Role In Pathogenesis Of Asthma Research Articles

Being born in autumn or winter is associated with asthma and allergic rhinitis in Finland.

Our population-based study has previously shown that being born in winter or spring was associated with adult-onset asthma. The aim was to study if season of birth (SOB) is associated with airway allergy and related diseases: NSAID exacerbated respiratory disease (N-ERD), asthma, allergic rhinitis (AR), nonallergic rhinitis (NAR), chronic rhinosinusitis with nasal polyps (CRSwNP) and CRS without nasal polyps (CRSsNP) in Finland. A randomly sampled retrospective registry-based follow-up data (n=74,868) of patients visiting Hospital District of Helsinki and Uusimaa (HUS) in Finland was used. The birth date, sex, visit date and comorbidities were collected from electronic health record data during visits from 2005 to 2019. The mean (SD, range) age of the sample was 34.53 (25.47, 0-102) years, with 48.7 % being men. We divided the whole population in four groups based on the season they were born (SOB-groups). When observing these four SOB-groups, the proportion of those having asthma was 43.1%, 42.1%, 41.1%, 42.7%, in winter, spring, summer, and autumn SOB-groups, respectively. The proportion of those having AR was 12.6%, 12.0%, 10.7%, 12.1%, respectively. When having summer as a reference, being born in any other time of year was significantly associated with AR and, being born in autumn or winter was associated with asthma. No significant association was observed in CRS or N-ERD or NAR groups in adjusted models. The study suggests that early life immunological events may have a role a role in pathogenesis of asthma and AR. As no association was observed between SOB and CRSsNP, CRSwNP, N-ERD or NAR, further studies on this are warranted.

Systemic Inflammation in Asthma: What Are the Risks and Impacts Outside the Airway?

Airway inflammation in asthma has been well recognized for several decades, with general agreement on its role in asthma pathogenesis, symptoms, propensity toward exacerbation, and decline in lung function. This has led to universal recommendation in asthma management guidelines to incorporate the use of inhaled corticosteroid as an anti-inflammatory therapy for all patients with persistent asthma symptoms. However, there has been limited attention paid to the presence and potential impact of systemic inflammation in asthma. Accumulating evidence from epidemiological observations and cohort studies points to a host of downstream organ dysfunction in asthma especially among patients with longstanding or more severe disease, frequent exacerbations, and underlying risk factors for organ dysfunction. Most studies to date have focused on cognitive impairment, depression/anxiety, metabolic syndrome, and cardiovascular abnormalities. In this review, we summarize some of the evidence demonstrating these abnormalities, highlight the proposed mechanisms and potential benefits of treatment in limiting these extrapulmonary abnormalities in patients with asthma. The goal of this commentary is to raise awareness of the importance of recognizing potential extra-pulmonary conditions associated with systemic inflammation of asthma. This area of treatment of patients with asthma is a large unmet need.

Lipid metabolism-related genes are involved in the occurrence of asthma and regulate the immune microenvironment

BackgroundLipid metabolism plays a pivotal role in asthma pathogenesis. However, a comprehensive analysis of the importance of lipid metabolism-related genes (LMRGs) in regulating the immune microenvironment in asthma remains lacking. The transcriptome matrix was downloaded from the Gene Expression Omnibus (GEO) dataset. Differentially expressed analysis and weighted gene coexpression network analysis (WGCNA) were conducted on the GSE74986 dataset to select hub LMRGs, and gene set enrichment analysis (GSEA) was conducted to explore their biological functions. The CIBERSORT algorithm was used to determine immune infiltration in the asthma and control groups, and the correlation of diagnostic biomarkers and immune cells was performed via Spearman correlation analysis. Subsequently, a competitive endogenous RNA (ceRNA) network was constructed to investigate the hidden molecular mechanism of asthma. The expression levels of the hub genes were further validated in the GSE143192 dataset, and RT‒qPCR and immunofluorescence were performed to verify the reliability of the results in the OVA asthma model. Lastly, the ceRNA network was confirmed by qRT-PCR and RNAi experiments in the characteristic cytokine (IL-13)-induced asthma cellular model.ResultsASAH1, ACER3 and SGPP1 were identified as hub LMRGs and were mainly involved in protein secretion, mTORC1 signaling, and fatty acid metabolism. We found more infiltration of CD8+ T cells, activated NK cells, and monocytes and less M0 macrophage infiltration in the asthma group than in the healthy control group. In addition, ASAH1, ACER3, and SGPP1 were negatively correlated with CD8+ T cells and activated NK cells, but positively correlated with M0 macrophages. Within the ceRNA network, SNHG9-hsa-miR-615-3p-ACER3, hsa-miR-212-5p and hsa-miR-5682 may play crucial roles in asthma pathogenesis. The low expression of ASAH1 and SGPP1 in asthma was also validated in the GSE74075 dataset. After SNHG9 knockdown, miR-615-3p expression was significantly upregulated, while that of ACER3 was significantly downregulated.ConclusionASAH1, ACER3 and SGPP1 might be diagnostic biomarkers for asthma, and are associated with increased immune system activation. In addition, SNHG9-hsa-miR-615-3p-ACER3 may be viewed as effective therapeutic targets for asthma. Our findings might provide a novel perspective for future research on asthma.

Identification of differences in CD4+ T-cell gene expression between people with asthma and healthy controls

Functional enrichment analysis of genome-wide association study (GWAS)-summary statistics has suggested that CD4+ T-cells play an important role in asthma pathogenesis. Despite this, CD4+ T-cells are under-represented in asthma transcriptome studies. To fill the gap, 3'-RNA-Seq was used to generate gene expression data on CD4+ T-cells (isolated within 2 h from collection) from peripheral blood from participants with well-controlled asthma (n = 32) and healthy controls (n = 11). Weighted Gene Co-expression Network Analysis (WGCNA) was used to identify sets of co-expressed genes (modules) associated with the asthma phenotype. We identified three modules associated with asthma, which are strongly enriched for GWAS-identified asthma genes, antigen processing/presentation and immune response to viral infections. Through integration of publicly available eQTL and GWAS summary statistics (colocalisation), and protein–protein interaction (PPI) data, we identified PTPRC, a potential druggable target, as a putative master regulator of the asthma gene-expression profiles. Using a co-expression network approach, with integration of external genetic and PPI data, we showed that CD4+ T-cells from peripheral blood from asthmatics have different expression profiles, albeit small in magnitude, compared to healthy controls, for sets of genes involved in immune response to viral infections (upregulated) and antigen processing/presentation (downregulated).

Winds of change a tale of: asthma and microbiome.

The role of the microbiome in asthma is highlighted, considering its influence on immune responses and its connection to alterations in asthmatic patients. In this context, we review the variables influencing asthma phenotypes from a microbiome perspective and provide insights into the microbiome's role in asthma pathogenesis. Previous cohort studies in patients with asthma have shown that the presence of genera such as Bifidobacterium, Lactobacillus, Faecalibacterium, and Bacteroides in the gut microbiome has been associated with protection against the disease. While, the presence of other genera such as Haemophilus, Streptococcus, Staphylococcus, and Moraxella in the respiratory microbiome has been implicated in asthma pathogenesis, indicating a potential link between microbial dysbiosis and the development of asthma. Furthermore, respiratory infections have been demonstrated to impact the composition of the upper respiratory tract microbiota, increasing susceptibility to bacterial diseases and potentially triggering asthma exacerbations. By understanding the interplay between the microbiome and asthma, valuable insights into disease mechanisms can be gained, potentially leading to the development of novel therapeutic approaches.

Air Pollution and Diet: Potential Interacting Exposures in Asthma.

To provide a review of emerging literature describing the impact of diet on the respiratory response to air pollution in asthma. Asthma phenotyping (observable characteristics) and endotyping (mechanistic pathways) have increased the specificity of diagnostic and treatment pathways and opened the doors to the identification of subphenotypes with enhanced susceptibility to exposures and interventions. Mechanisms underlying the airway immune response to air pollution are still being defined but include oxidative stress, inflammation, and activation of adaptive and innate immune responses, with genetic susceptibility highlighted. Of these, neutrophil recruitment and activation appear prominent; however, understanding neutrophil function in response to pollutant exposures is a research gap. Diet may play a role in asthma pathogenesis and morbidity; therefore, diet modification is a potential target opportunity to protect against pollutant-induced lung injury. In particular, in vivo and in vitro data suggest the potential for diet to modify the inflammatory response in the airways, including impacts on neutrophil recruitment and function. Murine models provide compelling results in regard to the potential for dietary components (including fiber, antioxidants, and omega-3 fatty acids) to buffer against the inflammatory response to air pollution in the lung. Precision lifestyle approaches to asthma management and respiratory protection in the context of air pollution exposures may evolve to include diet, pending the results of further epidemiologic and causal investigation and with neutrophil recruitment and activation as a candidate mechanism.

Low Serum Levels of Zinc, Selenium, and Vitamin D3 Are Biomarkers of Airway Inflammation and Poor Asthma Control: A Two-Centre Study.

Background Asthma is a chronic inflammatory disease with its control beingaffected by underlying oxidative stress. Trace elements, along with vitamin D3, play an important role in immune alterations leading to an imbalance of Th1/Th2 helper cells. However, their role in asthma pathogenesis and control is inconsistent and inconclusive. The objective of our study was to assess levels of serum trace elementslike zinc, copper, selenium, iron, magnesium,vitamin D3 levels, IgE, and HsCRP in asthmatic children, compare with healthy controls, and assess their association with the level of asthma control. Methods A cross-sectional study was conducted from 2019 to 2021 enrolling 100 asthmatic children and 75 healthy controls. The level of asthma control was assessed as uncontrolled, partly controlled, and controlled asthma as per GINA Guidelines. Mean and standard deviation were calculated for each element and mean differences between groups were analyzed by student t-test. A p-value of <0.05 was considered significant. Results The mean age was 8.75±2.89 yrs in cases and 9.04±2.79 in controls. A total of 57.6% of cases had atopic comorbidities. The mean serum zinc levels were 51±12.8 mg/dl, which was very low in asthmatic children as compared to 60±18.2mg/dl (p-value 0.0002) in healthy controls. Serum selenium was 13±3 µg/dl in asthmatics vs. 15±4 µg/dl (p-value 0.0002) in healthy controls. Serum copper was 115.2±21.92µg/dl vs. 125.3±31.99µg/dl (p-value 0.015), Serum vitamin D3 levels were 13.07±7.82ng/ml vs. 17.82±14.62 ng/ml(p-value 0.006) in both groups, respectively. SIgE and HsCRP were high in asthmatic children suggestive of eosinophilic inflammation. Serum zinc was 49±5.45 mg/dl in the uncontrolled group, 53±6.1 in the partly controlled, and 58±8.0 in the well-controlled group (p<0.0001). Serum selenium was 10± 3.0 µg/dlin the uncontrolled group vs. 13± 2.0 and 14± 2.0 µg/dl in the partly controlled and well-controlled groups, respectively (p-value <0.0001). Vitamin D3 wassignificantly low (9.32±5.95ng/dl) in the uncontrolled group vs. 12.99±4.97 and 13.40±5.92 ng/dl(p<0.005) in the partly controlled and well-controlled groups respectively. Vitamin D3 showed a strong positive correlation with zinc (r=0.4,p< 0.0001) and a negative correlation with inflammatory markers like SIgE and HsCRP. Conclusion Children with asthma had low zinc, selenium, and vitamin D3 levels, and were associated with airway inflammation and poor asthma control.

Obesity alters inflammatory response in thepathology of asthma (Review).

Obesity is one of the comorbidities in patients with asthma and obese patients with asthma present with a distinct phenotype with more severe disease outcomes and reduced responsiveness to standard therapies. Although the full mechanisms of obesity‑related asthma are still not completely understood, abnormal immune responses have been demonstrated to have a critical role in asthma pathogenesis. The present review summarizes the data from clinical, epidemiological and animal studies to provide an updated understanding of the immune responses in obesity‑related asthma, as well as the effect of various factors, such as oxidative stress, mitochondrial dysfunction, genetics and epigenetics, on asthmatic inflammation. Further studies on the in‑depth mechanisms are still required to develop novel preventive and therapeutic strategies for patients with asthma combined with obesity.

The role of the respiratory microbiome in asthma.

Asthma is a common airways disease and the human microbiome plays an increasingly recognised role in asthma pathogenesis. Furthermore, the respiratory microbiome varies with asthma phenotype, endotype and disease severity. Consequently, asthma therapies have a direct effect on the respiratory microbiome. Newer biological therapies have led to a significant paradigm shift in how we treat refractory Type 2 high asthma. While airway inflammation is the generally accepted mechanism of action of all asthma therapies, including both inhaled and systemic therapies, there is evidence to suggest that they may also alter the microbiome to create a more functionally balanced airway microenvironment while also influencing airway inflammation directly. This downregulated inflammatory cascade seen biochemically, and reflected in improved clinical outcomes, supports the hypothesis that biological therapies may in fact affect the microbiome-host immune system dynamic and thus represent a therapeutic target for exacerbations and disease control.

Role of adiponectin, resistin and monocyte chemo-attractant protein-1 in overweight/obese asthma phenotype in children

BackgroundAsthma is a chronic inflammatory disorder of the airways with diverse overlapping pathologies and phenotypes contributing to a significant heterogeneity in clinical manifestations. Obesity may modify asthma risk, phenotype, and prognosis. A suggested mechanism linking obesity and asthma is through systemic inflammation. Adipokines secreted by adipose tissue were suggested to provide a link between obesity and asthma.ObjectiveTo have an understanding for the contribution of adiponectin, resistin and MCP-1 to development of distinct asthma phenotype in overweight/obese children through assessment of their serum level and correlation to pulmonary function tests.Subjects and methodsThe study included 29 normal weight asthmatics, 23 overweight/obese asthmatic children and 30 controls. All cases were subjected to detailed history taking, thorough examination and pulmonary function tests. Serum adiponectin, resistin, MCP-1 and IgE were assessed to all recruited subjects.ResultsAdiponectin level was significantly higher in overweight/obese asthmatics (24900 ± 1600 ng/ml) compared to normal weight asthmatics (21700 ± 1700 ng/ml) and control (23000 ± 3200 ng/ml), (p < 0.001 & 0.051 respectively). Normal weight asthmatics had significantly lower adiponectin level than control, (p = 0.039). A significant low level of MCP-1 in overweight/obese asthmatics (149.5 (20—545) ng/L) compared to control (175 (28 -1123.5) ng/L), p = 0.037. No significant difference was found regarding resistin. Normal weight asthmatics had significantly lower FEV1% and FVC% compared to overweight/obese asthmatics (p = 0.036, 0.016 respectively). A significant positive correlation was found between (FEV1%, FVC) and BMI in normal weight asthmatics (P = 0.01, < 0.01 respectively) and a significant negative correlation between PEF and BMI (-0.42, p = 0.05) in obese/overweight asthmatics. Resistin/adiponectin ratio was not affected by sex, degree of asthma severity or level of asthma control in either normal weight or overweight/obese asthmatic.ConclusionThis work could suggest that adiponectin may play a role in overweight/obese asthma phenotype where it is possible to have a dual action (pro & anti- inflammatory). It seems that resistin had no role in asthma pathogenesis.

Secreted S100A4 causes asthmatic airway epithelial barrier dysfunction induced by house dust mite extracts via activating VEGFA/VEGFR2 pathway

The airway epithelial barrier dysfunction plays a crucial role in pathogenesis of asthma and causes the amplification of downstream inflammatory signal pathway. S100 calcium binding protein A4 (S100A4), which promotes metastasis, have recently been discovered as an effective inflammatory factor and elevated in bronchoalveolar lavage fluid in asthmatic mice. Vascular endothelial growth factor-A (VEGFA), is considered as vital regulator in vascular physiological activities. Here, we explored the probably function of S100A4 and VEGFA in asthma model dealt with house dust mite (HDM) extracts. Our results showed that secreted S100A4 caused epithelial barrier dysfunction, airway inflammation and the release of T-helper 2 cytokines through the activation of VEGFA/VEGFR2 signaling pathway, which could be partial reversed by S100A4 polyclonal antibody, niclosamide and S100A4 knockdown, representinga potential therapeutic target for airway epithelial barrier dysfunction in asthma.

Understanding fibroblast-immune cell interactions via co-culture models and their role in asthma pathogenesis.

Asthma is a chronic lung disease involving airway inflammation and fibrosis. Fibroblasts are the main effector cells important for lung tissue production which becomes abnormal in asthmatics and is one of the main contributors to airway fibrosis. Although fibroblasts were traditionally viewed solely as structural cells, they have been discovered to be highly active, and involved in lung inflammatory and fibrotic processes in asthma. In line with this, using 2D and 3D in vitro co-culture models, a complex interaction between lung fibroblasts and various immune cells important for the pathogenesis of asthma have been recently uncovered. Hence, in this review, we provide the first-ever summary of various studies that used 2D and 3D in vitro co-culture models to assess the nature of aberrant immune cell-fibroblast interactions and their contributions to chronic inflammation and fibrotic mechanisms in asthma pathogenesis.

Immune checkpoint molecules in prevention and development of asthma.

Allergic asthma is a respiratory disease initiated by type-2 immune responses characterized by secretion of alarmins, interleukin-4 (IL-4), IL-5, and IL-13, eosinophilic inflammation, and airway hyperresponsiveness (AHR). Immune checkpoints (ICPs) are inhibitory or stimulatory molecules expressed on different immune cells, tumor cells, or other cell types that regulate immune system activation and maintain immune homeostasis. Compelling evidence indicates a key role for ICPs in both the progression and prevention of asthma. There is also evidence of asthma development or exacerbation in some cancer patients receiving ICP therapy. The aim of this review is to provide an updated overview of ICPs and their roles in asthma pathogenesis, and to assess their implications as therapeutic targets in asthma.

Memory-like innate lymphoid cells in the pathogenesis of asthma.

Innate lymphoid cells (ILCs) are recently discovered innate immune cells that reside and self-renew in mucosal tissues and serve as the first line of defense against various external insults. They include natural killer (NK) cells, ILC1s, ILC2s, ILC3s, and lymphoid tissue inducer cells. The development and functions of ILC1-3 reflect those of their adaptive immunity TH1, TH2, and TH17 T-cell counterparts. Asthma is a heterogeneous disease caused by repeated exposure to specific allergens or host/environmental factors (e.g., obesity) that stimulate pathogenic pulmonary immune cells, including ILCs. Memory used to be a hallmark of adaptive immune cells until recent studies of monocytes, macrophages, and NK cells showed that innate immune cells can also exhibit greater responses to re-stimulation and that these more responsive cells can be long-lived. Besides, a series of studies suggest that the tissue-resident innate lymphoid cells have memory-like phenotypes, such as increased cytokine productions or epigenetic modifications following repetitive exposure to allergens. Notably, both clinical and mouse studies of asthma show that various allergens can generate memory-like features in ILC2s. Here, we discuss the biology of ILCs, their roles in asthma pathogenesis, and the evidence supporting ILC memory. We also show evidence suggesting memory ILCs could help drive the phenotypic heterogeneity in asthma. Thus, further research on memory ILCs may be fruitful in terms of developing new therapies for asthma.

Metabolic regulation by prostaglandin E2 impairs lung group 2 innate lymphoid cell responses.

Group 2 innate lymphoid cells (ILC2s) play a critical role in asthma pathogenesis. Non-steroidal anti-inflammatory drug (NSAID)-exacerbated respiratory disease (NERD) is associated with reduced signaling via EP2, a receptor for prostaglandin E2 (PGE2 ). However, the respective roles for the PGE2 receptors EP2 and EP4 (both share same downstream signaling) in the regulation of lung ILC2 responses has yet been deciphered. The roles of PGE2 receptors EP2 and EP4 on ILC2-mediated lung inflammation were investigated using genetically modified mouse lines and pharmacological approaches in IL-33-induced lung allergy model. The effects of PGE2 receptors and downstream signals on ILC2 metabolic activation and effector function were examined using in vitro cell cultures. Deficiency of EP2 rather than EP4 augments IL-33-induced mouse lung ILC2 responses and eosinophilic inflammation in vivo. In contrast, exogenous agonism of EP4 and EP2 or inhibition of phosphodiesterase markedly restricts IL-33-induced lung ILC2 responses. Mechanistically, PGE2 directly suppresses IL-33-dependent ILC2 activation through the EP2/EP4-cAMP pathway, which downregulates STAT5 and MYC pathway gene expression and ILC2 energy metabolism. Blocking glycolysis diminishes IL-33-dependent ILC2 responses in mice where endogenous PG synthesis or EP2 signaling is blocked but not in mice with intact PGE2 -EP2 signaling. We have defined a mechanism for optimal suppression of mouse lung ILC2 responses by endogenous PGE2 -EP2 signaling which underpins the clinical findings of defective EP2 signaling in patients with NERD. Our findings also indicate that exogenously targeting the PGE2 -EP4-cAMP and energy metabolic pathways may provide novel opportunities for treating the ILC2-initiated lung inflammation in asthma and NERD.

Protease-activated receptor-2: Role in asthma pathogenesis and utility as a biomarker of disease severity.

PAR2, a receptor activated by serine proteases, has primarily pro-inflammatory roles in the airways and may play a role in asthma pathogenesis. PAR2 exerts its effects in the lungs through activation of a variety of airway cells, but also activation of circulating immune cells. There is evidence that PAR2 expression increases in asthma and other inflammatory diseases, although the regulation of PAR2 expression is not fully understood. Here we review the available literature on the potential role of PAR2 in asthma pathogenesis and propose a model of PAR2-mediated development of allergic sensitization. We also propose, based on our previous work, that PAR2 expression on peripheral blood monocyte subsets has the potential to serve as a biomarker of asthma severity and/or control.

Asthma and Vitamin D Deficiency: Occurrence, Immune Mechanisms, and New Perspectives.

Asthma, as a chronic inflammatory condition of the airways, has a considerable prevalence among children. Vitamin D might play a role in asthma pathogenesis by affecting the development of the lung, regulating the immune responses, and remodeling of airway smooth muscle (ASM). Study results on the association between the serum level of vitamin D and asthma severity have suggested a converse relationship between lower vitamin D levels and more severe clinical courses. However, they are not consistent in these findings and have shown insignificant correlations, as well. The possible effects of vitamin D on asthma have led researchers to consider this vitamin a potential prophylactic and therapeutic tool for managing children with variant degrees of asthma. Adding vitamin D to the routine corticosteroid therapy of asthmatic children is another field of interest that has shown promising results. In this narrative review study, we aim to elaborate on the existing knowledge on the role of vitamin D in asthma pathogenesis and prognosis, explain the controversies that exist on the effectiveness of treating patients with vitamin D supplements, and make a general conclusion about how vitamin D actually is linked to asthma in children.

Cytokine TGFβ Gene Polymorphism in Asthma: TGF-Related SNP Analysis Enhances the Prediction of Disease Diagnosis (A Case-Control Study With Multivariable Data-Mining Model Development).

IntroductionTGF-β and its receptors play a crucial role in asthma pathogenesis and bronchial remodeling in the course of the disease. TGF-β1, TGF-β2, and TGF-β3 isoforms are responsible for chronic inflammation, bronchial hyperreactivity, myofibroblast activation, fibrosis, bronchial remodeling, and change the expression of approximately 1000 genes in asthma. TGF-β SNPs are associated with the elevated plasma level of TGF-β1, an increased level of total IgE, and an increased risk of remodeling of bronchi.MethodsThe analysis of selected TGF-β1, TGF-β2, TGF-β3-related single-nucleotide polymorphisms (SNP) was conducted on 652 DNA samples with an application of the MassARRAY® using the mass spectrometry (MALDI-TOF MS). Dataset was randomly split into training (80%) and validation sets (20%). For both asthma diagnosis and severity prediction, the C5.0 modelling with hyperparameter optimization was conducted on: clinical and SNP data (Clinical+TGF), only clinical (OnlyClinical) and minimum redundancy feature selection set (MRMR). Area under ROC (AUCROC) curves were compared using DeLong’s test.ResultsMinor allele carriers (MACs) in SNP rs2009112 [OR=1.85 (95%CI:1.11-3.1), p=0.016], rs2796821 [OR=1.72 (95%CI:1.1-2.69), p=0.017] and rs2796822 [OR=1.71 (95%CI:1.07-2.71), p=0.022] demonstrated an increased odds of severe asthma. Clinical+TGF model presented better diagnostic potential than OnlyClinical model in both training (p=0.0009) and validation (AUCROC=0.87 vs. 0.80,p=0.0052). At the same time, the MRMR model was not worse than the Clinical+TGF model (p=0.3607 on the training set, p=0.1590 on the validation set), while it was better in comparison with the Only Clinical model (p=0.0010 on the training set, p=0.0235 on validation set, AUCROC=0.85 vs. 0.87). On validation set Clinical+TGF model allowed for asthma diagnosis prediction with 88.4% sensitivity and 73.8% specificity.DiscussionDerived predictive models suggest the analysis of selected SNPs in TGF-β genes in combination with clinical factors could predict asthma diagnosis with high sensitivity and specificity, however, the benefit of SNP analysis in severity prediction was not shown.

TARGETING THE HISTONE DEMETHYLASE JMJD2B/KDM4B AS A NOVEL THERAPEUTIC APPROACH IN IL-13-MEDIATED FIBROSIS IN AIRWAY FIBROBLASTS OF SEVERE ASTHMATICS

TYPE: Abstract TOPIC: Allergy and Airway PURPOSE: Asthma is a heterogeneous disorder characterized by chronic inflammation and remodeling of the airways. Asthma responses are driven mainly by type 2 immune responses, where IL-13 plays a key role in asthma pathogenesis. We previously identified JMJD2B as an IL-13-regulated epigenetic modifier in asthmatic airway fibroblasts. Therefore, this study aimed to target JMJD2B to potentially alleviate IL-13-mediated fibrosis in asthma. METHODS: Bronchial fibroblasts isolated from asthmatic and healthy individuals were stimulated with IL-13 and treated with JIB-04, a pan-selective inhibitor of histone demethylase(s). Gene and protein expression of extracellular matrix markers were assessed using qRT-PCR, western blotting and matrix metalloproteinases (MMPs) activity assay. Chromatin immunoprecipitation (ChIP) assay was used to determine the bindig of JMJD2B to promoter region of Tissue inhibitors of matrix metalloproteinases (TIMPs). RESULTS: Here we show that JIB-04 inhibited JMJD2B activity by reducing the demethylation of its downstream target, H3K36me3, in asthmatic fibroblasts. Inhibition of JMJD2B significantly affected the viability of the bronchial fibroblasts at 48 hours. JMJD2B inhibition was further associated with the downregulation of extracellular matrix (ECM) proteins such as MMP-2, MMP-9, collagen-1, and fibronectin, and upregulation of TIMP-2, at both the gene and protein levels. This was accompanied by inhibition of IL-13 mediated MMPs activity. JIB-04 further prevented the association of JMJD2B on TIMP-2 promoter region. CONCLUSIONS: Our results demonstrate the potential of JMJD2B inhibition in attenuating IL-13-mediated fibrosis in asthma. CLINICAL IMPLICATIONS: Therapeutic targeting of JMJD2B using JIB-04 is a promising candidate to alleviate IL-13-mediated responses in chronic disorders such as asthma. DISCLOSURE: Nothing to declare. KEYWORD: Asthma

Sex Plays a Multifaceted Role in Asthma Pathogenesis.

Sex is considered an important risk factor for asthma onset and exacerbation. The prevalence of asthma is higher in boys than in girls during childhood, which shows a reverse trend after puberty—it becomes higher in adult females than in adult males. In addition, asthma severity, characterized by the rate of hospitalization and relapse after discharge from the emergency department, is higher in female patients. Basic research indicates that female sex hormones enhance type 2 adaptive immune responses, and male sex hormones negatively regulate type 2 innate immune responses. However, whether hormone replacement therapy in postmenopausal women increases the risk of current asthma and asthma onset remains controversial in clinical settings. Recently, sex has also been shown to influence the pathophysiology of asthma in its relationship with genetic or other environmental factors, which modulate asthmatic immune responses in the airway mucosa. In this narrative review, we highlight the role of sex in the continuity of the asthmatic immune response from sensing allergens to Th2 cell activation based on our own data. In addition, we elucidate the interactive role of sex with genetic or environmental factors in asthma exacerbation in women.