Role In Pathogenesis Of Asthma Research Articles

Immunization against TGF-β1 reduces collagen deposition but increases sustained inflammation in a murine asthma model

ABSTRACTTransforming growth factor (TGF)-β1 is involved in the processes of airway inflammation and remodeling; however, its reported roles in asthma pathogenesis are controversial. We sought both to investigate the effects of active immunization targeting TGF-β1 on allergen-induced airway inflammatory responses and to evaluate its possible application for asthma treatment. BALB/c mice were immunized with a virus-like-particle (VLP) vaccine presenting a TGF-β1 peptide. For the preventive intervention of acute allergic airway inflammation, immunization was conducted before sensitization and challenges with ovalbumin (OVA), and for the therapeutic treatment of chronic inflammatory responses, immunization was initiated after inflammatory responses were established. Preventive immunization with VLPs led to increased proinflammatory IL-4, IL-13, and IL-33 levels in the bronchoalveolar lavage fluids (BALF) with no significant effects on lung tissue inflammation and airway goblet cell hyperplasia. Therapeutic treatment showed that at 24 h after the fourth 2-day challenge with OVA following 2 intraperitoneal sensitizations, airway subepithelial collagen deposition was significantly ameliorated in vaccinated mice, whereas the lung histology and cytokine profile in the BALF were not changed. In contrast, after a 4-week recovery from the last OVA challenge, the vaccinated mice's collagen deposition remained reduced, but they sustained lung-tissue inflammation and goblet-cell hyperplasia; elevated IL-13, TNF, and IFN-γ levels in the BALF; and increased airway resistance, tissue resistance, and tissue elastance. In a conclusion, the role of TGF-β1 is complicated in allergic airway inflammatory responses. It is important to make a careful assessment in accordance with specific disease conditions when targeting TGF-β1 for a therapeutic purpose.

Molecular Mechanisms of Airway Hyperresponsiveness in a Murine Model of Steroid-Resistant Airway Inflammation.

IL-13 and IL-17A, produced mainly by Th2 and Th17 cells, respectively, have an influential role in asthma pathogenesis. We examined the role of IL-13 and IL-17A in mediating airway hyperresponsiveness (AHR), lung inflammation, and mucus metaplasia in a dual Th2/Th17 model of asthma. IL-13 and/or IL-17A were neutralized using mAbs. Th2/Th17 adoptive transfer induced a mixed asthma phenotype characterized by elevated eosinophilia and neutrophilia, tissue inflammation, mucus metaplasia, and AHR that were partially reversible with steroid treatment. Pulmonary inflammation and quasi-static lung compliance were largely unaffected by neutralization of IL-13 and/or IL-17A. However, neutralization of IL-13 alone or in combination with IL-17A significantly attenuated AHR and mucus metaplasia. Further, STAT6 activation was attenuated following IL-13 and IL-13/IL-17A Ab treatment. We next assessed the role of STAT6 in Th2/Th17-mediated allergic airway disease using STAT6(-/-) mice. STAT6(-/-) mice adoptively transferred with Th2/Th17 cells had decreased AHR compared with controls. These data suggest that IL-13 drives AHR and mucus metaplasia in a STAT6-dependent manner, without directly contributing to airway or tissue inflammation. IL-17A independently contributes to AHR, but it only partially mediates inflammation and mucus metaplasia in a mixed Th2/Th17 model of steroid-resistant asthma.

Using Structural and Dynamic NMR Analyses to Dissect the Pathologic Function of a Novel Chemokine

Chemokines are small, secreted proteins that bind G protein-coupled receptors (GPCRs) to orchestrate cellular chemotaxis in the immune system and beyond. While the ∼50 members of the chemokine family share a remarkably conserved tertiary structure, they still manage to coordinate diverse, non-redundant physiologic and pathologic functions in the human body. It is therefore assumed that more subtle nuances in the structure and dynamics of each chemokine-receptor pair are the key determinants of their biologic function. Here we present the molecular structure of CCL28, an especially intriguing chemokine recently identified to play a major role in asthma pathogenesis, solved by solution-state nuclear magnetic resonance spectroscopy (NMR). The structure reveals that while CCL28 adopts the conserved chemokine tertiary fold, it has a particularly curious structural feature not seen in other chemokines. An intrinsically disordered C-terminal domain of ∼30 residues extends from the globular core of the chemokine, part of which is tethered by a non-conserved disulfide bond. Dynamic NMR experiments including backbone 1H-15N heteronuclear NOE measurements, heteronuclear single quantum coherence (HSQC) titrations, and pulsed field gradient (PFG) diffusion measurements collectively indicate the disordered, dynamic nature of the C-terminal extension. Combined with mutational and in vitro functional studies, our findings suggest that the unique structural and dynamic features of CCL28 may be key determinants of its pathologic function.

Bidirectional Counterregulation of Human Lung Mast Cell and Airway Smooth Muscle β2 Adrenoceptors.

Human lung mast cells (HLMCs) play a central role in asthma pathogenesis through their relocation to the airway smooth muscle (ASM) bundles. β2 adrenoceptor (β2-AR)-agonists are used to relieve bronchoconstriction in asthma, but may reduce asthma control, particularly when used as monotherapy. We hypothesized that HLMC and human ASM cell (HASMC) responsiveness to β2-AR agonists would be attenuated when HLMCs are in contact with HASMCs. Cells were cultured in the presence of the short-acting β2-agonist albuterol, and the long-acting β2-agonists formoterol and olodaterol. Constitutive and FcεRI-dependent HLMC histamine release, HASMC contraction, and β2-AR phosphorylation at Tyr(350) were assessed. Constitutive HLMC histamine release was increased in HLMC-HASMC coculture and this was enhanced by β2-AR agonists. Inhibition of FcεRI-dependent HLMC mediator release by β2-agonists was greatly reduced in HLMC-HASMC coculture. These effects were reversed by neutralization of stem cell factor (SCF) or cell adhesion molecule 1 (CADM1). β2-AR agonists did not prevent HASMC contraction when HLMCs were present, but this was reversed by fluticasone. β2-AR phosphorylation at Tyr(350) occurred within 5 min in both HLMCs and HASMCs when the cells were cocultured, and was inhibited by neutralizing SCF or CADM1. HLMC interactions with HASMCs via CADM1 and Kit inhibit the potentially beneficial effects of β2-AR agonists on these cells via phosphorylation of the β2-AR. These results may explain the potentially adverse effects of β2-ARs agonists when used for asthma therapy. Targeting SCF and CADM1 may enhance β2-AR efficacy, particularly in corticosteroid-resistant patients.

Aeroallergen Sensitization in Asthmatics children and its association with Asthma severity

Introduction: Chronic low level exposure and sensitization to indoor allergens plays a major role in asthma pathogenesis and subsequent provocation of symptoms. Asthma severity is proportional to degree of aeroallergen exposure and sensitization. This study was conducted to determine the prevalence of sensitization to common aeroallergens and its association with asthma severity. Material and methods: Cross sectional observational study that evaluated 70 asthmatic patients from 5 – 18 years of age attending pediatric allergy asthma clinic at a tertiary care teaching hospital from January to December 2014. Skin prick test was performed on all these patients. Pattern of aeroallergen sensitization and its impact on asthma severity was studied. Results: Skin prick testing (SPT) was performed on 70 children above 5 years of age, with a mean (SD) age of 8.8 (2.99) years. 52 children (74%) were sensitized to at least one aeroallergen, suggesting atopy; 27(38.5%) were sensitized to more than one allergen. 65.3% children were sensitized to house dust mite; 46.1% to alternaria, 38.4% to cynodon and 19.2% to cockroach antigens. Frequency of aeroallergen sensitization correlated with increasing age. Asthma severity was associated with sensitization to house dust mite and cockroach. Conclusion: Approximately three fourth of asthmatic children in our study were sensitized to at least one aeroallergen showing that these children had atopic/ aeroallergen induced asthma. Sensitization was most commonly seen to dust mite, alternaria and cynodon. Children sensitized to dust mite and cockroach had more severe asthma.

IL-37 requires IL18Rα and SIGIRR to ameliorate experimental allergic asthma in mice

Rationale: Recently, the new cytokine interleukin (IL) 37 has been described as a negative regulator of the innate immune system. It reduces activation of DCs and the production of pro-inflammatory mediators in TLR stimulated murine and human macrophage, monocyte and epithelial cell lines. Results from the CLARA study gave the first hint towards an implication of IL-37 in asthma pathogenesis. However, until yet it is unknown, whether IL-37 plays a role in asthma pathogenesis by providing anti-inflammatory effects on an adaptive immune response and through which receptor it exerts such effects.

8-Oxoguanine DNA glycosylase-1-driven DNA base excision repair: role in asthma pathogenesis.

To provide both an overview and evidence of the potential cause of oxidative DNA base damage and repair signaling in chronic inflammation and histological changes associated with asthma. Asthma is initiated/maintained by immunological, genetic/epigenetic, and environmental factors. It is a world-wide health problem, as current therapies suppress symptoms rather than prevent/reverse the disease, largely due to gaps in understanding its molecular mechanisms. Inflammation, oxidative stress, and DNA damage are inseparable phenomena, but their molecular roles in asthma pathogenesis are unclear. It was found that among oxidatively modified DNA bases, 8-oxoguanine (8-oxoG) is one of the most abundant, and its levels in DNA and body fluids are considered a biomarker of ongoing asthmatic processes. Free 8-oxoG forms a complex with 8-oxoG DNA glycosylase-1 and activates RAS-family GTPases that induce gene expression to mobilize innate and adaptive immune systems, along with genes regulating airway hyperplasia, hyper-responsiveness, and lung remodeling in atopic and nonatopic asthma. DNA's integrity must be maintained to prevent mutation, so its continuous repair and downstream signaling 'fuel' chronic inflammatory processes in asthma and form the basic mechanism whose elucidation will allow the development of new drug targets for the prevention/reversal of lung diseases.

Exosome secretion by eosinophils: A possible role in asthma pathogenesis

Eosinophils secrete several granules that are involved in the propagation of inflammatory responses in patients with pathologies such as asthma. We hypothesized that some of these granules are exosomes, which, when transferred to the recipient cells, could modulate asthma progression. Eosinophils were purified from peripheral blood and cultured with or without IFN-γ or eotaxin. Multivesicular bodies (MVBs) in eosinophils were studied by using fluorescence microscopy, transmission electron microscopy (TEM), and flow cytometry. Exosome secretion was measured and exosome characterization was performed with TEM, Western blotting, and NanoSight analysis. Generation of MVBs in eosinophils was confirmed by using fluorescence microscopy and flow cytometry and corroborated by means of TEM. Having established that eosinophils contain MVBs, our aim was to demonstrate that eosinophils secrete exosomes. To do this, we purified exosomes from culture medium of eosinophils and characterized them. Using Western blot analysis, we demonstrated that eosinophils secreted exosomes and that the discharge of exosomes to extracellular media increases after IFN-γ stimulation. We measured exosome size and quantified exosome production from healthy and asthmatic subjects using nanotracking analysis. We found that exosome production was augmented in asthmatic patients. Our findings are the first to demonstrate that eosinophils contain functional MVBs and secrete exosomes and that their secretion is increased in asthmatic patients. Thus exosomes might play an important role in the progression of asthma and eventually be considered a biomarker.

Wogonin, a plant flavone from Scutellariae radix, attenuated ovalbumin-induced airway inflammation in mouse model of asthma via the suppression of IL-4/STAT6 signaling.

Bronchial asthma is a chronic inflammatory disease of the airways characterized by a marked infiltration of eosinophils at the site of inflammation. Eotaxins are potent chemoattractants for eosinophils and play important roles in pathogenesis of asthma. In the course of screening for eotaxin-3 inhibitors, we found that wogonin showed potent inhibitory activity of interleukin-4 (IL-4)-induced eotaxin-3 expression in BEAS-2B cells. In this study, we examined the effects of wogonin on IL-4/STAT6 signaling pathway and biological implication in a mouse model of asthma. Wogonin inhibited IL-4-induced activation and nuclear translocation of STAT6 which plays a key role in either the transcription of STAT6-response genes or Th2 cytokine-mediated inflammation. Oral administration of wogonin significantly reduced activation of STAT6 in the lung and the expression of eotaxin and RANTES in bronchoalveolar lavage fluids. Histological examination of lung tissue demonstrated that wogonin significantly inhibited allergen-induced eosinophilic inflammation. Administration of wogonin reduced the total IgE and ovalbumin-specific IgE levels compared with the ovalbumin-challenged group. All of these data demonstrated that wogonin could alleviate airway inflammation through inhibition of STAT6 activation induced by Th2 cytokines. Our finding implicates a potential therapeutic value of wogonin in the treatment of asthma through regulation of IL-4/STAT6 signaling pathway.

Comments on "Value of past clinical history in differentiating bronchial asthma from chronic obstructive pulmonary disorder in male smokers presenting with shortness of breath and fixed airway obstruction".

Sir, We read with great interest your article “Value of past clinical history in differentiating bronchial asthma from COPD in male smokers presenting with shortness of breath (SOB) and fixed airway obstruction”.[1] Authors have highlighted the importance of past history in differentiating asthma from chronic obstructive pulmonary disorder (COPD). But, recent insight into current evidence emphasizes the need for correct classification of asthma and COPD patients by recognizing the subgroup with overlap syndrome.[2] Traditionally asthma is considered a childhood/early adulthood onset disease with reversible airflow limitation while COPD is considered to manifest after 40 years of age and has irreversible or partially reversible airflow limitation. The pathogenesis of COPD has shown that it has much early origin than previously thought. In utero/childhood smoke exposure and decreased lung growth in early adulthood are linked to increased risk of COPD at a later age.[3] At one end COPD patients may have partially reversible airflow limitation and at the other end asthmatics may show partially irreversible obstruction due to airway remodeling by long-term disease process. Cytokines play a complex role in pathogenesis of asthma and COPD. According to textbook teaching COPD patients show neutrophilic inflammation while asthmatics show eosinophilic inflammation in their airway but a growing body of evidence is reporting existence of overlap between asthma and COPD. GINA guidelines have recently defined Asthma-COPD Overlap Syndrome (ACOS) as a distinct entity.[4] Neutrophilic inflammation does not respond to corticosteroids while eosinophilic inflammation is corticosteroid responsive. Sputum eosinophilia has been reported in 20-40% of sputum samples from stable COPD patients also.[5] Airway inflammation in asthmatics is mediated by Th2 cells which express signature interleukins (IL) for allergic (eosinophilic) inflammation i.e. IL-4, 5 and 13.[6] Bafadhel et al. reported that increased sputum IL-5 levels were associated with sputum eosinophilia in COPD patients which was attenuated by oral corticosteroid therapy.[7] Michael et al. reported three biological clusters on the basis of sputum cytokine profile of 86 asthmatics and 75 COPD patients.[8] Cluster 1 consisted of mainly asthmatics and had elevated sputum Th2 cytokines and eosinophils. Cluster 2 comprised both asthma and COPD patients with sputum neutrophil predominance. Cluster 3 had mainly COPD patients. This group had mixed neutrophilic and eosinophilic inflammation. In the light of current evidence, we therefore, emphasize that classification of the patients should be based on pathobiology rather than clinical phenotypes. Such classification is important not only for optimization of currently available therapies but also for enrolment of patients in future trials for upcoming therapies like anti-interleukin 5 monoclonal antibodies.

Evaluation of vitamin D levels in allergic and non-allergic asthma

Background and objectiveSome researches show that low vitamin D may play a role in asthma pathogenesis. The aim of this study was to evaluate the serum vitamin D level in asthmatics with different phenotypes and to determine its associations with lung function, IgE, eosinophil count and body mass index (BMI). Materials and methodsThe study population comprised 85 patients with asthma and 73 healthy persons. Patients with asthma were divided into groups according to phenotypes. Allergy was assessed using a skin prick test and measuring eosinophil count in peripheral blood and total IgE in serum. Lung function was evaluated by spirometry. Concentration of vitamin D (25(OH)D3) was measured using a commercial ELISA kit. Smoking history was assessed and BMI was calculated for all individuals. ResultsThe vitamin D level was lower in asthmatics than in the control group (14.36±0.57 vs. 22.13±0.84ng/mL, P<0.01). There were no significant differences in the vitamin D level between the groups with allergic and non-allergic asthma (14.36±0.77 vs. 14.35±0.74ng/mL). The low vitamin D level increased the risk of asthma 1.2 times (OR, 1.194; 95% CI, 1.109–1.286, P<0.01). The vitamin D level did not correlate with lung function and markers of allergy in asthmatic patients. The vitamin D level correlated with FEV1/FVC (rs=0.72, P<0.05) in smoking patients with asthma. Correlation between the vitamin D level and BMI was found in all studied subjects (rs=−0.18, P<0.05). ConclusionsThe vitamin D level was lower in asthmatic patients than in healthy individuals despite their hypersensitivity and increase risk of asthma. There was no relation between the vitamin D level and lung function, eosinophil count and total IgE level, whereas the lower vitamin D level was associated with higher BMI.

Pooled-analysis of the association between TIM-1 5383_5397 insertion/deletion polymorphism and asthma susceptibility.

The T cell immunoglobulin (Ig) domain and mucin domain 1 (TIM-1) gene play an important role in pathogenesis of asthma. We investigate the association between the TIM-1 5383_5397 insertion/deletion polymorphism (rs45623443) and the risk of asthma in an asthma case-control study, and added these data to a literature-based meta-analysis. The TIM-1 5383_5397 insertion/deletion polymorphism genotype was analyzed in 156 asthma patients and 162 healthy subjects from Han Chinese population. We combined our data with that from previously published studies and performed a meta-analysis to evaluate the effect of the gene. Through regression model, we found no significant association for TIM-1 5383_5397 insertion/deletion polymorphism in our cohort. Meta-analysis, comprising a total of 1,577 asthma cases and 1,781 controls, revealed that no significant association between and asthma susceptibility was observed (OR = 0.99, 95 % CI = 0.83-1.20 for Ins vs. Del; OR = 1.01, 95 % CI = 0.74-1.37 for Ins/Ins vs. Ins/Del + Del/Del; OR = 0.96, 95 % CI = 0.78-1.18 for Ins/Ins + Ins/Del vs. Del/Del). The present meta-analysis suggested that TIM-1 5383_5397 insertion/deletion polymorphism may not substantially contribute to asthma susceptibility. However, gene-gene and gene-environment interaction effects and other considerations involving this polymorphism may exit.

Let-7a is differentially expressed in bronchial biopsies of patients with severe asthma.

Asthma is a chronic inflammatory disease. Around 5 to 10% of patients classified as having severe asthma can-not be adequately controlled despite the use of all currently available therapeutic approaches. Previous studies have revealed the potential important role of miRNAs in the regulation of a variety of inflammatory processes, including asthma. Expression of selected miRNAs, specifically let-7a, miR-21 and miR-223, that were shown to have important roles in asthma pathogenesis, were analyzed in bronchial biopsies of 24 patients with asthma, 12 mild and 12 severe and 10 controls with no chronic disease. We found significantly reduced expression of let-7a in bronchial biopsies from patients with severe asthma in comparison to patients with mild asthma as well as in comparison to the non-asthmatic controls. On the other hand, no significant differences in miR-21 and miR-223 expression were found between the different groups analyzed. Reduced let-7a levels in bronchial biopsies of patients with severe therapy-resistant asthma could not only be used as a potential biomarker to discriminate between different asthma phenotypes, but also might be a target for modulation of treatment at the inflammatory site for a group of patients that are most affected and still lack effective treatment.

Serum Interleukin-5 Changes in Partly Controlled Atopic Asthmatic Children

BACKGROUND: Cytokines including Interleukin-5 play a key role in orchestrating the chronic inflammation of asthma. We aimed to determine the level of serum IL-5 in partly controlled atopic asthma in children and to assess the effect of different therapies on their levels.METHODS: The study included 40 children aged 6-12 years with partly controlled asthma. Cases were randomly divided into two groups; group ‘A’ receiving Leukotriene modifiers and group ‘B’ receiving inhaled corticosteroids; each for two months. They were compared to 20 healthy non-asthmatic, matched controls. Serum IL-5 was measured for cases on the first visit and two months after therapy. Absolute eosinophilic count and serum Ig-E were determined. Pulmonary function testing was performed using spirometer at the beginning and two months after regular therapy.RESULTS: Serum Interleukin-5 was significantly increased in asthmatic children during exacerbation and was significantly decreased after treatment. ROC curve analysis showed significant difference of IgE and PEFR after treatment with leukotriene modifier only.CONCLUSION: Serum IL-5 seems to have a role in asthma pathogenesis. Efficiency of the two therapies (ICs &amp; LTA) was similar in this group of patients. Both treatments led to significant decline in serum IL-5, IgE levels and eosinophilic count.

Is there a place for B cells as regulators of immune tolerance in allergic diseases?

Is there a place for B cells as regulators of immune tolerance in allergic diseases?

Exosomes Secretion By Eosinophils: A Possible Role In Asthma Pathogenesis

Exosomes Secretion By Eosinophils: A Possible Role In Asthma Pathogenesis

Increased Th2-like Invariant Natural Killer T cells in Peripheral Blood From Patients With Asthma.

PurposeInvariant natural killer T (iNKT) cells might play an important role in asthma pathogenesis in humans. Our previous study found no difference in the number of blood iNKT cells between asthma patients and controls. However, few studies have examined the function of blood iNKT cells in human asthma.MethodsTwenty asthma patients and eight controls were included in this study. Blood iNKT cells were identified using double staining with anti-Vα24 and anti-Vβ11 monoclonal antibodies (mAbs) or with 6B11 and anti-Vβ11 mAbs. Intracellular IL-4, IL-10, and IFN-γ cytokines were stained in blood iNKT cells using their respective mAbs and isotypes. In addition, their relationships with clinical parameters were analyzed.ResultsThe number of Vα24+Vβ11+ iNKT cells or 6B11+Vβ11+ iNKT cells did not differ between asthma patients and controls. However, among Vα24+Vβ11+iNKT cells, the proportion of IL-4+iNKT cells was increased in asthma patients compared to controls (7.0±3.0% vs 0.5%±0.4%, P<0.05). There were no differences in the proportions of IL-10+or IFN-γ+iNKT cells between the groups. The proportion of IL-4+ cells among 6B11+Vβ11+iNKT cells inversely correlated with FEV1, expressed as a percentage predicted value in asthma patients (Rs=-0.64, P<0.05, n=19).ConclusionsBlood iNKT cells are thought to be Th2-like, and IL-4-producing iNKT cells may be associated with lung function in human asthma.

Mycoplasma pneumoniae: Does it have a Role in Asthma Pathogenesis?

Mycoplasma pneumoniae: Does it have a Role in Asthma Pathogenesis?

Human Rhinovirus, Wheezing Illness, and the Primary Prevention of Childhood Asthma

Human Rhinovirus, Wheezing Illness, and the Primary Prevention of Childhood Asthma

Group 2 innate lymphoid cells in lung inflammation

Although allergic asthma is a heterogeneous disease, allergen-specific T helper 2 (Th2) cells producing the key cytokines involved in type 2 inflammation, interleukin-4 (IL-4), IL-5 and IL-13, are thought to play a major role in asthma pathogenesis. This model is challenged by the recent discovery of group 2 innate lymphoid cells (ILC2) that represent a critical innate source of type 2 cytokines. These ILC2 are activated by epithelial cell-derived cytokines, including IL-25 and IL-33, which have been implicated in the initiation of asthma. In this review, we will discuss recent studies supporting a significant role for ILC2 in lung inflammation, with special attention to allergen-induced asthma.