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T C Theoharides

Publications and source records attributed to T C Theoharides.

At least 73 records · Page 4Linked to original sources
PubMed1996

Mast cell and substance P-positive nerve involvement in a patient with both irritable bowel syndrome and interstitial cystitis.

Many patients with interstitial cystitis (IC) also have irritable bowel syndrome (IBS), both of which occur overwhelmingly in women, are characterized by pain, and worsen under stress. Bladder and colon biopsies of a female patient with both IC and IBS were evaluated immunohistochemically. There were 40 +/- 10 mast cells (MC)/mm2 (normal, less than 10) in the bladder, which were degranulated. The colon contained 148 +/- 11 MC/mm2 (normal, less than 50), mostly close to numerous substance P (SP)-positive nerves. Histamine, methylhistamine, and the unique MC enzyme tryptase were evaluated in 24-hour urine during two flare-ups. These results may help explain the concurrent presentation and the painful nature of these syndromes.

Chymases↗
PubMed1996

Intragranular activation of bladder mast cells and their association with nerve processes in interstitial cystitis.

OBJECTIVE: To investigate the presence of progesterone receptors and the extent and type of degranulation exhibited by the increased numbers of mast cells (MCs) found in interstitial cystitis (IC), a painful bladder disorder which occurs almost exclusively in women, worsens perimenstrually and is characterized by increased numbers of oestradiol receptor (OR)-positive MCs. PATIENTS AND METHODS: The state of MC degranulation was analysed blindly using electron microscopy of bladder biopsies from 26 patients with IC and six control patients which included five women with incontinence, with none of the established characteristics of IC, and one man with transitional carcinoma of the bladder. Emphasis was placed on preserving the secretory granule ultrastructure. The presence of progesterone receptors (PRs) in five patients with IC and three controls was investigated using commercially available antibodies against PRs. RESULTS: Over 85% of bladder MCs expressed high affinity PRs, but the number of PR-positive MCs in patients with IC did not differ significantly from that of controls despite the overall increase in MCs seen in IC. MCs were activated to various degrees and were often near to neuronal processes. The secretory granule content of MCs from patients with IC was in different stages of dissolution, ranging from heterogeneous loss of electron density to the appearance of crystalline substructure and target forms containing only remnants of the original material. Typical degranulation by compound exocytosis was not observed. MCs from control patients contained secretory granules with mostly intact, electron-dense granules. CONCLUSION: These findings indicate that the symptoms of IC may depend on an imbalance of the relative number of oestrogen receptors (ORs) to PRs on bladder MCs resulting in a 'progesterone deficient' state. This possibility is strengthened by demonstration that oestradiol augments the secretion of MC histamine in response to the neuropeptide substance P, which is pro-inflammatory, nociceptive and overexpressed in bladders with IC. Intragranular activation of bladder MCs is a characteristic pathological finding in patients with IC. The lack of extensive degranulation, typically seen in anaphylaxis, may indicate a unique mode of stimulation and/or differential release of mediators.

Adult↗
PubMed1996

The mast cell: a neuroimmunoendocrine master player.

This review of the literature on mast cells (MC) suggests that when activated they may play a central role in disease syndromes with a neural, immune and endocrine component exacerbated under stress. After a discussion of their biology, differential secretions and interaction with neurons, the effect of stress in causing MC degranulation is emphasized. The importance of MC in syndromes such as migraine, multiple sclerosis, interstitial cystitis and irritable bowel syndrome is assessed, along with possible therapeutic possibilities with compounds that inhibit MC activation.

Animals↗
PubMed1995

Elevated mast cell tryptase in cerebrospinal fluid of multiple sclerosis patients.

Multiple sclerosis (MS) lesions are associated with infiltration of T lymphocytes and macrophages that appear to mediate myelin destruction and gliosis (scarring). Mast cells are located perivascularly in the brain, are juxtaposed to neurons, and have been shown to secrete vasoactive and inflammatory mediators in response to neuropeptides and direct nerve stimulation. Mast cells have been previously identified in MS lesions, are activated by myelin basic protein, and can participate in the regulation of blood-brain barrier permeability, as well as in myelin destruction. Here, cerebrospinal fluid from MS patients and controls with other neurologic diseases was assayed for histamine, its major metabolite methylhistamine, and the specific mast cell marker tryptase. Histamine and methylhistamine were not elevated in MS. However, the mast cell specific proteolytic enzyme tryptase was significantly elevated in MS, suggesting that mast cell activation may be involved in the pathophysiology of this disease.

Adult↗
PubMed1995

Activation of bladder mast cells in interstitial cystitis: a light and electron microscopic study.

Interstitial cystitis, a sterile bladder condition, is characterized by urinary frequency, urgency, burning and suprapubic pain. Increasing evidence indicates that interstitial cystitis is a heterogeneous syndrome that reflects an immune response to a variety of triggers. More than 50% of the patients have allergies, 30% have the irritable bowel syndrome and almost 20% suffer from migraine headaches. Increased numbers of mast cells have been reported in interstitial cystitis. Mast cell activation, which is critical if these cells were to be implicated in this syndrome, has been investigated by electron microscopy, which definitively shows mast cell secretion. Recently, methylhistamine, the major metabolite of histamine, and the specific mast cell marker, tryptase, were shown to be significantly elevated in urine of interstitial cystitis patients. Bladder biopsies from 53 patients were analyzed blindly for the number and degree of activation of mast cells using 4 different stains for light microscopy, as well as electron microscopy. Controls included 16 patients with incontinence and chronic bacterial cystitis. Mast cells in controls were less than 10/mm.2 and were all nearly intact. Surprisingly, mast cells from 11 cancer patients averaged 50/mm.2 but almost all were intact. In contrast, mast cells from 26 interstitial cystitis patients averaged 40/mm.2 and more than 90% were activated to various degrees. Therefore, bladder mast cell activation is a characteristic pathological finding in at least a subset of patients with interstitial cystitis.

Adult↗
PubMed1995

Bladder mast cell expression of high affinity oestrogen receptors in patients with interstitial cystitis.

OBJECTIVE: To investigate the role of oestrogens in the pathophysiology of interstitial cystitis (IC), specifically with respect to activated bladder mast cells (MC), as well as urine concentrations of MC-derived histamine and methylhistamine, all of which are increased in patients with IC. This goal appeared important because IC is a bladder disorder which occurs almost exclusively in women, and is characterized by polyuria, nocturia and pelvic pain, which worsen perimenstrually. PATIENTS AND METHODS: Biopsies from six patients with IC and four control patients were analysed blindly for the presence of oestrogen receptors (OR) using both custom-made and commercially available antibodies against OR. RESULTS: Bladder MC alone were shown to express high-affinity OR and there was a higher number of such cells present in patients with IC compared with controls. The identity of MC in the bladder was documented with immunohistochemistry for tryptase. OR were also identified in human MC (HMC-1), a MC line kept in culture. These steps were necessary because of the unique finding that only MC express OR, in spite of the inflammatory infiltrate present. CONCLUSION: These findings may help to explain why IC occurs primarily in women, why IC and other associated symptoms tend to be worst at the midcycle, and may also suggest that prognostic usefulness of staining bladder biopsies for OR. These results are particularly interesting because oestradiol has been shown to augment MC histamine secretion in response to the neuropeptide, substance P, which may be released in certain neuroinflammatory disorders which have a high prevalence in women, such as IC and irritable bowel syndrome.

Cystitis↗
PubMed1995

Increased number of substance P positive nerve fibres in interstitial cystitis.

OBJECTIVE: To explore the presence of the neuropeptide substance P (SP) in the bladders of rats and humans and to investigate its relationship to mast cells (MCs) in interstitial cystitis (IC), a bladder disorder which occurs mostly in women and is characterized by frequency of voiding, nocturia and debilitating suprapubic pain. PATIENTS, MATERIALS AND METHODS: Bladder biopsies from eight women with untreated IC (mean age 36 years, range 29-58) and five control patients with no IC were analysed and compared with each other and with bladder tissue from 12 rats. Immunohistochemistry and image analysis were used to examine the density of SP-positive nerve fibres and their relationship with MCs. RESULTS: SP-containing nerve fibres were present in the bladder of both rats and humans. They were increased only in the submucosa, but not in the detrusor, of IC patients and were frequently seen in juxtaposition to MCs. CONCLUSION: SP, a neuropeptide secreted from sensory nerve endings, has been implicated in the pathophysiology of pain and has been shown to trigger MC secretion. Moreover, MC secretion by SP is augmented by oestradiol and bladder MCs have been shown to express high affinity oestrogen receptors. A functional relationship between SP and MCs may explain the pathophysiology of the neuro-inflammatory and painful nature of IC.

Adult↗
PubMed1995

Elevated mast cell tryptase in the urine of patients with interstitial cystitis.

OBJECTIVE: To investigate the number of tryptase positive bladder mast cells and the level of urine tryptase in interstitial cystitis (IC), a bladder disorder which occurs mostly in women and is characterized by suprapubic pain, frequency and nocturia. PATIENTS AND METHODS: Bladder biopsies from 37 women with IC and 15 control women with other bladder conditions (age range 18-63 years) were obtained during diagnostic bladder distension and frozen immediately. Mast cells positive for tryptase were identified by immunohistochemistry and evaluated by light microscopy. Tryptase was measured by solid phase radioimmunoassay in urine samples, collected immediately (spot) and during a period of 24 h, obtained from normal women volunteers, controls and patients with IC. To adequately quantify tryptase, the physiologically active tetramer was dissociated to inactive monomers with supersaturated NaCl (6.0 M), and then dialysed. RESULTS: The patients' spot urine sample tryptase levels were indistinguishable from those of controls, which included the normal women volunteers. However, the tryptase levels in 24 h urine samples were greatly elevated only in patients with IC, both before (P < 0.005), and especially after NaCl treatment and dialysis (P < 0.001). CONCLUSION: These results indicate that the tryptase levels of 24 h urine samples, combined with methylhistamine levels and the clinical criteria presently used, may possibly help to better identify IC.

Adolescent↗
PubMed1995

Stress-induced intracranial mast cell degranulation: a corticotropin-releasing hormone-mediated effect.

Stress is known to precipitate or worsen a number of disorders, such as migraines, in which mast cells are suspected of being involved by releasing vasoactive, nociceptive, and proinflammatory mediators. However, no functional association has been demonstrated yet between a migraine trigger and brain mast cell activation. Nontraumatic immobilization (restrain) stress has been shown to stimulate the hypothalamic-pituitary-adrenal axis and to cause redistribution of immune cells. Here, restrain stress caused degranulation in 70% of rat dura mast cells within 30 min, as shown both by light and electron microscopy. These morphologic findings were accompanied by cerebrospinal fluid elevation of rat mast cell protease I, but not II, indicating secretion from connective tissue type mast cells. Mast cell activation due to stress was abolished in animals that had been treated neonatally with capsaicin, indicating that neuropeptides in sensory nerve endings are involved in this response. Complete inhibition was also achieved by pretreating the animals ip with polyclonal antiserum to CRH. Mast cells in the dura were localized close to nerve processes containing substance P, but no CRH-positive fibers were identified even though these were found close to mast cells in the median eminence. This is the first time that stress is shown to activate intracranial mast cells; apparently through the sequential action of CRH and sensory neuropeptides. These findings may have implications for the pathophysiology and possible therapy of neuroinflammatory disorders such as migraines, which are induced or exacerbated by stress.

Animals↗
PubMed1995

Monocyte chemotactic protein-1 provokes mast cell aggregation and [3H]5HT release.

Monocyte chemotactic protein-1 (MCP-1) and MCP-3, the most active and representative compounds of the CC chemokine family, are proinflammatory cytokines that attract and activate specific types of leucocytes. We have used highly purified isolated rat peritoneal mast cells (RPMC) cultured for different lengths of time with and without MCP-1 (200, 100, 50 and 25 nM). Our data clearly show that MCP-1 (200 nM) causes a marked release of [3H]serotonin ([3H]5HT and histamine, which reach a peak at 40 min of incubation (56.6 +/- 5.3 and 34.7 +/- 6 above the control, respectively). In dose-response experiments, MCP-1 (200, 100, 50, 25, 12.5, 6.25 and 3.12 nM) provoked a dose-dependent release of [3H]5HT and histamine from RPMC, which was maximum at 200 nM. After preparation of the histidine decarboxylase (HDC) probe, a Northern blot analysis was determined for HDC mRNA. After 4 hr, steady-state levels of HDC mRNA were induced in a dose-dependent manner by MCP-1 (200-25 nM), compared to the controls. However, MCP-1 failed to prime RPMC in [3H]5HT and histamine release when C48/80 (0.05 micrograms/ml) or anti-IgE was used. In contrast, murine interleukin-3 (IL-3) in combination with MCP-1 (200 and 100 nM) provoked a greater release of histamine and [3H]5HT than the compounds alone. Moreover, RPMC treated with MCP-1 (200 nM) showed, under light microscopy (20x), greater clump formation, a phenomenon absent in the controls (untreated cells). The electron microscope studies revealed that treatment with MCP-1 (200 nM) promoted binding of RPMC and clearly demonstrated a communication between the cytoplasms of adjacent mast cells. Our report describes additional biological activities for MCP-1, suggesting for the first time that this human monocyte chemoattractant plays a fundamental role in histamine and serotonin release and cell aggregation in rat peritoneal mast cells.

Animals↗
PubMed1994

Neuronal involvement in the intestinal effects of Clostridium difficile toxin A and Vibrio cholerae enterotoxin in rat ileum.

BACKGROUND/AIMS: Activation of intestinal mast cells and neurons is involved in intestinal inflammation and diarrhea. This study compared the effects of neuronal inhibitors and inhibition of intestinal sensory afferent nerves on the intestinal actions of Clostridium difficile toxin A, an inflammatory enterotoxin, and cholera toxin, a noninflammatory enterotoxin. METHODS: The effects of lidocaine, hexamethonium, atropine, and long-term pretreatment of capsaicin on fluid secretion, mannitol permeability, myeloperoxidase (MPO) activity, and release of rat mast cell protease II (RMCPII) were measured in toxin A- and cholera toxin-exposed loops in vivo. RESULTS: Lidocaine, hexamethonium, and capsaicin, but not atropine, inhibited toxin A-mediated secretion and MPO activity, but only capsaicin reduced mannitol permeability. Lidocaine, but not capsaicin, reduced secretion and permeability caused by cholera toxin. Toxin A caused release of RMCPII from rat ileum in vivo and in vitro; this was inhibited by lidocaine or capsaicin, whereas cholera toxin had no effect on release of RMCPII. CONCLUSIONS: Neuronal mechanisms are important in the in vivo effects of these two enterotoxins. Capsaicin-sensitive sensory afferent neurons and mast cells are involved in the intestinal mechanism of toxin A, but not cholera toxin.

Animals↗
PubMed1994

Increased urine histamine and methylhistamine in interstitial cystitis.

Interstitial cystitis is a painful bladder disorder occurring mostly in women, and is presently diagnosed by clinical presentation, as well as the presence of mucosal glomerulations and inflammation on bladder distention. An increased number of bladder mast cells have been implicated in the pathophysiology of interstitial cystitis but previous reports of spot urine histamine have not confirmed bladder mast cell activation. The availability of easily measurable objective criteria could make the diagnosis easier. Histamine and its major metabolite, methylhistamine, were measured in spot and 24-hour urine specimens from a number of normal female volunteers, control patients and interstitial cystitis patients. In interstitial cystitis patients the histamine levels were only slightly increased in the spot (p < 0.01) and 24-hour urine (p < 0.03) collections. Methylhistamine, on the other hand, was greatly elevated in spot (p < 10(-10)) and 24-hour (p < 0.0008) urine samples. These results indicate that methylhistamine levels could serve as useful diagnostic end points for interstitial cystitis.

Adolescent↗
PubMed1994

Treatment of secretory otitis media with local instillation of hydroxyzine.

The study is a preliminary single-blind, placebo- and prednisolone-controlled investigation of the treatment of 156 children with otitis media with effusion (secretory otitis media, SOM), ranging from 2 to 12 years. The protocol involved tympanotomy and placement of a ventilation tube (grommet), through which control or drug solutions were introduced. Other parameters and coexisting symptoms which could contribute to SOM were also examined. Patients were divided into 3 groups as follows: group A: control (normal saline, 2 ml); group B: prednisolone (25 mg in 2 ml); group C: hydroxyzine pamoate (10(-5) M in 2 ml). The results indicate that in those children treated with hydroxyzine, the rate of relapse was significantly reduced and so was the amount of histamine present in middle ear effusions. The effectiveness of hydroxyzine is discussed in the context of the pathophysiology of SOM, especially with respect to mast cells and their activation by allergic and nonallergic means.

Child↗
PubMed1994

Hydroxyzine in the treatment of interstitial cystitis.

Hydroxyzine is a piperazine, tricyclic, H1-receptor antagonist with unique properties, especially the inhibition of mast cell and neuronal secretion. Preliminary results indicate is has an unusual ability to reduce interstitial cystitis symptoms. The long history, lack of major side effects, wide availability, low cost, and apparent effectiveness of hydroxyzine compel presentation of these preliminary results.

Administration, Oral↗
PubMed1994

The role of the mast cell in interstitial cystitis.

The bladder mast cell contains many granules, each of which can secrete many vasoactive and nociceptive molecules. A number of conditions, such as extreme cold, drugs, neuropeptides, stress, trauma, and toxins, can trigger the mast cell to secrete some of its contents; they, in turn, can sensitize sensory neurons, which can further activate mast cells by releasing neurotransmitters or neuropeptides. Additionally, the mast cell can directly cause vasodilation and bladder mucosa damage while also attracting inflammatory cells, thus causing many of the problems seen in interstitial cystitis. The mast cell appears to be involved in the pathogenesis of interstitial cystitis. Although it is not pathognomonic of the disease, mastocytosis does occur in a significant subset of interstitial cystitis patients. Because interstitial cystitis is now regarded as a syndrome caused by multiple factors, it is conceivable that one cause of interstitial cystitis is associated with bladder mastocytosis and mast cell activation. The fact that mast cells are also increased in patients with transitional cell carcinoma of the bladder does not diminish the importance of mastocytosis in interstitial cystitis, because the mast cells are not activated in carcinoma but are activated in interstitial cystitis. Perhaps the common strand between these two bladder diseases is the putative allergens/carcinogens in bladder urine that breach the protective lining of the bladder and then elicit an immune response in the bladder wall. Furthermore, the majority of patients with a history of bladder tumors receive multiple courses of intravesical chemotherapy (such as thiotepa) or immunotherapy (bacille Calmette-Guerin), and it is possible that these agents damage the bladder lining or provoke an inflammation in the bladder wall. The theory of a defective/deficient bladder glycosaminoglycan layer in interstitial cystitis is also consonant with this putative chain of events in the pathogenesis of interstitial cystitis. Thus these two theories interstitial cystitis causation--a glycosaminoglycan deficiency and bladder mastocytosis--may well operate in concert to cause bladder inflammation and the symptoms of interstitial cystitis. Clinicians may be at a distinct disadvantage because they are faced with a multitude of potential mast cell triggers and numerous mediators secreted. It may, therefore, be advisable to block or inhibit the mast cell from responding to many of these various stimuli. Specific mast cell mediators should be assayed as possible diagnostic tools, and potential mast cell inhibitors should be tried under controlled conditions to determine the extent of therapeutic benefit.

Animals↗