Interstitial Cystitis: A Neuroimmunoendocrine Disordera

Authors

  • THEOHARIDES C. THEOHARIDES,

    Corresponding author
    1. Department of Pharmacology and Experimental Therapeutics, Tufts University School of Medicine and New England Medical Center, Boston, Massachusetts 02111 USA
    2. Department of Internal Medicine, Tufts University School of Medicine and New England Medical Center, Boston, Massachusetts 02111 USA
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  • XINZHU PANG,

    1. Department of Pharmacology and Experimental Therapeutics, Tufts University School of Medicine and New England Medical Center, Boston, Massachusetts 02111 USA
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  • RICHARD LETOURNEAU,

    1. Department of Pharmacology and Experimental Therapeutics, Tufts University School of Medicine and New England Medical Center, Boston, Massachusetts 02111 USA
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  • GRANNUM R. SANT

    1. Department of Urology, Tufts University School of Medicine and New England Medical Center, Boston, Massachusetts 02111 USA
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  • a

    This work was supported in part by a grant from Kos Pharmaceuticals (FL), grants DK42409 and DK44816 from the NIH/NIDDK, as well as a pilot grant from the Interstitial Cystitis Association (NY).

Address for correspondence: T. C. Theoharides, Ph.D., M.D., Department of Pharmacology and Experimental Therapeutics, Tufts University School of Medicine, New England Medical Center, Boston, Massachusetts 02111; Telephone: 617-636-6866; Fax: 617-636-6456; e-mail: ttheoharides@infonet.tufts.edu

Abstract

Abstract: Interstitial cystitis (IC) is a sterile bladder condition occurring primarily in females. It is characterized by frequency, nocturia, and suprapubic pain. IC symptoms are exacerbated during ovulation and under stress, thus implicating neurohormonal processes. The most prevalent theories to explain the pathophysiology of IC appear to be altered bladder lining and increased number of activated bladder mast cells. A defective bladder glycosaminoglycan (GAG) layer could allow penetration of allergic triggers, as well as chemicals, food preservatives, drugs, toxins, and adherent bacteria, all of which can activate bladder mast cells. Vasoactive, nociceptive, and proinflammatory molecules released can lead to immune cell infiltration and can sensitize neurons to secrete neurotransmitters or neuropeptides that can further activate mast cells. Mast cell-derived proteases can directly cause tissue damage, and it is noteworthy that urine tryptase is elevated in IC. Bladder mast cells are located close to neuronal processes, which are increased in IC, and they can be activated in situ by acetylcholine (ACh) and substance P (SP). Such activation is augmented by estradiol, which acquires significance in view of the fact that human bladder mast cells express estrogen receptors, but few progesterone receptors, which may explain the worsening of IC symptoms during ovulation. Finally, acute psychological stress in rats leads to mast cell activation that can be reduced by depletion of SP or neutralization of peripheral immune corticotropin-releasing hormone (CRH). These findings suggest that IC could be a syndrome with neural, immune, and endocrine components, in which activated mast cells play a central role.

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