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1.  Evidence questioning cromolyn’s effectiveness and selectivity as a “mast cell stabilizer” in mice 
Cromolyn, widely characterized as a “mast cell stabilizer”, has been used in mice to investigate the biological roles of mast cells in vivo. However, it is not clear to what extent cromolyn can either limit the function of mouse mast cells or influence biological processes in mice independently of effects on mast cells. We confirmed that cromolyn (at 10 mg/kg in vivo or 10 – 100 μM in vitro) can inhibit IgE-dependent mast cell activation in rats in vivo (measuring Evans blue extravasation in passive cutaneous anaphylaxis and increases in plasma histamine in passive systemic anaphylaxis) and in vitro (measuring peritoneal mast cell β-hexosaminidase release and prostaglandin D2 synthesis). However, under the conditions tested, cromolyn did not inhibit those mast cell-dependent responses in mice. In mice, cromolyn also failed to inhibit the ear swelling or leukocyte infiltration at sites of passive cutaneous anaphylaxis. Nor did cromolyn inhibit IgE-independent degranulation of mouse peritoneal mast cells induced by various stimulators in vitro. At 100 mg/kg, a concentration ten times higher than that which inhibited passive systemic anaphylaxis in rats, cromolyn significantly inhibited the increases in plasma concentrations of mouse mast cell protease-1 (but not of histamine) during passive systemic anaphylaxis, but had no effect on the reduction in body temperature in this setting. Moreover, this concentration of cromolyn (100 mg/kg) also inhibited LPS-induced TNF production in genetically mast cell-deficient C57BL/6-KitW-sh/W-sh mice in vivo. These results question cromolyn’s effectiveness and selectivity as an inhibitor of mast cell activation and mediator release in the mouse.
doi:10.1038/labinvest.2012.116
PMCID: PMC3580174  PMID: 22906983
Anaphylaxis; cromolyn; disodium cromoglycate; DSCG; mast cell; mouse; rat
2.  Effects of Sodium Cromoglycate on Iranian Asthmatic Subjects Without Exposure to any Bronchoconstrictor agent 
Cromolyn sodium, a mast cell stabilizing agent, provides an immediate protective effect against the exercise-induced bronchoconstriction while being used before the exercise. However, cromolyn is ineffective in reversing asthmatic bronchospasm; it is used as a maintenance therapy and has a prophylactic role in chronic asthma.
The purpose of this study was to determine the extent of change in baseline lung function tests following a single dose of cromolyn sodium in adult asthmatics.
Forty volunteers (33 women and 7 men) with moderate to severe persistent asthma were randomly assigned to receive 20 mg cromolyn, 40 mg cromolyn or cromolyn-placebo. The percent of improvement in lung function parameters was compared among the groups, during 1 h of inhalation.
Low dose of cromolyn induced more improvement in most lung function parameters such as forced expiratory flow volume in one second, forced vital capacity and peak expiratory flow compared with other groups. After 15 min, the improvement percentage of baseline forced expiratory flow volume in one second was 3.35 ± 1.5, for sodium cromoglycate-20 mg group compared with 0.98 ± 1.43 and - 0.68 ± 1.2 for sodium cromoglycate-placebo and sodium cromoglycate-40 mg, groups respectively. However, the differences between means were not significant. Furthermore, based on the definition of American Thoracic Society (ATS) for a ”significant post-bronchodilator response” developed in a few patients 15 min after the inhalation of 20 mg cromolyn sodium.
It is suggested that probably the inhalation of 20 mg of cromolyn sodium could immediately improve the lung function in few adults with asthma.
PMCID: PMC3832161  PMID: 24250478
Cromolyn sodium; Lung function tests; Forced expiratory flow volume in one second; Bronchial asthma; Adults
3.  Mast Cell Inhibition Attenuates Myocardial Damage, Adverse Remodeling and Dysfunction during Fulminant Myocarditis in Rat 
Background
Myocarditis is a life-threatening heart disease characterized by myocardial inflammation, necrosis and chronic fibrosis. While mast cell inhibition has been suggested to prevents fibrosis in rat myocarditis, little is known about its effectiveness in attenuating cardiac remodeling and dysfunction in myocarditis. Thus, we sought to test the hypothesis that mast cell inhibition will attenuate the inflammatory reaction and associated left ventricular (LV) remodeling and dysfunction after fulminant autoimmune myocarditis.
Methods and Results
To induce experimental autoimmune myocarditis, we immunized 30 rats with porcine cardiac myosin twice at a 7-day interval. On day 8 animals were randomized into treatment either with an intraperitoneal (IP) injection of 25mg/kg of cromolyn sodium (n=13), or an equivalent volume (~0.5ml IP) of normal saline (n=11). All animals were scanned by serial echocardiography studies before treatment (baseline echocardiogram) and after 20 days of cromolyn sodium (28 days after immunization). Furthermore, serial cardiac magnetic resonance was performed in a subgroup of 12 animals. After 20 days of treatment (28 days from first immunization), hearts were harvested for histopathological analysis. By echocardiography, cromolyn sodium prevented LV dilatation and attenuated LV dysfunction, compared with controls. Postmortem analysis of hearts showed that cromolyn sodium reduced myocardial fibrosis, as well as the number and size of cardiac mast cells in the inflamed myocardium, compared with controls.
Conclusions
Our study suggests that mast cell inhibition with cromolyn sodium attenuates adverse LV remodeling and dysfunction in myocarditis. This mechanism-based therapy is clinically relevant and could improve the outcome of patients at risk for inflammatory cardiomyopathy and heart failure.
doi:10.1177/1074248412458975
PMCID: PMC3968541  PMID: 23172937
myocarditis; cardiac remodeling; mast cells; fibrosis
4.  Mast Cells Mediate Hyperoxia-Induced Airway Hyper-reactivity in Newborn Rats 
Pediatric research  2010;68(1):70-74.
Premature infants are at increased risk of developing airway hyper-reactivity following oxidative stress and inflammation. Mast cells contribute to airway hyper-reactivity partly by mediator release, so we sought to determine if blocking mast cell degranulation or recruitment prevents hyperoxia-induced airway hyper-reactivity, mast cell accumulation, and airway smooth muscle changes. Rats were exposed at birth to air or 60% O2 for 14 days, inducing significantly increased airway hyper-reactivity (AHR) in the latter group, induced by nebulized methacholine challenge, measured by forced oscillometry. Daily treatment (postnatal days 1-14) with intraperitoneal cromolyn prevented hyperoxia-induced AHR, as did treatment with imatinib on postnatal days 5-14, compared with vehicle treated controls. Cromolyn prevented mast cell degranulation in the trachea but not hilar airways, and blocked mast cell accumulation in the hilar airways. Imatinib treatment completely blocked mast cell accumulation in tracheal/hilar airway tissues. Hyperoxia-induced AHR in neonatal rats is mediated, at least in part, via the mast cell.
doi:10.1203/PDR.0b013e3181e0cd97
PMCID: PMC3061400  PMID: 20386143
5.  Double-masked, randomized, parallel-group study comparing olopatadine 0.1% ophthalmic solution with cromolyn sodium 2% and levocabastine 0.05% ophthalmic preparations in children with seasonal allergic conjunctivitis 
Background: It is estimated that >50% of medications have not been tested in children. Physicians need pediatric data to guide them in treating children. Olopatadine hydrochloride ophthalmic solution 0.1% is a topical antiallergic agent that is both an antihistamine with high affinity and selectivity for the histamine H1 receptor and a mast cell stabilizer that inhibits the release of histamine and other proinflammatory mediators from human conjunctival mast cells. The efficacy and tolerability of olopatadine has been demonstrated by comparative studies in adults and children with seasonal allergic conjunctivitis (SAC).
Objective: Pediatric patient data were extracted from 2 clinical trials to assess the efficacy and tolerability of olopatadine hydrochloride ophthalmic solution 0.1% compared with those of cromolyn sodium ophthalmic solution 2% and levocabastine ophthalmic solution 0.05% as treatment for SAC in children.
Methods: In study 1, conducted at 15 centers in 7 countries (Europe and Australia) from October 1995 to December 1997, olopatadine was instilled BID and placebo (vehicle) BID for 6 weeks and compared with cromolyn instilled QID. Study 2, conducted at 17 centers in 8 countries (Europe and Australia) from November 1998 to June 2000, compared olopatadine BID with levocabastine BID. In both studies, children of either sex and any race, aged 4 to 11 years, and having proven grass pollen allergies were assigned to treatment in a double-masked, randomized fashion. Slit-lamp examination, the physician's impression scale, and self-ratings were used to obtain efficacy data. Data analyses were based on pollen concentrations. The tolerability assessments were based on visual acuity, pupil diameter, intraocular pressure, and a dilated fundus examination.
Results: Study 1 comprised 30 children (olopatadine [n = 13] and cromolyn sodium [n = 17]; 18 boys, 12 girls; mean age, 7.9 years [range, 4–11 years]). Study 2 comprised 22 children (olopatadine [n = 10] and levocabastine [n = 12]; 12 boys, 10 girls; mean age, 8.6 years [range, 5–11 years]). In study 1, ocular itching (P = 0.010), redness seen on slit-lamp examination (P = 0.003), and eyelid swelling (P = 0.034) were significantly less intense with olopatadine than with cromolyn sodium during the peak pollen period. In study 2, redness seen on slit-lamp examination (P = 0.040) and self-rated ocular redness (P = 0.024) were significantly less intense with olopatadine than levocabastine during the peak pollen period. Olopatadine was well tolerated.
Conclusion: Olopatadine hydrochloride ophthalmic solution 0.1% was more effective than both cromolyn sodium 2% and levocabastine 0.05% ophthalmic preparations in controlling ocular signs and symptoms of SAC in children and was well tolerated when administered twice daily for 6 weeks.
doi:10.1016/S0011-393X(04)90032-X
PMCID: PMC3997093  PMID: 24764588
seasonal allergic rhinoconjunctivitis; eye drops; olopatadine; placebo; levocabastine; cromolyn sodium
6.  Quercetin Is More Effective than Cromolyn in Blocking Human Mast Cell Cytokine Release and Inhibits Contact Dermatitis and Photosensitivity in Humans 
PLoS ONE  2012;7(3):e33805.
Mast cells are immune cells critical in the pathogenesis of allergic, but also inflammatory and autoimmune diseases through release of many pro-inflammatory cytokines such as IL-8 and TNF. Contact dermatitis and photosensitivity are skin conditions that involve non-immune triggers such as substance P (SP), and do not respond to conventional treatment. Inhibition of mast cell cytokine release could be effective therapy for such diseases. Unfortunately, disodium cromoglycate (cromolyn), the only compound marketed as a mast cell “stabilizer”, is not particularly effective in blocking human mast cells. Instead, flavonoids are potent anti-oxidant and anti-inflammatory compounds with mast cell inhibitory actions. Here, we first compared the flavonoid quercetin (Que) and cromolyn on cultured human mast cells. Que and cromolyn (100 µM) can effectively inhibit secretion of histamine and PGD2. Que and cromolyn also inhibit histamine, leukotrienes and PGD2 from primary human cord blood-derived cultured mast cells (hCBMCs) stimulated by IgE/Anti-IgE. However, Que is more effective than cromolyn in inhibiting IL-8 and TNF release from LAD2 mast cells stimulated by SP. Moreover, Que reduces IL-6 release from hCBMCs in a dose-dependent manner. Que inhibits cytosolic calcium level increase and NF-kappa B activation. Interestingly, Que is effective prophylactically, while cromolyn must be added together with the trigger or it rapidly loses its effect. In two pilot, open-label, clinical trials, Que significantly decreased contact dermatitis and photosensitivity, skin conditions that do not respond to conventional treatment. In summary, Que is a promising candidate as an effective mast cell inhibitor for allergic and inflammatory diseases, especially in formulations that permit more sufficient oral absorption.
doi:10.1371/journal.pone.0033805
PMCID: PMC3314669  PMID: 22470478
7.  Evaluation of Thioperamide Effects Using Rat's Trachea Model 
Objectives
Thioperamide is used as an antagonist to the histamine H3 receptor. During administration of the drug, the trachea may be affected via nasal or oral inhalation. This study was to determine the effects of thioperamide on the trachea of rats in vitro.
Methods
We tested the effectiveness of thioperamide on isolated rat trachea submersed in Kreb's solution in a muscle bath. Changes in tracheal contractility in response to the application of parasympathetic mimetic agents were measured. The following assessments of thioperamide were performed: 1) effect on tracheal smooth muscle resting tension; 2) effect on contraction caused by 10-6 M methacholine as a parasympathetic mimetic; 3) effect of the drug on electrically-induced tracheal smooth muscle contractions.
Results
Thioperamide induced a significant relaxation response at a preparation concentration up to 10-4 M. The drug also inhibited the electrical field stimulation induced spike contraction. However, thioperamide alone had a minimal effect on the basal tension of the trachea at increasing concentrations.
Conclusion
The study indicated that high concentrations of thioperamide might actually antagonize cholinergic receptors and block parasympathetic function of the trachea.
doi:10.3342/ceo.2013.6.1.12
PMCID: PMC3604264  PMID: 23526076
Trachea; Asthma; In vitro; Thioperamide
8.  Contributions of Histamine, Prostanoids, and Neurokinins to Edema Elicited by Edema Toxin from Bacillus anthracis▿  
Infection and Immunity  2007;75(4):1895-1903.
Bacillus anthracis edema toxin (ET), composed of protective antigen and an adenylate cyclase edema factor (EF), elicits edema in host tissues, but the target cells and events leading from EF-mediated cyclic-AMP production to edema are unknown. We evaluated the direct effect of ET on several cell types in vitro and tested the possibility that mediators of vascular leakage, such as histamine, contribute to edema in rabbits given intradermal ET. ET increased the transendothelial electrical resistance of endothelial monolayers, a response that is mechanistically inconsistent with the in vivo vascular leakage induced by ET. Screening of several drugs by intradermal treatment prior to toxin injection demonstrated reduced ET-induced vascular leakage with a cyclo-oxygenase inhibitor (indomethacin), agents that interfere with histamine (pyrilamine or cromolyn), or a neurokinin antagonist (spantide). Systemic administration of indomethacin or celecoxib (cyclo-oxygenase inhibitors), pyrilamine, aprepitant (a neurokinin 1 receptor antagonist), or indomethacin with pyrilamine significantly reduced vascular leakage associated with ET. Although the effects of pyrilamine, cromolyn, or aprepitant on ET-induced vascular leakage suggest a possible role for mast cells (MC) and sensory neurons in ET-induced edema, ET did not elicit degranulation of human skin MC or substance P release from NT2N cells in vitro. Our results indicate that ET, acting indirectly or directly on a target yet to be identified, stimulates the production/release of multiple inflammatory mediators, specifically neurokinins, prostanoids, and histamine. These mediators, individually and through complex interactions, increase vascular permeability, and interventions directed at these mediators may benefit hosts infected with B. anthracis.
doi:10.1128/IAI.01632-06
PMCID: PMC1865696  PMID: 17261611
9.  Cromolyn ameliorates acute and chronic injury in a rat lung transplant model 
BACKGROUND
Mast cells have been associated with obliterative bronchiolitis (OB) in human pulmonary allografts, although their role in the development of OB remains unknown.
METHODS
In this study, we evaluated the role of mast cells in pulmonary allograft rejection using an orthotopic rat pulmonary allograft model that utilizes chronic aspiration of gastric fluid to reliably obtain OB. Pulmonary allograft recipients (n = 35) received chronic aspiration of gastric fluid with (n = 10) and without (n = 16) treatment with a mast cell membrane stabilizer, cromolyn sodium, or chronic aspiration with normal saline (n = 9) as a control.
RESULTS
The acute graft injury associated with long ischemic time in the model (6 hours total ischemic time; typical acute graft injury rate ~30%) was apparently blocked by cromolyn, because peri-operative mortality associated with the acute graft injury was not observed in any of the animals receiving cromolyn (p = 0.045). Further, the rats receiving cromolyn developed significantly fewer OB lesions than those treated with gastric fluid alone (p < 0.001), with a mean reduction of 46% of the airways affected.
CONCLUSIONS
These findings provide impetus for further studies aimed at elucidating the effects of cromolyn and the role of mast cells in pulmonary allotransplantation.
doi:10.1016/j.healun.2014.03.004
PMCID: PMC4336160  PMID: 24768366
mast cells; aspiration; pulmonary allograft; gastric fluid; obliterative bronchiolitis
10.  Pancreatic and pulmonary mast cells activation during experimental acute pancreatitis 
AIM: To study the activation of pancreatic and pulmonary mast cells and the effect of mast cell inhibition on the activation of peritoneal and alveolar macrophages during acute pancreatitis.
METHODS: Pancreatitis was induced by intraductal infusion of 5% sodium taurodeoxycholate in rats. The mast cell inhibitor cromolyn was administered intraperitoneally (i.p.) 30 min before pancreatitis induction. The pancreatic and pulmonary tissue damage was evaluated histologically and mast cells and their state of activation were evaluated. Peritoneal and alveolar macrophages were obtained and the expression of tumor necrosis factor α was determined. Myeloperoxidase activity was measured to evaluate the effect of mast cell inhibition on the progression of the inflammatory process. Finally, the effect of plasma on cultured mast cells or macrophages was evaluated in vitro.
RESULTS: The mast cell stabilizer significantly reduced inflammation in the pancreas and lung and the activation of alveolar macrophages but had no effect on peritoneal macrophages. Mast cell degranulation was observed in the pancreas during pancreatitis but no changes were observed in the lung. Plasma from rats with pancreatitis could activate alveolar macrophages but did not induce degranulation of mast cells in vitro.
CONCLUSION: Pancreatic mast cells play an important role in triggering the local and systemic inflammatory response in the early stages of acute pancreatitis. In contrast, lung mast cells are not directly involved in the inflammatory response related to pancreatic damage.
doi:10.3748/wjg.v16.i27.3411
PMCID: PMC2904888  PMID: 20632444
Cytokines; Inflammation; Macrophages; Mast cells; Pancreatitis
11.  ROLE OF MENINGEAL MAST CELLS IN INTRATHECAL MORPHINE EVOKED GRANULOMA FORMATION 
Anesthesiology  2013;118(3):664-678.
Background
Intrathecal morphine forms granulomas that arise from the adjacent arachnoid membrane. We propose that these inflammatory cells exit the meningeal vasculature secondary to meningeal mast cell degranulation.
Methods
Three sets of experiments were accomplished in dogs. 1) Ex vivo Meningeal mast cell degranulation. Histamine release was measured ex vivo from canine dura incubated with opiates. 2) In vivo cutaneous mast cell degranulation. Flare areas on the dog abdomen were measured after subcutaneous opiates. 3) In vivo granuloma pharmacology. Dogs with lumbar intrathecal catheters received infusion of intrathecal saline or intrathecal morphine. Intrathecal morphine dogs received: i) No other treatment (Control); ii) Twice daily subcutaneous naltrexone; iii) Intrathecal co-infusion of cromolyn; or, iv) Twice daily subcutaneous cromolyn for the 24–28 day study course.
Results
1) Morphine but not fentanyl evoked dural histamine release, which was blocked by cromolyn but not naloxone. 2) Wheal/flare was produced by subcutaneous morphine, methadone, hydromorphone, but not fentanyl, and was unaffected by naltrexone but prevented by cromolyn. 3) Granulomas occurred in all dogs receiving intrathecal morphine (15/15); subcutaneous naltrexone had no effect on granulomas (6/6), but was reduced by concurrent intrathecal cromolyn (0/5) or twice daily subcutaneous cromolyn (1 of 5).
Conclusions
The pharmacology of cutaneous/dural MC degranulation and intrathecal granulomas are comparable, not mediated by opioid receptors, and reduced by agents preventing MC degranulation. If an agent produces cutaneous MC degranulation at concentrations produced by intrathecal delivery, the agent may initiate granulomas.
doi:10.1097/ALN.0b013e31828351aa
PMCID: PMC3788115  PMID: 23426209
12.  CRF Induces Intestinal Epithelial Barrier Injury via the Release of Mast Cell Proteases and TNF-α 
PLoS ONE  2012;7(6):e39935.
Background and Aims
Psychological stress is a predisposing factor in the onset and exacerbation of important gastrointestinal diseases including irritable bowel syndrome (IBS) and the inflammatory bowel diseases (IBD). The pathophysiology of stress-induced intestinal disturbances is known to be mediated by corticotropin releasing factor (CRF) but the precise signaling pathways remain poorly understood. Utilizing a porcine ex vivo intestinal model, the aim of this study was to investigate the mechanisms by which CRF mediates intestinal epithelial barrier disturbances.
Methodology
Ileum was harvested from 6–8 week-old pigs, mounted on Ussing Chambers, and exposed to CRF in the presence or absence of various pharmacologic inhibitors of CRF-mediated signaling pathways. Mucosal-to-serosal flux of 4 kDa-FITC dextran (FD4) and transepithelial electrical resistance (TER) were recorded as indices of intestinal epithelial barrier function.
Results
Exposure of porcine ileum to 0.05–0.5 µM CRF increased (p<0.05) paracellular flux compared with vehicle controls. CRF treatment had no deleterious effects on ileal TER. The effects of CRF on FD4 flux were inhibited with pre-treatment of tissue with the non-selective CRF1/2 receptor antagonist Astressin B and the mast cell stabilizer sodium cromolyn (10−4 M). Furthermore, anti-TNF-α neutralizing antibody (p<0.01), protease inhibitors (p<0.01) and the neural blocker tetrodotoxin (TTX) inhibited CRF-mediated intestinal barrier dysfunction.
Conclusion
These data demonstrate that CRF triggers increases in intestinal paracellular permeability via mast cell dependent release of TNF-α and proteases. Furthermore, CRF-mast cell signaling pathways and increases in intestinal permeability require critical input from the enteric nervous system. Therefore, blocking the deleterious effects of CRF may address the enteric signaling of mast cell degranulation, TNFα release, and protease secretion, hallmarks of IBS and IBD.
doi:10.1371/journal.pone.0039935
PMCID: PMC3386952  PMID: 22768175
13.  A nebulized complex traditional Chinese medicine inhibits Histamine and IL-4 production by ovalbumin in guinea pigs and can stabilize mast cells in vitro 
Background
Traditional Chinese medicines have been used for anti-asthma treatment for several centuries in many Asian countries, and have been shown to effectively relieve symptoms. Our previous study demonstrated that a complex traditional Chinese medicine (CTCM) administered in nebulized form through the intratracheal route is effective against early-phase air-flow obstruction and can inhibit IL-5 production in ovalbumin (OVA)-sensitized guinea pigs. However, the antiasthmatic mechanisms of CTCMs are still unclear.
Methods
In this study, we examined the underlying mechanism of a CTCM that we used in our previous study in order to ascertain its function in the early-phase response to OVA challenge.
In each group, 10–12 unsensitized or OVA-sensitized guinea pigs were treated with nebulized CTCM before OVA challenge, and the airway responses of the animals to OVA were recorded. Bronchoalveolar lavage fluid (BALF) samples were collected 5 min after OVA challenge, and the histamine and IL-4 contents in the BALF were measured. P815 cells (a mouse mast cell line) were untreated or pretreated with CTCM or cromolyn sodium (a mast cell stabilizer), and incubated with Compound 48/80 (mast cell activator) for 9 hr. The levels of histamine and IL-4 released from the cells were quantified.
Results
We found that the inhibition of bronchoconstriction by the CTCM was attenuated by pretreatment with propranolol, suggesting that the CTCM has a bronchodilator effect that is associated with beta-adrenergic receptor. Our results also showed that the CTCM inhibited histamine and IL-4 secretion in the OVA-induced airway hypersensitivity in guinea pigs at 5 min post-OVA challenge, and in vitro study revealed that the CTCM is able to stabilize mast cells.
Conclusion
In conclusion, our results suggested that the CTCM is a kind of bronchodilator and also a mast cell stabilizer. Our findings provide useful information regarding the possible mechanism of the CTCM, and show its potential for application in the treatment of allergenic airway disease.
doi:10.1186/1472-6882-13-174
PMCID: PMC3716888  PMID: 23849630
Asthma; Nebulization; Drug delivery; Chinese medicine; Ovalbumin
14.  Cromolyn cream for recalcitrant idiopathic vulvar vestibulitis: results of a placebo controlled study 
Objective: Patients with chronic idiopathic vulvar vestibulitis have increased mast cells when biopsied, and cromolyn has been suggested as a treatment. The purpose of this study was to assess the efficacy of 4% cromolyn cream in women with vulvar vestibulitis.
Methods: A prospective, double blind, randomised, placebo controlled study was initiated at two centres. Patients with vulvar vestibulitis were assigned to apply cromolyn or placebo cream to the vestibule. Symptoms (burning, irritation) and signs (erythema, extent of erythema, tenderness) were recorded on a 0–3 scale. In the sexually active patient subgroup, dyspareunia was also evaluated.
Results: 13 of the 26 evaluable patients received cromolyn. Patients in the cromolyn arm were more likely to have failed therapy with amitriptyline (p = 0.05), but the two groups were otherwise similar upon study entry. Overall, scores decreased from a median of 9 to 5 (p = 0.001) during the study, but the level of improvement was similar between both groups. Improvement was unrelated to duration of symptoms, fluconazole use, or sexual activity. Five patients (38%) taking cromolyn and six (46%) taking placebo felt they had a 50% or greater reduction in symptoms. In the 21 sexually active patients, the total score decreased from a mean of 12 to 8 (p = 0.005), but there was no statistically significant difference between study arms.
Conclusions: Cromolyn cream did not confer a significant benefit in patients with vulvar vestibulitis. The large placebo response suggests the need for large well controlled studies of other treatment modalities.
Key Words: cromolyn cream; vulvar vestibulitis
doi:10.1136/sti.77.1.53
PMCID: PMC1758319  PMID: 11158692
15.  Management of Allergic Rhinitis 
Allergic rhinitis is the most common chronic childhood disease. Reduced quality of life is frequently caused by this IgE-mediated disease, including sleep disturbance with subsequent decreased school performance. Asthma and exercise-induced bronchospasm are commonly seen concurrently with allergic rhinitis, and poorly controlled allergic rhinitis negatively affects asthma outcomes. Nonsedating antihistamines or intranasal azelastine are effective agents to manage allergic rhinitis, often in combination with oral decongestants. For moderate to severe persistent disease, intranasal corticosteroids are the most effiective agents. Some patients require concomitant intranasal corticosteroids and nonsedating antihistamines for optimal management. Other available agents include leukotriene receptor antagonists, intranasal cromolyn, intranasal ipratropium, specific immunotherapy, and anti-IgE therapy.
doi:10.5863/1551-6776-10.3.159
PMCID: PMC3468067  PMID: 23118635
allergic rhinitis; drug therapy; management; pediatrics
16.  Pharmaceutical stabilization of mast cells attenuates experimental atherogenesis in low-density lipoprotein receptor-deficient mice 
Atherosclerosis  2013;229(2):304-309.
Mast cells (MCs) contribute to atherogenesis by releasing pro-inflammatory mediators to activate vascular cells and other inflammatory cells. This study examined whether MC activation or stabilization affects diet-induced atherosclerosis in low-density lipoprotein receptor-deficient (Ldlr−/−) mice. When Ldlr−/− mice consumed an atherogenic diet for 3 or 6 months, MC activation with compound 48/80 (C48/80) increased aortic arch intima and total lesion areas, and plasma total cholesterol, LDL, and triglyceride levels, whereas MC stabilization with cromolyn reduced these parameters. There were significant differences in arch intima and total lesion areas, and plasma total cholesterol, LDL, and triglyceride levels between C48/80-treated and cromolyn-treated mice. To examine a therapeutic application of cromolyn in atherosclerosis, we fed Ldlr−/− mice an atherogenic diet for 3 months followed by giving mice cromolyn for additional 3 months. Cromolyn did not affect aortic arch intima area, but significantly reduced lipid deposition in the thoracic-abdominal aortas. In aortic arches, however, cromolyn treatment significantly reduced lesion contents of Mac-3+ macrophages, CD4+ T cells, activated MCs, and lesion cell proliferation. While plasma total cholesterol and LDL levels increased and high-density lipoprotein (HDL) levels decreased from 3 months to 6 months of an atherogenic diet, cromolyn treatment decreased significantly plasma total cholesterol, LDL, and triglyceride levels and increased HDL levels above those of 3-month time point. These observations demonstrate that MC stabilization reduces lesion inflammation, ameliorates plasma lipid profiles, and may serve as a potential therapy for this cardiovascular disease.
doi:10.1016/j.atherosclerosis.2013.05.025
PMCID: PMC3724238  PMID: 23880180
mast cell; atherosclerosis; cromolyn; C48/80; LDL receptor-deficient mice
17.  Involvement of mast cells in monocrotaline-induced pulmonary hypertension in rats 
Respiratory Research  2011;12(1):60.
Background
Mast cells (MCs) are implicated in inflammation and tissue remodeling. Accumulation of lung MCs is described in pulmonary hypertension (PH); however, whether MC degranulation and c-kit, a tyrosine kinase receptor critically involved in MC biology, contribute to the pathogenesis and progression of PH has not been fully explored.
Methods
Pulmonary MCs of idiopathic pulmonary arterial hypertension (IPAH) patients and monocrotaline-injected rats (MCT-rats) were examined by histochemistry and morphometry. Effects of the specific c-kit inhibitor PLX and MC stabilizer cromolyn sodium salt (CSS) were investigated in MCT-rats both by the preventive and therapeutic approaches. Hemodynamic and right ventricular hypertrophy measurements, pulmonary vascular morphometry and analysis of pulmonary MC localization/counts/activation were performed in animal model studies.
Results
There was a prevalence of pulmonary MCs in IPAH patients and MCT-rats as compared to the donors and healthy rats, respectively. Notably, the perivascular MCs were increased and a majority of them were degranulated in lungs of IPAH patients and MCT-rats (p < 0.05 versus donor and control, respectively). In MCT-rats, the pharmacological inhibitions of MC degranulation and c-kit with CSS and PLX, respectively by a preventive approach (treatment from day 1 to 21 of MCT-injection) significantly attenuated right ventricular systolic pressure (RVSP) and right ventricular hypertrophy (RVH). Moreover, vascular remodeling, as evident from the significantly decreased muscularization and medial wall thickness of distal pulmonary vessels, was improved. However, treatments with CSS and PLX by a therapeutic approach (from day 21 to 35 of MCT-injection) neither improved hemodynamics and RVH nor vascular remodeling.
Conclusions
The accumulation and activation of perivascular MCs in the lungs are the histopathological features present in clinical (IPAH patients) and experimental (MCT-rats) PH. Moreover, the accumulation and activation of MCs in the lungs contribute to the development of PH in MCT-rats. Our findings reveal an important pathophysiological insight into the role of MCs in the pathogenesis of PH in MCT- rats.
doi:10.1186/1465-9921-12-60
PMCID: PMC3104382  PMID: 21535881
18.  Mast Cell Stabilization Alleviates Acute Lung Injury after Orthotopic Autologous Liver Transplantation in Rats by Downregulating Inflammation 
PLoS ONE  2013;8(10):e75262.
Background
Acute lung injury (ALI) is one of the most severe complications after orthotopic liver transplantation. Amplified inflammatory response after transplantation contributes to the process of ALI, but the mechanism underlying inflammation activation is not completely understood. We have demonstrated that mast cell stabilization attenuated inflammation and ALI in a rodent intestine ischemia/reperfusion model. We hypothesized that upregulation of inflammation triggered by mast cell activation may be involve in ALI after liver transplantation.
Methods
Adult male Sprague–Dawley rats received orthotopic autologous liver transplantation (OALT) and were executed 4, 8, 16, and 24 h after OALT. The rats were pretreated with the mast cell stabilizers cromolyn sodium or ketotifen 15 min before OALT and executed 8 h after OALT. Lung tissues and arterial blood were collected to evaluate lung injury. β-hexosaminidase and mast cell tryptase levels were assessed to determine the activation of mast cells. Tumor necrosis factor α (TNF-α), interleukin (IL)-1β and IL-6 in serum and lung tissue were analyzed by enzyme-linked immunosorbent assay. Nuclear factor-kappa B (NF-κB) p65 translocation was assessed by Western blot.
Results
The rats that underwent OALT exhibited severe pulmonary damage with a high wet-to-dry ratio, low partial pressure of oxygen, and low precursor surfactant protein C levels, which corresponded to the significant elevation of pro-inflammatory cytokines, β-hexosaminidase, and tryptase levels in serum and lung tissues. The severity of ALI progressed and maximized 8 h after OALT. Mast cell stabilization significantly inhibited the activation of mast cells, downregulated pro-inflammatory cytokine levels and translocation of NF-κB, and attenuated OALT-induced ALI.
Conclusions
Mast cell activation amplified inflammation and played an important role in the process of post-OALT related ALI.
doi:10.1371/journal.pone.0075262
PMCID: PMC3792971  PMID: 24116032
19.  Mast Cells Play No Role in the Pathogenesis of Postoperative Ileus Induced by Intestinal Manipulation 
PLoS ONE  2014;9(1):e85304.
Introduction
Intestinal manipulation (IM) during abdominal surgery results in intestinal inflammation leading to hypomotility or ileus. Mast cell activation is thought to play a crucial role in the pathophysiology of postoperative ileus (POI). However, this conclusion was mainly drawn using mast cell-deficient mouse models with abnormal Kit signaling. These mice also lack interstitial cells of Cajal (ICC) resulting in aberrant gastrointestinal motility even prior to surgery, compromising their use as model to study POI. To avoid these experimental weaknesses we took advantage of a newly developed knock-in mouse model, Cpa3Cre/+, devoid of mast cells but with intact Kit signaling.
Design
The role of mast cells in the development of POI and intestinal inflammation was evaluated assessing gastrointestinal transit and muscularis externa inflammation after IM in two strains of mice lacking mast cells, i.e. KitW-sh/W-sh and Cpa3Cre/+ mice, and by use of the mast cell stabilizer cromolyn.
Results
KitW-sh/W-sh mice lack ICC networks and already revealed significantly delayed gastrointestinal transit even before surgery. IM did not further delay intestinal transit, but induced infiltration of myeloperoxidase positive cells, expression of inflammatory cytokines and recruitment of monocytes and neutrophils into the muscularis externa. On the contrary, Cpa3Cre/+ mice have a normal network of ICC and normal gastrointestinal. Surprisingly, IM in Cpa3Cre/+ mice caused delay in gut motility and intestinal inflammation as in wild type littermates mice (Cpa3+/+). Furthermore, treatment with the mast cell inhibitor cromolyn resulted in an inhibition of mast cells without preventing POI.
Conclusions
Here, we confirm that IM induced mast cell degranulation. However, our data demonstrate that mast cells are not required for the pathogenesis of POI in mice. Although there might be species differences between mouse and human, our results argue against mast cell inhibitors as a therapeutic approach to shorten POI.
doi:10.1371/journal.pone.0085304
PMCID: PMC3887017  PMID: 24416383
20.  Sensory Nerve Induced Inflammation Contributes to Heterotopic Ossification 
Journal of Cellular Biochemistry  2011;112(10):2748-2758.
Heterotopic ossification (HO), or bone formation in soft tissues, is often the result of traumatic injury. Much evidence has linked the release of BMPs (bone morphogenetic proteins) upon injury to this process. HO was once thought to be a rare occurrence, but recent statistics from the military suggest that as many as 60% of traumatic injuries, resulting from bomb blasts, have associated HO. In this study, we attempt to define the role of peripheral nerves in this process. Since BMP2 has been shown previously to induce release of the neuroinflammatory molecules, substance P (SP) and calcitonin gene related peptide (CGRP), from peripheral, sensory neurons, we examined this process in vivo. SP and CGRP are rapidly expressed upon delivery of BMP2 and remain elevated throughout bone formation. In animals lacking functional sensory neurons (TRPV1−/−), BMP2-mediated increases in SP and CGRP were suppressed as compared to the normal animals, and HO was dramatically inhibited in these deficient mice, suggesting that neuroinflammation plays a functional role. Mast cells, known to be recruited by SP and CGRP, were elevated after BMP2 induction. These mast cells were localized to the nerve structures and underwent degranulation. When degranulation was inhibited using cromolyn, HO was again reduced significantly. Immunohistochemical analysis revealed nerves expressing the stem cell markers nanog and Klf4, as well as the osteoblast marker osterix, after BMP2 induction, in mice treated with cromolyn. The data collectively suggest that BMP2 can act directly on sensory neurons to induce neurogenic inflammation, resulting in nerve remodeling and the migration/release of osteogenic and other stem cells from the nerve. Further, blocking this process significantly reduces HO, suggesting that the stem cell population contributes to bone formation.
doi:10.1002/jcb.23225
PMCID: PMC3329372  PMID: 21678472
HETEROTOPIC OSSIFICATION; NEUROGENIC INFLAMMATION; BONE MORPHOGENETIC PROTEIN TYPE 2; NEURAL CREST STEM CELLS
21.  The Mast Cell Degranulator Compound 48/80 Directly Activates Neurons 
PLoS ONE  2012;7(12):e52104.
Background
Compound 48/80 is widely used in animal and tissue models as a “selective” mast cell activator. With this study we demonstrate that compound 48/80 also directly activates enteric neurons and visceral afferents.
Methodology/Principal Findings
We used in vivo recordings from extrinsic intestinal afferents together with Ca++ imaging from primary cultures of DRG and nodose neurons. Enteric neuronal activation was examined by Ca++ and voltage sensitive dye imaging in isolated gut preparations and primary cultures of enteric neurons. Intraluminal application of compound 48/80 evoked marked afferent firing which desensitized on subsequent administration. In egg albumen-sensitized animals, intraluminal antigen evoked a similar pattern of afferent activation which also desensitized on subsequent exposure to antigen. In cross-desensitization experiments prior administration of compound 48/80 failed to influence the mast cell mediated response. Application of 1 and 10 µg/ml compound 48/80 evoked spike discharge and Ca++ transients in enteric neurons. The same nerve activating effect was observed in primary cultures of DRG and nodose ganglion cells. Enteric neuron cultures were devoid of mast cells confirmed by negative staining for c-kit or toluidine blue. In addition, in cultured enteric neurons the excitatory action of compound 48/80 was preserved in the presence of histamine H1 and H2 antagonists. The mast cell stabilizer cromolyn attenuated compound 48/80 and nicotine evoked Ca++ transients in mast cell-free enteric neuron cultures.
Conclusions/Significance
The results showed direct excitatory action of compound 48/80 on enteric neurons and visceral afferents. Therefore, functional changes measured in tissue or animal models may involve a mast cell independent effect of compound 48/80 and cromolyn.
doi:10.1371/journal.pone.0052104
PMCID: PMC3525567  PMID: 23272218
22.  Effects of (R,R)- and (R,R/S,S)-Formoterol on Airway Relaxation and Contraction in an Experimental Rat Model 
Background: Racemic (R,R/S,S)-formoterol is a long-acting β-agonist composed of a 50:50 mixture of (R,R)- and (S,S)-enantiomers.
Objective: The aim of this study was to determine whether (R,R)-formoterol and (R,R/S,S)-formoterol have differing effects on airway contraction and relaxation in vitro.
Methods: Cylindrical airway segments 3-mm long were isolated from the mid-trachea of healthy Sprague-Dawley rats and placed in a modified Krebs-Henseleit solution. Dose-response curves of bethanechol-induced contraction (measured as milligrams of tension) and the concentration of bethanechol that elicited 50% to 75% of maximal contraction (EC50–75) were determined. The air-way cylinders were then precontracted with bethanechol at the EC50–75 and exposed to different concentrations of (R,R)-formoterol (0.0001–1.0 μM) or (R,R/S,S)-formoterol (0.0002–2.0 μM). Each concentration of the 2 formoterol formulations contained the same amount of (R,R)-enantiomer (eg, [R,R]-formoterol 0.0001 μM and [R,R/S,S]-formoterol 0.0002 1JM contained the same amount of [R,R]-enantiomer). The relaxation percentage in response to formoterol was calculated as a reduction in tension (in milligrams) in relation to baseline tension in the precontracted state, with each tracheal cylinder serving as its own control. To determine the effect of (R,R)-formoterol on airway contraction, tracheal cylinders were incubated with (R,R)- or (R,R/S,S)-formoterol before electrical field stimulation (EFS).
Results: Tracheae from 56 three-week-old Sprague-Dawley rats were used in the study. The relaxation percentage of precontracted trachea was significantly greater after exposure to (R,R)-formoterol than to (R,R/S,S)-formoterol at a 2-fold higher concentration (P = 0.03; general linear model with repeated measures analysis comparing the 2 groups of animals). However, in a post hoc analysis, the mean (SE) relaxation percentage of precontracted trachea was significantly greater only after exposure to (R,R)-formoterol 0.01 μM than to (R,R/S,S)-formoterol 0.02 μM (15.6% [5.8%] vs 39.0% [5.6%]; P < 0.05, unpaired t test). EFS-induced airway contraction was significantly less in tracheal cylinders incubated in (R,R)-formoterol compared with those incubated in (R,R/S,S)-formoterol at a 2-fold higher concentration (P = 0.05; general linear model with repeated measures analysis comparing the 2 groups of animals). However, in the post hoc analysis, mean (SE) EFS-induced tracheal contraction was significantly less only in (R,R)-formoterol 0.01 μM compared with (R,R/S,S)-formoterol 0.02 μM at 10 V (1070 [55] mgvs 1225 [28] mg; P < 0.05, unpaired t test).
Conclusion: We found that (R,R)-formoterol may induce greater relaxation of precontracted airway smooth muscle cells than (R,R/S,S)-formoterol and that (R,R)-formoterol may have a greater inhibitory effect on the endogenous cholinergic and excitatory nonadrenergic, noncholinergic contractile airway responses than (R,R/S,S)-formoterol. We speculate that the presence of the (S,S)-enantiomer in (R,R/S,S)-formoterol may impair airway relaxation of pre-contracted trachea in rats.
doi:10.1016/j.curtheres.2007.08.005
PMCID: PMC3967278  PMID: 24683215
(R,R)-formoterol; (R,R/S,S)-formoterol; electrical field stimulation; airway contraction; airway relaxation
23.  Mast cell stabilization: novel medication for obesity and diabetes 
Summary
Mast cells are essential in allergic responses and beyond. White adipose tissue from obese humans contains large numbers of mast cells. Serum mast cell tryptase levels are also significantly higher in obese subjects than in lean subjects, suggesting a role of these inflammatory cells in obesity and diabetes. Two types of mast cell-deficient mice, along with corresponding wild-type control mice, were fed a Western diet to induce obesity and diabetes. We also used two anti-allergy drugs, cromolyn and ketotifen (Zaditor), to treat wild-type mice during intake of a Western diet or after the onset of obesity and diabetes, to examine the possible prevention or reversal of these conditions. Mast cell deficiency or pharmacological stabilization reduced body weight gain and improved glucose and insulin sensitivities. These common, side effect-free drugs also reduced pre-established obesity and diabetes without noticeable toxicity. Mechanistic studies suggest that mast cells participate in these metabolic disorders by affecting energy expenditure, protease expression, angiogenesis, apoptosis, and preadipocyte differentiation. These observations open a new era of basic research regarding mast cells, and offer hope to patients suffering from these metabolic disorders.
doi:10.1002/dmrr.1272
PMCID: PMC3318912  PMID: 22069285
mast cell; obesity; diabetes; cromolyn; ketotifen (Zaditor)
24.  The Mechanism of Sevoflurane Preconditioning-Induced Protections against Small Intestinal Ischemia Reperfusion Injury Is Independent of Mast Cell in Rats 
Mediators of Inflammation  2013;2013:378703.
The study aimed to investigate whether sevoflurane preconditioning can protect against small intestinal ischemia reperfusion (IIR) injury and to explore whether mast cell (MC) is involved in the protections provided by sevoflurane preconditioning. Sprague-Dawley rats exposed to sevoflurane or treated with MC stabilizer cromolyn sodium (CS) were subjected to 75-minute superior mesenteric artery occlusion followed by 2-hour reperfusion in the presence or absence of MC degranulator compound 48/80 (CP). Small intestinal ischemia reperfusion resulted in severe intestinal injury as demonstrated by significant elevations in intestinal injury scores and p47phox and gp91phox, ICAM-1 protein expressions and malondialdehyde and IL-6 contents, and MPO activities as well as significant reductions in SOD activities, accompanied with concomitant increases in mast cell degranulation evidenced by significant increases in MC counts, tryptase expression, and β-hexosaminidase concentrations, and those alterations were further upregulated in the presence of CP. Sevoflurane preconditioning dramatically attenuated the previous IIR-induced alterations except MC counts, tryptase, and β-hexosaminidase which were significantly reduced by CS treatment. Furthermore, CP exacerbated IIR injury was abrogated by CS but not by sevoflurane preconditioning. The data collectively indicate that sevoflurane preconditioning confers protections against IIR injury, and MC is not involved in the protective process.
doi:10.1155/2013/378703
PMCID: PMC3867927  PMID: 24369442
25.  Mast Cells and Wound Healing 
Advances in Wound Care  2012;1(1):23-28.
Background
Mast cells (MC) are ubiquitous resident cells, traditionally viewed as effector cells of allergic reactions that can store and synthesize de novo many mediators upon activation by a variety of stimuli. Exciting new insights are unveiling MC involvement in the pathogenesis of connective tissue disorders including wound healing and fibrosis.
The Problem
Abnormal wound repair is associated with an increased number of MC strategically located around blood vessels. Therapeutic local manipulation of MC population and reactivity may help improve and even prevent impaired repair processes for which there is no cure.
Basic/Clinical Science Advances
Chymase, a MC-restricted protease, is pre-stored in MC cytoplasmic granules with other mediators. The development of a highly specific inhibitor targeting chymase established its pivotal effect on fibrosis pathogenesis in a mouse model of silica-induced fibrosis. This novel finding evokes the potential therapeutic relevance of chymase inhibition to prevent aberrant wound healing.
Clinical Care Relevance
MC are increased in number in a variety of fibrotic diseases, compared to normal scars. Chymase has become a rising target prompting the development of chymase-specific inhibitors to be used as prophylactic or therapeutic agents. Another emerging strategy may consist in evaluating the efficacy of mast cell stabilizing drugs such as cromolyn in abnormal wound healing—drugs which are already approved for human use in other MC-driven disorders.
Conclusion
Limited treatment success of dysregulated wound healing underscores the need for novel targets be considered such as MC and/or MC-derived mediators and the necessity to design new therapeutic strategies for wounds that remain difficult to treat.
doi:10.1089/wound.2011.0357
PMCID: PMC3623594  PMID: 24527274

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