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EDITORIAL: CELLULAR FACTORS AND THE OBSTRUCTED BLADDER
0022-5347/00/1644-1334/0 THE JOURNAL OF UROLOGY® Copyright © 2000 by AMERICAN UROLOGICAL ASSOCIATION, INC.®
Vol. 164, 1334 –1335, October 2000 Printed in U.S.A.
EDITORIAL: CELLULAR FACTORS AND THE OBSTRUCTED BLADDER KEY WORDS: bladder; hydrostatic pressure; muscle, smooth; mitogens
When the bladder is subjected to prolonged outlet obstruction, several pathological changes may occur in the bladder wall that may functionally alter bladder compliance. These undesired alterations in bladder wall dynamics may give rise to numerous clinical conditions ranging from mild bladder irritability to upper tract dilatation and subsequent renal damage. Despite the abundance of clinical and basic science research on the effects of bladder outlet obstruction there are still several vitally important questions to which we currently lack answers. How do histological changes in the obstructed bladder wall (muscle hypertrophy and excess extracellular matrix protein deposition) correlate with alterations in bladder wall compliance? Why do some obstructive changes in the bladder wall persist after obstruction is relieved and what factors govern reversibility? What role do nerves and innervation have in the development of obstructive changes? Why is there such variability in the way that individual bladders respond to outlet obstruction? To answer these questions, we must first have a better understanding of the mechanisms that translate the condition of increased stress on the bladder wall to cellular messages that induce alterations in smooth muscle growth and contractility, extracellular matrix protein production and neurophysiological stability in the bladder wall. It is likely that a complex interplay occurs between bladder cells, and the surrounding stroma and nerves that directs what types of changes develop in bladder wall architecture and compliance. Identifying the cellular factors involved in this interplay would have significant functional implications in our ability to prevent and treat pathological changes in the obstructed bladder. During the last decade there has been a push in pediatric urology research to identify cellular factors in the obstructed bladder wall responsible for specific alterations in smooth muscle cell growth and function. Two factors currently being investigated at several laboratories that may be important for abnormal muscle growth in the obstructed bladder are angiotensin II and heparin binding epidermal growth factor. Angiotensin II has been shown to be mitogenic to cultured bladder smooth muscle cells1 and inhibiting angiotensin converting enzyme inhibition decreases the hyperplastic muscle response in the obstructed rabbit bladder.2 Park et al demonstrated that mechanical stretch activates heparin binding epidermal growth factor gene expression in bladder smooth muscle cells in vitro, which is partially mediated by autocrine angiotensin II secretion.3 Borer et al further showed that heparin binding epidermal growth factor gene expression and protein production are increased in the muscle layer of the obstructed mouse bladder.4 These in vitro and in vivo observations imply that angiotensin II and heparin binding epidermal growth factor are mitogenic factors to bladder smooth muscle cells, and increased heparin binding epidermal growth factor production may depend on mechanically induced autocrine angiotensin II secretion from smooth muscle cells. In this issue of The Journal Haberstroh et al (page 1329) provide further evidence to support this hypothesis. In their study conditioned medium from smooth muscle cells subjected to sustained hydrostatic pressure had a mitogenic effect on quiescent smooth muscle cells not subjected to hydrostatic pressure. This mitogenic response was inhibited by the heparin binding epidermal growth factor antagonist CRM197. They also observed that hydrostatic pressure only
induced smooth muscle cell proliferation. Given these observations they suggest that heparin binding epidermal growth factor is released from smooth muscle cells in response to hydrostatic pressure and this soluble heparin binding epidermal growth factor in turn induces smooth muscle cell mitogenesis via an autocrine and/or paracrine mechanism. If this scenario is true, as suggested by the title of this article, one would expect to detect inhibition of the hyperplastic response of smooth muscle cells by CRM197 when cells are subjected to sustained hydrostatic pressure only. These important data are lacking in the current study and would greatly strengthen the validity of the conclusions. Haberstroh et al also suggest that CRM197 may have clinical application for preventing bladder tissue hypertrophy and altered bladder compliance in bladder outlet obstruction. While this hypothesis may also ultimately be found to be true, the observations in this study do not support this statement since CRM197 inhibited the hyperplastic and not the hypertrophic response of bladder smooth muscle cells. It cannot be interpreted from the available data whether smooth muscle cells in this in vitro assay have a hypertrophic response to hydrostatic pressure and heparin binding epidermal growth factor or whether this response may be inhibited by CRM197. However, if further research and the administration of CRM197 in animal models of bladder outlet obstruction demonstrate that it does inhibit muscle hypertrophy, this agent would potentially have important clinical usefulness. Reviewing this series brings to mind several general thoughts that deserve comment. When considering studies of in vitro cultured cells, one must remember that these cells are in a highly artificial environment and in vitro observations do not always translate into in vivo reality. Similarly although in vitro models of mechanical stress (sustained hydrostatic pressure or cyclical stretch) are novel and important cell culture tools, they do not necessarily replicate the in vivo setting of bladder outlet obstruction. Yet it is the hope of all investigators who use various cell culture models that in vitro observations of these models are partially reflective of events in vivo and clinically effective treatments would result from these observations. Using animal models to validate in vitro observations is an important adjunct to cell culture research. However, one must always keep in mind that animal organs are not human organs and they may react to pathological conditions differently. For example, a histological hallmark of the obstructed rabbit bladder is the development of serosal hyperplasia, which does not occur in humans.5 Nevertheless, the basis of human clinical trials and experimental treatment protocols must first come from observations made in the basic science laboratory. Bladder research and urology research as a whole are entering an exciting time, in that the cellular and molecular basis of disease is becoming more clear every day. Current basic science research efforts will be truly translational in nature and have far-reaching clinical implications. In the setting of bladder obstruction we would hopefully have new treatment modalities other than surgically relieving obstruction and waiting to see the response of the bladder. Molecular and/or histological markers may help us to prognosticate which patients would do well with observation only and which would require further therapy. Further identification of the important cellular factors involved in obstructive bladder wall changes would lead to the development of antago-
1334
CELLULAR FACTORS AND OBSTRUCTED BLADDER
nists to these factors. Clinically this advance would impact our ability to reverse pathological changes in the bladder wall and also prevent them in the face of ongoing partial obstruction. Earl Y. Cheng Department of Pediatric Urology Children’s Hospital of Oklahoma and University of Oklahoma Health Sciences Center Oklahoma City, Oklahoma REFERENCES
1. Cheng, E. Y., Grammatopoulos, T., Lee, C. et al: Angiotensin II and basic fibroblast growth factor induce neonatal bladder stromal cell mitogenesis. J Urol, part 2, 156: 593, 1996
1335
2. Cheng, E. Y., Lee, C., Decker, R. S. et al: Captopril (an inhibitor of angiotensin converting enzyme) inhibits obstructive changes in the neonatal rabbit bladder. Urology, 50: 465, 1997 3. Park, J. M., Borer, J. G., Freeman, M. R. et al: Stretch activates heparin-binding EGF-like growth factor expression in bladder smooth muscle cells. Am J Physiol, 275: C1247, 1998 4. Borer, J. G., Park, J. M., Atala, A. et al: Heparin-binding EGFlike growth factor expression increases selectively in bladder smooth muscle in response to lower urinary tract obstruction. Lab Invest, 79: 1335, 1999 5. Monson, F. C., Goldschmidt, M. H., Zderic, S. A. et al: Use of a previously undescribed elastic lamina serosa to characterize connective tissue hypertrophy of the rabbit bladder wall following partial outlet obstruction. Neurourol Urodyn, 7: 385, 1988
Vol. 164, 1334 –1335, October 2000 Printed in U.S.A.
EDITORIAL: CELLULAR FACTORS AND THE OBSTRUCTED BLADDER KEY WORDS: bladder; hydrostatic pressure; muscle, smooth; mitogens
When the bladder is subjected to prolonged outlet obstruction, several pathological changes may occur in the bladder wall that may functionally alter bladder compliance. These undesired alterations in bladder wall dynamics may give rise to numerous clinical conditions ranging from mild bladder irritability to upper tract dilatation and subsequent renal damage. Despite the abundance of clinical and basic science research on the effects of bladder outlet obstruction there are still several vitally important questions to which we currently lack answers. How do histological changes in the obstructed bladder wall (muscle hypertrophy and excess extracellular matrix protein deposition) correlate with alterations in bladder wall compliance? Why do some obstructive changes in the bladder wall persist after obstruction is relieved and what factors govern reversibility? What role do nerves and innervation have in the development of obstructive changes? Why is there such variability in the way that individual bladders respond to outlet obstruction? To answer these questions, we must first have a better understanding of the mechanisms that translate the condition of increased stress on the bladder wall to cellular messages that induce alterations in smooth muscle growth and contractility, extracellular matrix protein production and neurophysiological stability in the bladder wall. It is likely that a complex interplay occurs between bladder cells, and the surrounding stroma and nerves that directs what types of changes develop in bladder wall architecture and compliance. Identifying the cellular factors involved in this interplay would have significant functional implications in our ability to prevent and treat pathological changes in the obstructed bladder. During the last decade there has been a push in pediatric urology research to identify cellular factors in the obstructed bladder wall responsible for specific alterations in smooth muscle cell growth and function. Two factors currently being investigated at several laboratories that may be important for abnormal muscle growth in the obstructed bladder are angiotensin II and heparin binding epidermal growth factor. Angiotensin II has been shown to be mitogenic to cultured bladder smooth muscle cells1 and inhibiting angiotensin converting enzyme inhibition decreases the hyperplastic muscle response in the obstructed rabbit bladder.2 Park et al demonstrated that mechanical stretch activates heparin binding epidermal growth factor gene expression in bladder smooth muscle cells in vitro, which is partially mediated by autocrine angiotensin II secretion.3 Borer et al further showed that heparin binding epidermal growth factor gene expression and protein production are increased in the muscle layer of the obstructed mouse bladder.4 These in vitro and in vivo observations imply that angiotensin II and heparin binding epidermal growth factor are mitogenic factors to bladder smooth muscle cells, and increased heparin binding epidermal growth factor production may depend on mechanically induced autocrine angiotensin II secretion from smooth muscle cells. In this issue of The Journal Haberstroh et al (page 1329) provide further evidence to support this hypothesis. In their study conditioned medium from smooth muscle cells subjected to sustained hydrostatic pressure had a mitogenic effect on quiescent smooth muscle cells not subjected to hydrostatic pressure. This mitogenic response was inhibited by the heparin binding epidermal growth factor antagonist CRM197. They also observed that hydrostatic pressure only
induced smooth muscle cell proliferation. Given these observations they suggest that heparin binding epidermal growth factor is released from smooth muscle cells in response to hydrostatic pressure and this soluble heparin binding epidermal growth factor in turn induces smooth muscle cell mitogenesis via an autocrine and/or paracrine mechanism. If this scenario is true, as suggested by the title of this article, one would expect to detect inhibition of the hyperplastic response of smooth muscle cells by CRM197 when cells are subjected to sustained hydrostatic pressure only. These important data are lacking in the current study and would greatly strengthen the validity of the conclusions. Haberstroh et al also suggest that CRM197 may have clinical application for preventing bladder tissue hypertrophy and altered bladder compliance in bladder outlet obstruction. While this hypothesis may also ultimately be found to be true, the observations in this study do not support this statement since CRM197 inhibited the hyperplastic and not the hypertrophic response of bladder smooth muscle cells. It cannot be interpreted from the available data whether smooth muscle cells in this in vitro assay have a hypertrophic response to hydrostatic pressure and heparin binding epidermal growth factor or whether this response may be inhibited by CRM197. However, if further research and the administration of CRM197 in animal models of bladder outlet obstruction demonstrate that it does inhibit muscle hypertrophy, this agent would potentially have important clinical usefulness. Reviewing this series brings to mind several general thoughts that deserve comment. When considering studies of in vitro cultured cells, one must remember that these cells are in a highly artificial environment and in vitro observations do not always translate into in vivo reality. Similarly although in vitro models of mechanical stress (sustained hydrostatic pressure or cyclical stretch) are novel and important cell culture tools, they do not necessarily replicate the in vivo setting of bladder outlet obstruction. Yet it is the hope of all investigators who use various cell culture models that in vitro observations of these models are partially reflective of events in vivo and clinically effective treatments would result from these observations. Using animal models to validate in vitro observations is an important adjunct to cell culture research. However, one must always keep in mind that animal organs are not human organs and they may react to pathological conditions differently. For example, a histological hallmark of the obstructed rabbit bladder is the development of serosal hyperplasia, which does not occur in humans.5 Nevertheless, the basis of human clinical trials and experimental treatment protocols must first come from observations made in the basic science laboratory. Bladder research and urology research as a whole are entering an exciting time, in that the cellular and molecular basis of disease is becoming more clear every day. Current basic science research efforts will be truly translational in nature and have far-reaching clinical implications. In the setting of bladder obstruction we would hopefully have new treatment modalities other than surgically relieving obstruction and waiting to see the response of the bladder. Molecular and/or histological markers may help us to prognosticate which patients would do well with observation only and which would require further therapy. Further identification of the important cellular factors involved in obstructive bladder wall changes would lead to the development of antago-
1334
CELLULAR FACTORS AND OBSTRUCTED BLADDER
nists to these factors. Clinically this advance would impact our ability to reverse pathological changes in the bladder wall and also prevent them in the face of ongoing partial obstruction. Earl Y. Cheng Department of Pediatric Urology Children’s Hospital of Oklahoma and University of Oklahoma Health Sciences Center Oklahoma City, Oklahoma REFERENCES
1. Cheng, E. Y., Grammatopoulos, T., Lee, C. et al: Angiotensin II and basic fibroblast growth factor induce neonatal bladder stromal cell mitogenesis. J Urol, part 2, 156: 593, 1996
1335
2. Cheng, E. Y., Lee, C., Decker, R. S. et al: Captopril (an inhibitor of angiotensin converting enzyme) inhibits obstructive changes in the neonatal rabbit bladder. Urology, 50: 465, 1997 3. Park, J. M., Borer, J. G., Freeman, M. R. et al: Stretch activates heparin-binding EGF-like growth factor expression in bladder smooth muscle cells. Am J Physiol, 275: C1247, 1998 4. Borer, J. G., Park, J. M., Atala, A. et al: Heparin-binding EGFlike growth factor expression increases selectively in bladder smooth muscle in response to lower urinary tract obstruction. Lab Invest, 79: 1335, 1999 5. Monson, F. C., Goldschmidt, M. H., Zderic, S. A. et al: Use of a previously undescribed elastic lamina serosa to characterize connective tissue hypertrophy of the rabbit bladder wall following partial outlet obstruction. Neurourol Urodyn, 7: 385, 1988