Date of Award

2012

Degree Type

Dissertation

Department

Chemistry

First Advisor

Daneshgari, Firouz

Subject Headings

Pelvic pain -- Research, Mast cells -- Research, Interstitial cystitis -- Research, Autoimmune diseases -- Research, CCL2, MCP-1, Chronic pelvic pain, Mast cell, Experimental autoimmune cystitis, IC/PBS, Uroplakin 3A, Bladder

Abstract

Interstitial cystitis/painful bladder syndrome (IC/PBS) is a chronic inflammatory bladder condition with unknown pathophysiology. Chronic pelvic pain is one of the most important and disturbing symptoms of IC/PBS, beside urinary frequency, urgency, and nocturia. Increased amounts of mast cells (MCs) and CCL2 have been found in bladder tissue and urine, respectively. Whether or not there is a causal relationship between CCL2, MCs, and pelvic pain in IC/PBS is unknown. Methods: Female BALB/c mice were immunized with a peptide consisting of residues 65-84 of the bladder urothelium-specific protein uroplakin 3A to induce experimental autoimmune cystitis (EAC), a model for human IC/PBS. Referred visceral pelvic pain was measured using von Frey monofilaments at different times after immunization. Lidocaine was instilled into the bladder, colon and uterus to locate the source of the pelvic pain. CCL2 expression in tissues was measured by qRT-PCR and ELISA, and MCs in the bladder were quantified by toluidine blue staining. An MC stabilizer (cromolyn sodium), histamine H1 receptor blocker (cetirizine), and histamine H2 receptor blocker (ranitidine) were administered orally to show the relation of MCs with the pain. CCL2-/- and CCR2-/- mice, and CCR2 (CCL2 receptor) antagonist treatment were used to delineate the causative effect of CCL2 on MC accumulation and chronic pelvic pain.Results: All mice immunized with the uroplakin 3A peptide developed pelvic pain within 5 days and up to 40 days after immunization. Lidocaine alleviated the pain only when it was installed into the bladder of EAC mice, confirming the bladder origin of the pain. The amounts of CCL2 mRNA and protein, and the numbers of MCs were markedly increased in bladder tissue up to 40 days after immunization with peptide compared with controls. Administrations of cromolyn sodium and ranitidine significantly decreased pelvic pain in the model. Moreover, immunization did not establish chronic pelvic pain or accumulation of MCs in MCP-1-/- or CCR2-/- mice, compar

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