Increased bladder permeability in interstitial cystitis/painful bladder syndrome

Abstract

The definition of interstitial cystitis (IC) has evolved over the years from being a well-defined entity characterized by diagnostic lesion (Hunner's ulcer) in the urothelium to a clinical diagnosis by exclusion (painful bladder syndrome (PBS). Although the etiology is unknown, a central theme has been an association with increased permeability of the bladder. This article reviews the evidence for increased permeability being important to the symptoms of IC/PBS and in treating the disorder. Recent work showing cross-communication among visceral organs is also reviewed to provide a basis for understanding IC/PBS as a systemic disorder of a complex, interconnected system consisting of the bladder, bowel and other organs, nerves, cytokine-responding cells and the nervous system.

Keywords: Animal; Cystitis; Interstitial; Irritable Bowel Syndrome; Models; Permeability; Urinary bladder.

Figure 1

Schematic illustration of bladder anatomy. The stroma is composed of the detrusor muscle, connective tissue, nerves, and the veins, arteries and capillaries of the connective system. The urothelium sits atop the lamina propria. The nerves, and capillaries do not penetrate the lamina propria but do connect with it. Therefore the bladder urothelium is less well supplied than are other epithelia. Also found are neurons, including the sensory, sympathetic and parasympathetic systems. These generally are found adjacent to the lamina propria, indicating the lamina may respond to neural signals. The basal layer is the lowest layer of cells. These are generally the only cells that divide. The stem cells, here one is shown in pink, also exist within the basal cell layer. Atop the basal cells is a layer of 3-5 cells deep comprised of intermediate cells. Not shown is that these cells maintain a connection via a cytoplasmic process to the lamina propria (not shown). Most likely this connection serves a cell communication function. The outer layer of cells, or umbrella cells, are highly specialized and terminally differentiated. They may be multinucleated as the result of cell fusion. Their lifetime is as much as 6 months or more. Loss of an umbrella cell immediately leads to the underlying intermediate cell to differentiate and replace the lost umbrella cell. The umbrella cells are coated with a dense layer of GAG, mostly if not exclusively, chondroitin sulfate. They also have tight junctions here shown in red along their basolateral surfaces. Together the uroplakin plaques (not shown) and GAG on the apical surface plus the tight junctions combine to make the urothelium the least permeable mammalian epithelium. GAG, glycosaminoglycan.

Figure 2

Schematic of mechanisms producing increased bladder permeability. (A) Organic cations in the urine neutralize the GAG layer producing increased permeability. This occurs because they are present in abnormally high amounts or Tamm-Horsfall protein, the anionic cation scavenger in urine is defective with missing glycosylation. The increased permeability allows potassium ions and other molecules to pass into the urothelium or deeper, causing irritation, triggering inflammatory cells, and sending sensory signals. Upregulation of sensory fibers occurs; (B) the sensory signaling from the bladder affects other tissues as well as the bladder to cause increased bowel permeability. Increased bowel permeability from causes within the bowel (e.g., IBS) also signals back to the bladder causing increased bladder permeability by unknown mechanisms. Communication is through the dorsal root ganglia. The pain signal is also transmitted to the brain where chronic pain can rewire the brain; (C) signaling through the vagus nerve releases neurotransmitters and cytokines that activate mast cells and macrophages that then increase bladder permeability; (D) long-term effects on the brain, such as early life stress may potentiate some individuals toward IC/PBS by mechanisms that are not well understood. GAG, glycosaminoglycan; IBS, irritable bowel syndrome; IC/PBS, interstitial cystitis/painful bladder syndrome.