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Mast Cells and CP/CPPS

Mast cells could be the key to both chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) and bladder pain syndrome/interstitial cystitis (BPS/IC). They degranulate and promote inflammation both under stress-invoked neurological and food-related allergic stimuli.

Recently, renowned mast cell and IC researcher TC Theoharides discovered that mast cells are often not found on biopsy because of understaining (Urology 2001 Oct;58(4):605-6 "Massive extracellular tryptase from activated bladder mast cells in interstitial cystitis." Theoharides TC, Kempuraj D, Sant GR.) The management of this website speculates that both IC and CP/CPPS may be a mild form of systemic mastocystosis, which is difficult to diagnose.

Mast Cells and Prostatitis

J Urol. 2001 Jul;166(1):323-8.

Cell Relationship In A Wistar Rat Model Of Spontaneous Prostatitis

Keith IM, Jin J, Neal Jr D, Teunissen BD, Moon TD.

Departments of Comparative Bioscience and Surgery, University of Wisconsin and Veterans Affairs Medical Center, Madison, Wisconsin, and University of Southern Illinois, Springfield, Illinois.

PURPOSE: Prostatitis in men is a painful, noninfectious inflammatory condition. It is similar to bladder pain syndrome/interstitial cystitis (BPS/IC) which is associated with increased bladder mast cell and sensory nerve fiber density as well as suprapubic pain. Certain strains of rats may provide a useful model for studies of the development of spontaneous prostatitis. We evaluated the time course, and involvement of mast cells and sensory nerve fibers in this process using Wistar rats.

MATERIALS AND METHODS: The prostates of 4, 6, 8, 10 and 13-week-old male Wistar rats were examined for the degree of inflammation, innervation, mast cell density and nerve mast cell relationship using histochemical and immunocytochemical studies. Bacterial cultures of tissue were performed at 13 weeks.

RESULTS: The inflammatory cell index increased progressively with age. Inflammation was moderate and consisted mostly of lymphocytes and macrophages associated with occasional glandular epithelial necrosis and edema. The density of nerve fibers immunoreacting with the neuronal marker protein gene produce 9.5 increased gradually with age and fibers immuno-positive for the sensory neuropeptide calcitonin gene-related peptide more than doubled by 13 weeks compared with by 4 weeks. The density of visible mast cells declined after 4 weeks in a pattern that corresponded with the increased percent of mast cells undergoing degranulation. For the mast cells with calcitonin gene-related peptide immuno-positive nerve fibers within a distance of 40 &mgr;m. distance correlated significantly with the degree of degranulation. Bacterial cultures were negative at 13 weeks.

CONCLUSIONS: Our results confirm previous reports of spontaneous prostatitis in Wistar rats and indicate that moderate inflammation may occur in 80% of rats at as early as age 13 weeks. While the correlation of the nerve mast cell axis with mast cell degranulation does not prove our hypothesis of mast cell mediated inflammatory mediator release in the development of nonbacterial prostatitis, it suggests that such a relationship is possible.

Mast Cells and Nerve Fibers in BPS/IC

J Urol 1998;159:2252 Urology, suppl., 49: 41-47, 1997

Mast Cells and Nerve Fibers in Bladder Pain Syndrome/Interstitial Cystitis (BPS/IC)- An Algorithm for Histologic Diagnosis Via Quantitative Image Analysis and Morphometry (QIAM)

M. A. Hofmeister; F. He; T. L. Ratliff; T. Mahoney; M. J. Becich
Division of Cellular and Molecular Pathology, University of Pittsburgh School of Medicine, Pittsburgh and The Imaging Source, Mars, Pennsylvania, and Division of Urology, University of Iowa Medical School, Iowa City, Iowa

Objective. To develop and evaluate a diagnostic algorithm based on the alteration of mast cell and nerve fiber observed in bladder tissue of patients with bladder pain syndrome/interstitial cystitis (BPS/IC) (BPS/IC).

Materials and Methods. Non-IC samples from 6 control groups (N = 10, 10, 13, 2, 11, and 3, respectively) and nonclassic interstitial cystitis (NC-IC, N = 20) were stained with Giemsa stain in order to calculate the detrusor to mucosa mast cell ratio (DMMCR) using quantitative image analysis and morphometry (QIAM). Immunohistochemical staining for S-100 protein was also performed to quantify nerve fiber proliferation in the detrusor muscle of the bladder.

Results. The average DMMCR of NC-IC was 1.19, Bacille Calmette-Guerin (BCG) cystitis was 0.84 and microscopically normal bladder tissue from patients with bladder or prostate cancer was 0.45. No case of IC that we examined had a DMMCR <0.5. The number and percentage area of nerve fibers in the detrusor in IC were increased compared to controls and BCG (IC, 2.01%; BCG, 0.95%; control, 1.3%).

Conclusion. A diagnostic algorithm is proposed for IC based on the findings that indicate that: 1) if the DMMCR >0.75, then IC is present; 2) if the DMMCR <0.5, then IC is negative; and 3) if the DMMCR is between 0.5 and 0.75, a quantitative S-100 protein staining analysis can be employed to evaluate nerve fiber proliferation to detect those marginal cases of NC-IC. The findings of the study also suggest that a neuroimmune process or mediation may be involved in the pathogenesis of IC.

Editorial Comment: This proposed diagnostic algorithm is based on a retrospective study. A future prospective study for confirmation is proposed. As the authors state, "the relationship between the nerve fibers and mast cells in IC may provide additional avenues of research into possible etiologies and pathogenic mechanisms of IC. From such studies new treatments may be targeted not only at the symptoms but at the cause."

Alan J. Wein, M.D.

Stress Increases Number of Mast Cells in Bladder

J Urol 2001;165:235-239

Role Of Afferent Neurons In Stress Induced Degenerative Changes Of The Bladder

From the Departments of Histology-Embryology, and Pharmacology and Clinical Pharmacology, Marmara University, Medical Faculty, Istanbul, Turkey


Purpose: We investigated the role of afferent C fibers in morphological changes of the rat bladder during stress.

Materials and Methods: Wistar albino rats were exposed to cold immobilization stress. Different routes of capsaicin administration before cold immobilization stress were studied. Capsaicin was given to neonates, around the vagus (perivagal) or celiac (periceliac), or perivagal plus periceliac. From each group samples of bladder were randomly chosen for morphological evaluation using electron microscopy.

Results: Stress exposure led to pathological changes, including an increased number of mast cells, degenerated urothelium and dilated tight junctions, in the bladder. Capsaicin given neonatally and around the vagal and celiac ganglia prevented these stress induced degenerative bladder changes.

Conclusions: Activation of capsaicin sensitive afferent neurons locally and centrally may be involved in stress related pathological changes in the rat bladder.

CNS Induced Neurogenic Cystitis Is Associated With Bladder Mast Cell Degranulation In The Rat

J Urol 2000;164:852-855

CNS Induced Neurogenic Cystitis Is Associated With Bladder Mast Cell Degranulation In The Rat


From the Departments of Neurosurgery, Cell Biology, Microbiology & Immunology, Georgetown University Medical Center, Washington, District of Columbia, and the Department of Anatomy, University of California, San Francisco, California


Purpose: To determine if bladder mast cell degranulation is involved in the genesis of neurogenic cystitis induced by pseudorabies virus (PRV) invasion of the central nervous system (CNS).

Materials and Methods: Rats received a total of 4 × 106 plaque forming units (pfu) of PRV-Bartha in the abductor caudalis dorsalis (ACD) muscle. Granulated bladder mast cells per mm2 of bladder tissue and urine histamine content were monitored as the cystitis developed over the next few days. In a subgroup of rats, intravesical resiniferatoxin was used to remove capsaicin-sensitive sensory bladder afferents, while another subgroup was pretreated with a mast cell degranulator.

Results: PRV injection into the ACD muscle leads to neurogenic cystitis. Histamine levels were elevated in the urine of virus injected rats before any behavioral or microscopical signs of cystitis were present. When the cystitis became clinically manifest, urine histamine returned to control levels, and the number of granulated mast cells dropped significantly. Rats in which capsaicin-sensitive afferents had been removed did not show any signs of cystitis, or increase in urine histamine, or change in the number of granulated mast cells. Pretreatment of animals with a mast cell degranulator completely prevented the appearance of cystitis without altering the CNS disease.

Conclusion: These results provide further evidence that mast cells are involved in neurogenic cystitis induced by changes in CNS activity.