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Airway remodeling in asthma has been classically considered to be the result of inflammatory changes. In this study, the investigators show that bronchoconstriction alone can result in changes consistent with airway remodeling. Asthma is a common chronic respiratory condition characterized clinically by an excessive tendency toward reversible airway narrowing. This may arise in response to everyday environmental exposure and is worsened both by intercurrent infection and, in sensitized persons, by allergen exposure. In pathological terms, asthma is characterized by airway inflammation and by structural changes in airway tissues, such as epithelial goblet-cell hyperplasia, subepithelial collagen deposition, and smooth-muscle hypertrophy — collectively referred to as airway remodeling. 1 – 3 Since an inhaled-allergen challenge in atopic asthma induces eosinophilic inflammation of the airway and changes in the extracellular matrix, 4 and since a reduction in airway . . .

Exercise-induced bronchoconstriction (EIB) is highly prevalent in athletes. The objective of this study was to assess the therapeutic efficacy of daily tangeretin combined with whey protein supplementation over a period of 4 weeks in professional athletes with EIB. Using a placebo-controlled, double-blind, paired, randomized trial design, a cohort of 30 professional athletes with EIB, consisting of 14 females and 16 males, was divided into two groups: the tangeretin combined with whey protein intervention group (TIG), and the placebo control group (PCG). Both the TIG and PCG underwent exercise challenge tests (ECT) and VO tests before (ECT , V1) and after (ECT , V2) the intervention. Blood (eosinophils, neutrophils, and basophils) and serum (interleukin-5, IL-5; interleukin-8, IL-8; Clara cell secretory protein-16, CC16; immunoglobulin E, IgE) levels were measured early in the morning of ECT and ECT , respectively. Lung function was assessed immediately before and post-ECT immediately. Tangeretin combined with whey protein use for 4 weeks attenuated the decrease in forced expiratory volume in 1 s (FEV ) post trials (∆FEV (ECT1-ECT2): mean (SD) TIG -7.51(6.9)% vs. PCG -2.33(11.49)%,  = 0.013). Tangeretin also substantially attenuated IL-5 concentration (∆IL-5(T -T ): Tangeretin -19.4% vs Placebo + 8.37%,  = 0.022); IL-8 concentration (∆IL-8(T -T ): Tangeretin -17.28% vs Placebo + 6.1%,  = 0.012); CC16 concentration (∆CC16(T -T ): Tangeretin -11.77% vs Placebo + 24.19%); and IgE concentration in the serum (∆IgE(T -T ): Tangeretin -24.1% vs Placebo -3.9%), and significantly decreased neutrophil count (∆N(T -T ): Tangeretin -11.34% vs Placebo + 0.3%) and eosinophil count in blood (∆N(T -T ): Tangeretin -38.5% vs Placebo + 4.35%). Compared with V1, VO (  = 0.042) and TLim (  = 0.05) of V2 were significantly increased in the TIG, and there was no significant change in the PCG. Meanwhile, six athletes in the TIG and 0 athletes in the PCG became EIB-negative at ECT ; the overall negative conversion rate of EIB was 40.00% in TCG. Additionally, the number of cough symptoms decreased from 9 to 3 and dyspnea from 4 to 2 in the TIG. After high-intensity exercise, athletes with EIB achieved significant improvements in lung function and blood inflammatory factors by combining tangeretin and whey protein supplementation. EIB athletes also showed longer exercise endurance and VO at 4 weeks after TI. In addition, some patient symptoms disappeared after combination supplementation. The effect of this treatment on professional athletes with EIB was beneficial.

Cold temperatures (<−15°C) increase exercise‐induced bronchoconstriction (EIB), while hypoxic‐induced hyperventilation exacerbates respiratory muscle fatigue for a given exercising task. This study aimed to determine the individual and combined effects of cold and normobaric hypoxia on the respiratory system responses to high‐intensity exercise. Fourteen trained male runners (V̇O2max ${{\\dot{V}}_{{{\\mathrm{O}}}_2}{\\mathrm{max}}}$ : 64 ± 5 mL/kg/min) randomly performed an incremental cardiopulmonary exercise test (CPET) to volitional exhaustion under four environmental conditions: normothermic (18°C) normoxia (FIO2 ${{F}_{{\\mathrm{I}}{{{\\mathrm{O}}}_2}}}$ : 20.9%) and hypoxia (FIO2 ${{F}_{{\\mathrm{I}}{{{\\mathrm{O}}}_2}}}$ : 13.5%), and cold (−20°C) normoxia and hypoxia. Ventilatory responses during exercise and lung function (LF), maximal inspiratory (MIP) and expiratory (MEP) pressure measurements before and after exercise were evaluated. Volume of air forcefully exhaled in 1 s (FEV1), FEV1/forced vital capacity (FVC), peak expiratory flow, forced expiratory flow during the mid (25–75%) portion of the FVC, and maximal expiratory flow at 50% of FVC were affected by cold exposure. No significant pre‐ to post‐exercise change in MIP and MEP was found, independent of environmental conditions. Greater LF impairments in cold‐normoxia and coldhypoxia were associated with the lowest peak ventilatory responses during exercise. Cold exposure was found to negatively impact peak ventilatory responses and post‐exercise LF, further highlighting a relationship between EIB presence and the blunted ventilatory response in the cold. Respiratory muscle strength remained unchanged after exercise regardless of the environmental condition, suggesting no detrimental effect of hypoxia on this parameter when intermittent short‐duration high‐intensity exercises are performed. Future studies should investigate the combined cold‐hypoxic effect on longer exercise durations at a sustained high intensity, accounting for differences between normobaric and hypobaric hypoxia exposures. What is the central question of this study? What are the independent and combined effects of cold and normobaric hypoxia on respiratory responses to high‐intensity exercise? What is the main finding and its importance? Cold exposure impaired lung function and peak ventilatory responses during high‐intensity exercise, with greater impairments observed under combined cold‐hypoxia condition. The findings highlight a link between exercise‐induced bronchoconstriction and reduced ventilatory capacity in cold environments. Respiratory muscle strength remained unaffected post‐exercise across all conditions, suggesting no detrimental impact of hypoxia during short‐duration high‐intensity tasks.

Allergen immunotherapy for patients with allergies begins with weekly escalating doses of allergen under medical supervision to monitor and treat IgE mast cell-mediated anaphylaxis. There is currently no treatment to safely desensitize mast cells to enable robust allergen immunotherapy with therapeutic levels of allergen. Here, we demonstrated that liposomal nanoparticles bearing an allergen and a high-affinity glycan ligand of the inhibitory receptor CD33 profoundly suppressed IgE-mediated activation of mast cells, prevented anaphylaxis in Tg mice with mast cells expressing human CD33, and desensitized mice to subsequent allergen challenge for several days. We showed that high levels of CD33 were consistently expressed on human skin mast cells and that the antigenic liposomes with CD33 ligand prevented IgE-mediated bronchoconstriction in slices of human lung. The results demonstrated the potential of exploiting CD33 to desensitize mast cells to provide a therapeutic window for administering allergen immunotherapy without triggering anaphylaxis.

Mechanical forces are essential for organ function, but excessive or dysregulated forces can promote pathologic conditions. In asthma, bronchoconstriction narrows the airway, compressing the airway epithelium and activating mechanotransduction, yet key regulators of mechanotransduction remain unclear. Here we show that Hic-5, a focal adhesion adaptor, is a key regulator of epithelial mechanotransduction. In human airway epithelial cells at air–liquid interface exposed to mechanical compression that mimics bronchoconstriction, we find that compression induces Hic-5 expression in airway basal cells. We further validated these in vitro findings by reanalyzing single-cell RNA-seq data from patients with asthma undergoing bronchoconstriction after allergen challenge, which revealed increased Hic-5 expression in airway basal cells. Hic-5 knockdown in human airway epithelial cells markedly attenuates mechanoresponses to compression, including stress fiber formation, differential gene expression, and increased secretion of endothelin-1 (ET-1). Through secretion of ET-1, a potent bronchoconstrictor, Hic-5 drives epithelial mechanotransduction and promotes a feed-forward cycle of bronchoconstriction, thereby highlighting dysregulated mechanical forces as active drivers of human disease. Hic-5 drives epithelial mechanotransduction linking bronchoconstriction to asthma pathogenesis and reinforces a feed-forward bronchoconstriction loop through endothelin-1, thereby establishing dysregulated mechanical forces as active drivers of disease

Variable airflow obstruction is a pathophysiological hallmark of asthma; however, the interactions between acute bronchoconstriction and the cough reflex are poorly understood. We performed a randomised, single-blind, placebo-controlled, crossover study to investigate the interaction between bronchoconstriction and cough in asthma. Capsaicin was administered to evoke coughs and methacholine to induce bronchoconstriction. We demonstrated that acute bronchoconstriction increased capsaicin-evoked coughs, which improved as airway calibre spontaneously resolved. However, capsaicin-evoked coughing had no impact on methacholine-induced bronchoconstriction. This study provides evidence that bronchoconstriction increases the activation of capsaicin-responsive airway nerves, but the precise mechanisms and mediators involved require further evaluation.Trial registration numberISRCTN14900082.

Abstract Exaggerated airway smooth muscle (ASM) contraction regulated by the Gq family of G protein-coupled receptors causes airway hyperresponsiveness in asthma. Activation of Gq-coupled G protein-coupled receptors leads to phospholipase C (PLC)-mediated generation of inositol triphosphate (IP3) and diacylglycerol (DAG). DAG signaling is terminated by the action of DAG kinase (DGK) that converts DAG into phosphatidic acid (PA). Our previous study demonstrated that DGKζ and α isoform knockout mice are protected from the development of allergen-induced airway hyperresponsiveness. Here we aimed to determine the mechanism by which DGK regulates ASM contraction. Activity of DGK isoforms was inhibited in human ASM cells by siRNA-mediated knockdown of DGKα and ζ, whereas pharmacological inhibition was achieved by pan DGK inhibitor I (R59022). Effects of DGK inhibition on contractile agonist-induced activation of PLC and myosin light chain (MLC) kinase, elevation of IP3, and calcium levels were assessed. Furthermore, we used precision-cut human lung slices and assessed the role of DGK in agonist-induced bronchoconstriction. DGK inhibitor I attenuated histamine- and methacholine-induced bronchoconstriction. DGKα and ζ knockdown or pretreatment with DGK inhibitor I resulted in attenuated agonist-induced phosphorylation of MLC and MLC phosphatase in ASM cells. Furthermore, DGK inhibition decreased Gq agonist-induced calcium elevation and generation of IP3 and increased histamine-induced production of PA. Finally, DGK inhibition or treatment with DAG analog resulted in attenuation of activation of PLC in human ASM cells. Our findings suggest that DGK inhibition perturbed the DAG:PA ratio, resulting in inhibition of Gq-PLC activation in a negative feedback manner, resulting in protection against ASM contraction.

Asthma, a common disorder that affects >250 million people worldwide, is defined by exaggerated bronchoconstriction to inflammatory mediators including acetylcholine (ACh), bradykinin and histamine—also termed airway hyper-responsiveness. Nearly 10% of people with asthma have severe, treatment-resistant disease, which is frequently associated with immunoglobulin-E sensitization to ubiquitous fungi, typically Aspergillus fumigatus ( Af ). Here we show that a major Af allergen, Asp f13 , which is a serine protease, alkaline protease 1 (Alp 1), promotes airway hyper-responsiveness by infiltrating the bronchial submucosa and disrupting airway smooth muscle (ASM) cell-extracellular matrix (ECM) interactions. Alp 1-mediated ECM degradation evokes pathophysiological RhoA-dependent Ca 2+ sensitivity and bronchoconstriction. These findings support a pathogenic mechanism in asthma and other lung diseases associated with epithelial barrier impairment, whereby ASM cells respond directly to inhaled environmental allergens to generate airway hyper-responsiveness. Airway hyper-responsiveness, a hallmark of asthma, is often associated with sensitization to fungi. Here, the authors show that a fungal protease allergen Asp f13 / Alp1 from Aspergillus fumigatus can promote airway hyper-responsiveness in asthma via its effect on the airway smooth muscle cells.

Hyperventilation of hot humid air induces transient bronchoconstriction in patients with asthma; the underlying mechanism is not known. Recent studies showed that an increase in temperature activates vagal bronchopulmonary C-fiber sensory nerves, which upon activation can elicit reflex bronchoconstriction. This study was designed to test the hypothesis that the bronchoconstriction induced by increasing airway temperature in patients with asthma is mediated through cholinergic reflex resulting from activation of these airway sensory nerves. Specific airway resistance (SR(aw)) and pulmonary function were measured to determine the airway responses to isocapnic hyperventilation of humidified air at hot (49°C; HA) and room temperature (20-22°C; RA) for 4 minutes in six patients with mild asthma and six healthy subjects. A double-blind design was used to compare the effects between pretreatments with ipratropium bromide and placebo aerosols on the airway responses to HA challenge in these patients. SR(aw) increased by 112% immediately after hyperventilation of HA and by only 38% after RA in patients with asthma. Breathing HA, but not RA, triggered coughs in these patients. In contrast, hyperventilation of HA did not cause cough and increased SR(aw) by only 22% in healthy subjects; there was no difference between their SR(aw) responses to HA and RA challenges. More importantly, pretreatment with ipratropium completely prevented the HA-induced bronchoconstriction in patients with asthma. Bronchoconstriction induced by increasing airway temperature in patients with asthma is mediated through the cholinergic reflex pathway. The concomitant increase in cough response further indicates an involvement of airway sensory nerves, presumably the thermosensitive C-fiber afferents.

Background Exercise-induced bronchoconstriction (EIB) is common in children with asthma but can be present also in children without asthma, especially athletes. Differential diagnosis includes several conditions such as exercise-induced laryngeal obstruction (EILO), cardiac disease, or physical deconditioning. Detailed medical history, clinical examination and specific tests are mandatory to exclude alternative diagnoses. Given the high prevalence of EIB in children and its potential impact on health, sport performance, and daily levels of physical activity, health care professionals should be aware of this condition and able to provide a specific work-up for its identification. The aims of the present study were: (a) to assess the agreement among hospital pediatricians and primary care pediatricians of Emilia-Romagna Region (Italy) about the management of EIB in children and (b) formulate statements in a consensus document to help clinicians in daily clinical practice. Methods According to Delphi method, a panel of specialists scored 40 statements that were then revised and discussed during online meetings to reach full consensus. Statements were then formulated. Results To obtain full consensus, the questionnaire was administered in two rounds after full discussion of the uncertain topics on the basis of the latest evidence on EIB published over the last 10 years. Despite an overall agreement on EIB management, some gaps emerged in the sections dedicated to diagnosis and treatment. Nine summary statements on definition, pathogenesis, diagnostic work-up, treatment, and follow-up were eventually formulated. Conclusions This study describes the knowledge of EIB in a group of pediatricians and highlights gaps and uncertainties in diagnosis and treatment. The creation of statements shared by the specialists of the same area may improve the management of EIB in children. However, more research and evidence are needed to better clarify the best treatment and to standardize the best diagnostic protocol limiting useless examinations but at the same time assuring the best management.