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Physiological Reviews Oct 2022The mucus clearance system is the dominant mechanical host defense system of the human lung. Mucus is cleared from the lung by cilia and airflow, including both... (Review)
Review
The mucus clearance system is the dominant mechanical host defense system of the human lung. Mucus is cleared from the lung by cilia and airflow, including both two-phase gas-liquid pumping and cough-dependent mechanisms, and mucus transport rates are heavily dependent on mucus concentration. Importantly, mucus transport rates are accurately predicted by the gel-on-brush model of the mucociliary apparatus from the relative osmotic moduli of the mucus and periciliary-glycocalyceal (PCL-G) layers. The fluid available to hydrate mucus is generated by transepithelial fluid transport. Feedback interactions between mucus concentrations and cilia beating, via purinergic signaling, coordinate Na absorptive vs Cl secretory rates to maintain mucus hydration in health. In disease, mucus becomes hyperconcentrated (dehydrated). Multiple mechanisms derange the ion transport pathways that normally hydrate mucus in muco-obstructive lung diseases, e.g., cystic fibrosis (CF), chronic obstructive pulmonary disease (COPD), non-CF bronchiectasis (NCFB), and primary ciliary dyskinesia (PCD). A key step in muco-obstructive disease pathogenesis is the osmotic compression of the mucus layer onto the airway surface with the formation of adherent mucus plaques and plugs, particularly in distal airways. Mucus plaques create locally hypoxic conditions and produce airflow obstruction, inflammation, infection, and, ultimately, airway wall damage. Therapies to clear adherent mucus with hydrating and mucolytic agents are rational, and strategies to develop these agents are reviewed.
Topics: Cystic Fibrosis; Humans; Lung; Mucociliary Clearance; Mucus; Pulmonary Disease, Chronic Obstructive
PubMed: 35001665
DOI: 10.1152/physrev.00004.2021 -
Annals of the American Thoracic Society Nov 2018The lung is continuously exposed to particles, toxicants, and microbial pathogens that are cleared by a complex mechanical, innate, and acquired immune system.... (Review)
Review
The lung is continuously exposed to particles, toxicants, and microbial pathogens that are cleared by a complex mechanical, innate, and acquired immune system. Mucociliary clearance, mediated by the actions of diverse conducting airway and submucosal gland epithelial cells, plays a critical role in a multilayered defense system by secreting fluids, electrolytes, antimicrobial and antiinflammatory proteins, and mucus onto airway surfaces. The mucociliary escalator removes particles and pathogens by the mechanical actions of cilia and cough. Abnormalities in mucociliary clearance, whether related to impaired fluid secretion, ciliary dysfunction, lack of cough, or the disruption of epithelial cells lining the respiratory tract, contribute to the pathogenesis of common chronic pulmonary disorders. Although mucus and other airway epithelial secretions play a critical role in protecting the lung during acute injury, impaired mucus clearance after chronic mucus hyperproduction causes airway obstruction and infection, which contribute to morbidity in common pulmonary disorders, including chronic obstructive pulmonary disease, asthma, idiopathic pulmonary fibrosis, cystic fibrosis, bronchiectasis, and primary ciliary dyskinesia. In this summary, the molecular and cellular mechanisms mediating airway mucociliary clearance, as well as the role of goblet cell metaplasia and mucus hyperproduction, in the pathogenesis of chronic respiratory diseases are considered.
Topics: Cell Differentiation; Cilia; Epithelial Cells; Humans; Lung Diseases; Mucins; Mucociliary Clearance; Mucus
PubMed: 30431340
DOI: 10.1513/AnnalsATS.201802-128AW -
Immunological Reviews Jul 2014The gastrointestinal tract is covered by mucus that has different properties in the stomach, small intestine, and colon. The large highly glycosylated gel-forming mucins... (Review)
Review
The gastrointestinal tract is covered by mucus that has different properties in the stomach, small intestine, and colon. The large highly glycosylated gel-forming mucins MUC2 and MUC5AC are the major components of the mucus in the intestine and stomach, respectively. In the small intestine, mucus limits the number of bacteria that can reach the epithelium and the Peyer's patches. In the large intestine, the inner mucus layer separates the commensal bacteria from the host epithelium. The outer colonic mucus layer is the natural habitat for the commensal bacteria. The intestinal goblet cells secrete not only the MUC2 mucin but also a number of typical mucus components: CLCA1, FCGBP, AGR2, ZG16, and TFF3. The goblet cells have recently been shown to have a novel gate-keeping role for the presentation of oral antigens to the immune system. Goblet cells deliver small intestinal luminal material to the lamina propria dendritic cells of the tolerogenic CD103(+) type. In addition to the gel-forming mucins, the transmembrane mucins MUC3, MUC12, and MUC17 form the enterocyte glycocalyx that can reach about a micrometer out from the brush border. The MUC17 mucin can shuttle from a surface to an intracellular vesicle localization, suggesting that enterocytes might control and report epithelial microbial challenge. There is communication not only from the epithelial cells to the immune system but also in the opposite direction. One example of this is IL10 that can affect and improve the properties of the inner colonic mucus layer. The mucus and epithelial cells of the gastrointestinal tract are the primary gate keepers and controllers of bacterial interactions with the host immune system, but our understanding of this relationship is still in its infancy.
Topics: Animals; Enterocytes; Gastrointestinal Tract; Goblet Cells; Humans; Immune System; Mucins; Mucous Membrane; Mucus; Peyer's Patches
PubMed: 24942678
DOI: 10.1111/imr.12182 -
Current Biology : CB Aug 2021Mucus is a slimy hydrogel that lines the mucosal surfaces in our body, including the intestines, stomach, eyes, lungs and urogenital tract. This glycoprotein-rich...
Mucus is a slimy hydrogel that lines the mucosal surfaces in our body, including the intestines, stomach, eyes, lungs and urogenital tract. This glycoprotein-rich network is truly the jack of all trades. As a barrier, it lubricates surfaces, protects our cells from physical stress, and selectively allows the passage of nutrients while clearing out pathogens and debris. As a home to our microbiota, it supports a level of microbial diversity that is unattainable with most culture methods. As a reservoir of complex carbohydrate structures called glycans, it plays critical roles in controlling cell adhesion and signaling, and it alters the behavior and spatial distribution of microbes. On top of all this, mucus regulates the passage of sperm during fertilization, heals wounds, helps us smell, and prevents the stomach from digesting itself, to name just a few of its functions. Given these impressive features, it is no wonder that mucus crosses boundaries of species and kingdoms - mucus gels are made by organisms ranging from the simplest metazoans to corals, snails, fish, and frogs. It is also no surprise that mucus is exploited in everyday applications, including foods, cosmetics, and other products relevant to medicine and industry.
Topics: Animals; Intestines; Microbiota; Mucous Membrane; Mucus; Nutrients
PubMed: 34375594
DOI: 10.1016/j.cub.2021.06.093 -
Annals of Allergy, Asthma & Immunology... Nov 2023Airways diseases are typically accompanied by inflammation, which has long been known to contribute to obstruction, mucus hypersecretion, dyspnea, cough, and other... (Review)
Review
Airways diseases are typically accompanied by inflammation, which has long been known to contribute to obstruction, mucus hypersecretion, dyspnea, cough, and other characteristic symptoms displayed in patients. Clinical interventions, therefore, often target inflammation to reverse lung pathology and reduce morbidity. The airways and lungs are densely innervated by subsets of nerve fibers, which are not only impacted by pulmonary inflammation but, in addition, likely serve as important regulators of immune cell function. This bidirectional neuroimmune crosstalk is supported by close spatial relationships between immune cells and airway nerve fibers, complementary neural and immune signaling pathways, local specialized airway chemosensory cells, and dedicated reflex circuits. In this article, we review the recent literature on this topic and present state-of-the-art evidence supporting the role of neuroimmune interactions in airway inflammation. In addition, we extend this evidence to synthesize considerations for the clinical translation of these discoveries to improve the management of patients with airway disease.
Topics: Humans; Inflammation; Pneumonia; Lung; Cough; Signal Transduction; Mucus
PubMed: 37517657
DOI: 10.1016/j.anai.2023.07.020 -
International Journal of Molecular... Nov 2020Preterm births are a global health priority that affects 15 million babies every year worldwide. There are no effective prognostic and therapeutic strategies relating to... (Review)
Review
Preterm births are a global health priority that affects 15 million babies every year worldwide. There are no effective prognostic and therapeutic strategies relating to preterm delivery, but uterine infections appear to be a major cause. The vaginal epithelium is covered by the cervicovaginal mucus, which is essential to health because of its direct involvement in reproduction and functions as a selective barrier by sheltering the beneficial lactobacilli while helping to clear pathogens. During pregnancy, the cervical canal is sealed with a cervical mucus plug that prevents the vaginal flora from ascending toward the uterine compartment, which protects the fetus from pathogens. Abnormalities of the cervical mucus plug and bacterial vaginosis are associated with a higher risk of preterm delivery. This review addresses the current understanding of the cervicovaginal mucus and the cervical mucus plug and their interactions with the microbial communities in both the physiological state and bacterial vaginosis, with a focus on gel-forming mucins. We also review the current state of knowledge of gel-forming mucins contained in mouse cervicovaginal mucus and the mouse models used to study bacterial vaginosis.
Topics: Animals; Cervix Uteri; Female; Humans; Infectious Disease Transmission, Vertical; Mice; Microbiota; Mucins; Mucus; Pregnancy; Pregnancy Complications, Infectious; Vagina; Vaginosis, Bacterial
PubMed: 33158227
DOI: 10.3390/ijms21218266 -
Gut Microbes 2022The immune system in the large intestine is separated from commensal microbes and comparatively rare enteric pathogens by a monolayer of diverse epithelial cells... (Review)
Review
The immune system in the large intestine is separated from commensal microbes and comparatively rare enteric pathogens by a monolayer of diverse epithelial cells overlaid with a compact and adherent inner mucus layer and a looser outer mucus layer. Microorganisms, collectively referred to as the mucus-associated (MA) microbiota, physically inhabit this mucus barrier, resulting in a dynamic and incessant dialog to maintain both spatial segregation and immune tolerance. Recent major findings reveal novel features of the crosstalk between the immune system and mucus-associated bacteria in health and disease, as well as disease-related peripheral immune signatures indicative of host responses to these organisms. In this brief review, we integrate these novel observations into our overall understanding of host-microbiota mutualism at the colonic mucosal border and speculate on the significance of this emerging knowledge for our understanding of the prevention, development, and progression of chronic intestinal inflammation.
Topics: Colon; Gastrointestinal Microbiome; Humans; Immune System; Inflammation; Intestinal Mucosa; Mucus; Symbiosis
PubMed: 35239459
DOI: 10.1080/19490976.2022.2041342 -
Advanced Drug Delivery Reviews Dec 2022The surfaces of human internal organs are lined by a mucus layer that ensures symbiotic relationships with commensal microbiome while protecting against potentially... (Review)
Review
The surfaces of human internal organs are lined by a mucus layer that ensures symbiotic relationships with commensal microbiome while protecting against potentially injurious environmental chemicals, toxins, and pathogens, and disruption of this layer can contribute to disease development. Studying mucus biology has been challenging due to the lack of physiologically relevant human in vitro models. Here we review recent progress that has been made in the development of human organ-on-a-chip microfluidic culture models that reconstitute epithelial tissue barriers and physiologically relevant mucus layers with a focus on lung, colon, small intestine, cervix and vagina. These organ-on-a-chip models that incorporate dynamic fluid flow, air-liquid interfaces, and physiologically relevant mechanical cues can be used to study mucus composition, mechanics, and structure, as well as investigate its contributions to human health and disease with a level of biomimicry not possible in the past.
Topics: Humans; Colon; Lab-On-A-Chip Devices; Microbiota; Microfluidics; Mucus; Models, Biological
PubMed: 36179916
DOI: 10.1016/j.addr.2022.114542 -
International Journal of Molecular... Sep 2022Mucociliary clearance is a critical defense mechanism for the lungs governed by regionally coordinated epithelial cellular activities, including mucin secretion, cilia... (Review)
Review
Mucociliary clearance is a critical defense mechanism for the lungs governed by regionally coordinated epithelial cellular activities, including mucin secretion, cilia beating, and transepithelial ion transport. Cystic fibrosis (CF), an autosomal genetic disorder caused by the dysfunction of the cystic fibrosis transmembrane conductance regulator (CFTR) channel, is characterized by failed mucociliary clearance due to abnormal mucus biophysical properties. In recent years, with the development of highly effective modulator therapies, the quality of life of a significant number of people living with CF has greatly improved; however, further understanding the cellular biology relevant to CFTR and airway mucus biochemical interactions are necessary to develop novel therapies aimed at restoring gene expression in the lungs. In this article, we discuss recent advances of transcriptome analysis at single-cell levels that revealed a heretofore unanticipated close relationship between secretory MUC5AC and MUC5B mucins and CFTR in the lungs. In addition, we review recent findings on airway mucus biochemical and biophysical properties, focusing on how mucin secretion and CFTR-mediated ion transport are integrated to maintain airway mucus homeostasis in health and how CFTR dysfunction and restoration of function affect mucus properties.
Topics: Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Humans; Mucociliary Clearance; Mucus; Quality of Life
PubMed: 36142171
DOI: 10.3390/ijms231810232 -
Current Opinion in Biotechnology Aug 2018Mucus is a hydrogel that exhibits complex selective permeability, permitting the passage of some particles while restricting the passage of other particles including... (Review)
Review
Mucus is a hydrogel that exhibits complex selective permeability, permitting the passage of some particles while restricting the passage of other particles including important therapeutics. In this review, we discuss biochemical mechanisms underlying mucus penetration and mucus binding, emphasizing the importance of steric, electrostatic, and hydrophobic interactions. We discuss emerging techniques for engineering nanoparticle surface chemistries for mucus penetration as well as recent advances in tuning mucus interactions with small molecule, peptide, or protein therapeutics. Finally, we highlight recent work suggesting that mucus permeability can serve as a biomarker for disease and physiological states such as pregnancy.
Topics: Animals; Disease; Health; Humans; Mucus; Permeability; Tissue Engineering
PubMed: 29674157
DOI: 10.1016/j.copbio.2018.03.010