Importance of myeloid dendritic cells in persistent airway disease after repeated allergen exposure

RATIONALE: There is conflicting information about the development and resolution of airway inflammation and airway hyperresponsiveness (AHR) after repeated airway exposure to allergen in sensitized mice. METHODS: Sensitized BALB/c and C57BL/6 mice were exposed to repeated allergen challenge on 3, 7, or 11 occasions. Airway function in response to inhaled methacholine was monitored; bronchoalveolar lavage fluid inflammatory cells were counted; and goblet cell metaplasia, peribronchial fibrosis, and smooth muscle hypertrophy were quantitated on tissue sections. Bone marrow-derived dendritic cells were generated after differentiation of bone marrow cells in the presence of growth factors. RESULTS: Sensitization to ovalbumin (OVA) in alum, followed by three airway exposures to OVA, induced lung eosinophilia, goblet cell metaplasia, mild peribronchial fibrosis, and peribronchial smooth muscle hypertrophy; increased levels of interleukin (IL)-4, IL-5, IL-13, granulocyte-macrophage colony-stimulating factor, transforming growth factor-beta(1), eotaxin-1, RANTES (regulated on activation, normal T-cell expressed and secreted), and OVA-specific IgG1 and IgE; and resulted in AHR. After seven airway challenges, development of AHR was markedly decreased as was the production of IL-4, IL-5, and IL-13. Levels of IL-10 in both strains and the level of IL-12 in BALB/c mice increased. After 11 challenges, airway eosinophilia and peribronchial fibrosis further declined and the cytokine and chemokine profiles continued to change. At this time point, the number of myeloid dendritic cells and expression of CD80 and CD86 in lungs were decreased compared with three challenges. After 11 challenges, intratracheal instillation of bone marrow-derived dendritic cells restored AHR and airway eosinophilia. CONCLUSIONS: These data suggest that repeated allergen exposure leads to progressive decreases in AHR and allergic inflammation, through decreases in myeloid dendritic cell numbers.     

Role of the LTB4/BLT1 pathway in allergen-induced airway hyperresponsiveness and inflammation.

LTB4, a proinflammatory lipid mediator generated from arachidonic acid through the action of 5-lipoxygenase, has been known for over two decades and is implicated in a wide variety of inflammatory disorders. BLT1, a G-protein-coupled receptor, has recently been identified as a high affinity receptor specific for LTB4. Recent studies in allergen-induced airway hyperresponsiveness and inflammation using mice lacking BLT1 have shown crucial new roles for leukotriene B4 and BLT1 in Th2 cytokine IL-13 production from lung T cells and recruitment of antigen-specific effector CD8+ T cells, suggesting novel mechanisms for their actions. The leukotriene B4-BLT1 pathway is an important target for the treatment of bronchial asthma.     

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

We previously reported that 17β-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 TGFβ1, which was completely abolished in E₂-treated asthmatic mice. We conclude that estrogen replacement therapy effectively ameliorates the pathologic profile of murine allergic asthma.     

Glycogen synthase kinase-3beta inhibition attenuates asthma in mice

RATIONALE: Persistent activation of nuclear factor-kappaB has been associated with the development of asthma. Glycogen synthase kinase-3beta is known to regulate the activity of nuclear factor-kappaB. OBJECTIVES: We hypothesized that inhibition of glycogen synthase kinase-3beta may have anti-inflammatory effects in allergic asthma. METHODS: BALB/c mice sensitized and challenged with ovalbumin developed airway inflammation. Bronchoalveolar lavage fluid was assessed for total and differential cell counts, and for cytokine and chemokine levels. Lung tissues were examined for cell infiltration and mucus hypersecretion, and for the expression of inflammatory biomarkers. Serum immunoglobulin E levels were determined by enzyme-linked immunosorbant assay. Airway hyperresponsiveness was monitored by direct airway resistance analysis. MEASUREMENTS AND MAIN RESULTS: Intravenous administration of 4-benzyl-2-methyl-1,2,4-thiadiazolidine-3,5-dione (TDZD-8), a selective glycogen synthase kinase-3beta inhibitor, significantly inhibited ovalbumin-induced increases in total cell counts, eosinophil counts, and IL-5, IL-13, and eotaxin levels recovered in bronchoalveolar lavage fluid in a dose-dependent manner. TDZD-8 substantially reduced the serum levels of ovalbumin-specific IgE. Histologic studies showed that TDZD-8 dramatically inhibited ovalbumin-induced lung tissue eosinophilia and airway mucus production. TDZD-8 also markedly suppressed ovalbumin-induced mRNA expression of intercellular adhesion molecule-1, vascular cell adhesion molecule-1, Muc5ac, and three members of the chitinase family (acidic mammalian chitinase, Ym1, and Ym2). In addition, TDZD-8 significantly reduced ovalbumin-induced airway hyperresponsiveness to inhaled methacholine. Western blot analysis of whole lung lysates revealed that TDZD-8 markedly attenuated the phosphorylation of the nuclear factor-kappaB subunit p65 from ovalbumin-challenged mice. CONCLUSIONS: Our findings suggest that inhibition of glycogen synthase kinase-3beta may provide a novel means for the treatment of allergic airway inflammation.     

Factor B of the alternative complement pathway regulates development of airway hyperresponsiveness and inflammation

Exposure to inhaled allergens leads to increases in airway hyperresponsiveness (AHR) and inflammation, associated with increased levels of biologically active fragments derived from the complement C3 and C5 family of proteins. Further, complement activation during allergen challenge in sensitized animals is necessary for the development of AHR and airway inflammation. To define the complement pathway involved, we studied mice deficient in complement factor 4 (C4-/-), a critical component of the classical pathway, or factor B (fB-/-), an essential protein in the alternative complement pathway. WT, C4-/-, and fB-/- mice were sensitized to ovalbumin and subsequently exposed to nebulized ovalbumin (1% in saline) on 3 consecutive days. After allergen sensitization and challenge, fB-/- mice demonstrated significantly lower airway responsiveness to methacholine and less airway inflammation. In contrast, C4-/- mice showed no reduction in AHR and airway inflammation compared with WT mice. Tissue inflammation, goblet cell hyperplasia, and IL-4, IL-5, and IL-13 levels in BAL fluid were significantly reduced in fB-/- mice compared with C4-/- and WT mice. The development of AHR and airway inflammation in sensitized fB-/- mice could be restored after intranasal administration of purified factor B before the airway challenge. In addition, administration of a neutralizing anti-factor B mAb to sensitized mice before airway challenge reduced the development of AHR and airway inflammation. These results demonstrate that in sensitized hosts complement activation through the alternative pathway after allergen exposure is critical to the development of AHR and airway inflammation.     

Oral treatment with live Lactobacillus reuteri inhibits the allergic airway response in mice

RATIONALE: Clinical trials have demonstrated that probiotics may be effective in the treatment and prevention of atopic disease in children but there have been few reports of therapeutic effects of oral probiotics outside the gastrointestinal tract. OBJECTIVES: We investigated the effect of two probiotic organisms on the response to antigen challenge in a mouse model of allergic airway inflammation. METHODS: We used an ovalbumin-sensitized asthma model in BALB/c and Toll-like receptor 9-deficient mice. Animals were treated with probiotic organisms via gavaging needle before antigen challenge. After antigen challenge, airway responsiveness to methacholine, influx of inflammatory cells to the lung, and cytokine levels in bronchoalveolar lavage fluid were assessed. RESULTS: Oral treatment with live Lactobacillus reuteri but not Lactobacillus salivarius significantly attenuated the influx of eosinophils to the airway lumen and parenchyma and reduced the levels of tumor necrosis factor, monocyte chemoattractant protein-1, IL-5, and IL-13 in bronchoalveolar lavage fluid of antigen-challenged animals, but there was no change in eotaxin or IL-10. L. reuteri but not L. salivarius also decreased allergen-induced airway hyperresponsiveness. These responses were dependent on Toll-like receptor 9 and were associated with increased activity of indoleamine 2,3-dioxygenase. Killed organisms did not mimic the ability of the live L. reuteri to attenuate inflammation or airway hyperresponsiveness. CONCLUSION: Oral treatment with live L. reuteri can attenuate major characteristics of an asthmatic response in a mouse model of allergic airway inflammation. These results suggest that oral treatment with specific live probiotic strains may have therapeutic potential in the treatment of allergic airway disease.     

Antiinflammatory effects of genistein,a tyrosine kinase inhibitor,on a guinea pig model of asthma

Protein tyrosine kinase signaling cascade plays a pivotal role in the activation of inflammatory cells. The purpose of this study was to investigate the effects of genistein, a broad-spectrum protein tyrosine kinase inhibitor, on airway inflammation in an in vivo guinea pig model of asthma. Guinea pigs were actively sensitized by intraperitoneal injections of ovalbumin. Aerosolized ovalbumin induced acute bronchoconstriction in conscious animals in a dose-dependent manner. Genistein (15 mg/kg given intraperitoneally) markedly inhibited ovalbumin-induced, but not histamine- and methacholine-induced, acute bronchoconstriction. In addition, genistein significantly reduced ovalbumin-induced increases in total cell counts and eosinophils recovered in bronchoalveolar lavage fluid, airway eosinophilia, and eosinophil peroxidase activity in cell-free bronchoalveolar lavage fluid and markedly attenuated ovalbumin-induced airway hyperresponsiveness to inhaled methacholine. Immunoblot analysis of lung lysates isolated from genistein-pretreated animals showed that epidermal growth factor-induced tyrosine phosphorylation in lung tissues was inhibited by genistein. These results implicate that inhibition of tyrosine kinase signaling cascade may have therapeutic potential for allergic airway inflammation.     

Inhaled p38alpha mitogen-activated protein kinase antisense oligonucleotide attenuates asthma in mice

The p38 mitogen-activated protein kinase (MAPK) plays a critical role in the activation of inflammatory cells. Therefore, we investigated the antiinflammatory effects of a respirable p38alpha MAPK antisense oligonucleotide (p38alpha-ASO) in a mouse asthma model. A potent and selective p38alpha-ASO was characterized in vitro. Inhalation of aerosolized p38alpha-ASO using an aerosol chamber dosing system produced measurable lung deposition of ASO and significant reduction of ovalbumin (OVA-)-induced increases in total cells, eosinophils, and interleukin 4 (IL-4), IL-5, and IL-13 levels in bronchoalveolar lavage fluid, and dose-dependent inhibition of airway hyperresponsiveness in allergen-challenged mice. Furthermore, inhaled p38alpha-ASO markedly inhibited OVA-induced lung tissue eosinophilia and airway mucus hypersecretion. Quantitative polymerase chain reaction analysis of bronchoalveolar lavage fluid cells and peribronchial lymph node cells showed that p38alpha-ASO significantly reduced p38alpha MAPK mRNA expression. Nose-only aerosol exposure of mice verified the p38alpha-ASO-induced inhibition of OVA-induced pulmonary eosinophilia, mucus hypersecretion, and airway hyperresponsiveness. None of the effects of the p38alpha-ASO were produced by a six-base mismatched control oligonucleotide. These findings demonstrate antisense pharmacodynamic activity in the airways after aerosol delivery and suggest that a p38alpha MAPK ASO approach may have therapeutic potential for asthma and other inflammatory lung diseases.     

Lipopolysaccharides promote a shift from Th2-derived airway eosinophilic inflammation to Th17-derived neutrophilic inflammation in an ovalbumin-sensitized murine asthma model

Introduction: The currently available treatments for severe asthma are insufficient. Infiltration of neutrophils rather than eosinophils into the airways is an important inflammatory characteristic of severe asthma. However, the mechanism of the phenotypic change from eosinophilic to neutrophilic inflammation has not yet been fully elucidated. Methods: In the current study, we examined the effect of lipopolysaccharides (LPS) on eosinophilic asthmatic mice sensitized with ovalbumin (OVA), as well as the roles of interleukin (IL)-17A/T helper (Th) 17 cells on the change in the airway inflammatory phenotype from eosinophilic to neutrophilic inflammation in asthmatic lungs of IL-17A-deficient mice. Results: Following exposure of OVA-induced asthmatic mice to LPS, neutrophil-predominant airway inflammation rather than eosinophil-predominant inflammation was observed, with increases in airway hyperresponsiveness (AHR), the IL-17A level in bronchoalveolar lavage fluid (BALF) and Th17 cells in the spleen and in the pulmonary hilar lymph nodes. Moreover, the neutrophilic asthmatic mice showed decreased mucus production and Th2 cytokine levels (IL-4 and IL-5). In contrast, IL-17A knockout (KO) mice exhibited eosinophil-predominant lung inflammation, decreased AHR, mucus overproduction and increased Th2 cytokine levels and Th2 cells. Conclusion: These findings suggest that the eosinophilic inflammatory phenotype of asthmatic lungs switches to the neutrophilic phenotype following exposure to LPS. The change in the inflammatory phenotype is strongly correlated with the increases in IL-17A and Th17 cells.     

Tumor necrosis factor-alpha negatively regulates airway hyperresponsiveness through gamma-delta T cells.

Tumor necrosis factor (TNF)-alpha is a potent cytokine with immunomodulatory, proinflammatory, and pathobiologic activities. Although TNF-alpha is thought to play a role in mediating airway inflammation and airway hyperresponsiveness (AHR), its function is not well defined. TNF-alpha-deficient mice and mice expressing TNF-alpha in their lungs because of a TNF-alpha transgene placed under the control of the surfactant protein (SP)-C promoter (SP-C/TNF-alpha-transgenic mice) were sensitized to ovalbumin (OVA) and subsequently challenged with OVA via the airways; airway function in response to inhaled methacholine was monitored. In the TNF-alpha-deficient mice, AHR was significantly increased over that in controls. In contrast, the transgenic mice failed to develop AHR. In addition, sensitized/ challenged TNF-alpha-deficient mice had significantly increased numbers of eosinophils and higher levels of interleukin (IL)-5 and IL-10 in their bronchoalveolar lavage fluid than were found for control mice. However, in SP-C/TNF-alpha-transgenic mice, both the numbers of eosinophils and levels of IL-5 and IL-10 were significantly lower than in sensitized/challenged transgene-negative mice. gammadelta T cells have been shown to be activated by TNF-alpha and to negatively regulate AHR. Depletion of gammadelta T cells in the TNF-alpha-transgenic mice in the present study increased AHR, whereas depletion of these cells had no significant effect in TNF-alpha-deficient mice. These data indicate that TNF-alpha can negatively modulate airway responsiveness, controlling airway function in allergen-induced AHR through the activation of gammadelta T cells.     

Is interleukin-13 critical in maintaining airway hyperresponsiveness in allergen-challenged mice?

Interleukin (IL)-13 is regarded as being a central effector in the pathophysiology of airway hyperresponsiveness. We have described a mouse model in which chronic allergen exposure results in sustained airway hyperresponsiveness and aspects of airway remodeling, and here sought to demonstrate that this component of airway hyperresponsiveness is independent of biologically active IL-13. Sensitized mice were subjected to either brief or chronic periods of allergen exposure and studied 24 hours after brief or 4 weeks after chronic allergen inhalation. A soluble murine anti-IL-13 receptor fusion protein that specifically binds to and neutralizes IL-13 was given daily during the 4 days before the day of outcome measurements in both protocols. Outcome measurements included airway responses to intravenous methacholine, bronchoalveolar lavage fluid cell counts, and airway morphometry. Compared with the saline control, brief allergen challenge resulted in airway hyperresponsiveness, which was prevented by anti-IL-13 treatment. Chronic allergen challenge resulted in sustained airway hyperresponsiveness and indices of airway remodeling; IL-13 blockade failed to reverse this sustained airway hyperresponsiveness. These results confirm that IL-13 is critical for the development of airway hyperresponsiveness associated with brief allergen exposure, but is not necessary to maintain the sustained airway hyperresponsiveness associated with airway remodeling.     

Immunomodulatory effects of feeding with Bifidobacterium longum on allergen-induced lung inflammation in the mouse

BackgroundThe intestinal microbiota has important effects on host immune responses and feeding with certain commensal organisms has anti-inflammatory effects in a variety of diseases, including experimental asthma. The aim of the current study was to examine how robust the effects of feeding with the commensal strain, Bifidobacterium longum (Bif) were on the pulmonary responses to allergen sensitization and challenge.MethodsBALB/c mice were given two intraperitoneal injections of ovalbumin (10 μg in alum) on days 0 and 7 and were fed daily with Bif or vehicle from days 0–14. Challenges with ovalbumin (10 μg) were administered intra-nasally once on day 14 or three times on days 14, 15 and 16 and the lung inflammatory response was assessed one day later.ResultsBif feeding attenuated airway inflammation following a single ovalbumin challenge, reducing bronchoalveolar lavage (BAL) eosinophilia, BAL fluid IL-4 protein and BAL cell IL-4 and IFN-γ mRNA levels. However, BAL fluid IL-5 protein was increased. There was an accompanying increase in lung regulatory T cells assessed by flow cytometry. Responses to triple challenge with ovalbumin were much less affected by Bif feeding, including unchanged cytokine levels, ovalbumin-specific IgE and airway hyperresponsiveness to methacholine.ConclusionThese results show modest immunoregulatory effects of oral feeding with Bif with inhibition of certain components of allergen-induced airway inflammation that is associated with the expansion of regulatory T cells in the lungs but that is overcome by repeated allergen exposure.     

Role of macrophage migration inhibitory factor in ovalbumin-induced airway inflammation in rats.

Macrophage migration inhibitory factor (MIF) is a pro-inflammatory cytokine that reportedly counteracts the anti-inflammatory effect of endogenous glucocorticoids. There have only been a few reports that demonstrate a potential link between MIF and bronchial asthma. In an attempt to further clarify the precise role of MIF in asthma, the present authors examined the effect of anti-MIF antibody (Ab) on airway inflammation and airway hyperresponsiveness in an ovalbumin-immunised rat asthma model. Actively immunised Brown Norway rats received ovalbumin inhalation with or without treatment of anti-MIF Ab. The levels of MIF in bronchoalveolar lavage fluid were significantly elevated after the ovalbumin challenge. An immunohistochemical study revealed positive immunostaining for MIF in bronchial epithelium, even in nonsensitised rats, and the MIF staining in bronchial epithelium was enhanced after the ovalbumin challenge. Anti-MIF Ab significantly decreased the number of total cells, neutrophils and eosinophils in the bronchoalveolar lavage fluid of the ovalbumin-challenged rats, and also attenuated the ovalbumin-induced airway hyperresponsiveness to ovalbumin and methacholine. However, anti-MIF Ab did not affect the level of serum ovalbumin-specific IgE, suggesting that anti-MIF Ab did not suppress immunisation itself. The results indicate that macrophage migration inhibitory factor plays a crucial role in airway inflammation and airway hyperresponsiveness in asthma.     

Inhibition of complement activation decreases airway inflammation and hyperresponsiveness

Studies in murine models have suggested the involvement of the complement anaphylatoxins (C3a and C5a) in the development of allergic asthma. We investigated the effects of inhibiting complement activation after sensitization but before allergen challenge on the development of allergic airway inflammation and airway hyperresponsiveness. To prevent complement activation, we used a recombinant soluble form of the mouse membrane complement inhibitor complement receptor-related gene y (Crry) fused to the IgG1 hinge, CH2 and CH3 domains (Crry-Ig), which has decay-accelerating activity for both the classic and alternative pathways of complement as well as cofactor activity for factor I-mediated cleavage of C3b and C4b. C57BL/6 mice were sensitized (Days 1 and 14) and challenged (Days 24-26) with ovalbumin. Crry-Ig was administered after allergen sensitization either as an intraperitoneal injection or by nebulization before allergen challenge. Crry-Ig significantly prevented the development of airway hyperresponsiveness, decreased airway and lung eosinophilia as well as the numbers of lung lymphocytes, decreased levels of interleukin (IL)-4, IL-5, and IL-13 in bronchoalveolar lavage fluid and decreased serum ovalbumin-specific IgE and IgG1. These results suggest that prevention of complement activation may have a therapeutic role in the treatment of allergic airway inflammation and asthma in sensitized individuals.     

Characteristics of lower airway inflammatory changes in the minimal persistent inflammation of allergic rhinitis in mice

Objective: This study aims to establish an experimental mouse model of minimal persistent inflammation (MPI), observe the features of inflammation and hyper-responsiveness of the upper/lower airways, and explore the relationship between inflammation and hyper-responsiveness in the upper/lower airways. Methods: Sixty-four female BALB/c mice were randomly divided into four groups: allergic rhinitis (AR) group as positive control, MPI group, negative control group and blank control group. Mice were given high and low-concentrated ovalbumin solution after basic and intensive sensitization to establish AR model and MPI model. Nasal mucosa and lung tissues were stained to observe eosinophil infiltration, goblet cell hyperplasia, and expression of intercellular adhesion molecule 1 (ICAM-1). Airway hyper-responsiveness was assessed. Levels of specific immunoglobulin E (sIgE), interleukin (IL)-4 and IL-5 in peripheral blood, nasal lavage fluid (NLF), and bronchoalveolar lavage fluid (BALF) were detected by Enzyme-linked immunosorbent assay. Results: The eosinophil infiltration and expression of ICAM-1 on nasal mucosa and in lung tissues in the AR and MPI groups were significantly elevated compared to control groups. Goblet cells count increased only in the nasal mucosa and not in lung tissues. Eosinophil and neutrophil count of NLF and BALF in the AR and MPI groups increased significantly compared to control groups. Level of IL-4 did not increase significantly, but sIgE and IL-5 did. Conclusions: Mice in the MPI status exhibits lower airway inflammation and hyper-responsiveness with increase in eosinophil count, goblet cells, ICAM-1, IL-4, and IL-5. These results provide further evidence for the importance of MPI of AR in lower airway diseases.     

Anti-interleukin-9 antibody treatment inhibits airway inflammation and hyperreactivity in mouse asthma model

Numerous in vitro and in vivo studies in both animals and patients with asthma have shown that interleukin (IL)-9 is an important inflammatory mediator in asthma. To examine the effects of IL-9 antagonism on airway inflammation, ovalbumin-sensitized BALB/c mice were intravenously given anti-IL-9 antibody or an isotype-matched control antibody 30 minutes before challenge with aerosolized ovalbumin. Airway response to methacholine was measured, and samples of bronchoalveolar lavage fluid (BALF) were obtained 24 hours after the last antigen challenge. Lung tissue was harvested and examined histopathologically. After ovalbumin challenge, there were significant increases in airway hyperreactivity, the numbers of inflammatory cells in lung, and IL-4, IL-5, and IL-13 production in BALF. Treatment with anti-IL-9 antibody significantly prevented airway hyperreactivity in response to methacholine inhalation. Blockade of IL-9 reduced the numbers of eosinophils (0.3 +/- 0.1 x 10(5) and 23.6 +/- 0.5 x 10(5)/ml, anti-IL-9 antibody/control immunoglobulin G) and lymphocytes (0.2 +/- 0.2 x 10(5) and 0.8 +/- 0.1 x 10(5)/ml) in BALF. Anti-IL-9 antibody treatment also reduced the concentrations of IL-4 (from 70.6 +/- 4.6 to 30.8 +/- 5.2 pg/ml), IL-5 (from 106.4 +/- 12 to 54.4 +/- 6.6 pg/ml), and IL-13 (from 44.2 +/- 7.6 to 30.1 +/- 5.5 pg/ml) in BALF. Macrophage-derived cytokine expression in the airways was also decreased by IL-9 blockade. Taken together, our findings emphasize the importance of IL-9 in the pathogenesis of asthma and suggest that blockade of IL-9 may be a new therapeutic strategy for bronchial asthma.