![]() CS is principally associated with protein cores to form proteoglycans. They are distributed in the matrix of connective tissue all over the body, and on the surface cells of organ systems.Ĭhondroitin sulphate (CS) is the most abundant GAG located on the urothelial luminal surface and was found to contribute to barrier function in studies on both human and animal models. ĭistribution of urothelial GAGs: In mammalian tissue there are four main structural families of GAGs: chondroitin and dermatan sulphates, heparins and heparan sulphates, hyaluronate, and keratan sulphate. We also know that barrier dysfunction may be a secondary effect in some conditions such as acute spinal cord injury, hypoperfusion, ageing and hormonal changes. However, although barrier dysfunction appears to play an important role in BPS/IC, and this has been demonstrated in several trials, a multi-factorial aetiology is likely. Loss of this barrier function has been associated with molecular and histological changes and gene expression consequent to passage of irritant substances from the urine into the urothelial cellular layer these include recruitment of inflammatory cytokines, overexpression of pro-inflammatory genes and neural upregulation. Most uncharged low molecular weight solutes and macromolecular solutes cannot get through this. Urothelial GAGs have a high density of negative charge at the surface which leads to a physical phenomenon of a strong ordering of water molecules at the surface of the bladder into a gel via a process known as electrostatic entrapment. “Loss of barrier function has been associated with molecular and histological changes, and gene expression consequent to passage of irritant substances from the urine.” Proteoglycans play a number of important roles in the extracellular matrix and on cell surfaces. They are bound to a core protein to form a proteoglycan. The GAG layer is composed of polyanionic chains of variable length constructed from repeating disaccharide units, which contain a hexosamine residue and a uronic acid. These mediate many fundamental cellular processes, including cell-matrix and cell-cell adhesion, motility, growth and signalling. The vascularity of the bladder wall is a key factor in the preservation of barrier function.Ĭomposition and function of the GAG layer: Animal cells ubiquitously display a large array of glycoproteins, glycolipids, and proteoglycans on their surface. This barrier is not impermeable: it is balanced with regards to inflow and outflow of substances. This consists of several uroplakins, a GAG layer, tight junctions and adherence cell junctions – this collectively forms a permeability barrier for substances in the urine such as solutes, potassium and bacteria from entering the urothelium. The luminal surface of the umbrella cell membrane is covered by a specialised asymmetrical structure called a glycocalyx. The urothelium comprises a number of distinct layers of which the surface cell layer is composed of umbrella cells. Structure of the urothelial barrier: The bladder acts as a reservoir during the storage phase of the micturition cycle and is therefore subjected to exposure to various urinary constituents and shear stress from large volume changes. This review seeks to provide an update on the current clinical and pre-clinical evidence for intravesical GAG replenishment therapies. As a corollary, various inflammatory and chronic conditions of the bladder, including the painful bladder syndrome / interstitial cystitis (BPS/IC), have been associated with barrier dysfunction.Īlthough significant advances have been made in this area, much remains to be known what we do know is that it is a lot more complex than we previously thought. ![]() The barrier function and cellular signalling properties have without doubt now established the urothelium as a first responder to various physiological and non-physiological stimuli or stress, be it mechanical, chemical, microbiological, or hormonal. However, the active role of the urothelium in normal physiology and in the genesis of lower urinary tract dysfunction has become apparent only in recent years. The barrier function of the glycosaminoglycan (GAG) layer of the urothelium was identified by Parsons in 1975, and intravesical therapies to treat chronic inflammatory conditions of the bladder were developed soon after.
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