Mast Cell Involvement in Interstitial Cystitis

Lynes, William L.; Flynn, Stuart D.; Shortliffe, Linda D.; Lemmers, Michael J.; Zipser, Robert D.; Roberts, L. Jackson; Stamey, Thomas A.

doi:10.1016/s0022-5347(17)43359-3

Cited by 132 publications

(76 citation statements)

References 17 publications

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“…A few studies have demonstrated increased innervation of the bladder suburothelial and detrusor layers by PGP9.5-positive, substance P-positive, or sympathetic nerve fibers in patients with IC/PBS (14, 38, 66, 80 -82). Mast cells and other inflammatory mediators that are responsive to NGF (56), and increased in the urinary bladder of IC/PBS patients (67,83,92), might further sensitize bladder afferent neurons. In NGF-OE mice, chronic NGF overexpression resulted in marked hyperinnervation of the bladder by sensory afferent and sympathetic nerve fibers and an increase in bladder mast cells.…”

Section: Discussionmentioning

confidence: 99%

Overexpression of NGF in mouse urothelium leads to neuronal hyperinnervation, pelvic sensitivity, and changes in urinary bladder function

Schnegelsberg¹,

Sun

Cain

et al. 2010

American Journal of Physiology-Regulatory, Integrative and Comp

151

275

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Schnegelsberg B, Sun T, Cain G, Bhattacharya A, Nunn PA, Ford AP, Vizzard MA, Cockayne DA. Overexpression of NGF in mouse urothelium leads to neuronal hyperinnervation, pelvic sensitivity, and changes in urinary bladder function. Am J Physiol Regul Integr Comp Physiol 298: R534 -R547, 2010. First published December 23, 2009; doi:10.1152/ajpregu.00367.2009.-NGF has been suggested to play a role in urinary bladder dysfunction by mediating inflammation, as well as morphological and functional changes, in sensory and sympathetic neurons innervating the urinary bladder. To further explore the role of NGF in bladder sensory function, we generated a transgenic mouse model of chronic NGF overexpression in the bladder using the urothelium-specific uroplakin II (UPII) promoter. NGF mRNA and protein were expressed at higher levels in the bladders of NGF-overexpressing (NGF-OE) transgenic mice compared with wild-type littermate controls from postnatal day 7 through 12-16 wk of age. Overexpression of NGF led to urinary bladder enlargement characterized by marked nerve fiber hyperplasia in the submucosa and detrusor smooth muscle and elevated numbers of tissue mast cells. There was a marked increase in the density of CGRP-and substance P-positive C-fiber sensory afferents, neurofilament 200-positive myelinated sensory afferents, and tyrosine hydroxylase-positive sympathetic nerve fibers in the suburothelial nerve plexus. CGRP-positive ganglia were also present in the urinary bladders of transgenic mice. Transgenic mice had reduced urinary bladder capacity and an increase in the number and amplitude of nonvoiding bladder contractions under baseline conditions in conscious open-voiding cystometry. These changes in urinary bladder function were further associated with an increased referred somatic pelvic hypersensitivity. Thus, chronic urothelial NGF overexpression in transgenic mice leads to neuronal proliferation, focal increases in urinary bladder mast cells, increased urinary bladder reflex activity, and pelvic hypersensitivity. NGF-overexpressing mice may, therefore, provide a useful transgenic model for exploring the role of NGF in urinary bladder dysfunction. nerve growth factor; urothelium; transgenic mouse; bladder hypersensitivity; inflammation; afferent innervation NGF IS A POTENT NEUROTROPHIN that exerts pleiotropic effects in the peripheral and central nervous system. It regulates sensory and sympathetic neuronal development and maintenance (41) and plays a role in painful somatic and visceral inflammation (3,15,32,70,84,85). The effects of NGF are mediated through the TrkA and p75 NTR receptors and are tissue specific. It is well documented that NGF plays an important role in inflammation of the urinary bladder, colon, and lung (21,31,93,100). Although the contribution of NGF to urinary bladder function is unclear, it seems to play a role in urinary bladder hyperreflexia or overactivity (15,16,23,34,40,78,111). NGF administered intrathecally (107), intravesically (23), intramuscularly to the detrusor smooth muscle ...

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Section: Discussionmentioning

confidence: 99%

Overexpression of NGF in mouse urothelium leads to neuronal hyperinnervation, pelvic sensitivity, and changes in urinary bladder function

Schnegelsberg¹,

Sun

Cain

et al. 2010

American Journal of Physiology-Regulatory, Integrative and Comp

151

275

View full text Add to dashboard Cite

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“…Acetic acid infusion could induce the infl ammation in the urinary bladder and could increase PGE 2 contents in the bladder (3,9,10,24). Indeed PGE 2 in the urine was increased cystitis patients (13). These data indicated that PGE 2 did not play a part of normal micturition and may play a part of the micturition refl ex during acetic acid infusion.…”

Section: Discussionmentioning

confidence: 89%

“…PGE 2 infusion into the urinary bladder facilitated the micturition refl ex (11) and made contraction of the detrusor smooth muscles (19). PGE 2 could be released from the immune cells during the infl ammation and from fi broblast cells in the submucosal connective tissue (13,16). Hence PGE 2 receptors were present in the urinary bladder (19), we speculate that systematic administration of loxoprofen might act in the urinary bladder for reduction of PGE 2 during the acetic acid infusion.…”

Section: Discussionmentioning

confidence: 98%

Loxoprofen inhibits facilitated micturition reflex induced by acetic acid urinary bladder infusion of the rats

2005

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Prostaglandins (PGs) are well known as one of the chemical mediators of infl ammation. Nonsteroidal anti-infl ammatory drugs (NSAIDs), PG synthesis inhibitors, are used for anti-nociception and/or anti-infl ammation. We examine the effect of loxoprofen, an NSAID, on micturiton in acetic acid-induced bladder infl ammation of the rats. In cystometrogram study with saline infusion into the urinary bladder, loxoprofen did not alter the interval of bladder contraction (IC, 107% of the control). IC was shortened by acetic acid infusion (65% of the control) and loxoprofen prolonged the IC (162% of acetic acid infused period). This prolonged IC was approximately same as the control. Loxoprofen did not alter the threshold pressure and the maximal voiding pressure. These data suggest that PGE 2 might not play a part of normal micturition and may play a part of the micturition refl ex during acetic acid infusion. That is, loxoprofen might be useful for pathological hyperrefl ex of the micturition.Urinary bladder controls two different physiological stages; storage of urine and micturition refl ex. Previous studies have mainly investigated the reflex pathway of the micturition (5, 25). In contrast, recent studies were interested in the storage mechanisms because over active bladder was commonly seen in elder people (2,8,21). During storage of the urine in the bladder, smooth muscles were stretched and it activated the afferent fi bers in the pelvic nerve (18). The activities were mediated through the sacral spinal cord and it stimulated the potine micturition center (6).When inflammation of the urinary bladder occurred, painful sensation was noticed and frequency of the micturition were increased (14). As indicated in many reports, infl ammation of the urinary bladder could excite the detrusor muscles with chemical mediators (17) and activate the afferent nerve terminals (1, 7).Prostagrandins (PGs) have been investigated for one of the chemical mediators of the infl ammation. In general, cyclooxgenase (COX) isoenzymes synthesize PGs from arachidonic acid at many organs including bladder smooth muscles and urothelium (4, 15). Indeed, PGE 2 in the urine was increased at the interstitial cystitis patients (11). Recent animal studies also demonstrated that COX-2 and PGE 2 were increased in cystitis rats (9, 24). Thus PGE 2 must be important for changing the micturition refl ex of the bladder infl ammation.Nonsteroidal anti-inflammatory drugs (NSAIDs) are widely used for treatment of the infl ammation. Under anesthesia, NSAIDs increased the bladder capacity during the infl ammation in rats (23). It has been reported that anesthesia have infl uence to the micturition refl ex (26). So unanesthetized animals experiments must be performed. Hence we used

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“…The number of mast cells has been shown to be increased in bladder bi opsies from some IC patients. 16 Decreasing mast-cell activity might, therefore, decrease bladder inflammation. As histamine, released in many instances by mast cells, has been implicated in the pathophysiology of IC, antihistamines have been used with varying efficacy for the treatment of this disease.…”

Section: Glomerulationsmentioning

confidence: 99%