Airway Hyperresponsiveness Research Articles

Parasympathetic Airway Hyperreactivity Is Enhanced in Acute but Not Chronic Eosinophilic Asthma Mouse Models.

Airway hyperreactivity in asthma is mediated by airway nerves, including sensory nerves in airway epithelium and parasympathetic nerves innervating airway smooth muscle. Isolating the function of these two nerve populations in vivo, to distinguish how each is affected by inflammatory processes and contributes to hyperreactivity in asthma, has been challenging. In this study, we used optogenetic acti-vation of airway nerves in vivo to study parasympathetic contributions to airway hyperreactivity in two mouse models of asthma: 1) acute challenge with house dust mite antigen, and 2) chronic airway hy-pereosinophilia due to genetic IL-5 overexpression in airways. Overall airway hyperreactivity, as meas-ured by bronchoconstriction to an inhaled agonist, was increased in both models. In contrast, optoge-netic stimulation of isolated efferent parasympathetic nerves induced bronchoconstriction only in the acute house dust mite antigen challenge group. Using whole mount tissue immunofluorescence and modeling software, we then measured, in three dimensions, the interactions between eosinophils and parasympathetic nerves in both models and found that eosinophils were more numerous and more proximal to airway parasympathetic nerves in antigen challenged and IL-5 transgenic mice than in their respective controls, but were not significantly different between the two asthma models. Thus even though eosinophils were increased around nerves in both models, parasympathetic nerves only mediated airway hyperreactivity in the antigen challenged mice. This study demonstrates divergent effects of acute versus chronic eosinophilia on parasympathetic airway nerve activity and points to eo-sinophil-nerve interactions as a key regulator of airway hyperreactivity in antigen challenged mice.

(−)-Epigallocatechin-3-gallate (EGCG) ameliorates ovalbumin-induced asthma by inhibiting inflammation via the TNF-α/TNF-R1/NLRP3 signaling pathway

(−)-Epigallocatechin-3-gallate (EGCG) is a polyphenol in green tea with potential lung-protective effects. However, the effects of EGCG on airway inflammation in asthma remain unclear. The aim of this study was to investigate the effect and mechanism of EGCG on asthmatic airway inflammation. In this study, the therapeutic effects of EGCG on ovalbumin (OVA)-induced asthmatic mice were tested first. Second, the effects of EGCG on airway inflammation, airway hyperresponsiveness (AHR), airway mucus hypersecretion, cell apoptosis and differential genes were investigated. Finally, the relationships between the effects of EGCG on airway inflammation and the TNF-α/TNF-R1/NLRP3 signaling pathway in asthmatic mice were explored. The results showed that EGCG could attenuate AHR, alleviate the symptoms of alveolar wall thickening and inflammatory cell infiltration, decrease the levels of inflammatory cytokines and airway mucus markers, reduce apoptosis and reactive oxygen species (ROS) and increase the mitochondrial membrane potential (MMP) in primary lung cells in asthmatic mice. Additionally, EGCG significantly inhibited the activation of the TNF-α/TNF-R1/NLRP3 signaling pathway in the lung tissues of asthmatic mice. The lowest binding free energies of EGCG with TNF-α, TNF-R1 and NLRP3 were −11.6, −11.6 and −8.2 kcal/mol, respectively. Moreover, the equilibrium dissociation constant (KD) of EGCG and TNF-R1was 26.05 μmol/L. EGCG-mediated inhibition of TNF-α/TNF-R1/NLRP3 signaling pathway activation was blocked in LPS-induced BEAS-2B and RAW264.7 cells overexpressing TNF-α. Consequently, EGCG effectively attenuated AHR and inhibited airway inflammation and airway mucus hypersecretion in asthmatic mice, and these effects may be closely related to the TNF-α/TNF-R1/NLRP3 signaling pathway.

A Recent Update on Ayurvedic Anti-asthmatic Formulations: Highlighting the Role of Major Anti-asthmatic Plants

Abstract: Asthma is a chronic heterogeneous airway obstruction disorder defined by a complex cascade of pathophysiological conditions that lead to recurring bronchial hyper-responsiveness and underlying inflammation, lowering the patient’s quality of life. Despite the availability of various synthetic medications for the management of asthma, it has become one of the leading causes of death worldwide. Furthermore, the present allopathic treatment possesses severe long-term negative effects, which make people more attracted to the safer and easily available indigenous traditional and Ayurvedic system of medicine. Ayurveda is regarded as the “Mother of all healing” and “Science of Life,” which treats all the ailments, including asthma, by restoring a balance between three main components of the body- Vata, Pitta, and Dosha. Various clinically effective and less toxic anti- asthmatic Ayurvedic herbal preparations are available for the management of asthma and related complications which act by causing mast cell deactivation, inhibition of Th1, Th2, Th7 response, Tcell suppression, etc., therefore, efforts have been made to compile all the relevant literature related to the ayurvedic anti-asthmatic formulations and scrutinize the efficacy of selected plants present in the majority in those formulations in asthma along with the structure and mode of action of phytoconstituent responsible for designing novel molecules with better efficacy. Research on these selected plants can also have economic significance as various constituents isolated from these plants for their anti-asthmatic effect can further be explored to discover their potential in medicinal, diagnostic and cosmetic field.

N-cadherin antagonism is bronchoprotective in severe asthma models.

Severe asthma induces substantial mortality and chronic disability due to intractable airway obstruction, which may become resistant to currently available therapies including corticosteroids and β-adrenergic agonist bronchodilators. A key effector of these changes is exaggerated airway smooth muscle (ASM) cell contraction to spasmogens. No drugs in clinical use effectively prevent ASM hyperresponsiveness in asthma across all severities. We find that N-cadherin, a membrane cell-cell adhesion protein up-regulated in ASM from patients with severe asthma, is required for the development of airway obstruction induced by allergic airway inflammation in mice. Inhibition of N-cadherin by ADH-1 reduced airway hyperresponsiveness independent of allergic inflammation, prevented bronchoconstriction, and actively promoted bronchodilation of airways ex vivo. ADH-1 inhibited ASM contraction by disrupting N-cadherin-δ-catenin interactions, which decreased intracellular actin remodeling. These data provide evidence for an intercellular communication pathway mediating ASM contraction and identify N-cadherin as a potential therapeutic target for inhibiting bronchoconstriction in asthma.

Paraoxonase-1 Is a Pivotal Regulator Responsible for Suppressing Allergic Airway Inflammation Through Adipose Stem Cell-Derived Extracellular Vesicles

Although adipose stem cell (ASC)-derived extracellular vesicles (EVs) are as effective as ASCs in the suppression of Th2 cell-mediated eosinophilic inflammation, the role of identified pulmonary genes has not been well documented. Thus, we assessed the immunomodulatory effects of paraoxonase-1 (PON1) on allergic airway inflammation in a mouse model of asthma. Five-week-old female C57BL/6 mice were sensitized to ovalbumin (OVA) by intraperitoneal injection and challenged intranasally with OVA. To evaluate the effect of PON1 on allergic airway inflammation, the intranasal and intraperitoneal injections of recombinant mouse serum PON1 (5 μg/50 μL) were performed before the OVA challenge. We evaluated airway hyperresponsiveness (AHR), total inflammatory cells, and eosinophils in the bronchoalveolar lavage fluid (BALF), lung histology, serum immunoglobulin (Ig), cytokine profiles of BALF and lung draining lymph nodes (LLNs), the expression of interleukin (IL)-25 and transforming growth factor (TGF)-β in mouse lung epithelial cell (MLE-12 cell), and dendritic cell (DC) differentiation. The intraperitoneal and intranasal administration of PON1 significantly decreased AHR, total inflammatory cells and eosinophils in BALF, eosinophilic airway inflammation, serum total, and OVA-specific IgE. PON1 treatment, which marked reduced IL-4, IL-5, and IL-13 in the BALF and LLN but significantly increased interferon-γ and TGF-β. Furthermore, PON1 treatment significantly decreased the expression of IL-25 and increased TGF-β in MLE-12 cells. The expressions of CD40, CD80, and CD86 in immature DCs were significantly increased by PON1 treatment. The administration of PON1 ameliorated allergic airway inflammation and improved AHR through the downregulation of IL-4, IL-5, and IL-13 and upregulation of TGF-β in asthmatic mice. Furthermore, PON1 treatment decreased Th2-mediated inflammation induced by Aspergillus protease antigen by decreasing IL-25 and increasing TGF-β.

Current Biologic Therapies for Severe Asthma and Real-World Data: Are Expectations Being Met?

Advances in knowledge about clinical features, physiology, and underlying immunology are leading to targeted therapies and a new era of therapies. Biological treatments for severe asthma have changed the way this disease is managed, especially in patients who do not respond adequately to conventional treatments with corticosteroids and bronchodilators. These treatments block the action of different molecules involved in the immune response and in the inflammation of the airways, bronchoconstriction, bronchial hyperresponsiveness, and excessive mucus production. Currently, there are sufficient real-life data to corroborate the good results obtained in clinical trials by these type of drugs for severe asthma patients. Observational studies reveal their efficacy and safety, reducing exacerbations, leading to fewer emergency room visits and hospitalizations, and improving quality of life with better asthma control and better functional status.

Transforming growth factor-β3/Smad2/Smad3 signaling pathway inhibition and autophagy by the Yunpi-Xiefei-Huatan decoction ameliorated airway inflammation and mucus hypersecretion in asthmatic rats

Ethnopharmacological relevanceThe Yunpi-Xiefei-Huatan decoction (YXHD) is a traditional Chinese medicine that can improve asthma-related symptoms, including cough, phlegm in the throat, and shortness of breath. However, the YXHD mechanism on asthma has not yet been elucidated. Study aimThe aim of this study is to investigate the effect of YXHD on airway inflammation, mucus hypersecretion, and autophagy modulation in asthma. Materials and methodsThe YXHD chemical constituents were observed and analyzed using high-performance liquid chromatography-mass spectrometry. Ovalbumin sensitization and stimulation were used to establish an asthma rat model. A total of 80 Sprague-Dawley (SD) rats were segmented into eight groups at random: a Normal (NC) group, a Model (Mod) group, a YXHD low-dose group (10 g/kg/d), a YXHD moderate-dose group (20 g/kg/d), a YXHD high-dose group (40 g/kg/d), a Rapamycin group (4 mg/kg/d), a 3-methyladenine (3-MA) group (15 mg/kg/d), and a Dexamethasone (DEX) group (0.5 mg/kg/d). Whole-body plethysmography (WBP) detection was used to evaluate airway hyperresponsiveness. An enzyme-linked immunosorbent assay (ELISA) was used to detect inflammatory factors in the peripheral blood. Inflammatory cells in the bronchoalveolar lavage fluid (BALF) were also counted. Pathological changes in the lung tissues were marked using hematoxylin and eosin (H&E) staining and periodic acid-Schiff (PAS) staining. The localization of MUC5AC and the co-localization of LC3B + MUC5AC were observed using immunofluorescence. The expressions of autophagy and the TGF-β3/Smad2/Smad3 pathway in the lung tissues were detected using a Western blot assay (WB) and qPCR, and the autophagosomes in the lung tissues were detected using a transmission electron microscope (TEM). ResultsTwenty signal peaks were identified using ultra-high performance liquid chromatography with quadrupole time-of-flight mass spectrometry (UPLC-QTOF-MS) technology. The TGF-β3/Smad2/Smad3 signal pathway activation was induced using ovalbumin (OVA) exposure in the rats. The upregulated expression of autophagy, enhanced MUC5AC fluorescence and LC3B fluorescence, and their co-localized expression in the airway epithelium indicated inflammatory cell infiltration and excessive mucus secretion in the lungs. This resulted in airway hyper-responsiveness. The YXHD inhibited the activation of the TGF-β3/Smad2/Smad3 signaling pathway, and autophagy expression reduced inflammatory factors, abnormal mucus secretion, and airway hyperresponsiveness. ConclusionThe YXHD improved lung function, relieved lung inflammation, and inhibited airway mucus secretions in asthmatic rat models. Its mechanism may have been related to the blockage of the TGF-β3/Smad2/Smad3 signaling pathway and autophagy downregulation.

Lung function outcomes in adults born extremely preterm across three decades of advancing perinatal medicine.

Advances in perinatal medicine from 1980 to 2000 improved survival in extremely preterm (EP) neonates. Long-term effects of these developments remain unclear, and we aimed to investigate potential cohort effects on adult lung function. Three 18-year-old population-based cohorts born at ≤28 weeks gestation or with birthweight ≤1000 g during 1982-85, 1991-92 and 1999-2000 and term-controls underwent spirometry, body plethysmography, and tests of lung diffusing capacity, bronchodilator reversibility, and airway hyperresponsiveness. We used Welch's t-tests to compare term- with EP-born as a group and split by bronchopulmonary dysplasia (BPD), and regression models to test group/cohort interactions. In all EP-born cohorts, z-scores for FEV1, FEV1/FVC, FEF25%-75%, DLCO and KCO were reduced compared with term-born. For the 82-85, 91-92 and 99-00 cohorts, deficits for z-FEV1 and z-DLCO were 1.23 and 0.53; 0.68 and 0.92; and 0.51 and 0.57, respectively (p ≤0.01 for all). Cohort analyses showed stable lung function across the three cohorts overall, but improvements across cohorts for the BPD subgroups in z-FEV1, z-FEV1/FVC, and z-FEF25%-75%. Adults born EP across three formative decades of neonatal care had stable lung function overall, with notable improvements in BPD subgroups across cohorts.

Antidiabetic Medication and Asthma Attacks

ImportanceElevated body mass index (BMI) and type 2 diabetes are prevalent in asthma and are associated with an increase in the risk of asthma attacks. In experimental studies, the diabetes medications metformin and glucagon-like peptide-1 receptor agonists (GLP-1RA) have mitigated airway inflammation, hyperresponsiveness, and remodeling. However, epidemiological evidence is limited.ObjectiveTo estimate the association of metformin and add-on antidiabetic medications (GLP-1RA, dipeptidyl peptidase-4 inhibitors, sulphonylureas, sodium-glucose cotransporter-2 inhibitors, and insulin) with asthma attacks.Design, Setting, and ParticipantsThe study used data from the UK Clinical Practice Research Datalink (CPRD) Aurum linked hospital admissions and mortality data from 2004 to 2020. A triangulation approach was used that applied 2 distinct approaches to enhance robustness: a self-controlled case series (SCCS) and a metformin new user cohort with inverse probability of treatment weighting (IPTW). Eligible participants were new users of metformin with type 2 diabetes. To evaluate the association between metabolic phenotypes (BMI, glycemic control) and asthma phenotypes (type 2 inflammation, asthma severity), interaction analyses were conducted. Negative control analyses were conducted to assess for bias.ExposureThe primary exposure was metformin; secondary exposures included add-on antidiabetic medications.Main OutcomesThe primary outcome was first asthma exacerbation (short course of oral corticosteroids, unscheduled asthma-related hospital attendance, or death) during 12-month follow-up. Incidence rate ratios (IRRs) with 95% CIs were estimated using fixed-effect conditional Poisson models in the SCCS, and hazard ratios (HRs) were estimated using weighted Cox proportional hazards models in the cohort.ResultsOf more than 2 million adults with asthma, 4278 patients (2617 women [61.2%]; mean [SD] age, 52.9 [13.6] years) were identified for the SCCS and 8424 patients (4690 women [55.7%]; unexposed: mean [SD] age, 61.6 [13.2] years; exposed: mean [SD] age, 59.7 [13.7] years) for the IPTW cohort. Metformin was found to be associated with fewer asthma attacks of similar magnitude in both approaches (SCCS: IRR, 0.68; 95% CI, 0.62-0.75; IPTW: HR, 0.76; 95% CI, 0.67-0.85). Negative control analyses did not find evidence of significant bias. Hemoglobin A1c levels, BMI, blood eosinophil cell counts, and asthma severity did not modify the association. The only add-on antidiabetic medication to have an additive association was GLP-1RA (SCCS: IRR, 0.60; 95% CI, 0.49-0.73).Conclusions and RelevanceThe results of this cohort study suggest that metformin was associated with a lower rate of asthma attacks, with further reductions with the use of GLP-1RA. This appeared to be associated with mechanisms other than through glycemic control or weight loss and occurred across asthma phenotypes.

Fetal microchimeric cells influence maternal lung health following term and preterm births

Fetal microchimerism, the presence of fetal cells in maternal tissues, has garnered interest for its potential role in maternal physiology. In this study, we aimed to explore the impact of fetal microchimeric cells on maternal lung health following term and preterm delivery, particularly in the context of infection-induced preterm birth and subsequent allergic challenges. We characterized the immune cells in maternal lungs using a transgenic mouse model (mT+ Ve, Td Tomato) and high dimensional mass cytometry (CyTOF) techniques. We evaluated their influence on lung function and inflammation. Our findings revealed distinct differences in the immune cell composition of maternal lungs between term and preterm deliveries. Mice delivered preterm significantly increased in fetal-specific cells, such as activated macrophages and Tbet + Ve memory B-cells, compared to term-delivered mice. Conversely, term deliveries showed elevated levels of CD4 cells. Furthermore, preterm-delivered dams demonstrated heightened airway hyperresponsiveness, pro-inflammatory cytokine expression, cellular infiltration, and lung mucous production compared to term-delivered dams. Co-culture experiments demonstrated that microchimeric cells from preterm births stimulated the production of inflammatory cytokines IL-6 and TNF-α in lung epithelial cells. These findings shed light on the complex immune dynamics postpartum and their role in lung complications after preterm birth. Understanding these mechanisms could provide insights for targeted interventions to improve maternal lung health in at-risk populations.

Exploring Cistanche's therapeutic potential and molecular mechanisms in asthma treatment

Asthma, a prevalent chronic respiratory disease, is characterized by airway inflammation and hyperresponsiveness, significantly impacting global health. Current treatments, including corticosteroids, face limitations due to variable patient responses and side effects. This study explores the therapeutic potential of Cistanche, a traditional Chinese medicinal herb, in an asthmatic mouse model induced by house dust mites (HDM). We employed a multidisciplinary approach, including transcriptomics, mass spectrometry, Weighted Gene Co-expression Network Analysis (WGCNA), and experimental validation in animal and cellular models. Our findings demonstrate that Cistanche significantly attenuates airway hyperresponsiveness, cellular infiltration, and mucus hypersecretion in asthmatic mice. Transcriptomic analysis identified 643 differentially expressed genes (DEGs), with Cistanche treatment disrupting pathways associated with IL-4, IL-5, and eosinophils. Gene Set Enrichment Analysis (GSEA) revealed Cistanche's involvement in glucocorticoid processes, suggesting its potential as an alternative or complementary therapy to conventional glucocorticoids. Liquid Chromatography-High Resolution Mass Spectrometry (LCHRMS) analysis identified Pinoresinol 4-O-Beta-D-Glucopyranoside (PG) as a key active component of Cistanche, with targets predominantly associated with the PI3K-AKT pathway. WGCNA analysis of an asthma dataset identified the "skyblue" module as highly associated with asthma, with inducible nitric oxide synthase (iNOS) emerging as a core gene. Molecular docking confirmed a strong binding affinity between PG and iNOS, with Cistanche treatment down-regulating iNOS expression, suggesting a potential mechanism for its anti-inflammatory effects. In conclusion, Cistanche exhibits therapeutic effects in asthma by modulating immune responses and targeting key asthma-related genes and proteins. Our study provides novel insights into the treatment of asthma with natural products and highlights the potential of Cistanche as an alternative or complementary therapeutic agent. Further research is warranted to validate these findings and explore the integration of Cistanche into clinical asthma management.

Omics techniques reveal the pathogenesis of microbial communities in asthma

Abstract. The presence of airway hyperresponsiveness in asthma provides the basis for constriction in bronchus response to a variety of stimuli, leading to limited airflow, dyspnea, wheezing, and chest tightness, threatening patients lives. Statistics have shown that asthma is more prevalent in the adolescents and children than in the adults, suggesting that early ecological dysregulation of the gut and airway microbiome contributes to the occurrence of asthma, especially in the preschool years children. With the development of high-throughput sequence technologies such as genomics, it has become possible to study the association of pathophysiological processes of allergic reactions and ecological dysregulation using the multi-omics techniques. In this review, the author first briefly introduces the classification of asthma, summarizes the pathogenesis of microorganisms in asthma, providing a new direction and ideas for the research of the pathogenesis, diagnosis, and treatment of asthma.

Astragalus polysaccharide alleviates asthma by modulating gut microbiota and serum metabolomics.

The aim of the present study was to examine the effects of Astragalus polysaccharide (APS) on gut microbiota and serum metabolites in asthmatic mice. For this purpose, a total of 36 BALB/c female mice were selected and randomly classified into the following groups: i) The normal control group sensitized with phosphate-buffered saline; ii) the asthma group sensitized and challenged with ovalbumin (OVA); iii) the OVA + APS (2.5 g/kg) treatment group; iv) the OVA + APS (5.0 g/kg) treatment group; v) the OVA + APS (10 g/kg) treatment group; and vi) the OVA + dexamethasone (2 mg/kg) treatment group, with 6 mice in each group. OVA was used to establish the mouse model of asthma. In the APS group, the asthmatic mice were intragastrically administered APS at various doses at 1 h prior to each OVA stimulation. The airway hyperreactivity (AHR) was measured, and hematoxylin and eosin staining was employed to evaluate pulmonary inflammatory infiltration. In addition, 16S rRNA sequencing and ultra-performance liquid chromatography-tandem mass spectrometry were used to detect the changes in the mouse gut microbiota and serum metabolites. The results revealed that compared with the asthma model group, APS improved airway inflammation and eosinophil infiltration in asthmatic mice. In asthmatic mice, the gut microbial imbalance mainly manifested as a low abundance of Bacteroidetes and a high abundance of Firmicutes, yielding an increased F/B ratio. In the high-dose APS group, the abundance of Firmicutes was reduced, and the abundance of Bacteroidetes was increased, which thereby decreased the F/B ratio and corrected the gut microbial imbalance. Through blood metabolomics, 145 and 105 significantly differential metabolites were detected in the medium- and high-dose APS groups, respectively. Moreover, Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis demonstrated that the metabolic pathways in the medium-dose APS group included the biosynthesis of unsaturated fatty acids and the biosynthesis of arginine. On the other hand, the metabolic pathways enriched in high-dose APS group were the biosynthesis of unsaturated fatty acids, and pyrimidine metabolism. On the whole, the present study demonstrates that APS may regulate the gut microbiota and the metabolites to improve airway inflammation and AHR in asthmatic mice.

Mycophenolate Mofetil, an Inhibitor of Inosine Monophosphate Dehydrogenase, and Tofacitinib, a Janus Kinase Inhibitor, Attenuate Airway Inflammation and Hyperresponsiveness in a Mouse Model of Allergic Asthma.

Treatment-resistant asthma remains an unresolved clinical problem and a challenge for current medical science. Consequently, there is a growing and urgent need to develop novel or alternative therapeutic options for the treatment of asthma. The research problem raised in this study was to assess and compare mycophenolate mofetil (MMF), an inhibitor of inosine monophosphate dehydrogenase, and tofacitinib (TFB), a Janus kinase inhibitor, for anti-asthmatic properties, and consequently to determine whether these agents may have potential as alternative options for treatment of allergic asthma. For this purpose, we assessed the effect of administration of MMF and TFB on the development of a mouse model of allergic airway inflammation (AAI) and accompanying CD4+ (cluster of differentiation 4) T-cell immune response in the lung-draining mediastinal lymph nodes (MLNs) and lungs, i.e., in the inductive and effector sites, respectively, of the immune response underlying the development of allergic asthma. The results from a histopathological scoring system demonstrated that the administration of MMF and TFB did not prevent or abolish ovalbumin-induced AAI, but strongly attenuated its severity. The pulmonary function tests revealed that the treatment with MMF and TFB significantly reduced methacholine-induced bronchoconstriction. These results indicate that the treatment with TFB and MMF attenuated the development of ovalbumin-induced AAI. The magnitude of the anti-asthmatic effect was comparable between both agents. The study revealed that the impairment of the clonal expansion of effector CD4+ T cells in the MLNs is a critical event in the mechanism underlying the anti-asthmatic effect of MMF and TFB. Apart from this, the findings of the study strongly suggest that the suppression of the interleukin-33/suppression of tumorigenicity-2 signaling pathway may constitute an additional mechanism responsible for producing this effect. In turn, the results indicate that the anti-asthmatic action induced by the studied agents is not mediated by the generation of forkhead box protein 3-expressing CD4+ regulatory T cells. Clinical implication of the results: the results suggest that MMF and TFB may exert anti-asthmatic action, and thus they may be considered therapeutic options for the treatment of allergic asthma cases resistant to conventional/existing treatment.

The extract from Quzhou Aurantii Fructus attenuates cough variant asthma through inhibiting the TRPV1/Ca2+/NFAT/TSLP pathway and ferroptosis via TRPV1 mediation in ovalbumin-induced mice

Ethnopharmacological relevanceCough variant asthma (CVA), a prevalent chronic inflammatory disease, is the most common cause of chronic cough. Over the years, the aqueous extract of Quzhou Aurantii Fructus (QAFA) has been widely used to treat respiratory diseases, particularly cough. Aim of the studyThis study aimed to elucidate the therapeutic effect of QAFA on allergen-induced CVA, providing deep insights into the underlying mechanisms. Materials and methodsUltra-high performance liquid chromatography quadrupole time-of-flight mass spectrometry (UPLC–Q-TOF–MS) was employed to characterize the compositions, while UPLC was used to quantify the contents of its major components in QAFA. CVA model was established via sensitization and atomization with ovalbumin (OVA), and received 600 and 1200 mg/kg of QAFA via intragastric gavage. Cough response was assessed by stimulation with capsaicin (CAP). Then, airway hyperresponsiveness (AHR), ELISA, western blotting, RT-qPCR, and histological analyses, were applied to assess pulmonary function, pathological changes, and investigate mechanisms in CVA mice following QAFA treatment through the TRPV1/Ca2+-dependent NFAT-induced expression of TSLP and ferroptosis. Additionally, the effects and mechanisms of QAFA were validated using IL-4, CAP for stimulation, capsazepine (CPZ) for inhibition, and TRPV1 siRNA transfection in cells. ResultsChemical analysis revealed that QAFA primarily contained sixteen compounds, with four main components including narirutin, naringin, hesperidin, and neohesperidin. In vivo, QAFA treatment alleviated cough and AHR, while concurrently reducing airway inflammation and mucus secretion in CVA mice. These effects were achieved by suppressing the TRPV1/NFAT/TSLP pathway and modulating the expression of ferroptosis-related proteins. In vitro, siTRPV1-transfected BEAS-2B cells demonstrated the involvement of the TRPV1 channel in IL-4-mediated Ca2+ influxes, ferroptosis, and regulation of TSLP production. QAFA and CPZ suppressed IL-4-induced TSLP production via the TRPV1/NFAT pathway and regulated the levels of ferroptosis-related proteins, while CAP counteracted the effect of QAFA on TSLP production in BEAS-2B cells. Furthermore, QAFA reduced IL-4 or CAP induced Ca2+ influx and IL-4 induced ferroptosis through TRPV1 mediation. ConclusionsThis study demonstrated that QAFA improved pulmonary function and alleviated asthmatic inflammatory response in treating CVA probably through suppressing the TRPV1/Ca2+/NFAT/TSLP pathway and ferroptosis via TRPV1 mediation.

Subtype prevalence and treatment implication in adolescents and adults with mild-to-moderate asthma: 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.

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.

The added value of targeting airway hyperresponsiveness by blocking TSLP in the management of severe asthma.

Airways hyperresponsiveness (AHR) is a pathognomonic event of asthma in which the airways are reactive to various bronchoconstrictor stimuli at 'doses' that normally have no bronchoconstrictor effect in non-asthmatics. AHR is an objective measure of clinical efficacy, and the introduction of biologics revived interest as a marker of disease and its pathophysiologic mechanism. This article aims to discuss the mechanisms of AHR, focusing on the role of epithelial damage and TSLP production, and promote its correct assessment for the evaluation of patients with severe asthma, to predict the risk of exacerbations and outcomes, and the eligibility for treatment with an anti-TSLP agent. AHR is a complex trait of asthma, induced by the concurrence of many pathophysiological factors and related to different clinical manifestations. Recent evidence demonstrates the important role of airway epithelial damage and TSLP production in many of these events. A therapeutic response based on AHR control could be considered as a condition of disease remission and seems a promising new goal for the management of patients with severe asthma.