Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P15088 (mast cell)
 14,925 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Interstitial cystitis (IC) is a debilitating disease that has been adversely affecting the quality of women's lives for many years. The trigger in IC is not entirely known, and a role for the sensory nerves in its pathogenesis has been suggested. In addition to inflammation, increased mast cell numbers in the detrusor muscle have been reported in a subset of IC patients. Experimentally, several lines of evidence support a central role for substance P and neurokinin-1 (NK-1) receptors in cystitis. The availability of mice genetically deficient in neurokinin-1 receptor (NK-1R(-/-)) allows us to directly evaluate the importance of substance P in cystitis. An unexpected finding of this investigation is that NK-1R(-/-) mice present increased numbers of mast cells in the bladder when compared with wild-type control mice. Despite the increase in mast cell numbers, no concomitant inflammation was observed. In addition, bladder instillation of wild-type mice with a sensitizing antigen induces activation of mast cells and an acute inflammatory response characterized by plasma extravasation, edema, and migration of neutrophils. Antigen-sensitized NK-1R(-/-) mice also exhibit bladder mast cell degranulation in response to antigen challenge. However, NK-1R(-/-) mice are protected from inflammation, failing to present bladder inflammatory cell infiltrate or edema in response to antigen challenge. This work presents the first evidence of participation of NK-1 receptors in cystitis and a mandatory participation of these receptors on the chain of events linking mast cell degranulation and inflammation.
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PMID:Neurokinin-1 (NK-1) receptor is required in antigen-induced cystitis. 1070 92

Mast cell numbers are significantly increased in bladder disorders including malignancy and interstitial cystitis, but their precise role has been difficult to determine. We characterized the role of mast cells on gene regulation associated with antigen-induced bladder inflammation in mice. For this purpose, we examined the responses in mast cell-deficient (Kit(W)/Kit(W-v)), congenic normal (+/+), and Kit(W)/Kit(W-v) mice that were reconstituted with bone marrow stem cells (BMR) to restore mast cells. All mice were actively sensitized and challenged intravesically with either saline or specific antigen. Bladder inflammation occurred in +/+ and BMR but not the Kit(W)/Kit(W-v) mice. Gene expression was determined using mouse cDNA expression arrays. Self-organizing maps, performed without preconditions, indicated gene expression changes dependent on the presence of mast cells. These genes were upregulated in bladders isolated from antigen challenge of +/+, not altered in Kit(W)/Kit(W-v), and were upregulated in BMR mice. Taken together these results demonstrate an important role for mast cells in allergic cystitis and indicate that mast cells can alter their environment by regulating tissue gene expression.
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PMID:Mast cell regulation of inflammation and gene expression during antigen-induced bladder inflammation in mice. 1159 90

Inflammatory bladder disorders such as interstitial cystitis (IC) deserve attention since a major problem of the disease is diagnosis. IC affects millions of women and is characterized by severe pain, increased frequency of micturition, and chronic inflammation. Characterizing the molecular fingerprint (gene profile) of IC will help elucidate the mechanisms involved and suggest further approaches for therapeutic intervention. Therefore, in the present study we used established animal models of cystitis to determine the time course of bladder inflammatory responses to antigen, Escherichia coli lipopolysaccharide (LPS), and substance P (SP) by morphological analysis and cDNA microarrays. The specific aim of the present study was to compare bladder inflammatory responses to antigen, LPS, and SP by morphological analysis and cDNA microarray profiling to determine whether bladder responses to inflammation elicit a specific universal gene expression response regardless of the stimulating agent. During acute bladder inflammation, there was a predominant infiltrate of polymorphonuclear neutrophils into the bladder. Time-course studies identified early, intermediate, and late genes that were commonly up-regulated by all three stimuli. These genes included: phosphodiesterase 1C, cAMP-dependent protein kinase, iNOS, beta-NGF, proenkephalin B and orphanin, corticotrophin-releasing factor (CRF) R, estrogen R, PAI2, and protease inhibitor 17, NFkB p105, c-fos, fos-B, basic transcription factors, and cytoskeleton and motility proteins. Another cluster indicated genes that were commonly down-regulated by all three stimuli and included HSF2, NF-kappa B p65, ICE, IGF-II and FGF-7, MMP2, MMP14, and presenilin 2. Furthermore, we determined gene profiles that identify the transition between acute and chronic inflammation. During chronic inflammation, the urinary bladder presented a predominance of monocyte/macrophage infiltrate and a concomitant increase in the expression of the following genes: 5-HT 1c, 5-HTR7, beta 2 adrenergic receptor, c-Fgr, collagen 10 alpha 1, mast cell factor, melanocyte-specific gene 2, neural cell adhesion molecule 2, potassium inwardly-rectifying channel, prostaglandin F receptor, and RXR-beta cis-11-retinoic acid receptor. We conclude that microarray analysis of genes expressed in the bladder during experimental inflammation may be predictive of outcome. Further characterization of the inflammation-induced gene expression profiles obtained here may identify novel biomarkers and shed light into the etiology of cystitis.
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PMID:Gene expression profiling of mouse bladder inflammatory responses to LPS, substance P, and antigen-stimulation. 1205 14

The purpose of this study was to investigate the effect of botulinum toxin type A on bladder function and histology in a rat chemical cystitis model. The study included 41 female Sprague-Dawley rats with chemical cystitis induced by intravesical instillation of hydrochloric acid. The acid instillation was repeated monthly to maintain chronic inflammation. The treatment group (n=21) received 2-3 units of botulinum toxin type A injected into the bladder detrusor at the 3, 6, 9 and 12 o'clock positions, and the control group (n=20) underwent saline injection into the bladder detrusor at the same positions. Urodynamic studies were performed in all rats before the treatment and at death. The rats were killed at 1 week, 2 weeks, 1 month and 2 months after treatment. The bladders were removed and examined histologically for mast cells and inflammatory changes. The cystometric findings showed that, at the beginning and end of the experiment, the increases in the maximum bladder capacity and compliance were significantly higher in the treatment group than in the control group (P=0.000 and P=0.025, respectively). The histological studies revealed similar mast cell counts and leukocyte infiltration for the treatment and control groups. In conclusion, in this rat chemical cystitis model, botulinum toxin type A injected into the bladder detrusor led to a functional improvement. Thus, botulinum toxin type A injection may be an alternative, minimally invasive choice to other surgical treatment options in the treatment of a chronic inflammatory condition to improve deteriorated bladder function.
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PMID:Botulinum toxin type A may improve bladder function in a rat chemical cystitis model. 1259 22

Recent advances in basic and clinical research indicate that interstitial cystitis (IC) is a form of neurogenic inflammation, thereby opening new avenues for research into this painful disease. With this in mind, we have recently developed a rat model of neurogenic inflammation of the bladder produced by a central nervous system viral disease. As in IC, the inflammation in this model develops without direct injury or trauma to the bladder, is non-infectious, and is limited to the bladder. Our most recent studies aimed at further testing the similarity of this animal model to IC by assessing the urine content in histamine with the occurrence of mast cell degranulation in the bladder wall. We further verified for a sex difference in the occurrence of the disease. Our results showed increased levels of urine histamine and mast cell activation during the early stages of the disease. We additionally observed that females had a greater degree of plasma extravasation, while males had a greater cellular infiltration together with worse behavioral signs. Gonadectomy prevented the bladder inflammation altogether in both males and females. These findings further validate our model of neurogenic cystitis to study the neurogenic component of IC.
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PMID:Experimental neurogenic cystitis. 1508 15

Interstitial cystitis (IC) is a chronic bladder inflammatory disease of unknown etiology that shares similarities with Crohn's disease and psoriasis. IC, often regarded as a neurogenic cystitis, is associated with urothelial lesions that likely compromise the bladder permeability barrier and thereby contribute to patient morbidity. Here, we use a murine model of neurogenic cystitis to investigate the mechanism of urothelial lesion formation and find that urothelial apoptosis induces formation of lesions. Lesions formed in wild-type mice but not in mice deficient in TNF, TNF receptors, or mast cells. In urothelial cultures, only siRNAs targeting TNFR1, but not TNFR2, blocked TNF-induced apoptosis, indicating a primary role for TNFR1. Trans-epithelial resistance, a measure of bladder barrier function, decreased during neurogenic cystitis in wild-type and TNFR2(-/-) mice but was stabilized in TNF(-/-) mice. Anti-TNF antibodies both altered bladder mast cell localization and stabilized barrier function. Based on these findings, we conclude that mast cell activation and release of TNF drive urothelial apoptosis and lesion formation in a murine neurogenic cystitis model, and we hypothesize that anti-TNF therapy may stabilize bladder barrier function in IC patients.
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PMID:Urothelial lesion formation is mediated by TNFR1 during neurogenic cystitis. 1662 79

Irritable bowel syndrome and interstitial cystitis frequently overlap. We have shown that acute colitis sensitizes urinary bladder afferents to both mechanical and chemical stimuli and that chronic colitis similarly produces neurogenic cystitis. We hypothesize that chronic irritation of the colon releases neuropeptides from bladder afferents, leading to receptor sensitization and neurogenic inflammation. Female Sprague-Dawley rats received intrarectal trinitrobenzenesulfonic acid (TNBS) or vehicle 3 days following either systemic capsaicin (CP) pretreatment or vehicle. Ten days later, action potentials of single-unit pelvic C-fiber afferents with receptive fields in the bladder were recorded under urethane anesthesia during graded bladder distensions (UBD) or intravesical capsaicin (vCP) administration. In controls, UBD increased bladder afferent firing in proportion to intravesical pressure. At intravesical pressures of 30 mmHg and above, the percent increase in afferent firing was significantly accentuated following TNBS compared with controls (1,222 +/- 176 vs. 624 +/- 54%, P < 0.01). The response to vCP was also enhanced (4,126 +/- 775 vs. 1,979 +/- 438%, P < 0.01). Systemic depletion of neuropeptides from sensory nerves abolished these effects. Histological examination of the bladders revealed an increase in mast cell density in TNBS-treated animals compared with controls (18.02 +/- 1.25 vs. 3.11 +/- 0.27 mast cells/x100 field, P < 0.01). This effect was significantly ameliorated with CP (10.25 +/- 0.95, P < 0.5 vs. TNBS-treated animals). In summary, chronic colonic irritation in the rat sensitizes urinary bladder afferents to noxious stimuli and causes mast cell infiltration in the bladder. Depletion of neuropeptides from sensory afferents diminishes these effects, suggesting they play an important role.
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PMID:Sensitization of pelvic nerve afferents and mast cell infiltration in the urinary bladder following chronic colonic irritation is mediated by neuropeptides. 1692 45

Barrier dysfunction of the urinary bladder is postulated to contribute to patient morbidity in the bladder inflammatory disease interstitial cystitis (IC). IC is often considered a neurogenic cystitis, but the mechanisms underlying barrier dysfunction are unclear. In murine neurogenic cystitis induced by pseudorabies virus (PRV), we previously observed formation of urothelial lesions characterized by urothelial apoptosis and urothelial discontinuities. Lesion formation was preceded by mast cell trafficking to the lamina propria, and trafficking was mediated by tumor necrosis factor-alpha (TNF). Here, we found that supernatants of TNF-treated urothelial cultures promoted chemotaxis of bone marrow-derived mast cells in vitro that was blocked by anti-RANTES antibodies but unaffected by anti-TNF antibodies. In vivo, PRV infection of wild-type mice induced RANTES expression in the urothelium that was temporally coincident with lamina propria mast cell accumulation (maximum at days 3-4 following infection) and was not induced in TNF(-/-) mice, TNFR1/2(-/-) mice, or mice treated with anti-TNF antibodies. Anti-RANTES antibodies blocked PRV-induced lamina propria mast cell accumulation 56% and reduced the prevalence of animals with detectable lesions 42%, relative to isotype control antibodies. Bladder barrier function was quantified by measuring transepithelial resistance (TER). PRV induced a 49% loss of TER in the presence of control antibodies, but mice treated with anti-RANTES antibodies exhibited reduced TER loss (16%, P < 0.01). These data demonstrate that RANTES plays a key role in the pathogenesis of neurogenic cystitis and suggest that chemokines may represent novel therapeutic targets for IC patients with mast cell-associated disease.
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PMID:RANTES mediates TNF-dependent lamina propria mast cell accumulation and barrier dysfunction in neurogenic cystitis. 1724 92

Interstitial cystitis (IC) is a syndrome of bladder hypersensitivity with symptoms of urgency, frequency, and chronic pelvic pain. Although no consensus has been reached on the underlying cause of IC, several pathophysiologic mechanisms, including epithelial dysfunction, mast cell activation, and neurogenic inflammation, have been proposed. Despite multiple different causes of urinary cystitis, the bladder's response to cystitis is limited and typical. Animal experiments have shown upregulation of proteinase-activated receptors, tryptase, beta-nerve growth factor, inducible nitric oxide synthase, nuclear transcription factor-kappaB, c-Fos, phosphodiesterase 1C, cyclic adenosine monophosphate (cAMP)-dependent protein kinase, and proenkephalin B. After the noxious stimulus has abated, downregulation of genes appears to follow. Distention of the bladder results in the release of adenosine triphosphate (ATP) from urothelial cells, which activates purinergic P2X3 receptors. Activation by ATP of P2X3-expressing afferents is a fundamental signaling factor in bladder sensation and appears to play a role in bladder reflexes. Fos proteins present in spinal cord neurons have been shown to be upregulated in animals that have undergone cyclophosphamide-induced chemical cystitis. These and other findings suggest that neural upregulation occurs both peripherally and centrally in subjects with chronic cystitis. It is unclear whether neural mechanisms and inflammation are the cause of IC or the result of other initiating events. Neural upregulation is known to play a role in the chronicity of pain, urgency, and frequency and represents an exciting area of research that may lead to additional treatments and a better understanding of IC.
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PMID:Neural upregulation in interstitial cystitis. 1746 76

Mast cells accessing the brain parenchyma through the blood-brain barrier in healthy animals are limited to pre-cortical sensory relays - the olfactory bulb and the thalamus. We have demonstrated that unilateral repetitive stimulation of the abdominal wall generates asymmetry in midline thalamic mast cell (TMC) distribution in cyclophosphamide-injected rats, consisting of contralateral side-prevalence with respect to the abdominal wall stimulation. TMC asymmetry 1) was generated in strict relation with cystitis, and was absent in disease-free and mesna-treated animals, 2) was restricted to the anterior portion of the paraventricular pars anterior and reuniens nuclei subregion, i.e., the rostralmost part of the paraventricular thalamic nucleus, the only thalamic area associated with viscero-vagal and somatic inputs, via the nucleus of the solitary tract, and via the medial contingent of the spinothalamic tract, respectively, and 3) originated from somatic tissues, i.e., the abdominal wall where bladder inflammation generates secondary somatic hyperesthesia leading to referred pain in humans. Present data suggest that TMCs may be involved in thalamic sensory processes, including some aspects of visceral pain and abnormal visceral/somatic interactions.
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PMID:The effects of viscero-somatic interactions on thalamic mast cell recruitment in cystitic rats. 1771 48


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