The urinary bladder is often the site of subacute or chronic inflammation, in the absence of infection, as in interstitial cystitis (IC), a painful bladder disorder occurring mostly in women. Symptoms of urinary frequency and pelvic pain commonly worsen perimenstrually and under stress in IC. Bladder mastocytosis with mast cell activation has been documented in IC. We also showed that acute immobilizationstress in rodents induced bladder mast cell activation, a process that was dependent on the neuropeptides neurotensin (NT) and substance P (SP), as it was absent in rodents treated with capsaicin to deplete sensory nerve fibers of their SP content and was also inhibited by the NT receptor antagonist SR48692. Moreover, pretreatment of bladder with estradiol increased the stimulatory effect of SP, by activating high affinity estrogen receptors that we have identified on bladder mast cells. It was recently shown that bladder inflammation could not occur in mast cell deficient mice infected with the neurotropic pseudorabies virus. Mast cells are located perivascularly close to nerve processes and may secrete many vasoactive, proinflammatory and neurosensitizing molecules in response to allergic triggers, as well as by direct nerve stimulation and by acute immobilization stress. Corticotropin releasing hormone (CRH) is released from the hypothalamus under stress and activates the hypothalamic-pituitary-adrenal (HPA) axis. However, both CRH and its structurally related urocortin (Ucn) are also released in the periphery where they have proinflammatory effects. CRH and Ucn induced rat skin mast cell activation and increased vascular permeability, both of which were inhibited by pretreatment with neutralizing antiserum to CRH or the CRH-receptor (CRH-R) antagonist, antalarmin. CRH or acute stress-induced skin vascular permeability was absent in W/W v mast cell deficient mice, but was present in their +/+ controls indicating it is mast cell dependent. Acute stress also triggered rat bladder mast cell activation that was blocked by a NT-receptor antagonist. The proinflammatory cytokines interleukin-6 (IL-6) and tumor necrosisfactor-alpha (TNF-alpha) were recently shown to be elevated in urine of IC patients. We are hypothesizing that acute stress releases (CRH) and/or (Ucn) in the bladder leading, directly or through SP or NT, to mast cell activation, increased vascular permeability and the expression of proinflammatory molecules. We propose to use normal and genetically deficient female mice to investigate the effect of acute stress and CRH/Ucn on: (1) bladder mast cell and urothelial Nuclear Factor kappa B (NF-kappaB)activation, as well as the levels of histamine,lL-6 and TNF-alpha in the urine collected from an indwelling catheter; (2) bladder vascular permeability quantitated by 99Technetium-gluceptate (99Tc) extravasation; (3) Vascular permeability, urine mediator release, as well as NF-kappaB activation in W/W v mast cell deficient mice, as well as in CRH knock-out mice and their +/+ controls; (4) mouse bladder mast cell and urothelial NF-KB activation, as well as secretion of histamine, IL-6 or TNF-alpha induced by intravesical administration of CRH/Ucn. These studies will help us understand how acute stress triggers bladder mast cell activation leading to increased vascular permeability and proinflammatory molecule release. Our findings may be relevant to the pathophysiology of IC and may suggest new therapeutic approaches.
| Theoharides, Theoharis C (2014) Mast cells in irritable bowel syndrome and ulcerative colitis: function not numbers is what makes all the difference. Dig Dis Sci 59:897-8 |
| Petra, Anastasia I; Panagiotidou, Smaro; Stewart, Julia M et al. (2014) Spectrum of mast cell activation disorders. Expert Rev Clin Immunol 10:729-39 |
| Miniati, A; Weng, Z; Zhang, B et al. (2014) Stimulated human melanocytes express and release interleukin-8, which is inhibited by luteolin: relevance to early vitiligo. Clin Exp Dermatol 39:54-7 |
| Theoharides, Theoharis C; Rozniecki, Jacek J; Sahagian, Gary et al. (2008) Impact of stress and mast cells on brain metastases. J Neuroimmunol 205:1-7 |
| Theoharides, Theoharis C; Whitmore, Kristine; Stanford, Edward et al. (2008) Interstitial cystitis: bladder pain and beyond. Expert Opin Pharmacother 9:2979-94 |
| Theoharides, Theoharis C (2007) Treatment approaches for painful bladder syndrome/interstitial cystitis. Drugs 67:215-35 |
| Theoharides, Theoharis C; Kempuraj, Duraisamy; Tagen, Michael et al. (2007) Differential release of mast cell mediators and the pathogenesis of inflammation. Immunol Rev 217:65-78 |
| Sant, Grannum R; Kempuraj, Duraisamy; Marchand, James E et al. (2007) The mast cell in interstitial cystitis: role in pathophysiology and pathogenesis. Urology 69:34-40 |
| Theoharides, Theoharis C; Sant, Grannum R (2005) Immunomodulators for treatment of interstitial cystitis. Urology 65:633-8 |
| Theoharides, Theoharis C (2004) Panic disorder, interstitial cystitis, and mast cells. J Clin Psychopharmacol 24:361-4 |
Showing the most recent 10 out of 11 publications
