ovalbumin and montelukast

ovalbumin has been researched along with montelukast* in 47 studies

Other Studies

47 other study(ies) available for ovalbumin and montelukast

ArticleYear
Survey the effect of drug treatment on modulation of cytokines gene expression in allergic rhinitis.
    Fundamental & clinical pharmacology, 2023, Volume: 37, Issue:2

    Allergic rhinitis as common airway disease has high prevalence in all peoples worldwide. In allergic diseases, Th2 cells release type 2 cytokines that support the inflammation in airways. All the drugs used for allergic rhinitis do not cure completely, and the choice of drugs according to cost and efficacy is very important in all groups of atopic patients. Therefore, in this study, the effect of commercial drugs on cytokine gene expression has been studied. Male Balb/c mice were divided into six groups. Allergic rhinitis was induced in five of the six groups with ovalbumin, and four of these five groups were treated with salbutamol, budesonide, theophylline, and montelukast. The fifth group was used as positive control group and the sixth group as negative control group. For the survey, RNA was extracted, cDNA was synthesized, and quantitative real-time PCR was done for 21 genes. The four drugs had different effects on mRNA expression of cytokines (IL-1b, 2, 4, 5, 7, 8, 9, 11, 12, 13, 17, 18, 22, 25, 31, 33, 37, IFN-γ, TNF-α, TGF-β1, and eotaxin) in the allergic rhinitis groups. Salbutamol can be used during pregnancy and breastfeeding, but it has some side effects. Budesonide in the inhaled form is generally safe in pregnancy. Theophylline cannot control allergic attack in the long run. Montelukast is not useful in the treatment of acute allergic attacks. Immunomodulatory and anti-inflammatory effects of drugs in control of allergic rhinitis via Th2 cytokines can be new approaches in molecular medicine.

    Topics: Albuterol; Animals; Budesonide; Cytokines; Disease Models, Animal; Gene Expression; Male; Mice; Mice, Inbred BALB C; Ovalbumin; Rhinitis, Allergic; Theophylline

2023
Potential synergistic effects of novel hematopoietic prostaglandin D synthase inhibitor TAS-205 and different types of anti-allergic medicine on nasal obstruction in a Guinea pig model of experimental allergic rhinitis.
    European journal of pharmacology, 2020, May-15, Volume: 875

    Nasal obstruction is one of the most bothersome symptoms of allergic rhinitis (AR) affecting sleep-related quality of life in AR patients. Although several treatments were tested to control nasal obstruction, some patients with moderate to severe AR do not respond to current treatments, including the combined administration of different types of anti-allergic medicine. Thus, new options for AR treatment are needed. This study aimed to evaluate the effects of combined treatment with a novel inhibitor of hematopoietic prostaglandin D synthase (HPGDS), TAS-205, and different types of anti-allergic medicine on nasal obstruction in AR. Firstly, we demonstrated that TAS-205 selectively inhibited prostaglandin D

    Topics: Acetates; Animals; Anti-Allergic Agents; Cell Line; Cyclopropanes; Disease Models, Animal; Drug Synergism; Drug Therapy, Combination; Enzyme Inhibitors; Guinea Pigs; Humans; Intramolecular Oxidoreductases; Lipocalins; Male; Morpholines; Nasal Mucosa; Nasal Obstruction; Ovalbumin; Piperidines; Prostaglandin D2; Pyrroles; Quality of Life; Quinolines; Rats; Rhinitis, Allergic; Sulfides; Terfenadine

2020
Characterization of cysteinyl leukotriene-related receptors and their interactions in a mouse model of asthma.
    Prostaglandins, leukotrienes, and essential fatty acids, 2019, Volume: 141

    Identification of the characterization of cysteinyl leukotrienes receptor (CysLTRs) could facilitate our understanding of these receptors' role in asthma. We aimed to investigate the localization and interactions of CysLTRs using a mouse model of asthma. BALB/c mice were administered ovalbumin (OVA) to induce allergic asthma. Some mice were administered the antagonists of CysLTR1, CysLTR2, and purinergic receptor P2Y12 (P2Y12R) (montelukast, HAMI 3379 and clopidogrel, respectively). The expression levels of CysLTR1, CysLTR2, and P2Y12R on lung tissues and inflammatory cells were evaluated by western blot, flow cytometry, and immunochemistry. CysLTR1 and P2Y12R were significantly up-regulated in lung tissues (P < 0.05 for each) from mouse after being sensitized and challenged with OVA (OVA/OVA). The ratio of CysLTR1: CysLTR2: P2Y12R in lungs of negative control (NC) mice was shifted from 1:0.43:0.35 to 1:0.65:1.34 in OVA/OVA mice. Montelukast significantly diminished the up-regulation of CysLTR1, CysLTR2, and P2Y12R (P < 0.05 for each), while the effects of HAMI 3379 and clopidogrel were predominant on the expression of CysLTR2 and P2Y12R, respectively. Montelukast predominantly diminished the cell count, while clopidogrel potently inhibited the release of interleukin (IL)-4, IL-5, and IL-13. Our study demonstrated the interactions between CysLTRs, thereby highlighting the potential synergistic effects of CysLTR antagonists in asthma treatment.

    Topics: Acetates; Animals; Asthma; Clopidogrel; Cyclohexanecarboxylic Acids; Cyclopropanes; Disease Models, Animal; Drug Therapy, Combination; Eosinophils; Female; Inflammation; Interleukins; Leukotriene Antagonists; Mice; Mice, Inbred BALB C; Ovalbumin; Phthalic Acids; Purinergic P2Y Receptor Antagonists; Quinolines; Receptors, Leukotriene; Receptors, Purinergic P2Y12; Sulfides; Th2 Cells

2019
Montelukast reverses airway remodeling in actively sensitized young mice.
    Pediatric pulmonology, 2018, Volume: 53, Issue:6

    Asthma is characterized by airway hyperresponsiveness (AHR) and inflammation leading to airway remodeling (AR). In children, AR may occur very early prior to the age of 6 years. Treatments to prevent or reverse AR are unknown.. We sought to determine (i) whether short allergenic sensitization at a young age in a mouse model may induce enhanced AR and inflammation compared to adults; (ii) the effect of Montelukast on such AR.. Immature and adult Balb/c mice were sensitized and challenged with ovalbumin. AHR and AR were measured using cultured precision-cut lung slices and inflammation by bronchoalveolar lavage. Experiments were repeated after administration of Montelukast.. OVA-challenged mice developed AHR to methacholine regardless of age of first exposure to OVA. Young mice developed greater thickened basement membrane, increased smooth muscle mass, and increased area of bronchovascular fibrosis compared with adult mice. Cellular infiltrates in BAL differed depending upon animal age at first exposure with higher eosinophilia measured in younger animals. Montelukast decreased ASM mass, BAL cellularity.. We provide thus evidence for a greater degree of AR after allergenic sensitization and challenge in younger mice versus adults. This study provides proof of concept that airway remodeling can be prevented and reversed in this case by anti-asthmatic drug Montelukast in this model.

    Topics: Acetates; Age Factors; Airway Remodeling; Allergens; Animals; Anti-Asthmatic Agents; Asthma; Bronchoalveolar Lavage Fluid; Cyclopropanes; Disease Models, Animal; Female; Lung; Mice, Inbred BALB C; Ovalbumin; Quinolines; Sulfides

2018
[Effects of montelukast sodium and bacterial lysates on airway remodeling and expression of transforming growth factor-β1 and Smad7 in guinea pigs with bronchial asthma].
    Zhongguo dang dai er ke za zhi = Chinese journal of contemporary pediatrics, 2018, Volume: 20, Issue:12

    To study the effect of montelukast sodium (MK), a leukotriene receptor antagonist, and bacterial lysates (OM-85BV), used alone or in combination, on airway remodeling and the expression of transforming growth factor-β1 (TGF-β1) and Smad7 in guinea pigs with bronchial asthma and their correlation.. A total of 40 male Hartley guinea pigs were randomly divided into normal control group, asthma group, MK group, OM-85BV group, and MK+OM-85BV group, with 8 guinea pigs in each group. Intraperitoneal injection of 10% ovalbumin (OVA) for sensitization and aerosol inhalation of 1% OVA for challenge were performed to establish a model of airway remodeling of asthma in all of the groups apart from the normal control group, which were treated with normal saline. In the stage of challenge by aerosol inhalation, the guinea pigs in the MK, OM-85BV, and MK+OM-85BV groups were given corresponding suspension by gavage, and those in the normal control and asthma groups were given an equal volume of normal saline by gavage. Bronchoalveolar lavage fluid (BALF) of the guinea pigs was collected within 24 hours after challenge, and ELISA was used to measure the levels of TGF-β1 and Smad7 in BALF. The guinea pigs were sacrificed and the pathological section of lung tissue was prepared to observe the degree of airway remodeling. An image analysis technique was used to measure perimeter of the basement membrane (Pbm), total bronchial wall area (Wat), and airway bronchial smooth muscle area (Wam). Pearson linear regression was used to investigate the correlation between two variables.. According to the lung pathological section, compared with the normal control group, the asthma, MK, OM-85BV, and MK+OM-85BV groups had significant thickening of bronchial smooth muscle and alveolar wall, significantly higher Wat/Pbm and Wam/Pbm, a significantly higher level of TGF-β1, and a significantly lower level of Smad7 (P<0.05). Compared with the asthma group, the MK, OM-85BV, and MK+OM-85BV groups had a significant improvement in pathological injury, significantly lower Wat/Pbm and Wam/Pbm, a significantly lower level of TGF-β1, and a significantly higher level of Smad7 (P<0.05). The MK+OM-85BV group had significantly greater improvements than the MK group and the OM-85BV group (P<0.05). The expression of TGF-β1 was negatively correlated with that of Smad7 and positively correlated with Wat/Pbm and Wam/Pbm, and the expression of Smad7 was negatively correlated with Wat/Pbm and Wam/Pbm (P<0.01).. MK and OM-85BV, used alone or in combination, can reduce airway remodeling in guinea pigs with asthma, and MK combined with OM-85BV has the best effect, possibly by reducing TGF-β1 expression, increasing Smad7 expression, and improving the TGF-β1/Smad7 imbalance.

    Topics: Acetates; Airway Remodeling; Animals; Asthma; Cell Extracts; Cyclopropanes; Guinea Pigs; Lung; Male; Ovalbumin; Quinolines; Sulfides; Transforming Growth Factor beta1

2018
Leukotriene receptor antagonist attenuated airway inflammation and hyperresponsiveness in a double-stranded RNA-induced asthma exacerbation model.
    Allergology international : official journal of the Japanese Society of Allergology, 2017, Volume: 66S

    Viral infections are the most common triggers of asthma exacerbation, but the key molecules involved in this process have not been fully identified. Although cysteinyl leukotrienes (cysLTs) have been postulated as the key mediators, their precise roles remain largely unclear. To investigate the roles of cysLTs in virus-induced asthma exacerbation, we developed a murine model using a viral double-stranded RNA analog, polyinosinic-polycytidylic acid (poly I:C), and analyzed the effect of leukotriene receptor antagonist (LTRA) administration.. A/J mice were immunized with ovalbumin (OVA) + alum (days 0, 28, 42, and 49), followed by intranasal challenge with OVA (phase 1: days 50-52) and poly I:C (phase 2: days 53-55). Montelukast was administered during poly I:C challenge (phase 2) in the reliever model or throughout the OVA and poly I:C challenges (phases 1 and 2) in the controller model. Airway responsiveness to acetylcholine chloride was assessed, and bronchoalveolar lavage (BAL) was performed on day 56.. Administration of poly I:C to OVA-sensitized and -challenged mice increased the number of eosinophils and levels of IL-13, IL-9, CCL3, and CXCL1 in BAL fluid (BALF) and tended to increase airway responsiveness. Montelukast significantly attenuated the poly I:C-induced increase in the number of eosinophils and levels of IL-13, IL-9, and CCL3 in BALF and airway hyperresponsiveness in both the reliever and controller models.. This is the first report showing that LTRA functionally suppressed the pathophysiology of a virus-induced asthma exacerbation model, suggesting the importance of cysLTs as a potential treatment target.

    Topics: Acetates; Alum Compounds; Animals; Anti-Asthmatic Agents; Asthma; Bronchoalveolar Lavage Fluid; Cyclopropanes; Cysteine; Cytokines; Disease Models, Animal; Disease Progression; Eosinophils; Immunization; Inflammation Mediators; Leukotriene Antagonists; Leukotrienes; Male; Mice; Ovalbumin; Poly I-C; Quinolines; Respiratory Hypersensitivity; RNA, Double-Stranded; RNA, Viral; Sulfides

2017
Antiallergic effect of piperine on ovalbumin-induced allergic rhinitis in mice.
    Pharmaceutical biology, 2015, Volume: 53, Issue:9

    Allergic rhinitis (AR) is a global health problem that affects a large number of population. Piperine (PIP) has been reported to exhibit anti-inflammatory, anti-histaminic, and immunomodulatory activities; however, its antiallergic profile has not been studied.. The objective of the study was to investigate the antiallergic potential of PIP in ova-albumin (OVA)-induced AR, mast cell degranulation (MSD), and OVA-induced paw edema.. Mice were sensitized with OVA alternately on 1, 3, 5, 7, 9, 11, and 13th day. They were treated with either vehicle, PIP (10, 20, and 40 mg/kg, p.o.), or montelukast (10 mg/kg, p.o.) from the 14th to 20th day. On the 21st day, intranasal (OVA: 5% µl) challenge was done. Animals were evaluated for physiological parameters, biochemical parameters, spleen weight, expression of interleukins (IL-6 and IL-1β), and immunoglobin-E (IgE). Histopathology of nasal mucosa, lungs, and spleen was carried out. MSD and paw edema studies were made to understand the mechanism of action.. PIP (10, 20, and 40 mg/kg, p.o.) showed a significant dose-dependent protection with respect to nasal rubbing, redness of nose, and sneezing (p < 0.001) following nasal challenge. PIP dose dependently reduced histamine, NO concentration (p < 0.001), as well as reduced expression of IL-6, IL-1β, and IgE (p < 0.001) as compared with the control group. Histopathology showed inhibition of infiltration of eosinophils and hyperplasia. It dose dependently reduced MSD and paw edema (p < 0.001).. PIP acts by mast cell-stabilizing activity, exhibits immunomodulatory and anti-inflammatory activity, thereby providing an effective treatment for AR.

    Topics: Acetates; Alkaloids; Animals; Anti-Allergic Agents; Benzodioxoles; Biomarkers; Cell Degranulation; Cyclopropanes; Disease Models, Animal; Dose-Response Relationship, Drug; Edema; Eosinophils; Histamine; Immunoglobulin E; Inflammation Mediators; Interleukin-1beta; Interleukin-6; Mast Cells; Nitric Oxide; Ovalbumin; Piperidines; Polyunsaturated Alkamides; Quinolines; Rhinitis, Allergic; Spleen; Sulfides; Time Factors

2015
Aerosolized montelukast polymeric particles-an alternative to oral montelukast-alleviate symptoms of asthma in a rodent model.
    Pharmaceutical research, 2014, Volume: 31, Issue:11

    Cysteinyl leukotrienes (CysLTs) propagate inflammatory reactions that result from allergen exposure in asthma. Montelukast, a CysLT type-1 receptor antagonist, disrupts mediator-receptor interactions and minimizes inflammatory response. In this study, we have evaluated anti-asthmatic efficacy of inhalable montelukast-loaded large porous particulate formulations in ovalbumin-induced rat airway inflammation model that mimics asthma.. The anti-inflammatory effects of a montelukast-loaded formulation were investigated in rats by measuring the total protein content, levels of injury markers and number of inflammatory cells in the bronchoalveolar lavage fluid (BALF). The histopathological studies assessed the morphological and structural changes that occur in asthmatic lungs. Animals were also challenged with methacholine to examine the airway hyper-reactivity.. Compared with healthy animals, asthmatic animals showed a 3.8- and 4.77-fold increase in the protein content and number of inflammatory cells in BALF, respectively. Intratracheal montelukast particles reduced the protein content by 3.3-fold and the number of inflammatory cells by 2.62-fold. Also, montelukast particles reduced the lactate dehydrogenase (LDH) and myeloperoxidase (MPO) levels by a 4.87- and 6.8-fold in BALF, respectively. Montelukast particles reduced the airway wall thickness by 2.5-fold compared with untreated asthmatic lungs. Further, particulate formulation protected the lungs against methacholine-induced bronchial provocation (p < 0.05).. Respirable large porous particles containing montelukast alleviated allergen-induced inflammatory response in an animal model and prevented histological changes associated with asthma. Thus montelukast-loaded large porous polylactic acid (PLA) particles could be an aerosolized delivery approach for administration of currently available oral montelukast.

    Topics: Acetates; Aerosols; Animals; Anti-Asthmatic Agents; Anti-Inflammatory Agents; Asthma; Bronchoalveolar Lavage Fluid; Cyclopropanes; Cysteine; Disease Models, Animal; Inflammation; L-Lactate Dehydrogenase; Lactic Acid; Leukotrienes; Lung; Ovalbumin; Peroxidase; Polyesters; Polymers; Quinolines; Rats; Rats, Sprague-Dawley; Sulfides

2014
Comparison of the efficacy of KOB03, ketotifen, and montelukast in an experimental mouse model of allergic rhinitis.
    International immunopharmacology, 2013, Volume: 16, Issue:2

    KOB03 is a polyherbal medicine derived from an oriental prescription traditionally used to treat allergic diseases. In the present study, we compared the efficacy of KOB03 with modern drugs such as ketotifen and montelukast in an experimental mouse model of allergic rhinitis (AR). Ketotifen is a H1 receptor antagonist and montelukast is a leukotriene receptor antagonist. Mice were treated with KOB03, ketotifen or montelukast in an established AR mouse model using ovalbumin (OVA)-sensitized/challenged BALB/c mice. The treatment of KOB03 had inhibitory effects on symptom scores, serum levels of OVA-specific IgE, histamine, leukotriene C4, IL-4, TNF-α, and IL-1β in AR mice, and the histolopathological changes of nasal mucosa with mucin release and inflammation. AR mice treated with KOB03 had significantly lower serum levels of OVA-specific IgE, LTC4, IL-4, and IL-1β than mice treated with ketotifen, whereas they only had significantly lower serum levels of OVA-specific IgE and IL-4 than those treated with montelukast. In addition, the histolopathological changes of nasal mucosa with eosinophil infiltration were significantly lower in the KOB03-treated mice than those in the ketotifen and montelukast-treated group. These results suggest that KOB03 has therapeutic potential for treating AR like other modern medicines.

    Topics: Acetates; Animals; Anti-Allergic Agents; Antigens; Cyclopropanes; Cytokines; Disease Models, Animal; Histamine H1 Antagonists; Immunoglobulin E; Ketotifen; Leukotriene Antagonists; Leukotriene C4; Male; Mice; Mice, Inbred BALB C; Nasal Mucosa; Ovalbumin; Plant Extracts; Quinolines; Rhinitis, Allergic; Rhinitis, Allergic, Perennial; Sulfides

2013
Therapeutic potential of curcumin in experimentally induced allergic rhinitis in guinea pigs.
    International immunopharmacology, 2013, Volume: 17, Issue:1

    In the present experiments, the possible role of curcumin in ovalbumin induced allergic rhinitis in guinea pig model was investigated. Various allergic rhinitis symptoms viz sneezing, rubbing frequencies, lacrimation and nasal congestion at various humidity conditions as well as on repeated sensitization were studied. The biochemical changes like serum IgE, IL-4 and nitric oxide (NO) in nasal lavage and eosinophil peroxidase activity in nasal homogenates were determined in allergic rhinitis. Curcumin treatment significantly reduced the symptoms (sneezing, rubbing frequencies, lacrimation and nasal congestion) and improved the histopathological alterations (reduction in inflammatory cells infiltration) of nasal mucosa in allergic rhinitis. Furthermore, curcumin treatment prevented significantly elevation of serum IgE, IL-4, NO in nasal lavage and eosinophil peroxidase in nasal homogenate. In the present experimental findings, we suggest that curcumin is a promising anti-allergic agent that may be useful in the clinical management of allergic rhinitis.

    Topics: Acetates; Animals; Cromolyn Sodium; Curcumin; Cyclopropanes; Dose-Response Relationship, Drug; Eosinophil Peroxidase; Female; Gene Expression Regulation; Guinea Pigs; Humidity; Interleukin-4; Male; Nitric Oxide; Ovalbumin; Quinolines; Rhinitis, Allergic; Rhinitis, Allergic, Perennial; Sulfides

2013
Mast cell mediators cause early allergic bronchoconstriction in guinea-pigs in vivo: a model of relevance to asthma.
    Clinical science (London, England : 1979), 2013, Volume: 125, Issue:11

    One feature of allergic asthma, the EAR (early allergic reaction), is not present in the commonly used mouse models. We therefore investigated the mediators involved in EAR in a guinea-pig in vivo model of allergic airway inflammation. Animals were sensitized using a single OVA (ovalbumin)/alum injection and challenged with aerosolized OVA on day 14. On day 15, airway resistance was assessed after challenge with OVA or MCh (methacholine) using the forced oscillation technique, and lung tissue was prepared for histology. The contribution of mast cell mediators was investigated using inhibitors of the main mast cell mediators [histamine (pyrilamine) and CysLTs (cysteinyl-leukotrienes) (montelukast) and prostanoids (indomethacin)]. OVA-sensitized and challenged animals demonstrated AHR (airway hyper-responsiveness) to MCh, and lung tissue eosinophilic inflammation. Antigen challenge induced a strong EAR in the sensitized animals. Treatment with a single compound, or indomethacin together with pyrilamine or montelukast, did not reduce the antigen-induced airway resistance. In contrast, dual treatment with pyrilamine together with montelukast, or triple inhibitor treatment, attenuated approximately 70% of the EAR. We conclude that, as in humans, the guinea-pig allergic inflammation model exhibits both EAR and AHR, supporting its suitability for in vivo identification of mast cell mediators that contribute to the development of asthma. Moreover, the known mast cell mediators histamine and leukotrienes were major contributors of the EAR. The data also lend further support to the concept that combination therapy with selective inhibitors of key mediators could improve asthma management.

    Topics: Acetates; Animals; Asthma; Bronchial Hyperreactivity; Constriction, Pathologic; Cyclopropanes; Disease Models, Animal; Guinea Pigs; Histamine Antagonists; Hypersensitivity; Indomethacin; Leukotriene Antagonists; Lung; Mast Cells; Ovalbumin; Prostaglandin Antagonists; Pyrilamine; Quinolines; Sulfides

2013
Protection of montelukast on OVA-induced eosinophilic gastroenteritis via modulating IL-5, eotaxin-1 and MBP expression.
    Immunopharmacology and immunotoxicology, 2013, Volume: 35, Issue:5

    The aim of this study was to further explore the possible mechanisms of montelukast on oral mice ovalbumin-induced eosinophilic gastroenteritis in a mouse model. The results indicated that montelukast could prevent levels of eotaxin-1 and interleukin-5 in intestinal mucosa homogenate when compared with model group. Interestingly, the increase of major basic protein expression in jejunal tissue also was attenuated by treated with montelukast.

    Topics: Acetates; Animals; Chemokine CCL11; Cyclopropanes; Enteritis; Eosinophil Major Basic Protein; Eosinophilia; Gastritis; Gene Expression Regulation; Interleukin-5; Leukotriene Antagonists; Mice; Mice, Inbred BALB C; Ovalbumin; Quinolines; Sulfides

2013
Restoration of the normal Clara cell phenotype after chronic allergic inflammation.
    International journal of experimental pathology, 2013, Volume: 94, Issue:6

    Bronchiolar Clara cells play a critical role in lung homoeostasis. The main goal of this study was to evaluate the effects of chronic allergy on these cells and the efficacy of budesonide (BUD) and montelukast (MK) in restoring their typical phenotypes after ovalbumin-induced chronic allergy in mice. Chronic allergy induced extensive bronchiolar Alcian blue-periodic acid-Schiff (AB/PAS)-positive metaplasia. In addition, cells accumulated numerous big electron-lucent granules negative for Clara cell main secretory protein (CC16), and consequently, CC16 was significantly reduced in bronchoalveolar lavage. A concomitant reduction in SP-D and CYP2E1 content was observed. The phenotypic changes induced by allergy were pharmacologically reversed by both treatments; MK was more efficient than BUD in doing so. MK decreased AB/PAS reactivity to control levels whereas they remained persistently elevated after BUD. Moreover, most non-ciliated cells recovered their normal morphology after MK, whereas for BUD normal cells coexisted with 'transitional' cells that contained remnant mucous granules and stained strongly for CC16 and SP-D. Glucocorticoids were also less able to reduce inflammatory infiltration and maintained higher percentage of neutrophils, which may have contributed to prolonged mucin expression. These results show that chronic allergy-induced mucous metaplasia of Clara cells affects their defensive mechanisms. However, anti-inflammatory treatments were able to re-establish the normal phenotype of Clara cell, with MK being more efficient at restoring a normal profile than BUD. This study highlights the role of epithelial cells in lung injuries and their contribution to anti-inflammatory therapies.

    Topics: Acetates; Animals; Anti-Asthmatic Agents; Anti-Inflammatory Agents; Asthma; Bronchi; Budesonide; Chronic Disease; Cyclopropanes; Cytochrome P-450 CYP2E1; Disease Models, Animal; Epithelium; Female; Mice; Mice, Inbred BALB C; Ovalbumin; Phenotype; Pulmonary Surfactant-Associated Protein D; Quinolines; Sulfides; Uteroglobin

2013
Effects of montelukast on subepithelial/peribronchial fibrosis in a murine model of ovalbumin induced chronic asthma.
    International immunopharmacology, 2013, Volume: 17, Issue:3

    Montelukast, a leukotriene receptor antagonist, is used commercially as a maintenance treatment for asthma and to relieve allergic symptoms. In this study, we evaluated the protective effects of montelukast against the airway inflammation and fibrosis using a murine model of ovalbumin (OVA) induced chronic asthma. The animals received OVA challenge three times a week for 4 weeks. Montelukast (30 mg/kg) was administrated orally once a day for 4 weeks. The administration of montelukast caused a reduction in elevated interleukin (IL)-4, IL-13, eotaxin, immunoglobulin (Ig), inflammatory cell infiltration into the airways, and mucus production after repeated OVA challenges. To investigate the antifibrotic mechanism of montelukast, we examined the expression of profibrotic mediators, including vascular endothelial growth factor (VEGF), transforming growth factor (TGF)-β1, and Smad3 proteins in the lung tissue using western blotting and immunohistochemistry. The administration of montelukast reduced the overexpression of profibrotic proteins in the lung tissue, which was confirmed by immnunohistochemistry. These results are consistent with a histopathological examination of lung tissue with Masson's trichrome stain. In conclusion, the administration of montelukast reduced airway inflammation and pulmonary fibrosis by reducing the release of Th2 cytokines and the expression of VEGF, TGF-β1/Smad3 in the lung tissue.

    Topics: Acetates; Allergens; Animals; Anti-Asthmatic Agents; Asthma; Bronchoalveolar Lavage Fluid; Cyclopropanes; Cytokines; Disease Models, Animal; Female; Immunoglobulin E; Leukotriene Antagonists; Lung; Mice; Mice, Inbred BALB C; Mucus; Ovalbumin; Pulmonary Fibrosis; Quinolines; Smad3 Protein; Sulfides; Transforming Growth Factor beta1; Vascular Endothelial Growth Factor A

2013
Antileukotriene reverts the early effects of inflammatory response of distal parenchyma in experimental chronic allergic inflammation.
    BioMed research international, 2013, Volume: 2013

    Compare the effects of montelukast or dexamethasone in distal lung parenchyma and airway walls of guinea pigs (GP) with chronic allergic inflammation.. GP have inhaled ovalbumin (OVA group-2x/week/4weeks). After the 4th inhalation, GP were treated with montelukast or dexamethasone. After 72 hours of the 7th inhalation, GP were anesthetised, and lungs were removed and submitted to histopathological evaluation.. Montelukast and dexamethasone treatments reduced the number of eosinophils in airway wall and distal lung parenchyma compared to OVA group (P < 0.05). On distal parenchyma, both treatments were effective in reducing RANTES, NF- κ B, and fibronectin positive cells compared to OVA group (P < 0.001). Montelukast was more effective in reducing eotaxin positive cells on distal parenchyma compared to dexamethasone treatment (P < 0.001), while there was a more expressive reduction of IGF-I positive cells in OVA-D group (P < 0.001). On airway walls, montelukast and dexamethasone were effective in reducing IGF-I, RANTES, and fibronectin positive cells compared to OVA group (P < 0.05). Dexamethasone was more effective in reducing the number of eotaxin and NF- κ B positive cells than Montelukast (P < 0.05).. In this animal model, both treatments were effective in modulating allergic inflammation and remodeling distal lung parenchyma and airway wall, contributing to a better control of the inflammatory response.

    Topics: Acetates; Administration, Inhalation; Animals; Chronic Disease; Cyclopropanes; Dexamethasone; Disease Models, Animal; Guinea Pigs; Hypersensitivity; Inflammation; Leukotriene Antagonists; Lung; Ovalbumin; Quinolines; Sulfides

2013
Influence of inhaled beclomethasone and montelukast on airway remodeling in mice.
    Inflammopharmacology, 2013, Volume: 21, Issue:1

    This study examined the effect of montelukast and beclomethasone on airway remodeling in murine model of asthma. Mice were sensitized by i.p. injection of ovalbumin (OVA) on days 0 and 14, and then challenged by nebulization of 1% OVA 3 days/week for 6 or 10 weeks. Results of 6-week OVA-challenged group showed moderate inflammation, but the 10-week OVA-challenged group exhibited mild inflammation. The OVA challenge (6 and 10 weeks) exhibited marked airway fibrosis, illustrated by significant increase in goblet cell hyperplasia and epithelial thickness, increased lung content of collagen and transforming growth factor-β(1), together with a decrease in nitric oxide production; also, there was an increase in bronchoalveolar lavage fluid level of interleukin-13. Administration of montelukast or beclomethasone before each OVA challenge was capable of restoring most of the measured parameters to near normal levels. Inhalation of beclomethasone has a similar role in airway remodeling as montelukast, but its effects in regulating inflammatory changes is less pronounced than montelukast.

    Topics: Acetates; Administration, Inhalation; Airway Remodeling; Animals; Anti-Asthmatic Agents; Asthma; Beclomethasone; Cyclopropanes; Disease Models, Animal; Inflammation; Male; Mice; Ovalbumin; Quinolines; Severity of Illness Index; Sulfides; Time Factors

2013
Effects of corticosteroid, montelukast and iNOS inhibition on distal lung with chronic inflammation.
    Respiratory physiology & neurobiology, 2013, Jan-15, Volume: 185, Issue:2

    We evaluated the effects of anti-iNOS (1400W - W) associated with leukotriene antagonist (montelukast - M) or corticosteroid (dexamethasone - D) on distal lung of guinea pigs (GP) with chronic pulmonary inflammation.. GP were inhaled with ovalbumin (OVA-2×/week/4 weeks), treated with M (OVAM), D (OVAD) and/or W (OVAW, OVADW, OVAMW) and distal lungs were evaluated by morphometry.. Isolated treatments were not sufficient to reduce all parameters. In OVADW, all parameters were reduced with greater reduction in elastic fibers, TIMP-1, IL-4, IL-5, IFN-gamma and PGF2-alpha compared with OVAD (p<0.05). OVAMW potentiated the reduction of actin, elastic fibers, TIMP-1, IL-4, IL-5, TGF-beta, IFN-gamma, iNOS, and PGF2-alpha to a greater extent than OVAM (p<0.05). A reduction of TIMP-1, IL-4, IL-5, TGF-beta, IFN-gamma and iNOS was observed in OVADW compared with OVAMW (p<0.05).. Although anti-iNOS paired with montelukast or dexamethasone yields better results than isolated treatments, the most effective pairing for controlling inflammation, oxidative stress and remodeling in this asthma model was found to be corticosteroids and anti-iNOS.

    Topics: Acetates; Amidines; Animals; Anti-Inflammatory Agents; Benzylamines; Chronic Disease; Cyclopropanes; Cytokines; Dexamethasone; Disease Models, Animal; Enzyme Inhibitors; Eosinophils; Guinea Pigs; Lung; Male; Ovalbumin; Pneumonia; Quinolines; Statistics, Nonparametric; Sulfides

2013
The effects of montelukast on eosinophilic gastroenteritis in a mouse model.
    Immunopharmacology and immunotoxicology, 2013, Volume: 35, Issue:2

    Gastrointestinal eosinophilic (EG) is a rare and heterogeneous condition characterized by patchy or diffuse eosinophilic infiltration of gastrointestinal tissue. Pharmacological study so far has demonstrated that montelukast, an oral leukotriene receptor antagonist, might be considered in patients with this disease. The aim of this study was to evaluate the effect of montelukast on oral ovalbumin (OVA) allergen induced EG inflammation in mice and to suggest some mechanisms underlying this effect. Twenty-four mice were divided into three experimental groups: PBS control, OVA group, and montelukast treated group. The mice were sensitized intraperitoneally and challenged intragastrically with OVA, and were treated with montelukast. Gastrointestinal symptoms were observed after challenged intragastrically with OVA. Eosinophils count in blood, serum OVA specific IgE and gastrointestinal histology were evaluated. Montelukast could significantly reduce the severity of oral allergen-induced eosinophilic inflammation, villous atrophy, and associated symptoms of weight loss associated with diarrhea. Montelukast also could ameliorate OVA-induced gastrointestinal pathological lesions, which was associated with the decrease of IgE and LTD4 levels, and this might be one of the important mechanisms of montelukast that protected gastrointestinal injury from EG. These findings indicated that montelukast therapy may be a novel therapeutic approach for EG and other eosinophil-mediated diseases.

    Topics: Acetates; Animals; Body Weight; Cyclopropanes; Enteritis; Eosinophilia; Eosinophils; Female; Gastric Mucosa; Gastritis; Gastroenteritis; Immunoglobulin E; Inflammation; Jejunum; Leukotriene D4; Mice; Mice, Inbred BALB C; Ovalbumin; Quinolines; Stomach; Sulfides

2013
A novel prostacyclin agonist protects against airway hyperresponsiveness and remodeling in mice.
    American journal of respiratory cell and molecular biology, 2012, Volume: 47, Issue:2

    Airway remodeling in bronchial asthma results from chronic, persistent airway inflammation. The effects of the reversal of airway remodeling by drug interventions remain to be elucidated. We investigated the effects of ONO-1301, a novel prostacyclin agonist with thromboxane inhibitory activity, on the prevention and reversibility of airway remodeling in an experimental chronic asthma model. Mice sensitized and challenged to ovalbumin (OVA) three times a week for 5 consecutive weeks were administered ONO-1301 or vehicle twice a day from the fourth week of OVA challenges. Twenty-four hours after the final OVA challenge, airway hyperresponsiveness (AHR) was assessed, and bronchoalveolar lavage was performed. Lung specimens were excised for staining to detect goblet-cell metaplasia, airway smooth muscle, and submucosal fibrosis. Mice administered ONO-1301 showed limited increases in AHR compared with mice administered the vehicle. The histological findings of airway remodeling were improved in ONO-1301-treated mice compared with vehicle-treated mice. Presumably, these therapeutic effects of ONO-1301 are attributable to the up-regulation of production of hepatocyte growth factor (HGF) in lung tissue, because the neutralization of HGF by antibodies prevented the effects of ONO-1301 on AHR and airway remodeling. Mice administered ONO-1301 showed similar levels of AHR and airway remodeling as mice administered montelukast, a cysteinyl-leukotriene-1 receptor antagonist, and lower levels were observed in mice administered dexamethasone. These data suggest that ONO-1301 exerts the effect of reversing airway remodeling, at least in part through an elevation of HGF in the lungs, and may be effective as an anti-remodeling drug in the treatment of asthma.

    Topics: Acetates; Airway Remodeling; Animals; Asthma; Bronchial Hyperreactivity; Bronchoalveolar Lavage Fluid; Cyclopropanes; Dexamethasone; Epoprostenol; Female; Goblet Cells; Hepatocyte Growth Factor; Inflammation; Lung; Metaplasia; Mice; Mice, Inbred BALB C; Muscle, Smooth; Ovalbumin; Pulmonary Fibrosis; Pyridines; Quinolines; Receptors, Leukotriene; Sulfides; Thromboxanes; Up-Regulation

2012
Effects of a cysteinyl leukotriene dual 1/2 receptor antagonist on antigen-induced airway hypersensitivity and airway inflammation in a guinea pig asthma model.
    International archives of allergy and immunology, 2011, Volume: 155 Suppl 1

    Little is known about the role of the cysteinyl leukotriene (cysLT) 2 receptor in the pathophysiology of asthma. The aim of this study is to investigate the effects of a cysLT1 receptor antagonist (montelukast) and a dual cysLT1/2 receptor antagonist (BAY-u9773) on airway hypersensitivity and airway inflammation induced by antigen challenge in ovalbumin (OVA)-sensitized guinea pigs.. Male Hartley guinea pigs sensitized with OVA were intraperitoneally administered 0.1, 1, or 10 mg/kg of montelukast or 0.1 mg/kg of BAY-u9773 and then challenged with inhaled OVA. Airway reactivity to acetylcholine, inflammatory cells in bronchoalveolar lavage (BAL) fluid, and eosinophil infiltration in airway walls after OVA challenge were evaluated.. Pretreatment with 1 or 10 mg/kg, but not 0.1 mg/kg, of montelukast significantly suppressed airway hypersensitivity and eosinophil infiltration into the BAL fluid. Moreover, 0.1 mg/kg of BAY-u9773 significantly suppressed the development of these markers. The suppressive effects of BAY-u9773, although not significantly different, trended toward being greater than those of montelukast. Although all of the doses of montelukast tested and 0.1 mg/kg of BAY-u9773 significantly suppressed eosinophil infiltration in airway walls, the suppressive effect of BAY-u9773 was significantly greater than that of 0.1 mg/kg of montelukast.. Signaling may contribute to the pathophysiology of asthma via the cysLT1/2 receptor.

    Topics: Acetates; Acetylcholine; Animals; Asthma; Bronchial Hyperreactivity; Bronchial Provocation Tests; Bronchoalveolar Lavage Fluid; Cyclopropanes; Eosinophils; Guinea Pigs; Inflammation; Leukotriene Antagonists; Lung; Male; Ovalbumin; Quinolines; Receptors, Leukotriene; SRS-A; Sulfides

2011
Effects of combination therapy with montelukast and carbocysteine in allergen-induced airway hyperresponsiveness and airway inflammation.
    British journal of pharmacology, 2010, Volume: 160, Issue:6

    Montelukast and S-carbocysteine have been used in asthmatic patients as an anti-inflammatory or mucolytic agent respectively. S-carbocysteine also exhibits anti-inflammatory properties.. Ovalbumin (OVA) sensitized BALB/c mice were challenged with OVA for 3 days followed by single OVA re-challenge (secondary challenge) 2 weeks later. Forty-eight hours after secondary challenge, mice were assessed for airway hyperresponsiveness (AHR) and cell composition in bronchoalveolar lavage (BAL) fluid. Suboptimal doses of 10 mg.kg(-1) of S-carbocysteine by intraperitoneal injection (ip), 20 mg.kg(-1) of montelukast by gavage, the combination of S-carbocysteine and montelukast or 3 mg.kg(-1) of dexamethasone as a control were administered from 1 day before the secondary challenge to the last experimental day. Isolated lung cells were cultured with OVA and montelukast to determine the effects on cytokine production.. Treatment with S-carbocysteine or montelukast reduced both AHR and the numbers of eosinophils in BAL fluid. Neutralizing IFN-gamma abolished the effects of S-carbocysteine on these airway responses. Combination of the two drugs showed further decreases in both AHR and eosinophils in the BAL fluid. Goblet cell metaplasia and Th2-type cytokines, interleukin (IL)-4, IL-5 and IL-13, in BAL fluid were decreased with montelukast treatment. Conversely, S-carbocysteine increased Th1-type cytokines, IFN-gamma and IL-12 in BAL fluid.. The combination of two agents, montelukast and S-carbocysteine, demonstrated additive effects on AHR and airway inflammation in a secondary allergen model most likely through independent mechanisms of action.

    Topics: Acetates; Animals; Anti-Asthmatic Agents; Anti-Inflammatory Agents; Bronchial Hyperreactivity; Bronchoalveolar Lavage Fluid; Carbocysteine; Cyclopropanes; Dexamethasone; Drug Synergism; Drug Therapy, Combination; Eosinophils; Female; Inflammation; Injections, Intraperitoneal; Mice; Mice, Inbred BALB C; Ovalbumin; Quinolines; Sulfides

2010
Leukotrienes produced in allergic lung inflammation activate alveolar macrophages.
    Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology, 2010, Volume: 26, Issue:3

    It has been well-documented that leukotrienes (LTs) are released in allergic lung inflammation and that they participate in the physiopathology of asthma. A role for LTs in innate immunity has recently emerged: Cys-LTs were shown to enhance FcgammaR-mediated phagocytosis by alveolar macrophages (AMs). Thus, using a rat model of asthma, we evaluated FcgammaR-mediated phagocytosis and killing of Klebsiella pneumoniae by AMs. The effect of treatment with a cys-LT antagonist (montelukast) on macrophage function was also investigated. Male Wistar rats were immunized twice with OVA/alumen intraperitoneally and challenged with OVA aerosol. After 24 h, the animals were killed, and the AMs were obtained by bronchoalveolar lavage. Macrophages were cultured with IgG-opsonized red blood cells (50:1) or IgG-opsonized K. pneumoniae (30:1), and phagocytosis or killing was evaluated. Leukotriene C(4) and nitric oxide were quantified by the EIA and Griess methods, respectively. The results showed that AMs from sensitized and challenged rats presented a markedly increased phagocytic capacity via FcgammaR (10X compared to controls) and enhanced killing of K. pneumoniae (4X higher than controls). The increased phagocytosis was inhibited 15X and killing 3X by treatment of the rats with montelukast, as compared to the non-treated group. cys-LT addition increased phagocytosis in control AMs but had no effect on macrophages from allergic lungs. Montelukast reduced nitric oxide (39%) and LTC(4) (73%). These results suggest that LTs produced during allergic lung inflammation potentiate the capacity of AMs to phagocytose and kill K. pneumonia via FcgammaR.

    Topics: Acetates; Allergens; Animals; Asthma; Cyclopropanes; Cysteine; Disease Models, Animal; Klebsiella pneumoniae; Leukotriene Antagonists; Leukotriene C4; Leukotrienes; Lung; Macrophages, Alveolar; Male; Nitric Oxide; Ovalbumin; Phagocytosis; Pneumonia; Quinolines; Rats; Rats, Wistar; Receptors, IgG; Sulfides

2010
15-lipoxygenase metabolites play an important role in the development of a T-helper type 1 allergic inflammation induced by double-stranded RNA.
    Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology, 2009, Volume: 39, Issue:6

    We recently demonstrated that the T-helper type 1 (Th1) immune response plays an important role in the development of non-eosinophilic inflammation induced by airway exposure of an allergen plus double-stranded RNA (dsRNA). However, the role of lipoxygenase (LO) metabolites in the development of Th1 inflammation is poorly understood.. To evaluate the role of LO metabolites in the development of Th1 inflammation induced by sensitization with an allergen plus dsRNA.. A Th2-allergic inflammation mouse model was created by an intraperitoneal injection of lipopolysaccharide-depleted ovalbumin (OVA, 75 microg) and alum (2 mg) twice, and the Th1 model was created by intranasal application of OVA (75 microg) and synthetic dsRNA [10 microg of poly(I : C)] four times, followed by an intranasal challenge with 50 microg of OVA four times. The role of LO metabolites was evaluated using two approaches: a transgenic approach using 5-LO(-/-) and 15-LO(-/-) mice, and a pharmacological approach using inhibitors of cysteinyl leucotriene receptor-1 (cysLTR1), LTB4 receptor (BLT1), and 15-LO.. We found that the Th1-allergic inflammation induced by OVA+dsRNA sensitization was similar between 5-LO(-/-) and wild-type (WT) control mice, although Th2 inflammation induced by sensitization with OVA+alum was reduced in the former group. In addition, dsRNA-induced Th1 allergic inflammation, which is associated with down-regulation of 15-hydroxyeicosateraenoic acids production, was not affected by treatment with cysLTR1 or BLT1 inhibitors, whereas it was significantly lower in 12/15-LO(-/-) mice compared with WT control mice. Moreover, dsRNA-induced allergic inflammation and the recruitment of T cells following an allergen challenge were significantly inhibited by treatment with a specific 15-LO inhibitor (PD146176).. 15-LO metabolites appear to be important mediators in the development of Th1-allergic inflammation induced by sensitization with an allergen plus dsRNA. Our findings suggest that the 15-LO pathway is a novel therapeutic target for the treatment of virus-associated asthma characterized by Th1 inflammation.

    Topics: Acetates; Allergens; Alum Compounds; Animals; Arachidonate 15-Lipoxygenase; Arachidonate 5-Lipoxygenase; Cyclopropanes; Disease Models, Animal; Fatty Alcohols; Fluorenes; Glycols; Hypersensitivity; Inflammation; Leukotriene Antagonists; Lipoxygenase Inhibitors; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Knockout; Ovalbumin; Poly I-C; Quinolines; Receptors, Leukotriene; Receptors, Leukotriene B4; RNA, Double-Stranded; Sulfides; Th1 Cells; Th2 Cells

2009
Role of sphingosine-1-phosphate (S1P) and the S1P(2) receptor in allergen-induced, mast cell-dependent contraction of rat lung parenchymal strips.
    Naunyn-Schmiedeberg's archives of pharmacology, 2009, Volume: 380, Issue:4

    Lung parenchymal strips isolated from ovalbumin-sensitized rats manifest a mast cell-dependent, biphasic contraction when challenged with allergen. The first phase is mediated by the release of preformed 5-HT while the second phase is dependent on de novo synthesis of leukotrienes. Sphingosine 1-phosphate (S1P) is a sphingolipid metabolite which is readily generated in mast cells and has been demonstrated to be an important regulator of allergen-induced mast cell activation. We have used the parenchymal strip to explore the role of sphingosine 1-phosphate and the S1P(2) receptor in the two components of the acute response to allergen. Lung parenchymal strips were prepared from Brown Norway rats actively sensitized to ovalbumin. The strips were set up in organ baths and contractile responses measured isometrically. The inhibitors of sphingosine kinase, D-erythro-NN-dimethylsphingosine (dimethylsphingosine) and 4-[4-(4-chloro-phenyl)-thiazol-2-ylamino]-phenol (SKI-II) inhibited concentration-dependently both phases of the contractile response induced by 0.1 microg ml(-1) ovalbumin. The effects were seen at concentrations similar to those which inhibit the purified enzyme and were selective in that neither the contractile response to adenosine nor that to 5-hydroxytryptamine was affected. JTE-013 (a selective S1P(2) receptor antagonist) also blocked the response to ovalbumin (0.1 microg ml(-1)). However, the concentrations of JTE-013 required (microM) were substantially higher than its affinity for the S1P(2) receptors (nM). However, when tested against a lower concentration of ovalbumin (0.03 microg ml(-1)), JTE-013 inhibited the response with nM potency. These data demonstrate the importance of S1P and the S1P(2) receptor as regulators of allergen-induced activation of mast cells in their natural environment in the rat lung.

    Topics: Acetates; Adenosine; Allergens; Animals; Bronchoconstriction; Cyclopropanes; Dose-Response Relationship, Drug; Enzyme Inhibitors; Injections, Subcutaneous; Leukotriene Antagonists; Lung; Lysophospholipids; Male; Mast Cells; Methysergide; Ovalbumin; Phosphotransferases (Alcohol Group Acceptor); Pyrazoles; Pyridines; Quinolines; Rats; Rats, Inbred BN; Receptors, Lysosphingolipid; Serotonin; Serotonin Antagonists; Signal Transduction; Sphingosine; Sulfides; Thiazoles

2009
Inhaled montelukast inhibits cysteinyl-leukotriene-induced bronchoconstriction in ovalbumin-sensitized guinea-pigs: the potential as a new asthma medication.
    International immunopharmacology, 2009, Volume: 9, Issue:11

    Oral cysteinyl-leukotriene (LT) receptor antagonists such as montelukast are used for reducing airway inflammation and exacerbations. However, inhaled therapy using LT receptor antagonists has not been studied. In the present study, the effect of inhaled montelukast was investigated on airway hyperresponsiveness measured by cysteinyl-LT induced bronchoconstriction in an animal model of asthma. Bronchoconstriction responses were induced by inhaled LTC4 and LTD4 (0.2 microg/ml each) or three doses of intravenous LTC4 and LTD4 (0.3, 1, 3 microg/kg) in ovalbumin (OVA)-sensitized Hartley male guinea-pigs. The response was measured by the change in peak pressure of airway opening (Pao). The effect of montelukast was evaluated by the comparison of bronchoconstriction responses between the groups of animals pre-treated with 15-min inhalation of 10mg/ml montelukast and saline. To evaluate the tissue injury which might be caused by montelukast inhalation, lung tissues were examined for the histology. The broncoconstriction responses induced by inhaled LTC4 and LTD4 were enhanced by OVA sensitization in the guinea-pigs. In sensitized animals, the significant increases in peak Pao were 18.5+/-2.1 cmH(2)O by LTC4 inhalation and 25.0+/-1.6 cmH(2)O by LTD4 inhalation on average. Prior treatment of inhaled montelukast potently suppressed the peak Pao increases induced by both inhaled and intravenous LTC4 and LTD4 (all P<0.01 vs. saline control). Moreover, the suppression of inhaled montelukast against LTD4-induced bronchoconstriction was observed for at least up to 24h. According to the histological examination, montelukast inhalation produced no injury to the lung tissue. Inhaled montelukast, a cysteinyl-LT receptor antagonist, was effective in inhibiting cysteinyl-LT-induced acute bronchoconstriction, and may have the potential for clinical use as a new asthma drug.

    Topics: Acetates; Administration, Inhalation; Animals; Asthma; Bronchial Hyperreactivity; Bronchoconstriction; Cyclopropanes; Cysteine; Disease Models, Animal; Guinea Pigs; Immunologic Factors; Leukotriene Antagonists; Leukotriene C4; Leukotriene D4; Leukotrienes; Lung; Male; Ovalbumin; Quinolines; Sulfides

2009
Cough reflex sensitivity is increased in the guinea pig model of allergic rhinitis.
    Journal of physiology and pharmacology : an official journal of the Polish Physiological Society, 2008, Volume: 59 Suppl 6

    Increased cough reflex sensitivity is found in patients with allergic rhinitis and may contribute to cough caused by rhinitis. We have reported that cough to citric acid is enhanced in the guinea pig model of allergic rhinitis. Here we address the hypothesis that the cough reflex sensitivity is increased in this model. The data from our previous studies were analyzed for the cough reflex sensitivity. The allergic inflammation in the nose was induced by repeated intranasal instillations of ovalbumin in the ovalbumin-sensitized guinea pigs. Cough was induced by inhalation of doubling concentrations of citric acid (0.05-1.6 M). Cough threshold was defined as the lowest concentration of citric acid causing two coughs (C2, expressed as geometric mean [95% confidence interval]). We found that the cough threshold was reduced in animals with allergic rhinitis. C2 was 0.5 M [0.36-0.71 M] and 0.15 M [0.1-0.23 M] prior and after repeated intranasal instillations of ovalbumin, respectively, P<0.01, n=36). C2 was not affected in control animals (n=29). We have reported that the selective leukotriene cys-LT1 receptor antagonist montelukast inhibited cough enhancement in this model. We found that this was accompanied by inhibition of the changes in cough reflex sensitivity. C2 was reduced in animals with allergic rhinitis treated orally with vehicle (0.57 M [0.28-1.1] vs. 0.09 M [0.04-0.2 M], P<0.05, n=8), but not in animals treated with montelukast (0.57 M [0.22-1.4 M] vs. 0.52 M [0.17-1.6 M], NS, n=8). We conclude that the cough reflex sensitivity is increased in the guinea pig model of allergic rhinitis. Our results suggest that guinea pig is a suitable model for mechanistic studies of increased cough reflex sensitivity in rhinitis.

    Topics: Acetates; Allergens; Animals; Anti-Asthmatic Agents; Citric Acid; Cough; Cyclopropanes; Guinea Pigs; Inflammation; Leukotriene Antagonists; Male; Nasal Mucosa; Ovalbumin; Quinolines; Reflex; Rhinitis, Allergic, Seasonal; Sulfides

2008
Effect of montelukast in a guinea pig model of cough variant asthma.
    Pulmonary pharmacology & therapeutics, 2008, Volume: 21, Issue:1

    Cough variant asthma is known as a major cause of chronic cough. Fundamental features of cough variant asthma are prolonged non-productive cough responding to bronchodilator therapy, no history of wheezing or dyspnea attack, normal cough sensitivity and slightly increased bronchial responsiveness. Recently, we reported the animal model of cough variant asthma. The aim of this study was to clarify the involvement of cysteinyl leukotrienes (cysLTs) in this model by using a specific leukotriene receptor antagonist, montelukast. Cough number and specific airway resistance (sRaw) were measured during the antigen inhalation (1.5 min) and following 18.5 min, which was carried out 72 h after the first antigen inhalation in actively sensitized guinea pigs, and then total cell number and cell differentials in bronchoalveolar lavage fluid (BALF) were measured. Montelukast significantly reduced the antigen re-inhalation-induced cough, increase in sRaw, and increase in total cell number in BALF. In conclusion, cysLTs may play an important part in antigen-induced cough associated with bronchoconstriction and airway inflammation in cough variant asthma.

    Topics: Acetates; Airway Resistance; Animals; Anti-Asthmatic Agents; Asthma; Bronchial Provocation Tests; Bronchoalveolar Lavage Fluid; Cough; Cyclopropanes; Disease Models, Animal; Guinea Pigs; Leukotrienes; Male; Ovalbumin; Quinolines; Sulfides

2008
Montelukast inhibits inflammatory responses in small airways of the Guinea-pig.
    Pulmonary pharmacology & therapeutics, 2008, Volume: 21, Issue:2

    Increased resistance in the small airways is a major contributor of airway obstruction in asthma. The role of leukotrienes (LT) in determining inflammation and obstruction of small size bronchi is not completely understood. Here, we have examined the effect of the cysteinyl-leukotriene (CysLT 1) receptor antagonist, montelukast, against the bronchoconstriction and inflammatory responses induced by exogenous leukotriene and by allergen challenge in small size (

    Topics: Acetates; Animals; Bronchi; Bronchoconstriction; Capillary Permeability; Cyclopropanes; Eosinophils; Guinea Pigs; Hypersensitivity; In Vitro Techniques; Leukotriene Antagonists; Male; Microcirculation; Ovalbumin; Quinolines; Receptors, Leukotriene; Sulfides

2008
Differential responses to various classes of drugs in a model of allergic rhinitis in guinea pigs.
    Pulmonary pharmacology & therapeutics, 2008, Volume: 21, Issue:2

    Different drugs from various pharmacological classes were compared for their ability to protect against the nasal effects of acute allergen challenge in a guinea pig model. In the model, sneezing and nose rubbing were recorded after an initial allergen challenge in guinea pigs previously sensitized to egg albumin. Four days later the same guinea pigs were re-challenged a second time when anesthetised. In these anaesthetized animals, nasal airway pressure, pulmonary inflation pressure and cellular infiltration into nasal lavage fluid were measured. The drug tested were autacoid antagonists (mepyramine--3mg/kg, cetirizine--3mg/kg and montelukast--10mg/kg), L-NAME (10 or 20mg/kg), heparin (20mg/kg) and dexamethasone (20mg/kg) given either intraperitoneally or intravenously; all were given shortly before challenge. Sneezing induced by allergen challenge was statistically significantly reduced by mepyramine, cetirizine and dexamethasone whereas only cetirizine reduced nose rubbing. Changes in nasal airway pressure due to allergen exposure were reduced by cetirizine, montelukast, L-NAME, and heparin, but not by mepyramine, nor dexamethasone. In the presence of L-NAME, nasal airway pressure actually changed in the opposite direction. Cellular infiltration, as assessed by cytometry in nasal lavage fluid 60min after acute allergen challenge, was reduced by montelukast and heparin but not by antihistamines, L-NAME nor dexamethasone. This pattern of effects of the drugs, given by doses and routes previously described in the literature as being effective was not completely consistent with expected responses. The lack of effect of dexamethasone probably reflects the fact that it was given acutely whereas in the clinic chronic administration is used. The two antihistamines were not identical in their actions, presumably reflecting the fact that cetirizine has therapeutic actions not entirely confined to blockade of H1 receptors. Montelukast has not been reported to have major effects on sneezing and itching in the clinic but reduces nasal obstruction (lower nasal airway pressure or nasal patency). Montelukast's effects on cellular infiltration indicate the possible involvement of leukotrienes. Heparin has actions on inflammatory cell infiltration. This could explain its profile of reducing both cellular infiltration, and increased nasal airway pressure.

    Topics: Acetates; Acute Disease; Animals; Cetirizine; Cyclopropanes; Dexamethasone; Disease Models, Animal; Guinea Pigs; Heparin; Histamine H1 Antagonists; Male; Nasal Obstruction; NG-Nitroarginine Methyl Ester; Ovalbumin; Pyrilamine; Quinolines; Rhinitis, Allergic, Seasonal; Sneezing; Sulfides

2008
Effects of KP-496, a novel dual antagonist at the cysteinyl leukotriene receptor 1 and the thromboxane A(2) receptor, on airway obstruction in guinea pigs.
    British journal of pharmacology, 2008, Volume: 153, Issue:4

    KP-496 is a novel dual antagonist for cysteinyl leukotriene receptor 1 (CysLT(1)) and thromboxane A(2) (TXA(2)) receptor (TP). The aim of this study was to evaluate the pharmacological profile of inhaled KP-496 and its effects on airway obstruction.. Antagonist activities of inhaled KP-496 were investigated using bronchoconstriction induced in guinea pigs by LTD(4) or U46619, a stable TXA(2) mimetic. Guinea pigs sensitized with injections of ovalbumin were used to assess the effects of inhaled KP-496 on bronchoconstriction induced by antigen (i.v.). Another set of guinea pigs were sensitized and challenged with ovalbumin by inhalation and the effects of inhaled KP-496 on immediate and late airway responses and airway hyperresponsiveness were investigated.. KP-496 significantly inhibited LTD(4)- and U46619-induced bronchoconstriction in a dose-dependent manner. The inhibitory effects of KP-496 (1%) were comparable to those of montelukast (a CysLT(1) antagonist, p.o., 0.3 mg kg(-1)) or seratrodast (a TP antagonist, p.o., 3 mg kg(-1)). KP-496 (1%) and oral co-administration of montelukast (10 mg kg(-1)) and seratrodast (20 mg kg(-1)) significantly inhibited antigen-induced bronchoconstriction, whereas administration of montelukast or seratrodast separately did not inhibit antigen-induced bronchoconstriction. KP-496 exhibited dose-dependent and significant inhibitory effects on the immediate and late airway responses and airway hyperresponsiveness following antigen challenge.. KP-496 exerts effects in guinea pigs which could be beneficial in asthma. These effects of KP-496 were greater than those of a CysLT(1) antagonist or a TP antagonist, in preventing antigen-induced airway obstruction.

    Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Acetates; Administration, Inhalation; Administration, Oral; Airway Obstruction; Animals; Anti-Asthmatic Agents; Benzoates; Benzoquinones; Bronchoconstriction; Cyclopropanes; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Therapy, Combination; Guinea Pigs; Heptanoic Acids; Leukotriene Antagonists; Leukotriene D4; Lung; Male; Membrane Proteins; Ovalbumin; Prostaglandin Antagonists; Quinolines; Receptors, Leukotriene; Receptors, Thromboxane A2, Prostaglandin H2; Respiratory Hypersensitivity; Sulfides; Thiazoles; Time Factors

2008
Heterogeneous effect of leucotriene CysLT1 receptor antagonists on antigen-induced motor and inflammatory responses in guinea-pig airways.
    Autonomic & autacoid pharmacology, 2007, Volume: 27, Issue:1

    1. The effect of montelukast or MEN91507, selective leucotriene CysLT1 receptor antagonists, on antigen-induced airway inflammation and bronchoconstriction were compared in anaesthetized guinea-pigs. 2. In sensitized animals, ovalbumin (0.3 mg kg(-1), i.v.)-induced microvascular leakage in trachea, intrapulmonary airways, total lung (parenchyma and intrapulmonary airways) and urinary bladder was reduced by MEN91507 (0.01-1 micromol kg(-1), i.v.), whereas montelukast (0.01-1 micromol kg(-1), i.v.) antagonized the effect of the antigen only in the lung and urinary bladder. 3. Ovalbumin (1 mg kg(-1), i.v.)-induced bronchoconstriction was dose dependently antagonized by MEN91507 (10-30 micromol kg(-1), i.v.), whereas the effect of montelukast (0.1-30 micromol kg(-1), i.v.) was marginal (15-30% inhibition). Neither MEN91507 nor montelukast (30 micromol kg(-1), i.v.) affected the bronchoconstrictor response induced by acetylcholine (0.3 micromol kg(-1), i.v.) in sensitized animals. 4. It is concluded that montelukast and MEN91507 display a differential activity against the effect of endogenous leucotrienes, despite the fact that both compounds show a similar antagonist profile against exogenous leucotrienes acting through CysLT1 receptors.

    Topics: Acetates; Animals; Antigens; Benzopyrans; Bronchoconstriction; Cyclopropanes; Dose-Response Relationship, Drug; Evans Blue; Guinea Pigs; Inflammation; Injections, Intravenous; Leukotriene Antagonists; Male; Membrane Proteins; Ovalbumin; Quinolines; Receptors, Leukotriene; Respiratory System; Sulfides; Tetrazoles

2007
Cysteinyl leukotriene upregulates IL-11 expression in allergic airway disease of mice.
    The Journal of allergy and clinical immunology, 2007, Volume: 119, Issue:1

    Chronic airway inflammation and airway remodeling are important features of bronchial asthma. IL-11 is one of the important mediators involved in the process of airway inflammation and remodeling. Cysteinyl leukotrienes (cysLTs) play roles in recruitment of inflammatory cells, airway smooth muscle contraction, vascular leakage, increased mucus secretion, decreased mucociliary clearance, and airway fibrosis.. An aim of the present study was to determine the effect of the cysLTs on the regulation of IL-11 expression.. We used a C57BL/6 mouse model of allergic airway disease and murine tracheal epithelial cells to examine the effects of cysLTs on the regulation of IL-11 expression.. Our present study with an ovalbumin-induced murine model of allergic airway disease revealed that levels of leukotriene C(4) (LTC(4)) in bronchoalveolar lavage fluids were increased and that administration of montelukast or pranlukast reduced the increased levels of LTC(4); the increased expression of IL-11 protein and mRNA in lung tissues; airway inflammation, bronchial hyperresponsiveness; the increased levels of TGF-beta(1), IL-4, and IL-13 in bronchoalveolar lavage fluids and lung tissues; and airway fibrosis. In addition, LTC(4) stimulates epithelial cells to produce IL-11. Our results also showed that cysLT type 1 receptor antagonists downregulated the activity of a transcription factor, nuclear factor kappaB, and BAY 11-7085 substantially reduced the increased levels of IL-11 after ovalbumin inhalation.. These results suggest that cysLTs regulate the IL-11 expression in allergic airway disease.. These findings provide one of the molecular mechanisms for the effects of cysLTs on airway inflammation and fibrosis in allergic airway diseases.

    Topics: Acetates; Animals; Bronchoalveolar Lavage Fluid; Cells, Cultured; Chromones; Collagen; Cyclopropanes; Epithelial Cells; Female; Interleukin-11; Interleukin-13; Interleukin-4; Leukotriene Antagonists; Leukotriene C4; Leukotriene D4; Lung; Mice; Mice, Inbred C57BL; Nitriles; Ovalbumin; Quinolines; Respiratory Hypersensitivity; RNA, Messenger; Sulfides; Sulfones; Transcription Factor RelA

2007
Lipoxin A4 stable analogs reduce allergic airway responses via mechanisms distinct from CysLT1 receptor antagonism.
    FASEB journal : official publication of the Federation of American Societies for Experimental Biology, 2007, Volume: 21, Issue:14

    Cellular recruitment during inflammatory/immune responses is tightly regulated. The ability to dampen inflammation is imperative for prevention of chronic immune responses, as in asthma. Here we investigated the ability of lipoxin A4 (LXA4) stable analogs to regulate airway responses in two allergen-driven models of inflammation. A 15-epi-LXA4 analog (ATLa) and a 3-oxa-15-epi-LXA4 analog (ZK-994) prevented excessive eosinophil and T lymphocyte accumulation and activation after mice were sensitized and aerosol-challenged with ovalbumin. At <0.5 mg/kg, these LXA4 analogs reduced leukocyte trafficking into the lung by >50% and to a greater extent than equivalent doses of the CysLT1 receptor antagonist montelukast. Distinct from montelukast, ATLa treatment led to marked reductions in cysteinyl leukotrienes, interleukin-4 (IL-4), and IL-10, and both ATLa and ZK-994 inhibited levels of IL-13. In cockroach allergen-induced airway responses, both intraperitoneal and oral administration of ZK-994 significantly reduced parameters of airway inflammation and hyper-responsiveness in a dose-dependent manner. ZK-994 also significantly changed the balance of Th1/Th2-specific cytokine levels. Thus, the ATLa/LXA4 analog actions are distinct from CysLT1 antagonism and potently block both allergic airway inflammation and hyper-reactivity. Moreover, these results demonstrate these analogs' therapeutic potential as new agonists for the resolution of inflammation.

    Topics: Acetates; Allergens; Animals; Anti-Asthmatic Agents; Anti-Inflammatory Agents, Non-Steroidal; Antigens, Plant; Cyclopropanes; Disease Models, Animal; Leukotriene Antagonists; Lipoxins; Male; Membrane Proteins; Mice; Mice, Inbred BALB C; Ovalbumin; Phenyl Ethers; Quinolines; Receptors, Leukotriene; Respiratory Hypersensitivity; Structure-Activity Relationship; Sulfides

2007
The effects of montelukast on tissue inflammatory and bone marrow responses in murine experimental allergic rhinitis: interaction with interleukin-5 deficiency.
    Immunology, 2007, Volume: 122, Issue:3

    The cysteinyl leukotrienes (cysLTs) are potent lipid mediators in allergic disease, acting through the receptors, cysLT1R and cysLTR2, and are produced by eosinophils derived from eosinophil/basophil (Eo/B) bone marrow (BM) progenitors. We have demonstrated the suppressive effects of either interleukin-5 (IL-5) deficiency or montelukast on eosinophil recruitment in murine allergic rhinitis, but neither of them fully abrogated the symptoms caused by residual inflammation and cytokine redundancy in eliciting BM Eo/B responses. We hypothesized that IL-5 deficiency and montelukast act synergistically to suppress tissue inflammatory and BM responses. Our objective was to investigate the effects of the cysLT1R antagonist, montelukast, on in vivo tissue inflammatory and BM responses in murine experimental allergic rhinitis with or without IL-5 deficiency. Three groups of age-matched BALB/c mice with or without IL-5 deficiency were tested: controls (ovalbumin sensitization and challenge, placebo treatment) and two montelukast-treated groups (2.5 mg/kg or 5 mg/kg). Nasal symptoms, BM and nasal mucosal eosinophils, basophils, and BM Eo/B colony-forming units (CFU) were evaluated. Montelukast decreased nasal symptoms in a dose-dependent manner, and significantly decreased the number of eosinophils in both BM and nasal tissue in IL-5-replete mice compared to controls. In IL-5-deficient mice, in which eosinophilia was absent, montelukast significantly decreased both nasal symptoms and basophils in BM and nasal mucosal tissue, and lowered IL-5-responsive Eo/B-CFU ex vivo, compared to controls. The addition of cysLT1R blockade to IL-5 deficiency more fully attenuates symptoms and upper airway inflammation than either factor alone, providing evidence of systemic, BM mechanisms in allergic rhinitis.

    Topics: Acetates; Animals; Basophils; Bone Marrow; Colony-Forming Units Assay; Cyclopropanes; Dose-Response Relationship, Drug; Drug Evaluation, Preclinical; Eosinophils; Hematopoietic Stem Cells; Interleukin-5; Leukotriene Antagonists; Mice; Mice, Inbred BALB C; Nasal Mucosa; Ovalbumin; Quinolines; Rhinitis, Allergic, Perennial; Sulfides

2007
Comparative study to elucidate the mechanism underlying the difference in airway hyperresponsiveness between two mouse strains.
    International immunopharmacology, 2007, Dec-20, Volume: 7, Issue:14

    The mechanism underlying airway hyperresponsiveness (AHR), a characteristic feature of asthma, remains obscure. We attempted to elucidate the mechanism responsible for the different degrees of AHR in two mouse strains, BALB/c and C57BL/6, following exposure to an anaphylactic trigger. When ovalbumin (OVA)-sensitized mice were challenged daily with OVA for up to three consecutive days, the BALB/c mice showed a higher degree of airway responsiveness to methacholine than did C57BL/6. Following the OVA challenge, eosinophils and macrophages in bronchoalveolar lavage fluid (BALF) from BALB/c increased significantly in number compared to those from C57BL/6. BALB/c mice also exhibited a higher serum IgE level than that of C57BL/6 after OVA challenge. The enhanced AHR and eosinophilic infiltration in BALF were significantly reduced by pretreatment with a selective cysteinyl-leukotriene type 1 receptor (cysLT(1)R) antagonist, montelukast. In the in vitro study, cysLT production was significantly lower in the dissected lung tissue from BALB/c than in tissue from C57BL/6 when both groups were stimulated with saline. The lungs from BALB/c generated significantly larger amounts of cysLTs on incubation with OVA rather than with saline, while the lungs from C57BL/6 did not show any significant increase in cysLTs with antigen stimulation. Significant upregulation of cysLT(1)R and cysLT(2)R mRNA expression was induced by OVA challenge in the lungs of BALB/c, but not in those of C57BL/6. It is suggested that, after an anaphylactic reaction, the degree of AHR is dependent on the genetic background and that cysLTs play an important role in the mechanism involved.

    Topics: Acetates; Administration, Inhalation; Animals; Bronchial Provocation Tests; Bronchoalveolar Lavage Fluid; Cyclopropanes; Cysteine; Eosinophils; Immunoglobulin G; Leukotriene Antagonists; Leukotrienes; Macrophages; Methacholine Chloride; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Ovalbumin; Quinolines; Receptors, Leukotriene; Respiratory Hypersensitivity; Species Specificity; Sulfides

2007
Expression of urocortin in rat lung and its effect on pulmonary vascular permeability.
    The Journal of endocrinology, 2006, Volume: 189, Issue:1

    Urocortin (UCN), a newly identified, 40-amino-acid, corticotropin-releasing hormone (CRH) structurally related peptide, has been demonstrated to be expressed in the central nervous system and many peripheral tissues of rats and man. This study aimed to investigate the expression profile of UCN in rat lung and the effect of UCN on lung vascular permeability. The expression of UCN mRNA was detected by reverse transcriptase PCR (RT-PCR). UCN peptide was measured by immunohistochemistry and Western blot analysis. We found that both UCN mRNA and peptide were obviously expressed in rat lung. Immunohistochemistry results showed that UCN peptide is mainly expressed in bronchial epithelium mucosa and alveolar epithelium. We also found that rats receiving inhalation aerosol of UCN had a significant elevation of lung vascular permeability compared with rats receiving vehicle and ovalbumin (OVA) by the Evans blue (EB) technique. UCN aerosol inhalation resulted in obvious pulmonary congestion and edema observed under light microscope by hematoxylin and eosin (HE) staining. The nonselective peptide CRH receptor antagonist astressin markedly reduced lung vascular permeability triggered by UCN. Enhanced pulmonary vascular permeability induced by UCN was markedly inhibited by pretreatment with the mast-cell stabilizer cromolyn and histamine-1 (H1) receptor antagonist azelastine respectively, but not by the leukotriene receptor antagonist montelukast. In summary, in the present study, we demonstrated for the first time that UCN is expressed in rat lung and contributes to an increase in lung vascular permeability through activation of CRH receptors. Mast cells and histamine may be involved in this effect of UCN. Peripherally produced UCN in lung may act as an autocrine and paracrine proinflammatory factor.

    Topics: Acetates; Administration, Inhalation; Aerosols; Animals; Blotting, Western; Bronchi; Capillary Permeability; Corticotropin-Releasing Hormone; Cromolyn Sodium; Cyclopropanes; Epithelium; Histamine H1 Antagonists; Immunohistochemistry; Leukotriene Antagonists; Lung; Male; Mast Cells; Ovalbumin; Peptide Fragments; Phthalazines; Pulmonary Alveoli; Quinolines; Rats; Rats, Sprague-Dawley; Respiratory Mucosa; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Sulfides; Urocortins

2006
Suppressive effect of verproside isolated from Pseudolysimachion longifolium on airway inflammation in a mouse model of allergic asthma.
    International immunopharmacology, 2006, Volume: 6, Issue:6

    Allergic inflammation of the airways has a critical role in asthma development. We investigated a suppressive effect of verproside (3,4-dihydroxy catalpol) isolated from the extract of Pseudolysimachion longifolium on asthmatic parameters--such as immunoglobulin E (IgE) level, cytokine release, eosinophilia, airway hyperresponsiveness and mucus hypersecretion--in an OVA-sensitized/challenged mouse model. Verproside significantly inhibited the increase of total IgE and the cytokines IL-4 and IL-13 in plasma and bronchoalveolar lavage fluid, and also effectively suppressed airway hyperresponsiveness, eosinophilia and mucus hypersecretion in OVA-induced asthmatic mice. The efficacy of verproside was comparable to montelukast, an anti-asthmatic drug that is currently available. These results suggest that verproside could be a major marker in herbal medicines that are used for asthma treatment, and could also act as a lead for anti-asthmatic drugs.

    Topics: Acetates; Animals; Anti-Asthmatic Agents; Asthma; Bronchoalveolar Lavage Fluid; Cyclopropanes; Disease Models, Animal; Female; Glucosides; Immunoglobulin E; Interleukin-13; Interleukin-4; Iridoid Glucosides; Iridoids; Lung; Methacholine Chloride; Mice; Mice, Inbred BALB C; Molecular Structure; Mucus; Ovalbumin; Plant Extracts; Pneumonia; Pulmonary Eosinophilia; Quinolines; Sulfides; Veronica

2006
Effect of montelukast on bacterial sinusitis in allergic mice.
    Annals of allergy, asthma & immunology : official publication of the American College of Allergy, Asthma, & Immunology, 2006, Volume: 97, Issue:3

    In mice, allergic rhinitis augments the infectious and inflammatory response to Streptococcus pneumoniae-induced sinusitis.. To investigate the effects of cysteinyl leukotriene antagonism on the severity of bacterial infection.. We performed 3 parallel, placebo-controlled experiments. In the first, mice were ovalbumin sensitized and ovalbumin challenged to show the effects of montelukast on the allergic inflammation; in the second, we evaluated the effect of montelukast on S. pneumoniae infection; in the third, we used mice that were both allergic and infected. Montelukast was given starting 2 days after sensitization until the day before euthanasia. One day after drug treatment began, the mice were inoculated intranasally with S. pneumoniae in the infected groups. Nasal hypersensitivity was measured with histamine challenges before the first sensitization and on the day before euthanasia. On the fifth day after infection, mice were euthanized, nasal lavage was performed, bacteria were cultured, and inflammatory cells in the sinuses were quantified.. Mice that were infected only tended toward having increased bacterial counts from nasal lavage in the montelukast-treated group. The mice that were allergic and infected experienced significantly higher bacterial counts (P < .05). All 3 montelukast treatment groups had significantly decreased eosinophil counts as well as T-lymphocyte counts.. Montelukast reduces the manifestations of allergic rhinitis in mice. Surprisingly, montelukast led to an increase in bacterial growth in infected mice. This suggests an effect of the cysteinyl leukotrienes on the innate response to bacterial infection.

    Topics: Acetates; Animals; Cyclopropanes; Female; Flow Cytometry; Hypersensitivity; Leukotriene Antagonists; Male; Mice; Mice, Inbred BALB C; Nasal Lavage Fluid; Ovalbumin; Pneumococcal Infections; Quinolines; Sinusitis; Streptococcus pneumoniae; Sulfides

2006
Antileukotriene treatment and allergic rhinitis-related cough in guinea pigs.
    Journal of physiology and pharmacology : an official journal of the Polish Physiological Society, 2005, Volume: 56 Suppl 4

    Experimental allergic rhinitis produces enhanced cough response in awake guinea pigs. Leukotriene receptor antagonists, as anti-inflammatory agents, have been effective in treatment of asthma and allergic rhinitis to inhibit the early and late allergic response. In the present study, we evaluated the effect of montelukast (Singulair, Merck, USA) on the cough reflex in an experimental model of allergen-induced rhinitis in guinea pigs. Guinea pigs (n=16) were sensitized with intraperitoneal ovalbumin (OVA). The animals were then used to develop a model of allergic rhinitis by repeated intranasal instillation of 0.5% OVA at weekly intervals for 8 weeks. Allergic rhinitis was evaluated from the occurrence of typical clinical symptoms including sneezing, conjunctival and nasal secretion, or nasal acoustic phenomenon. Between the 6(th) and 8(th) nasal challenge (NCh) the animals (n=8) were treated daily for 14 days with oral montelukast (10mg/kg). Cough was induced by citric acid aerosol inhalation in gradually increasing concentration (0.05-1.6 M) and was evaluated before sensitization and then after the 1(st), 6(th), and 8(th) nasal challenge when rhinitis symptoms were most conspicuous. The intensity of cough was significantly increased after the first and repeated nasal OVA challenges, and reduced after the 8(th) NCh that was preceded with montelukast treatment [9(6-14) vs. 16.5(14-22) vs. 25.5(23-42) vs. 8.5(8-13); P=0.0003]. We conclude that antileukotriene therapy suppresses the stimulating effect of experimental allergic rhinitis on the chemically-induced cough in awake guinea pigs.

    Topics: Acetates; Administration, Oral; Animals; Citric Acid; Cough; Cyclopropanes; Disease Models, Animal; Guinea Pigs; Laryngeal Mucosa; Leukotriene Antagonists; Male; Membrane Proteins; Ovalbumin; Quinolines; Receptors, Leukotriene; Rhinitis, Allergic, Perennial; Sulfides; Time Factors

2005
Montelukast modulates lung CysLT(1) receptor expression and eosinophilic inflammation in asthmatic mice.
    Acta pharmacologica Sinica, 2004, Volume: 25, Issue:10

    To determine the expressions of cysteinyl leukotriene receptors, CysLT1 and CysLT2, in airway eosinophilic inflammation of OVA-induced asthmatic mice and the modulation by montelukast, a CysLT1 receptor antagonist.. Asthma model was induced by chronic exposure to ovalbumin (OVA) in C57BL/6 mice. The eosinophils in bronchoalveolar lavage (BAL) fluid and lung tissues were counted, IL-5 level in BAL fluid was measured, and CysLT1 and CysLT2 receptor mRNA expressions were detected by semi-quantitative RT-PCR.. Montelukast (6 mg/kg, once per day for 20 d) significantly suppressed the increased eosinophils in BAL fluid and lung tissue, and increased IL-5 level in BAL fluid in OVA challenged mice. OVA challenge increased CysLT1 but decreased CysLT2 receptor mRNA expression. Montelukast inhibited the increased CysLT1 but not the reduced CysLT2 expression after OVA challenge.. CysLT receptors are modulated immunologically, and montelukast inhibits up-regulation of CysLT1 receptor and airway eosinophilic inflammation in asthmatic mice.

    Topics: Acetates; Animals; Anti-Asthmatic Agents; Asthma; Bronchoalveolar Lavage Fluid; Cyclopropanes; Eosinophils; Interleukin-5; Leukocyte Count; Leukotriene Antagonists; Lung; Male; Membrane Proteins; Mice; Mice, Inbred C57BL; Ovalbumin; Quinolines; Receptors, Leukotriene; RNA, Messenger; Sulfides; Up-Regulation

2004
Cysteinyl leukotriene receptor antagonist regulates vascular permeability by reducing vascular endothelial growth factor expression.
    The Journal of allergy and clinical immunology, 2004, Volume: 114, Issue:5

    Inflammation of the asthmatic airway is usually accompanied by increased vascular permeability and plasma exudation. Cysteinyl leukotrienes (cysLTs) potently elicit increased vascular permeability in airways, leading to airway edema. Vascular endothelial growth factor (VEGF) is 1 of the most potent proangiogenic cytokines and also increases vascular permeability so that plasma proteins can leak into the extravascular space. However, the mechanisms by which cysLTs induce increased vascular permeability are not clearly understood.. An aim of the current study was to determine the role of the cysLTs, more specifically in the increase of vascular permeability.. We used a BALB/c mouse model of allergic asthma to examine effects of cysLT receptor antagonists on bronchial inflammation and airway hyperresponsiveness, more specifically on the increase of vascular permeability.. These mice develop the following typical pathophysiological features of asthma in the lungs: increased numbers of inflammatory cells of the airways, airway hyperresponsiveness, increased vascular permeability, and increased levels of VEGF. Administration of cysLT receptor antagonists markedly reduced plasma extravasation and VEGF levels in allergen-induced asthmatic lungs.. These results indicate that cysLT receptor antagonists modulate vascular permeability by reducing VEGF expression and suggest that cysLT receptor may regulate the VEGF expression.

    Topics: Acetates; Animals; Bronchial Hyperreactivity; Capillary Permeability; Chromones; Cyclopropanes; Cytokines; Female; Indoles; Membrane Proteins; Mice; Mice, Inbred BALB C; NF-kappa B; Ovalbumin; Quinolines; Receptors, Leukotriene; Receptors, Vascular Endothelial Growth Factor; Sulfides; Transcription Factor RelA; Vascular Endothelial Growth Factor A

2004
[Effects of montelukast on apoptosis and Fas mRNA expression of eosinophils in airway of asthmatic guinea pigs].
    Yao xue xue bao = Acta pharmaceutica Sinica, 2004, Volume: 39, Issue:10

    To study the effect of montelukast on apoptosis and Fas mRNA expression of eosinophils in airway of asthmatic guinea pigs.. Experimental asthma model of guinea pigs was induced by ovalbumin. The eosinophils in broncho-alveolar lavage fluid (BALF) were separated by density gradient centrifugation. The apoptosis of eosinophils was labeled by TdT-mediated dUTP nick end labeling (TUNEL) technique. Fas mRNA expression of eosinophils was detected by reverse transcription-polymerase chain reaction (RT-PCR).. After treatment with montelukast, the number of eosinophils in BALF of asthmatic guinea pigs decreased significantly. The apoptosis index as well as Fas mRNA expression of eosinophils were elevated significantly. There were statistical differences between the therapeutic group and the model group.. Apoptosis of eosinophils is highly correlated with the increased expression of Fas mRNA. Enhancing expression of Fas mRNA and promoting apoptosis of eosinophils subsequentely may be an important mechanism for montelukast to antagonize airway inflammation of asthma.

    Topics: Acetates; Animals; Anti-Asthmatic Agents; Apoptosis; Asthma; Cyclopropanes; Eosinophils; fas Receptor; Female; Guinea Pigs; Leukotriene Antagonists; Male; Ovalbumin; Quinolines; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Sulfides

2004
Anti-inflammatory effects of high-dose montelukast in an animal model of acute asthma.
    Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology, 2003, Volume: 33, Issue:3

    Asthmatic inflammation is mediated by a network of cytokines, chemokines and adhesion molecules. Corticosteroids are the only effective agents available to control asthmatic inflammation. We investigated the effect of high-dose montelukast (MK), a selective cysteinyl leukotriene receptor 1 antagonist, on mediators of airway inflammation.. The aim of this study was to determine the effect of a 3-day course of high-dose MK on mediators of airway inflammation induced by a single allergen challenge in sensitized mice.. Ovalbumin (OVA)-sensitized BALB/c mice were treated with 25 mg/kg of MK or saline intravenously for 3 days. On the third day, a single inhalation challenge with OVA was given. Cellular infiltration was assessed in the bronchoalveolar lavage (BAL) and in the lung. Expression of IL-4, IL-5, IL-13 and eotaxin in the BAL, and the lung was determined. Serum IL-5 and total IgE was measured. IL-5 and eotaxin mRNA expression in the lung was determined. Finally, eotaxin and VACM-1 expression in the lung was assessed by immunohistochemistry.. MK reduced the number of eosinophils in the BAL by > 90%. There was also significant reduction in IL-5 in the BAL, lung and the serum, and IL-5 mRNA expression in the lung. IL-4 level in the lung and BAL, and IL-13 level in the lung also significantly decreased. Serum IgE level and lung VCAM-1 expression was also significantly lower in treated animals, but eotaxin protein and mRNA expression in the lung remained unchanged.. MK exerts its anti-inflammatory effect through the suppression of T helper type-2 (Th2) cytokines. The use of high-dose MK as an anti-inflammatory agent in acute asthma should be further explored.

    Topics: Acetates; Administration, Inhalation; Animals; Asthma; Bronchoalveolar Lavage Fluid; Chemokines, CC; Cyclopropanes; Eosinophils; Humans; Immunoglobulin E; Interleukins; Leukocyte Count; Leukotriene Antagonists; Mice; Mice, Inbred BALB C; Models, Animal; Ovalbumin; Quinolines; RNA, Messenger; Sulfides; Th2 Cells; Vascular Cell Adhesion Molecule-1

2003
[Effect of montelukast on the apoptosis of lymphocytes in asthmatic rats and its molecular mechanism].
    Sichuan da xue xue bao. Yi xue ban = Journal of Sichuan University. Medical science edition, 2003, Volume: 34, Issue:1

    To investigate the effect of montelukast(MK) on the apoptosis of lymphocytes and the associated molecular mechanism in asthmatic rats in vivo and in vitro.. The asthmatic model was established by sensitizing and challenging SD rat with ovalbumin (OVA). Forty male SD rats were randomly divided into control group, asthma group, MK-treated group and Dexamethason (DXM)-treated group. T lymphocytes were labeled with CD(4)+ and CD(8)+ antibodies and then labeled with TdT-mediated dUTP nick end labeling (TUNEL) to detect apoptotic cells, and immunohistochemical staining of Fas antigen (CD95) was performed to detect Fas positive cells. The influences of MK on apoptosis and Fas antigen spontaneous expression on CD(4)+ / CD(8)+ lymphocytes in vivo and in vitro were assayed.. The apoptosis rates of T lymphocytes from peripheral blood and lung tissue of asthmatic rats pre-treated by MK were significantly elevated as compared with those in normal control and asthma groups. In vitro culture MK was found to induce in dose- and time-dependent manner the apoptosis of peripheral blood lymphocytes pre-treated with OVA. A synergic effect of MK and DXM was demonstrated, i.e. MK in 10(-6) mol/L concentration markedly promoted the induction of apoptosis and expression of Fas antigen by 10(-6) mol/L DXM.. MK could induce apoptosis of peripheral blood and lung lymphocytes (mainly CD(4)+) in asthmatic rats, which may be mediated by Fas system. The induction of apoptosis of lymphocytes by MK may contribute to anti-inflammation mechanisms. Furthermore, a synergic effect of MK and DXM on the induction of apoptosis of lymphocytes might exist.

    Topics: Acetates; Animals; Anti-Asthmatic Agents; Apoptosis; Asthma; CD4-Positive T-Lymphocytes; Cells, Cultured; Cyclopropanes; Male; Ovalbumin; Quinolines; Random Allocation; Rats; Rats, Sprague-Dawley; Sulfides

2003
A role for cysteinyl leukotrienes in airway remodeling in a mouse asthma model.
    American journal of respiratory and critical care medicine, 2002, Jan-01, Volume: 165, Issue:1

    Airway inflammation and remodeling in chronic asthma are characterized by airway eosinophilia, hyperplasia of goblet cells and smooth muscle, and subepithelial fibrosis. We examined the role of leukotrienes in a mouse model of allergen-induced chronic lung inflammation and fibrosis. BALB/c mice, after intraperitoneal ovalbumin (OVA) sensitization on Days 0 and 14, received intranasal OVA periodically Days 14-75. The OVA-treated mice developed an extensive eosinophil and mononuclear cell inflammatory response, goblet cell hyperplasia, and mucus occlusion of the airways. A striking feature of this inflammatory response was the widespread deposition of collagen beneath the airway epithelial cell layer and also in the lung interstitium in the sites of leukocytic infiltration that was not observed in the saline-treated controls. The cysteinyl leukotriene(1) (CysLT(1)) receptor antagonist montelukast significantly reduced the airway eosinophil infiltration, mucus plugging, smooth muscle hyperplasia, and subepithelial fibrosis in the OVA-sensitized/challenged mice. The presence of Charcot-Leyden-like crystals in airway macrophages and the increased interleukin (IL)-4 and IL-13 mRNA expression in lung tissue and protein in BAL fluid seen in OVA-treated mice were also inhibited by CysLT(1) receptor blockade. These data suggest an important role for cysteinyl leukotrienes in the pathogenesis of chronic allergic airway inflammation with fibrosis.

    Topics: Acetates; Acute Disease; Allergens; Analysis of Variance; Animals; Asthma; Bronchoalveolar Lavage Fluid; Chronic Disease; Cyclopropanes; Disease Models, Animal; Drug Evaluation, Preclinical; Eosinophils; Fibrosis; Glycoproteins; Goblet Cells; Hyperplasia; Inflammation; Leukotriene Antagonists; Leukotrienes; Lysophospholipase; Macrophages, Alveolar; Mice; Ovalbumin; Quinolines; Respiratory Mechanics; Sulfides

2002
Mediator involvement in antigen-induced bronchospasm and microvascular leakage in the airways of ovalbumin sensitized Brown Norway rats.
    British journal of pharmacology, 2001, Volume: 132, Issue:2

    1. To determine which mediators are involved in antigen-induced bronchospasm and microvascular leakage in the airways of ovalbumin sensitised Brown Norway rats we investigated the effect of a histamine H(1) receptor antagonist, mepyramine, a 5-HT receptor antagonist, methysergide, and a cys-leukotriene-1 receptor antagonist, montelukast. 2. Ovalbumin at 1 mg kg(-1) i.v. caused a significant increase in microvascular leakage in the airways and at 3 mg kg(-1) i.v. caused a significant increase in airways resistance. 3. Histamine (1 mg kg(-1) i.v.), 5-HT (0.1 mg kg(-1) i.v.) and leukotriene D(4) (LTD(4), 50 microg kg(-1) i.v.) caused a significant increase in microvascular leakage in the airways. 4. Mepyramine (1 mg kg(-1) i.v.), methysergide (0.1 mg kg(-1) i.v.), or montelukast (30 mg kg(-1) i.v.) inhibited histamine, 5-HT or LTD(4) -induced microvascular leakage respectively. 5. Methysergide (0.1 mg kg(-1) i.v.) reduced ovalbumin-induced microvascular leakage in the trachea and at 0.3 mg kg(-1) i.v. inhibited bronchospasm (38 and 58%, respectively). Montelukast (30 mg kg(-1) p.o.) reduced ovalbumin-induced microvascular leakage in airway tissue to basal levels (78%) and inhibited ovalbumin-induced bronchospasm (50%). Mepyramine (3 mg kg(-1) i.v.) had no effect on ovalbumin-induced leakage or bronchospasm. 6. A combination of all three compounds (mepyramine, methysergide and montelukast) reduced ovalbumin-induced microvascular leakage in airway tissue to basal levels (70 - 78%) and almost completely inhibited bronchospasm (92%). 7. Antigen-induced bronchospasm appears to equally involve the activation of 5-HT and cys-leukotriene-1 receptors whereas ovalbumin-induced microvascular leakage appears to be predominantly mediated by cys-leukotriene-1 receptors.

    Topics: Acetates; Animals; Anti-Asthmatic Agents; Bronchi; Bronchial Spasm; Capillary Permeability; Cyclopropanes; Histamine; Histamine H1 Antagonists; Leukotriene D4; Male; Methysergide; Ovalbumin; Pyrilamine; Quinolines; Rats; Rats, Inbred BN; Respiratory Hypersensitivity; Serotonin; Serotonin Antagonists; Sulfides; Trachea

2001
Montelukast, a leukotriene receptor antagonist, inhibits the late airway response to antigen, airway eosinophilia, and IL-5-expressing cells in Brown Norway rats.
    The Journal of allergy and clinical immunology, 1999, Volume: 104, Issue:6

    Asthma is characterized by airflow obstruction, inflammatory cell infiltration, and the synthesis of mediators, such as T(H2) cytokines and leukotrienes, in the airways. Cysteinyl leukotriene (cysLT) receptor antagonists have recently been associated with clinical improvement of asthma and reduced airway inflammation. Whether the beneficial effects of cysLT antagonists are mediated through the modulation of cytokine expression has not been determined.. The aim of the study was to determine the presence of eosinophils and IL-5 messenger (m)RNA(+) cells within the lungs of antigen-challenged Brown Norway rats after treatment with the cysLT(1) receptor antagonist montelukast (MK).. Ovalbumin-sensitized Brown Norway rats were treated with either MK or saline before ovalbumin challenge. Pulmonary mechanics were monitored for 8 hours. Subsequently, immunocytochemistry and in situ hybridization were used to examine bronchoalveolar lavage (BAL) fluid and lung tissue for cells expressing major basic protein (eosinophils) and IL-5 mRNA, respectively. Simultaneous in situ hybridization and immunocytochemistry was used to phenotype the cells expressing mRNA encoding IL-5.. Animals treated with MK had significantly lower lung resistance and fewer eosinophils and IL-5 mRNA(+) cells within BAL fluid and lung tissue compared with that found in saline-treated animals. Colocalizaton studies revealed that the majority of IL-5 mRNA(+) cells were T cells and that the number of IL-5 mRNA(+)/CD3(+) or IL-5 mRNA(+)/major basic protein(+) cells were significantly less within BAL from animals treated with MK than from those treated with saline.. These results indicate that the cysLT(1) receptor antagonist MK can diminish the pulmonary response to antigen, tissue eosinophilia, and the number of cells expressing IL-5 mRNA, suggesting that leukotrienes may also regulate the allergic response through the modulation of inflammation and cytokine synthesis.

    Topics: Acetates; Airway Resistance; Animals; Antigens; Area Under Curve; Bronchoalveolar Lavage Fluid; Cyclopropanes; Eosinophils; Gene Expression; Immunohistochemistry; Immunophenotyping; In Situ Hybridization; Interleukin-5; Leukotriene Antagonists; Lung; Myelin Basic Protein; Ovalbumin; Quinolines; Rats; Rats, Inbred BN; RNA, Messenger; Sulfides

1999
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