A slippery slope: On the origin, role and physiology of mucus☆
Graphical abstract
Introduction
The mucosal barriers of the human body are integral not only to protect against immunological, chemical and mechanical stresses, but have also increasingly gained prominence for their key role in drug delivery. Mucosa consists of one or more layers of epithelial cells overlying a layer of loose connective tissue, the lamina propria; which is a key part of the mucosal immune system, and followed by the submucosa, consisting of submucosal glands and muscular layers. Some specialized mucosal epithelial cells (such as goblet cells) secrete mucus glycoproteins, which form a layer of viscoelastic mucus on the surface of epithelia. Mucus per se is a semi-permeable network that enables the exchange of nutrients, water, gases, hormones and gametes, whilst being impermeable to most bacteria and pathogens due to its steric obstruction and adhesion properties [1], [2]. Cell surface mucins are a prominent feature of the apical glycocalyx of all mucosal epithelia [3].
The properties and functions of mucus secretions are adapted to suit the anatomical location, and can change (as cause or consequence) in disease states where mucus hypersecretion or altered mucin expression is observed [3], [4]. Indeed, the differing compositions of the mucosa and mucus of the eye, nose, lower respiratory tract, gastrointestinal tract, cervix and vagina are all individually unique and adapted to perform the functions of these barriers seamlessly, whilst simultaneously protecting the underlying epithelium. For instance, the epithelia of the respiratory tract form a mucociliary escalator [4] that aids the movement and expulsion of trapped inhaled foreign bodies, whereas the transmembrane mucins tethered in the periciliary layer (PCL) form a sieve restricting particles > 40 nm from translocating into the PCL, thereby maintaining sterility [5], [6]. In turn, a double-layer mucus architecture in the hostile zones of the stomach and colon protect the underlying lining from acid, enzymes (pepsin and proteases) and microbial aggressors [7], [8]. Endogenous hormone secretion from the epithelia of the cervix and vagina also changes the viscoelasticity of cervical mucus in different stages of the menstrual cycle, to either promote or prevent conception [9]. Dietary influences have also been observed to modulate the colonic mucus; low-fibre diets, for instance, have been shown to lead to thinning of mucus owing to associated bacterial colonization [10], [11]. This thinning exposes the epithelium to bacterial contact and translocation into the mucosa, eliciting an immunological response and further damage and inflammation, as seen in ulcerative colitis [12]. These properties of mucus in the healthy state, however, make it an excellent guard against immunological as well as chemical and mechanical damage, thereby allowing the mucosa to carry out its normal physiological functions.
While mucus precludes the permeation of drugs, proteins, peptides and nanoparticulate drug delivery systems [13], [14], certain capsid viruses have been observed to diffuse through cervicovaginal mucus at rates similar to that in water [15], implying that this barrier cannot restrict surface neutral particles from reaching and infecting the epithelium. Additionally, the mucus pore size and rheology also influence this phenomenon [16]. This property has been exploited towards the design of muco-inert polyethylene glycol coated nanoparticles that are muco-penetrating for cervico-vaginal and ocular delivery [17], [18]. Overall, this knowledge can be used to design drug delivery systems to diffuse ‘upstream’ against the secretion and shedding of mucus to deliver drugs to epithelia.
Furthermore, mucus secreting epithelia continuously secrete and turnover mucus to create a physiological clearance mechanism. However, this protective mechanism can also cause undesirable drug clearance, a common barrier to drug delivery. As such, in order to deliver the drug payload, and hence achieve the desired drug exposure, prolonged contact of the formulation at the target site is desirable. Mucoadhesive systems have been employed by virtue of their ability to interact with the mucin glycoprotein; whereby mucoadhesive excipients by swelling and interdiffusion of the polymer chains bond with mucin fibres through hydrogen bonding, disulfide bonding, electrostatic and/or hydrophobic interactions. An in-depth review of mucoadhesion as a concept to increase residence time is beyond the scope of this review which focuses on the physiological aspects of mucosa and mucus and therefore the following references [19], [20], [21], [22], [23] will provide the reader with greater insight in the area of mucoadhesion.
This article reviews the mucosal histology in relation to the arrangement of goblet cells and submucosal glands. The biosynthesis and release mechanism of mucin from the goblet cells and the physiological and mechanical characteristics of the mucus lining different epithelia are here discussed. Additionally, the functionality of the mucus lining and its dynamic composition are discussed in their role of health and disease.
Section snippets
Mucosa and mucus: histological, biosynthetic, biochemical and rheological overview
The mucosal epithelium is interspersed with goblet cells which secrete mucus and protect the epithelial cells. If antigenic materials translocate through the epithelium, it triggers an immune response in the underlying lamina propria and submucosa which can comprise the connective tissues of the mucosa [24], [25]. The immune response is characterized by inflammation and epithelial destruction, exacerbating the damage. Therefore, mucus serves as a tenacious semipermeable barrier allowing only
The slippery slope: variations in mucus along the gastrointestinal (GI) tract
The gastrointestinal wall is composed of four different layers: the mucosa, the submucosa, the muscularis and the serosa. The mucosa is further subdivided into three main layers: the muscularis mucosa, lamina propria and the epithelium. The mucus largely establishes the first barrier for absorption through the gastrointestinal tract. Fig. 3 illustrates the mucus architecture along the gastrointestinal tract of humans.
Sweeping the dirt away: mucosa and mucus of the respiratory tract
The nasal cavity has an anterior chamber, the nasal vestibule which is followed by the respiratory tract which is highly folded providing a high surface area to volume ratio. The nasal vestibule consists of keratinized stratified squamous epithelial cells and the respiratory regions consisting of the inferior, middle and superior turbinates are made of pseudostratified ciliated columnar cells (Fig. 5) with microvilli and cilia thereby providing an area of 120 cm2 [131]. This region produces the
Is the cervical and vaginal mucus similar?
The cervix connects the vagina with the uterus and functioning as an entrance into the female endometrial and abdominal cavities. Therefore, a protection mechanism has to be in place to avoid external microorganisms to gain access. The vagina wall is structured in a lamina propria and an epithelium of non-cornified stratified squamous cells. The thickness of this epithelial barrier is higher in puberty and after menopause. The luminal pH decreases after puberty to about pH 4–5, depending on the
Protecting the sclera: the pre-corneal tear film and conjunctival epithelium
The eye (Fig. 6) is covered by a wet surface epithelium over coating the cornea, conjunctiva and other inner surfaces, which has similar functions as other wet surfaces, including lubrication, protection against damage, fluid loss and pathogens infection [209], [210]. The epithelium of the cornea also plays a role in the transmission of light and refraction. The tear film is composed by an outer lipid layer and by the inner aqueous layer which is composed by anti-bacteria proteins and mucins.
Conclusion
This review has served to highlight the adaptations of mucosal surfaces and mucus to promote their optimal and healthy functioning. Factors including mucus hydrophobicity, viscoelasticity, turnover and thickness, as well as epithelial dynamics (such as mucociliary clearance in the respiratory tract) work together to enable mucus to function as a tenacious semi-permeable barrier. However, this useful mucus barrier can also create a slippery slope of challenges to mucosal drug and gene delivery
Acknowledgements
We thank Atheer Awad for assisting with the technicalities involved in preparing the graphical abstract.
Funding source
This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
Conflicts of interest
None.
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This review is part of the Advanced Drug Delivery Reviews theme issue on “Technological strategies to overcome the mucus barrier in mucosal drug delivery”