Inhibition Of Airway Hyperresponsiveness Research Articles

Anti-inflammatory and anti-asthmatic effects of Viola mandshurica W. Becker (VM) ethanolic (EtOH) extract on airway inflammation in a mouse model of allergic asthma

Aim of the study We investigated the efficacy of Viola mandshurica W. Becker (VM) ethanolic (EtOH) extract in the treatment of bronchial asthma in an ovalbumin (OVA)-induced asthmatic BALB/c mouse model. Materials and methods Female BALB/c mice were sensitized with intraperitoneal (i.p.) ovalbumin (OVA) on days 0 and 14, and were next given intranasal OVA on days 28–30. Randomized treatment groups of sensitized mice received VM EtOH extract, dexamethasone, or placebo, orally, from days 28 to 30. Results VM EtOH extract significantly inhibited increases in total immunoglobulin E (IgE) and cytokines IL-4 and IL-13 levels in serum and bronchoalveolar lavage fluid (BALF), and also effectively suppressed airway hyperresponsiveness (AHR), eosinophilia, and mucus hypersecretion, in mice with OVA-induced asthma. Conclusions The results suggest that VM EtOH extract and allied extracts could be useful herbal medicines for asthma treatment, and that VM may also be a valuable lead material for anti-asthma drug development.

Anti-inflammatory and anti-asthmatic effects of tiarellic acid in a mouse model of allergic asthma

Asthma is an inflammatory disease of the airways, and the current focus in managing asthma is the control of inflammation. We investigated anti-inflammatory and anti-asthmatic effects of tiarellic acid isolated from Tiarella polyphylla [1] on asthmatic parameters–such as immunoglobulin E (IgE) level, cytokine release, eosinophilia, airway hyperresponsiveness (AHR) and mucus hypersecretion–in an ovalbumin (OVA)-sensitized/challenged mouse model. Tiarellic acid significantly inhibited increases in total immunoglobulin E (IgE), T-helper-2-type cytokines such as interleukin (IL)-4 and IL-13 in bronchoalveolar lavage fluid (BALF), and also effectively suppressed airway hyperresponsiveness, eosinophilia, and mucus hypersecretion, in the asthmatic mouse model. The efficacy of tiarellic acid was comparable to montelukast, an anti-asthmatic drug that is currently available. These results suggest that tiarellic acid could be a major marker in herbal medicines that are used for asthma treatment, and could also act as a lead for the development of anti-inflammatory and anti-asthmatic drugs. Reference: [1] Park, S.H. et al. (2002) Arch. Pharm. Res. 25:57–60.

Clarithromycin suppresses airway hyperresponsiveness and inflammation in mouse models of asthma

Macrolide antibiotics, a class of potent antimicrobials, also possess immunomodulatory/anti-inflammatory properties. These properties are considered fundamental for the efficacy of macrolide antibiotics in the treatment of diffuse panbronchiolitis and cystic fibrosis. In patients with asthma, macrolide antibiotics have been reported to reduce airway hyperresponsiveness and improve pulmonary function. However, their beneficial actions in asthmatics possibly could be attributed to antimicrobial activity against atypical pathogens (e.g. Chlamydia pneumoniae), corticosteroid-sparing effect (inhibition of exogenous corticosteroid metabolism), and/or their anti-inflammatory/immunomodulatory effects. In order to investigate whether efficacy of macrolide antibiotics in asthma results from their immunomodulatory/anti-inflammatory activity, the influence of clarithromycin pretreatment (2 h before challenge) was examined on ovalbumin-induced airway hyperresponsiveness and airway inflammation in the mouse. Clarithromycin treatment (200 mg/kg intraperitoneally) decreased IL-4, IL-5, IL-13, CXCL2 and CCL2 concentrations in bronchoalveolar lavage fluid and markedly reduced inflammatory cell accumulation in bronchoalveolar lavage fluid and into the lungs, as revealed by histopathological examination. Furthermore, clarithromycin-induced reduction in inflammation was accompanied by normalization of airway hyperresponsiveness. In summary, in ovalbumin-induced mouse models, clarithromycin efficiently inhibited two important pathological characteristics of asthma, airway hyperresponsiveness and inflammation. These data suggest that the efficacy of clarithromycin, as well as of other macrolide antibiotics, in asthmatic patients could be attributed to their anti-inflammatory/immunomodulatory properties, and not only to their antimicrobial activity or exogenous corticosteroid-sparing effects.

Vaccine-Induced CD8+ T Cell-Dependent Suppression of Airway Hyperresponsiveness and Inflammation

Suppressing the abnormalities associated with asthma has been difficult to accomplish using immunotherapy or vaccination once the disease is established. The effector cells necessary for effective immunization/vaccination and immunotherapy of asthma are also not well understood. Therefore, we vaccinated allergen (OVA)-sensitized mice to determine whether therapeutic immunization could suppress airway hyperresponsiveness (AHR) and inflammation and to identify key immune effector cells and cytokines. Mice were immunized with a vaccine comprised of Ag and cationic liposome-DNA complexes (CLDC), a vaccine which has previously been shown to elicit strong CD4(+) and CD8(+) T cell responses and activation of Th1 immunity. We showed that immunization with the OVA-CLDC vaccine significantly suppressed AHR, eosinophilia, goblet cell metaplasia, and Th2 cytokine production. In contrast, immunization with CLDC alone suppressed eosinophilia and Th2 cytokine production, but failed to suppress AHR and goblet cell changes. Using adoptive transfer experiments, we found that suppression of AHR was mediated by Ag-specific CD8(+) T cells and was dependent on IFN-gamma production by the transferred T cells. Thus, we conclude that generation of strong, allergen-specific CD8(+) T cell responses by immunization may be capable of suppressing AHR and allergic airway inflammation, even in previously sensitized and challenged mice.

Non-depleting anti-CD4 antibody alleviates ovalbumin-induced airway inflammation and T-helper type 2 responses in mice (140.13)

Abstract Bronchial asthma is an emerged chronic inflammatory disorder of the airways. It is becoming urgent to identify target molecules for the preventive and therapeutic purposes. Non-depleting anti-CD4 monoclonal antibody, YTS177, has been used to induce immunotolerance in allograft transplantation through antigen-specific Treg cells. This study aims for determining whether YTS177 is able to inhibit the ovalbumin (OVA)-induced allergic inflammation in an asthmatic murine model. The injection of YTS177 before and after OVA-sensitization was able to suppress airway hyperresponsiveness, pulmonary eosinophilia, OVA-specific immunoglobulin (Ig) E synthesis, and the production of T helper (Th) 2 cytokines from OVA-activated splenocytes. Furthermore, YTS177 had the therapeutic capacity to relieve the attack of asthmatic symptoms when it was administrated after the mice were sensitized and challenged with OVA. However, the depletion of CD25+ cells did not reverse YTS177-induced hyporesponsive status. The state might be resulted from the angery of CD4+ T cells with the increased level of anergy factor-Cbl-b in activated CD4+ cells cultured with YTS177. Moreover, the high level of cell cycle inhibitor p27Kip1 and increased number of G1 phase arrested-T cells were detected. Therefore, p27Kip1 might be involved in the preventive and therapeutic efficacy of YTS177 for allergic diseases.

Anti-inflammatory and anti-asthmatic effects of resveratrol, a polyphenolic stilbene, in a mouse model of allergic asthma

Asthma is an inflammatory disease of the airways, and the current focus in managing asthma is the control of inflammation. Resveratrol (3,4,5-trihydroxystilbene) is a polyphenolic stilbene found in the skins of red fruits, including grapes, that may be responsible for some of the health benefits ascribed to consumption of red wine. We investigated the suppressive effects of resveratrol on asthmatic parameters such as cytokine release, eosinophilia, airway hyperresponsiveness, and mucus hypersecretion, in an OVA-induced allergic mouse model of asthma. Resveratrol significantly inhibited increases in T-helper-2-type cytokines such as IL-4 and IL-5 in plasma and bronchoalveolar lavage fluid (BALF), and also effectively suppressed airway hyperresponsiveness, eosinophilia, and mucus hypersecretion, in the asthmatic mouse model. The efficacy of resveratrol was similar to that of dexamethasone, a glucocorticoid used as a positive control. These results suggest that resveratrol may have applications in the treatment of bronchial asthma.

IL‐12p40 is essential for the down‐regulation of airway hyperresponsiveness in a mouse model of bronchial asthma with prolonged antigen exposure

We previously reported a mouse model of bronchial asthma showing eosinophilic inflammation, but not airway hyperresponsiveness (AHR), after prolonged antigen exposure. This model showed an increase of IL-12 in the lung. The aim of this study was to investigate the role of IL-12p40 in a murine asthma model with prolonged antigen exposures. An ovalbumin (OVA)-induced asthma model was first established in wild-type (WT) and IL-12p40-deficient (IL-12p40(-/-)) mice. Both strains of mice were further exposed to either OVA (prolonged exposure group) or phosphate-buffered saline (positive control group) 3 days per week for 3 weeks. During week 4, both groups of mice were given a final challenge with OVA. Prolonged antigen exposures resulted in marked suppression of airway eosinophilia in both WT and IL-12p40(-/-) mice. However, AHR persisted in IL-12p40(-/-) but not in WT mice. There were no significant differences of IL-5, IL-13 or IFN-gamma levels in bronchoalveolar lavage fluid between WT and IL-12p40(-/-) mice. The hydroxyproline content of the lung and peribronchial fibrosis were, however, significantly increased in IL-12p40(-/-) mice. The results suggest that endogenous IL-12p40 is essential for inhibition of AHR and peribronchial fibrosis, but not eosinophilic inflammation, in a murine asthma model with prolonged antigen exposures.

Effects of Pranlukast Hydrate on Airway Hyperresponsiveness in Non-Asthmatic Patients with Japanese Cedar Pollinosis

Recent studies have suggested that allergic rhinitis is closely related to bronchial asthma, reflecting the "one airway-one disease" hypothesis. It is unclear if the effects of pranlukast, a leukotriene-receptor antagonist, are consistent with this hypothesis. The goal of the study was to determine if pranlukast has effects on the upper and lower airways through a comparison of the effects of fexofenadine and pranlukast on airway hyperresponsiveness in non-asthmatic patients with cedar pollinosis before the Japanese cedar pollen season and during the peak pollen season. Patients received fexofenadine hydrochloride plus oral mequitazine (fexofenadine group) or pranlukast hydrate plus oral mequitazine (pranlukast group) as an initial treatment. Subsequent changes in airway responsiveness to acetylcholine were measured. Among patients in whom coughing developed during the peak pollen season, airway responsiveness significantly increased in the fexofenadine group. In the pranlukast group, airway responsiveness did not increase significantly, regardless of the presence or absence of coughing. The results indicate that pranlukast hydrate inhibits airway hyperresponsiveness in non-asthmatic patients with Japanese cedar pollinosis. In turn, this suggests that cysteinyl leukotrienes have a role in increased airway responsiveness.

Estrogen Replacement Therapy Prevents Airway Dysfunction in a Murine Model of Allergen-Induced Asthma

We previously reported that 17beta-estradiol (E2) prevents hyperresponsiveness to carbachol of murine asthmatic tracheal rings in vitro. We now investigated whether E2 is similarly effective in reducing airway hyperreactivity in a murine model of allergic asthma in vivo. Female ovariectomized BALB/c mice were rendered asthmatic by a 25-day protocol of sensitization to ovalbumin. Under positive-pressure ventilation, anesthetized asthmatic mice exhibited a dramatic increase in airway responsiveness to increasing doses of inhaled methacholine compared to PBS-sensitized controls, as reflected in decreased dynamic compliance of the respiratory system and increased tissue damping, tissue elastance, and airway resistance. Furthermore, asthmatic mice exhibited hypercellularity and increased protein concentration in the bronchoalveolar lavage, strong signs of peribronchial cuffing with inflammatory cells and increased goblet cell activity. To test the effects of estrogen, three additional groups of mice were implanted subcutaneously with different amounts of slow-release E2 pellets at the time of ovariectomy and rendered asthmatic as before. E2 dose-dependently inhibited airway hyperresponsiveness to methacholine, reduced bronchoalveolar lavage hypercellularity, and virtually eliminated histologic signs of inflammation and goblet cell hyperactivity. The inflammation and airway hyperactivity in asthmatic mice was associated with an increase in bronchoalveolar lavage levels of TGFbeta1, which was completely abolished in E2-treated asthmatic mice. We conclude that estrogen replacement therapy effectively ameliorates the pathologic profile of murine allergic asthma.

Attenuation of allergen-induced airway hyperresponsiveness is mediated by airway regulatory T cells

Understanding the mechanisms involved in respiratory tolerance to inhaled allergens could potentially result in improved therapies for asthma and allergic diseases. Airway hyperresponsiveness (AHR) is a major feature of allergic asthma, thus the aim of the current study was to investigate mechanisms underlying suppression of allergen-induced AHR during chronic allergen exposure. Adult BALB/c mice were systemically sensitized with ovalbumin (OVA) in adjuvant and then challenged with a single 3 or 6 wk of OVA aerosols. Airway and parenchymal responses to inhaled methacholine (MCh), inflammatory cell counts, cytokines, OVA-specific IgE and IgG(1), parenchymal histology, and numbers of airway CD4(+)69(+) activated and CD4(+)25(+)FoxP3(+) regulatory T (Treg) cells were assessed 24 h after the final aerosol. Single OVA challenge resulted in AHR, eosinophilia, increased serum OVA-specific IgE, and T helper 2 (Th2) cytokines in bronchoalveolar lavage (BAL) but no difference in numbers of Treg compared with control mice. Three weeks of OVA challenges resulted in suppression of AHR and greater numbers of airway Treg cells and increased transforming growth factor-beta(1) (TGFbeta(1)) compared with control mice despite the presence of increased eosinophilia, OVA-specific IgE and IgG(1), and airway remodeling. Six weeks of OVA challenges restored AHR, whereas airway Treg numbers, TGFbeta(1), BAL eosinophilia, and Th2 cytokines returned to control levels. Partial in vivo depletion or adoptive transfer of Treg cells restored or inhibited AHR, respectively, but did not affect TGFbeta(1) or Th2 cytokine production. In conclusion, AHR suppression is mediated by airway Treg cells and potentially via a paracrine induction of TGFbeta(1) in the airways.

Novel triple neurokinin receptor antagonist CS-003 inhibits respiratory disease models in guinea pigs

Neurokinins are known to induce neurogenic inflammation related to respiratory diseases. The effects of CS-003 ([1-{2-[( 2R)-(3,4-dichlorophenyl)-4-(3,4,5-trimethoxybenzoyl)morpholin-2-yl]ethyl}spiro[benzo[ c]thiophene-1( 3H),4'-piperidine]-( 2S)-oxide hydrochloride]), a novel triple neurokinin receptor antagonist, on several respiratory disease models were evaluated in guinea pigs. As we have already shown that CS-003 is intravenously effective, we first determined if CS-003 was orally effective. CS-003 dose-dependently inhibited substance P-induced tracheal vascular hyperpermeability, neurokinin A- and neurokinin B-induced bronchoconstriction with ID 50 values of 3.6, 1.3 and 0.89 mg/kg (p.o.), respectively. CS-003 (10 mg/kg, p.o.) inhibited the number of coughs induced by capsaicin aerosol ( P < 0.01) and the antitussive effect was comparable to that of codeine. CS-003 (10 mg/kg, p.o.) also inhibited airway hyperresponsiveness to methacholine chloride in ovalbumin-induced asthma models ( P < 0.01), a milder one and a severer one. On the other hand, montelukast (10 mg/kg, p.o.), a leukotriene receptor antagonist, significantly inhibited the hyperresponsiveness only in the milder model ( P < 0.05). In an ovalbumin-induced rhinitis model, oral administration of CS-003 inhibited nasal blockade in a dose-dependent manner and the inhibitory effect was comparable to that of dexamethasone (10 mg/kg, p.o.). CS-003 (i.v.) also dose-dependently inhibited cigarette smoke-induced bronchoconstriction, tracheal vascular hyperpermeability and mucus secretion. These data show that CS-003, a potent orally active triple neurokinin receptor antagonist, may be useful for the treatment of respiratory diseases associated with neurokinins, such as allergic asthma, allergic rhinitis, chronic obstructive pulmonary disease and cough.

Glucocorticoids inhibited airway hyperresponsiveness through downregulation of CPI-17 in bronchial smooth muscle

Glucocorticoids are the most effective anti-inflammatory treatment for asthma, and inhaled corticosteroids are the most effective long-term control therapy for persistent asthma. In the present study, to determine the mechanism of the inhibitory effect of glucocorticoids on airway hyperresponsiveness, the effects of glucocorticoids on the expression and activation of PKC-potentiated protein phosphatase 1 inhibitory protein of 17 kDa (CPI-17) were examined in bronchial smooth muscles of antigen-induced airway hyperresponsive rats. Repeated antigen inhalation to animals sensitized with DNP- Ascaris antigen caused a marked bronchial smooth muscle hyperresponsiveness to acetylcholine, accompanied by upregulation and acetylcholine-induced activation of CPI-17 to result in an increase in myosin light chain (MLC) phosphorylation. Treatment with glucocorticoids (prednisolone or beclomethasone, 10 mg/kg, i.p., respectively) significantly inhibited the airway hyperresponsiveness, and markedly reduced both the protein and mRNA levels of CPI-17 in bronchial smooth muscle. The acetylcholine-induced activation of CPI-17, i.e., phosphorylation of CPI-17, was also significantly inhibited by glucocorticoids. Glucocorticoids also prevented the augmented acetylcholine-induced MLC phosphorylation observed in the airway hyperresponsive rats. Therefore, glucocorticoids might inhibit the airway hyperresponsiveness through the inhibition of overexpression and activation of CPI-17.

Redox-Regulated Mechanisms in Asthma

Homeostasis of the reduction-oxidation (redox) state is critical to protection from oxidative stress in the lungs. Therefore, the lungs have high levels of antioxidants, including glutathione, heme oxygenase, and superoxide dismutase. The numbers of inflammatory cells -- particularly eosinophils -- are increased in the airways of asthma patients, and these pulmonary inflammatory cells release large amounts of harmful reactive oxygen species and reactive nitrogen species. Human thioredoxin 1 (TRX1) is a redox-active protein of approximately 12 kDa that contains a (32)Cys-Gly-Pro-(35)Cys sequence necessary for its activity. The strong reducing activity of the sequence results from the cysteine residues acting as proton donors and cleaving disulfide (S-S) bonds in the target protein. Endogenous or exogenous TRX1 or both protect the lungs against ischemia-reperfusion injury, influenza infection, bleomycin-induced injury, or lethal pulmonary inflammation caused by interleukin-2 and interleukin-18. We showed that exogenous TRX1 inhibits airway hyperresponsiveness and pulmonary inflammation accompanied by eosinophilia in mouse models of asthma. Recently, we reported that exogenous TRX1 improves established airway remodeling in a prolonged antigen-exposure mouse asthma model. Exogenous and endogenous TRX1 also prevents the development of airway remodeling. Here, we discuss the role and clinical benefits of TRX1 in asthma.

Forms of Vitamin E have Opposing Effects on Experimental Asthma

We previously reported that the endothelial cell adhesion molecule VCAM‐1 signals through reactive oxygen species generated by NOX2 and that this regulates leukocyte trafficking in vitro and in vivo. Therefore, we determined whether leukocyte migration is modulated by two major dietary forms of the antioxidant vitamin E, (d)‐α‐tocopherol (aT) and (d)‐γ‐tocopherol (gT). Mice were treated daily with physiological levels of aT or gT after sensitization and before challenge with the antigen ovalbumin, a model of experimental asthma. aT significantly inhibited inflammation in the lung and inhibited airway hyperresponsiveness (AHR). Surprisingly, gT exacerbated inflammation and AHR in the lung. Most interestingly, when gT and aT were co‐administered, gT ablated the benefit of aT. In addition, gT antagonized aT inhibition of leukocyte transendothelial migration in vitro. In summary, aT and gT have opposing effects on inflammation. These data have implications on the design and interpretation of clinical studies with mixed tocopherols in supplements and diets. Reported studies indicate that aT is beneficial for experimental asthma in mice and for asthma in Europeans who consume diets low gT but not for Americans who consume diets high in gT, suggesting that differences in the outcomes in these reports on vitamin E may, in part, reflect the opposing effects of α‐tocopoherol and γ‐tocopherol.(NIH R01 HL069428 to JC‐M)

Neonatal vaccination with Bacillus Calmette‐Guérin elicits long‐term protection in mouse‐allergic responses

Mycobacterium bovis Bacillus Calmette-Guérin (BCG) vaccination has been shown to inhibit allergic airway inflammation in animal models, associated with the regulation of allergen-specific T-cell immunity. However, little is known about whether neonatal BCG treatment could inhibit allergic inflammation by regulating allergen-specific T-cell response in aged mice. This study was aimed to investigate the impact of neonatal BCG treatment on allergic asthma and possible mechanism(s) underlying the action of BCG in different ages of mice. C57BL/6 neonates were vaccinated with BCG on days 1, 7 and 14, sensitized with ovalbumin (OVA) at 5 and 7 weeks of age, and then challenged with allergen at 9 or 45 weeks of age for early- or late-challenged asthma. Their airway inflammation and allergen-specific T-cell responses were characterized. Following early-challenge, BCG vaccination inhibited airway hyper-responsiveness (AHR), infiltration of eosinophils and mucous overproduction (P < 0.05), and shifted OVA-specific predominant Th2- to Th1-type cytokine responses in both the bronchoalveolar lavage fluid and the splenocyte supernatants (P < 0.05). In late-challenged mice, neonatal BCG treatment attenuated AHR and eosinophilia (P < 0.05), but failed to modulate allergen-specific cytokine responses. Our data suggest that neonatal BCG vaccination has a long-term effect on inhibiting AHR and eosinophilia, which is associated with the modulation of Th1/Th2 cytokine production in early-, but not in late-challenged mice. Thus, different mechanisms may mediate the long-term protective effect of BCG neonatal vaccination differently in younger adult and aged mice.

Chronic Exposure to Beta-Blockers Attenuates Inflammation and Mucin Content in a Murine Asthma Model

Single-dose administration of beta-adrenoceptor agonists produces bronchodilation and inhibits airway hyperresponsiveness (AHR), and is the standard treatment for the acute relief of asthma. However, chronic repetitive administration of beta-adrenoceptor agonists may increase AHR, airway inflammation, and risk of death. Based upon the paradigm shift that occurred with the use of beta-blockers in congestive heart failure, we previously determined that chronic administration of beta-blockers decreased AHR in a murine model of asthma. To elucidate the mechanisms for the beneficial effects of beta-blockers, we examined the effects of chronic administration of several beta-adrenoceptor ligands in a murine model of allergic asthma. Administration of beta-blockers resulted in a reduction in total cell counts, eosinophils, and the cytokines IL-13, IL-10, IL-5, and TGF-beta1 in bronchoalveolar lavage, and attenuated epithelial mucin content and morphologic changes. The differences in mucin content also occurred if the beta-blockers were administered only during the ovalbumin challenge phase, but administration of beta-blockers for 7 days was not as effective as administration for 28 days. These results indicate that in a murine model of asthma, chronic administration of beta-blockers reduces inflammation and mucous metaplasia, cardinal features of asthma that may contribute to airflow obstruction and AHR. Similar to heart failure, our results provide a second disease model in which beta-blockers producing an acutely detrimental effect may provide a therapeutically beneficial effect with chronic administration.

The suppressive effects of YM-58483/BTP-2, a store-operated Ca 2+ entry blocker, on inflammatory mediator release in vitro and airway responses in vivo

YM-58483/BTP-2, 4-methyl-4′-[3,5- bis(trifluoromethyl)-1H-pyrazol-1- yl]-1,2,3-thiadiazole-5-carboxanilide, blocks the store-operated Ca 2+ entry (SOCE) that mediates the activation of non-excitable cells. This study investigated the pharmacological profile and therapeutic potential of YM-58483 as anti-asthma drug. YM-58483 inhibited DNP antigen-induced histamine release from and leukotrienes (LTs) production in IgE-primed RBL-2H3 cells, a rat basophilic leukemia cell line, with IC 50 values of 460 and 310 nM, respectively. Prednisolone did not inhibit either of these responses. YM-58483 also inhibited phytohemagglutinin-P (PHA)-stimulated IL-5 and IL-13 production in human peripheral blood cells with IC 50 values of 125 and 148 nM, respectively, which is approximately 5 times less potent than prednisolone. YM-58483 (30 mg/kg, p.o.) significantly suppressed ovalbumin (OVA)-induced bronchoconstriction in OVA-sensitized guinea pigs, whereas prednisolone did not. YM-58483 (3–30 mg/kg, p.o.) and prednisolone (100 mg/kg, p.o.) both significantly and completely suppressed airway hyperresponsiveness (AHR) caused by OVA exposure. Since YM-58483 inhibits two major characteristic symptoms of bronchial asthma, namely bronchoconstriction and AHR via the suppression of inflammatory mediator and cytokine production, SOCE inhibition is a potential approach for treatment.

Dexamethasone Does Not Inhibit Airway CXC Chemokine Expression and Neutrophilia in a Murine Model of Asthma: Mechanism of Steroid Resistance in Asthma

Although glucocorticoids (GCs) are effective in controlling asthma in the majority of patients, a subset of asthmatics fails to demonstrate a satisfactory response, even to systemic GC therapy. This population is referred to as being steroid-resistant. The actual mechanism underlying steroid resistance in asthma remains to be elucidated. Methods: We have investigated how dexamethasone (DEX) regulates asthmatic phenotypes in a murine model of asthma, in which mice received i.p. immunization twice, followed by two bronchoprovocations with aerosolized OVA with a one-week interval, which we have recently described. Results: Pretreatment with DEX resulted in an inhibition of NF-κB activation in asthmatic lungs, and also inhibited bronchoalveolar lavage (BAL) levels of NF-κB -dependent cytokines such as TNF-α and CC chemokines [eotaxin and monocyte chemotactic protein (MCP)-1]. DEX was effective in suppressing airway hyperresponsiveness (AHR) at 10 h, Th2-dependent asthmatic phenotypes such as airway eosinophilia, BAL levels of Th2 cytokines (IL-5 and IL-13), and mucin production. However, DEX failed to suppress BAL levels of CXC chemokines [macrophage inflammatory protein-2 (MIP-2) and keratinocyte-derived chemokine (KC)] and airway neutrophilia. Conclusion: Airway neutrophilia is among the phenomena observed in patients with severe GC-resistant asthma. This study will provide insight into the molecular basis for airway neutrophila seen in steroid-resistant asthma. Further studies are required to delineate the underlying mechanism of CXC chemokine expression in asthma.

Effects of cryptoporus polysaccharide on rat allergic rhinitis associated with inhibiting eotaxin mRNA expression

Aqueous extract from the fruiting body of Cryptoporus volvatus has been reported to present anti-tumor, anti-allergy, anti-inflammation and immunomodulatory activities. However, the effect mechanisms of anti-allergy and anti-inflammation are poorly understood. The aim of study is to evaluate whether Cryptoporus polysaccharides (CP) extracted from fruiting body of Cryptoporus volvatus decrease the development of nasal symptoms, airway hyperresponsiveness (AHR) to methacholine (MCh) and the infiltration of eosinophils in nasal mucosa in rat model of allergic rhinitis, and investigate a possible action mechanism of CP by detecting the expression of eotaxin mRNA in nasal mucosa and lung tissues. Rats were immunized with ovalbumin and consecutive topical antigen instillation was performed. Repeated intranasal ovalbumin challenge caused rhinitis symptom, AHR to MCh, eosinophil infiltration and histological alterations into the nasal mucosa and increase of eotaxin mRNA expression in nasal mucosa and lung tissue were examined. Pretreatment with CP 3, 9 and 27 mg kg −1 (ig) decreased the numbers of sneezing 27.4%, 38.4% and 44.3% and nasal rubbing 27.5%, 34.9% and 47.7% comparison with model group, respectively. CP caused a dose-related inhibition of MCh-induced AHR. CP 27 mg kg −1 decreased the expression of eotaxin mRNA in the nasal mucosa by 35%. These results suggest CP can relieve the symptom, eosinophil infiltration and injury of tissue in nasal mucosa and lung tissue and AHR of allergic rhinitis in rats. Its action mechanism may be associated with the decrease of eotaxin mRNA expression.

Suppressive effect of verproside isolated from Pseudolysimachion longifolium on airway inflammation in a mouse model of allergic asthma

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.