Biomedical subjects

T C Theoharides

Publications and source records attributed to T C Theoharides.

At least 19 recordsLinked to original sources

PubMed2001

Acute stress increases permeability of the blood-brain-barrier through activation of brain mast cells.

Disruption of the blood-brain-barrier (BBB) is important in the pathophysiology of various inflammatory conditions of the central nervous system (CNS), such as multiple sclerosis (MS), in which breakdown of the BBB precedes any clinical or pathological findings. There is some evidence that relapsing-remitting MS attacks may be correlated with certain types of acute stressful episodes. Stress typically activates the hypothalamic-pituitary-adrenal (HPA) axis through the release of corticotropin releasing hormone (CRH), leading to production of glucocorticoids that down regulate immune responses. However, acute stress also has pro-inflammatory effects that appear to be mediated through activation of mast cells. Here we show that acute stress by immobilization increased permeability of rat BBB to intravenous 99Technetium gluceptate (99Tc). This effect was statistically significant in the diencephalon and the cerebellum, while it was absent in the cerebral cortex where there are not mast cells. Immobilization stress also induced activation of mast cells in diencephalon, the site where most mast cells are found in the rat brain. Both BBB permeability and mast cell activation were inhibited by the 'mast cell stabilizer' disodium cromoglycate (cromolyn). These results expand the pathophysiology of mast cells and implicate them in CNS disorders, that may possibly be induced or exacerbated by stress.

Acute Disease↗

PubMed2001

Elevated interleukin-6 levels in patients with asymptomatic left ventricular systolic dysfunction.

BACKGROUND: Elevated interleukin-6 (IL-6) levels are present in patients with New York Heart Association (NYHA) class III and IV congestive heart failure (CHF) and are associated with a poor prognosis. We sought to determine whether elevated IL-6 levels are also present in patients with left ventricular (LV) dysfunction but without clinical symptoms. METHODS: Blood samples were obtained from the femoral artery of 58 patients who underwent cardiac catheterization for recognized clinical indications. In a subgroup of 44 patients, samples were also obtained from the femoral vein, the left main coronary artery, and the coronary sinus. Patients with prior coronary artery bypass surgery, recent acute coronary syndrome, or steroid therapy were excluded. All samples were obtained before heparin or contrast administration. IL-6 was measured by enzyme-linked immunosorbent assay and values are expressed in picograms per milliliter. RESULTS: Three groups of patients were identified: controls, no CHF, LV ejection fraction >/=0.55 (n = 32); asymptomatic LV systolic dysfunction, no CHF, LV ejection fraction <0.55 (n = 14); and CHF, pulmonary edema (n = 12). IL-6 levels were higher at all sampling sites in both the asymptomatic LV systolic dysfunction and CHF groups compared with controls with the IL-6 levels inversely related to LV ejection fraction. CONCLUSIONS: Elevated IL-6 levels are present in patients with LV dysfunction even in the absence of the clinical syndrome of CHF. These data suggest that IL-6 may be involved in the progression of subclinical LV dysfunction to clinical CHF. IL-6 may be a marker of patients at risk for progression to clinical CHF or a novel target for therapeutic intervention.

Female↗

PubMed2001

New agents for the medical treatment of interstitial cystitis.

Interstitial cystitis (IC) is a painful, sterile, disorder of the urinary bladder characterised by urgency, frequency, nocturia and pain. IC occurs primarily in women but also in men with recent findings indicating that chronic, abacterial prostatitis may be a variant of this condition. The prevalence of IC has ranged from about 8 - 60 cases/100,000 female patients depending on the population evaluated. About 10% of patients have severe symptoms that are associated with Hunner's ulcers on bladder biopsy; the rest could be grouped in those with or without bladder inflammation. Symptoms of IC are exacerbated by stress, certain foods and ovulatory hormones. Many patients also experience allergies, irritable bowel syndrome (IBS) and migraines. There have been various reports indicating dysfunction of the bladder glycosaminoglycan (GAG) protective layer and many publications showing a high number of activated bladder mast cells. Increasing evidence suggests that neurogenic inflammation and/or neuropathic pain is a major component of IC pathophysiology. Approved treatments so far include intravesical administration of dimethylsulphoxide (DMSO) or oral pentosanpolysulphate (PPS). New treatments focus on the combined use of drugs that modulate bladder sensory nerve stimulation (neurolytic agents), inhibit neurogenic activation of mast cells, or provide urothelial cytoprotection, together with new drugs with anti-inflammatory activity.

Analgesics↗

PubMed2000

Sites of interleukin-6 release in patients with acute coronary syndromes and in patients with congestive heart failure.

This study examines the source of elevated interleukin-6 (IL-6) levels in patients with acute coronary syndrome (ACS) and congestive heart failure (CHF). IL-6 is elevated in the peripheral blood of patients with ACS and CHF, but it is not known if this proinflammatory cytokine is from a cardiac or extracardiac source. Blood samples were obtained from the femoral artery, femoral vein, left main coronary artery, and coronary sinus in 57 patients during cardiac catheterization. IL-6 levels from 12 patients with ACS and 12 patients with CHF were compared with the IL-6 levels in 33 patients who had neither of these clinical conditions. Median IL-6 levels in the peripheral and coronary circulation were a minimum fivefold higher in patients with ACS or CHF relative to control patients. An elevated transcardiac IL-6 gradient (coronary sinus-left main level) was present in patients with ACS (median 5.2; 25th and 75th percentiles 3.9 and 29.3 pg/ml, respectively) compared with control patients (median 0, -0.7 and 0.5 pg/ml; p < 0.001), but not in patients with CHF (median 0.4, -0.7 and 3.5 pg/ml; p = NS). Elevated IL-6 levels in patients with ACS derive from a cardiac source, presumably from "inflamed" coronary plaques and areas of myocardial necrosis, whereas elevated levels in patients with CHF are most likely the result of extracardiac production.

Adult↗

PubMed2000

Hydroxyzine inhibits experimental allergic encephalomyelitis (EAE) and associated brain mast cell activation.

Experimental allergic encephalomyelitis (EAE) has been used as an animal model for the human demyelinating disease multiple sclerosis (MS). In acute MS or EAE, early disruption in the integrity of the blood-brain-barrier (BBB) precedes brain infiltration by inflammatory cells or any clinical evidence of disease. BBB permeability could be affected by vasoactive mediators and cytokines released from perivascular brain mast cells. We investigated the number and degree of activation of brain mast cells in EAE and the effect of the heterocyclic histamine-1 receptor antagonist hydroxyzine, a piperazine compound known to also block mast cells. Acute EAE was induced in Lewis rats by immunization with whole guinea pig spinal cord homogenate and complete Freund's adjuvant (CFA). A second group of animals were treated orally with hydroxyzine for one day before immunization and then continuously for 14 days. Control rats were treated with CFA or hydroxyzine alone. The clinical progression of EAE was assessed on days 10, 12 and 14 after immunization. The number of metachromatic mast cells and the degree of degranulation was assessed in the thalamus with light microscopy. At day 14, there was a three-fold increase in the number of brain mast cells with EAE, as compared to controls. These cells were positive for the immunoglobulin E binding protein (FcepsilonRI), while those from control rats were not. Over 40% of all thalamic mast cells studied in EAE showed partial staining or extruded secretory granule indicative of secretion. Hydroxyzine treatment inhibited (p<0.05) the progression and severity of EAE by 50% and the extent of mast cell degranulation by 70% (p<0.05). These findings indicate that brain mast cells are associated with EAE development and that inhibition of their activation correlates positively with the clinical outcome.

Animals↗

PubMed2000

Effect of an antioxidant (quercetin) on sodium-lauryl-sulfate-induced skin irritation.

Quercetin is a bioflavonoid with antioxidant and anti-inflammatory activity. The purpose of this study was to examine the effect of quercetin on acute skin irritation, with special interest in the skin barrier function recovery. Acute irritant contact dermatitis was induced in 15 patients by 24-h occlusion of 2% sodium lauryl sulfate (SLS) (day (D) 1). The influence of application on SLS-irritated skin of topical quercetin for 5 consecutive Ds, compared to vehicle and controls, was studied. Parameters measured were transepidermal water loss (TEWL) and erythema index. Final measurements were taken on D 7 after a 1-D rest period. TEWL and the erythema index continued to rise 2 D after application of SLS and 1 D after treatment with quercetin, vehicle or controls. Both TEWL and erythema values at D 7 did not return to values before the SLS barrier disruption at all the test sites. Therefore, quercetin topically applied after induction of irritant contact dermatitis does not appear to increase the recovery of barrier function and erythema caused by SLS.

Administration, Cutaneous↗

PubMed2000

Chondroitin sulphate inhibits connective tissue mast cells.

1. Mast cells derive from the bone marrow and are responsible for the development of allergic and possibly inflammatory reactions. Mast cells are stimulated by immunoglobulin E (IgE) and specific antigen, but also by a number of neuropeptides such as neurotensin (NT), somatostatin or substance P (SP), to secrete numerous pro-inflammatory molecules that include histamine, cytokines and proteolytic enzymes. 2. Chondroitin sulphate, a major constituent of connective tissues and of mast cell secretory granules, had a dose-dependent inhibitory effect on rat peritoneal mast cell release of histamine induced by the mast cell secretagogue compound 48/80 (48/80). This inhibition was stronger than that of the clinically available mast cell 'stabilizer' disodium cromoglycate (cromolyn). Inhibition by chondroitin sulphate increased with the length of preincubation and persisted after the drug was washed off, while the effect of cromolyn was limited by rapid tachyphylaxis. 3. Immunologic stimulation of histamine secretion from rat connective tissue mast cells (CTMC) was also inhibited, but this effect was weaker in umbilical cord-derived human mast cells and was absent in rat basophilic leukemia (RBL) cells which are considered homologous to mucosal mast cells (MMC). Oligo- and monosaccharides were not as effective as the polysaccharides. 4. Inhibition, documented by light and electron microscopy, involved a decrease of intracellular calcium ion levels shown by confocal microscopy and image analysis. Autoradiography at the ultrastructural level showed that chondroitin sulphate was mostly associated with plasma and perigranular membranes. 5. Chondroitin sulphate appears to be a potent mast cell inhibitor of allergic and nonimmune stimulation with potential clinical implications.

Animals↗

PubMed2000

Cloning and cellular localization of the rat mast cell 78-kDa protein phosphorylated in response to the mast cell "stabilizer" cromolyn.

Disodium cromoglycate (cromolyn) inhibits mast cell secretion, but its mechanism has not been elucidated. One possibility is the phosphorylation of a 78-kDa mast cell protein, two fragments of which are homologous to moesin, a member of the ezrin, radixin, moesin family. These proteins appear to be involved in signal transduction by regulating functional associations between the cell surface and the cytoskeleton. Moesin cDNA was cloned from rat basophil leukemia cells, which are similar to mucosal mast cells, and polyclonal antiserum was prepared against recombinant moesin expressed in Escherichia coli. Moesin phosphorylated in mast cells treated with cromolyn shifted from the soluble to the precipitable fraction and associated with Sepharose-linked beta-actin. Recombinant moesin also associated with Sepharose-linked beta-actin, and so did purified RBL moesin, but only if the latter was first denatured. Moesin thus appears to have actin binding sites that are not exposed under normal conditions but may become available by in vivo phosphorylation or by denaturation. Immunocytochemistry using confocal microscopy showed moesin to be primarily localized on the inner aspect of the plasma membrane and around secretory granules. Double immunocytochemistry for moesin and actin colocalized them in most areas. Ultracryoimmunoelectron microscopy to preserve the antigenicity of moesin identified the protein close to the plasma and secretory granule membranes. Cromolyn appeared to induce clustering of moesin around secretory granules. It is hypothesized that conformational changes of moesin, regulated by phosphorylation/dephosphorylation, may lead to positional rearrangements with respect to the membrane/cytoskeleton that could possibly regulate mast cell secretion.

Actins↗

PubMed2000

Pentosanpolysulfate inhibits mast cell histamine secretion and intracellular calcium ion levels: an alternative explanation of its beneficial effect in interstitial cystitis.

PURPOSE: Mast cells are ubiquitous cells derived from the bone marrow and are responsible for allergic reactions as they release numerous vasodilatory, nociceptive and pro-inflammatory molecules in response to immunoglobulin E (IgE) and specific antigen. Mast cell secretion is also triggered by a number of peptides, such as bradykinin and substance P, and may also be involved in the development of inflammatory responses. An example is interstitial cystitis, which is a sterile painful bladder disorder that has been associated with a defective glycosaminoglycan bladder mucosal layer and an increased number of activated mast cells. Pentosanpolysulfate is a synthetic, sulfated polysaccharide that has been approved for the treatment of interstitial cystitis on the premise that it may replenish the defective glycosaminoglycan layer. We hypothesize that pentosanpolysulfate may also have an additional or alternate action on bladder mast cells. We report that pentosanpolysulfate has a powerful dose dependent inhibitory effect on mast cell release of histamine induced by the mast cell secretagogue compound 48/80. MATERIALS AND METHODS: Inhibition of mast cell secretion was documented by light and electron microscopy and extended to stimulation by substance P or IgE and antigen. RESULTS: The inhibition was more potent than that seen with the clinically available mast cell stabilizer disodium cromoglycate (cromolyn). Maximal inhibition by pentosanpolysulfate was apparent within 1 minute, was unaffected by the length of pre-incubation and persisted after the drug was washed off. In contrast, the effect of cromolyn was limited by rapid tachyphylaxis. In addition, while cromolyn has no effect on mucosal or rat basophilic leukemia cells, pentosanpolysulfate inhibited histamine secretion from both. Confocal microscopy using a calcium indicator dye showed that pentosanpolysulfate decreased intracellular calcium ion levels. CONCLUSIONS: Pentosanpolysulfate appears to be a potent inhibitor of allergic and nonimmune mast cell stimulation, which is an alternative explanation of its benefit in interstitial cystitis.

Animals↗

PubMed2000

The effects of plant flavonoids on mammalian cells: implications for inflammation, heart disease, and cancer.

Flavonoids are nearly ubiquitous in plants and are recognized as the pigments responsible for the colors of leaves, especially in autumn. They are rich in seeds, citrus fruits, olive oil, tea, and red wine. They are low molecular weight compounds composed of a three-ring structure with various substitutions. This basic structure is shared by tocopherols (vitamin E). Flavonoids can be subdivided according to the presence of an oxy group at position 4, a double bond between carbon atoms 2 and 3, or a hydroxyl group in position 3 of the C (middle) ring. These characteristics appear to also be required for best activity, especially antioxidant and antiproliferative, in the systems studied. The particular hydroxylation pattern of the B ring of the flavonoles increases their activities, especially in inhibition of mast cell secretion. Certain plants and spices containing flavonoids have been used for thousands of years in traditional Eastern medicine. In spite of the voluminous literature available, however, Western medicine has not yet used flavonoids therapeutically, even though their safety record is exceptional. Suggestions are made where such possibilities may be worth pursuing.

Animals↗

PubMed1999

Morphological and functional demonstration of rat dura mater mast cell-neuron interactions in vitro and in vivo.

Mast cells derive from a distinct bone marrow precursor and mature in tissues under the influence of stem cell factor, nerve growth factor (NGF) and certain interleukins. Intracranial mast cells first appear in the meninges and are located perivascularly close to neurons. They can be activated by antidromic stimulation of the trigeminal nerve, as well as by acute immobilization stress. Substance P (SP) and corticotropin-releasing hormone (CRH) are particularly potent in stimulating mast cell release of vasoactive, inflammatory and nociceptive molecules. These findings have suggested that mast cells may be involved in neuroinflammatory conditions, such as migraines. In this study, dura mast cells were shown to have characteristics of connective tissue mast cells (CTMC) as they contained histamine, heparin and rat mast cell protease I (RMCP-I). Mast cells were localized close to SP-positive neurons immunocytochemically and mast cell-neuron contacts were also documented using scanning electron microscopy. Dura stimulated by SP and carbachol in situ released histamine. Preincubation of dura with estradiol slightly augmented histamine release by SP, an effect possibly mediated through estrogen receptors identified on dura mast cells. Acute stress by immobilization led to dura mast cell degranulation which was prevented by pretreatment with a neutralizing antibody to CRH or a CRH receptor antagonist. The present results further clarify the biology of intracranial mast cells and support their involvement in the pathophysiology of migraines which are precipitated or worsened by stress.

Animals↗

PubMed1999

Ca2+ and phorbol ester effect on the mast cell phosphoprotein induced by cromolyn.

Several phosphoproteins are involved in stimulus-secretion coupling. The beta and gamma subunits of immunoglobulin E binding protein (FC epsilonRI) and three other protein bands get phosphorylated during stimulation of mast cell secretion. These additional proteins of 42, 59 and 68 kDa are also phosphorylated when secretion is stimulated by compound 48/80 (C48/80). A 78 kDa band, however, is phosphorylated as secretion wanes after stimulation with C48/80 and by the anti-allergic drug disodium cromoglycate (cromolyn). Phosphorylation was blocked by protein kinase C inhibitors. We investigated the isozyme involved by first showing that a cation ionophore prevented the phosphorylation of the 78 kDa protein, while a Ca2+ chelator did not affect phosphorylation even though it enhanced the inhibitory effect of cromolyn. This protein was identified as moesin by immunoprecipitation. Protein kinase C activators had no effect on 78 kDa protein phosphorylation either in the presence or absence of Ca2+ ions, but prevented its phosphorylation by cromolyn. Protein phosphatase inhibitors prolonged the duration, but not the amount of phosphate incorporated in the 78 kDa protein band while cromolyn had no effect on protein phosphatase action in vitro. The insensitivity of the 78 kDa protein phosphorylation to calcium and protein kinase C activators suggests that an atypical protein kinase C isozyme may be involved. Western blot analysis identified the presence of isozymes alpha, beta, delta and zeta, of which only the latter fits the profile suggested by the present findings.

Animals↗

PubMed1999

Acute immobilization stress triggers skin mast cell degranulation via corticotropin releasing hormone, neurotensin, and substance P: A link to neurogenic skin disorders.

Many skin disorders, such as atopic dermatitis and psoriasis, worsen during stress and are associated with increased numbers and activation of mast cells which release vasoactive, nociceptive, and proinflammatory mediators. Nontraumatic acute psychological stress by immobilization has been shown to induce mast cell degranulation in the rat dura and colon. Moreover, intradermal injection of corticotropin-releasing hormone (CRH) or its analogue urocortin (10(-5)-10(-7) M) induced skin mast cell degranulation and increased vascular permeability. Here, we investigated the effect of acute immobilization stress on skin mast cell degranulation by light microscopy and electron microscopy. Immobilization for 30 min resulted (P < 0.05) in degranulation of 40.7 +/- 9.1% of skin mast cells compared to 22.2 +/- 7.3% in controls killed by CO(2) or 17.8 +/- 2.4% in controls killed by pentobarbital. Pretreatment intraperitoneally (ip) with antiserum to CRH for 60 min prior to stress reduced (P < 0.05) skin mast cell degranulation to 21.0 +/- 3. 3%. Pretreatment with the neurotensin (NT) receptor antagonist SR48692 reduced (P < 0.05) mast cell degranulation to 12.5 +/- 3.4%, which was significantly (P < 0.05) below control levels. In animals treated neonatally with capsaicin to deplete their sensory neurons of their neuropeptides, such as substance P (SP), mast cell degranulation due to immobilization stress was reduced to about 15%. This is the first time that stress has been shown to trigger skin mast cell degranulation, an action not only dependent on CRH, but apparently also involving NT and SP. These findings may have implications for the pathophysiology and possible therapy of neuroinflammatory skin disorders such as atopic dermatitis, neurogenic pruritus, or psoriasis, which are induced or exacerbated by stress.

Acute Disease↗

PubMed1999

Neurotensin mediates rat bladder mast cell degranulation triggered by acute psychological stress.

OBJECTIVES: An increased number of activated mast cells have been documented in interstitial cystitis (IC), a painful bladder disorder occurring primarily in women and exacerbated by stress. Mast cells in the bladder and in the intestine are often found in juxtaposition to neurons, where they are activated by neuropeptides and neurotransmitters as well as by acute psychological stress. This work was undertaken to investigate whether the neuropeptide neurotensin (NT) is involved in the activation of bladder mast cells by acute psychological stress. METHODS: Male 300-g Sprague-Dawley rats were either kept on the bench in a quiet procedure room or stressed by confining them one at a time for 30 minutes in a clear Plexiglas immobilizer and then killed with carbon dioxide. The bladder was removed and fixed with 4% paraformaldehyde. Frozen sections were either stained with acidified toluidine blue or processed for NT immunocytochemical analysis. An immunosorbent assay was used to also measure NT in bladder homogenate before and after stress. RESULTS: Bladder mast cell activation in control rats was 37.3 +/- 1.4%, as judged by extrusion of granule contents. Degranulation in stressed animals increased to 75.3 +/- 5.5% (P = 0.0003). Treatment of the animals neonatally with capsaicin decreased mast cell degranulation to 48.9 +/- 7.5% (P = 0.008), a 35.1% inhibition. Intraperitoneal administration of the nonpeptide NT receptor antagonist SR48692 sixty minutes before stress decreased bladder mast cell degranulation to 25.2 +/- 3.6% (P = 0.00007), a 66.5% inhibition. This value is 32.5% below control levels, indicating that NT is involved in basal mast cell degranulation. Stress also reduced the total bladder NT content. CONCLUSIONS: The present results indicate that NT mediates the effect of acute, nontraumatic psychological stress on bladder mast cell degranulation. They further suggest that NT receptor antagonists may be useful in subpopulations of patients with IC in whom symptoms worsen under stress.

Acute Disease↗

PubMed1999

Differential effect of flavonoids on inhibition of secretion and accumulation of secretory granules in rat basophilic leukemia cells.

Rat basophilic leukemia (RBL) cells resemble mucosal mast cells (MMC) and develop few secretory granules under normal culture conditions. RBL cells have been used for the study of secretion and for the possible involvement of MMC in food allergies and irritable bowel syndrome (IBS). The flavonoid quercetin is one of very few molecules that inhibit RBL cell proliferation and constitutive histamine release; it also induces synthesis of rat mast cell protease (RMCP) II and accumulation of secretory granules. Even though quercetin is available as a food supplement over the counter, some early studies had indicated it may be carcinogenic. We, therefore, compared the effect of quercetin to that of other flavonoids with similar structure. Flavone, kaempferol, myricetin and morin were investigated for their action on RBL cell secretion of beta-hexosaminidase stimulated by anti-DNP serum and DNP-BSA, as well as on secretory granule development. Quercetin, myricetin and kaempferol inhibited RBL cell secretion significantly only at 10(-4) M. Flavone inhibited secretion at 10(-4), 10(-5) and 10(-6) M; it also maximally induced secretory granule accumulation as evidenced by light and electron microscopy. In contrast, morin which differs structurally only by one extra hydroxyl group had minimal effect. These results indicate that flavone is capable of inhibiting stimulated secretion and inducing secretory granule development at reasonable concentrations.

Animals↗

PubMed1999

Dual effect of spermine on mast cell secretion exhibits different calcium and temperature requirements.

Mast cells release many biologically active molecules upon stimulation by a variety of molecules such as immunoglobulin E (IgE) and specific antigen, anaphylatoxins, as well as a number of cationic compounds which include drugs, kinins and neuropeptides. The effect of the naturally occurring polyamine spermine was studied because, even though it is polycationic, it has been implicated in the modulation of secretory processes in a variety of cells. In particular, it was previously shown that oxidation products of spermine inhibit mast cell secretion. High concentrations of spermine (5 x 10(-3) M) added at 37 degrees C induced mast cell secretion that had similar characteristics with that triggered by compound 48/80 (48/80). However, spermine inhibited mast cell secretion in a dose-dependent manner as long as it was added at 4-10 degrees C for at least 10 min in the absence of Ca++ before warming the cells to 37 degrees C and triggering them with 48/80. These findings were true both for purified rat peritoneal mast cells and for rat skin mast cells in situ. Addition of calcium after the cells had been warmed to 37 degrees C could not reverse this inhibition. The inhibition seen when spermine was added at 4 degrees C was, however, overcome if phorbol myristate acetate (PMA) or NaF, which activate PKC and G proteins respectively, were added to mast cells at 37 degrees C together with Ca++. These results indicate that polyamines could be important modulators of the activation state of mast cells and might help further define the biochemical events involved in mast cell secretion.

Animals↗

PubMed1999

Interstitial cystitis.

Interstitial cystitis is a complex inflammatory condition of the bladder. The pathophysiology of interstitial cystitis is incompletely understood, although altered epithelial permeability, mast cell activation and sensory afferent nerve upregulation play critical roles. A unified understanding of the pathogenesis of interstitial cystitis is emerging and this will hopefully lead to the introduction of novel therapies for pain and irritative voiding symptoms. Interstitial cystitis is a common disease among women and is frequently misdiagnosed as prostatitis and benign prostatic hyperplasia among men.

Animals↗

PubMed1999

Potent mast cell degranulation and vascular permeability triggered by urocortin through activation of corticotropin-releasing hormone receptors.

Urocortin (Ucn) is related to corticotropin-releasing hormone (CRH), and both are released in the brain under stress where they stimulate CRH 1 and 2 receptors (CRHR). Outside the brain, they may have proinflammatory actions through activation of mast cells, which are located perivascularly close to nerve endings and degranulate in response to acute psychological stress. Here, we report that a concentration of intradermal Ucn as low as 10 nM induced dose-dependent rat skin mast cell degranulation and increased vascular permeability. This effect appeared to be equipotent to that of calcitonin gene-related peptide and neurotensin. Ucn-induced skin vasodilation was inhibited by pretreatment with the mast cell stabilizer disodium cromoglycate (cromolyn) and was absent in the mast cell-deficient W/Wv mice. The selective nonpeptide CRH receptor 1 antagonist, antalarmin and the nonselective peptide antagonist astressin both reduced vascular permeability triggered by Ucn but not that by Substance P or histamine. In contrast, the peptide antagonist alpha-helical CRH-(9-41) reduced the effect of all three. The vasodilatory effect of Ucn was largely inhibited by pretreatment with H1 receptor antagonists, suggesting that histamine is the major mediator involved in vitro. Neuropeptide depletion of sensory neurons, treatment with the ganglionic blocker hexamethonium, or in situ skin infiltration with the local anesthetic lidocaine did not affect Ucn-induced vascular permeability, indicating that its in situ effect was not mediated through the peripheral nervous system. These results indicate that Ucn is one of the most potent triggers of rat mast cell degranulation and skin vascular permeability. This effect of Ucn may explain stress-induced disorders, such as atopic dermatitis or psoriasis, and may lead to new forms of treatment.

Animals↗