Inhibition of airway inflammation and hyperresponsiveness by budesonide via upregulation of indoleamine 2,3 dioxygenase in a murine model of acute asthma
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Objective To investigate the inhibitory effects of aerosol budesonide on the expression of indoleamine 2,3 dioxygenase (IDO),airway inflammation,and airway hyperresponsiveness in a murine model of bronchial asthma (asthma).Methods 18 BALB/c mice were randomly divided into 3 groups,including the control group,ovalbumin (OVA) group and budesonide group.Mice were sensitized and challenged by OVA.24 h after the last challenge,airway responsiveness to acetylcholine chloride (Ach) was measured.Hematoxylin & eosin staining was used to assess the inflammatory cell infiltrates.Levels of Th2 cytokines (IL-4 and IL-13) in bronchoalveolar lavage fluid (BALF),and total IgE and OVA-specific IgE (OVA-sIgE) in serum were relevantly detected by ELISA.The protein expression of IDO was determined by western blot analysis.Results The airway resistance in the OVA group was obviously increased in a dose-dependent manner following administration of Ach,whereas only a slight increase could be detected in the control group.Treatment with budesonide led to a sharp decrease in airway resistance compared with the OVA group (P ＜0.05).Total IgE and OVA-sIgE in serum,total inflammatory cells and differential eosinophils as well as Th2 cytokines in BALF were significantly increased in the OVA group.These inflammatory indices were remarkably decreased by treatment with budesonide (P ＜0.05).The pulmonary expression of IDO was apparently declined in the OVA group.Treatment with budesonide enhanced the pulmonary expression of IDO in comparison with the OVA group (P ＜ 0.05).Conclusions Budesonide could inhibit the airway inflammation and hyperresponsiveness by upregulating the expression of IDO in allergic asthma.
Key words:
Bronchial asthma; Indoleamine 2,3 dioxygenase; Budesonide; Dendritic cell; Regulatory T cellIn this study, we investigated whether 4‐hydroxycinnamic acid (HA) has a palliative effect on asthmatic inflammatory responses using a mouse model of ovalbumin (OVA)‐induced allergic asthma. The mice were divided into five groups, each consisting of seven females (normal control phosphate‐buffered saline); OVA (OVA sensitization/challenge); dexamethasone (DEX, OVA sensitization/challenge + dexamethasone 3 mg/kg); HA‐10 and HA‐20 OVA sensitization/challenge + HA 10 and 20 mg/kg, respectively). Mice treated with HA showed a reduction in airway hyperresponsiveness and in the number of inflammatory cells in bronchoalveolar lavage fluid (BALF) compared with asthmatic control. HA treatment also reduced the levels of interleukin (IL)‐5 and IL‐13 in BALF and of OVA‐specific immunoglobulin E in the serum compared with asthmatic control. HA treatment relieved airway inflammation and mucus overproduction caused by OVA exposure. Additionally, HA inhibited the increases in levels of nuclear factor kappa B, inducible nitric oxide synthase, and cyclooxygenase‐2 that normally occur after OVA exposure. HA treatment also reduced the activity and protein level of matrix metalloproteinase‐9. Taken together, HA effectively suppressed asthmatic airway inflammation and mucus production caused by OVA exposure. These findings indicate that HA has the potential to be used as a therapeutic agent for asthma.
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Allergic asthma is a chronic inflammatory airway disease that is characterized by airway hyperresponsiveness (AHR), accumulation of eosinophils and goblet cell hyperplasia. The efficacy of attenuated E. coli (AEC) strain has been reported in various disease. To evaluate the effect of AEC in mice model of Ovalbumin (OVA)-induced AHR. Materials and method: AHR was induced in Female BALB/c mice (18-20 g) by intraperitoneal injection of OVA (50 μL, emulsified in 0.8 mg aluminium hydroxide) on day 7, 8, 9 and 20 followed by intranasal challenges of OVA on days 20, 23, 27, 30 and 34. OVA control mice will receive an equal volume of saline. Mice were treated with either AEC (108 CFU/ml) or montelukast (10 mg/kg) or vehicle on day 0, 7, 20 and 27 immediately before administration of OVA. AHR to methacholine were assessed on day 35, 24 h after the last pulmonary challenge. Treatment with AEC caused significant restoration in OVA-induced alteration in the cellular count of bronchoalveolar lavage fluid, hematological count, and pulmonary function test. Elevated levels of OVA-induced oxido-nitrosative stress was significantly decreased by AEC treatment. Total IgE, OVA-specific IgE and IgG1 in serum as well as lung TNF-α, IL-4, IL-5, IL-8 and IL-10 levels was significantly reduced by AEC. Histological aberration induced by OVA was reduced by AEC treatment. AEC inhibits OVA-induced AHR in mice via down-regulation of nitroso-oxidative stress, cytokine, and chemokine, as well as IgE and IgG, releases supporting its anti-inflammatory and bronchodilator role during the allergic response.
Methacholine
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Allergic Inflammation
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Aerobic training (AT) decreases airway allergic inflammation in sensitized mice; however the anti-inflammatory mechanisms are poorly known. Aim: Evaluate the mechanisms involved during an AT in asthma animal model.Method: 160 Balb/c mice were divided in 4 groups (n=24 each): Control (CT), AT, Ovalbumin (OVA), OVA+AT. OVA groups were sensitized with i.p. OVA+Al(OH)-3 and OVA-inhalations that continued during AT. AT begun after chronic airway inflammation, and it was performed at 50% maximal exercise capacity (60 min/session; 5xweek) and it was performed for 1, 3, 7, 15 or 30 days. After those periods, mice were euthanized and then analyzed the eosinophil counting (BALF), expression of IL-4, IL-5, NF-kB, IL-10, IL-1ra, Eotaxin, RANTES and ICAM-1 by immunohistochemistry in tissue lung slices. Results: OVA-induced an increase in eosinophil migration and the expression of Th2 cytokines, NF-kB, Eotaxin, RANTES and ICAM-1 over time (*p
Allergic Inflammation
Allergic response
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Background. CrataBL is a protein isolated from Crataeva tapia bark. It has been shown to exhibit several biological properties, including anti-inflammatory, analgesic, antitumor, and insecticidal activities. There are no studies evaluating the role of CrataBL in experimental asthma models. Aim. To evaluate the effects of CrataBL on lung mechanics, inflammation, remodeling, and oxidative stress activation of mice with allergic pulmonary inflammation. Materials and Methods. BALB/c mice (6-7 weeks old, 25-30g) were divided into four groups: nonsensitized and nontreated mice (C group, n=8); ovalbumin- (OVA-) sensitized and nontreated mice (OVA group, n=8); nonsensitized and CrataBL-treated mice (C+CR group, n=8); OVA-sensitized and CrataBL-treated mice (OVA+CR group, n=8). We evaluated hyperresponsiveness to methacholine, bronchoalveolar lavage fluid (BALF), pulmonary inflammation, extracellular matrix remodeling, and oxidative stress markers. Results. CrataBL treatment in OVA-sensitized mice (OVA+CR group) attenuated the following variables compared to OVA-sensitized mice without treatment (OVA group) (all p<0.05): (1) respiratory system resistance (Rrs) and elastance (Ers) after methacholine challenge; (2) total cells, macrophages, polymorphonuclear cells, and lymphocytes in BALF; (3) eosinophils and volume fraction of collagen and elastic fibers in the airway and alveolar wall according to histopathological and morphometry analysis; (4) IL-4-, IL-5-, IL-13-, IL-17-, IFN-γ-, MMP-9-, TIMP-1-, TGF-β-, iNOS-, and NF-kB-positive cells and volume of 8-iso-PGF2α in airway and alveolar septa according to immunohistochemistry; and (5) IL-4, IL-5, and IFN-γ according to an ELISA. Conclusion. CrataBL contributes to the control of hyperresponsiveness, pulmonary inflammation, extracellular matrix remodeling, and oxidative stress responses in an animal model of chronic allergic pulmonary inflammation.
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Objective:To investigate the inhibitory effects and mechanism of budesonide on Th2-dominated immune response in a murine model of asthma.Methods:Twenty-four 6-week-old healthy BALB/c mice,SPF grade,were randomly divided into 3 groups,including the normal control group,the asthma group,and the budesonide group.Mice in the budesonide group were exposed to an aerosol of budesonide daily during ovalbumin(OVA) challenge.The murine asthma model was established by OVA sensitization and challenge.Twenty-four hours after the last airway provocation,acetylcholine(Ach) was administered via caudalis vein,and the airway resistance was measured by pulmonary function detector.The levels of IL-4 and IL-13 in branchoalveolar lavage fluid(BALF) and total IgE in serum were determined by enzyme-linked immunosorbent assay(ELISA).Total and differential cell counts in BALF were calculated by light microscopy.The airway inflammatory infiltration was detected by haematoxylin and eosin(HE) staining.The pulmonary thymic stromal lymphopoietin was determined by Western blot analysis.Results:As compared with the control group,the airway hyperreactivity,airway inflammation,cell count and eosinophil percentage in BALF,levels of total serum IgE and BALF IL-4 and IL-13,and thymic stromal lymphopoietin(TSLP) expression in the lung were significantly increased in the asthma group(P 0.05).As compared with the asthma group,all the above indices mentioned in the budesonide group were decreased significantly(P 0.05).Conclusion:Budesonide could reduce the allergen-induced airway inflammation and hyperreactivity by downregulating the expressions of pulmonary TSLP and Th2 cytokines,which may be an important mechanism of corticosteroids for the treatment of asthma.
Thymic stromal lymphopoietin
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Cellular infiltration
Intraperitoneal injection
Methacholine
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Interleukin (IL)-23/Th17 axis plays an important role in the pathophysiology of asthma and eczema, however, there are some conflicting data about the effects of this system on allergic airway inflammation. In the present study, we aim to dissect the spatiotemporal differences in the roles of IL-23 in an epicutaneously-sensitized asthma model of mice. C57BL/6 mice were sensitized to ovalbumin (OVA) by patch application on the skin, followed by airway exposure to aerosolized OVA. During sensitization and/or challenge phase, either a specific neutralizing antibody (Ab) against IL-23 or control IgG was injected intraperitoneally. On days 1 and 8 after the final OVA exposure, airway inflammation and responsiveness to methacholine, immunoglobulin levels in serum, and cytokine release from splenocytes were evaluated. Skin Il23a mRNA levels were evaluated with quantitative RT-PCR. Patch application time-dependently increased the expression of Il23a mRNA expression in the skin. Treatment with the anti-IL-23 Ab during sensitization phase alone significantly reduced the number of eosinophils in bronchoalveolar lavage fluids and peribronchial spaces after allergen challenge compared with treatment with control IgG. Anti-IL-23 Ab also reduced serum levels of OVA-specific IgG1. In contrast, treatment with the anti-IL-23 Ab during the challenge phase alone rather exacerbated airway hyperresponsiveness to methacholine with little effects on airway eosinophilia or serum IgG1 levels. IL-23 expressed in the skin during the sensitization phase plays an essential role in the development of allergic phenotypes, whereas IL-23 in the airways during the challenge phase suppresses airway hy- perresponsiveness.
Methacholine
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Objective
To investigate the effect of tetrandrine(Tet) on the expression of nuclear factor-κB(NF-κB),inducible nitric oxide synthase(iNOS),airway inflammation and hyperresponsiveness in a murine model of bronchial asthma(asthma).
Methods
Thirty-two SPF BALB/c mice were randomly divided into 4 groups,including control group,asthma group,dexamethasone group(glucocorticoid group) and atetrandrine group(Tet group).Mice were sensitized and challenged by ovalbumin(OVA).Twentyfour hours after the last challenge,airway resistance was measured by pulmonary function detector. Hematoxylin& eosin(HE)staining was used to observe the airway inflammatory cells infiltration.Levels of total Ig E and OVA-specific IgE(OVA-sIgE) in serum and Th2 cytokines(IL-4 and IL-13) in bronchoalveolar lavage fluid(BALF) were detected by enzyme-linked immunosorbent assay(ELISA). Total number of inflammatory cells in BALF were counted with a microscope.Smears of BALF cells were stained with Wright's staining for eosinophils differential count.The protein expression of NF-κB and iNOS were determined by western blot analysis.
Results
Compared to the control group,the airway resistance,airway eosinophilia,total inflammatory cells and differential eosinophils count in BALF,total IgE and OVA-sIgE in serum,Th2 cytokines(IL-4 and IL-13)in BALF,as well as the protein expression of NF-κB and iNOS were significantly increased in asthma group(P< 0.05).In comparison with the asthma group,all the above indicators were remarkably decreased by treatment with either dexamethasone or tetrandrine(P< 0.05).
Conclusions
Tetrandrine may inhibit airway inflammation and hyperresponsiveness through downregulation of the expression of NF-κB and iNOS in asthmatic mice.
Key words:
Asthma; Tetrandrine; Nuclear factor-κB; Inducible nitric oxide synthase
Tetrandrine
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Aerobic training (AT) reduces the use of corticosteroids by asthmatics; however the anti-inflammatory effects are poorly known. Aim: Investigate the effect of AT in the expression of glucocorticoid receptor (GR) in an asthma animal model. Method: 96 Balb/c mice were divided in 4 groups (n=24 each): Control (CT), AT, Ovalbumin(OVA), OVA+AT. OVA groups received i.p. OVA+Al(OH)-3 and OVA-inhalations that continued during AT. AT (50% max. exercise capacity; 60 min.; 5 x week) begun after chronic airway inflammation and it was performed for 1, 3 or 7 days. After euthanasia, it was analyzed the expression of GR in the airway smooth muscle (ASM); eosinophil counting (BALF); and expression of IL-4, IL-5, NF-kB, eotaxin and RANTES by immunohistochemistry in tissue lung slices. Airway remodeling was quantified by ASM and epithelium thickness and collagen fiber content by image analysis. Results: OVA reduced the expression of GR and increased the eosinophil migration, expression of Th2 cytokines, and airway remodeling (p
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