration through mucus. Recently a number of other polymers were explored as alternatives to PEGylation. These alternatives include poly(2-alkyl-2-oxazolines), polysarcosine, poly(vinyl alcohol), other hydroxyl-containing non-ionic water-soluble polymers, zwitterionic polymers (polybetaines) and mucolytic enzymes. This review discusses the studies reporting the use of these polymers or potential application to facilitate mucus permeation of nanoparticles.
Topics: Biocompatible Materials; Humans; Mucus; Nanoparticles; Polyethylene Glycols; Surface Properties
PubMed: 28736302
DOI: 10.1016/j.addr.2017.07.015 -
Advanced Drug Delivery Reviews Jan 2018Mucosal administration of drugs and drug delivery systems has gained increasing interest. However, nanoparticles intended to protect and deliver drugs to epithelial... (Review)
Review
Mucosal administration of drugs and drug delivery systems has gained increasing interest. However, nanoparticles intended to protect and deliver drugs to epithelial surfaces require transport through the surface-lining mucus. Translation from bench to bedside is particularly challenging for mucosal administration since a variety of parameters will influence the specific barrier properties of the mucus including the luminal fluids, the microbiota, the mucus composition and clearance rate, and the condition of the underlying epithelia. Besides, after administration, nanoparticles interact with the mucosal components, forming a biomolecular corona that modulates their behavior and fate after mucosal administration. These interactions are greatly influenced by the nanoparticle properties, and therefore different designs and surface-engineering strategies have been proposed. Overall, it is essential to evaluate these biomolecule-nanoparticle interactions by complementary techniques using complex and relevant mucus barrier matrices.
Topics: Animals; Drug Delivery Systems; Humans; Mucus; Nanoparticles; Surface Properties
PubMed: 29117511
DOI: 10.1016/j.addr.2017.11.002 -
Advanced Drug Delivery Reviews Jan 2018The increasing interest in developing tools to predict drug absorption through mucosal surfaces is fostering the establishment of epithelial cell-based models.... (Review)
Review
The increasing interest in developing tools to predict drug absorption through mucosal surfaces is fostering the establishment of epithelial cell-based models. Cell-based in vitro techniques for drug permeability assessment are less laborious, cheaper and address the concerns of using laboratory animals. Simultaneously, in vitro barrier models that thoroughly simulate human epithelia or mucosae may provide useful data to speed up the entrance of new drugs and new drug products into the clinics. Nevertheless, standard cell-based in vitro models that intend to reproduce epithelial surfaces often discard the role of mucus in influencing drug permeation/absorption. Biomimetic models of mucosae in which mucus production has been considered may not be able to fully reproduce the amount and architecture of mucus, resulting in biased characterization of permeability/absorption. In these cases, artificial mucus may be used to supplement cell-based models but still proper identification and quantification are required. In this review, considerations regarding the relevance of mucus in the development of cell-based epithelial and mucosal models mimicking the gastro-intestinal tract, the cervico-vaginal tract and the respiratory tract, and the impact of mucus on the permeability mechanisms are addressed. From simple epithelial monolayers to more complex 3D structures, the impact of the presence of mucus for the extrapolation to the in vivo scenario is critically analyzed. Finally, an overview is provided on several techniques and methods to characterize the mucus layer over cell-based barriers, in order to intimately reproduce human mucosal layer and thereby, improve in vitro/in vivo correlation.
Topics: Animals; Drug Delivery Systems; Gastric Mucosa; Humans; Intestine, Small; Models, Biological; Mucus
PubMed: 28751201
DOI: 10.1016/j.addr.2017.07.019 -
Medecine Sciences : M/S Oct 2018Mucus is the first line of innate mucosal defense in all mammals. Gel‑forming mucins control the rheological properties of mucus hydrogels by forming a network in... (Review)
Review
Mucus is the first line of innate mucosal defense in all mammals. Gel‑forming mucins control the rheological properties of mucus hydrogels by forming a network in which hydrophilic and hydrophobic regions coexist, and it has been revealed that the network is formed through both covalent links and reversible links such as hydrophobic interactions in order to modulate the structure as a function of the physiological necessities. Here, we review the structure and functions of the mucus in terms of the gel-forming mucins protein-protein interactions, also called interactome. Since it is difficult to characterize the low energy reversible interactions due to their dependence on physico-chemical environment, their role is not well understood. Still, they constitute a promising target to counteract mucus abnormalities observed in mucus-associated diseases.
Topics: Animals; Elasticity; Gels; Humans; Mucins; Mucus; Rheology; Viscosity
PubMed: 30451674
DOI: 10.1051/medsci/2018206 -
Journal of Physiology and Pharmacology... Sep 1997A continuous, adherent mucus gel layer with mucosal bicarbonate secretion is the initial protective barrier in the stomach and duodenum against erosion by the gastric... (Review)
Review
A continuous, adherent mucus gel layer with mucosal bicarbonate secretion is the initial protective barrier in the stomach and duodenum against erosion by the gastric juice. H. pylori resides within the adherent mucus gel layer close to the epithelial surface. The barrier function of the mucus layer in vivo depends on (i) its thickness, and (ii) its gel structure, a property which is linearly dependent on the polymeric mucin content. We have shown in vivo that H. pylori colonisation alone did not decrease the thickness of the adherent gastric mucus barrier, although there was a mean 20% decrease in mucus thickness in those H. pylori positive subjects with underlying gastric atrophy. There was, however, a significant mean 18% reduction in the gel-forming polymeric mucin content of mucus from H. pylori subjects, independent of underlying atrophy. Studies in vitro suggest this loss of gel structure might arise from a H. pylori mediated, high local pH generated by urease activity rather than by proteolysis. This study shows that H. pylori infection alone does not compromise the overall integrity of the mucus barrier in vivo. However, in the immediate environment of the organism there appears to be a localised loss of mucus gel structure. The mucus barrier is compromised if H. pylori associated gastric atrophy or peptic ulceration follows.
Topics: Animals; Bicarbonates; Compressive Strength; Gastric Mucins; Gastric Mucosa; Helicobacter Infections; Helicobacter pylori; Humans; Mucus
PubMed: 9376612
DOI: No ID Found -
Advanced Drug Delivery Reviews Jan 2018The mucosa of the gastrointestinal tract, eyes, nose, lungs, cervix and vagina is lined by epithelium interspersed with mucus-secreting goblet cells, all of which... (Review)
Review
The mucosa of the gastrointestinal tract, eyes, nose, lungs, cervix and vagina is lined by epithelium interspersed with mucus-secreting goblet cells, all of which contribute to their unique functions. This mucus provides an integral defence to the epithelium against noxious agents and pathogens. However, it can equally act as a barrier to drugs and delivery systems targeting epithelial passive and active transport mechanisms. This review highlights the various mucins expressed at different mucosal surfaces on the human body, and their role in creating a mucoid architecture to protect epithelia with specialized functions. Various factors compromising the barrier properties of mucus have been discussed, with an emphasis on how disease states and microbiota can alter the physical properties of mucus. For instance, Akkermansia muciniphila, a bacterium found in higher levels in the gut of lean individuals induces the production of a thickened gut mucus layer. The aims of this article are to elucidate the different physiological, biochemical and physical properties of bodily mucus, a keen appreciation of which will help circumvent the slippery slope of challenges faced in achieving effective mucosal drug and gene delivery.
Topics: Animals; Drug Delivery Systems; Humans; Mucus
PubMed: 29108861
DOI: 10.1016/j.addr.2017.10.014 -
Frontiers in Bioscience (Scholar... Jan 2013Structure of human cervical mucus plays a pivotal role in female fertility and protection of reproductive health. Investigation of biochemical and biophysical structure... (Review)
Review
Structure of human cervical mucus plays a pivotal role in female fertility and protection of reproductive health. Investigation of biochemical and biophysical structure of cervical mucus remains a challenge due to complex structural proteins, high content of oligosaccharides and cyclic variability of its structure. We present the current knowledge on chemical and biophysical features of cervical mucus and regulation of its secretion, relevant clinical observations and underexplored elements. The latter relates to biochemical background of physical properties and antimicrobial activity of cervical mucus, and regulation of its production.
Topics: Animals; Cervix Mucus; Female; Humans; Proteins
PubMed: 23277065
DOI: 10.2741/s386 -
ACS Biomaterials Science & Engineering Apr 2022Mucus is a complex viscoelastic gel and acts as a barrier covering much of the soft tissue in the human body. High vascularization and accessibility have motivated drug... (Review)
Review
Mucus is a complex viscoelastic gel and acts as a barrier covering much of the soft tissue in the human body. High vascularization and accessibility have motivated drug delivery to various mucosal surfaces; however, these benefits are hindered by the mucus layer. To overcome the mucus barrier, many nanomedicines have been developed, with the goal of improving the efficacy and bioavailability of drug payloads. Two major nanoparticle-based strategies have emerged to facilitate mucosal drug delivery, namely, mucoadhesion and mucopenetration. Generally, mucoadhesive nanoparticles promote interactions with mucus for immobilization and sustained drug release, whereas mucopenetrating nanoparticles diffuse through the mucus and enhance drug uptake. The choice of strategy depends on many factors pertaining to the structural and compositional characteristics of the target mucus and mucosa. While there have been promising results in preclinical studies, mucus-nanoparticle interactions remain poorly understood, thus limiting effective clinical translation. This article reviews nanomedicines designed with mucoadhesive or mucopenetrating properties for mucosal delivery, explores the influence of site-dependent physiological variation among mucosal surfaces on efficacy, transport, and bioavailability, and discusses the techniques and models used to investigate mucus-nanoparticle interactions. The effects of non-homeostatic perturbations on protein corona formation, mucus composition, and nanoparticle performance are discussed in the context of mucosal delivery. The complexity of the mucosal barrier necessitates consideration of the interplay between nanoparticle design, tissue-specific differences in mucus structure and composition, and homeostatic or disease-related changes to the mucus barrier to develop effective nanomedicines for mucosal delivery.
Topics: Drug Delivery Systems; Humans; Mucous Membrane; Mucus; Nanoparticles; Pharmaceutical Preparations
PubMed: 35294187
DOI: 10.1021/acsbiomaterials.2c00047 -
American Journal of Respiratory and... Mar 2020Non-cystic fibrosis bronchiectasis is characterized by airway mucus accumulation and sputum production, but the role of mucus concentration in the pathogenesis of these... (Comparative Study)
Comparative Study
Non-cystic fibrosis bronchiectasis is characterized by airway mucus accumulation and sputum production, but the role of mucus concentration in the pathogenesis of these abnormalities has not been characterized. This study was designed to: ) measure mucus concentration and biophysical properties of bronchiectasis mucus; ) identify the secreted mucins contained in bronchiectasis mucus; ) relate mucus properties to airway epithelial mucin RNA/protein expression; and ) explore relationships between mucus hyperconcentration and disease severity. Sputum samples were collected from subjects with bronchiectasis, with and without chronic erythromycin administration, and healthy control subjects. Sputum percent solid concentrations, total and individual mucin concentrations, osmotic pressures, rheological properties, and inflammatory mediators were measured. Intracellular mucins were measured in endobronchial biopsies by immunohistochemistry and gene expression. MUC5B (mucin 5B) polymorphisms were identified by quantitative PCR. In a replication bronchiectasis cohort, spontaneously expectorated and hypertonic saline-induced sputa were collected, and mucus/mucin concentrations were measured. Bronchiectasis sputum exhibited increased percent solids, total and individual (MUC5B and MUC5AC) mucin concentrations, osmotic pressure, and elastic and viscous moduli compared with healthy sputum. Within subjects with bronchiectasis, sputum percent solids correlated inversely with FEV and positively with bronchiectasis extent, as measured by high-resolution computed tomography, and inflammatory mediators. No difference was detected in rs35705950 SNP allele frequency between bronchiectasis and healthy individuals. Hypertonic saline inhalation acutely reduced non-cystic fibrosis bronchiectasis mucus concentration by 5%. Hyperconcentrated airway mucus is characteristic of subjects with bronchiectasis, likely contributes to disease pathophysiology, and may be a target for pharmacotherapy.
Topics: Aged; Bronchiectasis; Cohort Studies; Erythromycin; Female; Humans; Male; Middle Aged; Mucus; Queensland; Respiratory System; Sputum
PubMed: 31765597
DOI: 10.1164/rccm.201906-1219OC