Seeking common pathophysiology in asthma, atopy and sinusitis

Asthma and chronic sinusitis are inexplicably common airway diseases that are linked to atopy and allergic inflammation. T helper type 2 (Th2) cells and the associated cytokines are believed to play crucial pathogenic roles in asthma, but the environmental factors that instigate allergic airway disease remain poorly understood. Environmental proteinases are highly allergenic and are candidate inducers of airway Th2 responses. Determining the proteinases and their sources that are relevant to airway disease, however, remains challenging. In this Opinion, we summarize the evidence that implicates fungi as both a relevant source of allergenic proteinases and a potential cause of asthma, atopy and chronic sinusitis through airway infection. Clarification of the extrinsic causes of these processes will markedly improve diagnosis, prognosis and therapy.     

Allergic Airway Inflammation Decreases Lung Bacterial Burden following Acute Klebsiella pneumoniae Infection in a Neutrophil- and CCL8-Dependent Manner

The Th17 cytokines interleukin-17A (IL-17A), IL-17F, and IL-22 are critical for the lung immune response to a variety of bacterial pathogens, including Klebsiella pneumoniae. Th2 cytokine expression in the airways is a characteristic feature of asthma and allergic airway inflammation. The Th2 cytokines IL-4 and IL-13 diminish ex vivo and in vivo IL-17A protein expression by Th17 cells. To determine the effect of IL-4 and IL-13 on IL-17-dependent lung immune responses to acute bacterial infection, we developed a combined model in which allergic airway inflammation and lung IL-4 and IL-13 expression were induced by ovalbumin sensitization and challenge prior to acute lung infection with K. pneumoniae. We hypothesized that preexisting allergic airway inflammation decreases lung IL-17A expression and airway neutrophil recruitment in response to acute K. pneumoniae infection and thereby increases the lung K. pneumoniae burden. As hypothesized, we found that allergic airway inflammation decreased the number of K. pneumoniae-induced airway neutrophils and lung IL-17A, IL-17F, and IL-22 expression. Despite the marked reduction in postinfection airway neutrophilia and lung expression of Th17 cytokines, allergic airway inflammation significantly decreased the lung K. pneumoniae burden and postinfection mortality. We showed that the decreased lung K. pneumoniae burden was independent of IL-4, IL-5, and IL-17A and partially dependent on IL-13 and STAT6. Additionally, we demonstrated that the decreased lung K. pneumoniae burden associated with allergic airway inflammation was both neutrophil and CCL8 dependent. These findings suggest a novel role for CCL8 in lung antibacterial immunity against K. pneumoniae and suggest new mechanisms of orchestrating lung antibacterial immunity.     

Severity of Allergic Airway Disease Due to House Dust Mite Allergen Is Not Increased after Clinical Recovery of Lung Infection with Chlamydia pneumoniae in Mice

Chlamydia pneumoniae is associated with chronic inflammatory lung diseases like bronchial asthma and chronic obstructive pulmonary disease. The existence of a causal link between allergic airway disease and C. pneumoniae is controversial. A mouse model was used to address the question of whether preceding C. pneumoniae lung infection and recovery modifies the outcome of experimental allergic asthma after subsequent sensitization with house dust mite (HDM) allergen. After intranasal infection, BALB/c mice suffered from pneumonia characterized by an increased clinical score, reduction of body weight, histopathology, and a bacterial load in the lungs. After 4 weeks, when infection had almost resolved clinically, HDM allergen sensitization was performed for another 4 weeks. Subsequently, mice were subjected to a methacholine hyperresponsiveness test and sacrificed for further analyses. As expected, after 8 weeks, C. pneumoniae-specific antibodies were detectable only in infected mice and the titer was significantly higher in the C. pneumoniae/HDM allergen-treated group than in the C. pneumoniae/NaCl group. Intriguingly, airway hyperresponsiveness and eosinophilia in bronchoalveolar lavage fluid were significantly lower in the C. pneumoniae/HDM allergen-treated group than in the mock/HDM allergen-treated group. We did observe a relationship between experimental asthma and chlamydial infection. Our results demonstrate an influence of sensitization to HDM allergen on the development of a humoral antibacterial response. However, our model demonstrates no increase in the severity of experimental asthma to HDM allergen as a physiological allergen after clinically resolved severe chlamydial lung infection. Our results rather suggest that allergic airway disease and concomitant cellular changes in mice are decreased following C. pneumoniae lung infection in this setting.     

The common γ-chain cytokine IL-7 promotes immunopathogenesis during fungal asthma

Asthmatics sensitized to fungi are reported to have more severe asthma, yet the immunopathogenic pathways contributing to this severity have not been identified. In a pilot assessment of human asthmatics, those subjects sensitized to fungi demonstrated elevated levels of the common γ-chain cytokine IL-7 in lung lavage fluid, which negatively correlated with the lung function measurement PC20. Subsequently, we show that IL-7 administration during experimental fungal asthma worsened lung function and increased the levels of type 2 cytokines (IL-4, IL-5, IL-13), proallergic chemokines (CCL17, CCL22) and proinflammatory cytokines (IL-1α, IL-1β). Intriguingly, IL-7 administration also increased IL-22, which we have previously reported to drive immunopathogenic responses in experimental fungal asthma. Employing IL22^CreR26R^eYFP reporter mice, we identified γδ T cells, iNKT cells, CD4 T cells and ILC3s as sources of IL-22 during fungal asthma; however, only iNKT cells were significantly increased after IL-7 administration. IL-7-induced immunopathogenesis required both type 2 and IL-22 responses. Blockade of IL-7Rα in vivo resulted in attenuated IL-22 production, lower CCL22 levels, decreased iNKT cell, CD4 T-cell and eosinophil recruitment, yet paradoxically increased dynamic lung resistance. Collectively, these results suggest a complex role for IL-7 signaling in allergic fungal asthma.     

Intelectin contributes to allergen-induced IL-25, IL-33, and TSLP expression and type 2 response in asthma and atopic dermatitis

The epithelial and epidermal innate cytokines IL-25, IL-33, and thymic stromal lymphopoietin (TSLP) have pivotal roles in the initiation of allergic inflammation in asthma and atopic dermatitis (AD). However, the mechanism by which the expression of these innate cytokines is regulated remains unclear. Intelectin (ITLN) is expressed in airway epithelial cells and promotes allergic airway inflammation. We hypothesized that ITLN is required for allergen-induced IL-25, IL-33, and TSLP expression. In two asthma models, Itln knockdown reduced allergen-induced increases in Il-25, Il-33, and Tslp and development of type 2 response, eosinophilic inflammation, mucus overproduction, and airway hyperresponsiveness. Itln knockdown also inhibited house dust mite (HDM)-induced early upregulation of Il-25, Il-33, and Tslp in a model solely inducing airway sensitization. Using human airway epithelial cells, we demonstrated that HDM-induced increases in ITLN led to phosphorylation of epidermal growth factor receptor and extracellular-signal regulated kinase, which were required for induction of IL-25, IL-33, and TSLP expression. In two AD models, Itln knockdown suppressed expression of Il-33, Tslp, and Th2 cytokines and eosinophilic inflammation. In humans, ITLN1 expression was significantly increased in asthmatic airways and in lesional skin of AD. We conclude that ITLN contributes to allergen-induced Il-25, Il-33, and Tslp expression in asthma and AD.     

Changes in indoor allergen and fungal levels predict changes in asthma activity among young adults

BACKGROUND: Exposures to allergens are thought to be important risk factors for asthma. We conducted a longitudinal study of indoor allergen and fungal levels in Melbourne homes between 1996 and 1998 to examine the effect of changes in allergen exposure upon asthma and associated outcomes. METHODS: Participants were visited at home in 1996 (n=485) and 1998 (n=360), when dust and air samples were collected from their bedrooms and assayed for Der p 1, Fel d 1, ergosterol and fungal propagules. Subjects then attended the lung function laboratory to complete a questionnaire, spirometry, methacholine challenge and skin prick testing. The associations between the change in allergen levels and change in clinical outcomes were examined using multiple logistic and linear regression. RESULTS: Participants whose Cladosporium fungal exposure doubled had 52% greater odds of having had an attack of asthma in the last 12 months. A doubling of fungal exposure was also associated with 53% greater odds of developing atopy. A doubling of Fel d 1 floor levels was associated with 73% increased odds of doctor-diagnosed asthma. A doubling of Der p 1 levels in bed dust was associated with a 64% greater odds of persistent bronchial hyper-reactivity. CONCLUSIONS: These findings provide evidence that changes in indoor levels of fungi and house dust mites can affect the risk of development and persistence of asthma and atopy in adults. Further studies are required to establish any benefit of sustained reductions in indoor allergen exposures, and to determine whether these effects are truly 'allergic' or because of immune stimulation in the airway through other less specific mechanisms.     

Allergic Lung Inflammation Reduces Tissue Invasion and Enhances Survival from Pulmonary Pneumococcal Infection in Mice,Which Correlates with Increased Expression of Transforming Growth Factor β1 and SiglecFlow Alveolar Macrophages

Asthma is generally thought to confer an increased risk for invasive pneumococcal disease (IPD) in humans. However, recent reports suggest that mortality rates from IPD are unaffected in patients with asthma and that chronic obstructive pulmonary disease (COPD), a condition similar to asthma, protects against the development of complicated pneumonia. To clarify the effects of asthma on the subsequent susceptibility to pneumococcal infection, ovalbumin (OVA)-induced allergic lung inflammation (ALI) was induced in mice followed by intranasal infection with A66.1 serotype 3 Streptococcus pneumoniae. Surprisingly, mice with ALI were significantly more resistant to lethal infection than non-ALI mice. The heightened resistance observed following ALI correlated with enhanced early clearance of pneumococci from the lung, decreased bacterial invasion from the airway into the lung tissue, a blunted inflammatory cytokine and neutrophil response to infection, and enhanced expression of transforming growth factor β1 (TGF-β1). Neutrophil depletion prior to infection had no effect on enhanced early bacterial clearance or resistance to IPD in mice with ALI. Although eosinophils recruited into the lung during ALI appeared to be capable of phagocytizing bacteria, neutralization of interleukin-5 (IL-5) to inhibit eosinophil recruitment likewise had no effect on early clearance or survival following infection. However, enhanced resistance was associated with an increase in levels of clodronate-sensitive, phagocytic SiglecF^low alveolar macrophages within the airways following ALI. These findings suggest that, while the risk of developing IPD may actually be decreased in patients with acute asthma, additional clinical data are needed to better understand the risk of IPD in patients with different asthma phenotypes.     

Constitutive production of IL-13 promotes early-life Chlamydia respiratory infection and allergic airway disease

Deleterious responses to pathogens during infancy may contribute to infection and associated asthma. Chlamydia respiratory infections in early life are common causes of pneumonia and lead to reduced lung function and asthma. We investigated the role of interleukin-13 (IL-13) in promoting early-life Chlamydia respiratory infection, infection-induced airway hyperresponsiveness (AHR), and severe allergic airway disease (AAD). Infected infant Il13^−/− mice had reduced infection, inflammation, and mucus-secreting cell hyperplasia. Surprisingly, infection of wild-type (WT) mice did not increase IL-13 production but reduced IL-13Rα2 decoy receptor levels compared with sham-inoculated controls. Infection of WT but not Il13^−/− mice induced persistent AHR. Infection and associated pathology were restored in infected Il13^−/− mice by reconstitution with IL-13. Stat6^−/− mice were also largely protected. Neutralization of IL-13 during infection prevented subsequent infection-induced severe AAD. Thus, early-life Chlamydia respiratory infection reduces IL-13Rα2 production, which may enhance the effects of constitutive IL-13 and promote more severe infection, persistent AHR, and AAD.     

Acellular Pertussis Vaccine Protects against Exacerbation of Allergic Asthma Due to Bordetella pertussis in a Murine Model

The prevalence of asthma and allergic disease has increased in many countries, and there has been speculation that immunization promotes allergic sensitization. Bordetella pertussis infection exacerbates allergic asthmatic responses. We investigated whether acellular pertussis vaccine (Pa) enhanced or prevented B. pertussis-induced exacerbation of allergic asthma. Groups of mice were immunized with Pa, infected with B. pertussis, and/or sensitized to ovalbumin. Immunological, pathological, and physiological changes were measured to assess the impact of immunization on immune deviation and airway function. We demonstrate that immunization did not enhance ovalbumin-specific serum immunoglobulin E production. Histopathological examination revealed that immunization reduced the severity of airway pathology associated with sensitization in the context of infection and decreased bronchial hyperreactivity upon methacholine exposure of infected and sensitized mice. These data demonstrate unequivocally the benefit of Pa immunization to health and justify selection of Pa in mass vaccination protocols. In the absence of infection, the Pa used in this study enhanced the interleukin-10 (IL-10) and IL-13 responses and influenced airway hyperresponsiveness to sensitizing antigen; however, these data do not suggest that Pa contributes to childhood asthma overall. On the contrary, wild-type virulent B. pertussis is still circulating in most countries, and our data suggest that the major influence of Pa is to protect against the powerful exacerbation of asthma-like pathology induced by B. pertussis.     

B lymphocytes regulate airway granulocytic inflammation and cytokine production in a murine model of fungal allergic asthma

Sensitization to fungi often leads to a severe form of asthma that is particularly difficult to manage clinically, resulting in increased morbidity and hospitalizations in these patients. Although B lymphocytes might exacerbate asthma symptoms through the production of IgE, these cells might also be important in the protective response against inhaled fungi. Through cytokine release and T-cell interactions, these lymphocytes might also influence the development and maintenance of airway wall fibrosis. J_H^−/− mice lack the JH gene for the heavy chain component of antibodies, which is critical for B-cell function and survival. These animals have facilitated the elucidation of the role of B lymphocytes in a number of immune responses; however, J_H^−/− mice have not been used to study fungal allergy. In this study, we examined the role of B lymphocytes using an Aspergillus fumigatus murine fungal aeroallergen model that mimics human airway disease that is triggered by environmental fungal exposure. We compared disease progression in sensitized wild-type BALB/c and J_H^−/− mice that were exposed to repeated fungal exposure and found no differences in airway hyperresponsiveness, overall pulmonary inflammation or collagen deposition around the large airways. However, the levels of the Th2-type cytokines IL-4 and IL-13 were significantly attenuated in the airways of J_H^−/− mice relative to the BALB/c controls. By contrast, levels of the inflammatory cytokines IL-17A and IL-6 were significantly elevated in the J_H^−/− animals, and there was significantly more robust airway eosinophilia and neutrophilia than in control animals. Taken together, these findings demonstrate that B lymphocytes help to regulate granulocytic responses to fungal exposure in the pulmonary compartment.     

Prevention of asthma during the first 5 years of life: a randomized controlled trial

BACKGROUND: Early life exposures may be important in the development of asthma and allergic disease. OBJECTIVE: To test house dust mite (HDM) avoidance and dietary fatty acid modification, implemented throughout the first 5 years of life, as interventions to prevent asthma and allergic disease. METHODS: We recruited newborns with a family history of asthma antenatally and randomized them, separately, to HDM avoidance or control and to dietary modification or control. At age 5 years, they were assessed for asthma and eczema and had skin prick tests for atopy. RESULTS: Of 616 children randomized, 516 (84%) were evaluated at age 5 years. The HDM avoidance intervention resulted in a 61% reduction in HDM allergen concentrations (microg/g dust) in the child's bed but no difference in the prevalence of asthma, wheeze, or atopy (P > .1). The prevalence of eczema was higher in the active HDM avoidance group (26% vs 19%; P = .06). The ratio of omega-6 to omega-3 fatty acids in plasma was lower in the active diet group (5.8 vs 7.4; P < .0001). However, the prevalence of asthma, wheezing, eczema, or atopy did not differ between the diet groups (P > .1). CONCLUSION: Further research is required to establish whether other interventions can be recommended for the prevention of asthma and allergic disease. CLINICAL IMPLICATIONS: House dust mite avoidance measures and dietary fatty acid modification, as implemented in this trial during infancy and early childhood, did not prevent the onset of asthma, eczema, or atopy in high-risk children.     

Fungus-associated asthma: overcoming challenges in diagnosis and treatment

With regard to fungal colonization and fungal sensitization, the goals of fungus-associated asthma management are as follows: 1) to survey fungi colonizing the airways of patients repeatedly; 2) to evaluate the tendency of the colonizing fungi to sensitize patients and the influence on clinical manifestations of asthma; 3) to follow disease development to allergic bronchopulmonary mycosis or sinobronchial allergic mycosis; and 4) to determine whether fungal eradication from the airway of patients is beneficial from the viewpoints of future risk factors. Recent developments in molecular biological analyses have facilitated the identification of basidiomycetous fungi that were not previously thought to be of concern in fungal allergy. The total control of fungus-associated asthma will be accomplished by environmental management established from the viewpoint of both the ecology and life cycle of the responsible fungi.     

Amelioration of ovalbumin-induced allergic airway disease following Der p 1 peptide immunotherapy is not associated with induction of IL-35

In the present study, we show therapeutic amelioration of established ovalbumin (OVA)-induced allergic airway disease following house dust mite (HDM) peptide therapy. Mice were sensitized and challenged with OVA and HDM protein extract (Dermatophagoides species) to induce dual allergen sensitization and allergic airway disease. Treatment of allergic mice with peptides derived from the major allergen Der p 1 suppressed OVA-induced airway hyperresponsiveness, tissue eosinophilia, and goblet cell hyperplasia upon rechallenge with allergen. Peptide treatment also suppressed OVA-specific T-cell proliferation. Resolution of airway pathophysiology was associated with a reduction in recruitment, proliferation, and effector function of T_H2 cells and decreased interleukin (IL)-17⁺ T cells. Furthermore, peptide immunotherapy induced the regulatory cytokine IL-10 and increased the proportion of Fox p3⁺ cells among those expressing IL-10. Tolerance to OVA was not associated with increased IL-35. In conclusion, our results provide in vivo evidence for the creation of a tolerogenic environment following HDM peptide immunotherapy, leading to the therapeutic amelioration of established OVA-induced allergic airway disease.     

Critical roles of regulatory B and T cells in helminth parasite-induced protection against allergic airway inflammation

The prevalence of allergic asthma and incidences of helminth infections in humans are inversely correlated. Although experimental studies have established the causal relation between parasite infection and allergic asthma, the mechanism of the parasite-associated immunomodulation is not fully elucidated. Using a murine model of asthma and nematode parasite Heligmosomoides polygyrus, we investigated the roles of regulatory B cells (B_reg) and T cells (T_reg) in mediation of the protection against allergic asthma by parasite. H. polygyrus infection significantly suppressed ovalbumin (OVA)-induced allergic airway inflammation (AAI) evidenced by alleviated lung histopathology and reduced numbers of bronchoalveolar inflammatory cell infiltration, and induced significant responses of interleukin (IL)-10⁺ B_reg, IL-10⁺ T_reg and forkhead box protein 3 (FoxP3)⁺ T_reg in mesenteric lymph node and spleen of the mice. Adoptive transfer of IL-10⁺ B_reg and IL-10⁺ T_reg cell prevented the lung immunopathology in AAI mice. Depletion of FoxP3⁺ T_reg cells in FoxP3-diphtheria toxin (DT) receptor transgenic mice by diphtheria toxin (DT) treatment exacerbated airway inflammation in parasite-free AAI mice and partially abrogated the parasite-induced protection against AAI. IL-10⁺ B_reg cells were able to promote IL-10⁺ T_reg expansion and maintain FoxP3⁺ T_reg cell population. These two types of T_regs failed to induce CD19⁺ B cells to transform into IL-10⁺ B_reg cells. These results demonstrate that B_reg, IL-10⁺ T_reg and FoxP3⁺ T_reg cells contribute in A discrepant manner to the protection against allergic airway immunopathology by parasiteS. B_reg cell might be a key upstream regulatory cell that induces IL-10⁺ T_reg response and supports FoxP3⁺ T_reg cell population which, in turn, mediate the parasite-imposed immunosuppression of allergic airway inflammation. These results provide insight into the immunological relationship between parasite infection and allergic asthma.     

In vitro immunostimulatory potential of fungal β-glucans in pacific red snapper (Lutjanus peru) cells

This study attempts to describe the immunostimulatory effects of three fungal glucans on innate immunity responses in an in vitro assays using Pacific red snapper leukocytes. First, the yield glucans obtained was higher in Aspergillus niger, follow by Aspergillus ochraceus and Alternaria botrytis (40, 20 and 10%, respectively). Structural characterization of these fungal glucans by proton nuclear magnetic resonance (NMR) indicated structures containing (1–6)-branched (1–3)-β-D-glucan. The immunostimulatory activity of fungal glucans were assessed in head-kidney leukocytes at 24 h using colorimetric assays and molecular gene expression. In addition, the response against bacterial infection using Aeromonas hydrophila was evaluated by flow cytometry with annexin V/propidium iodide. Leukocytes responded positively to fungal glucans where the viability was higher than 80%. Interestingly, A. niger β-glucans enhanced the phagocytic ability and capacity in head-kidney leukocytes. Immunological assays reveled an increased in nitric oxide production, myeloperoxidase, superoxide dismutase and catalase activities, in fish stimulated with A. niger β-glucans. Induction of cytokines (IL-1β, TNF-α, IL-6, IL-8 and IL-12) were more pronounced in A. niger β-glucans leukocytes stimulated compared to other group. Finally, flow cytometry assay showed that A. botrytis and A. niger β-glucans were able to inhibit apoptosis caused by Aeromonas hydrophila in the Pacific red snapper leukocytes indicating an immunostimulant potent response by fungi derived-glucans. These results strongly support the idea that fungal β-glucans can stimulate the immune mechanism in head-kidney leukocytes and that Aspergillus niger β-glucan possess immunostimulatory properties cell increasing viability, and reducing necrotic cell death caused by Aeromonas hydrophila.     

Interleukin-5 reduces the expression of uteroglobin-related protein (UGRP) 1 gene in allergic airway inflammation

Airway inflammation is thought to play a major role in the pathogenesis of bronchial asthma. The precise role of individual inflammatory cells, mediator and asthma related genes in allergic lung diseases is not completely understood. The uteroglobin-related protein (UGRP) 1 was proposed to be an asthma candidate gene and play a role in regulating lung inflammation, however its precise function in the airways remains obscure. In this investigation, we used a mouse model of allergic airway inflammation to establish a relationship between UGRP 1 and IL-5 in airway inflammation. Ovalbumin (OVA) challenged mice demonstrate eosinophilia in airway tissues and high levels of IL-5 in bronchoalveolar lavage (BAL) fluid analogous to that found in bronchial asthma. Interestingly, these "OVA-challenged" mice show down-regulation of Ugrp1 expression as compared with the control group. Regression analysis further demonstrates a significant negative correlation between Ugrp1 mRNA expression in the lung and IL-5 levels in BAL fluid with r = 0.948 and P < 0.0001 when IL-5 levels were normalized by log transformation. Intranasal instillation of IL-5 to mice revealed an inhibitory effect of IL-5 on the expression of Ugrp1 mRNA. Together, these results indicate an involvement of IL-5 in the down-regulation of Ugrp1 expression in airway inflammation such as allergic asthma disease.     

Atopy in childhood. III. Relationship with pulmonary function and airway responsiveness

The relationship between atopy and pulmonary function in children, and how these relate directly or indirectly to airway hyperresponsiveness, is uncertain. We have examined these relationships in a sample of 13-year-old children. A questionnaire on respiratory symptoms, skin-prick tests to 11 common allergens, spirometry and an abbreviated methacholine challenge test were completed by 662 members (341 boys) of a birth cohort of New Zealand children followed longitudinally to age 13. There was a significant relationship between the presence and degree of atopy, and baseline pulmonary function. Low FEV1/VC ratios were associated with a greater likelihood of airway responsiveness, not only in subjects with diagnosed asthma, but also in the full cohort and in the sub-group of 426 children who denied asthma or current wheeze. The relationships between baseline FEV1/VC and airway responsiveness were stronger in atopic than in non-atopic children, with the strongest relationships in children sensitive to house dust mite and/or cat dander. In the presence of atopy, progressively lower levels of lung function were strongly associated with a higher prevalence of airway responsiveness (P<0.001). In non-atopic subjects, only those with the most impaired lung function (FEV1/VC < 75%) showed any substantive prevalence of airway responsiveness. The relationship between the degree of atopy and the FEV1/VC ratio, although significant in univariate analysis, became completely non-significant after accounting for airway responsiveness. In 13-year-old children, atopy, especially to house dust mite and cat dander, was correlated with pulmonary function expressed as FEV1/VC ratio. Airway responsiveness likewise correlated with impaired baseline lung function. The apparent relationship of lung function to atopy occurred primarily as a result of the relationship between atopy and airway responsiveness. Atopy and impaired lung function were additive factors predicting airway responsiveness.     

Effect of combination treatment with Lactobacillus rhamnosus and corticosteroid in reducing airway inflammation in a mouse asthma model

BackgroundAsthma is a complex multifactorial chronic airway inflammatory disease with diverse phenotypes and levels of severity and is associated with significant health and economic burden. In a certain population of asthma patients, the symptoms cannot be well controlled with steroid. There has been long standing interest in the use of probiotics for treating allergic diseases. The purpose of this study is to investigate whether the combination of Lactobacillus rhamnosus GG (LGG) with prednisolone could reduce the dosage of glucocorticoid in controlling airway inflammation in a murine model for allergic asthma.Material and methodsWe used Der p 2-sensitized asthma model in female BALB/c mice. The animals were treated with 75 μl or 50 μl oral prednisolone or combination treatment of these two doses of oral prednisolone with LGG. Airway hyperresponsiveness, serum specific IgE/IgG1/IgG2a, infiltrating inflammatory cells in lung and cytokines were assessed.ResultsCompared to 75 μl prednisolone, a lower dose of prednisolone with 50 μl was less satisfactory in suppressing airway hyperresponsives, serum IgE and IgG1, Th2 cytokines and inflammatory cytokines such as IL-6, IL-8 and IL-17 as well as infiltrating inflammatory cells. However, combination of 50 μl prednisolone and LGG decreased airway resistance and serum IgE and IgG1, inhibited the production of IL-4, IL-5, IL-6, IL-8, IL-13 and IL-17, upregulated serum IgG2a and enhanced Th1 immune response.ConclusionsLGG may reduce the dosage of prednisolone and thus may be beneficial in the treatment of asthma.     

Inflammasome activation is required for human rhinovirus-induced airway inflammation in naive and allergen-sensitized mice

Activation of the inflammasome is a key function of the innate immune response that regulates inflammation in response to microbial substances. Inflammasome activation by human rhinovirus (RV), a major cause of asthma exacerbations, has not been well studied. We examined whether RV induces inflammasome activation in vivo, molecular mechanisms underlying RV-stimulated inflammasome priming and activation, and the contribution of inflammasome activation to RV-induced airway inflammation and exacerbation. RV infection triggered lung mRNA and protein expression of pro-IL-1β and NLRP3, indicative of inflammasome priming, as well as cleavage of caspase-1 and pro-IL-1β, completing inflammasome activation. Immunofluorescence staining showed IL-1β in lung macrophages. Depletion with clodronate liposomes and adoptive transfer experiments showed macrophages to be required and sufficient for RV-induced inflammasome activation. TLR2 was required for RV-induced inflammasome priming in vivo. UV irradiation blocked inflammasome activation and RV genome was sufficient for inflammasome activation in primed cells. Naive and house dust mite-treated NLRP3−/− and IL-1β−/− mice, as well as IL-1 receptor antagonist-treated mice, showed attenuated airway inflammation and responsiveness following RV infection. We conclude that RV-induced inflammasome activation is required for maximal airway inflammation and hyperresponsiveness in naive and allergic mice. The inflammasome represents a molecular target for RV-induced asthma exacerbations.