Pathogenesis Of Allergic Airway Disease Research Articles

Current research into A20 mediation of allergic respiratory diseases and its potential usefulness as a therapeutic target.

Allergic airway diseases are characterized by excessive and prolonged type 2 immune responses to inhaled allergens. Nuclear factor κB (NF-κB) is a master regulator of the immune and inflammatory response, which has been implicated to play a prominent role in the pathogenesis of allergic airway diseases. The potent anti-inflammatory protein A20, termed tumor necrosis factor-α-inducible protein 3 (TNFAIP3), exerts its effects by inhibiting NF-κB signaling. The ubiquitin editing abilities of A20 have attracted much attention, resulting in its identification as a susceptibility gene in various autoimmune and inflammatory disorders. According to the results of genome-wide association studies, several TNFAIP3 gene locus nucleotide polymorphisms have been correlated to allergic airway diseases. In addition, A20 has been found to play a pivotal role in immune regulation in childhood asthma, particularly in the protection against environmentally mediated allergic diseases. The protective effects of A20 against allergy were observed in conditional A20-knockout mice in which A20 was depleted in the lung epithelial cells, dendritic cells, or mast cells. Furthermore, A20 administration significantly decreased inflammatory responses in mouse models of allergic airway diseases. Here, we review emerging findings elucidating the cellular and molecular mechanisms by which A20 regulates inflammatory signaling in allergic airway diseases, as well as discuss its potential as a therapeutic target.

Activation of STAT6 by intranasal allergens correlated with the development of eosinophilic chronic rhinosinusitis in a mouse model.

Eosinophilic chronic rhinosinusitis (ECRS) is a chronic inflammatory disease characterized by prominent eosinophilic infiltration along with a T-helper-2 (Th2) response. It has been well documented that signal transducer and activator of transcription 6 (STAT6) is a nuclear transcription factor that mediates Th2-type immunity and is implicatory of STAT1 and STAT3 in the pathogenesis of allergic airway diseases. However, little is known about the association between STATs and ECRS. Here, we explored the relationship between STAT1, STAT3, and/or STAT6 and eosinophilic inflammation accompanied by Th2-type immunity in a mouse model of ECRS. An ovalbumin (OVA)-staphylococcal enterotoxin B (SEB)-induced ECRS murine model was first established. The mucosal histological alterations were determined using hematoxylin and eosin staining. The number of eosinophils in peripheral blood was measured using a blood cell analyzer. The cytokine (IL-4, IL-5, IL17 A and IFN-γ) expression levels in the sinonasal mucosa and total and OVA-specific IgE from serum were measured using ELISA. Then, the protein levels of STAT1, STAT3, STAT6, phosphorylated STAT1 (p-STAT1), p-STAT3, p-STAT6, T-box expressed in T-cells (T-bet), GATA binding protein 3 (GATA-3), and retinoic acid receptor-related orphan receptor γ (RORγt) in the sinonasal mucosa were examined by immunohistochemical staining or Western blotting. Local administration of OVA combined with SEB (OVA + SEB) induced multiple polyp-like lesions, accompanied by prominent eosinophilic infiltration in the sinonasal mucosa. The OVA- and OVA+SEB-treated groups showed significantly higher eosinophil counts from peripheral blood and total and OVA-specific IgE levels from serum than those in the PBS- and SEB-treated groups. The levels of p-STAT6 were markedly increased by OVA + SEB exposure, as well as GATA-3, IL-4, and IL-5, but did not affect STAT6, p-STAT1, p-STAT3, T-bet, RORγt, IFN-γ, or IL-17A. Furthermore, an eosinophil count in the sinonasal mucosa showed a positive correlation with the level of p-STAT6 in the ECRS mouse model. Signal transducer and activator of transcription 6 signaling could be activated in the OVA+SEB-induced ECRS model and might be a crucial signal transducer in the development of Th2-skewed ECRS.

Glutathione-S-transferase P promotes glycolysis in asthma in association with oxidation of pyruvate kinase M2

BackgroundInterleukin-1-dependent increases in glycolysis promote allergic airways disease in mice and disruption of pyruvate kinase M2 (PKM2) activity is critical herein. Glutathione-S-transferase P (GSTP) has been implicated in asthma pathogenesis and regulates the oxidation state of proteins via S-glutathionylation. We addressed whether GSTP-dependent S-glutathionylation promotes allergic airways disease by promoting glycolytic reprogramming and whether it involves the disruption of PKM2. MethodsWe used house dust mite (HDM) or interleukin-1β in C57BL6/NJ WT or mice that lack GSTP. Airway basal cells were stimulated with interleukin-1β and the selective GSTP inhibitor, TLK199. GSTP and PKM2 were evaluated in sputum samples of asthmatics and healthy controls and incorporated analysis of the U-BIOPRED severe asthma cohort database. ResultsAblation of Gstp decreased total S-glutathionylation and attenuated HDM-induced allergic airways disease and interleukin-1β-mediated inflammation. Gstp deletion or inhibition by TLK199 decreased the interleukin-1β-stimulated secretion of pro-inflammatory mediators and lactate by epithelial cells. 13C-glucose metabolomics showed decreased glycolysis flux at the pyruvate kinase step in response to TLK199. GSTP and PKM2 levels were increased in BAL of HDM-exposed mice as well as in sputum of asthmatics compared to controls. Sputum proteomics and transcriptomics revealed strong correlations between GSTP, PKM2, and the glycolysis pathway in asthma. ConclusionsGSTP contributes to the pathogenesis of allergic airways disease in association with enhanced glycolysis and oxidative disruption of PKM2. Our findings also suggest a PKM2-GSTP-glycolysis signature in asthma that is associated with severe disease.

Contribution of Regulatory T Cell Methylation Modifications to the Pathogenesis of Allergic Airway Diseases.

Regulatory T (Treg) cells are a subtype of CD4+ T cells that play a significant role in the protection from autoimmunity and the maintenance of immune tolerance via immune regulation. Epigenetic modifications of Treg cells (i.e., cytosine methylation at the promoter region of the transcription factor, Forkhead Box P3) have been found to be closely associated with allergic diseases, including allergic rhinitis, asthma, and food allergies. In this study, we highlighted the recent evidence on the contribution of epigenetic modifications in Treg cells to the pathogenesis of allergic diseases. Moreover, we also discussed directions for future clinical treatment approaches, with a particular emphasis on Treg cell-targeted therapies for allergic disorders.

Transcriptomic analysis reveals diverse gene expression changes in airway macrophages during experimental allergic airway disease.

Background: Airway macrophages (AMs) are the most abundant leukocytes in the healthy airway lumen and have a highly specialised but plastic phenotype that is governed by signals in the local microenvironment. AMs are thought to maintain immunological homeostasis in the steady state, but have also been implicated in the pathogenesis of allergic airway disease (AAD). In this study, we aimed to better understand these potentially contrasting AM functions using transcriptomic analysis. Methods: Bulk RNA sequencing was performed on AMs (CD11c + Siglec F + CD64 + CD45 + SSC hi) flow cytometry sorted from C57BL/6 mice during experimental AAD driven by repeated house dust mite inhalation (AMs HDM), compared to control AMs from non-allergic mice. Differentially expressed genes were further analysed by hierarchical clustering and biological pathway analysis. Results: AMs HDM showed increased expression of genes associated with antigen presentation, inflammatory cell recruitment and tissue repair, including several chemokine and matrix metalloproteinase genes. This was accompanied by increased expression of mitochondrial electron transport chain subunit genes and the retinoic acid biosynthetic enzyme gene Raldh2. Conversely, AMs HDM displayed decreased expression of a number of cell cycle genes, genes related to cytoskeletal functions and a subset of genes implicated in antimicrobial innate immunity, such as Tlr5, Il18 and Tnf. Differential gene expression in AMs HDM was consistent with upstream effects of the cytokines IL-4 and IFN-γ, both of which were present at increased concentrations in lung tissue after HDM treatment. Conclusions: These data highlight diverse gene expression changes in the total AM population in a clinically relevant mouse model of AAD, collectively suggestive of contributions to inflammation and tissue repair/remodelling, but with decreases in certain steady state cellular and immunological functions.

Transcriptomic analysis reveals diverse gene expression changes in airway macrophages during experimental allergic airway disease

Background: Airway macrophages (AMs) are the most abundant leukocytes in the healthy airway lumen and have a highly specialised but plastic phenotype that is governed by signals in the local microenvironment. AMs are thought to maintain immunological homeostasis in the steady state, but have also been implicated in the pathogenesis of allergic airway disease (AAD). In this study, we aimed to better understand these potentially contrasting AM functions using transcriptomic analysis. Methods: Bulk RNA sequencing was performed on AMs (CD11c + Siglec F + CD64 + CD45 + SSC hi) flow cytometry sorted from C57BL/6 mice during experimental AAD driven by repeated house dust mite inhalation (AMs HDM), compared to control AMs from non-allergic mice. Differentially expressed genes were further analysed by hierarchical clustering and biological pathway analysis. Results: AMs HDM showed increased expression of genes associated with antigen presentation, inflammatory cell recruitment and tissue repair, including several chemokine and matrix metalloproteinase genes. This was accompanied by increased expression of mitochondrial electron transport chain subunit genes and the retinoic acid biosynthetic enzyme gene Raldh2. Conversely, AMs HDM displayed decreased expression of a number of cell cycle genes, genes related to cytoskeletal functions and a subset of genes implicated in antimicrobial innate immunity, such as Tlr5, Il18 and Tnf. Differential gene expression in AMs HDM was consistent with upstream effects of the cytokines IL-4 and IFN-γ, both of which were present at increased concentrations in lung tissue after HDM treatment. Conclusions: These data highlight diverse gene expression changes in the total AM population in a clinically relevant mouse model of AAD, collectively suggestive of contributions to inflammation and tissue repair/remodelling, but with decreases in certain steady state cellular and immunological functions.

Study of Interleukin 23 Gene Polymorphism in Egyptian Patients with Allergic Rhinitis

Objective: Polymorphism of the interleukin-23 receptor gene corresponds with susceptibility to several immune-related diseases. For the terminal differentiation of IL-17-producing effector T-helper cells in vivo, the interleukin-23 receptor gene is of vital importance. As shown recently, Th17 cells probably have a great influence on the pathogenesis of allergic airway diseases. Our intention was to establish an association between polymorphisms in the IL-23R gene and allergic rhinitis (AR) in Egyptians. Methods: we included 100 AR patients and 75 control Egyptian subjects in a case-control study. The study involved obtaining blood samples for DNA extraction, genotyping and determination of a selected single-nucleotide polymorphisms in IL-23R by performing TaqMan assay PCR. Results: A substantially growing prevalence of the homozygous rs7517847 GG genotype and G allele appeared in the AR patients unlike that observed in the control individuals (p 0.001). Conclusions: To the best of our knowledge, this is the first study to demonstrate an important association between polymorphisms in IL-23R and AR in the Egyptian population. A strong association between rs7517847 in a SNP of IL-23R, and AR was identified.

Transcriptomic analysis reveals diverse gene expression changes in airway macrophages during experimental allergic airway disease

Background: Airway macrophages (AMs) are the most abundant leukocytes in the healthy airway lumen and have a highly specialised but plastic phenotype that is governed by signals in the local microenvironment. AMs are thought to maintain immunological homeostasis in the steady state, but have also been implicated in the pathogenesis of allergic airway disease (AAD). In this study, we aimed to better understand these potentially contrasting AM functions using transcriptomic analysis. Methods: Bulk RNA sequencing was performed on AMs flow cytometry sorted from C57BL/6 mice during experimental AAD driven by repeated house dust mite inhalation (AMs HDM), compared to control AMs from non-allergic mice. Differentially expressed genes were further analysed by hierarchical clustering and biological pathway analysis. Results: AMs HDM showed increased expression of genes associated with antigen presentation, inflammatory cell recruitment and tissue repair, including several chemokine and matrix metalloproteinase genes. This was accompanied by increased expression of mitochondrial electron transport chain subunit genes and the retinoic acid biosynthetic enzyme gene Raldh2. Conversely, AMs HDM displayed decreased expression of a number of cell cycle genes, genes related to cytoskeletal functions and a subset of genes implicated in antimicrobial innate immunity, such as Tlr5, Il18 and Tnf. Differential gene expression in AMs HDM was consistent with upstream effects of the cytokines IL-4 and IFN-γ, both of which were present at increased concentrations in lung tissue after HDM treatment. Conclusions: These data highlight diverse gene expression changes in the total AM population in a clinically relevant mouse model of AAD, collectively suggestive of contributions to inflammation and tissue repair/remodelling, but with decreases in certain steady state cellular and immunological functions.

Pyruvate Kinase M2 Promotes Expression of Proinflammatory Mediators in House Dust Mite-Induced Allergic Airways Disease.

Asthma is a chronic disorder characterized by inflammation, mucus metaplasia, airway remodeling, and hyperresponsiveness. We recently showed that IL-1-induced glycolytic reprogramming contributes to allergic airway disease using a murine house dust mite model. Moreover, levels of pyruvate kinase M2 (PKM2) were increased in this model as well as in nasal epithelial cells from asthmatics as compared with healthy controls. Although the tetramer form of PKM2 converts phosphoenolpyruvate to pyruvate, the dimeric form of PKM2 has alternative, nonglycolysis functions as a transcriptional coactivator to enhance the transcription of several proinflammatory cytokines. In the current study, we examined the impact of PKM2 on the pathogenesis of house dust mite-induced allergic airways disease in C57BL/6NJ mice. We report, in this study, that activation of PKM2, using the small molecule activator, TEPP46, augmented PKM activity in lung tissues and attenuated airway eosinophils, mucus metaplasia, and subepithelial collagen. TEPP46 attenuated IL-1β-mediated airway inflammation and expression of proinflammatory mediators. Exposure to TEPP46 strongly decreased the IL-1β-mediated increases in thymic stromal lymphopoietin (TSLP) and GM-CSF in primary tracheal epithelial cells isolated from C57BL/6NJ mice. We also demonstrate that IL-1β-mediated increases in nuclear phospho-STAT3 were decreased by TEPP46. Finally, STAT3 inhibition attenuated the IL-1β-induced release of TSLP and GM-CSF, suggesting that the ability of PKM2 to phosphorylate STAT3 contributes to its proinflammatory function. Collectively, these results demonstrate that the glycolysis-inactive form of PKM2 plays a crucial role in the pathogenesis of allergic airways disease by increasing IL-1β-induced proinflammatory signaling, in part, through phosphorylation of STAT3.

MTOR-Mediated Autophagy Is Involved in the Protective Effect of Ketamine on Allergic Airway Inflammation.

Unresolved inflammation underpins the pathogenesis of allergic airway diseases, such as asthma. Ketamine, accepted as a promising therapy for resistant asthma, has been demonstrated to attenuate allergic airway inflammation. However, the anti-inflammatory mechanism by ketamine in this setting is largely unknown. We aimed to investigate whether autophagy was involved in the protective effect of ketamine on allergic airway inflammation. Female C57BL/6 mice were sensitized to ovalbumin (OVA) and treated with ketamine at 25, 50, or 100 mg/kg prior to OVA challenge. In this model, the pulmonary morphological findings and airway inflammation were significantly inhibited at 50 mg/kg but not at 25 or 100 mg/kg. Moreover, 50 mg/kg ketamine abrogated the increased concentrations of inflammatory cytokines in bronchoalveolar lavage fluid (BALF) of allergic mice, as well as activated the expression of phosphorylated mammalian target of rapamycin (p-MTOR) and inhibited autophagy in allergic mice. To confirm whether the effect of 50 mg/kg ketamine on asthma was mediated by inhibiting autophagy, rapamycin was administered to mice sensitized to OVA and exposed to 50 mg/kg ketamine. All of the effect of 50 mg/kg ketamine was reversed by rapamycin treatment, including increased p-MTOR and decreased autophagy. Taken together, the present study demonstrates that 50 mg/kg ketamine inhibits allergic airway inflammation by suppressed autophagy, and this effect is mediated by the activation of MTOR in the lungs of allergic mice.

New aspects of neuroinflammation and neuroimmune crosstalk in the airways

Neuroimmune interaction has long been discussed in the pathogenesis of allergic airway diseases, such as allergic asthma. Mediators released during inflammation can alter the function of both sensory and parasympathetic neurons innervating the airways. Evidence has been provided that the inflammatory response can be altered by various mediators that are released by sensory and parasympathetic neurons and vice versa. Our aim is to demonstrate recent developments in the reciprocal neuroimmune interaction and to include, if available, data from invivo and clinical studies.

Potential Role of Interleukin-25/Interleukin-33/Thymic Stromal Lymphopoietin-Fibrocyte Axis in the Pathogenesis of Allergic Airway Diseases.

Objective:Allergic airway diseases (AADs) are a group of heterogeneous disease mediated by T-helper type 2 (Th2) immune response and characterized with airway inflammation and remodeling, including allergic asthma, allergic rhinitis, and chronic rhinosinusitis with allergic background. This review aimed to discuss the abnormal epithelial-mesenchymal crosstalk in the pathogenesis of AADs.Data Sources:Articles referred in this review were collected from the database of PubMed published in English up to January 2018.Study Selection:We had done a literature search using the following terms “allergic airway disease OR asthma OR allergic rhinitis OR chronic sinusitis AND IL-25 OR IL-33 OR thymic stromal lymphopoietin OR fibrocyte”. Related original or review articles were included and carefully analyzed.Results:It is now believed that abnormal epithelial-mesenchymal crosstalk underlies the pathogenesis of AADs. However, the key regulatory factors and molecular events involved in this process still remain unclear. Epithelium-derived triple cytokines, including interleukin (IL)-25, IL-33, and thymic stromal lymphopoietin (TSLP), are shown to act on various target cells and promote the Th2 immune response. Circulating fibrocyte is an important mesenchymal cell that can mediate tissue remodeling. We previously found that IL-25-circulating fibrocyte axis was significantly upregulated in patients with asthma, which may greatly contribute to asthmatic airway inflammation and remodeling.Conclusions:In view of the redundancy of cytokines and “united airway” theory, we propose a new concept that IL-25/IL-33/TSLP-fibrocyte axis may play a vital role in the abnormal epithelial-mesenchymal crosstalk in some endotypes of AADs. This novel idea will guide potential new intervention schema for the common treatment of AADs sharing common pathogenesis in the future.

Biased Generation and In Situ Activation of Lung Tissue-Resident Memory CD4 T Cells in the Pathogenesis of Allergic Asthma.

Asthma is a chronic inflammatory disease mediated by allergen-specific CD4 T cells that promote lung inflammation through recruitment of cellular effectors into the lung. A subset of lung T cells can persist as tissue-resident memory T cells (TRMs) following infection and allergen induction, although the generation and role of TRM in asthma persistence and pathogenesis remain unclear. In this study, we used a mouse model of chronic exposure to intranasal house dust mite (HDM) extract to dissect how lung TRMs are generated and function in the persistence and pathogenesis of allergic airway disease. We demonstrate that both CD4+ and CD8+ T cells infiltrate into the lung tissue during acute HDM exposure; however, only CD4+ TRMs, and not CD8+ TRMs, persist long term following cessation of HDM administration. Lung CD4+ TRMs are localized around airways and are rapidly reactivated upon allergen re-exposure accompanied by the rapid induction of airway hyperresponsiveness independent of circulating T cells. Lung CD4+ TRM activation to HDM challenge is also accompanied by increased recruitment and activation of dendritic cells in the lungs. Our results indicate that lung CD4+ TRMs can perpetuate allergen-specific sensitization and direct early inflammatory signals that promote rapid lung pathology, suggesting that targeting lung CD4+ TRMs could have therapeutic benefit in alleviating recurrent asthma episodes.

IL-1/inhibitory κB kinase ε–induced glycolysis augment epithelial effector function and promote allergic airways disease

Emerging studies suggest that enhanced glycolysis accompanies inflammatory responses. Virtually nothing is known about the relevance of glycolysis in patients with allergic asthma. We sought to determine whether glycolysis is altered in patients with allergic asthma and to address its importance in the pathogenesis of allergic asthma. We examined alterations in glycolysis in sputum samples from asthmatic patients and primary human nasal cells and used murine models of allergic asthma, as well as primary mouse tracheal epithelial cells, to evaluate the relevance of glycolysis. In a murine model of allergic asthma, glycolysis was induced in the lungs in an IL-1-dependent manner. Furthermore, administration of IL-1β into the airways stimulated lactate production and expression of glycolytic enzymes, with notable expression of lactate dehydrogenase Aoccurring in the airway epithelium. Indeed, exposure of mouse tracheal epithelial cells to IL-1β or IL-1α resulted in increased glycolytic flux, glucose use, expression of glycolysis genes, and lactate production. Enhanced glycolysis was required for IL-1β- or IL-1α-mediated proinflammatory responses and the stimulatory effects of IL-1β on house dust mite (HDM)-induced release of thymic stromal lymphopoietin and GM-CSF from tracheal epithelial cells. Inhibitor of κB kinase ε was downstream of HDM or IL-1β and required for HDM-induced glycolysis and pathogenesis of allergic airways disease. Small interfering RNA ablation of lactate dehydrogenase Aattenuated HDM-induced increases in lactate levels and attenuated HDM-induced disease. Primary nasal epithelial cells from asthmatic patients intrinsically produced more lactate compared with cells from healthy subjects. Lactate content was significantly higher in sputum supernatants from asthmatic patients, notably those with greater than 61% neutrophils. Apositive correlation was observed between sputum lactate and IL-1β levels, and lactate content correlated negatively with lung function. Collectively, these findings demonstrate that IL-1β/inhibitory κB kinase ε signaling plays an important role in HDM-induced glycolysis and pathogenesis of allergic airways disease.

Notch ligands DLL4 and Jagged1 exert differential effects in allergic airway inflammation

Abstract Notch is a pleiotropic signaling family that has been implicated in pathogenesis of allergic airway diseases; however, the distinct function of individual Notch ligands remains elusive. By using an OVA-induced murine asthma model, we investigated whether Notch ligands, Jagged1 and DLL4, exert differential effects during allergic airway inflammation. We found that whilst Jagged1 inhibition mitigated Th2-dominated airway inflammation, blockage of DLL4 aggravated the Th2-mediated asthma phenotypes. Additionally, blockage of Jagged1 signaling enhanced IL-17 production and neutrophilic airway infiltration. In vitro, exogenous Jagged1 induced Th2-skewed responses, whereas augmented DLL4 signaling displayed a dual role by promoting expansion of both Tregs and Th17. In vivo, DLL4 blockage impaired Treg differentiation which plausibly resulted in exaggerated asthma phenotypes. On the contrary, administration of DLL4-expressing antigen-presenting cells promoted endogenous Treg expansion and ameliorated the allergic responses. Therefore, whilst Jagged1 induces Th2-skewed inflammation, DLL4 elicits an essential self-regulatory mechanism via Treg-mediated pathway that overcomes Jagged1-induced Th2 responses and facilitates resolution of the airway inflammation. These findings uncover a disparate function of Jagged1 and DLL4 in allergic airway diseases, suggesting the feasibility of Notch ligand-specific targeting in therapy of allergic airway diseases.

Notch Ligand DLL4 Alleviates Allergic Airway Inflammation via Induction of a Homeostatic Regulatory Pathway

Notch is a pleiotropic signaling family that has been implicated in pathogenesis of allergic airway diseases; however, the distinct function of individual Notch ligands remains elusive. We investigated whether Notch ligands, Jagged1 and DLL4, exert differential effects in OVA-induced allergic asthma. We found that whilst Jagged1 inhibition mitigated Th2-dominated airway inflammation, blockage of DLL4 aggravated the Th2-mediated asthma phenotypes. Additionally, Jagged1 signaling blockage enhanced IL-17 production and neutrophilic airway infiltration. In vitro, exogenous Jagged1 induced Th2-skewed responses, whereas augmented DLL4 signaling displayed a dual role by promoting expansion of both Tregs and Th17. In vivo, DLL4 blockage impaired Treg differentiation which plausibly resulted in exaggerated asthma phenotypes. On the contrary, administration of DLL4-expressing antigen-presenting cells promoted endogenous Treg expansion and ameliorated the allergic responses. Therefore, whilst Jagged1 induces Th2-skewed inflammation, DLL4 elicits an essential self-regulatory mechanism via Treg-mediated pathway that counterbalances Jagged1-induced Th2 responses and facilitates resolution of the airway inflammation to restore homeostasis. These findings uncover a disparate function of Jagged1 and DLL4 in allergic airway diseases, hinting feasibility of Notch ligand-specific targeting in therapy of allergic airway diseases.

CD38 in the pathogenesis of allergic airway disease: Potential therapeutic targets.

CD38 is an ectoenzyme that catalyzes the conversion of β-nicotinamide adenine dinucleotide (β-NAD) to cyclic adenosine diphosphoribose (cADPR) and adenosine diphosphoribose (ADPR) and NADP to nicotinic acid adenine dinucleotide phosphate (NAADP) and adenosine diphosphoribose-2'-phosphate (ADPR-P). The metabolites of NAD and NADP have roles in calcium signaling in different cell types including airway smooth muscle (ASM) cells. In ASM cells, inflammatory cytokines augment CD38 expression and to a greater magnitude in cells from asthmatics, indicating a greater capacity for the generation of cADPR and ADPR in ASM from asthmatics. CD38 deficient mice develop attenuated airway responsiveness to inhaled methacholine following allergen sensitization and challenge compared to wild-type mice indicating its potential role in asthma. Regulation of CD38 expression in ASM cells is achieved by mitogen activated protein kinases, specific isoforms of PI3 kinases, the transcription factors NF-κB and AP-1, and post-transcriptionally by microRNAs. This review will focus on the role of CD38 in intracellular calcium regulation in ASM, contribution to airway inflammation and airway hyperresponsiveness in mouse models of allergic airway inflammation, the transcriptional and post-transcriptional mechanisms of regulation of expression, and outline approaches to inhibit its expression and activity.

TLR2, TLR4 AND MyD88 Mediate Allergic Airway Disease (AAD) and Streptococcus pneumoniae-Induced Suppression of AAD.

BackgroundExposure to non-pathogenic Streptococcus pneumoniae and vaccination are inversely associated with asthma. Studies in animal models demonstrate that airway administration of S. pneumoniae (live or killed), or its vaccines or components, suppresses the characteristic features of asthma in mouse models of allergic airway disease (AAD). These components could be developed into immunoregulatory therapies. S. pneumoniae components are recognized by Toll-like receptors (TLR) 2 and TLR4, and both induce inflammatory cell responses through the adaptor protein myeloid differentiation primary response gene 88 (MyD88). The involvement of TLR2, TLR4 and MyD88 in the pathogenesis of AAD and asthma is incompletely understood, and has not been studied in S. pneumoniae-mediated suppression of AAD. We investigated the role of TLR2, TLR4 and MyD88 in the development of AAD and S. pneumoniae-mediated suppression of AAD.Methods and FindingsOVA-induced AAD and killed S. pneumoniae-mediated suppression of AAD were assessed in wild-type, TLR2-/-, TLR4-/-, TLR2/4-/- and MyD88-/- BALB/c mice. During OVA-induced AAD, TLR2, TLR4 and MyD88 were variously involved in promoting eosinophil accumulation in bronchoalveolar lavage fluid and blood, and T-helper type (Th)2 cytokine release from mediastinal lymph node T cells and splenocytes. However, all were required for the induction of airways hyperresponsiveness (AHR). In S. pneumoniae-mediated suppression of AAD, TLR2, TLR4 and MyD88 were variously involved in the suppression of eosinophilic and splenocyte Th2 responses but all were required for the reduction in AHR.ConclusionsThese results highlight important but complex roles for TLR2, TLR4 and MyD88 in promoting the development of OVA-induced AAD, but conversely in the S. pneumoniae-mediated suppression of AAD, with consistent and major contributions in both the induction and suppression of AHR. Thus, TLR signaling is likely required for both the development of asthma and the suppression of asthma by S. pneumoniae, and potentially other immunoregulatory therapies.

Pulmonary function tests in air conditioner users

Background : Modernization has been implicated in the pathogenesis of allergic airway diseases. House dust, mites, and indoor air pollutants have been reported to cause elevation of serum IgE levels and/or enhancement of eosinophil activity. A component of modern lifestyle is the intense use of air-conditioners (AC) that has increased the risk of atopic sensitization. Aim : To assess the effect of air conditioners on pulmonary function tests in healthy non-smokers. Methods : The study included 100 subjects using AC and 100 subjects who were not using AC. After ethical committee approval, pulmonary function tests were done for both study groups by using Medspiror. The data obtained was tabulated and analyzed. Results : The lung functions particularly Forced vital capacity (FVC), and Forced expiratory volume in 1 second (FEV1), were affected more in AC users. FVC and FEV1 were found to be significantly reduced and FEV1/FVC was found to be normal. Conclusion : As FVC and FEVFEV1 were found to be significantly reduced and FEV1/FVC was found to be normal, this is suggestive of predisposition of AC users towards restrictive type of respiratory disorders. Key Words : Air-conditioner; pulmonary function tests; smokers; allergy; Med-spiror

Inhibition of Protein Kinase C Delta Attenuates Allergic Airway Inflammation through Suppression of PI3K/Akt/mTOR/HIF-1 Alpha/VEGF Pathway

Vascular endothelial growth factor (VEGF) is supposed to contribute to the pathogenesis of allergic airway disease. VEGF expression is regulated by a variety of stimuli such as nitric oxide, growth factors, and hypoxia-inducible factor-1 alpha (HIF-1α). Recently, inhibition of the mammalian target of rapamycin (mTOR) has been shown to alleviate cardinal asthmatic features, including airway hyperresponsiveness, eosinophilic inflammation, and increased vascular permeability in asthma models. Based on these observations, we have investigated whether mTOR is associated with HIF-1α-mediated VEGF expression in allergic asthma. In studies with the mTOR inhibitor rapamycin, we have elucidated the stimulatory role of a mTOR-HIF-1α-VEGF axis in allergic response. Next, the mechanisms by which mTOR is activated to modulate this response have been evaluated. mTOR is known to be regulated by phosphoinositide 3-kinase (PI3K)/Akt or protein kinase C-delta (PKC δ) in various cell types. Consistent with these, our results have revealed that suppression of PKC δ by rottlerin leads to the inhibition of PI3K/Akt activity and the subsequent blockade of a mTOR-HIF-1α-VEGF module, thereby attenuating typical asthmatic attack in a murine model. Thus, the present data indicate that PKC δ is necessary for the modulation of the PI3K/Akt/mTOR signaling cascade, resulting in a tight regulation of HIF-1α activity and VEGF expression. In conclusion, PKC δ may represent a valuable target for innovative therapeutic treatment of allergic airway disease.