BERKELEY, CA (UroToday.com) - Interstitial cystitis (IC) represents a real conundrum for the urologist. First, the diagnosis is by exclusion, which means there are no objective diagnostic criteria. This lack probably means that it is a heterogeneous disorder. Second, and probably related to the first problem, is that clinical trials of most treatments have not fared well with poor response rates being observed.
|"These findings convincingly demonstrate that restoring the permeability barrier by artificial means does produce a physiologic effect and reduces the recruitment of inflammatory cells."|
One of the main theories about IC is that the so-called "GAG layer" (GAG is the acronym for glycosaminoglycan) is damaged or absent in IC and that the lack of the GAG layer allows urine solutes to penetrate into the bladder. This theory was first proposed by C. Lowell Parsons over 20 years ago.[1,2] The symptoms of pain and urgency are proposed to result from penetration of potassium ions, which depolarize sensory nerves, and a maladaptive response to the resulting low-level inflammation is proposed to result in upregulation of sensory nerves, possibly involving VEGF signaling.[4-6]
Because of my earlier interest in GAG biology, Lowell Parsons interested me in the problem of IC and how the GAG layer contributes to the impermeability of the bladder. I showed early that the bladder was, in fact, densely coated with GAG [7,8] and quantified the amount while also showing that it consisted mainly of a mixture of chondroitin sulfate (ChS) and heparan sulfate (HS).  When we showed that this layer was deficient in IC patients  and Lowell Parsons showed that the semi-synthetic GAG pentosan polysulfate (Elmiron) was effective in relieving the symptoms for many IC patients, this led to the introduction of Elmiron as a therapeutic. The concept of "GAG replenishment therapy" entered the lexicon. Subsequently heparin, hyaluronan (Cystistat) [10,11] and chondroitin sulfate (Uracyst)  have also been used and found to be effective in at least some patients.
Clearly, however, damage to the GAG layer was not the entire story. In IC patients, immunohistochemical analysis showed that a number of other differentiation- and barrier-related proteins were expressed abnormally in biopsies.[13,14] Conspicuously absent were any studies showing how GAG replenishment therapy might actually work. We addressed this problem in several papers, culminating in the current one. A major problem with IC research is the absence of any animal models that replicate the human disease. Given that often the layer of luminal cells ("umbrella" cells) is compromised or absent, we and others have used a model in which these cells are removed by dilute acid, protamine sulfate or cyclophoshphamide. This is an acute model, whereas IC is a chronic disease, but nonetheless, this model produces bladder permeability. We first showed that chondroitin sulfate binds specifically to damaged areas of the urothelium, thus supporting the GAG replenishment therapy hypothesis . We used chondroitin sulfate in these studies because heparan, pentosan polysulfate and hyaluronan all have pharmacologic effects, which are much less for chondroitin sulfate thereby making an effect on the barrier more evident. We next demonstrated that when chondroitin sulfate bound to the damaged bladder surface that it did, in fact, restore impermeability to 86Rb+ ions, a mimetic for K+ to control levels, thereby providing very strong evidence that the "GAG layer" does play a major role in producing the impermeability of the urothelium.
These findings still did not show whether restoring the impermeability of the bladder produced a physiologic effect, which led to the current study. We decided that if restoring the barrier was effective, it would substantially inhibit the recruitment of inflammatory cells. C. Dirk Engels, one of our Urology residents doing his research rotation in my lab, took a strong interest in this problem. We first had to overcome the problem that when the acid treatment was used, the superficial layer of cells did not desquamate immediately. Premature treatment with chondroitin sulfate would simply lead to its loss with the cells when they did desquamate. We therefore waited 24 hours before administering the chondroitin sulfate. We then examined the presence of inflammatory cells in the suburothelial space. Mast cells were stained with toluidine blue, lymphocytes were labeled with CD45, and neutrophils were labeled with myeloperoxidase. Dirk Engels carefully counted entire transverse sections (not just a field here or there) taken from near the middle half of the bladder. We very clearly showed that treatment of the damaged urothelium with chondroitin sulfate markedly inhibited the recruitment of both mast cells and neutrophils. Lymphocytes were not affected by the damage and or by the chondroitin sulfate treatment. These findings convincingly demonstrate that restoring the permeability barrier by artificial means does produce a physiologic effect and reduces the recruitment of inflammatory cells. These findings therefore provide a physiologic basis for "GAG replenishment therapy," at least insofar as this acute model is concerned.
Where these studies need to go next is human patients, to demonstrate that the human bladder is, in fact, more permeable and that GAG replenishment does restore it to the normal impermeable state. This would also allow the optimal dosing schedule to be determined and might identify patents likely to benefit from long-term therapy. IC is a horrible disease, causing untold suffering in its victims. It ruins lives not only of the sufferers but of their families as well. I am very happy if my efforts contribute to an effective treatment.
- Parsons CL, Lilly JD, Stein P: Epithelial dysfunction in nonbacterial cystitis (interstitial cystitis). J Urol 1991, 145: 732-735.
- Parsons CL, Boychuk D, Jones S, Hurst RE, Callahan H: Bladder surface glycosaminoglycans: an epithelial permeability barrier. J Urol 1990, 143: 139-142.
- Parsons CL, Stein PC, Bidair M, Lebow D: Abnormal sensitivity to intravesical potassium in interstitial cystitis and radiation cystitis. Neurourol Urodyn 1994, 13: 515-520.
- Saban MR, Davis CA, Avelino A, Cruz F, Maier J, Bjorling DE, Sferra TJ, Hurst RE, Saban R: VEGF signaling mediates bladder neuroplasticity and inflammation in response to BCG. BMC Physiol 2011, 11: 16 PM:22059553.
- Saban MR, Backer JM, Backer MV, Maier J, Fowler B, Davis CA, Simpson C, Wu XR, Birder L, Freeman MR, Soker S, Hurst RE, Saban R: VEGF receptors and neuropilins are expressed in the urothelial and neuronal cells in normal mouse urinary bladder and are upregulated in inflammation. Am J Physiol Renal Physiol 2008, 295: F60-F72 PM:18463314.
- Saban R, Saban MR, Maier J, Fowler B, Tengowski M, Davis CA, Wu XR, Culkin DJ, Hauser P, Backer J, Hurst RE: Urothelial expression of Neuropilins and VEGF receptors in control and interstitial cystitis patients. Am J Physiol Renal Physiol 2008, 295: F1613-F1623 PM:18815217.
- Hurst RE, Zebrowski R: Identification of proteoglycans present at high density on bovine and human bladder luminal surface. J Urol 1994, 152: 1641-1645.
- Hurst RE, Rhodes SW, Adamson PB, Parsons CL, Roy JB: Functional and structural characteristics of the glycosaminoglycans of the bladder luminal surface. J Urol 1987, 138: 433-437.
- Hurst RE, Roy JB, Min KW, Veltri RW, Marley G, Patton K, Shackelford, DL, Stein P, Parsons CL: A deficit of chondroitin sulfate proteoglycans on the bladder uroepithelium in interstitial cystitis. Urology 1996, 48: 817-821.
- Nordling J, Jorgensen S, Kallestrup E: Cystistat for the treatment of interstitial cystitis: a 3-year follow-up study. Urology 2001, 57: 123 PM:11378112.
- Morales A, Emerson L, Nickel JC, Lundie M: Intravesical hyaluronic acid in the treatment of refractory interstitial cystitis. J Urol 1996, 156: 45-48.
- Steinhoff G, Ittah B, Rowan S: The efficacy of chondroitin sulfate 0.2% in treating interstitial cystitis. Can J Urol 2002, 9: 1454-1458.
- Hauser PJ, Dozmorov MG, Bane BL, Slobodov G, Culkin DJ, Hurst RE: Abnormal expression of differentiation related proteins and proteoglycan core proteins in the urothelium of patients with interstitial cystitis. J Urol 2008, 179: 764-769 PM:18082196.
- Slobodov G, Feloney M, Gran C, Kyker KD, Hurst RE, Culkin DJ: Abnormal Expression of Molecular Markers for Bladder Impermeability and Differentiation in Urothelium of Interstitial Cystitis Patients. J Urol 2004, 171: 1554-1558 PM:15017219.
- Hauser PJ, Buethe DA, Califano J, Sofinowski TM, Culkin DJ, Hurst RE: Restoring barrier function to acid damaged bladder by intravesical chondroitin sulfate. J Urol 2009, 182: 2477-2482 PM:19765766.
Robert E. Hurst, PhD as part of Beyond the Abstract on UroToday.com. This initiative offers a method of publishing for the professional urology community. Authors are given an opportunity to expand on the circumstances, limitations etc... of their research by referencing the published abstract.
Professor of Urology and Director of Basic Research
Member, Peggy and Charles Stephenson Oklahoma Cancer Center
Adjunct Professor of Biochemistry and Molecular Biology
Adjunct Professor of Occupational and Environmental Health
105 Biomedical Sciences Building
Oklahoma University Health Sciences Center
940 S.L. Young Blvd.
Oklahoma City, OK 73104 USA