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Advanced Drug Delivery Reviews Feb 2009Mucus is a viscoelastic and adhesive gel that protects the lung airways, gastrointestinal (GI) tract, vagina, eye and other mucosal surfaces. Most foreign particulates,... (Review)
Review
Mucus is a viscoelastic and adhesive gel that protects the lung airways, gastrointestinal (GI) tract, vagina, eye and other mucosal surfaces. Most foreign particulates, including conventional particle-based drug delivery systems, are efficiently trapped in human mucus layers by steric obstruction and/or adhesion. Trapped particles are typically removed from the mucosal tissue within seconds to a few hours depending on anatomical location, thereby strongly limiting the duration of sustained drug delivery locally. A number of debilitating diseases could be treated more effectively and with fewer side effects if drugs and genes could be more efficiently delivered to the underlying mucosal tissues in a controlled manner. This review first describes the tenacious mucus barrier properties that have precluded the efficient penetration of therapeutic particles. It then reviews the design and development of new mucus-penetrating particles that may avoid rapid mucus clearance mechanisms, and thereby provide targeted or sustained drug delivery for localized therapies in mucosal tissues.
Topics: Animals; Drug Carriers; Gene Transfer Techniques; Humans; Mucous Membrane; Mucus; Nanoparticles; Viscosity
PubMed: 19133304
DOI: 10.1016/j.addr.2008.11.002 -
International Journal of Molecular... Feb 2023Due to mucin's important protective effect on epithelial tissue, it has garnered extensive attention. The role played by mucus in the digestive tract is undeniable. On... (Review)
Review
Due to mucin's important protective effect on epithelial tissue, it has garnered extensive attention. The role played by mucus in the digestive tract is undeniable. On the one hand, mucus forms "biofilm" structures that insulate harmful substances from direct contact with epithelial cells. On the other hand, a variety of immune molecules in mucus play a crucial role in the immune regulation of the digestive tract. Due to the enormous number of microorganisms in the gut, the biological properties of mucus and its protective actions are more complicated. Numerous pieces of research have hinted that the aberrant expression of intestinal mucus is closely related to impaired intestinal function. Therefore, this purposeful review aims to provide the highlights of the biological characteristics and functional categorization of mucus synthesis and secretion. In addition, we highlight a variety of the regulatory factors for mucus. Most importantly, we also summarize some of the changes and possible molecular mechanisms of mucus during certain disease processes. All these are beneficial to clinical practice, diagnosis, and treatment and can provide some potential theoretical bases. Admittedly, there are still some deficiencies or contradictory results in the current research on mucus, but none of this diminishes the importance of mucus in protective impacts.
Topics: Intestinal Mucosa; Mucus; Epithelial Cells; Biofilms; Epithelium
PubMed: 36835646
DOI: 10.3390/ijms24044227 -
MSphere Aug 2022The pathological properties of airway mucus in cystic fibrosis (CF) are dictated by mucus concentration and composition, with mucins and DNA being responsible for mucus...
The pathological properties of airway mucus in cystic fibrosis (CF) are dictated by mucus concentration and composition, with mucins and DNA being responsible for mucus viscoelastic properties. As CF pulmonary disease progresses, the concentrations of mucins and DNA increase and are associated with increased mucus viscoelasticity and decreased transport. Similarly, the biophysical properties of bacterial biofilms are heavily influenced by the composition of their extracellular polymeric substances (EPS). While the roles of polymer concentration and composition in mucus and biofilm mechanical properties have been evaluated independently, the relationship between mucus concentration and composition and the biophysical properties of biofilms grown therein remains unknown. Pseudomonas aeruginosa biofilms were grown in airway mucus as a function of overall concentration and DNA concentration to mimic healthy, and CF pathophysiology and biophysical properties were evaluated with macro- and microrheology. Biofilms were also characterized after exposure to DNase or DTT to examine the effects of DNA and mucin degradation, respectively. Identifying critical targets in biofilms for disrupting mechanical stability in highly concentrated mucus may lead to the development of efficacious biofilm therapies and ultimately improve CF patient outcomes. Overall mucus concentration was the predominant contributor to biofilm viscoelasticity and both DNA degradation and mucin reduction resulted in compromised biofilm mechanical strength. Pathological mucus in cystic fibrosis (CF) is highly concentrated and insufficiently cleared from the airway, causing chronic inflammation and infection. Pseudomonas aeruginosa establishes chronic infection in the form of biofilms within mucus, and this study determined that biofilms formed in more concentrated mucus were more robust and less susceptible to mechanical and chemical challenges compared to biofilms grown in lower concentrated mucus. Neither DNA degradation nor disulfide bond reduction was sufficient to fully degrade biofilms. Mucus rehydration should remain a priority for treating CF pulmonary disease with concomitant multimechanistic biofilm degradation agents and antibiotics to clear chronic infection.
Topics: Biofilms; Cystic Fibrosis; DNA; Humans; Mucins; Mucus; Pseudomonas aeruginosa
PubMed: 35968965
DOI: 10.1128/msphere.00291-22 -
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 -
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 -
Frontiers in Cellular and Infection... 2017The human gut is colonized by a variety of large amounts of microbes that are collectively called intestinal microbiota. Most of these microbial residents will grow... (Review)
Review
The human gut is colonized by a variety of large amounts of microbes that are collectively called intestinal microbiota. Most of these microbial residents will grow within the mucus layer that overlies the gut epithelium and will act as the first line of defense against both commensal and invading microbes. This mucus is essentially formed by mucins, a family of highly glycosylated protein that are secreted by specialize cells in the gut. In this Review, we examine how commensal members of the microbiota and pathogenic bacteria use mucus to their advantage to promote their growth, develop biofilms and colonize the intestine. We also discuss how mucus-derived components act as nutrient and chemical cues for adaptation and pathogenesis of bacteria and how bacteria can influence the composition of the mucus layer.
Topics: Animals; Bacteria; Bacterial Adhesion; Biofilms; Gastrointestinal Microbiome; Humans; Intestinal Mucosa; Mice; Mucins; Mucus; Virulence
PubMed: 28929087
DOI: 10.3389/fcimb.2017.00387 -
Journal of Bacteriology Mar 2021Intestinal mucus is the first line of defense against intestinal pathogens. It acts as a physical barrier between epithelial tissues and the lumen that enteropathogens...
Intestinal mucus is the first line of defense against intestinal pathogens. It acts as a physical barrier between epithelial tissues and the lumen that enteropathogens must overcome to establish a successful infection. We investigated the motile behavior of two strains (El Tor C6706 and Classical O395) in mucus using single-cell tracking in unprocessed porcine intestinal mucus. We determined that can penetrate mucus using flagellar motility and that alkaline pH increases swimming speed and, consequently, improves mucus penetration. Microrheological measurements indicate that changes in pH between 6 and 8 (the physiological range for the human small intestine) had little effect on the viscoelastic properties of mucus. Finally, we determined that acidic pH promotes surface attachment by activating the mannose-sensitive hemagglutinin (MshA) pilus in El Tor C6706 without a measurable change in the total cellular concentration of the secondary messenger cyclic dimeric GMP (c-di-GMP). Overall, our results support the hypothesis that pH is an important factor affecting the motile behavior of and its ability to penetrate mucus. Therefore, changes in pH along the human small intestine may play a role in determining the preferred site for during infection. The diarrheal disease cholera is still a burden for populations in developing countries with poor sanitation. To develop effective vaccines and prevention strategies against , we must understand the initial steps of infection leading to the colonization of the small intestine. To infect the host and deliver the cholera toxin, has to penetrate the mucus layer protecting the intestinal tissues. However, the interaction of with intestinal mucus has not been extensively investigated. In this report, we demonstrated using single-cell tracking that can penetrate intestinal mucus using flagellar motility. In addition, we observed that alkaline pH improves the ability of to penetrate mucus. This finding has important implications for understanding the dynamics of infection, because pH varies significantly along the small intestine, between individuals, and between species. Blocking mucus penetration by interfering with flagellar motility in , reinforcing the mucosa, controlling intestinal pH, or manipulating the intestinal microbiome will offer new strategies to fight cholera.
Topics: Animals; Bacterial Proteins; Cholera; Cholera Toxin; Gene Expression Regulation, Bacterial; Humans; Hydrogen-Ion Concentration; Intestinal Mucosa; Mucus; Swine; Vibrio cholerae
PubMed: 33468594
DOI: 10.1128/JB.00607-20 -
Cold Spring Harbor Perspectives in... Nov 2012Our model of the MUC2 mucin shows a well-organized netlike gel that is cross-linked by six different covalent and noncovalent bonds. When the MUC2 mucin is packed in the... (Review)
Review
Our model of the MUC2 mucin shows a well-organized netlike gel that is cross-linked by six different covalent and noncovalent bonds. When the MUC2 mucin is packed in the mucin granule it is organized by an amino-terminal concatenated ring platform formed at high calcium and low pH. This packing allows an ordered release and a normal mucin expansion when calcium is removed and pH increased by bicarbonate. This process is defective in the absence of cystic fibrosis transmembrane conductance regulator (CFTR)-dependent bicarbonate transport. The expanded secreted mucin is suggested to be self-organizing by properties inherited in the MUC2 mucin and by proteolytic processes.
Topics: Bicarbonates; Gels; Glycosylation; Humans; Mucin-2; Mucins; Mucus; Polysaccharides; Protein Conformation
PubMed: 23125206
DOI: 10.1101/cshperspect.a014159 -
Biological & Pharmaceutical Bulletin 2015Nasal mucociliary clearance is one of the most important factors affecting nasal delivery of drugs and vaccines. This is also the most important physiological defense... (Review)
Review
Nasal mucociliary clearance is one of the most important factors affecting nasal delivery of drugs and vaccines. This is also the most important physiological defense mechanism inside the nasal cavity. It removes inhaled (and delivered) particles, microbes and substances trapped in the mucus. Almost all inhaled particles are trapped in the mucus carpet and transported with a rate of 8-10 mm/h toward the pharynx. This transport is conducted by the ciliated cells, which contain about 100-250 motile cellular appendages called cilia, 0.3 µm wide and 5 µm in length that beat about 1000 times every minute or 12-15 Hz. For efficient mucociliary clearance, the interaction between the cilia and the nasal mucus needs to be well structured, where the mucus layer is a tri-layer: an upper gel layer that floats on the lower, more aqueous solution, called the periciliary liquid layer and a third layer of surfactants between these two main layers. Pharmacokinetic calculations of the mucociliary clearance show that this mechanism may account for a substantial difference in bioavailability following nasal delivery. If the formulation irritates the nasal mucosa, this mechanism will cause the irritant to be rapidly diluted, followed by increased clearance, and swallowed. The result is a much shorter duration inside the nasal cavity and therefore less nasal bioavailability.
Topics: Cilia; Humans; Mucins; Mucociliary Clearance; Mucus; Pharmaceutical Preparations
PubMed: 25739664
DOI: 10.1248/bpb.b14-00398 -
The European Respiratory Journal Jan 1998Respiratory tract mucus is a viscoelastic gel, the rheological properties of which are determined mainly by its content of mucous glycoproteins and water. The rheology... (Review)
Review
Respiratory tract mucus is a viscoelastic gel, the rheological properties of which are determined mainly by its content of mucous glycoproteins and water. The rheology and quantity of mucus, in concert with ciliary factors, are the major determinants of mucociliary clearance. A wide range of animal models for studying the secretion and clearance of mucus are available. Ex vivo models, such as the frog palate or excised bovine trachea, provide direct, meaningful data regarding the clearability of mucus. Rodent models of chronic bronchitis, based on irritant gas or cigarette smoke exposure, show important features of the human condition in a relatively short time. The rheological characterization of mucus is made difficult by the small quantities obtainable, particularly from normal animals. Large animal models, such as the dog or sheep, although more expensive, offer many advantages, such as the ability to carry out long-term serial measurements, and to make integrated measurements of the clearance of mucus, ciliary function, epithelial ion transport, and the rheology of mucus in the same preparation.
Topics: Animals; Cough; Disease Models, Animal; Elasticity; Humans; Models, Biological; Mucociliary Clearance; Mucus; Rheology; Viscosity
PubMed: 9543296
DOI: 10.1183/09031936.98.11010222