Pulmonary adaptation to repeated poly(I:C) exposure is impaired in asthmatic mice: an observational study.

BACKGROUND: While asthma exacerbations remain a major challenge in patient management, few animal models exist to explore the underlying mechanisms. Here, we established an animal model of asthma that can be used to study pathophysiological mechanisms and therapeutic strategies on asthma exacerbation. METHODS: Female BALB/c mice were sensitized and exposed to PBS or Dermatophagoides pteronyssinus (DerP) extract for 11 weeks. Asthmatic phenotype was assessed through lung inflammation, bronchial hyperresponsiveness and bronchial smooth muscle remodeling. Asthmatic and control mice were exposed once or three times to poly(I:C) to simulate virus-induced inflammation. RESULTS: Fourteen days after exposure to DerP, asthmatic mice showed resolution of inflammation with sustained bronchial hyperresponsiveness and bronchial smooth muscle remodeling compared to control. At this stage, when mice were subjected to a single exposure to poly(I:C), control and asthmatic mice were characterized by a significant increase in neutrophilic inflammation and bronchial hyperresponsiveness. When mice were repeatedly exposed to poly(I:C), control mice showed a significant decrease in neutrophilic inflammation and bronchial hyperresponsiveness, while asthmatic mice experienced worsening of these outcomes. CONCLUSIONS: This observational study report an asthmatic mouse model that can undergo exacerbation after repeated exposure to poly(I:C). Our findings on pulmonary adaptation in control mice may also pave the way for further research into the mechanism of adaptation that may be impaired in asthma and raise the question of whether asthma exacerbation may be a loss of adaptation.

Brainstem Dbh+ neurons control allergen-induced airway hyperreactivity.

Exaggerated airway constriction triggered by repeated exposure to allergen, also called hyperreactivity, is a hallmark of asthma. Whereas vagal sensory neurons are known to function in allergen-induced hyperreactivity1-3, the identity of downstream nodes remains poorly understood. Here we mapped a full allergen circuit from the lung to the brainstem and back to the lung. Repeated exposure of mice to inhaled allergen activated the nuclei of solitary tract (nTS) neurons in a mast cell-, interleukin-4 (IL-4)- and vagal nerve-dependent manner. Single-nucleus RNA sequencing, followed by RNAscope assay at baseline and allergen challenges, showed that a Dbh+ nTS population is preferentially activated. Ablation or chemogenetic inactivation of Dbh+ nTS neurons blunted hyperreactivity whereas chemogenetic activation promoted it. Viral tracing indicated that Dbh+ nTS neurons project to the nucleus ambiguus (NA) and that NA neurons are necessary and sufficient to relay allergen signals to postganglionic neurons that directly drive airway constriction. Delivery of noradrenaline antagonists to the NA blunted hyperreactivity, suggesting noradrenaline as the transmitter between Dbh+ nTS and NA. Together, these findings provide molecular, anatomical and functional definitions of key nodes of a canonical allergen response circuit. This knowledge informs how neural modulation could be used to control allergen-induced airway hyperreactivity.

The integrin receptor beta7 subunit mediates airway remodeling and hyperresponsiveness in allergen exposed mice.

BACKGROUND: Fibroblast differentiation to a myofibroblast phenotype is a feature of airway remodeling in asthma. Lung fibroblasts express the integrin receptor α4ß7 and fibronectin induces myofibroblast differentiation via this receptor. OBJECTIVES: To investigate the role of the ß7 integrin receptor subunit and α4ß7 integrin complex in airway remodeling and airway hyperresponsiveness (AHR) in a murine model of chronic allergen exposure. METHODS: C57BL/6 wild type (WT) and ß7 integrin null mice (ß7 -/-) were sensitized (days 1,10) and challenged with ovalbumin (OVA) three times a week for one or 4 weeks. Similar experiments were performed with WT mice in the presence or absence of α4ß7 blocking antibodies. Bronchoalveolar (BAL) cell counts, AHR, histological evaluation, soluble collagen content, Transforming growth factor-ß (TGFß) and Interleukin-13 (IL13) were measured. Phenotype of fibroblasts cultured from WT and ß7 -/- saline (SAL) and OVA treated mice was evaluated. RESULTS: Eosinophil numbers were similar in WT vs ß7-/- mice. Prolonged OVA exposure in ß7-/- mice was associated with reduced AHR, lung collagen content, peribronchial smooth muscle, lung tissue TGFß and IL13 expression as compared to WT. Similar findings were observed in WT mice treated with α4ß7 blocking antibodies. Fibroblast migration was enhanced in response to OVA in WT but not ß7 -/- fibroblasts. α-SMA and fibronectin expression were reduced in ß7-/- fibroblasts relative to WT. CONCLUSIONS: The ß7 integrin subunit and the α4ß7 integrin complex modulate AHR and airway remodeling in a murine model of allergen exposure. This effect is, at least in part, explained by inhibition of fibroblast activation and is independent of eosinophilic inflammation.

PM10 exposure induces bronchial hyperresponsiveness by upreguating acetylcholine muscarinic 3 receptor.

Exposure to particulate matter (PM10) can induce respiratory diseases that are closely related to bronchial hyperresponsiveness. However, the involved mechanism remains to be fully elucidated. This study aimed to demonstrate the effects of PM10 on the acetylcholine muscarinic 3 receptor (CHRM3) expression and the role of the ERK1/2 pathway in rat bronchial smooth muscle. A whole-body PM10 exposure system was used to stimulate bronchial hyperresponsiveness in rats for 2 and 4 months, accompanied by MEK1/2 inhibitor U0126 injection. The whole-body plethysmography system and myography were used to detect the pulmonary and bronchoconstrictor function, respectively. The mRNA and protein levels were determined by Western blotting, qPCR, and immunofluorescence. Enzyme-linked immunosorbent assay was used to detect the inflammatory cytokines. Compared with the filtered air group, 4 months of PM10 exposure significantly increased CHRM3-mediated pulmonary function and bronchial constriction, elevated CHRM3 mRNA and protein expression levels on bronchial smooth muscle, then induced bronchial hyperreactivity. Additionally, 4 months of PM10 exposure caused an increase in ERK1/2 phosphorylation and increased the secretion of inflammatory factors in bronchoalveolar lavage fluid. Treatment with the MEK1/2 inhibitor, U0126 inhibited the PM10 exposure-induced phosphorylation of the ERK1/2 pathway, thereby reducing the PM10 exposure-induced upregulation of CHRM3 in bronchial smooth muscle and CHRM3-mediated bronchoconstriction. U0126 could rescue PM10 exposure-induced pathological changes in the bronchus. In conclusion, PM10 exposure can induce bronchial hyperresponsiveness in rats by upregulating CHRM3, and the ERK1/2 pathway may be involved in this process. These findings could reveal a potential therapeutic target for air pollution induced respiratory diseases.

Protective Effects of Resveratrol Against Airway Hyperreactivity, Oxidative Stress, and Lung Inflammation in a Rat Pup Model of Bronchopulmonary Dysplasia.

Oxygen therapy provides an important treatment for preterm and low-birth-weight neonates, however, it has been shown that prolonged exposure to high levels of oxygen (hyperoxia) is one of the factors contributing to the development of bronchopulmonary dysplasia (BPD) by inducing lung injury and airway hyperreactivity. There is no effective therapy against the adverse effects of hyperoxia. Therefore, this study was undertaken to test the hypothesis that natural phytoalexin resveratrol will overcome hyperoxia-induced airway hyperreactivity, oxidative stress, and lung inflammation. Newborn rats were exposed to hyperoxia (fraction of inspired oxygen - FiO2>95 % O2) or ambient air (AA) for seven days. Resveratrol was supplemented either in vivo (30 mg·kg-1·day-1) by intraperitoneal administration or in vitro to the tracheal preparations in an organ bath (100 mikroM). Contractile and relaxant responses were studied in tracheal smooth muscle (TSM) using the in vitro organ bath system. To explain the involvement of nitric oxide in the mechanisms of the protective effect of resveratrol against hyperoxia, a nitric oxide synthase inhibitor - Nomega-nitro-L-arginine methyl ester (L-NAME), was administered in some sets of experiments. The superoxide dismutase (SOD) and glutathione peroxidase (GPx) activities and the tumor necrosis factor-alpha (TNF-alpha) and interleukin-1beta (IL-1beta) levels in the lungs were determined. Resveratrol significantly reduced contraction and restored the impaired relaxation of hyperoxia-exposed TSM (p<0.001). L-NAME reduced the inhibitory effect of resveratrol on TSM contractility, as well as its promotion relaxant effect (p<0.01). Resveratrol preserved the SOD and GPx activities and decreased the expression of TNF-alpha and IL-1beta in hyperoxic animals. The findings of this study demonstrate the protective effect of resveratrol against hyperoxia-induced airway hyperreactivity and lung damage and suggest that resveratrol might serve as a therapy to prevent the adverse effects of neonatal hyperoxia. Keywords: Bronchopulmonary dysplasia, Hyperoxia, Airway hyperreactivity, Resveratrol, Pro-inflammatory cytokines.

Evaluation of airway responsiveness and pulmonary function test results among obese and non-obese patients with obstructive sleep apnea syndrome.

OBJECTIVE: In this research, we aimed to elucidate the effect of obstructive sleep apnea syndrome (OSAS) and obesity on pulmonary volumes and bronchial hyperreactivity, and particularly the effect of supine position on pulmonary volume and functions. PATIENTS AND METHODS: This was a prospective, cross-sectional study with a total of 96 patients (age range, 20-65 years). Based on the body mass index (BMI) and Apnea-Hypopnea Index (AHI) scores, the patients were divided into four groups: Group 1: AHI≥15/h, BMI≥30 kg/m2 (n=24), Group 2: AHI≥15/h, BMI<30 kg/m2 (n=24), Group 3: AHI<15/h, BMI≥30 kg/m2 (n=24), and Group 4: AHI<15/h, BMI<30 kg/m2 (n=24). All patients first had static and dynamic pulmonary function tests and carbon monoxide diffusion tests (TLco and Kco) in the sitting and supine positions. A bronchial provocation test with methacholine was applied to all patients in the sitting position one day later. Analysis of variance (ANOVA) and multivariate linear regression was used in the statistical analysis. RESULTS: Airway responsiveness was observed in 4 of the patients included in the study, and there was no statistically significant difference between the groups. A statistically significant decrease was observed in forced vital capacity (FVC), forced expiratory volume in one second (FEV1), peak expiratory flow (PEF), total lung capacity (TLC) and functional residual capacity (FRC), especially in  Group 1 in sitting position compared to Group 4 (p=0.001, p=0.001, p=0.025, p=0.043, and p=0.001, respectively). Changes in pulmonary functions in the transition from sitting to a supine position did not show any significant difference in the study groups (p<0.05). We observed no difference in the diffusion capacity in the sitting and supine positions among the groups (p<0.05). CONCLUSIONS: The severity of AHI and BMI particularly affect the lower airway, but changes in the position did not show any significant difference in the study groups.

Statin administration or blocking PCSK9 alleviates airway hyperresponsiveness and lung fibrosis in high-fat diet-induced obese mice.

BACKGROUND: Obesity is associated with airway hyperresponsiveness and lung fibrosis, which may reduce the effectiveness of standard asthma treatment in individuals suffering from both conditions. Statins and proprotein convertase subtilisin/kexin-9 inhibitors not only reduce serum cholesterol, free fatty acids but also diminish renin-angiotensin system activity and exhibit anti-inflammatory effects. These mechanisms may play a role in mitigating lung pathologies associated with obesity. METHODS: Male C57BL/6 mice were induced to develop obesity through high-fat diet for 16 weeks. Conditional TGF-ß1 transgenic mice were fed a normal diet. These mice were given either atorvastatin or proprotein convertase subtilisin/kexin-9 inhibitor (alirocumab), and the impact on airway hyperresponsiveness and lung pathologies was assessed. RESULTS: High-fat diet-induced obesity enhanced airway hyperresponsiveness, lung fibrosis, macrophages in bronchoalveolar lavage fluid, and pro-inflammatory mediators in the lung. These lipid-lowering agents attenuated airway hyperresponsiveness, macrophages in BALF, lung fibrosis, serum leptin, free fatty acids, TGF-ß1, IL-1ß, IL-6, and IL-17a in the lung. Furthermore, the increased RAS, NLRP3 inflammasome, and cholecystokinin in lung tissue of obese mice were reduced with statin or alirocumab. These agents also suppressed the pro-inflammatory immune responses and lung fibrosis in TGF-ß1 over-expressed transgenic mice with normal diet. CONCLUSIONS: Lipid-lowering treatment has the potential to alleviate obesity-induced airway hyperresponsiveness and lung fibrosis by inhibiting the NLRP3 inflammasome, RAS and cholecystokinin activity.

Clinical implications of airway obstruction with normal or low FEV1 in childhood and adolescence.

BACKGROUND: Airway obstruction is defined by spirometry as a low forced expiratory volume in 1 s (FEV1) to forced vital capacity (FVC) ratio. This impaired ratio may originate from a low FEV1 (classic) or a normal FEV1 in combination with a large FVC (dysanaptic). The clinical implications of dysanaptic obstruction during childhood and adolescence in the general population remain unclear. AIMS: To investigate the association between airway obstruction with a low or normal FEV1 in childhood and adolescence, and asthma, wheezing and bronchial hyperresponsiveness (BHR). METHODS: In the BAMSE (Barn/Child, Allergy, Milieu, Stockholm, Epidemiology; Sweden) and PIAMA (Prevention and Incidence of Asthma and Mite Allergy; the Netherlands) birth cohorts, obstruction (FEV1:FVC ratio less than the lower limit of normal, LLN) at ages 8, 12 (PIAMA only) or 16 years was classified as classic (FEV1

Airway hyperresponsiveness in asthma: The role of the epithelium.

Airway hyperresponsiveness (AHR) is a key clinical feature of asthma. The presence of AHR in people with asthma provides the substrate for bronchoconstriction in response to numerous diverse stimuli, contributing to airflow limitation and symptoms including breathlessness, wheeze, and chest tightness. Dysfunctional airway smooth muscle significantly contributes to AHR and is displayed as increased sensitivity to direct pharmacologic bronchoconstrictor stimuli, such as inhaled histamine and methacholine (direct AHR), or to endogenous mediators released by activated airway cells such as mast cells (indirect AHR). Research in in vivo human models has shown that the disrupted airway epithelium plays an important role in driving inflammation that mediates indirect AHR in asthma through the release of cytokines such as thymic stromal lymphopoietin and IL-33. These cytokines upregulate type 2 cytokines promoting airway eosinophilia and induce the release of bronchoconstrictor mediators from mast cells such as histamine, prostaglandin D2, and cysteinyl leukotrienes. While bronchoconstriction is largely due to airway smooth muscle contraction, airway structural changes known as remodeling, likely mediated in part by epithelial-derived mediators, also lead to airflow obstruction and may enhance AHR. In this review, we outline the current knowledge of the role of the airway epithelium in AHR in asthma and its implications on the wider disease. Increased understanding of airway epithelial biology may contribute to better treatment options, particularly in precision medicine.

A new tidal breathing measurement device detects bronchial obstruction during methacholine challenge test.

PURPOSE: Bronchial hyperresponsiveness (BHR), a hallmark of bronchial asthma, is typically diagnosed through a methacholine inhalation test followed by spirometry, known as the methacholine challenge test (MCT). While spirometry relies on proper patients' cooperation and precise execution of forced breathing maneuvers, we conducted a comparative analysis with the portable nanomaterial-based sensing device, SenseGuard™, to non-intrusively assess tidal breathing parameters. MATERIALS AND METHODS: In this prospective study, 37 adult participants with suspected asthma underwent sequential spirometry and SenseGuard™ measurements after inhaling increasing methacholine doses. RESULTS: Among the 37 participants, 18 were MCT responders, 17 were non-responders and 2 were excluded due to uninterpretable data. The MCT responders exhibited a significant lung function difference when comparing the change from baseline to maximum response. This was evident through a notable decrease in forced expiratory volume in 1 â€‹s (FEV1) levels in spirometry, as well as in prominent changes in tidal breathing parameters as assessed by SenseGuard™, including the expiratory pause time (Trest) to total breath time (Ttot) ratio, and the expiratory time (Tex) to Ttot ratio. Notably, the ratios Trest/Ttot (∗p â€‹= â€‹0.02), Tex/Ttot (∗p â€‹= â€‹0.002), and inspiratory time (Tin) to Tex (∗p â€‹= â€‹0.04) identified MCT responders distinctly, corresponding to spirometry (∗p â€‹< â€‹0.0001). CONCLUSIONS: This study demonstrates that tidal breathing assessment using SenseGuard™ device reliably detects clinically relevant changes of respiratory parameter during the MCT. It effectively distinguishes between responders and non-responders, with strong agreement to conventional spirometry-measured FEV1. This technology holds promise for monitoring clinical respiratory changes in bronchial asthma patients pending further studies.

Therapeutic ketosis decreases methacholine hyperresponsiveness in mouse models of inherent obese asthma.

Obese asthmatics tend to have severe, poorly controlled disease and exhibit methacholine hyperresponsiveness manifesting in proximal airway narrowing and distal lung tissue collapsibility. Substantial weight loss in obese asthmatics or in mouse models of the condition decreases methacholine hyperresponsiveness. Ketone bodies are rapidly elevated during weight loss, coinciding with or preceding relief from asthma-related comorbidities. As ketone bodies may exert numerous potentially therapeutic effects, augmenting their systemic concentrations is being targeted for the treatment of several conditions. Circulating ketone body levels can be increased by feeding a ketogenic diet or by providing a ketone ester dietary supplement, which we hypothesized would exert protective effects in mouse models of inherent obese asthma. Weight loss induced by feeding a low-fat diet to mice previously fed a high-fat diet was preceded by increased urine and blood levels of the ketone body ß-hydroxybutyrate (BHB). Feeding a ketogenic diet for 3 wk to high-fat diet-fed obese mice or genetically obese db/db mice increased BHB concentrations and decreased methacholine hyperresponsiveness without substantially decreasing body weight. Acute ketone ester administration decreased methacholine responsiveness of normal mice, and dietary ketone ester supplementation of high-fat diet-fed mice decreased methacholine hyperresponsiveness. Ketone ester supplementation also transiently induced an "antiobesogenic" gut microbiome with a decreased Fermicutes/Bacteroidetes ratio. Dietary interventions to increase systemic BHB concentrations could provide symptom relief for obese asthmatics without the need for the substantial weight loss required of patients to elicit benefits to their asthma through bariatric surgery or other diet or lifestyle alterations.

Ding Chuan Tang Attenuates Airway Inflammation and Eosinophil Infiltration in Ovalbumin-Sensitized Asthmatic Mice.

Asthma is a T helper 2 (Th2) cell-associated chronic inflammatory diseases characterized with airway obstruction, increased mucus production, and eosinophil infiltration. Conventional medications for asthma treatment cannot fully control the symptoms, and potential side effects are also the concerns. Thus, complement or alternative medicine (CAM) became a new option for asthma management. Ding Chuan Tang (DCT) is a traditional Chinese herbal decoction applied mainly for patients with coughing, wheezing, chest tightness, and asthma. Previously, DCT has been proved to improve children airway hyperresponsiveness (AHR) in a randomized and double-blind clinical trial. However, the mechanisms of how DCT alleviates AHR remain unclear. Since asthmatic features such as eosinophil infiltration, IgE production, and mucus accumulation are relative with Th2 responses, we hypothesized that DCT may attenuate asthma symptoms through regulating Th2 cells. Ovalbumin (OVA) was used as a stimulant to sensitize BALB/c mice to establish an asthmatic model. AHR was detected one day before sacrifice. BALF and serum were collected for immune cell counting and antibody analysis. Splenocytes were cultured with OVA in order to determine Th2 cytokine production. Lung tissues were collected for histological and gene expression analyses. Our data reveal that DCT can attenuate AHR and eosinophil accumulation in the 30-day sensitization asthmatic model. Histological results demonstrated that DCT can reduce cell infiltration and mucus production in peribronchial and perivascular site. In OVA-stimulated splenocyte cultures, a significant reduction of IL-5 and IL-13 in DCT-treated mice suggests that DCT may alleviate Th2 responses. In conclusion, the current study demonstrates that DCT has the potential to suppress allergic responses through the reduction of mucus production, eosinophil infiltration, and Th2 activity in asthma.

Novel acute hypersensitivity pneumonitis model induced by airway mycosis and high dose lipopolysaccharide.

BACKGROUND: Inhalation of fungal spores is a strong risk factor for severe asthma and experimentally leads to development of airway mycosis and asthma-like disease in mice. However, in addition to fungal spores, humans are simultaneously exposed to other inflammatory agents such as lipopolysaccharide (LPS), with uncertain relevance to disease expression. To determine how high dose inhalation of LPS influences the expression of allergic airway disease induced by the allergenic mold Aspergillus niger (A. niger). METHODS: C57BL/6J mice were intranasally challenged with the viable spores of A. niger with and without 1 µg of LPS over two weeks. Changes in airway hyperreactivity, airway and lung inflammatory cell recruitment, antigen-specific immunoglobulins, and histopathology were determined. RESULTS: In comparison to mice challenged only with A. niger, addition of LPS (1 µg) to A. niger abrogated airway hyperresponsiveness and strongly attenuated airway eosinophilia, PAS+ goblet cells and TH2 responses while enhancing TH1 and TH17 cell recruitment to lung. Addition of LPS resulted in more severe, diffuse lung inflammation with scattered, loosely-formed parenchymal granulomas, but failed to alter fungus-induced IgE and IgG antibodies. CONCLUSIONS: In contrast to the strongly allergic lung phenotype induced by fungal spores alone, addition of a relatively high dose of LPS abrogates asthma-like features, replacing them with a phenotype more consistent with acute hypersensitivity pneumonitis (HP). These findings extend the already established link between airway mycosis and asthma to HP and describe a robust model for further dissecting the pathophysiology of HP.

Anisakis pegreffii Extract Induces Airway Inflammation with Airway Remodeling in a Murine Model System.

Exposure of the respiratory system to the Anisakis pegreffii L3 crude extract (AE) induces airway inflammation; however, the mechanism underlying this inflammatory response remains unknown. AE contains allergens that promote allergic inflammation; exposure to AE may potentially lead to asthma. In this study, we aimed to establish a murine model to assess the effects of AE on characteristic features of chronic asthma, including airway hypersensitivity (AHR), airway inflammation, and airway remodeling. Mice were sensitized for five consecutive days each week for 4 weeks. AHR, lung inflammation, and airway remodeling were evaluated 24 h after the last exposure. Lung inflammation and airway remodeling were assessed from the bronchoalveolar lavage fluid (BALF). To confirm the immune response in the lungs, changes in gene expression in the lung tissue were assessed with reverse transcription-quantitative PCR. The levels of IgE, IgG1, and IgG2a in blood and cytokine levels in the BALF, splenocyte, and lung lymph node (LLN) culture supernatant were measured with ELISA. An increase in AHR was prominently observed in AE-exposed mice. Epithelial proliferation and infiltration of inflammatory cells were observed in the BALF and lung tissue sections. Collagen deposition was detected in lung tissues. AE exposure increased IL-4, IL-5, and IL-13 expression in the lung, as well as the levels of antibodies specific to AE. IL-4, IL-5, and IL-13 were upregulated only in LLN. These findings indicate that an increase in IL-4+ CD4+ T cells in the LLN and splenocyte resulted in increased Th2 response to AE exposure. Exposure of the respiratory system to AE resulted in an increased allergen-induced Th2 inflammatory response and AHR through accumulation of inflammatory and IL-4+ CD4+ T cells and collagen deposition. It was confirmed that A. pegreffii plays an essential role in causing asthma in mouse models and has the potential to cause similar effects in humans.

Dog Ownership in Early Life Increased the Risk of Nonatopic Asthma in Children.

BACKGROUND: It is still debatable whether dog ownership during early childhood is a risk factor for the development of allergic diseases. OBJECTIVE: We investigated the association of dog ownership in early life with sensitization and asthma in childhood. METHODS: Data from the Cohort for Childhood Origin of Asthma and Allergic diseases were used to investigate the association between dog ownership at any time from pregnancy to 1 year of age and sensitization to aeroallergens at 3 and 7 years old, bronchial hyperresponsiveness (BHR), and asthma at 7 years old. We analyzed the cytokine levels in cord blood (CB) and indoor environmental measurement concentrations in the mother's residence obtained at 36 weeks of pregnancy. RESULTS: Sensitization to dogs at age 3 and 7 did not differ between dog ownership and nonownership, but dog ownership during early life decreased the risk of sensitization to aeroallergens at age 7 (aOR = 0.44, 95% CI 0.21-0.90). Dog ownership significantly increased the risk of nonatopic BHR (aOR = 2.86; 95% CI 1.32-6.21). In addition, dog ownership was associated with asthma, especially nonatopic asthma at 7 years old (aOR = 2.73, 95% CI 1.02-7.32; aOR = 7.05, 95% CI 1.85-26.90, respectively). There were no significant differences in the concentrations of IL-13 or interferon-γ in CB or indoor environmental measurements according to dog ownership during pregnancy. CONCLUSION: Early-life dog exposure in this birth cohort has been shown to reduce atopy but increase the risk of nonatopic BHR and nonatopic asthma at 7 years old.

Baseline spirometry parameters as predictors of airway hyperreactivity in adults with suspected asthma.

BACKGROUND: Methacholine challenge tests (MCTs) are used to diagnose airway hyperresponsiveness (AHR) in patients with suspected asthma where previous diagnostic testing has been inconclusive. The test is time consuming and usually requires referral to specialized centers. Simple methods to predict AHR could help determine which patients should be referred to MCTs, thus avoiding unnecessary testing. Here we investigated the potential use of baseline spirometry variables as surrogate markers for AHR in adults with suspected asthma. METHODS: Baseline spirometry and MCTs performed between 2013 and 2019 in a large tertiary center were retrospectively evaluated. Receiver-operating characteristic curves for the maximal expiratory flow-volume curve indices (angle ß, FEV1, FVC, FEV1/FVC, FEF50%, FEF25-75%) were constructed to assess their overall accuracy in predicting AHR and optimal cutoff values were identified. RESULTS: A total of 2983 tests were analyzed in adults aged 18-40 years. In total, 14% of all MCTs were positive (PC20 ≤ 16 mg/ml). All baseline spirometry parameters were significantly lower in the positive group (p < 0.001). FEF50% showed the best overall accuracy (AUC = 0.688) and proved to be useful as a negative predictor when applying FEF50% ≥ 110% as a cutoff level. CONCLUSIONS: This study highlights the role of FEF50% in predicting AHR in patients with suspected asthma. A value of ≥ 110% for baseline FEF50% could be used to exclude AHR and would lead to a substantial decrease in MCT referrals.

Small Airway Dysfunction in Asthma Is Associated with Perceived Respiratory Symptoms, Non-Type 2 Airway Inflammation, and Poor Responses to Therapy.

BACKGROUND: Emerging evidence has indicated that small airway dysfunction (SAD) contributes to the clinical expression of asthma. OBJECTIVES: The aim of the study was to explore the relationships of SAD assessed by forced expiratory flow between 25 and 75% (FEF25-75%), with clinical and inflammatory profile and treatment responsiveness in asthma. METHOD: In study I, dyspnea intensity (Borg scale), chest tightness, wheezing and cough (visual analog scales, VASs), and pre- and post-methacholine challenge testing (MCT) were analyzed in asthma patients with SAD and non-SAD. In study II, asthma subjects with SAD and non-SAD underwent sputum induction, and inflammatory mediators in sputum were detected. Asthma patients with SAD and non-SAD receiving fixed treatments were prospectively followed up for 4 weeks in study III. Spirometry, Asthma Control Questionnaire (ACQ), and Asthma Control Test (ACT) were carried out to define treatment responsiveness. RESULTS: SAD subjects had more elevated ΔVAS for dyspnea (p = 0.027) and chest tightness (p = 0.032) after MCT. Asthma patients with SAD had significantly elevated interferon (IFN)-γ in sputum (p < 0.05), and Spearman partial correlation found FEF25-75% significantly related to IFN-γ and interleukin-8 (both having p < 0.05). Furthermore, multivariable regression analysis indicated SAD was significantly associated with worse treatment responses (decrease in ACQ ≥0.5 and increase in ACT ≥3) (p = 0.022 and p = 0.032). CONCLUSIONS: This study indicates that SAD in asthma predisposes patients to greater dyspnea intensity and chest tightness during bronchoconstriction. SAD patients with asthma are characterized by non-type 2 inflammation that may account for poor responsiveness to therapy.

Increased Gene expression of CCL2/CCR2 axis in bronchial smooth muscles of allergen-challenged mice.

PURPOSE: Augmented bronchial smooth muscle (BSM) contraction is a cause of airway hyperresponsiveness (AHR) in asthma. Increasing evidence suggest that C-C motif chemokine 2 (CCL2) modulates smooth muscle contractility by activating its binding partner C-C chemokine receptor type 2 (CCR2). In the present study, changes in the gene expression of CCL2/CCR2 axis were determined in the BSMs of a murine model of allergic asthma. MATERIALS AND METHODS: The ovalbumin (OA)-sensitized mice were repeatedly challenged with aerosolized OA to induce asthmatic reaction. Twenty-four hours after the last antigen challenge, total RNAs of the main BSM tissues and bronchoalveolar lavage fluids (BALFs) were obtained. RESULTS: Our published microarray data (GEO accession No. GSE116504) detected changes in gene expression associated with the chemokine signaling pathway (KEGG Map ID: 04062) in BSMs of mice with AHR induced by antigen exposure. Among them, quantitative RT-PCR analyses showed significant increase in mRNA expression of Ccl2 and Ccr2. Analysis of BALFs also revealed a significant increase in Ccl2 protein in the airways of the diseased animals. CONCLUSION: It is thus possible that, in association with the AHR, the CCL2/CCR2 axis is enhanced in the airways of allergic bronchial asthma.

Longitudinal predictors of bronchial hyperresponsiveness and FEV1 decline in bakers.

OBJECTIVE: To determine long-term predictors of bronchial hyperresponsiveness (BHR) and forced expiratory volume in one second (FEV1) decline. METHODS: A longitudinal study in 110 bakers in 4 industrial bakeries and 38 non-exposed workers was conducted at the workplace with a mean of 3.3 visits per subject over a period of 13 years and a mean duration of follow-up of 6 years in bakers and 8 years in non-exposed subjects. A respiratory health questionnaire was administered; occupational allergen skin prick tests, spirometry and a methacholine bronchial challenge test were performed at each visit. In each bakery, full-shift dust samples of the inhalable fraction were obtained in order to assess the exposure of each job assignment. The repeated measurements of BHR and FEV1 were analyzed using mixed effects logistic and linear regression models in subjects seen at least twice. RESULTS: BHR, respiratory symptoms and their simultaneous occurrence depended on the duration of exposure. FEV1 significantly decreased with duration of exposure and BHR at a preceding visit. This result persisted when adjusting for the effect of BHR at the current visit. The measured exposure levels were not a significant predictor for any outcome. Occupational sensitization was only a predictor of a decline in FEV1 when duration of exposure was not included. CONCLUSION: In flour-exposed industrial bakers, length of exposure and smoking are long-term determinants of BHR and of the decrease in FEV1. BHR at a preceding visit predicted lower FEV1 even when accounting for the effect of BHR at the current visit.