Inflammatory Airway Diseases Research Articles

Airway epithelial cells promote in vitro airway smooth muscle cell proliferation by activating the Wnt/β-catenin pathway

Asthma is a common chronic inflammatory airway disease, imposing a substantial health and economic burden on society and individuals. Current treatments primarily focus on symptom relief and lung function improvement, often failing to address the underlying pathology. Thus, exploring new therapeutic approaches is crucial. Airway smooth muscle cells (ASMCs) play a key role in regulating airway tone and airflow, while abnormal ASMCs proliferation contributes to airway remodeling in asthma. Airway epithelial cells (AECs), serving as the first barrier against pathogens and allergens, also have critical immune functions.This study focuses on the interaction between AECs and ASMCs, as AECs are more accessible for drug delivery due to their location at the airway surface. Investigating this relationship could facilitate novel interventions targeting AECs to inhibit pathological ASMCs activity. In our experiment, we isolated ASMCs and AECs from healthy mice and found that AECs significantly promoted ASMCs proliferation in co-culture. RNA sequencing revealed that this process might be linked to the activation of the canonical Wnt signaling pathway in ASMCs. By using Wnt pathway inhibitors (endo-IWR1) and siRNA to disrupt Wnt receptors, we reversed this phenotype. This finding suggests that AECs may promote ASMCsproliferation by activating the Wnt pathway in ASMCs. The Wnt/β-catenin pathway appears to play an important role in ASMCs proliferation, indicating that future pathological studies should consider the potential involvement of the Wnt pathway in airway remodeling.

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.

The anti-inflammatory role of therapeutic ultrasound and low-level laser in chronic rhinosinusitis: A fractional exhaled nitric oxide outcome hypothesis

Chronic rhinosinusitis is defined as a complex of disorders whose main feature is nasal and paranasal sinus mucosal inflammation for at least three months. Inflammation plays a key role in chronic rhinosinusitis. Fractional exhaled nitric oxide is used to monitor eosinophilic airway inflammation in the human lower airways. Fractional exhaled nitric oxide levels are paradoxically low in some chronic rhinosinusitis patients. This has been attributed to sinus ostia obstruction. However, a recent study has demonstrated that fractional exhaled nitric oxide levels could serve as a chronic rhinosinusitis inflammation biomarker independent of lower airway inflammatory disease and could be used as a treatment response biomarker. Therapeutic ultrasound and low-level laser therapy have been used in chronic rhinosinusitis management. Through a variety of mechanisms, ultrasound enhances bacterial killing. Low level laser therapy increases nitric oxide release and ATP levels. It also reduces inflammation and accelerates tissue repair. Fractional exhaled nitric oxide levels could be used to evaluate the anti-inflammatory actions of therapeutic ultrasound and low-level laser therapy in chronic rhinosinusitis patients. A hypothesis that fractional expired nitric oxide measurements could be a useful biomarker to evaluate their potential anti-inflammatory mechanisms and monitor their treatment efficacy is proposed. This could contribute to a better understanding of these therapies in chronic rhinosinusitis management. An improved understanding of treatment efficacy could lead to improved management strategies.

Hydrogen Gas Inhalation Alleviates Airway Inflammation and Oxidative Stress on Ovalbumin-Induced Asthmatic BALB/c Mouse Model

Airway inflammatory diseases, such as asthma, are a global public health concern owing to their chronic inflammatory effects on the respiratory mucosa. Molecular hydrogen (H2) has recently been recognized for its antioxidant and anti-inflammatory properties. In this study, we examined the therapeutic potential of H2 in airway inflammation using an ovalbumin (OVA)-induced BALB/c mouse model of allergic asthma. Female BALB/c mice were sensitized and challenged with OVA to induce airway inflammation, and 30 mice were randomly divided into five groups: NT (non-treatment), HTC (3% H2 treatment only), NC (negative control, OVA only), PC (positive control, OVA + intranasal 1 mg/mL salbutamol 50 μL), and HT (H2 treatment, OVA + inhaled 3% H2). Various inflammatory and oxidative stress (OS)-induced markers such as white blood cells (WBCs) and their differential counts, lung histology, cytokine levels such as interleukin (IL)-4, (IL)-5, (IL)-13, interferon-gamma (IFN-γ), tumor necrosis factor-alpha (TNF-α), granulocyte-macrophage colony-stimulating factor (GM-CSF), (IL)-10, reactive oxygen species (ROS), nitric oxide (NO), glutathione peroxidase (GPx), and catalase (CAT), and total immunoglobulin E (IgE) levels were investigated. Our results showed that inhaled H2 significantly reduced inflammatory cell infiltration, OS markers, and pro-inflammatory cytokine expression while upregulating antioxidant enzyme activity. Furthermore, H2 also significantly decreased serum IgE levels, a marker of allergic inflammation. Collectively, our findings suggest that H2 inhalation is a promising treatment option for airway inflammation, offering a novel approach with potential clinical applications.

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.

Causal relationships between allergic and autoimmune diseases with chronic rhinosinusitis

Chronic rhinosinusitis (CRS) is a prevalent inflammatory airway disease affecting over 10% of the global population, leading to considerable socio-economic impacts, especially in developing countries. The pathogenesis of CRS is multifactorial, involving potential contributions from both genetic and environmental factors. While the influence of allergic and autoimmune diseases on CRS has been observed, the causal relationships between these diseases and CRS remain unclear. We extracted data from large-scale genome-wide association studies (GWAS) and utilized a bidirectional two-sample Mendelian randomization (MR) analysis to explore the causal relationships between CRS and ten autoimmune and allergic diseases, including asthma, allergic rhinitis (AR), atopic dermatitis (AD), psoriasis, type 1 diabetes (T1D), hypothyroidism, celiac disease (CeD), multiple sclerosis (MS), rheumatoid arthritis (RA), and systemic lupus erythematosus (SLE). Additionally, we conducted colocalization analysis to determine whether the allergic/autoimmune diseases showing statistical causal relationships with CRS are driven by the same genetic variants. The MR analysis identified that AR (OR = 1.30; 95% CI = 1.21–1.40; P = 3.26E−13), asthma (OR = 1.35; 95% CI = 1.25–1.45; P = 1.35E−14), and AD (OR = 1.17; 95% CI = 1.06–1.30; P = 0.003) were significantly associated with an increased risk of developing CRS. Interestingly, psoriasis (OR = 0.05; 95% CI = 0.01–0.37; P = 0.004) appeared to have a protective effect against CRS. Associations for T1D and hypothyroidism were also suggestive as potential risk factors for CRS. No significant associations in the reverse MR analysis, suggesting a one-directional relationship. Colocalization analysis indicated that asthma (PP.H4 = 0.99) shared the same genetic variant (IL-33 rs3939286) with CRS. In conclusion, our study confirmed the causal relationships between allergic and autoimmune diseases (AR, asthma, AD, and psoriasis) and CRS. Notably, we identified a shared genetic variant, rs3939286 in the IL-33 gene, between asthma and CRS, suggesting that targeting the IL-33 pathway may provide a therapeutic strategy for both diseases.

Effect of polyunsaturated fatty acids intake on the occurrence of current asthma among children and adolescents exposed to tobacco smoke: NHANES 2007–2018

BackgroundAsthma is an airway inflammatory disease driven by multiple factors with a high incidence in children and adolescents. Environmental tobacco smoke exposure (TSE) and diet are inducing factors for asthma. The potential of omega-3 polyunsaturated fatty acids (PUFAs) to alleviate asthma symptoms by their anti-inflammatory effects has been explored. However, to date, no studies have explored the effect of dietary PUFAs intake on the asthma in children and adolescents exposed to tobacco smoke.ObjectiveWe aimed to examine the effect of dietary PUFAs intake on the current asthma in children and adolescents exposed to tobacco smoke.MethodsData of this cross-sectional were extracted from the National Health and Nutrition Examination Survey (NHANES) 2007–2018. Children and adolescents with serum cotinine concentration ≥ 0.05 ng/mL were defined to exposed to tobacco smoke. Dietary PUFAs intake information were obtained from 24 h recall interview. The weighted univariate and multivariate were utilized to explore the effect of PUFAs on the association of asthma and TSE, with adjusted odds ratios (AORs) and 95% confidence intervals (CIs). These moderating effects were further explored based on the age, gender and body mass index (BMI) and sedentary time.ResultsTotally, 7981 eligible children and adolescents were included, with the mean age of 11.96 ± 0.06 years old. Of whom, 1.024 (12.83%) had current asthma. After adjusted all covariates, we found children and adolescents with TSE had high occurrence of current asthma (AOR = 1.2, 95% CI 1.03–1.63); We also found omega-3 PUFAs intake (P for interaction = 0.010), not omega-6 PUFAs (P for interaction = 0.546), has a moderating effect on the association of TSE and current asthma. Moreover, we further observed that children and adolescents with TSE and low omega-3 PUFAs intake had high occurrence of current asthma (AOR = 1.58, 95% CI 1.19–2.10), while no significant association was found in children and adolescents with high omega-3 PUFAs intake (all P > 0.05). This moderating effect was more prominent in children and adolescents aged ≤ 12 years old (AOR = 1.62, 95% CI 1.06–2.47), girls (AOR = 2.14, 95% CI 1.15–3.98), overweight (AOR = 1.87, 95% CI 1.01–3.47) and sedentary time > 6 h (AOR = 1.96, 95% CI 1.00–3.86).ConclusionWe found dietary omega-3 PUFAs plays a moderating effect on the association of asthma and TSE in children and adolescents, especially in children and adolescents aged ≤ 12 years, girls, overweight or sedentary time > 6 h. This moderating effect suggested higher omega-3 intake has potential benefits in decreasing the occurrence of asthma in children and adolescents who exposed to tobacco smoke.

IL-1β-induced epithelial cell and fibroblast transdifferentiation promotes neutrophil recruitment in chronic rhinosinusitis with nasal polyps

Neutrophilic inflammation contributes to multiple chronic inflammatory airway diseases, including asthma and chronic rhinosinusitis with nasal polyps (CRSwNP), and is associated with an unfavorable prognosis. Here, using single-cell RNA sequencing (scRNA-seq) to profile human nasal mucosa obtained from the inferior turbinates, middle turbinates, and nasal polyps of CRSwNP patients, we identify two IL-1 signaling-induced cell subsets—LY6D+ club cells and IDO1+ fibroblasts—that promote neutrophil recruitment by respectively releasing S100A8/A9 and CXCL1/2/3/5/6/8 into inflammatory regions. IL-1β, a pro-inflammatory cytokine involved in IL-1 signaling, induces the transdifferentiation of LY6D+ club cells and IDO1+ fibroblasts from primary epithelial cells and fibroblasts, respectively. In an LPS-induced neutrophilic CRSwNP mouse model, blocking IL-1β activity with a receptor antagonist significantly reduces the numbers of LY6D+ club cells and IDO1+ fibroblasts and mitigates nasal inflammation. This study implicates the function of two cell subsets in neutrophil recruitment and demonstrates an IL-1-based intervention for mitigating neutrophilic inflammation in CRSwNP.

Erdosteine in the treatment of acute and chronic diseases of the respiratory system: resolution of the scientific forum of experts “In the Spotlight”

Airway mucus hypersecretion is a pathophysiologic manifestation of acute and chronic airway inflammatory disease. Mucolytics can reduce mucus viscosity and promote mucus discharge and therefore can be considered pathogenetically based therapy.The purpose of this publication with the resolution of the scientific forum of experts was to discuss pharmacological features, efficacy, and safety of erdosteine.Results. Experts of thescientific forum not only reviewed the results of clinical trials, but also voted on the use of mucoactive drugs according to the principle of Delphi consensus. Comparison of the efficacy and safety of mucoactive drugs (erdosteine, acetylcysteine, carbocysteine, ambroxol) in patients with respiratory diseases by the experts during voting showed that the highest level of agreement among the experts was achieved for the drug Elmucin® (erdosteine) in terms of its mucolytic activity and other pharmacological features, as well as when discussing the safety of the compared drugs in the officially recommended doses. The highest level of agreement was also noted on the erdosteine efficacy in COPD patients in reducing the frequency and duration of disease exacerbations, as well as reducing the risk of hospitalization of COPD patients when used long-term as part of combination therapy. The demonstrated safety profile was the most beneficial among the reviewed mucoactive drugs.Conclusion. Elmucin® is a mucolytic with pleiotropic effects such as complex mucoactive action, potent antioxidant, anti-inflammatory and antibacterial activity with anti-adhesive effect for pathogens that determine its clinical efficacy in the treatment of acute and chronic airway diseases.

Neutrophils in nasal polyps exhibit transcriptional adaptation and proinflammatory role depend on local polyp milieu.

Chronic rhinosinusitis with nasal polyps (CRSwNP) is an inflammatory upper airway disease, divided into eosinophilic CRSwNP (eCRSwNP) and noneosinophilic CRSwNP (neCRSwNP) according to eosinophilic levels. Neutrophils are major effector cells in CRSwNP. but their role in different inflammatory environments remain largely unclear. We performed an integrated transcriptome analysis of polyp-infiltrating neutrophils from CRSwNP patients, using healthy donor blood as a control. Flow cytometry and in vitro studies showed that neutrophils are activated in both CRSwNP type. The scRNA-sequencing analysis demonstrated that neutrophils were classified into five functional subsets, with GBP5+ neutrophils occurring mainly in neCRSwNPs and a high proportion of CXCL8+ neutrophils in both subendotypes. GBP5+ neutrophils exhibited significant IFN-I pathway activity in neCRSwNPs. CXCL8+ neutrophils displayed increased neutrophil activation scores and mainly secrete Oncostatin M (OSM), which facilitates communication with other cells. In vitro experiments revealed that OSM could enhance IL-13- or IL-17-mediated immune responses in nasal epithelial cells and fibroblasts. Our findings revealed that neutrophils exhibited transcriptional plasticity and activation when exposed to polyp tissue and exert their proinflammatory role in the pathogenesis of CRSwNP by releasing OSM to interact with epithelial cells and fibroblasts in a manner dependent on the inflammatory milieu.

Is it possible to go from control to super responder to remission in asthma?

Background: Asthma, a chronic airway inflammatory disease, traditionally focuses on symptom control and minimizing complications as per asthma guidelines. Recently, the concept of achieving clinical remission has emerged as a more ambitious treatment goal. Objective: This review explores clinical remission (on and off treatment), super-responders, and complete remission (on and off treatment) in asthma. It also examines the potential of biologics in achieving clinical remission for severe asthma. Methods: A literature review on clinical remission, super-responders, and complete remission in asthma, along with biologics and remission was conducted. Results: Leading allergist/pulmonologist groups and professional societies worldwide have proposed criteria for clinical remission. Whereas core elements such as no systemic corticosteroids, no exacerbations, and stable and/or improved lung function for at least a year are generally agreed on, specific details remain under debate. U.S. guidelines incorporate stricter criteria for clinical remission. In addition, the term “super-responder” describes patients with severe asthma and with major quality-of-life improvements after receiving biologics. Despite limited studies, biologics seem to produce remission rates (20‐40%), depending on the criteria used. Conclusion: A universally accepted definition for clinical remission in asthma remains under development. The concept of super-responder requires further investigation in research and clinical settings. Whereas early studies show promise, biologic therapies, although revolutionary for severe asthma treatment, do not guarantee clinical remission for most patients.

CD226 implicated in Akt-dependent apoptosis of CD4+ T cell contributes to asthmatic pathogenesis.

Asthma is a chronic airway inflammatory disease in which CD4+ T cell dysregulation occurs. Here, we investigated the molecular role and clinical significance of CD226, a costimulatory molecule of T lymphocytes, in the development of allergic asthma. Our results revealed that the expression of CD226 was significantly increased in CD4+ effector T cells, especially in T helper (Th) 2 cells and Th17 cells in patients with asthma. Moreover, CD4+ T cell-specific Cd226-knockout mice were generated and together with littermates were challenged with ovalbumin (OVA) to establish a model of allergic asthma. We found that CD226 deficiency in CD4+ T cells mitigated lung inflammation, IgE production, and eosinophil infiltration and reduced airway remodeling in experimental allergic asthma. However, the impact of CD226 on asthma was independent of Treg cell modulation. Through RNA-seq data analysis, the apoptosis pathway was screened. Mechanistically, CD226 deletion promoted CD4+ T cell late apoptosis via the activation of Caspase-3 in an Akt-dependent manner. Furthermore, blocking CD226 signaling with a recombinant fusion protein attenuated asthma features in mice and achieved a good therapeutic effect. Overall, this study revealed a unique role of CD226 in CD4+ T cell regulation in asthma pathogenesis. Therefore, targeting CD226 may provide new insights into the clinical treatment of asthma.

Optical chemical gas sensor based on spectral autocorrelation: A method for online detection of nitric oxide and ammonia in exhaled breath

The detection of nitric oxide (NO) and ammonia (NH3) in exhaled breath (EB) plays a crucial role in non-invasive diagnosis of airway inflammatory and kidney diseases. Here we report an optical chemical gas sensor for NO and NH3 based on spectral autocorrelation. In our sensor system, the target gas is removed through a chemical reaction with a sensing material and the spectrum of the target gas is extracted from the spectra obtained before and after the reaction by autocorrelation. Our method focuses on the ability of the material to eliminate the target gas without the need for detecting signals of the reaction, greatly relaxing the requirements on material properties. Fundamentally different from optical sensors that obtain spectra by spectral decoupling, our sensor relies on autocorrelation operation to acquire the spectrum of the target gas, thereby overcoming spectra overlap. Lab-based results show that the sensor enables detection of NO (2.28–451.82 ppb) and NH3 (11.52–12,725.42 ppb) with mean absolute errors (MAEs) of 0.79 ppb and 6.13 ppb and measurement accuracies of 0.8 % and 1.4 %, respectively. The EB experiment proves that the sensor can detect exhaled NO and NH3 and distinguish EB between healthy subjects and simulated patients.

Tezepelumab: a promising therapy for severe uncontrolled asthma

Asthma is a complex inflammatory airway disease affecting a significant global population, spanning from childhood through adulthood. Despite advances in treatment modalities, a significant subset of patients, approximately 10%, grapple with severe asthma, characterized by increased healthcare utilization and diminished quality of life. Tezepelumab, a monoclonal antibody targeting thymic stromal lymphopoietin (TSLP), offers promising therapeutic potential. TSLP is a protein released by a variety of cells, with a predominance of epithelial cells, in reaction to plenty of stimuli, such examples as viruses, aeroallergens, and others. Its action is upstream and pertains to initiating numerous subsequent innate and adaptive immune reactions, contributing to the continuation of asthma pathophysiological processes. Tezepelumab’s unique efficacy spans diverse severe asthma phenotypes, significantly reducing exacerbation rates across eosinophilic and non-eosinophilic subtypes. Its favorable safety profile and clinically meaningful improvements in asthma control, accompanied by reductions in cytokine levels and baseline biomarkers, underscore its broad impact on asthma inflammation. Its efficacy, irrespective of type 2 (T2) endotype, reinforces the idea that TSLP blockade broadly inhibits pathways crucial to asthma pathophysiology, rather than narrowly focusing on individual downstream factors, as previous biological treatments have. This review discusses the rationale for TSLP blockade and the efficacy of tezepelumab in severe asthma using data from key trials.

Nasal epithelial gene expression identifies relevant asthma endotypes in the ATLANTIS study

IntroductionAsthma is an inflammatory airways disease encompassing multiple phenotypes and endotypes. Several studies suggested gene expression in nasal epithelium to serve as a proxy for bronchial epithelium, being a non-invasive...

Sexual Dysfunction in Women with Asthma and Associated Factors

Background: Asthma is a common chronic inflammatory airway disease. Female sexual dysfunction (FSD) is frequently seen in asthmatics but often unnoticed in clinical practice. This study evaluated the associations between asthma disease characteristics and (FSD). Methods: A total of 73 female asthma patients who visited the chest department outpatient clinic and age-matched 73 healthy controls were enrolled. All the participants completed the questionnaires: female sexual function index (FSFI), BECK depression, and BECK anxiety inventory, and underwent pulmonary function tests. Patients with asthma completed an asthma quality of life questionnaire (AQLQ) and asthma control test (ACT). FSD risk factors were analyzed using logistic regression analysis. Results: About 68.8% of asthmatics had female sexual dysfunction. BECK anxiety and FSFI scores with all six subsets were statistically significantly lower than healthy individuals in asthmatics (p < 0.001). CRP levels, BECK anxiety, and depression scores had inverse (r = -0.386 r = -0.343 r = -0.286), and FEV1% had a positive correlation with FSFI total scores. About 37.5% of asthma patients with FSD were current smokers, the most compromised domain of the FSFI scale was sexual arousal with a mean of 2.94 ± 0.56 and their FEV1% was lower, and CRP was higher than the asthma patients without FSD (p < 0.001, p < 0.021). Smoking, high levels of CRP and BECK anxiety scores, and low FEV1% were found to be risk factors for FSD in regression analysis. Conclusions: Female sexual dysfunction is frequently present in asthma patients. Smokers, patients who have anxiety, lower FEV1% predicted values, and higher CRP levels tend to be susceptible to sexual dysfunction, which implicates inflammation as an underlying mechanism.

Traditional Chinese medicine Ze-Qi-Tang formula reduces inflammation in mice with asthma by inhibiting PI3K/AKT/NF-κB signaling pathway.

Asthma is a chronic airway inflammatory disease. The excessive proliferation of airway smooth muscle cells (ASMCs) is associated with airway remodeling. Ze-Qi-Tang (ZQT) is a popular traditional Chinese medicine preparation and has been confirmed to have therapeutic effects on lung diseases. This study is aimed to probe the biological function of ZQT in asthma. RT-qPCR and ELISA were utilized for testing the mRNA levels and concentrations of pro-inflammatory factors. Colony formation and transwell assay were applied to test cell viability and migration. The mouse model with asthma was established by ovalbumin (OVA) induction. Western blot was utilized for detecting the activation of PI3K/AKT/NF-κB pathway. We found that the concentrations of proinflammatory factors in cells induced by PDGF-BB could been suppressed by ZQT. ZQT-H treatment notably repressed cell viability and proliferation. Furthermore, we proved the suppressive effect of ZQT on airway inflammation in asthma mice. Additionally, we discovered that ZQT could suppress the PI3K/AKT/NF-κB pathway in PDGF-BB-induced ASMCs. To sum up, ZQT reduced airway inflammation and remodeling in mice with asthma via inactivating PI3K/AKT/NF-κB pathway.

Suppression of the DNA repair enzyme NEIL2 promotes persistent inflammation and genomic damage in subjects with stable COPD and during severe exacerbations.

Chronic obstructive pulmonary disease (COPD) is a chronic inflammatory airway disease that is an independent risk factor for lung cancer. NEIL2, a DNA glycolase involved in DNA repair during transcription, has also been associated with an increased incidence of malignancies in humans. NEIL2 knockout mouse models have demonstrated increased inflammation and oxidative DNA damage in the lungs after exposure to an inflammatory insult, but data are lacking regarding NEIL2 function in individuals with stable COPD and during severe acute exacerbations of COPD (AECOPD). We investigated whether NEIL2 levels and oxidative DNA damage to the transcribed genome are altered in individuals with stable COPD and AECOPD. The study was conducted at a single center in the US. Eligible subjects underwent a one-time 30 cc venous blood draw. The population consisted of 50 adults: 16 with stable COPD, 11 hospitalized for AECOPD, and 23 volunteers. We analyzed blood leukocytes for NEIL2 mRNA and DNA damage by RT-qPCR and LA-qPCR, respectively, in all groups. Plasma levels of seven biomarkers, CXCL1, CXCL8, CXCL9, CXCL10, CCL2, CCL11 and IL-6, were analyzed in the COPD groups using a magnetic bead panel (Millipore®). The NEIL2 mRNA levels were lower in individuals with stable COPD and AECOPD than in controls (0.72 for COPD, p = 0.0289; 0.407 for AECOPD, p = 0.0002). The difference in NEIL2 mRNA expression between the stable COPD group and AECOPD group was also statistically significant (p < 0.001). The fold change in DNA lesions per 10 kb of DNA was greater in the stable COPD (9.38, p < 0.0008) and AECOPD (15.81, p < 0.0004) groups than in the control group. The difference in fold change was also greater in the AECOPD group versus stable COPD p < 0.0236). Biomarker levels were not significantly different between the COPD groups. NEIL2 levels were correlated with plasma eosinophil levels in the stable COPD group (r = 0.737, p < 0.0027). NEIL2 mRNA levels are significantly reduced in COPD subjects and are associated with increased DNA damage and inflammation. These results reveal a mechanism that promotes persistent airway inflammation and oxidative genomic damage and increases the risk of malignancy in this population.

LRRK2 G2019S enhances immune response pathways and aggravates asthma in mouse models

Asthma is a complex inflammatory airway disease that arises from the interplay between genetic predisposition and environmental influences. Leucine-rich repeat kinase 2 (LRRK2), a gene commonly associated with Parkinson's disease, has recently gained attention for its role in immune regulation and inflammation beyond the brain. However, its involvement in asthma has not yet been reported. In this study, we used LRRK2 G2019S transgenic mice and LRRK2 knockout mice to establish asthmatic models to explore LRRK2 impact on asthma. We found that LRRK2 G2019S transgenic mice showed exacerbated airway hyperresponsiveness (AHR) and airway inflammation in asthma mouse models induced by house dust mite. RNA sequencing data unveiled that the LRRK2 G2019S mutation enhanced immune response pathways, including NOD-like receptor, cellular response to interferon β and activation of innate immune response signaling. Conversely, LRRK2 deficiency attenuated AHR and airway inflammation in the same asthma models. Our study offers new insights into the role of LRRK2 in allergic inflammation and highlights its potential as a therapeutic target for asthma.

Functions and Clinical Applications of Extracellular Vesicles in TH2 Cell-Mediated Airway Inflammatory Diseases: A Review.

Type 2 airway inflammation (T2AI), driven by type 2 innate lymphoid and CD4+ T helper 2 cells, leads to various diseases and conditions, such as chronic rhinosinusitis with nasal polyps, allergic rhinitis, and asthma. Emerging evidence suggests the involvement of extracellular vesicles (EVs) in these diseases. In this review, we describe the immunological T2AI pathogenic mechanisms, outline EV characteristics, and highlight their applications in the diagnosis and treatment of T2AI. An extensive literature search was conducted using appropriate strategies to identify relevant articles from various online databases. EVs in various biological samples showed disease-specific characteristics for chronic rhinosinusitis with nasal polyps, allergic rhinitis, and asthma, with some demonstrating therapeutic effects against these conditions. However, most studies have been limited to in vitro and animal models, highlighting the need for further clinical research on the diagnostic and therapeutic applications of EVs.