Cyto-Injury Factors in Urine: A Possible Mechanism for the Development of Interstitial Cystitis

Parsons, C. Lowell; Bautista, Sally L.; Stein, Paul C.; Zupkas, Paul

doi:10.1097/00005392-200010000-00078

Cited by 16 publications

(29 citation statements)

References 20 publications

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“…In our study, markedly increased NGF activity in the bladder wall with significant L6-S1 nNOS, NGF and c-fos expression was determined in instillated bladder with IC urine and normal human urine. According to Parsons et al [26], normal human urine contains heat-labile cationic material of low molecular weight (500-1,000 daltons) that is cytotoxic for uroepithelial cells and smooth muscle cells, Baykara/Erdogru/Gülkesen/Sargın/Savaş/ Ateş and the differences in the protective capacity of TammHorsfall protein may be one of the several factors effecting the balance between detrimental components and bladder defense mechanisms in IC patients. Increased bladder nociceptive activation due to leaky epithelium in IC might be the result of one or more disruptions in the system of normal bladder defense mechanisms owing to impairment of the protective capacity of Tamm-Horsfall protein, an increased level of injurious cation or an abnormality in factors inhibiting regeneration of injured uroepithelium.…”

Section: Discussionmentioning

confidence: 99%

Does Interstitial Cystitis Urine Include Possible Factors Effecting the Nociceptive System of the Spinal Cord?

Baykara¹,

Erdoğru²,

Gülkesen³

et al. 2003

Urol Int

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Introduction: We investigated the effect of interstitial cystitis (IC) urine on bladder layers and nociceptive centers in the spinal cord with determination of nerve growth factor (NGF), neuronal nitric oxide synthase (nNOS) and c-fos expressions. Material and Methods: Female rats were instilled into the bladder IC urine (Group-IC), normal urine (Group-NU) and saline (Group-S). NGF, nNOS and c-fos activity were determined in the L6–S1 medulla spinalis with identification of mast cell and NGF activity on bladder layers. Results: There was more NGF expression cell density in the bladder wall that was determined immunohistochemically in control and IC urine instillation groups than Group-S. While there was no difference in nNOS, NGF and c-fos activity between spinal cord regions except the lateral dorsal horn of the L6 section, localization of activities was different in Group-IC. Conclusions: The characteristics of the bladder wall and its nociceptive afferents after human urine instillation of some toxic compounds might be causative factors for IC. However, it is barely hard to conclude that different toxic compounds should be causative factors in IC urine in the pathogenesis of IC.

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Section: Discussionmentioning

confidence: 99%

Does Interstitial Cystitis Urine Include Possible Factors Effecting the Nociceptive System of the Spinal Cord?

Baykara¹,

Erdoğru²,

Gülkesen³

et al. 2003

Urol Int

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“…Parsons et al. suggested that cationic urinary components could potentially be cytotoxic to the urothelial cells, resulting in bladder mucosal injury 52,53 . Some dietary metabolites, medications and nutritional supplements also exert cytotoxic effects on the urothelium 26 .…”

Section: Pathophysiology Of Ic/bpsmentioning

confidence: 99%

Interstitial cystitis/bladder pain syndrome: The evolving landscape, animal models and future perspectives

et al. 2020

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Abbreviations & Acronyms BPS = bladder pain syndrome CCL2 = C-C motif ligand 2 CNS = central nervous system DMSO = dimethyl sulfoxide EAC = experimental autoimmune cystitis ESSIC = International Society for the Study of BPS FSS = functional somatic syndrome GAG = glycosaminoglycan IC = interstitial cystitis IFN-c = interferon-gamma IL = interleukin MC = mast cell NGF = nerve growth factor OVA = ovalbumin TCR = T-cell receptor TNF = tumor necrosis factor TLR = Toll-like receptor UCPPS = urological chronic pelvic pain syndrome UPK = uroplakin Upo = unpublished observation VEGF = vascular endothelial growth factor WAS = water avoidance stress Correspondence: Yoshiyuki Abstract: Interstitial cystitis/bladder pain syndrome is a debilitating condition of unknown etiology characterized by persistent pelvic pain with lower urinary tract symptoms and comprises a wide variety of potentially clinically useful phenotypes with different possible etiologies. Current clinicopathological and genomic evidence suggests that interstitial cystitis/bladder pain syndrome should be categorized by the presence or absence of Hunner lesions, rather than by clinical phenotyping based on symptomatology. The Hunner lesion subtype is a distinct inflammatory disease with proven bladder etiology characterized by epithelial denudation and enhanced immune responses frequently accompanied by clonal expansion of infiltrating B cells, with potential engagement of infection. Meanwhile, the non-Hunner lesion subtype is a noninflammatory disorder with little evidence of bladder etiology. It is potentially associated with urothelial malfunction and neurophysiological dysfunction, and frequently presents with somatic and/or psychological symptoms, that commonly result in central nervous sensitization. Animal models of autoimmune cystitis and neurogenic sensitization might serve as disease models for the Hunner lesion and non-Hunner lesion subtypes, respectively. Here, we revisit the taxonomy of interstitial cystitis/bladder pain syndrome according to current research, and discuss its potential pathophysiology and representative animal models. Categorization of interstitial cystitis/bladder pain syndrome based on cystoscopy is mandatory to design optimized treatment and research strategies for each subtype. A tailored approach that specifically targets the characteristic inflammation and epithelial denudation for the Hunner lesion subtype, or the urothelial malfunction, sensitized/altered nervous system and psychosocial problems for the non-Hunner lesion subtype, is essential for better clinical management and research progress in this complex condition.

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“…For the most part, their presence in urine may be attributable to secondary responses to the disease process and these are reactive products that are not involved in the initiation of IC. One agent that may be involved in inducing the disease is antiproliferative factor , and others are cationic urinary toxic factors capable of injuring the superficial epithelial cells . Our interest has been in protective factors in urine such as Tamm–Horsfall protein (THP), which reduces disease risk and potential toxic factors that could injure epithelial mucus and increase the risk of IC.…”

Section: Introductionmentioning

confidence: 99%

Role of urinary cations in the aetiology of bladder symptoms and interstitial cystitis

et al. 2014

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ObjectivesTo identify and characterise urinary cationic metabolites, defined as toxic factors, in patients with interstitial cystitis (IC) and in control subjects. To evaluate the cytotoxicity of the urinary cationic metabolite fraction of patients with IC vs control subjects and of individual metabolites in cultured urothelial cells. Subjects and MethodsCationic fractions (CFs) were isolated from the urine specimens of 62 patients with IC and 33 control subjects by solid-phase extraction. CF metabolites were profiled using C18 reverse-phase high performance liquid chromatography (RP-HPLC) with UV detection, quantified by area-under-thepeaks using known standards, and normalized to creatinine. RP-HPLC and liquid chromatography (LC)-mass spectrometry (MS)/tandem MS (MS/MS) were used to identify major CF peaks. HTB-4 urothelial cells were used to determine the cytotoxicity of CFs and of individual metabolites with and without Tamm-Horsfall protein (THP). ResultsRP-HPLC analysis showed that metabolite quantity was twofold higher in patients with IC compared with control subjects. The mean (SEM) for control subjects vs patients was 3.1 (0.2) vs 6.3 (0.5) mAU*min/μg creatinine (P < 0.001). LC-MS identified 20 metabolites. Patients with IC had higher levels of modified nucleosides, amino acids and tryptophan derivatives compared with control subjects. The CF cytotoxicity was higher for patients with IC compared with control subjects. The mean (SEM) for control subjects vs patients was −2.3 (2.0)% vs 36.7 (2.7)% (P < 0.001). A total of 17 individual metabolites were tested for their cytotoxicity. Cytotoxicity data for major metabolites were all significant (P < 0.001): 1-methyladenosine (51%), 5-methylcytidine (36%), 1-methyl guanine (31%), N 4 -acetylcytidine (24%), N 7 -methylguanosine (20%) and L-Tryptophan (16%). These metabolites were responsible for higher toxicity in patients with IC. The toxicity of all metabolites was significantly lower in the presence of control THP (P < 0.001). ConclusionsMajor urinary cationic metabolites were characterised and found to be present in higher amounts in patients with IC compared with control subjects. The cytotoxicity of cationic metabolites in patients with IC was significantly higher than in control subjects, and control THP effectively lowered the cytotoxicity of these metabolites. These data provide new insights into toxic factor composition as well as a framework in which to develop new therapeutic strategies to sequester their harmful activity, which may help relieve the bladder symptoms associated with IC.

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Cyto-Injury Factors in Urine: A Possible Mechanism for the Development of Interstitial Cystitis

Cited by 16 publications

References 20 publications

Does Interstitial Cystitis Urine Include Possible Factors Effecting the Nociceptive System of the Spinal Cord?

Does Interstitial Cystitis Urine Include Possible Factors Effecting the Nociceptive System of the Spinal Cord?

Interstitial cystitis/bladder pain syndrome: The evolving landscape, animal models and future perspectives

Role of urinary cations in the aetiology of bladder symptoms and interstitial cystitis

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