Airway Hyperresponsiveness Research Articles

Systolic and global right ventricular functions of children with bronchial asthma as compared with those of healthy controls using echocardiography: a single-centre cross-sectional observational study from Nigeria

BackgroundAsthma is the most prevalent chronic airway condition in children. It is characterised by hyperresponsiveness of the small airways leading to airway narrowing, which is usually reversible, with or without treatment. Asthma is known to cause right ventricular dysfunction, but not much is known of this effect among children with highest burden of asthma. The aim of this study is to compare the right ventricular functions of children with asthma, aged 6– ≤ 13 years, with those of their age and sex-matched apparently healthy control using transthoracic echocardiography. The systolic and global right ventricular functions were assessed using Tricuspid Annular Plane Systolic Function (TAPSE) and Tei index, respectively.ResultsSeventy cases and 68 controls were included in the final analysis of the results. The male-to-female ratios are 1.9:1 and 2:1 for the cases and controls, respectively, and their mean age were 8.82 (± 2.28) and 9.05 (2.50) years. There was no statistically significant difference between their sex (X2\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$${X}^{2}$$\\end{document}/P = 0.810/0.85) and their mean age (P = 0.554). The mean TAPSE of the cases (20.16 ± 2.15 mm) and the controls (20.28 ± 2.71 mm) did not differ significantly (P = 0.74), but the mean Tei index of the cases (0.56 ± 0.16) was significantly higher than that of the control (0.50 ± 0.10) (P = 0.007). Among the asthmatics, 17.1% (12/70) and 2.9% (2/70) had global and systolic RV dysfunctions, respectively; 2.9% (2/70) of the controls had RV global dysfunctions, but none had RV systolic dysfunction. The global dysfunction among the asthmatics was significantly associated with their age range and frequency of hospitalisation (X2\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$${X}^{2}$$\\end{document} /p of 6.051/0.014 and 7.209/0.021, respectively), and significantly correlates with their Body Mass Index, and peripheral oxygen saturation (r/P of −0.236/0.049 and − 2.490/0.038, respectively). None of the participants had right ventricular systolic dysfunction.ConclusionThis study shows that asthmatic patients have global RV dysfunction, and it is suggested that better control of asthma would preserve cardiac function.

Impact of Swimming Training on the Course and Symptoms of Bronchial Asthma and Respiratory System Function: A Literature Review

Introduction: Bronchial asthma is one of the most common inflammatory diseases among adults and children. It is characterized by the occurrence of bronchial obstruction, which is manifested, for instance, by a feeling of shortness of breath, wheezing, a feeling of tightness in the chest, a feeling of squeezing in the chest. In addition to pharmacological treatment, health behavior including sport is of great importance. In this publication, we will attempt to discuss the effects of swim training on asthma and respiratory system function. We will try to answer the question whether swimming is a safe form of exercise for patients with bronchial asthma.Material and methods: Review of the specialized literature in the field of pulmonology, guidelines for treatment of bronchial asthma and articles available on PubMed and Google Scholar database searching by the keywordsAim of the study: The aim of this publication is to review the available literature to answer the question of whether swimming training is a suitable form of exercise for asthmatic patients and what effect it has on respiratory functionConclusions: The treatment of bronchial asthma is based on the pharmacological treatment. In addition to medications, non-pharmacological methods and health behaviours are important. Appropriate physical activity for people with asthma may include swimming training, which has a beneficial effect on lung function and asthma symptoms management, especially in the paediatric population. There are studies that suggest that swimming carries a lower risk of causing bronchospasm than other sport activities, however, there are inconclusive reports on the effect of attending chlorinated swimming pools on the development of asthma and allergies. Studies on competitive and elite swimmers show that intensive swimming training, especially in chlorinated pools, can induce bronchial hyperresponsiveness and the risk of developing asthma, but this requires further research.

Evaluating serum periostin and YKL-40 as biomarkers for airway remodeling and hyperresponsiveness in pediatric asthma

BackgroundPeriostin and human chitinase-3-like protein 1 (YKL-40) have been suggested to be involved in the development of airway fibrosis and remodeling. This study aimed to investigate the relationship between serum periostin levels and airway hyperresponsiveness (AHR) and between serum YKL-40 levels and AHR in children with asthma, comparing periostin as a marker for Th2 inflammation and atopy with YKL-40. MethodsThe study involved children aged 6–15 years, comprising 75 with asthma and 29 healthy controls. We measured serum periostin and YKL-40 levels and performed exercise bronchial provocation tests, methacholine challenge tests, spirometry, and FeNO measurements. ResultsCompared to the healthy controls, asthmatic children exhibited significantly elevated levels of periostin (86.7 [71.0–104.0] vs 68.3 [56.0–82.0] ng/mL; P = 0.006) and YKL-40 (29.0 [15.0–39.5] vs 27.7 [14.0–34.1] ng/mL; P = 0.034). The subgroup analysis revealed that periostin levels were significantly higher in the atopic asthma group than in the healthy controls (P = 0.003), but not in the non-atopic asthma group. YKL-40 levels were elevated in both the atopic and non-atopic asthma groups compared to healthy controls (P = 0.012 and P = 0.001, respectively). Serum periostin levels were significantly correlated with the postexerceise maximum percentage decrease in forced expiratory volume (FEV1), as well as with fractional exhaled nitric oxide (FeNO) and blood eosinophil counts, but showed no significant correlation with overall lung function. Conversely, serum YKL-40 levels were significantly linked to the Z score of FEV1 and AHR to methacholine but not with AHR to exercise or FeNO or blood eosinophil count. ConclusionsPeriostin is linked to atopic asthma and correlates with exercise-induced bronchoconstriction, FeNO, and eosinophil counts, highlighting its role in Th2 inflammation. YKL-40 is a general asthma marker, indicating airway remodeling. These findings suggest that targeting these markers can improve personalized treatment strategies for pediatric asthma.

Fingolimod, a sphingosine-1-phosphate receptor modulator, prevents neonatal bronchopulmonary dysplasia and subsequent airway remodeling in a murine model.

Neonatal bronchopulmonary dysplasia (BPD) is associated with alveolar simplification and airway remodeling. Airway remodeling leads to deformation of airways characterized by peribronchial collagen deposition and hypertrophy of airway smooth muscle, which contribute to the narrowing of airways. Poorly developed lungs contribute to reduced lung function that deteriorates with the passage of time. We have earlier shown that sphingosine kinase 1 (SPHK 1)/sphingosine-1-phosphate (S1P)/S1P receptor1 (S1PR1) signaling plays a role in the pathogenesis of BPD. In this study, we investigated the role of fingolimod or FTY720, a known S1PR1 modulator approved for the treatment of multiple sclerosis in the treatment of BPD. Fingolimod promotes the degradation of S1PR1 by preventing its recycling, thus serving as the equivalent of an inhibitor. Exposure of neonatal mice to hyperoxia enhanced the expression of S1PR1 in both airways and alveoli as compared with normoxia. This increased expression of S1PR1 in the airways persisted into adulthood, accompanied by airway remodeling and airway hyperreactivity (AHR) after neonatal hyperoxia. Intranasal fingolimod at a much lower dose compared with the intraperitoneal route of administration during neonatal hyperoxia improved alveolarization in neonates and reduced airway remodeling and AHR in adult mice associated with improved lung function. The intranasal route was not associated with the lymphopenia seen with the intraperitoneal route of administration of the drug. An increase in S1PR1 expression in the airways was associated with an increase in the expression of enzyme lysyl oxidase (LOX) in the airways following hyperoxia, which was suppressed by fingolimod. This association warrants further investigation.NEW & NOTEWORTHY The role of the S1P receptor1 modulator, fingolimod, as an FDA-approved drug in preventing the recurrence of multiple sclerosis is established. Fingolimod prevented bronchopulmonary dysplasia (BPD) and its sequela of airway remodeling in a neonatal murine model. This protection was associated with the downregulation of lysyl oxidase signaling pathway. Fingolimod could be repurposed for the therapy of BPD.

The Effects of Turmeric and Mangosteen Pericarp Ethanol Extract on Eosinophil Count, TNF-α and TGF-β1 Gene Expression in Asthmatic Rat Model.

Asthma is a chronic respiratory disease that is characterized by inflammation, bronchial hyperreactivity, and airway remodeling. The long-term use of corticosteroids at high doses causes various side effects. Traditional herbal medicine has been suggested as an alternative therapy that is safe and effective in dealing with asthma. Natural plants such as turmeric and mangosteen are known to treat asthma and reduce inflammation. The purpose of this study was to investigate the effects of turmeric and mangosteen pericarp ethanol extracts on the eosinophil counts, TNF-α and TGF-β1 gene expression, and inflammatory cell counts in the histopathology of an asthmatic rat model. The preliminary study used 30 rats, which were divided into a normal group, negative control group (OVA-sensitized), turmeric normal group, mangosteen group, and positive control group. Blood samples were collected after the sensitization period to determine eosinophil counts. TNF-α and TGF-β1 gene expression, and histopathology were observed in the rat's lungs. The follow-up study used 30 rats divided into a normal group, negative control group (OVA-sensitized), combination of turmeric and mangosteen group (54m/200gr rats, 36mg/200gr rats, and 36mg/200gr rats), and positive control group. The examination procedures were the same as in the preliminary study. The administration of single ethanol extracts of turmeric and mangosteen significantly decreased eosinophils and improved the histopathological features of the lungs (inflammatory cell counts, bronchial inflammatory score, and bronchial smooth muscle thickness) (p<0.05). The combination of turmeric and mangosteen extracts at all doses significantly decreased eosinophils and improved the histopathological features of the lungs (inflammatory cell counts, bronchial inflammatory score, and bronchial smooth muscle thickness) (p<0.05). Both the single and combined administration of turmeric and mangosteen ethanol extracts did not cause significant changes in TNF-alpha and TGF-beta (p>0.05). Turmeric ethanol extract and mangosteen pericarp ethanol extract have a reductional effect on the parameters of asthma based on the eosinophil counts, the inflammatory cell counts and score, and bronchial smooth muscle thickness.

Subtype prevalence and treatment implication in adolescents and adults with mild-to-moderate asthma: A systematic review and meta-analysis

BackgroundInhaled corticosteroid (ICS) containing regimens are the mainstay for treating asthma despite usually being ineffective in non-eosinophilic asthma (NEA). Data on the prevalence of NEA versus eosinophilic asthma (EA) in mild-to-moderate asthmatics is limited. ObjectiveTo systematically review the subtype prevalence of mild-to-moderate asthma in adolescents and adults using sputum inflammatory cell analysis and their responses to ICS. MethodsWe searched electronic databases (PubMed, Scopus, EMBASE, Cochrane) for studies in adolescents and adults with mild-to-moderate asthma. The primary outcome was the prevalence of asthma subtypes based on sputum inflammatory cell analysis, categorized into EA and NEA. The secondary outcome involved comparing asthma outcomes between different subtypes following ICS therapy. Certainty of evidence was reported for each pooled analysis. ResultsEighteen studies involving 3,533 adolescents and adults with mild-to-moderate asthmatics were reviewed. The pooled prevalence (95% confidence interval, CI) of NEA was estimated at 40.39% (27.54, 53.93) in patients with ICS naïve with very low certainty of evidence. Upon reevaluating sputum cytology, approximately 20% to 30% of patients initially classified as having NEA transitioned to the EA subtype. EA patients showed significant improvements in asthma symptoms, FEV1 [standardized mean difference (95% CI): 0.79 (0.30, 1.27)], and airway hyperresponsiveness [1.34 (0.29, 2.40)] following ICS therapy, while NEA patients exhibited limited response. ConclusionA high proportion of adolescents and adults with mild-to-moderate asthma were identified as having the NEA subtype, which exhibited a poor response to ICS. A thorough diagnostic evaluation before initiating treatment should be integrated into clinical practice.

IL-18 biology in severe asthma

The role of interleukin-18 (IL-18) and inflammasomes in chronic inflammatory airway diseases, such as asthma and chronic obstructive pulmonary disease (COPD), has garnered significant attention in recent years. This review aims to provide an overview of the current understanding of IL-18 biology, the associated signaling pathways, and the involvement of inflammasome complexes in airway diseases. We explore the multifaceted role of IL-18 in asthma pathophysiology, including its interactions with other cytokines and contributions to both T2 and non-T2 inflammation. Importantly, emerging evidence highlights IL-18 as a critical player in severe asthma, contributing to chronic airway inflammation, airway hyperresponsiveness (AHR), and mucus impaction. Furthermore, we discuss the emerging evidence of IL-18’s involvement in autoimmunity and highlight potential therapeutic targets within the IL-18 and inflammasome pathways in severe asthma patients with evidence of infections and airway autoimmune responses. By synthesizing recent advancements and ongoing research, this review underscores the importance of IL-18 as a potential novel therapeutic target in the treatment of severe asthma and other related conditions.

Oxidative Stress and Antioxidants in Pediatric Asthma’s Evolution and Management

Within the pediatric population, bronchial asthma is one of the most prevalent chronic respiratory system diseases. The number of exacerbations, severity, and duration of symptoms all have a significant impact on children’s life quality. In the last decades, the prevention and management strategies of this pathology have focused on maintaining or even increasing the pulmonary function to maximum levels in early childhood, as it has been demonstrated that functional deficits at this level occurring before school age cause pathological manifestations later, in adulthood. The epithelium of the airways and implicitly that of the lung is the first barrier against the lesions caused by pro-oxidative factors. Both oxidative and antioxidative factors can be of endogenous origin (produced by the body) or exogenous (from the environment or diet). Good functioning of antioxidant defense mechanisms from the molecular level to the tissue level, and a balance between pro-oxidative factors and anti- oxidative factors, influence the occurrence of compensatory mechanisms at the level of the respiratory epithelium, causing the delay of local responses to the stress induced by chronic inflammation (bronchial remodeling, thickening of airway smooth muscles, bronchoconstriction, bronchial hyper-reactivity). These mechanisms underlie the pathophysiological changes in asthma. Numerous studies carried out among the pediatric population inclusively have demonstrated the effectiveness of antioxidants in the prophylaxis, slowing down and preventing the progression of this pathology. This review complements the scientific articles, aiming at emphasizing the complexity of oxidative physio-pathological pathways and their importance in the occurrence, development, and therapeutic response in asthma, providing a good understanding of the relationship between oxidative and antioxidative factors, and being a source of future therapeutic strategies.

Allele-specific micro-RNA-mediated regulation of ADAM33 in childhood allergic asthma.

A disintegrin and metalloprotease 33 (ADAM33) is associated with asthma susceptibility, and its genetic variations impact susceptibility and disease severity. However, the mechanisms remain unclear. This study aimed to investigate ADAM33 single nucleotide polymorphisms (SNPs) in childhood asthma susceptibility and explore their regulatory mechanisms. Eleven selected SNPs in ADAM33 were genotyped and identified the association with asthma susceptibility. In the validation cohort, we measured plasma sADAM33 levels and compared them with disease severity among children with different SNP genotypes. Computational predictions identified miRNAs targeting the SNP, and the impact of the SNP on miRNA regulation was confirmed using a dual luciferase reporter system. Finally, we validated the regulatory role of miRNAs on ADAM33 expression using an in vitro model with upregulated ADAM33 expression. Only rs3918400 was associated with asthma susceptibility. In the validation cohort, children with allergic asthma exhibited higher plasma sADAM33 levels. Among asthmatic children, those with the rs3918400 CT/TT genotype had higher sADAM33 levels, poorer asthma control, more severe airway hyper-responsiveness, lower FEV1% and higher dust mite-specific IgE activity compared to those with the CC genotype. miR-3928-5p bound strongly to the rs3918400 C allele and effectively reduced ADAM33 protein expression in CC genotype cells. However, the binding affinity of miR-3928-5p to the T allele was weaker, resulting in diminished negative regulation of protein expression. The rs3918400 SNP affects the negative regulation of ADAM33 by miR-3928-5p, potentially participating in a complex interplay of processes related to childhood asthma susceptibility.

Nanoparticles to Target Asthma.

Asthma is a heterogenous chronic lung disease that affects nearly 340 million people globally. Airway hyperresponsiveness, remodeling (thickening, fibrosis), and mucus hypersecretion are some hallmarks of asthma. With several current treatments having serious side effects from long-term use, and a proportion of patients with uncontrolled asthma, there is urgent need for new therapies. With increasing understanding of asthma pathophysiology, there is a recognized need to target therapies to specific cell types of the airway which necessitates identification of delivery systems that can overcome increased mucus and thickened airways. Nanoparticles (NPs) that are highly customizable (material, size, charge, surface modification) are a potential solution for delivery systems of a wide variety of cargoes (nucleic acids, proteins, and/or small molecules), as well as sole therapeutics for asthma. However, there is need to consider the safety of the NPs in terms of potential for inflammation, toxicity, non-specific targets, and accumulation in organs. Ongoing clinical trials using NPs, some FDA-approved for therapeutics in other diseases, provide confidence regarding potential safety and efficacy of NPs in asthma treatment. This review highlights the current state of the use of NPs in asthma, identifying opportunities for further improvements in NP design and utilization for targeting this chronic lung disease.

Diagnostic value of serum thymus and activation-regulated chemokine (TARC) in fatal asthma

ObjectivesAsthma, a chronic inflammatory airway disease, is characterized by airway hyperresponsiveness and structural changes. Accurate postmortem diagnosis is crucial because of legal and insurance implications, necessitating differentiation from other causes of sudden death. Thymus and activation-regulated chemokine (TARC) is a chemokine that potentially acts as a biomarker of asthma. This study evaluated the diagnostic value of serum TARC combined with immunoglobulin E (IgE) levels as biomarkers in forensic settings. ResultsThe subjects were 100 autopsy cases, categorized into fatal asthma (n = 25), acute myocardial infarction (AMI) (n = 37), and traumatic deaths (n = 38). TARC levels were significantly elevated in asthma (525.68 ± 801.87 pg/mL) compared with AMI (180.35 ± 109.37 pg/mL) and trauma (173.26 ± 105.01 pg/mL) cases. Similarly, serum IgE levels were higher in asthma (3363.72 ± 7023.46 KU/L) than in AMI (130.92 ± 260.79 KU/L) and trauma (134.53 ± 195.41 KU/L) cases. ROC curve analysis showed that serum TARC had a sensitivity of 68.0 % and specificity of 73.6 % (AUC 0.763, cut-off value of 225 pg/mL). In comparison, serum IgE had a sensitivity of 80 % and specificity of 86.1 % (AUC 0.881, cut-off value of 307 KU/L). The combined use of TARC and IgE increased the diagnostic specificity to 95.8 %. ConclusionsSerum TARC and IgE are valuable biomarkers for diagnosing fatal asthma in forensic settings. While serum TARC levels correlate with Th2-mediated inflammation, the combined measurement of TARC and IgE enhances the diagnostic accuracy, providing significant specificity for confirming asthma diagnosis.

Kiss1 receptor knockout exacerbates airway hyperresponsiveness and remodeling in a mouse model of allergic asthma

BackgroundIn asthma, sex-steroids signaling is recognized as a critical regulator of disease pathophysiology. However, the paradoxical role of sex-steroids, especially estrogen, suggests that an upstream mechanism or even independent of estrogen plays an important role in regulating asthma pathophysiology. In this context, in our previous studies, we explored kisspeptin (Kp) and its receptor Kiss1R’s signaling in regulating human airway smooth muscle cell remodeling in vitro and airway hyperresponsiveness (AHR) in vivo in a mouse (wild-type, WT) model of asthma. In this study, we evaluated the effect of endogenous Kp in regulating AHR and remodeling using Kiss1R knockout (Kiss1R−/−) mice.MethodsC57BL/6J WT (Kiss1R+/+) and Kiss1R−/− mice, both male and female, were intranasally challenged with mixed-allergen (MA) and/or phosphate-buffered saline (PBS). We used flexiVent analysis to assess airway resistance (Rrs), elastance (Ers), and compliance (Crs). Following this, broncho-alveolar lavage (BAL) was performed for differential leukocyte count (DLC) and cytokine analysis. Histology staining was performed using hematoxylin and eosin (H&E) for morphological analysis and Masson’s Trichrome (MT) for collagen deposition. Additionally, lung sections were processed for immunofluorescence (IF) of Ki-67, α-smooth muscle actin (α-SMA), and tenascin-c.ResultsInterestingly, the loss of Kiss1R exacerbated lung function and airway contractility in mice challenged with MA, with more profound effects in Kiss1R−/− female mice. MA-challenged Kiss1R−/− mice showed a significant increase in immune cell infiltration and proinflammatory cytokine levels. Importantly, the loss of Kiss1R aggravated Th2/Th17 biased cytokines in MA-challenged mice. Furthermore, histology of lung sections from Kiss1R−/− mice showed increased collagen deposition on airway walls and mucin production in airway cells compared to Kiss1R+/+ mice. In addition, immunofluorescence analysis showed loss of Kiss1R significantly aggravated airway remodeling and subsequently AHR.ConclusionsThese findings demonstrate the importance of inherent Kiss1R signaling in regulating airway inflammation, AHR, and remodeling in the pathophysiology of asthma.

Targeting TMEM16A ion channels suppresses airway hyperreactivity, inflammation, and remodeling in an experimental Guinea pig asthma model

Asthma is a chronic inflammatory disease characterized by airway hyperresponsiveness, inflammation, and remodeling. Calcium (Ca2+)-activated chloride (Cl−) channels, such as TMEM16A, are inferred to be involved in asthma. Therefore, the present study investigated the therapeutic potential of TMEM16A inhibition in a guinea pig model of ovalbumin (OVA)-induced allergic asthma. Guinea pigs were treated with a specific blocker, CaCCinh-A01 (10 μM), administered via inhalation. A significant reduction in cough reflex sensitivity and specific airway resistance was observed in animals treated with CaCCinh-A01, highlighting its potential to improve airway function. Despite a reduction in ciliary beating frequency (CBF), CaCCinh-A01 reduced airway mucus viscosity by decreasing the production of mucin-5AC (MUC5AC). The nonspecific reduction in the Th1/Th2 cytokine spectrum following CaCCinh-A01 treatment indicated the suppression of airway inflammation. Additionally, markers associated with airway remodeling were diminished, suggesting that CaCCinh-A01 may counteract structural changes in airway tissues. Therefore, inhibition appears to mitigate the pathological aspects of asthma, including airway hyperresponsiveness, inflammation, and remodeling. However, further studies are required to comprehensively evaluate the potential of TMEM16A as a therapeutic target for asthma.

STING-dependent induction of neutrophilic asthma exacerbation in response to house dust mite.

Severe refractory, neutrophilic asthma remains an unsolved clinical problem. STING agonists induce a neutrophilic response in the airways, suggesting that STING activation may contribute to the triggering of neutrophilic exacerbations. We aim to determine whether STING-induced neutrophilic lung inflammation mimics severe asthma. We developed new models of neutrophilic lung inflammation induced by house dust mite (HDM) plus STING agonists diamidobenzimidazole (diABZI) or cGAMP in wild-type, and conditional-STING-deficient mice. We measured DNA damage, cell death, NETs, cGAS/STING pathway activation by immunoblots, N1/N2 balance by flow cytometry, lung function by plethysmography, and Th1/Th2 cytokines by multiplex. We evaluated diABZI effects on human airway epithelial cells from healthy or patients with asthma, and validated the results by transcriptomic analyses of rhinovirus infected healthy controls vs patients with asthma. DiABZI administration during HDM challenge increased airway hyperresponsiveness, neutrophil recruitment with prominent NOS2+ARG1- type 1 neutrophils, protein extravasation, cell death by PANoptosis, NETs formation, extracellular dsDNA release, DNA sensors activation, IFNγ, IL-6 and CXCL10 release. Functionally, STING agonists exacerbated airway hyperresponsiveness. DiABZI caused DNA and epithelial barrier damage, STING pathway activation in human airway epithelial cells exposed to HDM, in line with DNA-sensing and PANoptosis pathways upregulation and tight-junction downregulation induced by rhinovirus challenge in patients with asthma. Our study identifies that triggering STING in the context of asthma induces cell death by PANoptosis, fueling the flame of inflammation through a mixed Th1/Th2 immune response recapitulating the features of severe asthma with a prognostic signature of type 1 neutrophils.

IRF3 Promotes Asthma Pathogenesis by Regulating Type 2 Innate Lymphoid Cells

ABSTRACT Background Allergic asthma is characterized by airway hyperresponsiveness triggered by inhaled allergens. Type 2 innate lymphoid cells (ILC2s) have been demonstrated to play a crucial role in promoting airway inflammation through the secretion of type 2 effector cytokines. However, the mechanisms underlying the functions of lung ILC2s remain unclear. Methods In this study, we investigated the expression of IRF3 in ILC2s in both human patients and mouse models of asthma. We utilized IRF3-deficient mice to assess the impact of IRF3 deficiency on ILC2 function in a model of IL33-induced asthma. Additionally, we explored the mechanisms underlying IRF3-mediated regulation of ILC2s, focusing on the involvement of the transcription factor Gata3. Results Our findings revealed elevated expression of IRF3 in ILC2s of patients and mice with asthma, suggesting a potential role for IRF3 in the pathogenesis of allergic asthma. Furthermore, we demonstrated that IRF3 deficiency impairedthe expansion and function of ILC2s in IL33-induced asthma, highlighting the importance of IRF3 in regulating ILC2-mediated responses. Importantly, we showed that the regulation of ILC2s by IRF3 was independent of Th2 cells and mediated by the transcription factor Gata3. Conclusion This study identifies IRF3 as a novel regulator of lung ILC2s and suggests its potential as a promising immunotherapeutic target for allergic asthma. These findings shed light on the intricate mechanisms underlying asthma pathogenesis and provide insights into potential strategies for the development of targeted therapies for this prevalent airway disease.

Elevated circulating group-2 innate lymphoid cells expressing activation markers and correlated tryptase AB1 levels in active ascariasis

IntroductionAscaris lumbricoides infection is one of the most common soil-transmitted helminthiasis and IgE response to this helminth may increase the risk of asthma, bronchial hyperreactivity and atopy. There is not enough evidence showing the role of group-2 innate lymphoid cells (ILC2) in the pathogenesis of helminth infections in humans. Here, we aimed to investigate and characterize the influence of Ascaris lumbricoides infection on circulating ILCs in endemically exposed subjects.MethodsNon-infected (NI; n=16) and Ascaris-infected (AI; n=16) subjects from an endemic area were included. Two consecutive stool samples from each subject were examined by Kato-Katz to define parasite infection. Antibodies to the ABA-1 antigen of Ascaris and Ascaris extract were measured by ELISA. ILC subsets and their activation markers (CD25, CD69, thymic stromal lymphopoietin receptor (TSLPR) were evaluated in its PBMC by flow cytometry. Proximity extension assay (PEA) was performed to explore plasma proteins associated to infection.ResultsNo significant differences in the relative or absolute frequencies of total ILCs, ILC1, ILC2 and ILC3 cells were observed regarding the infection status. However, within AI group, IgE-sensitized subjects to ABA-1 had higher frequencies and counts of ILC2 (p&amp;lt;0.05). Frequencies of CD25+, CD69+ and TSLPR+ ILC2 were higher in AI compared to the NI (p&amp;lt;0.01). Additionally, egg burden was positively correlated with CD69+ ILC2 frequencies (r=0.67; p=0.005). Tryptase alpha/beta 1 (TPSAB1), GP6 and several plasma proteins associated with cell growth and granulocyte chemotaxis were highly expressed in the AI group (p&amp;lt;0.05). Interestingly, TPSAB1 levels were positively correlated with ILC2 expressing activation markers frequencies, egg burden and IgE levels against Ascaris.DiscussionAscaris infection is associated with increased expression of ILC2 activation markers and TPSAB1, which may contribute to the type-2 response.

Requirement for Fucosyltransferase 2 in Allergic Airway Hyperreactivity and Mucus Obstruction.

Mucus hypersecretion is an important pathological problem in respiratory diseases. Mucus accumulates in the airways of people with asthma, and it contributes to airflow limitation by forming plugs that occlude airways. Current treatments have minimal effects on mucus or its chief components, the polymeric mucin glycoproteins MUC5AC and MUC5B. This treatment gap reflects a poor molecular understanding of mucins that could be used to determine how they contribute to airway obstruction. Due to the prominence of glycosylation as a defining characteristic of mucins, we investigated characteristics of mucin glycans in asthma and in a mouse model of allergic asthma. Mucin fucosylation was observed in asthma, and in healthy mice it was induced as part of a mucous metaplastic response to allergic inflammation. In allergically inflamed mouse airways, mucin fucosylation was dependent on the enzyme fucosyltransferase 2 (Fut2). Fut2 gene deficient mice were protected from asthma-like airway hyperreactivity and mucus plugging. These findings provide mechanistic and translational links between observations in human asthma and a mouse model that may help improve therapeutic targeting of airway mucus.

Exploring the effect of peppermint oil massage on pulmonary function in patients with bronchial asthma: insights from a case series

Bronchial asthma (BA) is a chronic inflammatory disorder characterized by airway hyperresponsiveness and obstruction, leading to symptoms such as coughing, wheezing, and shortness of breath. Management typically involves inhaled corticosteroids, but their adverse effects necessitate exploring alternative therapies. Aromatherapy massage, particularly using peppermint oil, may offer therapeutic benefits due to its anti-inflammatory and broncho dilatory properties. This study investigates the impact of upper back massage with peppermint oil on pulmonary function in BA patients. Three female patients with a history of poorly controlled BA participated in this case series. Each patient received a 20-minute upper back massage with peppermint oil daily for 10 days. Pulmonary function tests (PFTs) were conducted before and after the intervention, measuring forced vital capacity (FVC), forced expiratory volume in the first second (FEV1), the FEV1/FVC ratio, peak expiratory flow rate (PEFR), and forced expiratory flow (FEF 25-75%). All patients showed improvement in pulmonary function post-intervention. Case 1: FVC increased from 80% to 97%, FEV1 from 67% to 82%, and PEFR from 72% to 93%. Case 2: FVC improved from 69% to 81%, FEV1 from 64% to 76%, and FEF 25-75% from 40% to 50%. Case 3: FVC rose from 74% to 78%, FEV1 from 55% to 60%, and PEFR from 56% to 63%. Upper back massage using peppermint oil appears to enhance pulmonary function in individuals with bronchial asthma.

Aging, brain-derived neurotrophic factor, and allergen-induced pulmonary responses in mice.

Asthma in the elderly is being recognized as more severe, resistant to standard therapies, and having greater morbidity. Therefore, it comes important to understand the impact of aging-associated airway structure and function changes towards pathogenesis of asthma in the elderly. Here, airway smooth muscle plays important roles in airway hyperreactivity and structural remodeling. The role of smooth muscle in asthma can be modulated by growth factors (including neurotrophins such as brain-derived neurotrophic factor (BDNF)) and pro-inflammatory senescence factors. In this study, we investigated aging effects on airway hyperreactivity, structural remodeling, inflammation, and senescence in a mouse model of allergic asthma. C57BL/6J wildtype mice or smooth muscle-specific BDNF knockout mice at 4, 18 and 24 months of age were intranasally exposed to mixed allergens (ovalbumin, aspergillus, Alternaria, and house dust mite) over 4 weeks. Assessing lung function by FlexiVent, we found that compared with 4 month old mice, 18 and 24 month old C57BL/6J mice showed decreased airway resistance and increased airway compliance after PBS or MA treatment. Deletion of smooth muscle BDNF blunted airway hyperreactivity in aged mice. Lung histology analysis revealed that aging increased bronchial airway thickness and decreased lung inflammation. Multiplex assays showed that aging largely reduced allergen-induced lung expression of proinflammatory chemokines and cytokines. By immunohistochemistry staining, we found that aging increased bronchial airway expression of senescence markers, including p21, phospho-p53 and phospho-gH2A.X. Our data suggest that aging associated increase of airway senescence in the context of allergen exposure may contribute to asthma pathology in the elderly.

Transforming Care in SEA: Evidence and Considerations for Evolution of the Current Treatment Paradigm

This article reviews an industry symposium held on 8 September 2024 as part of the European Respiratory Society (ERS) Congress 2024 in Vienna, Austria, which brought together four experts to discuss the current treatment paradigm for severe eosinophilic asthma (SEA), including the role of biologics and background medication tapering. Katrin Milger-Kneidinger, Professor of Respiratory Medicine at the University Hospital of the Ludwig Maximilian University Munich (LMU), in Germany, and the MedUni Graz, in Austria, explored the critical role eosinophils play in SEA pathology and how biologic therapies targeting eosinophils can address key disease features, including airway remodelling, airway hyperresponsiveness (AHR), and mucus production. Felix Herth, Professor of Pulmonary and Critical Care Medicine at Thoraxklinik Heidelberg, Heidelberg University Hospital, in Germany, discussed persistent airflow obstruction (PAO) in patients with SEA, focusing on a typical patient profile to understand the clinical manifestation and opportunities for management. Stephanie Korn, Professor of Pulmonary and Respiratory Medicine at Thoraxklinik Heidelberg, Heidelberg University Hospital, in Germany, and Head of the Clinical Research Centre, Institute für Klinische Forschung (IKP) Pneumologie in Mainz, Germany, presented on remission as a clinical target in SEA, focusing on how biologics can help achieve remission in some patients. Lastly, in a discussion led by symposium chair Stefano Del Giacco, Professor of Medicine, Allergy, and Clinical Immunology, at the University of Cagliari, Sardinia, in Italy, the experts agreed that a positive practice change would be to get more patients with relevant clinical manifestations on biologics, and that background medication tapering, when appropriate, could lead to improved patient outcomes and quality of life (QoL) in SEA.