1 Laboratory of Epithelial Cell Biology, Department of Cell Biology and Physiology, 2 Renal-Electrolyte Division, Department of Medicine, and 3 Department of Pharmacology, University of Pittsburgh, Pittsburgh, Pennsylvania 15261
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ABSTRACT |
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Neural-epithelial interactions are hypothesized to play an important role in bladder function. We determined whether spinal cord injury (SCI) altered several indicators of urinary bladder epithelium barrier function, including continuity of the surface umbrella cell layer, transepithelial resistance (TER), and urea and water permeability. Within 2 h of SCI, significant changes in uroepithelium were noted, including disruption of the surface umbrella cells and an ~50% decrease in TER. By 24 h, TER reached a minimum and was accompanied by significant increases in water and urea permeability. Regeneration of the surface uroepithelium was accomplished by 14 days after SCI and was accompanied by a return to normal TER and urea and water permeabilities. This early disruption of the uroepithelial permeability and accompanying changes in uroepithelial morphology were prevented by pretreatment with hexamethonium (a blocker of ganglion transmission), indicating involvement of sympathetic or parasympathetic input to the urinary bladder. In addition, prior treatment with capsaicin worsened the effect of SCI on uroepithelial permeability, suggesting that capsaicin-sensitive afferents may play a protective role in the process. These results demonstrate that SCI results in a significant disruption of the urinary bladder uroepithelium and that these changes may be mediated in part by an interaction with bladder nerves.
uroepithelium; urea and water permeability; bladder nerves
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INTRODUCTION |
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THE STORAGE FUNCTION of the bladder depends on the presence of a barrier that prevents urine from being reabsorbed into the bloodstream and regulates the expulsion of urine from the body (14, 16, 17, 23, 34). During bladder filling, the outlet, which includes the bladder neck and the smooth and striated muscles of the urethra, remains closed and the smooth muscle of the bladder remains relaxed (14, 16, 17). The uroepithelium, which lines the mucosal surface of the bladder, forms the permeability barrier, which retains the urine and prevents the paracellular leakage of solutes and ions across the outermost, umbrella cell layer. Characteristics of the barrier include a high transepithelial resistance (TER) and low permeability to urea and water (27, 34). Intravesical pressure remains low during filling, and increased urine volume can be accommodated by unfolding of the mucosa and accompanying increases in the surface of the umbrella cell layer (51). When the bladder reaches capacity and voiding is initiated, the muscles of the outlet relax, and urine is expelled by contractions of the smooth detrusor muscle in the wall of the bladder.
The interplay between the outlet and the bladder is under control of the central nervous system as well as sympathetic, parasympathetic, and somatic nerves that innervate the detrusor muscle and outlet in a reciprocal fashion (14, 16, 17). Bladder innervation can be disrupted as a result of trauma or disease (14, 16, 17). For example, rostral lumbar spinal cord transection eliminates voluntary control of voiding and is accompanied by uncoordinated bladder and external urethral sphincter activity, termed detrusor-sphincter dyssynergia (7, 8, 10, 15, 16, 55). An additional consequence of spinal cord injury (SCI) is a high intravesical bladder pressure, which can lead to damage and malfunction of the upper urinary tract and hypertrophy of the smooth muscle mass (56). The latter is accompanied by enormous enlargement of the urinary bladder (32, 56). Although a great deal of attention has focused on alterations in the detrusor muscle and its innervation after SCI, much less is understood about changes in the uroepithelium and its associated barrier function that might accompany SCI.
An emerging body of literature indicates reciprocal communication
between the neuronal system and the uroepithelium. The urinary bladder
is innervated by several types of bladder afferents (A- and C
fibers), some of which are found in the muscle layers and some just
below and within the uroepithelium (5, 19, 33). Significantly, epithelium-associated afferent nerves are sensitive to
chemicals released from uroepithelial cells, including nitric oxide
(NO), prostaglandins, and ATP (2, 30, 36). The latter binds to P2X3 purinergic receptors on afferent nerves and
is likely to play an important role in detrusor contraction as well as
nociception (40, 53). In turn, uroepithelial cells respond
to various chemicals and neurotransmitters, including acetylcholine,
norepinephrine, ATP, calcitonin gene-related peptide, and substance P
(3-6). Changes elicited in the uroepithelium by a
variety of stimuli include the release of mediators such as NO and ATP
and increases in intracellular Ca2+ (3, 5, 6, 18, 48,
53). Whether neurotransmitters affect parameters associated with
uroepithelial barrier function, such as maintenance of a high TER or
low water and urea permeabilities, is not well understood, but
treatment with stress hormones, including norepinephrine, can lead
to disruption of tight junctions and loss of umbrella cells
(52).
To examine the relation between the nervous system and the uroepithelium, we have studied the effects of SCI on uroepithelial cell morphology as well as barrier function. We observed that SCI was accompanied by a rapid loss of barrier function, and these acute changes were prevented by pretreatment with the ganglion transmission blocker hexamethonium, whereas capsaicin potentiated the effects of SCI. Normal barrier function was observed 14-28 days after SCI. Our results indicate that neurotransmitter release shortly after SCI may play an important role in disrupting epithelial barrier function.
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MATERIALS AND METHODS |
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Materials and animals. Unless specified otherwise, all chemicals were obtained from Sigma (St. Louis, MO) and were of reagent grade or better. [14C]urea and [3H]water were obtained from American Radiolabeled Chemicals (St. Louis, MO). Female Sprague-Dawley rats weighing 275-350 g were fed a standard diet (Lab Diet 5P00, PMI Nutritional, Brentwood, MO) with free access to water before and after SCI. All animal studies were carried out with the approval of the University of Pittsburgh Animal Care and Use Committee, and animals were maintained according to the standards set forth in the American Physiological Society's "Guide for the Care and Use of Animals."
Rat model of SCI. Rats were anesthetized with halothane [2% (vol/vol) in oxygen], and after an epidural injection of lidocaine (Xylocaine, 5 µl) a laminectomy was aseptically performed at the T8-T9 spinal level. Gelfoam (Fisher) was placed between the cut ends of the spinal cord, and the muscle and skin were sutured. The animals were allowed to recover in the absence of anesthesia for 2 h, 1 day, 3 days, or 24 days. Sham-operated animals were placed under anesthesia, and the bone and muscle surrounding T8-T9 were removed, but the spinal cord was not transected. Sham-operated and SCI rats were given prophylactic antibiotic treatment (ampicillin, Polyflex, 100 mg/kg im daily) for 1 wk after the procedure and allowed free access to food and water. During the first 7-10 days after transection, urine was eliminated from the bladder by manual compression two to three times a day. After this time, spinal reflexes developed that allowed for autonomic control of micturition. To provide a control for effects of bladder distension that might follow acute spinalization, some spinal-intact animals were placed under continuous halothane anesthesia (which suppresses bladder reflexes) for 2.5 h before euthanasia and tissue removal. This amount of time allowed accumulation of urine volumes that were similar to those observed 2 h after SCI. In one animal with SCI, urine volume was 3 ml. The data for this animal were discarded, inasmuch as it was likely that the bladder was overdistended. In some experiments, animals were treated with hexamethonium (50 mg/kg iv; Sigma) 0.5 h before SCI. Other animals were injected with 5 µl of PBS beneath the dura of the spinal cord (via a 30-gauge needle) into the underlying gray matter, and the needle was removed without transection of the spinal cord. After incisions were sutured, the animals were allowed to recover for 2 h in the absence of anesthesia. In addition, a small number of animals (n = 4) were pretreated with capsaicin (100 mg/kg sc; Sigma) in 10% (vol/vol) ethanol-10% (vol/vol) Tween 80 in normal saline 4 days before further experimentation. Desensitization was confirmed by measuring the number of defensive forelimb eye-wipe movements in response to 100 µg/ml capsaicin solution (11). Control animals were given vehicle [10% (vol/vol) ethanol-10% (vol/vol) Tween 80 in normal saline] not containing capsaicin.
Measurements of water permeability, urea permeability, and TER. Water permeability, urea permeability, and TER were measured as described previously (24, 34). Briefly, after the treatments described above and at the designated time points, the animals were euthanized (by inhalation of medical-grade CO2 followed by thoracotomy) and the bladder was placed immediately into Ringer solution (in mM: 111.2 NaCl, 25 NaHCO3, 4.8 KCl, 2 CaCl2, 1.2 MgSO4, 1.2 KH2PO4, and 11.1 glucose) maintained at 37°C and constantly bubbled with 95% O2-5% CO2 to maintain pH at 7.4. The tissue was placed on a stretching rack with the epithelium facing downward. A ring with a 0.73-cm2 opening and surrounded by sharp metal pins was placed under the tissue and lifted up to spear the overlying tissue. Excess tissue surrounding the ring was removed with tissue scissors, and the ring and its associated bladder tissue were mounted between two halves of a modified Ussing chamber. The chambers, filled with Ringer solution, were maintained at 37°C, and the hemichambers were constantly stirred. The membranes were allowed to stabilize for 1 h before electrical measurements of TER to determine epithelial membrane integrity, and radiolabeled water and urea were added to measure permeability. Significant changes in TER were assessed by t-test.
14C-labeled (0.25 µCi/ml) urea and 3H-labeled (1 µCi/ml) water were added to the apical (luminal) side of the membrane, and both hemichambers were sampled (2 × 100 µl per hemichamber) at 15-min intervals throughout the experiment. After 1 h of baseline measurements, the ionophore nystatin (185 µM) was added to the apical side to increase permeability across the apical membrane. To determine the contribution of unstirred layers to the measured permeabilities, the apical membrane barrier was ablated by addition of 100 µl of Triton X-100 1 h after addition of nystatin. In all experiments, addition of nystatin and Triton X-100 abolished TER. Fluxes were calculated as described previously (24, 34). Significant changes in permeability were assessed by t-test.Scanning electron microscopy of uroepithelium. At the designated time points, rats were euthanized as described above, and the bladder was rapidly excised, cut along the dorsal margin, and placed in a fixative containing 2.0% (vol/vol) glutaraldehyde and 2.0% (wt/vol) paraformaldehyde in 100 mM sodium cacodylate, pH 7.4, 1 mM CaCl2, and 0.5 mM MgCl2 for 2-4 h at 4°C. The fixed tissue was washed for 15 min in 100 mM sodium cacodylate buffer, pH 7.4, and then treated with 1% (wt/vol) OsO4 in 100 mM sodium cacodylate buffer, pH 7.4, for 60 min at 4°C. After several rinses with distilled water, the tissue was cut into small blocks (~0.5-mm cubes), and the samples were washed three times over 45 min in PBS and then dehydrated for 15 min in a graded series of ethanol: 30, 50, 70, and 95% (vol/vol in water). The samples were then incubated three times for 45 min in absolute ethanol. The dehydrated samples were critical point dried, sputter coated with gold-palladium, and viewed in a Jeol JSM T300 scanning electron microscope at 20 kV. Images were captured on Kodak type 52 film, scanned on a Linotype-Hell Saphir Ultra II scanner, contrast corrected in Photoshop 6.0 (Adobe), assembled in Freehand 10.0 (Macromedia, San Francisco, CA), and output on a dye sublimation printer (model 8650PS, Kodak, Rochester, NY). All images are representative of similar results obtained from the bladders of at least three animals.
Transmission electron microscopy of uroepithelium. Bladder tissue was fixed and osmicated as described above and then cut into small blocks. After several water rinses, the samples were stained en bloc overnight with 0.5% uranyl acetate in water. Samples were dehydrated in a graded series of ethanol, embedded in epoxy resin (LX-112, Ladd), and sectioned with a diamond knife (Diatome). Sections, silver to pale gold in color, were mounted on butvar-coated copper grids, contrasted with uranyl acetate and lead citrate, and viewed at 80 kV in a Jeol 100 CX electron microscope. Images were printed and processed as described above. All images are representative of similar results obtained from the bladders of at least three animals.
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RESULTS |
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SCI is accompanied by decreases in TER, water permeability, and urea permeability. The uroepithelium forms a barrier that is characterized by its high resistance to ion flow and low permeabilities to water and urea (24, 28, 34). One indication of barrier function is TER, which measures the ability of the epithelium to impede paracellular (across the junctions) and transcellular (across the cell) ion flow. In umbrella cells, the combined low levels of paracellular ion flow and modest transcellular ion flow result in a high TER.
As controls, the TER was measured in animals that underwent no prior experimental manipulation. Sham controls were placed under anesthesia, and bone around the spinal cord was removed, but the spinal cord was not transected; then the animals were allowed to recover for up to 28 days. Distension controls were allowed to fill their bladders for 2.5 h but were unable to void because of anesthesia. The volume of urine in animals 2 h after SCI was 1.63 ± 0.4 ml, and in distension controls the urine volume was 1.53 ± 0.05 ml after 2.5 h. The TER values for all these controls were essentially identical (i.e., 1,802 ± 101
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SCI is accompanied by disruption of the uroepithelium.
Scanning and transmission electron microscopy (SEM and TEM,
respectively) were used to determine whether the functional changes in
the uroepithelium of SCI animals were accompanied by morphological changes in the uroepithelium of these animals. The ultrastructure of
umbrella cells from sham-operated animals (control) is shown in Figs.
2A and
3A. Identical morphology was
observed in untreated animals and distension controls and is not shown.
When examined by SEM, the umbrella cells of these control animals were
large (~40-50 µm across) and polyhedral in shape, and the
surface membrane was folded in a parallel array (Fig. 2A). A
thin tight junction complex circumscribed the perimeter of each cell
(Fig. 2B). In thin-section electron micrographs, the
uroepithelium contained an upper umbrella cell layer, two to three
intermediate cell layers, and a basal cell layer that rested on the
underlying connective tissue (Fig. 3A). Junctional complexes
were observed at higher magnification (arrow, Fig. 3B).
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Effect of hexamethonium and capsaicin on acute (2 h) effects of
SCI.
We were surprised to find significant changes in TER and the morphology
of the uroepithelium 2 h after SCI. To better understand the
underlying cause of these acute changes, we assessed whether blockers
of neurotransmission could prevent the acute SCI-dependent effects on
TER as well as urea and water permeability. Pretreatment with
hexamethonium, a blocker of ganglionic transmission, prevented the
decrease in TER observed in 2-h post-SCI animals (Fig.
4A). No
significant effect on water or urea permeability was noted in these
animals (Fig. 4, B and C). The protective effects
of hexamethonium were not observed 24 h after SCI, and the values for TER and urea and water permeability were similar to those of
untreated SCI animals (data not shown).
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DISCUSSION |
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SCI is accompanied by a number of well-described changes in normal bladder function: loss of voluntary control of micturition, bladder hyperactivity, bladder/sphincter dyssynergia, development of spinal cord reflexes (including unusual reflexes that are triggered by cold-water instillation or perineum stimulation), increased intravesical pressure, and bladder hypertrophy (21, 56). In experimental animal models, a hemorrhagic cystitis is often noted early after SCI, and in patients, SCI is well correlated with an increased incidence of bacterial cystitis and cancer (37, 39, 54). The effects of SCI on the uroepithelium, which forms the barrier between the urine and the underlying tissue, are not well understood.
Disruption of the uroepithelium in response to SCI. Many SCI patients exhibit mucosal ulceration and irritation (22). Using a well-described rat model system, we have observed that SCI is accompanied by considerable changes in uroepithelial morphology and barrier function. Within 2 h of SCI, we observed areas of disrupted uroepithelium that lacked surface umbrella cells, exposing the underlying intermediate cell layer. Consistent with this disruption, we noted that the TER of the uroepithelium was significantly decreased. Although this decrease could reflect increased ion transport, we believe that the morphology points to a disruption of tight junctions and cell-cell contact. In contrast, we noted only minor alterations in water and urea permeability. It could be that the underlying intermediate cells provide a reasonable barrier to water and urea at this early point after SCI. We observed what appeared to be the formation of tight junctions in the exposed intermediate cells, which is consistent with our recent observations that selective injury of the umbrella cell layer is accompanied by a rapid differentiation of the intermediate cell layer, including expression of uroplakin III and formation of tight junctions (23). However, it is possible that the tight junctions formed at these early stages are not as impermeable to ion flow as those found in differentiated umbrella cells.
A decrease in TER and a corresponding increase in water and urea permeability were observed 24 h after SCI. The uroepithelium at this point lacked umbrella cells in large areas and was generally covered by what appeared to be small intermediate and/or basal cells. By 3-4 days after SCI, the animals often had a hemorrhagic cystitis, which correlated with disruptions in the uroepithelium, significant decreases in TER, and an increase in water and urea permeability. The cause of this cystitis is unknown but is likely to reflect disruptions of the uroepithelium and vasculature and underlying inflammation provoked by infiltration of urine into the underlying tissue. Other possible factors are discussed below. By 4 wk after SCI, spinal reflexes were established, the animals could void involuntarily, and TER and water and urea permeability returned to baseline. The bladder appeared to be hypertrophied during this time, and the uroepithelium appeared generally normal; however, the surface umbrella cells were significantly smaller. This may indicate increased turnover of surface lining cells.Role of efferent nerves and other factors in epithelial injury. Several factors could contribute to the observed changes in the barrier function of the uroepithelium. The ability of hexamethonium, a ganglionic blocking agent, to prevent the epithelial disruptions and the corresponding decrease in TER after acute SCI indicate that efferent pathways arising from the autonomic nervous system could be involved in the acute stages of this response. Stimulation of neural pathways by insertion of a needle beneath the dura of the spinal cord into the gray matter was also sufficient to change the surface morphology of the umbrella cells, decrease TER, and increase urea permeability. However, the effect was not identical, because disruption of cell-cell junctions was not observed, indicating that the lesion associated with neural stimulation was in the apical membrane or tight junction barrier. Although it is possible that a drop in blood pressure after spinal transection may contribute to the uroepithelial alterations, this is unlikely, inasmuch as hexamethonium also results in a drop in blood pressure, and treatment with hexamethonium before SCI reversed the acute effects of SCI. Hexamethonium might act by suppressing sympathetic or parasympathetic input to the urinary bladder.
Cutting the spinal cord could stimulate neural release of stress hormones, such as catecholamines, which would contribute to the uroepithelial alterations after acute SCI. Altered catecholamine levels in a number of tissues have been demonstrated to influence mucosal integrity (44, 50). Our data have revealed that intravesical application of norepinephrine can significantly reduce epithelial viability (shown by decrease in TER compared with vehicle controls, data not shown). In further support of an effect of catecholamines on epithelial function, other studies have shown that administration of stressors, such as norepinephrine, results in a desquamation of the bladder urothelium (52). Although the mechanism has not been identified, there is some suggestion that the effect on mucosal integrity may be due to alterations in the tight junction, which leads to desquamation of the epithelial cells (52). One possible trigger for these events may be through secretion of a chemical mediator from epithelial cells such as NO, which in excess concentrations has been demonstrated to alter mucosal integrity (29, 41, 42, 46). We previously showed that adrenergic agonists, including thePossible protective role of afferent pathways.
Although activation of efferent pathways may have a detrimental
effect on barrier function, afferent pathways may have a protective role. The neurotoxin capsaicin was used to evaluate the involvement of capsaicin-sensitive small-diameter afferents (A- and C
fibers) in the changes in ultrastructure and permeability of the
bladder mucosa after an acute SCI. These changes were not prevented by capsaicin pretreatment, which desensitizes bladder afferents (13, 31). Capsaicin pretreatment enhanced the susceptibility of the mucosa to injury by further decreasing the TER compared with untreated SCI animals or capsaicin-treated controls. These results are consistent with reports that suggest a contribution by capsaicin-sensitive nerves,
which are sensitive to bladder distension and are located adjacent to
the bladder mucosa, to mucosal protection in various tissues after
injury or inflammation (1, 26). Studies suggest that this
protective effect may be due to substance P/calcitonin gene-related
peptide content in capsaicin-sensitive bladder nerves (38,
49). Although there was no significant difference in the surface
architecture between these treated animals and treated controls,
dilation of extracellular spaces or alterations in tight junctions
leading to increased permeability may not be evident using the present
morphological approaches. Thus further studies are needed to examine in
more detail the mechanism for these alterations in mucosal integrity.
Summary. Our results indicate that, in addition to affecting the detrusor muscle and its innervation, SCI also leads to a rapid disruption of the uroepithelial barrier. This was manifested in a loss of cell-cell interactions, decreases in TER, and increases in water and urea permeability. The present understanding is that SCI, which leads to loss of neural activity below the level of the lesion, blocks neurotransmitter release from transected nerves. However, our results indicate otherwise. The acute effects of SCI on uroepithelial function could be blocked by pretreatment with hexamethonium, indicating that release of neurotransmitters by bladder efferent nerves was at least partially responsible for the disruption of the uroepithelium. In addition, capsaicin treatment magnified the effects of SCI, indicating that capsaicin-sensitive afferent nerves may play a protective role in the process. Although the neurotransmitters and or inflammatory mediators that disrupt barrier function are not well understood, our observations indicate that the nerves that innervate the bladder may play an important role in regulating the barrier function of the uroepithelium. By modulating the release of neurotransmitters and/or inflammatory mediators, it may be possible to stem the disruption of the uroepithelium that accompanies SCI and other inflammatory conditions, such as interstitial cystitis.
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ACKNOWLEDGEMENTS |
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We thank W. C. de Groat for critical comments and suggestions.
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FOOTNOTES |
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This work was supported by National Institute of Diabetes and Digestive and Kidney Diseases Grants RO1-DK-54425 (to G. Apodaca), RO1-DK-54824 and RO1-DK-57284 (to L. A. Birder), and DK-48217 (to M. Zeidel).
Address for reprint requests and other correspondence: G. Apodaca, Renal Div., 982 Scaife Hall, University of Pittsburgh, 3550 Terrace St., Pittsburgh, PA 15261 (E-mail: gla6{at}pitt.edu).
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
First published January 14, 2003;10.1152/ajprenal.00359.2002
Received 7 October 2002; accepted in final form 7 January 2003.
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