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Editorial: Interstitial Cystitis
0022-534 7/94/1523-0879$03.00/0 THE JOURNAL OF UROLOGY Copyright© 1994 by AMERICAN UROLOGICAL AssOCIATION, INC.
Vol. 152, 879-880, September 1994
Printed in U.S.A.
EDITORIAL: INTERSTITIAL CYSTITIS As one reads through the literature regarding the subject of interstitial cystitis we are impressed by the fact that the same opening comments are strikingly repetitive, making some points very clear. Interstitial cystitis is a chronic syndrome with fairly characteristic symptoms and clinical findings. The practicing urologist should be familiar with the National Institute of Arthritis, and Digestive and Kidney Diseases symptoms and cystoscopic findings that one must have to qualify as an interstitial cystitis patient.1 Other diseases may cause similar symptoms and should obviously be absent in the interstitial cystitis patient, such as infection, malignancy and so forth. There is no doubt that multiple etiologies are capable of causing these symptoms. Therefore, we cannot look at this syndrome as a single disease. In our opinion, different initiating substances or events result in specific pathogenic pathways that could understandably result in the classical symptom complex. Therefore, we must be careful about trying to explain this disease with 1 simple theory. We cannot be too critical of a theory that explains 30 or 50% of the problem. Also, different stages of the disease and varying severity may result in different experimental results. Possibly, different initiating factors would result in a pathological pathway that may or may not be common to all. It is difficult for the clinical investigator to compile significant data because there is no specific marker for this disorder. We would judge that a common marker probably would be a final result of damage to the urinary tract caused by chronic insult. In any event, clinicians, and clinical and laboratory researchers now have a clearer picture of this entity as a real problem that causes a tremendous amount of suffering, mainly in the female population. Because of this fact we are obligated to attack this disorder with vigor clinically and in the research laboratory. What appears to be most important currently is to understand the pathogenesis of this disorder so that we can either treat or arrest the process. Two articles in this issue analyzed interleukin-6 and active kallikrein and their possible roles in interstitial cystitis. Interleukin-6, a cytokine, is a product of inflammatory cells activated by different stimuli. Not only is it present in many disease states but it also is valuable as a measure of disease activity. Lotz et al (page 869) demonstrated urinary interleukin-6 levels as an assessment of pain severity in the interstitial cystitis patient. The presence of interleukin-6 was determined in urine specimens capable of inducing the proliferation of a B9 hybridoma line. Further confirmation of interleukin-6 biological activity was noted by neutralization with specific antibody to interleukin-6. These investigators observed significantly elevated urinary levels of interleukin-6 in 71 interstitial cystitis patients compared to 20 controls with mean levels approximately 5-fold higher. The interleukin-6 measurements positively correlated with levels of pain. In situ hybridization further confirmed high urinary levels to be associated with the cellular origin of interleukin-6 in bladder tissue of 4 interstitial cystitis patients who were undergoing cystoplasty. Interleukin-6 was shown to be the product of activated endothelial cells, epithelial cells and interstitial stroma cells. Recent research presentations by others noted that a small number of interstitial cystitis patients had detectable levels of interleukin-6 in the urine.2 Weak signals of interleukin-6messenger ribonucleic acid were isolated from cultured urothelial cells activated by interferon--y and/or tumor necrosis factor, and the lack ofexpression ofmessenger ribonucleic acid for interleukin-6 was noted in interstitial cystitis blad-
der tissue specimens.3 These studies stated that low levels of interleukin-6 are present in some interstitial cystitis patient specimens without any correlation to the interstitial cystitis symptom of pain. Lotz et al clearly demonstrated the associ ation of elevated interleukin-6 cellular expression and urine levels with increased pain in the interstitial cystitis disease state, especially from interstitial cystitis patients at cysto plasty. A possible explanation for these divergent observa tions may be the expression ofinterleukin-6 at lower levels or not at all when specimens are obtained early in the disease or during quiescent periods. In painful end stage disease, at cystoplasty, interleukin-6 may be more actively expressed. Lotz et al looked upon urinary interleukin-6 as an indicator for distinguishing asymptomatic from symptomatic intersti tial cystitis and clearly eliminated interleukin-6 as a marker ofthe disease because ofthe presence ofinterleukin-6 in body fluids from numerous inflammatory diseases. They discussed the possibility of substance P, a principal mediator of pain and an activator ofinterleukin-6 expression, having a role in the regulation of interleukin-6 levels correlated with pain. Pang et al verified substance P-immunoreactive nerve fibers to be greater in interstitial cystitis patients relative to con trols,4 therefore, strengthening further investigations ofsub stance P and interleukin-6 as potential contributors in a neuroimmuno-interaction towards the severe progression of the interstitial cystitis disease state. Zuraw et al (page 874) cited from the literature that lysyl bradykinin, the end product of the kallikrein-kinin system, has been indicated as a potent mediator of pain, local edema formation and smooth muscle contraction. Kinins were noted to promote fibrosis and neuropeptide release, and contri bute to mast cell degranulation. The effects produced by this system seem to fit naturally the pathological conditions of interstitial cystitis. This study also demonstrated a predom inant mechanism for pain differences by increased activation of urinary prokallikrein to kallikrein. These researchers investigated the activation of the urinary kallikrein-kinin system in the pathophysiology of inter stitial cystitis bladder pain. Using a chromogenic assay, uri nary kallikrein was determined by cleavage of the synthetic substrate Val-Leu-Arg-pNA. As a group, 86 interstitial cystitis patients had significantly higher levels of kal likrein activity compared to 33 normal controls. Increased kallikrein activity was correlated with increasing symptoms of bladder pain and voiding frequency. Even with varying production of prokallikrein by the kidneys, the reason for a statistically significant difference between the controls and interstitial cystitis patients is the percentage ofprokallikrein converted to active kallikrein. This difference became more evident with the stratification ofpatients as to pain severity. The percentage of active kallikrein was not correlated with voiding frequency. Equally important in this study were the urinary kal likrein changes after therapeutic bladder hydrodistention. Five of 10 patients were successfully treated by hydrodisten tion and experienced a relief of the bladder symptoms. Of these interstitial cystitis patients 4 had marked decreases in urinary kallikrein levels after treatment compared to initial specimen collection before hydrodistention. The nonresponders to treatment showed an increase in urinary kallikrein levels. This is the first interstitial cystitis report of an objective mea surement correlated with a subjective pain reliefin response to treatment. The authors suggest that control of the active kallikrein levels may be due to the release ofproteases or inflammatory
879
880
INTERSTITIAL CYSTITIS
cathepsins. Increased bladder wall permeability has been cited in interstitial cystitis investigations as an etiology or an effect. 5• 6 The alteration of bladder permeability in intersti tial cystitis might allow the migration of these agents into the urine for activation of prokallikrein as well as the free mobility of the kinin end product inward to the tissue neu roreceptors for pain. In a recent editorial on interstitial cystitis similar points were discussed that we have eluded to in the present editorial. 7 Three articles in the February issue of the Jour nal dealt specifically with deficiencies in the bladder muco sal permeability and inflammatory/immunogenic mecha nisms. 3-10 The 2 articles in the present issue investigated an inflammatory pathway and mediation of pain. The literature is replete with theories as to the etiology, which is beyond the scope of this editorial. Probably because of the numerous inciting factors, one finds that different treatment modalities aimed at specific mechanisms seem to be successful in sub groups of patients. It is not at all difficult to understand why analgesics, antihistamines, anticholinergics, inhibitors of mast cell granulation, Hl and H2 blockers, anti-inflamma tory agents and affectors of smooth muscle physiology or neuromuscular stimulation may be successful in some pa tients. In the last 5 years, investigations have become more active because of stimulation through the Interstitial Cystitis Association and the National Institutes of Health. Not only are more data being accumulated as to etiology and epidemi ology but also laboratory investigation has become much more sophisticated. Interesting animal models are being de veloped to investigate further the pathogenesis and molecu lar alterations in this disease. S. Grant Mulholland and Dolores Shupp Byrne Department of Urology Thomas Jefferson University Philadelphia, Pennsylvania
REFERENCES
1. Gillenwater, J. Y. and Wein, A. J.: Summary of the National Institute of Arthritis, Diabetes, Digestive and Kidney Diseases workshop on interstitial cystitis, National Institutes of Health, Bethesda, Maryland, August 28 -29, 1987. J. Urol., 140: 203, 1988. 2. Felsen, D., Frye, S., Trimble, L. A., Bavendam, T. G., Parsons, C. L., Sim, Y. and Vaughan, E. D.: Inflammatory mediator profile in urine and bladder wash fluid of patients with inter stitial cystitis. Presented at the Symposium on Women's Uro logical Health Research, abstract, p. 121, March 11-13, 1994. 3. Liebert, M., Wedemeyer, G., Stein, J., Chung, M., Hubbel, A., Faerber, G. and Grossman, H. B.: Cytokine profiles in inter stitial cystitis. J. Urol., part 2, 151: 283A, abstract 224, 1994. 4. Pang, X., Marchand, J., Sant, G. R., Kream, R. M. and Theoharides, T. C.: Increased numbers of substance P (SP) positive nerve fibers associated with bladder mast cells in interstitial cystitis. Presented at Research Symposium on In terstitial Cystitis, abstract, p. 44, October 7- 8, 1993. 5. Parsons, C. L., Boychuk, D., Jones, S., Hurst, R. and Callahan, H.: Bladder surface glycosaminoglycans: an epithelial perme ability barrier. J. Urol., 143: 139, 1990. 6. Parsons, C. L., Lilly, J. D. and Stein, P.: Epithelial dysfunction in nonbacterial cystitis (interstitial cystitis). J. Urol., 145: 732, 1991. 7. Messing, E. M.: Interstitial cystitis. J. Urol., 151: 355, 1994. 8. Moskowitz, M. 0., Byrne, D. S., Callahan, H. J., Parsons, C. L., Valderrama, E. and Moldwin, R. M.: Decreased expression of glycoprotein component of bladder surface mucin (GPl) in interstitial cystitis. J. Urol., 151: 343, 1994. 9. Chelsky, M. J., Rosen, S. I., Knight, L. C., Maurer, A. H. Hanno, P. M. and Ruggieri, M. R.: Bladder permeability in interstitial cystitis is similar to that of normal volunteers: direct measure ment by transvesical absorption of 99mtechnetium-diethylene triaminepentaacetic acid. J. Urol., 151: 346, 1994. 10. Steinert, B. W., Diokno, A. C., Robinson, J. E. and Mitchell, B. A.: Complement C3, eosinophil cationic protein and symptom evaluation in interstitial cystitis. J. Urol., 151: 350, 1994.
Vol. 152, 879-880, September 1994
Printed in U.S.A.
EDITORIAL: INTERSTITIAL CYSTITIS As one reads through the literature regarding the subject of interstitial cystitis we are impressed by the fact that the same opening comments are strikingly repetitive, making some points very clear. Interstitial cystitis is a chronic syndrome with fairly characteristic symptoms and clinical findings. The practicing urologist should be familiar with the National Institute of Arthritis, and Digestive and Kidney Diseases symptoms and cystoscopic findings that one must have to qualify as an interstitial cystitis patient.1 Other diseases may cause similar symptoms and should obviously be absent in the interstitial cystitis patient, such as infection, malignancy and so forth. There is no doubt that multiple etiologies are capable of causing these symptoms. Therefore, we cannot look at this syndrome as a single disease. In our opinion, different initiating substances or events result in specific pathogenic pathways that could understandably result in the classical symptom complex. Therefore, we must be careful about trying to explain this disease with 1 simple theory. We cannot be too critical of a theory that explains 30 or 50% of the problem. Also, different stages of the disease and varying severity may result in different experimental results. Possibly, different initiating factors would result in a pathological pathway that may or may not be common to all. It is difficult for the clinical investigator to compile significant data because there is no specific marker for this disorder. We would judge that a common marker probably would be a final result of damage to the urinary tract caused by chronic insult. In any event, clinicians, and clinical and laboratory researchers now have a clearer picture of this entity as a real problem that causes a tremendous amount of suffering, mainly in the female population. Because of this fact we are obligated to attack this disorder with vigor clinically and in the research laboratory. What appears to be most important currently is to understand the pathogenesis of this disorder so that we can either treat or arrest the process. Two articles in this issue analyzed interleukin-6 and active kallikrein and their possible roles in interstitial cystitis. Interleukin-6, a cytokine, is a product of inflammatory cells activated by different stimuli. Not only is it present in many disease states but it also is valuable as a measure of disease activity. Lotz et al (page 869) demonstrated urinary interleukin-6 levels as an assessment of pain severity in the interstitial cystitis patient. The presence of interleukin-6 was determined in urine specimens capable of inducing the proliferation of a B9 hybridoma line. Further confirmation of interleukin-6 biological activity was noted by neutralization with specific antibody to interleukin-6. These investigators observed significantly elevated urinary levels of interleukin-6 in 71 interstitial cystitis patients compared to 20 controls with mean levels approximately 5-fold higher. The interleukin-6 measurements positively correlated with levels of pain. In situ hybridization further confirmed high urinary levels to be associated with the cellular origin of interleukin-6 in bladder tissue of 4 interstitial cystitis patients who were undergoing cystoplasty. Interleukin-6 was shown to be the product of activated endothelial cells, epithelial cells and interstitial stroma cells. Recent research presentations by others noted that a small number of interstitial cystitis patients had detectable levels of interleukin-6 in the urine.2 Weak signals of interleukin-6messenger ribonucleic acid were isolated from cultured urothelial cells activated by interferon--y and/or tumor necrosis factor, and the lack ofexpression ofmessenger ribonucleic acid for interleukin-6 was noted in interstitial cystitis blad-
der tissue specimens.3 These studies stated that low levels of interleukin-6 are present in some interstitial cystitis patient specimens without any correlation to the interstitial cystitis symptom of pain. Lotz et al clearly demonstrated the associ ation of elevated interleukin-6 cellular expression and urine levels with increased pain in the interstitial cystitis disease state, especially from interstitial cystitis patients at cysto plasty. A possible explanation for these divergent observa tions may be the expression ofinterleukin-6 at lower levels or not at all when specimens are obtained early in the disease or during quiescent periods. In painful end stage disease, at cystoplasty, interleukin-6 may be more actively expressed. Lotz et al looked upon urinary interleukin-6 as an indicator for distinguishing asymptomatic from symptomatic intersti tial cystitis and clearly eliminated interleukin-6 as a marker ofthe disease because ofthe presence ofinterleukin-6 in body fluids from numerous inflammatory diseases. They discussed the possibility of substance P, a principal mediator of pain and an activator ofinterleukin-6 expression, having a role in the regulation of interleukin-6 levels correlated with pain. Pang et al verified substance P-immunoreactive nerve fibers to be greater in interstitial cystitis patients relative to con trols,4 therefore, strengthening further investigations ofsub stance P and interleukin-6 as potential contributors in a neuroimmuno-interaction towards the severe progression of the interstitial cystitis disease state. Zuraw et al (page 874) cited from the literature that lysyl bradykinin, the end product of the kallikrein-kinin system, has been indicated as a potent mediator of pain, local edema formation and smooth muscle contraction. Kinins were noted to promote fibrosis and neuropeptide release, and contri bute to mast cell degranulation. The effects produced by this system seem to fit naturally the pathological conditions of interstitial cystitis. This study also demonstrated a predom inant mechanism for pain differences by increased activation of urinary prokallikrein to kallikrein. These researchers investigated the activation of the urinary kallikrein-kinin system in the pathophysiology of inter stitial cystitis bladder pain. Using a chromogenic assay, uri nary kallikrein was determined by cleavage of the synthetic substrate Val-Leu-Arg-pNA. As a group, 86 interstitial cystitis patients had significantly higher levels of kal likrein activity compared to 33 normal controls. Increased kallikrein activity was correlated with increasing symptoms of bladder pain and voiding frequency. Even with varying production of prokallikrein by the kidneys, the reason for a statistically significant difference between the controls and interstitial cystitis patients is the percentage ofprokallikrein converted to active kallikrein. This difference became more evident with the stratification ofpatients as to pain severity. The percentage of active kallikrein was not correlated with voiding frequency. Equally important in this study were the urinary kal likrein changes after therapeutic bladder hydrodistention. Five of 10 patients were successfully treated by hydrodisten tion and experienced a relief of the bladder symptoms. Of these interstitial cystitis patients 4 had marked decreases in urinary kallikrein levels after treatment compared to initial specimen collection before hydrodistention. The nonresponders to treatment showed an increase in urinary kallikrein levels. This is the first interstitial cystitis report of an objective mea surement correlated with a subjective pain reliefin response to treatment. The authors suggest that control of the active kallikrein levels may be due to the release ofproteases or inflammatory
879
880
INTERSTITIAL CYSTITIS
cathepsins. Increased bladder wall permeability has been cited in interstitial cystitis investigations as an etiology or an effect. 5• 6 The alteration of bladder permeability in intersti tial cystitis might allow the migration of these agents into the urine for activation of prokallikrein as well as the free mobility of the kinin end product inward to the tissue neu roreceptors for pain. In a recent editorial on interstitial cystitis similar points were discussed that we have eluded to in the present editorial. 7 Three articles in the February issue of the Jour nal dealt specifically with deficiencies in the bladder muco sal permeability and inflammatory/immunogenic mecha nisms. 3-10 The 2 articles in the present issue investigated an inflammatory pathway and mediation of pain. The literature is replete with theories as to the etiology, which is beyond the scope of this editorial. Probably because of the numerous inciting factors, one finds that different treatment modalities aimed at specific mechanisms seem to be successful in sub groups of patients. It is not at all difficult to understand why analgesics, antihistamines, anticholinergics, inhibitors of mast cell granulation, Hl and H2 blockers, anti-inflamma tory agents and affectors of smooth muscle physiology or neuromuscular stimulation may be successful in some pa tients. In the last 5 years, investigations have become more active because of stimulation through the Interstitial Cystitis Association and the National Institutes of Health. Not only are more data being accumulated as to etiology and epidemi ology but also laboratory investigation has become much more sophisticated. Interesting animal models are being de veloped to investigate further the pathogenesis and molecu lar alterations in this disease. S. Grant Mulholland and Dolores Shupp Byrne Department of Urology Thomas Jefferson University Philadelphia, Pennsylvania
REFERENCES
1. Gillenwater, J. Y. and Wein, A. J.: Summary of the National Institute of Arthritis, Diabetes, Digestive and Kidney Diseases workshop on interstitial cystitis, National Institutes of Health, Bethesda, Maryland, August 28 -29, 1987. J. Urol., 140: 203, 1988. 2. Felsen, D., Frye, S., Trimble, L. A., Bavendam, T. G., Parsons, C. L., Sim, Y. and Vaughan, E. D.: Inflammatory mediator profile in urine and bladder wash fluid of patients with inter stitial cystitis. Presented at the Symposium on Women's Uro logical Health Research, abstract, p. 121, March 11-13, 1994. 3. Liebert, M., Wedemeyer, G., Stein, J., Chung, M., Hubbel, A., Faerber, G. and Grossman, H. B.: Cytokine profiles in inter stitial cystitis. J. Urol., part 2, 151: 283A, abstract 224, 1994. 4. Pang, X., Marchand, J., Sant, G. R., Kream, R. M. and Theoharides, T. C.: Increased numbers of substance P (SP) positive nerve fibers associated with bladder mast cells in interstitial cystitis. Presented at Research Symposium on In terstitial Cystitis, abstract, p. 44, October 7- 8, 1993. 5. Parsons, C. L., Boychuk, D., Jones, S., Hurst, R. and Callahan, H.: Bladder surface glycosaminoglycans: an epithelial perme ability barrier. J. Urol., 143: 139, 1990. 6. Parsons, C. L., Lilly, J. D. and Stein, P.: Epithelial dysfunction in nonbacterial cystitis (interstitial cystitis). J. Urol., 145: 732, 1991. 7. Messing, E. M.: Interstitial cystitis. J. Urol., 151: 355, 1994. 8. Moskowitz, M. 0., Byrne, D. S., Callahan, H. J., Parsons, C. L., Valderrama, E. and Moldwin, R. M.: Decreased expression of glycoprotein component of bladder surface mucin (GPl) in interstitial cystitis. J. Urol., 151: 343, 1994. 9. Chelsky, M. J., Rosen, S. I., Knight, L. C., Maurer, A. H. Hanno, P. M. and Ruggieri, M. R.: Bladder permeability in interstitial cystitis is similar to that of normal volunteers: direct measure ment by transvesical absorption of 99mtechnetium-diethylene triaminepentaacetic acid. J. Urol., 151: 346, 1994. 10. Steinert, B. W., Diokno, A. C., Robinson, J. E. and Mitchell, B. A.: Complement C3, eosinophil cationic protein and symptom evaluation in interstitial cystitis. J. Urol., 151: 350, 1994.