Mast Cell-Derived Histamine Mediates Cystitis Pain

Department of Urology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, United States of America.
PLoS ONE (Impact Factor: 3.23). 02/2008; 3(5):e2096. DOI: 10.1371/journal.pone.0002096
Source: PubMed


Mast cells trigger inflammation that is associated with local pain, but the mechanisms mediating pain are unclear. Interstitial cystitis (IC) is a bladder disease that causes debilitating pelvic pain of unknown origin and without consistent inflammation, but IC symptoms correlate with elevated bladder lamina propria mast cell counts. We hypothesized that mast cells mediate pelvic pain directly and examined pain behavior using a murine model that recapitulates key aspects of IC.
Infection of mice with pseudorabies virus (PRV) induces a neurogenic cystitis associated with lamina propria mast cell accumulation dependent upon tumor necrosis factor alpha (TNF), TNF-mediated bladder barrier dysfunction, and pelvic pain behavior, but the molecular basis for pelvic pain is unknown. In this study, both PRV-induced pelvic pain and bladder pathophysiology were abrogated in mast cell-deficient mice but were restored by reconstitution with wild type bone marrow. Pelvic pain developed normally in TNF- and TNF receptor-deficient mice, while bladder pathophysiology was abrogated. Conversely, genetic or pharmacologic disruption of histamine receptor H1R or H2R attenuated pelvic pain without altering pathophysiology.
These data demonstrate that mast cells promote cystitis pain and bladder pathophysiology through the separable actions of histamine and TNF, respectively. Therefore, pain is independent of pathology and inflammation, and histamine receptors represent direct therapeutic targets for pain in IC and other chronic pain conditions.

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Available from: Charles N Rudick, Oct 09, 2015
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    • "Mast cell-deficient mice are unable to develop the appropriate pain behaviour and pathophysiology following of interstitial cystitis as well as the appropriate thermoregulatory responses during sepsis (Nautiyal et al., 2009; Rudick et al., 2008). This body of evidence supports the role of mast cells in triggering the inflammatory response and pursuing nociceptive activity. "
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    ABSTRACT: This review selectively explores some areas of pain research that, until recently, have been poorly understood. We have chosen four topics that relate to clinical pain and we discuss the underlying mechanisms and related pathophysiologies contributing to these pain states. A key issue in pain medicine involves crucial events and mediators that contribute to normal and abnormal pain signaling, but remain unseen without genetic, biomarker or imaging analysis. Here we consider how the altered genetic make-up of familial pains reveals the human importance of channels discovered by preclinical research, followed by the contribution of receptors as stimulus transducers in cold sensing and cold pain. Finally we review recent data on the neuro-immune interactions in chronic pain and the potential targets for treatment in cancer-induced bone pain.
    European Journal of Pharmacology 09/2013; 716(s 1–3):188–202. DOI:10.1016/j.ejphar.2013.01.069 · 2.53 Impact Factor
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    • "These results inspire additional investigations of the mechanism of pelvic pain in this model. The role of mast cells in the induction of cystitis pain has been reported [51], [52]. Our EAC model is suitable for studies of the involvement of mast cells and their regulation by T cells in the development of IC/PBS-related pelvic pain. "
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    ABSTRACT: The pathophysiology of interstitial cystitis/painful bladder syndrome (IC/PBS) is enigmatic. Autoimmunity and impaired urothelium might lead the underlying pathology. A major shortcoming in IC/PBS research has been the lack of an appropriate animal model. In this study, we show that the bladder specific uroplakin 3A-derived immunogenic peptide UPK3A 65-84, which contains the binding motif for IA(d) MHC class II molecules expressed in BALB/c mice, is capable of inducing experimental autoimmune cystitis in female mice of that strain. A highly antigen-specific recall proliferative response of lymph node cells to UPK3A 65-84 was observed, characterized by selectively activated CD4+ T cells with a proinflammatory Th1-like phenotype, including enhanced production of interferon γ and interleukin-2. T cell infiltration of the bladder and bladder-specific increased gene expression of inflammatory cytokines were observed. Either active immunization with UPK3A 65-84 or adoptive transfer of peptide-activated CD4+ T cells induced all of the predominant IC/PBS phenotypic characteristics, including increased micturition frequency, decreased urine output per micturition, and increased pelvic pain responses to stimulation with von Frey filaments. Our study demonstrates the creation of a more specific experimental autoimmune cystitis model that is the first inducible model for IC/PBS that manifests all of the major symptoms of this debilitating condition.
    PLoS ONE 08/2013; 8(8):e72067. DOI:10.1371/journal.pone.0072067 · 3.23 Impact Factor
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    • "In nonulcer IC/PBS, reports on mast cell numbers show large standard deviations, possibly due to heterogeneous patient subgroups. Mast cell accumulation in IC/PBS has been associated with bladder pain [9], apoptosis [10] and detrusor fibrosis [11]. Increased urinary concentrations of histamine and tryptase are common indicators of mast cell degranulation. "
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    ABSTRACT: The pathogenesis of interstitial cystitis/painful bladder syndrome (IC/PBS) is multifactorial, but likely involves urothelial cell dysfunction and mast cell accumulation in the bladder wall. Activated mast cells in the bladder wall release several inflammatory mediators, including histamine and tryptase. We determined whether mitogen-activated protein (MAP) kinases are activated in response to tryptase stimulation of urothelial cells derived from human normal and IC/PBS bladders. Tryptase stimulation of normal urothelial cells resulted in a 2.5-fold increase in extracellular signal regulated kinase 1/2 (ERK 1/2). A 5.5-fold increase in ERK 1/2 activity was observed in urothelial cells isolated from IC/PBS bladders. No significant change in p38 MAP kinase was observed in tryptase-stimulated normal urothelial cells but a 2.5-fold increase was observed in cells isolated from IC/PBS bladders. Inhibition of ERK 1/2 with PD98059 or inhibition of p38 MAP kinase with SB203580 did not block tryptase-stimulated iPLA2 activation. Incubation with the membrane phospholipid-derived PLA2 hydrolysis product lysoplasmenylcholine increased ERK 1/2 activity, suggesting the iPLA2 activation is upstream of ERK 1/2. Real time measurements of impedance to evaluate wound healing of cell cultures indicated increased healing rates in normal and IC/PBS urothelial cells in the presence of tryptase, with inhibition of ERK 1/2 significantly decreasing the wound healing rate of IC/PBS urothelium. We conclude that activation of ERK 1/2 in response to tryptase stimulation may facilitate wound healing or cell motility in areas of inflammation in the bladder associated with IC/PBS.
    PLoS ONE 07/2013; 8(7):e69948. DOI:10.1371/journal.pone.0069948 · 3.23 Impact Factor
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