Lower Airway Hyperresponsiveness Research Articles

The association between allergic rhinitis and airway dysfunction and nasal endothelial damage and oxidative stress.

Although lower airway hyperresponsiveness is present in approximately one in three patients with allergic rhinitis (AR), the underlying mechanism remains unclear. To evaluate nasal patency and pulmonary functions in AR independently of the presence of asthma and to investigate the relationships between these and nasal oxidative stress parameters and endothelial damage. Seventy adolescents with AR (AR group - 27 with asthma and 43 without asthma) and 30 healthy controls (HC group) were included in this prospective, cross-sectional study. Endocan and oxidative biomarkers [total oxidant status (TOS), total antioxidant status (TAS), and oxidative stress index (OSI)] in nasal lavage fluid specimens; peak nasal inspiratory flow (PNIF); fractional exhaled nitric oxide (FeNO), and impulse oscillometry (zR5, zR20, and R5-20 for resistance and zX5 and zX20 for reactance) were investigated. Nasal endocan, TOS, and OSI values were higher in the AR group and TAS in the HC group. There was no difference between AR groups with and without asthma in terms of nasal endocan and oxidative biomarkers. FeNO levels and airway resistance (zR5, zR20, and R5-20) were higher in the AR group than in the HC group. However, there was no difference between the groups in PNIF. X5 was higher among the AR without asthma than in the other groups. Correlation between OSI and R5-20 was observed in the AR group. In the linear regression model, (logged) OSI was significantly predicted (logged) R5-20. The airways of adolescents with AR without asthma were as much affected as those of the AR with asthma, and this effect was associated with nasal endothelial damage and an increase in oxidative stress.

The association between allergic rhinitis and airway dysfunction and nasal endothelial damage and oxidative stress.

Although lower airway hyperresponsiveness is present in approximately one in three patients with allergic rhinitis (AR), the underlying mechanism remains unclear. To evaluate nasal patency and pulmonary functions in AR independently of the presence of asthma and to investigate the relationships between these and nasal oxidative stress parameters and endothelial damage. Seventy adolescents with AR (AR group - 27 with asthma and 43 without asthma) and 30 healthy controls (HC group) were included in this prospective, cross-sectional study. Endocan and oxidative biomarkers [total oxidant status (TOS), total antioxidant status (TAS), and oxidative stress index (OSI)] in nasal lavage fluid specimens; peak nasal inspiratory flow (PNIF); fractional exhaled nitric oxide (FeNO), and impulse oscillometry (zR5, zR20, and R5-20 for resistance and zX5 and zX20 for reactance) were investigated. Nasal endocan, TOS, and OSI values were higher in the AR group and TAS in the HC group. There was no difference between AR groups with and without asthma in terms of nasal endocan and oxidative biomarkers. FeNO levels and airway resistance (zR5, zR20, and R5-20) were higher in the AR group than in the HC group. However, there was no difference between the groups in PNIF. X5 was higher among the AR without asthma than in the other groups. Correlation between OSI and R5-20 was observed in the AR group. In the linear regression model, (logged) OSI was significantly predicted (logged) R5-20. The airways of adolescents with AR without asthma were as much affected as those of the AR with asthma, and this effect was associated with nasal endothelial damage and an increase in oxidative stress.

Treatment of Allergic Asthma with Fenretinide Formulation (LAU-7b) Downregulates ORMDL Sphingolipid Biosynthesis Regulator 3 (Ormdl3) Expression and Normalizes Ceramide Imbalance.

Zona pellucida binding protein 2 (Zpbp2) and ORMDL sphingolipid biosynthesis regulator 3 (Ormdl3), mapped downstream of Zpbp2, were identified as two genes associated with airway hyper-responsiveness (AHR). Ormdl3 gene product has been shown to regulate the biosynthesis of ceramides. Allergic asthma was shown to be associated with an imbalance between very-long-chain ceramides (VLCCs) and long-chain ceramides (LCCs). We hypothesized that Fenretinide can prevent the allergic asthma-induced augmentation of Ormdl3 gene expression, normalize aberrant levels of VLCCs and LCCs, and treat allergic asthma symptoms. We induced allergic asthma by house dust mite (HDM) in A/J WT mice and Zpbp2 KO mice expressing lower levels of Ormdl3 mRNA than WT. We investigated the effect of a novel formulation of Fenretinide, LAU-7b, on the AHR, inflammatory cell infiltration, mucus production, IgE levels, and ceramide levels. Although lower Ormdl3 expression, which was observed in Zpbp2 KO mice, was associated with lower AHR, allergic Zpbp2 KO mice were not protected from inflammatory cell infiltration, mucus accumulation, or aberrant levels of VLCCs and LCCs induced by HDM. LAU-7b treatment protects both the Zpbp2 KO and WT mice. The treatment significantly lowers the gene expression of Ormdl3, normalizes the VLCCs and LCCs, and corrects all the other phenotypes associated with allergic asthma after HDM challenge, except the elevated levels of IgE. LAU-7b treatment prevents the augmentation of Ormdl3 expression and ceramide imbalance induced by HDM challenge and protects both WT and Zpbp2 KO mice against allergic asthma symptoms. SIGNIFICANCE STATEMENT: Compared with A/J WT mice, KO mice with Zpbp2 gene deletion have lower AHR and lower levels of Ormdl3 expression. The novel oral clinical formulation of Fenretinide (LAU-7b) effectively lowers the AHR and protects against inflammatory cell infiltration and mucus accumulation induced by house dust mite in both Zpbp2 KO and WT A/J mice. LAU-7b prevents Ormdl3 overexpression in WT allergic mice and corrects the aberrant levels of very-long-chain and long-chain ceramides in both WT and Zpbp2 KO allergic mice.

A retrospective study of clinical features of cough variant asthma in Chinese adults

BackgroundClinical features of cough variant asthma (CVA) in Chinese adults are largely uncertain.MethodsA total of 303 patients newly diagnosed as uncontrolled asthma (symptom control and future risk of adverse outcomes), including 175 CVA and 128 classic asthma (CA), were enrolled in this retrospective survey. Clinical features including basic characteristics, pulmonary function, airway hyperresponsiveness (AHR) and cell counts of induced sputum, were compared retrospectively. All patients were classified into four inflammatory subtypes based on the counts of induced sputum eosinophils and neutrophils as eosinophilic (E), neutrophilic (N), mixed granulocytic (M), and paucigranulocytic (P) subtypes. Inflammatory subtype distribution was also compared.ResultsCompared with CA patients, CVA patients were younger (P = 0.009), had a higher prevalence of female patients (P = 0.001), higher parameter values of baseline pulmonary function (P ≤ 0.01 for all), shorter duration of disease (P = 0.002), lower AHR (P = 0.001) and lower sputum eosinophil% (P = 0.009). There was a difference in the AHR distribution as the percentage of moderate and severe AHR in CVA was significantly lower than in CA (41.72% VS 64.70%, P = 0.001). The inflammatory subtype distribution was different as the proportion of E and M subtypes in CVA was lower than in CA (56.0% vs 67.19%, P = 0.049). The proportion of subtype P was the lowest and subtype M was the highest in both CVA and CA patients. There was a similar negative correlation of sputum eosinophil% with AHR in CVA and CA (r = − 0.337, P < 0.0001 and r = − 0.27, P = 0.026, respectively), and a positive correlation between sputum eosinophil% and improvement rate of FEV1 after inhalation of bronchodilator (ΔFEV1%) (r = 0.33, P = 0.01).ConclusionsCVA patients showed a better pulmonary function and lower airway inflammation in contrast to CA patients, which may participate in the pathogenesis of chronic cough in CVA.

Requirement for neuropeptide Y in the development of type 2 responses and allergen-induced airway hyperresponsiveness and inflammation.

Neuropeptide Y (NPY) is a neurotransmitter that is widely expressed in the brain and peripheral nervous system. Various immune cells express the NPY Y1 receptor. NPY modulates these cells via its Y1 receptor; however, involvement of NPY in the pathophysiology of bronchial asthma, particularly airway hyperresponsiveness (AHR), has not been defined. NPY-deficient and wild-type mice were intranasally sensitized and challenged to house dust mite (HDM) extract, and airway responses were monitored. After sensitization and challenge, NPY-deficient mice showed significantly lower AHR than wild-type mice, and numbers of eosinophils and levels of type 2 cytokines [interleukin (IL)-4, IL-5, and IL-13] in bronchoalveolar lavage fluid were significantly lower. Type 2 cytokine production from splenic mononuclear cells of HDM-sensitized mice was also significantly lower in NPY-deficient mice. Flow cytometry analysis showed that the number of CD4 T cells and CD11c+ antigen-presenting cells (APCs) was significantly lower in the lungs of NPY-deficient mice than in wild-type mice following sensitization and challenge. Significantly fewer CD11c+ APCs phagocytosed HDM in the mediastinal lymph nodes of NPY-deficient mice than in those of wild-type mice. Treatment with BIBO-3304, a NPY receptor antagonist, significantly suppressed development of HDM-induced AHR and inflammation in wild-type mice. These data identify an important contribution of NPY to allergen-induced AHR and inflammation through accumulation of dendritic cells in the airway and promotion of the type 2 immune response. Thus, manipulating NPY represents a novel therapeutic target to control allergic airway responses.

Characteristics of airway hyperresponsiveness in children with chest tightness variant asthma

Objective To analyze the characteristics of airway hyperresponsiveness and fractional exhaled nitric oxide (FeNO) in children with chest tightness variant asthma (CTVA) in comparison with cough variant asthma (CVA) and the typical asthma. Methods From January 2012 to June 2015, 37 atypical asthma children with chest tightness as the sole presenting manifestation were selected as subjects (CTVA group). Meanwhile, 100 children who were newly diagnosed as CVA and 100 children who were newly diagnosed as typical asthma were selected as control group.All of the children in 3 groups had completed FeNO measurement, spirometry and with either positive result of bronchial provocation test or positive result of bronchial dilation test.The differences in FeNO and spirometry data among 3 groups were analyzed. Results FeNO was 11.0(6.0, 33.0) ppb in CTVA group, but 28.0(16.0, 52.0) ppb in typical asthma group, which indicated that FeNO was significantly lower in CTVA group than that in typical asthma group (P 0.05). Conclusion CTVA children have lower airway hyperresponsiveness and lower FeNO than typical asthma children.CTVA children may have similar airway hyperresponsiveness as CVA children. Key words: Chest tightness variant asthma; Hyperresponsiveness; Asthma; Child

The R213G polymorphism in SOD3 protects against allergic airway inflammation.

Oxidative stress is important in the pathogenesis of allergic asthma. Extracellular superoxide dismutase (EC-SOD; SOD3) is the major antioxidant in lungs, but its role in allergic asthma is unknown. Here we report that asthmatics have increased SOD3 transcript levels in sputum and that a single nucleotide polymorphism (SNP) in SOD3 (R213G; rs1799895) changes lung distribution of EC-SOD, and decreases likelihood of asthma-related symptoms. Knockin mice analogous to the human R213G SNP had lower airway hyperresponsiveness, inflammation, and mucus hypersecretion with decreased interleukin-33 (IL-33) in bronchoalveolar lavage fluid and reduced type II innate lymphoid cells (ILC2s) in lungs. SOD mimetic (Mn (III) tetrakis (N-ethylpyridinium-2-yl) porphyrin) attenuated Alternaria-induced expression of IL-33 and IL-8 release in BEAS-2B cells. These results suggest that R213G SNP potentially benefits its carriers by resulting in high EC-SOD in airway-lining fluid, which ameliorates allergic airway inflammation by dampening the innate immune response, including IL-33/ST2-mediated changes in ILC2s.

Mycobacterium vaccae Nebulization Can Protect against Asthma in Balb/c Mice by Regulating Th9 Expression.

Asthma is a heterogeneous disease characterized by chronic airway inflammation. CD4(+) T-helper 9 (Th9) cells are closely linked to asthma, helping to regulate inflammation and immunity. Epidemiological studies showed that mycobacteria infections are negatively associated with asthma. Our previous research showed that inactivated Mycobacterium phlei nebulization alleviated the airway hyperresponsiveness and inflammation of asthma. However, the relationship between Th9 cells and mycobacteria remains unknown. Here, we evaluated the relationship between Mycobacterium vaccae nebulization and Th9 cells in asthmatic mice. Eighteen Balb/c mice were randomized into 3 groups of 6 mice each (normal control group, asthma control group, and nebulization asthma group [Neb. group]). The Neb. group was nebulized with M. vaccae one month before establishment of the asthmatic model with ovalbumin (OVA) sensitization, and the normal and asthma control groups were nebulized with phosphate-buffered saline. The hyperresponsiveness of the mouse airways was assessed using a non-invasive lung function machine. Lung airway inflammation was evaluated by hematoxylin and eosin and periodic acid-Schiff staining. Cytokine interlukin-9 (IL-9) concentration and OVA-specific IgE in the bronchoalveolar lavage fluid were measured by enzyme-linked immunosorbent assays. The percentages of γδTCR+ CD3+, IL-9+CD3+, IL-10+CD3+ lymphocytes, and IL9+γδT and IL-10+γδT cells were detected by flow cytometry. The airway inflammation and concentration of IL-9 and OVA-specific IgE were significantly reduced in the Neb. group compared to the asthma control group. The Neb. group had lower airway hyperresponsiveness, percentages of γδTCR+CD3+ and IL-9+CD3+ lymphocytes, and IL9+γδT cells, and higher percentages of IL-10+CD3+ lymphocytes and IL-10+γδT cells compared to the asthma control group. Thus, mouse bronchial asthma could be prevented by M. vaccae nebulization. The mechanism could involve M. vaccae-mediated effects on induction of IL-9 secretion and suppression of IL-10 secretion from γδT cells. γδT cells showed prominent IL-10 expression, indicating that they possibly belong to the Th9 family.

Lower airway inflammation and hyperresponsiveness in non-asthmatic patients with non-allergic rhinitis.

Potential associations between non-allergic rhinitis (NAR) and asthma have been verified epidemiologically, but these associations remain not very clear. It is necessary to further explore the possible implication of lower airway abnormities in NAR patients but without asthma. This study aims to determine lower airway hyperresponsiveness (AHR), inflammation and lung function in non-asthmatic patients with NAR. We recruited 262 non-asthmatic patients with NAR, 377 with AR and 264 healthy subjects. All subjects were non-smokers who underwent meticulous history taking, nasal examination, allergen skin prick test (SPT), blood routine test, measurement of fractional exhaled nitric oxide (FeNO), methacholine bronchial challenge test and induced sputum eosinophil count, in this order. Compared with healthy subjects, non-asthmatic patients with NAR yielded markedly lower FEV1/FVC, maximal mid-expiratory flow (MMEF), mid-expiratory flow when 50% of FVC has been expired (MEF50%) and mid-expiratory flow when 75% of FVC has been expired (MEF25%) (P<0.05). Differences in spirometry between group AR and NAR were unremarkable (P>0.05). Patients with NAR yielded higher rate of AHR and higher FeNO levels than healthy subjects but lower than those with AR. The proportion of lower airways disorders (sputum eosinophilia, high FeNO levels or AHR) was highest in group AR (70.8%), followed by NAR (53.4%) and healthy subjects (24.2%) (P<0.01). However, sputum eosinophils in NAR patients were not higher compared with healthy subjects (P>0.05). Sputum eosinophils and FeNO had significant correlation with positive AHR and MMEF in group AR but not in NAR. Non-asthmatic patients with NAR harbor lower AHR, small airways dysfunction and inflammation, despite being less significant than those with AR. This offers clues to unravel the link between NAR and asthma.

Proton-Sensing Ovarian Cancer G Protein-Coupled Receptor 1 on Dendritic Cells Is Required for Airway Responses in a Murine Asthma Model

Ovarian cancer G protein-coupled receptor 1 (OGR1) stimulation by extracellular protons causes the activation of G proteins and subsequent cellular functions. However, the physiological and pathophysiological roles of OGR1 in airway responses remain largely unknown. In the present study, we show that OGR1-deficient mice are resistant to the cardinal features of asthma, including airway eosinophilia, airway hyperresponsiveness (AHR), and goblet cell metaplasia, in association with a remarkable inhibition of Th2 cytokine and IgE production, in an ovalbumin (OVA)-induced asthma model. Intratracheal transfer to wild-type mice of OVA-primed bone marrow-derived dendritic cells (DCs) from OGR1-deficient mice developed lower AHR and eosinophilia after OVA inhalation compared with the transfer of those from wild-type mice. Migration of OVA-pulsed DCs to peribronchial lymph nodes was also inhibited by OGR1 deficiency in the adoption experiments. The presence of functional OGR1 in DCs was confirmed by the expression of OGR1 mRNA and the OGR1-sensitive Ca2+ response. OVA-induced expression of CCR7, a mature DC chemokine receptor, and migration response to CCR7 ligands in an in vitro Transwell assay were attenuated by OGR1 deficiency. We conclude that OGR1 on DCs is critical for migration to draining lymph nodes, which, in turn, stimulates Th2 phenotype change and subsequent induction of airway inflammation and AHR.

A single injection of a sustained-release prostacyclin analog (ONO-1301MS) suppresses airway inflammation and remodeling in a chronic house dust mite-induced asthma model

ONO-1301, a novel prostacyclin agonist with thromboxane A2 synthase inhibitory activity, is a useful agent for ameliorating airway allergic inflammation; however, its short-action feature implies a requirement for the frequent administration of this drug. Therefore, we investigated the effects of ONO-1301-loaded poly (d,l-lactic-co-glycolic acid) microspheres (ONO-1301MS; to release ONO-1301 for 3 weeks) on the airway inflammation and remodeling in chronic house dust mite (HDM)-induced model. Balb/c mice were exposed to an HDM extract intranasally for 5 days/week for 5 consecutive weeks. The mice received a single subcutaneous injection of ONO-1301MS or vehicle after 3 weeks of HDM exposure, followed by 2 additional weeks of HDM exposure. Forty-eight hours after the last HDM exposure, airway hyperresponsiveness to methacholine was assessed and bronchoalveolar lavage was performed. Lung specimens were excised and stained to check for goblet cell metaplasia, airway smooth muscle hypertrophy, and submucosal fibrosis. Mice receiving ONO-1301MS showed significantly lower airway hyperresponsiveness, airway eosinophilia, and induced T helper 2 cytokine production compared with mice receiving the vehicle. Histological findings such as goblet cell metaplasia, airway smooth muscle hypertrophy, and submucosal fibrosis were decreased in ONO-1301MS-treated mice compared with vehicle-treated mice. A single administration of ONO-1301MS achieved sustained elevation of its circulating level for 3 weeks. These data suggest that a single administration of ONO-1301MS may suppress airway hyperresponsiveness, airway allergic inflammation, and development of airway remodeling in chronic HDM-induced asthma model. This agent may be effective as an anti-inflammatory and remodeling drug in the practical treatment of asthma.

The role of the extracellular matrix protein mindin in airway response to environmental airways injury.

Background: Our previous work demonstrated that the extracellular matrix protein mindin contributes to allergic airways disease. However, the role of mindin in nonallergic airways disease has not previously been explored.Objectives: We hypothesized that mindin would contribute to airways disease after inhalation of either lipopolysaccharide (LPS) or ozone.Methods: We exposed C57BL/6J and mindin-deficient (–/–) mice to aerosolized LPS (0.9 μg/m3 for 2.5 hr), saline, ozone (1 ppm for 3 hr), or filtered air (FA). All mice were evaluated 4 hr after LPS/saline exposure or 24 hr after ozone/FA exposure. We characterized the physiological and biological responses by analysis of airway hyperresponsiveness (AHR) with a computer-controlled small-animal ventilator (FlexiVent), inflammatory cellular recruitment, total protein in bronchoalveolar lavage fluid (BALF), proinflammatory cytokine profiling, and ex vivo bronchial ring studies.Results: After inhalation of LPS, mindin–/– mice demonstrated significantly reduced total cell and neutrophil recruitment into the airspace compared with their wild-type counterparts. Mindin–/– mice also exhibited reduced proinflammatory cytokine production and lower AHR to methacholine challenge by FlexiVent. After inhalation of ozone, mice had no detectible differences in cellular inflammation or total BALF protein dependent on mindin. However, mindin–/– mice were protected from increased proinflammatory cytokine production and AHR compared with their C57BL/6J counterparts. After ozone exposure, bronchial rings derived from mindin–/– mice demonstrated reduced constriction in response to carbachol.Conclusions: These data demonstrate that the extracellular matrix protein mindin modifies the airway response to both LPS and ozone. Our data support a conserved role of mindin in production of proinflammatory cytokines and the development of AHR in two divergent models of reactive airways disease, as well as a role of mindin in airway smooth muscle contractility after exposure to ozone.

A prostacyclin agonist with thromboxane inhibitory activity for airway allergic inflammation in mice

ONO-1301 is a novel drug that acts as a prostacyclin agonist with thromboxane A(2) (TxA(2)) synthase inhibitory activity. We investigated the effect of ONO-1301 on development of airway allergic inflammation. Mice sensitized and challenged to ovalbumin (OVA) received ONO-1301, OKY-046 (TxA(2) synthase inhibitor), beraprost, a prostacyclin receptor (IP) agonist, ONO-1301 plus CAY10449 (selective IP antagonist) or vehicle during the challenge period. Twenty-four hours after the OVA challenge, airway hyperresponsiveness (AHR) to methacholine was assessed and bronchoalveolar lavage was performed. Lung specimens were excised for goblet cell staining and analysis of lung dendritic cells (DCs). Bone marrow-derived dendritic cells (BMDCs) were generated, in the presence or absence of drugs, for analysis of DC function. Mice that received ONO-1301 showed significantly lower AHR, airway eosinophilia, T-helper type 2 cytokine levels, mucus production and lung DCs numbers than vehicle-treated mice. These effects of ONO-1301 were mostly reversed by CAY10449. BMDCs treated with ONO-1301 alone showed lower DC functions, such as expression of costimulatory factors or stimulation to spleen T cells. These data suggest that ONO-1301 may suppress AHR and airway allergic inflammation through modulation of DCs, mainly mediated through the IP receptor. This agent may be effective as an anti-inflammatory drug in the treatment of asthma.

Toll like receptor-2 modulates both innate and adaptive immune responses during chronic fungal asthma in mice

We investigated the effect of TLR2 gene deletion in a murine model of chronic fungal asthma. TLR2 wildtype (TLR2(+/+)) and TLR2 deficient (TLR2(-/-)) mice were sensitized to soluble A. fumigatus antigens and challenged with live A. fumigatus conidia, and the extent of allergic airways disease was analyzed in both groups of mice at 3, 7, 14, and 30 days after conidia. At day 7 post-conidia, TLR2(-/-) mice exhibited significantly lower airway hyperresponsiveness, airway inflammation, and whole lung Th2 cytokine levels compared with the TLR2(+ / +) group. TLR2 deletion also significantly reduced mucus cell metaplasia and peribronchial fibrosis at day 30 after conidia. However, fungal material persisted in the TLR2(-/-) group, and at day 30 after conidia TLR2(-/-) mice exhibited enhanced airway neutrophil recruitment and airway hyperresponsiveness. Thus, during chronic fungal asthma in mice, TLR2 is a major contributor to the maintenance of the adaptive Th2-cytokine driven and anti-fungal innate responses.

Rhinobronchial syndrome: Pathogenesis and correlation with allergic rhinitis in children

In the rhinobronchial syndrome a direct causal relationship exists between local nasal irritation and bronchopulmonary disease. Although allergic rhinitis has often been associated with lower airway hyperresponsiveness, no direct relationship between the two has been shown to date. The aim of this study was to determine the role of allergic rhinitis in the pathogenesis of the rhinobronchial syndrome in children by evaluating the effect of topical nasal treatment on lower airway hyperresponsiveness. A total of 168 children presenting with aeroallergy and nasal disease associated with bronchopulmonary disease (asthma, chronic cough, bronchopulmonary infection) were evaluated at baseline and at 1 year of follow-up. Nearly half (83) were noted to have signs of allergic rhinitis and were treated with topical nasal medications (cortisones and antihistamines). Changes in upper and lower airway diseases were evaluated and potential causal relationships established. Allergic rhinitis treatment improved nasal disease symptoms in 67 (80.7%) patients; partial remission or lower healing rates were found in those with asthma (16.4%) and chronic cough (11.1%). Although often associated with lower airway hyperresponsiveness, allergic rhinitis in children does not appear to be a pathogenetic factor, as confirmed by the scarce effect the nasal treatment had on the bronchopulmonary disease. Instead, the frequent co-existence of nasal and bronchial symptoms may come under the concept of global allergy of the airways.

Indoleamine 2,3-Dioxygenase is not required for tolerance induction in the airways but is important for allergic airway disease (39.8)

Abstract Indoleamine 2,3 dioxgenase (IDO) has emerged as an important negative regulator of immune responses. However, the role of IDO in Th2 cell-mediated diseases is not completely clear. We investigated the role of IDO in the induction of inflammation or tolerance in the airways in response to ovalbumin (OVA). The results of these experiments show that IDO−/− mice are susceptible to tolerance induction. However, IDO−/− mice displayed significantly lower airway hyperresponsiveness (AHR), lower serum OVA-specific IgE and lower Th2 type cytokines (IL-5 and IL-13) in comparison to wt mice. In an OVA-induced chronic airway inflammation model, the IDO−/− mice also showed lower AHR and Th2 type cytokines in the lung and less infiltration of inflammatory cells in the airways. To dissect the mechanism underlying IDO-mediated promotion of allergic airway disease, we stimulated lung DC by allergens in vitro. The expression of important co-stimulatory molecules and MHC-II was lower in DCs from IDO−/− mice in comparison to those in DCs from wt control mice suggesting that the reduced airway Th2 type immune response in IDO−/− mice may be due, at least in part, to less effective co-stimulation between DCs and T cells. In summary, our data suggest that IDO is not required for the induction of airway tolerance, but may play a role in promoting Th2-induced allergic airway disease. Supported by NIH grants HL 77430 (to A.R) and HL60207 (to P.R.)

Differential role of CD4 and CD8 T cells in RSV immune pathology (43.28)

Abstract CD4 and CD8 T cells produce different cytokines during immune response. Using a model of respiratory syncytial virus (RSV) infection, isolated CD4 T cells were found to produce predominantly Th2, while CD8 produced predominantly Th1 cytokines. To better understand the contribution of CD4 and CD8 T cells in immune pathology during RSV infection, CD4 and CD8 T cells were depleted using specific depleting antibodies and immune response was compared with control mice during RSV infection. Depletion of CD8 T cells showed increased airway hyperresponsiveness (AHR), production of IL-13, as well as increased mucus-associated gene, Gob5, expression. Specific depletion of CD4 induced lower AHR compared to control mice, lower Th2 cytokines and reduced Gob5 production. PAS staining showed both control and CD8 depleted mice with increase mucus production and increased goblet cell hyperplasia whereas mice depleted of CD4 T cell did not produce mucus. These results indicate that CD8 T cells are protective whereas CD4 T cells are responsible for increased pathology observed during RSV infection. This work was supported in part by NIH RO1AI036302.

Role for macrophage migration inhibitory factor in asthma

Macrophage migration inhibitory factor (MIF) is an immunologic regulator that is expressed in inflammatory and autoimmune disorders. We investigated MIF's role in asthma using genetic approaches in a mouse model and in a cohort of asthma patients. Mice genetically deficient in MIF that were primed and aerosol-challenged with ovalbumin showed less pulmonary inflammation and lower airway hyperresponsiveness than genetically matched, wild-type controls. MIF deficiency also resulted in lower titers of specific IgE, IgG(1), and IgG(2a), and decreased pulmonary, T(H)2 cytokine levels. IL-5 concentrations were lower and corresponded to decreased eosinophil numbers in bronchoalveolar lavage fluid. T cell studies also showed a lower level of antigen-specific responses in MIF-KO versus wild-type mice. In an analysis of 151 white patients with mild, moderate, or severe asthma (Global Initiative for Asthma criteria), a significant association was found between mild asthma and the low-expression, 5-CATT MIF allele. Pharmacologic inhibition of MIF may be beneficial and could be guided by the MIF genotype of affected individuals.

Itch, sneeze and wheeze: the genetics of atopic allergy

In many developed countries over one-fifth of the population are affected by one or more atopic allergic disorders. Several time-trend studies indicate that the prevalence and severity of eczema, rhinitis, and asthma is rapidly increasing1,2,3; and this observation, coupled with the widespread geographical variations in disease prevalence noted by the International Studies of Asthma and Allergies in Childhood, points to the strong contribution of environment to the aetiology4. However, the tendency of atopic allergic conditions to cluster both within individuals and within families suggests that genetic factors are also important. Asthma is a condition characterized by reversible airflow obstruction and lower airway hyper-responsiveness, which results in episodic cough, wheeze and shortness of breath5. Inflammation of the nasal passages, manifesting as sneezing, nasal blockage and itchy rhinorrhoea, is the symptom complex known as rhinitis6. Eczema is the commonest cause of dermatitis in developed countries and affects approximately 20% of the general population7. The distribution of eczematous lesions varies with age, the face and trunk being most affected in infants whereas the flexor aspects of the limbs are typically affected in older children and adults. Advances in our understanding of the immunobiology of these disorders have shown them to have a common pathophysiological basis—an exaggerated and inappropriate IgE-mediated inflammation in response to allergen exposure—referred to as atopy8. The absence of objective and reliable criteria for defining either atopy or the atopic allergic conditions (eczema, rhinitis and asthma) has been and continues to be a major obstacle to establishing the genetic basis of atopic disorders. This review is based in the main on articles retrieved by searching Medline, EMBASE and OMIM (Online Mendelian Inheritance in Man) electronic databases. Key websites of possible relevance were also searched9, including those of the British Society for Human Genetics10, the European Society for Human Genetics11, and the Human Mutation Database12. Allergy and genetic texts were consulted, and the analysis was helped by personal contacts with several experts on human genetics.

Hyperresponsiveness as a Determinant of the Outcome in Chronic Obstructive Pulmonary Disease

A better outcome of patients with chronic obstructive pulmonary disease (COPD) appears to be determined by higher FEV1, smoking cessation, lower airway hyperresponsiveness, and, at least in the presence of therapy, with a higher reversibility of airflow obstruction. In our opinion, these findings provide a firm ground for smoking cessation and most likely for institution of early treatment directed at both the reversible part of airflow obstruction and airway hyperresponsiveness in patients with COPD. But there are large gaps in our understanding of the effects of bronchodilator and antiinflammatory drugs on airway hyperresponsiveness. After acute administration, sympathomimetics cause a larger reduction of airway hyperresponsiveness than do anticholinergics, both in asthma and in COPD. What happens after longer periods of treatment is not yet clear in COPD, whereas in asthma there may occur a deterioration of airway responsiveness. Corticosteroids appear to have a beneficial effect on lung function and the severity of airway hyperresponsiveness in asthma. In COPD, however, no definite conclusion can be drawn as to the beneficial effect of corticosteroids, but short-term effects are not promising. The available data from the literature strongly suggest the need for long-term studies with large groups of patients in order to assess a potential treatment effect. In this way, also, a subgroup of patients with COPD who improve with corticosteroids and/or bronchodilators may be found. It seems advisable to include both subjective (i.e., quality of life, complaints, symptoms) and objective (i.e., hospitalization, survival, FEV1, PEFR, PC20, and reversibility) data as investigational tools for outcome analysis.