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1.  Extracellular Cyclophilin Levels Associate with Parameters of Asthma in Phenotypic Clusters 
Objective
Leukocyte persistence during chronic (quiescent) phases of asthma is a major hallmark of the disease. The mechanisms regulating these persistent leukocyte populations are not clearly understood. An alternative family of chemoattracting proteins, cyclophilins, has recently been shown to contribute to leukocyte recruitment in animal models of allergic asthma. The goal of this study was to determine if cyclophilins are present in asthma patients during the chronic phase of disease, and to investigate whether levels of cyclophilins associate with clinical parameters of disease severity.
Methods
Nasal wash samples from an urban cohort of 137 6- to 20-year olds with physician-diagnosed asthma were examined for the presence of cyclophilin A (CypA), cyclophilin B (CypB), as well as several other classical chemokines. Linear, logistic, or ordinal regressions were performed to identify associations between cyclophilins, chemokines, and clinical parameters of asthma. The asthma cohort was further divided into previously established phenotypic clusters (Cluster 1 n=55; cluster 2 n=31; and cluster 3 n=51), and examined for associations.
Results
Levels of CypB in the asthma group were highly elevated compared to non-asthmatic controls, while a slight increase in MCP-1 was also observed. CypA and MCP-1 were associated with levels of eosinophil cationic protein (ECP; a marker of eosinophil activation). Cluster-specific associations were found for CypA and CypB and clinical asthma parameters [e.g. forced expiratory volume in 1 second (FEV1) and ECP].
Conclusions
Cyclophilins are present in nasal wash samples of asthma patients and may be a novel biomarker for clinical parameters of asthma severity.
doi:10.3109/02770903.2011.623334
PMCID: PMC4046105  PMID: 21999750
asthma; cyclophilin; chemokine; cluster analysis; phenotype
2.  Novel Approach to Inhibit Asthma-Mediated Lung Inflammation Using Anti-CD147 Intervention1 
Extracellular cyclophilins have been well described as chemotactic factors for various leukocyte subsets. This chemotactic capacity is dependent upon interaction of cyclophilins with the cell surface signaling receptor CD147. Elevated levels of extracellular cyclophilins have been documented in several inflammatory diseases. We propose that extracellular cyclophilins, via interaction with CD147, may contribute to the recruitment of leukocytes from the periphery into tissues during inflammatory responses. In this study, we examined whether extracellular cyclophilin-CD147 interactions might influence leukocyte recruitment in the inflammatory disease allergic asthma. Using a mouse model of asthmatic inflammation, we show that 1) extracellular cyclophilins are elevated in the airways of asthmatic mice; 2) mouse eosinophils and CD4+ T cells express CD147, which is up-regulated on CD4+ T cells upon activation; 3) cyclophilins induce CD147-dependent chemotaxis of activated CD4+ T cells in vitro; 4) in vivo treatment with anti-CD147 mAb significantly reduces (by up to 50%) the accumulation of eosinophils and effector/memory CD4+ T lymphocytes, as well as Ag-specific Th2 cytokine secretion, in lung tissues; and 5) anti-CD147 treatment significantly reduces airway epithelial mucin production and bronchial hyperreactivity to methacholine challenge. These findings provide a novel mechanism whereby asthmatic lung inflammation may be reduced by targeting cyclophilin-CD147 interactions.
PMCID: PMC2855298  PMID: 16982929
3.  A Cell-Impermeable Cyclosporine A Derivative Reduces Pathology in a Mouse Model of Allergic Lung Inflammation 
Although the main regulators of leukocyte trafficking are chemokines, another family of chemotactic agents is cyclophilins. Intracellular cyclophilins function as peptidyl-protyl cis-trans isomerases and are targets of the immunosuppressive drug, cyclosporine A (CsA). Cyclophilins can also be secreted in response to stress factors, with elevated levels of extracellular cyclophilins detected in several inflammatory diseases. Extracellular cyclophilins are known to have potent chemotactic properties, suggesting they might contribute to inflammatory responses by recruiting leukocytes into tissues. The objective of the current study was to determine the impact of blocking cyclophilin activity using a cell-impermeable derivative of CsA, MM218, to specifically target extracellular pools of cyclophilins. We show that treatment with this compound in a mouse model of allergic lung inflammation: 1) demonstrates up to 80% reduction in inflammation, 2) directly inhibits the recruitment of antigen-specific CD4+ T cells, and 3) works equally well when delivered at 100-fold lower doses to the airways. Our findings suggest that cell-impermeable analogs of CsA can effectively reduce inflammatory responses by targeting leukocyte recruitment mediated by extracellular cyclophilins. Specifically blocking the extracellular function(s) of cyclophilins may provide a novel approach for inhibiting the recruitment of one of the principal immune regulators of allergic lung inflammation, antigen-specific CD4+ T cells, into inflamed airways and lungs.
doi:10.4049/jimmunol.1001707
PMCID: PMC3603141  PMID: 21057089
4.  Preferential chemotaxis of activated human CD4+ T cells by extracellular cyclophilin A 
Journal of leukocyte biology  2007;82(3):613-618.
The recruitment and trafficking of leukocytes are essential aspects of the inflammatory process. Although chemokines are thought to be the main regulators of cell trafficking, extracellular cyclophilins have been shown recently to have potent chemoattracting properties for human leukocytes. Cyclophilins are secreted by a variety of cell types and are detected at high levels in tissues with ongoing inflammation. CD147 has been identified as the main signaling receptor for cyclophilin A (CypA) on human leukocytes. It is interesting that the expression of CD147 is elevated on leukocytes from inflamed tissue, suggesting a correlation among the presence of extracellular cyclophilins, CD147 expression, and inflammatory responses. Thus, cyclophilin-CD147 interactions may contribute directly to the recruitment of leukocytes into inflamed tissues. In the current studies, we show that activated human T lymphocytes express elevated levels of CD147, compared with resting T cells and that these activated T cells migrate more readily to CypA than resting cells. Furthermore, we show that unlike resting CD4+ T cells, the cyclophilin-mediated migration of activated T cells does not require interaction with heparan sulfate receptors but instead, is dependent on CD147 interaction alone. Such findings suggest that cyclophilin-CD147 interactions will be most potent when leukocytes are in an activated state, for example, during inflammatory responses. Thus, targeting cyclophilin-CD147 interactions may provide a novel approach for alleviating tissue inflammation.
doi:10.1189/jlb.0506317
PMCID: PMC2846690  PMID: 17540735
chemokines; inflammation
5.  Extracellular Cyclophilins Contribute to the Regulation of Inflammatory Responses1 
The main regulators of leukocyte trafficking during inflammatory responses are chemokines. However, another class of recently identified chemotactic agents is extracellular cyclophilins, the proteins mostly known as receptors for the immunosuppressive drug, cyclosporine A. Cyclophilins can induce leukocyte chemotaxis in vitro and have been detected at elevated levels in inflamed tissues, suggesting that they might contribute to inflammatory responses. We recently identified CD147 as the main signaling receptor for cyclophilin A. In the current study we examined the contribution of cyclophilin-CD147 interactions to inflammatory responses in vivo using a mouse model of acute lung injury. Blocking cyclophilin-CD147 interactions by targeting CD147 (using anti-CD147 Ab) or cyclophilin (using nonimmunosuppressive cyclosporine A analog) reduced tissue neutrophilia by up to 50%, with a concurrent decrease in tissue pathology. These findings are the first to demonstrate the significant contribution of cyclophilins to inflammatory responses and provide a potentially novel approach for reducing inflammation-mediated diseases.
PMCID: PMC2862457  PMID: 15972687
6.  Cyclophilin A cooperates with MIP-2 to augment neutrophil migration 
Background
Chemokines contribute to inflammatory responses by inducing leukocyte migration and extravasation. In addition, chemoattractants other than classical chemokines can also be present. Many chemokines have been demonstrated to cooperate, leading to an augmentation in leukocyte recruitment and providing a potential role for the presence of multiple chemoattractants. Extracellular cyclophilins are a group of alternative chemotactic factors, which can be highly elevated during various inflammatory responses and, as we have previously shown, can contribute significantly to neutrophil recruitment in an animal model of acute lung inflammation. In the current studies we investigated whether the most abundant extracellular cyclophilin, CypA, has the capacity to function in partnership with 2 classical chemokines known to be secreted in the same model, macrophage inflammatory protein (MIP)-2/CXCL2 and keratinocyte chemoattractant (KC)/CXCL1.
Methods
Neutrophil migration in response to combinations of CypA and MIP-2 or CypA and KC was measured by in vitro chemotaxis assays. Biochemical responses of neutrophils incubated with the combinations of chemoattractants were determined by changes in chemokine receptor internalization and actin polymerization measured by flow cytometry, and changes in intracellular calcium mobilization measured with a calcium sensitive fluorochrome.
Results
A combination of CypA and MIP-2, but not KC, augmented neutrophil migration. Based on the level of augmentation, the cooperation between CypA and MIP-2 appeared to be synergistic. Evidence that CypA and MIP-2 cooperate at the biochemical level was demonstrated by increases in receptor internalization, calcium mobilization, and actin polymerization.
Conclusion
These findings provide evidence for the capacity of extracellular cyclophilins to interact with classical chemokines, resulting in greater and more efficient leukocyte recruitment.
doi:10.2147/JIR.S20733
PMCID: PMC3218749  PMID: 22096373
chemokine; chemotaxis; inflammation
7.  Prolonged allergen challenge in mice leads to persistent airway remodelling 
Summary
Background
Inflammatory infiltrates, airway hyper-responsiveness, goblet cell hyperplasia and subepithelial thickening are characteristic of chronic asthma. Current animal models of allergen-induced airway inflammation generally concentrate on the acute inflammation following allergen exposure and fail to mimic all of these features.
Objective
The aim of this study was to use a murine model of prolonged allergen-induced airway inflammation in order to characterize the cells and molecules involved in the ensuing airway remodelling. Moreover, we investigated whether remodelling persists in the absence of continued allergen challenge.
Methods
Acute pulmonary eosinophilia and airways hyper-reactivity were induced after six serial allergen challenges in sensitized mice (acute phase). Mice were subsequently challenged three times a week with ovalbumin (OVA) (chronic phase) up to day 55. To investigate the persistence of pathology, one group of mice were left for another 4 weeks without further allergen challenge (day 80).
Results
The extended OVA challenge protocol caused significant airway remodelling, which was absent in the acute phase. Specifically, remodelling was characterized by deposition of collagen as well as airway smooth muscle and goblet cell hyperplasia. Importantly, these airway changes, together with tissue eosinophilia were sustained in the absence of further allergen challenge. Examination of cytokines revealed a dramatic up-regulation of IL-4 and tumour growth factor-β1 during the chronic phase. Interestingly, while IL-4 levels were significantly increased during the chronic phase, levels of IL-13 fell. Levels of the Th1-associated cytokine IFN-γ also increased during the chronic phase.
Conclusion
In conclusion, we have demonstrated that prolonged allergen challenge results in persistent airway wall remodelling.
PMCID: PMC3428844  PMID: 15005746
airway remodelling; allergic airway inflammation; asthma; eosinophils; Th2 cytokines
8.  Compartmentalized chemokine-dependent regulatory T cell inhibition of allergic pulmonary inflammation 
Background
Induction of endogenous regulatory T cells (Tregs) represents an exciting new potential modality for treating allergic diseases such as asthma. Tregs have been implicated in the regulation of asthma but the anatomic location where they exert their regulatory function, and the mechanisms controlling their migration necessary for their suppressive function in asthma are not known. Understanding these aspects of Treg biology will be important for harnessing their power in the clinic.
Objective
To determine the anatomic location where Tregs exert their regulatory function in the sensitization and effector phases of allergic asthma, and to determine the chemokine receptors that control the migration of Tregs to these sites in vivo in mice and in humans.
Methods
The clinical efficacy and the anatomic location of adoptively transferred chemokine receptor-deficient CD4+CD25+ Foxp3+ Tregs was determined in the sensitization and effector phases of allergic airway inflammation in mice. The chemokine receptor expression profile was determined on Tregs recruited into the human airway following bronchoscopic segmental allergen challenge of subjects with asthma.
Results
We show that CCR7, but not CCR4, is required on Tregs to suppress allergic airway inflammation during the sensitization phase. In contrast, CCR4, but not CCR7, is required on Tregs to suppress allergic airway inflammation during the effector phase. Consistent with our murine studies, humans with allergic asthma had an increase in CCR4 expressing functional Tregs in the lung following segmental allergen challenge.
Conclusion
The location of Treg function differs during allergic sensitization and during allergen-induced recall responses in the lung, and that this differential localization is critically dependent on differential chemokine function.
doi:10.1016/j.jaci.2013.03.002
PMCID: PMC3703653  PMID: 23632297
Asthma; regulatory T cells; chemokines; CCR4; CCR7; segmental allergen challenge
9.  A novel subset of CD4+ TH2 memory/effector cells that produce inflammatory IL-17 cytokine and promote the exacerbation of chronic allergic asthma 
The Journal of Experimental Medicine  2010;207(11):2479-2491.
Memory CD4+ T cells that produce both Th2 and Th17 cytokines are increased in the blood of patients with atopic asthma and in the lungs of asthmatic mice, where they contribute to inflammation.
The inflammatory cytokine interleukin (IL)-17 is involved in the pathogenesis of allergic diseases. However, the identity and functions of IL-17–producing T cells during the pathogenesis of allergic diseases remain unclear. Here, we report a novel subset of TH2 memory/effector cells that coexpress the transcription factors GATA3 and RORγt and coproduce TH17 and TH2 cytokines. Classical TH2 memory/effector cells had the potential to produce IL-17 after stimulation with proinflammatory cytokines IL-1β, IL-6, and IL-21. The number of IL-17-TH2 cells was significantly increased in blood of patients with atopic asthma. In a mouse model of allergic lung diseases, IL-17–producing CD4+ TH2 cells were induced in the inflamed lung and persisted as the dominant IL-17–producing T cell population during the chronic stage of asthma. Treating cultured bronchial epithelial cells with IL-17 plus TH2 cytokines induced strong up-regulation of chemokine eotaxin-3, Il8, Mip1b, and Groa gene expression. Compared with classical TH17 and TH2 cells, antigen-specific IL-17–producing TH2 cells induced a profound influx of heterogeneous inflammatory leukocytes and exacerbated asthma. Our findings highlight the plasticity of TH2 memory cells and suggest that IL-17–producing TH2 cells may represent the key pathogenic TH2 cells promoting the exacerbation of allergic asthma.
doi:10.1084/jem.20101376
PMCID: PMC2964570  PMID: 20921287
10.  Is Chronic Asthma Associated with Shorter Leukocyte Telomere Length at Midlife? 
Rationale: Asthma is prospectively associated with age-related chronic diseases and mortality, suggesting the hypothesis that asthma may relate to a general, multisystem phenotype of accelerated aging.
Objectives: To test whether chronic asthma is associated with a proposed biomarker of accelerated aging, leukocyte telomere length.
Methods: Asthma was ascertained prospectively in the Dunedin Multidisciplinary Health and Development Study cohort (n = 1,037) at nine in-person assessments spanning ages 9–38 years. Leukocyte telomere length was measured at ages 26 and 38 years. Asthma was classified as life-course-persistent, childhood-onset not meeting criteria for persistence, and adolescent/adult-onset. We tested associations between asthma and leukocyte telomere length using regression models. We tested for confounding of asthma-leukocyte telomere length associations using covariate adjustment. We tested serum C-reactive protein and white blood cell counts as potential mediators of asthma-leukocyte telomere length associations.
Measurements and Main Results: Study members with life-course-persistent asthma had shorter leukocyte telomere length as compared with sex- and age-matched peers with no reported asthma. In contrast, leukocyte telomere length in study members with childhood-onset and adolescent/adult-onset asthma was not different from leukocyte telomere length in peers with no reported asthma. Adjustment for life histories of obesity and smoking did not change results. Study members with life-course-persistent asthma had elevated blood eosinophil counts. Blood eosinophil count mediated 29% of the life-course-persistent asthma-leukocyte telomere length association.
Conclusions: Life-course-persistent asthma is related to a proposed biomarker of accelerated aging, possibly via systemic eosinophilic inflammation. Life histories of asthma can inform studies of aging.
doi:10.1164/rccm.201402-0370OC
PMCID: PMC4214127  PMID: 24956257
asthma; telomere; aging; longitudinal; developmental phenotype
11.  Absence of α4 but not β2 integrins restrains development of chronic allergic asthma using mouse genetic models 
Experimental hematology  2009;37(6):715-727.e3.
Objective
Chronic asthma is characterized by ongoing recruitment of inflammatory cells and airway hyperresponsiveness leading to structural airway remodeling. Although α4β1 and β2 integrins regulate leukocyte migration in inflammatory diseases and play decisive roles in acute asthma, their role has not been explored under the chronic asthma setting. To extend our earlier studies with α4Δ/Δ and β2−/− mice, which showed that both a4 and b2 integrins have nonredundant regulatory roles in acute ovalbumin (OVA)-induced asthma, we explored to what extent these molecular pathways control development of structural airway remodeling in chronic asthma.
Materials and Methods
Control, α4Δ/Δ, and β2−/−mouse groups, sensitized by intraperitoneal OVA as allergen, received intratracheal OVA periodically over days 8 to 55 to induce a chronic asthma phenotype. Post-OVA assessment of inflammation and pulmonary function (airway hyperresponsiveness), together with airway modeling measured by goblet cell metaplasia, collagen content of lung, and transforming growth factor β1 expression in lung homogenates, were evaluated.
Results
In contrast to control and β2−/− mice, α4Δ/Δ mice failed to develop and maintain the composite chronic asthma phenotype evaluated as mentioned and subepithelial collagen content was comparable to baseline. These data indicate that β2 integrins, although required for inflammatory migration in acute asthma, are dispensable for structural remodeling in chronic asthma.
Conclusion
α4 integrins appear to have a regulatory role in directing transforming growth factor β-induced collagen deposition and structural alterations in lung architecture likely through interactions of Th2 cells, eosinophils, or mast cells with endothelium, resident airway cells, and/or extracellular matrix.
doi:10.1016/j.exphem.2009.03.010
PMCID: PMC3696022  PMID: 19463772
12.  Lung Macrophages Contribute to House Dust Mite Driven Airway Remodeling via HIF-1α 
PLoS ONE  2013;8(7):e69246.
HIF-1α is a transcription factor that is activated during hypoxia and inflammation and is a key regulator of angiogenesis in vivo. During the development of asthma, peribronchial angiogenesis is induced in response to aeroallergens and is thought to be an important feature of sustained chronic allergic inflammation. Recently, elevated HIF-1α levels have been demonstrated in both the lung tissue and bronchoalveolar lavage of allergic patients, respectively. Therefore, we investigated the role of HIF-1α on the development of angiogenesis and inflammation following acute and chronic allergen exposure. Our data shows that intranasal exposure to house dust mite (HDM) increases the expression of HIF-1α in the lung, whilst reducing the expression of the HIF-1α negative regulators, PHD1 and PHD3. Blockade of HIF-1α in vivo, significantly decreased allergic inflammation and eosinophilia induced by allergen, due to a reduction in the levels of IL-5 and Eotaxin-2. Importantly, HIF-1α blockade significantly decreased levels of VEGF-A and CXCL1 in the lungs, which in turn led to a profound decrease in the recruitment of endothelial progenitor cells and a reduction of peribronchial angiogenesis. Furthermore, HDM or IL-4 treatment of primary lung macrophages resulted in significant production of both VEGF-A and CXCL1; inhibition of HIF-1α activity abrogated the production of these factors via an up-regulation of PHD1 and PHD3. These findings suggest that novel strategies to reduce the expression and activation of HIF-1α in lung macrophages may be used to attenuate allergen-induced airway inflammation and angiogenesis through the modulation of VEGF-A and CXCL1 expression.
Clinical Relevance
This study provides new insights into the role of HIF-1α in the development of peribronchial angiogenesis and inflammation in a murine model of allergic airway disease. These findings indicate that strategies to reduce activation of macrophage derived HIF-1α may be used as a target to improve asthma pathology.
doi:10.1371/journal.pone.0069246
PMCID: PMC3720585  PMID: 23935964
13.  CXCR2 Mediates the Recruitment of Endothelial Progenitor Cells During Allergic Airways Remodeling 
Stem cells (Dayton, Ohio)  2009;27(12):3074-3081.
Airway remodeling is a central feature of asthma and includes the formation of new peribronchial blood vessels, which is termed angiogenesis. In a number of disease models, bone marrow-derived endothelial progenitor cells (EPCs) have been shown to contribute to the angiogenic response. In this study we set out to determine whether EPCs were recruited into the lungs in a model of allergic airways disease and to identify the factors regulating EPC trafficking in this model. We observed a significant increase in the number of peribronchial blood vessels at day 24, during the acute inflammatory phase of the model. This angiogenic response was associated with an increase in the quantity of EPCs recoverable from the lung. These EPCs formed colonies after 21 days in culture and were shown to express CD31, von Willebrand factor, and vascular endothelial growth factor (VEGF) receptor 2, but were negative for CD45 and CD14. The influx in EPCs was associated with a significant increase in the proangiogenic factors VEGF-A and the CXCR2 ligands, CXCL1 and CXCL2. However, we show directly that, while the CXCL1 and CXCL2 chemokines can recruit EPCs into the lungs of allergen-sensitized mice, VEGF-A was ineffective in this respect. Further, the blockade of CXCR2 significantly reduced EPC numbers in the lungs after allergen exposure and led to a decrease in the numbers of peribronchial blood vessels after allergen challenge with no effect on inflammation. The data presented here provide in vivo evidence that CXCR2 is critical for both EPC recruitment and the angiogenic response in this model of allergic inflammation of the airways.
doi:10.1002/stem.222
PMCID: PMC3385349  PMID: 19785013
CXC chemokines; Progenitor cell; Asthma; Angiogenesis
14.  Immune response to allergens in sheep sensitized to house dust mite 
Background
House dust mite (HDM) allergens are a major cause of allergic asthma. Most studies using animal models of allergic asthma have used rodents sensitized with the 'un-natural' allergen ovalbumin. It has only recently been recognized that the use of animal models based on HDM provide a more relevant insight into the allergen-induced mechanisms that underpin human allergic disease. We have previously described a sheep model of human allergic asthma that uses Dermatophagoides pteronyssinus HDM. The present study extends our understanding of the immune effects of HDM and the allergens Der p 1 and Der p 2 in the sheep model of asthma.
Methods
Peripheral blood sera from non-sensitized (control) sheep and sheep sensitized to HDM was collected to determine immunoglobulin (Ig) reactivities to HDM, Der p 1 and Der p 2 by ELISA. Bronchoalveolar lavage (BAL) fluid collected following allergen challenge was also assessed for the presence of HDM-specific antibodies. To examine the cellular immune response to HDM allergens, T cell proliferation and cutaneous responses were assessed in sensitized and control sheep.
Results
Strong HDM- and Der p 1-specific IgE, IgG1, IgG2 and IgA serum responses were observed in sensitized sheep, while detectable levels of HDM-specific IgG1 and IgA were seen in BAL fluid of allergen-challenged lungs. In contrast, minimal antibody reactivity was observed to Der p 2. Marked T cell proliferation and late phase cutaneous responses, accompanied by the recruitment of eosinophils, indicates the induction of a cellular and delayed-type hypersensitivity (DTH) type II response by HDM and Der p 1 allergen, but not Der p 2.
Conclusion
This work characterizes the humoral and cellular immune effects of HDM extract and its major constituent allergens in sheep sensitized to HDM. The effects of allergen in HDM-sensitized sheep were detectable both locally and systemically, and probably mediated via enzymatic and immune actions of the major HDM allergen Der p 1. This study extends our understanding of the actions of this important allergen relevant to human allergic asthma and its effects in sheep experimentally sensitized to HDM allergens.
doi:10.1186/1476-9255-5-16
PMCID: PMC2577637  PMID: 18937841
15.  Combined Sensitization of Mice to Extracts of Dust Mites, Ragweed and Aspergillus Breaks through Tolerance and Establishes Chronic Features of Asthma in Mice 
Background
Existing asthma models develop tolerance when chronically exposed to the same allergen.
Objective
To establish a chronic model that sustains features of asthma long after discontinuation of allergen exposure.
Methods
We immunized and exposed mice to a combination of single, double or triple allergens (dust-mite, ragweed, and Aspergillus) intranasally for 8 weeks. Airway hyperreactivity and morphological features of asthma were studied 3 weeks after the allergen exposure. Signaling effects of the allergens were studied on dendritic cells.
Results
Sensitization and repeated exposure to a single allergen induced tolerance. Sensitization to double, and especially triple allergens broke through tolerance and established AHR, eosinophilic inflammation, mast cell and smooth muscle hyperplasia, mucus production and airway remodeling that persisted at least 3 weeks after allergen exposure. Mucosal exposure to triple allergens in the absence of an adjuvant was sufficient to induce chronic airway inflammation. Anti-IL5 and -IL13 antibodies inhibited inflammation and AHR in the acute asthma model but not in the chronic triple allergen model. Multiple allergens produce a synergy in p38 MAPK signaling and maturation of dendritic cells, which provides a heightened T cell co-stimulation at a level that cannot be achieved with a single allergen.
Conclusions
Sensitivity to multiple allergens leads to chronic asthma in mice. Multiple allergens synergize in dendritic cell signaling and T cell stimulation that allows escape from the single allergen-associated tolerance development.
Clinical Implications
We have developed a model of chronic asthma that allows for the study and treatment of long-lasting features of asthma obviating the need for acute de novo allergen challenges.
doi:10.1016/j.jaci.2009.02.009
PMCID: PMC2683988  PMID: 19348928
chronic asthma; mouse; inflammation; airway hyperreactivity; tolerance; dendritic cells
16.  Asthmatic Airway Neutrophilia after Allergen Challenge Is Associated with the Glutathione S-Transferase M1 Genotype 
Rationale: Asthma is a heterogeneous lung disorder characterized by airway inflammation and airway dysfunction, manifesting as hyperresponsiveness and obstruction. Glutathione S-transferase M1 (GSTM1) is a multifunctional phase II enzyme and regulator of stress-activated cellular signaling relevant to asthma pathobiology. A common homozygous deletion polymorphism of the GSTM1 gene eliminates enzyme activity.
Objectives: To determine the effect of GSTM1 on airway inflammation and reactivity in adults with established atopic asthma in vivo.
Methods: Nineteen GSTM1 wild-type and eighteen GSTM1-null individuals with mild atopic asthma underwent methacholine and inhaled allergen challenges, and endobronchial allergen provocations through a bronchoscope.
Measurements and Main Results: The influx of inflammatory cells, panels of cytokines and chemokines linked to asthmatic inflammation, F2-isoprostanes (markers of oxidative stress), and IgE were measured in bronchoalveolar lavage fluid at baseline and 24 hours after allergen instillation. Individuals with asthma with the GSTM1 wild-type genotype had greater baseline and allergen-provoked airway neutrophilia and concentrations of myeloperoxidase than GSTM1-null patients. In contrast, the eosinophilic inflammation was unaffected by GSTM1. The allergen-stimulated generation of acute-stress and proneutrophilic mediators, tumor necrosis factor-α, CXCL-8, IL-1β, and IL-6, was also greater in the GSTM1 wild-type patients. Moreover, post-allergen airway concentrations of IgE and neutrophil-generated mediators, matrix metalloproteinase-9, B-cell activating factor, transforming growth factor-β1, and elastase were higher in GSTM1 wild-type individuals with asthma. Total airway IgE correlated with B-cell activating factor concentrations. In contrast, levels of F2-isoprostane were comparable in both groups. Finally, GSTM1 wild-type individuals with asthma required lower threshold concentrations of allergen to produce bronchoconstriction.
Conclusions: The functional GSTM1 genotype promotes neutrophilic airway inflammation in humans with atopic asthma in vivo.
doi:10.1164/rccm.201204-0786OC
PMCID: PMC3570644  PMID: 23204253
atopic asthma; GSTM1 polymorphism; inflammatory asthma phenotypes; neutrophilic airway inflammation
17.  IL-17-producing peripheral blood CD177+ neutrophils increase in allergic asthmatic subjects 
Background
A T helper cell (TH) 17-biased response has been observed in patients with allergic asthma, particularly in those with neutrophil accumulation in the lung. Therefore, we sought to test the hypothesis that neutrophils might be an important source of interleukin (IL)-17 in allergic asthma.
Methods
Whole peripheral blood cells from non-asthmatic control subjects (n = 17) and patients with mild asthma (n = 7), moderate but persistent asthma (n = 4), or acute asthma (n = 6) were analyzed for IL-17A expression in CD177+ neutrophils. IL-17A expression was also analyzed in CD3+CD4+ and CD3+CD8+ lymphocyte populations. Asthmatic patients were classified as allergic to fungi, indoor allergens, or other allergens (e.g., pollen) based on a positive intradermal allergy test reaction.
Results
The percentage of CD177+ neutrophils in whole blood of asthmatic patients was higher than in healthy controls and highest in the moderate asthma group. Furthermore, the percentage of CD177+IL-17+ neutrophils was elevated in patients with mild asthma, whereas the CD4+ IL-17+ lymphocyte population was higher in asthmatic patients and highest in those with moderate but persistent asthma. We also found that the four patients that were allergic to fungi had the highest percentage of CD177+IL17+ neutrophils and CD8+IL17+ lymphocytes.
Conclusion
IL17+CD177+ Neutrophils increase in allergic asthma patients especially when allergic to fungi. This cell population, through release of IL-17, might be contributing during the initial phase asthmatic disease and/or during disease progression but its role has not yet been established.
doi:10.1186/1710-1492-9-23
PMCID: PMC3704811  PMID: 23822853
Neutrophils; IL-17; Allergic asthma; Blood
18.  Lipoxin A4 stable analogs reduce allergic airway responses via mechanisms distinct from CysLT1 receptor antagonism 
Cellular recruitment during inflammatory/immune responses is tightly regulated. The ability to dampen inflammation is imperative for prevention of chronic immune responses, as in asthma. Here we investigated the ability of lipoxin A4 (LXA4) stable analogs to regulate airway responses in two allergen-driven models of inflammation. A 15-epi-LXA4 analog (ATLa) and a 3-oxa-15-epi-LXA4 analog (ZK-994) prevented excessive eosinophil and T lymphocyte accumulation and activation after mice were sensitized and aerosol-challenged with ovalbumin. At <0.5 mg/kg, these LXA4 analogs reduced leukocyte trafficking into the lung by >50% and to a greater extent than equivalent doses of the CysLT1 receptor antagonist montelukast. Distinct from montelukast, ATLa treatment led to marked reductions in cysteinyl leukotrienes, interleukin-4 (IL-4), and IL-10, and both ATLa and ZK-994 inhibited levels of IL-13. In cockroach allergen-induced airway responses, both intraperitoneal and oral administration of ZK-994 significantly reduced parameters of airway inflammation and hyper-responsiveness in a dose-dependent manner. ZK-994 also significantly changed the balance of Th1/Th2-specific cytokine levels. Thus, the ATLa/LXA4 analog actions are distinct from CysLT1 antagonism and potently block both allergic airway inflammation and hyper-reactivity. Moreover, these results demonstrate these analogs’ therapeutic potential as new agonists for the resolution of inflammation.
doi:10.1096/fj.07-8653com
PMCID: PMC3005621  PMID: 17625069
resolution; lipid mediators; leukocytes
19.  Peripheral Erythrocytes Decrease upon Specific Respiratory Challenge with Grass Pollen Allergen in Sensitized Mice and in Human Subjects 
PLoS ONE  2014;9(1):e86701.
Background and Aims
Specific hyper-responsiveness towards an allergen and non-specific airway hyperreactivity both impair quality of life in patients with respiratory allergic diseases. We aimed to investigate cellular responses following specific and non-specific airway challenges locally and systemically in i) sensitized BALB/c mice challenged with grass pollen allergen Phl p 5, and in ii) grass pollen sensitized allergic rhinitis subjects undergoing specific airway challenge in the Vienna Challenge Chamber (VCC).
Methods and Results
BALB/c mice (n = 20) were intraperitoneally immunized with grass pollen allergen Phl p 5 and afterwards aerosol challenged with either the specific allergen Phl p 5 (n = 10) or the non-specific antigen ovalbumin (OVA) (n = 10). A protocol for inducing allergic asthma as well as allergic rhinitis, according to the united airway concept, was used. Both groups of exposed mice showed significantly reduced physical activity after airway challenge. Specific airway challenge further resulted in goblet cell hyperplasia, enhanced mucous secretion, intrapulmonary leukocyte infiltration and lymphoid follicle formation, associated with significant expression of IL-4, IL-5 and IL-13 in splenocytes and also partially in lung tissue. Concerning circulating blood cell dynamics, we observed a significant drop of erythrocyte counts, hemoglobin and hematocrit levels in both mouse groups, challenged with allergen or OVA. A significant decrease in circulating erythrocytes and hematocrit levels after airway challenges with grass pollen allergen was also found in grass pollen sensitized human rhinitis subjects (n = 42) at the VCC. The effects on peripheral leukocyte counts in mice and humans however were opposed, possibly due to the different primary inflammation sites.
Conclusion
Our data revealed that, besides significant leukocyte dynamics, particularly erythrocytes are involved in acute hypersensitivity reactions to respiratory allergens. A rapid recruitment of erythrocytes to the lungs to compensate for hypoxia is a possible explanation for these findings.
doi:10.1371/journal.pone.0086701
PMCID: PMC3899302  PMID: 24466205
20.  Association of Adenotonsillectomy with Asthma Outcomes in Children: A Longitudinal Database Analysis 
PLoS Medicine  2014;11(11):e1001753.
Rakesh Bhattacharjee and colleagues use data from a US private health insurance database to compare asthma severity measures in children one year before and one year after they underwent adenotonsillectomy with asthma measures in those who did not undergo adenotonsillectomy.
Please see later in the article for the Editors' Summary
Background
Childhood asthma and obstructive sleep apnea (OSA), both disorders of airway inflammation, were associated in recent observational studies. Although childhood OSA is effectively treated by adenotonsillectomy (AT), it remains unclear whether AT also improves childhood asthma. We hypothesized that AT, the first line of therapy for childhood OSA, would be associated with improved asthma outcomes and would reduce the usage of asthma therapies in children.
Methods and Findings
Using the 2003–2010 MarketScan database, we identified 13,506 children with asthma in the United States who underwent AT. Asthma outcomes during 1 y preceding AT were compared to those during 1 y following AT. In addition, 27,012 age-, sex-, and geographically matched children with asthma without AT were included to examine asthma outcomes among children without known adenotonsillar tissue morbidity. Primary outcomes included the occurrence of a diagnostic code for acute asthma exacerbation (AAE) or acute status asthmaticus (ASA). Secondary outcomes included temporal changes in asthma medication prescriptions, the frequency of asthma-related emergency room visits (ARERs), and asthma-related hospitalizations (ARHs). Comparing the year following AT to the year prior, AT was associated with significant reductions in AAE (30.2%; 95% CI: 25.6%–34.3%; p<0.0001), ASA (37.9%; 95% CI: 29.2%–45.6%; p<0.0001), ARERs (25.6%; 95% CI: 16.9%–33.3%; p<0.0001), and ARHs (35.8%; 95% CI: 19.6%–48.7%; p = 0.02). Moreover, AT was associated with significant reductions in most asthma prescription refills, including bronchodilators (16.7%; 95% CI: 16.1%–17.3%; p<0.001), inhaled corticosteroids (21.5%; 95% CI: 20.7%–22.3%; p<0.001), leukotriene receptor antagonists (13.4%; 95% CI: 12.9%–14.0%; p<0.001), and systemic corticosteroids (23.7%; 95% CI: 20.9%–26.5%; p<0.001). In contrast, there were no significant reductions in these outcomes in children with asthma who did not undergo AT over an overlapping follow-up period. Limitations of the MarketScan database include lack of information on race and obesity status. Also, the MarketScan database does not include information on children with public health insurance (i.e., Medicaid) or uninsured children.
Conclusions
In a very large sample of privately insured children, AT was associated with significant improvements in several asthma outcomes. Contingent on validation through prospectively designed clinical trials, this study supports the premise that detection and treatment of adenotonsillar tissue morbidity may serve as an important strategy for improving asthma control.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
The global burden of asthma has been rising steadily over the past few decades. Nowadays, about 200–300 million adults and children worldwide are affected by asthma, a chronic condition caused by inflammation of the airways (the tubes that carry air in and out of the lungs). Although asthma can develop at any age, it is often diagnosed in childhood—asthma is one of the commonest chronic diseases in children. In the US, for example, asthma affects around 7.1 million children under the age of 18 years and is the third leading cause of hospitalization of children under the age of 15 years. In people with asthma, the airways can react very strongly to allergens such as animal fur or to irritants such as cigarette smoke. Exercise, cold air, and infections can trigger asthma attacks, which can be fatal. The symptoms of asthma include wheezing, coughing, chest tightness, and shortness of breath. Asthma cannot be cured, but drugs can relieve its symptoms and prevent acute asthma attacks.
Why Was This Study Done?
Recent studies have found an association between severe childhood asthma and obstructive sleep apnea (OSA). In OSA, airway inflammation promotes hypertrophy (excess growth) of the adenoids and the tonsils, immune system tissues in the upper airway. During sleep, the presence of hypertrophic adenotonsillar tissues predisposes the walls of the throat to collapse, which results in apnea—a brief interruption in breathing. People with OSA often snore loudly and frequently wake from deep sleep as they struggle to breathe. Childhood OSA, which affects 2%–3% of children, can be effectively treated by removal of the adenoids and tonsils (adenotonsillectomy). Given the association between childhood OSA and severe asthma and given the involvement of airway inflammation in both conditions, might adenotonsillectomy also improve childhood asthma? Here, the researchers analyze data from the MarketScan database, a large database of US patients with private health insurance, to investigate whether adenotonsillectomy is associated with improvements in asthma outcomes and with reductions in the use of asthma therapies in children.
What Did the Researchers Do and Find?
The researchers used the database to identify 13,506 children with asthma who had undergone adenotonsillectomy and to obtain information about asthma outcomes among these children for the year before and the year after the operation. Because asthma severity tends to decrease with age, the researchers also used the database to identify 27,012 age-, sex-, and geographically matched children with asthma who did not have the operation so that they could examine asthma outcomes over an equivalent two-year period in the absence of complications related to adenotonsillar hypertrophy. Comparing the year after adenotonsillectomy with the year before the operation, adenotonsillectomy was associated with a 30% reduction in acute asthma exacerbations, a 37.9% reduction in acute status asthmaticus (an asthma attack that is unresponsive to the drugs usually used to treat attacks), a 25.6% reduction in asthma-related emergency room visits, and a 35.8% reduction in asthma-related hospitalizations. By contrast, among the control children, there was only a 2% reduction in acute asthma exacerbations and only a 7% reduction in acute status asthmaticus over an equivalent two-year period. Adenotonsillectomy was also associated with significant reductions (changes unlikely to have occurred by chance) in prescription refills for most types of drugs used to treat asthma, whereas there were no significant reductions in prescription refills among children with asthma who had not undergone adenotonsillectomy. The study was limited by the lack of measures of race and obesity, which are both associated with severity of asthma.
What Do These Findings Mean?
These findings show that in a large sample of privately insured children in the US, adenotonsillectomy was associated with significant improvements in several asthma outcomes. These results do not show, however, that adenotonsillectomy caused a reduction in the severity of childhood asthma. It could be that the children who underwent adenotonsillectomy (but not those who did not have the operation) shared another unknown factor that led to improvements in their asthma over time. To prove a causal link, it will be necessary to undertake a randomized controlled trial in which the outcomes of groups of children with asthma who are chosen at random to undergo or not undergo adenotonsillectomy are compared. However, with the proviso that there are some risks associated with adenotonsillectomy, these findings suggest that the detection and treatment of adenotonsillar hypertrophy may help to improve asthma control in children.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001753.
The US Centers for Disease Control and Prevention provides information on asthma, including videos, games, and links to other resources for children with asthma
The American Lung Association provides detailed information about asthma and a fact sheet on asthma in children; it also has information about obstructive sleep apnea
The National Sleep Foundation provides information on snoring and obstructive sleep apnea in children
The UK National Health Service Choices website provides information (including some personal stories) about asthma, about asthma in children, and about obstructive sleep apnea
The “Global Asthma Report 2014” will be available in October 2014
MedlinePlus provides links to further information on asthma, on asthma in children, on sleep apnea, and on tonsils and adenoids (in English and Spanish)
doi:10.1371/journal.pmed.1001753
PMCID: PMC4219664  PMID: 25369282
21.  A comparison between intratracheal and inhalation delivery of Aspergillus fumigatus conidia in the development of fungal allergic asthma in C57BL/6 mice 
Fungal biology  2010;115(1):21-29.
Summary
Allergic asthma is a debilitating disease of the airways characterized by airway hyperresponsiveness, eosinophilic inflammation, goblet cell metaplasia with associated mucus hypersecretion, and airway wall remodelling events, particularly subepithelial fibrosis and smooth muscle cell hyperplasia. Animal models that accurately mimic these hallmarks of allergic airways disease are critical for studying mechanisms associated with the cellular and structural changes that lead to disease pathogenesis. Aspergillus fumigatus, is a common aeroallergen of human asthmatics. The intratracheal (IT) delivery of A. fumigatus conidia into the airways of sensitized mice has been described as a model of allergic disease. Here, we compared the IT model with a newly developed inhalation (IH) challenge model. The IH model allowed multiple fungal exposures, which resulted in an exacerbation to the allergic asthma phenotype. Increased recruitment of eosinophils and lymphocytes, the hallmark leukocytes of asthma, were noted with the IH model as compared to the IT model in which macrophages and neutrophils were more prominent. Immunoglobulin E (IgE) production was significantly greater after IH challenge, while that of IgG2a was higher after IT challenge. Airway wall remodelling was pronounced in IH-treated mice, particularly after multiple allergen challenges. Although the IT model may be appropriate for the examination of the played by innate cells in the acute response to fungus, it fails to consistently reproduce the chronic remodelling hallmarks of allergic asthma. The ability of the IH challenge to mimic these characteristics recommends it as a model suited to study these important events.
doi:10.1016/j.funbio.2010.09.013
PMCID: PMC3053007  PMID: 21215951
Aspergillus fumigatus; Allergic asthma; Inhalation challenge model
22.  The Chemokine Receptor D6 Has Opposing Effects on Allergic Inflammation and Airway Reactivity 
Rationale: The D6 chemokine receptor can bind and scavenge several chemokines, including the T-helper 2 (Th2)–associated chemokines CCL17 and CCL22. Although D6 is constitutively expressed in the lung, its pulmonary function is unknown.
Objectives: This study tested whether D6 regulates pulmonary chemokine levels, inflammation, or airway responsiveness during allergen-induced airway disease.
Methods: D6-deficient and genetically matched C57BL/6 mice were sensitized and challenged with ovalbumin. ELISA and flow cytometry were used to measure levels of cytokines and leukocytes, respectively. Mechanical ventilation was used to measure airway reactivity.
Results: The ability of D6 to diminish chemokine levels in the lung was chemokine concentration dependent. CCL17 and CCL22 were abundant in the airway, and their levels were attenuated by D6 when they were within a defined concentration range. By contrast, airway concentrations of CCL3, CCL5, and CCL11 were low and unaffected by D6. Allergen-challenged D6-deficient mice had more dendritic cells, T cells, and eosinophils in the lung parenchyma and more eosinophils in the airway than similarly challenged C57BL/6 mice. By contrast, D6-deficient mice had reduced airway responses to methacholine compared with C57BL/6 mice. Thus, D6 has opposing effects on inflammation and airway reactivity.
Conclusions: The ability of D6 to scavenge chemokines in the lung is dependent on chemokine concentration. The absence of D6 increases inflammation, but reduces airway reactivity. These findings suggest that inhibiting D6 function might be a novel means to attenuate airway responses in individuals with allergic asthma.
doi:10.1164/rccm.200606-839OC
PMCID: PMC1899265  PMID: 17095748
chemokines; lung; D6; allergic; transforming growth factor–; β
23.  Skin-Derived TSLP Triggers Progression from Epidermal-Barrier Defects to Asthma 
PLoS Biology  2009;7(5):e1000067.
A skin-derived cytokine with high systemic availability provides a mechanistic explanation for atopic march and highlights a potential therapeutic target for preventing the development of asthma among people with atopic dermatitis.
Asthma is a common allergic lung disease frequently affecting individuals with a prior history of eczema/atopic dermatitis (AD); however, the mechanism underlying the progression from AD to asthma (the so-called “atopic march”) is unclear. Here we show that, like humans with AD, mice with skin-barrier defects develop AD-like skin inflammation and are susceptible to allergic asthma. Furthermore, we show that thymic stromal lymphopoietin (TSLP), overexpressed by skin keratinocytes, is the systemic driver of this bronchial hyper-responsiveness. As an AD-like model, we used mice with keratinocyte-specific deletion of RBP-j that sustained high systemic levels of TSLP. Antigen-induced allergic challenge to the lung airways of RBP-j–deficient animals resulted in a severe asthmatic phenotype not seen in similarly treated wild-type littermates. Elimination of TSLP signaling in these animals blocked the atopic march, demonstrating that high serum TSLP levels were required to sensitize the lung to allergic inflammation. Furthermore, we analyzed outbred K14-TSLPtg mice that maintained high systemic levels of TSLP without developing any skin pathology. Importantly, epidermal-derived TSLP was sufficient to trigger the atopic march, sensitizing the lung airways to inhaled allergens in the absence of epicutaneous sensitization. Based on these findings, we propose that in addition to early treatment of the primary skin-barrier defects, selective inhibition of systemic TSLP may be the key to blocking the development of asthma in AD patients.
Author Summary
Eczema (atopic dermatitis) is a common allergic skin inflammation that has a particularly high prevalence among children. Importantly, a large proportion of people suffering from eczema go on to develop asthma later in life. Although the susceptibility of eczema patients to asthma is well documented, the mechanism that mediates “atopic march”—the progression from eczema to asthma—is unclear. We used genetic engineering to generate mice with chronic skin-barrier defects and a subsequent eczema-like disorder. With these mice, we were able to investigate how skin-specific defects predisposed the lungs to allergic asthma. We identified thymic stromal lymphopoietin (TSLP), a cytokine that is secreted by barrier-defective skin into the systemic circulation, as the agent sensitizing the lung to allergens. We demonstrated that high systemic levels of skin-derived TSLP were both required and sufficient to render lung airways hypersensitive to allergens. Thus, these data suggest that early treatment of skin-barrier defects to prevent TSLP overexpression, and systemic inhibition of TSLP, may be crucial in preventing the progression from eczema to asthma.
doi:10.1371/journal.pbio.1000067
PMCID: PMC2700555  PMID: 19557146
24.  Segmental Allergen Challenge Enhances Chitinase Activity and Levels of CCL18 in Mild Atopic Asthma 
Background
Allergic airway inflammation contributes to the airway remodeling that has been linked to increased obstruction and morbidity in asthma. However, the mechanisms by which allergens contribute to airway remodeling in humans are not fully established. CCL18, chitotriosidase (CHIT1) and YKL-40 are readily detectable in the lungs and contribute to remodeling in other fibrotic diseases, but their involvement in allergic asthma is unclear.
Objective
We hypothesized that CCL18, YKL-40, and CHIT1 bioactivity are enhanced in allergic asthma subjects after segmental allergen challenge and are related to increased profibrotic and Th2-associated mediators in the lungs.
Methods
Levels of CCL18 and YKL-40 protein and CHIT1 bioactivity in bronchoalveolar lavage (BAL) fluid, as well as CCL18, YKL-40, and CHIT1 mRNA levels in BAL cells, were evaluated in patients with asthma at baseline and 48 h after segmental allergen challenge. We also examined the correlation between CCL18 and YKL-40 levels and CHIT1 activity with the levels of other profibrotic factors and chemokines previously shown to be up-regulated after allergen challenge.
Results
CHIT1 activity and YKL-40 and CCL18 levels were elevated after segmental allergen challenge and these levels correlated with those of other profibrotic factors, T cell chemokines, and inflammatory cells after allergen challenge. CCL18 and YKL-40 mRNA levels also increased in BAL cells after allergen challenge.
Conclusions & Clinical Relevance
Our results suggest that CCL18 and YKL-40 levels and CHIT1 activity are enhanced in allergic airway inflammation and thus may contribute to airway remodeling in asthma.
doi:10.1111/cea.12032
PMCID: PMC3623278  PMID: 23331560
asthma; segmental bronchoprovocation; CHIT1; YKL-40; CCL18
25.  Glutathione S-transferase P1 Ile105Val polymorphism modulates allergen-induced airway inflammation in human atopic asthmatics in vivo 
Background
Glutathione S-transferase P1 is a Phase II cytoprotective and detoxifying enzyme that is widely expressed in human airways. The glutathione S-transferase P1 Ile105Val polymorphism has been linked with atopic disorders and asthma. Yet, little is known about the regulation of allergic inflammation by glutathione S-transferase P1 in human asthmatics.
Objective
To establish the effect of the glutathione S-transferase P1 Ile105Val polymorphism on allergen-induced airway inflammation and oxidant stress, and nonspecific bronchial hyperresponsiveness to methacholine and reactivity to specific allergen in mild human atopic asthmatics in vivo.
Methods
Five Val105/Val105, twelve Val105/Ile105, and twenty Ile105/Ile105 mild atopic asthmatics underwent methacholine challenge, inhaled allergen challenge, and endobronchial allergen provocation through a bronchoscope. A panel of inflammatory cytokines and chemokines, F2-isoprostanes and isofuranes, markers of oxidative stress, thromboxane B2, and immunoglobulin E were measured in bronchoalveolar lavage fluid at baseline and 24 hrs after allergen instillation.
Results
Asthmatics with glutathione S-transferase P1 Val105/Val105 compared to asthmatics with the glutathione S-transferase P1 Val105/Ile105 and Ile105/Ile105 had greater generation of acute phase cytokines (TNF-α, IL-6, CXCL8), IL-12, CCL11, thromboxane B2, and immunoglobulin E at 24 hrs after local allergen challenge. The GSTP1 genotype had no effect on airway hyperresponsiveness to methacholine and the reactivity to specific allergen.
Conclusion
The glutathione S-transferase P1 Ile105Val polymorphism markedly modifies allergen-provoked airway inflammation in atopic asthmatics in vivo. Modulation of the biochemical milieu in response to allergen provides a mechanistic explanation for regulatory effects of glutathione S-transferase P1 polymorphism on airway pathophysiology, and may guide improvement of future therapeutic methods in human atopic asthmatics. These findings must me confirmed in a larger study population of asthmatics with various ethnicities.
doi:10.1111/cea.12086
PMCID: PMC3633143  PMID: 23600543
Glutathione S-transferase P1; Ile105Val polymorphism; atopic asthma; allergen challenge; methacholine challenge; allergic inflammation; oxidant stress

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