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Respirology (Carlton, Vic.) May 2023
Topics: Humans; Respiratory Function Tests; Asthma; Bronchi; Bronchial Provocation Tests; Methacholine Chloride; Bronchial Hyperreactivity; Forced Expiratory Volume
PubMed: 36722470
DOI: 10.1111/resp.14463 -
PloS One 2023Over the past 50 years, the prevalence of allergic respiratory diseases has been increasing. The Hygiene hypothesis explains this progression by the decrease in the...
INTRODUCTION
Over the past 50 years, the prevalence of allergic respiratory diseases has been increasing. The Hygiene hypothesis explains this progression by the decrease in the bio-diversity of early microbial exposure. This study aims to evaluate the effect of early-life farm exposure on airway hyperresponsiveness and cough hypersensitivity in an allergic airway inflammation rabbit model.
METHOD
A specific environment was applied to pregnant rabbits and their offspring until six weeks after birth. Rabbits were housed in a pathogen-free zone for the control group and a calf barn for the farm group. At the end of the specific environmental exposure, both groups were then housed in a conventional zone and then sensitized to ovalbumin. Ten days after sensitization, the rabbit pups received ovalbumin aerosols to provoke airway inflammation. Sensitization to ovalbumin was assessed by specific IgE assay. Cough sensitivity was assessed by mechanical stimulation of the trachea, and bronchial reactivity was assessed by methacholine challenge. The farm environment was characterized by endotoxin measurement.
RESULTS
A total of 38 rabbit pups were included (18 in the farm group). Endotoxin levels in the farm environment varied from 30 to 1854 EU.m-3. There was no significant difference in specific IgE values to ovalbumin (p = 0.826) between the two groups. The mechanical threshold to elicit a cough did not differ between the two groups (p = 0.492). There was no difference in the number of cough (p = 0.270) or the intensity of ventilatory responses (p = 0.735). After adjusting for age and weight, there was no difference in respiratory resistance before and after methacholine challenge.
CONCLUSION
Early exposure to the calf barn did not affect cough sensitivity or bronchial reactivity in ovalbumin-sensitized rabbits. These results suggest that not all farm environments protect against asthma and atopy. Continuous exposure to several sources of microbial diversity is probably needed.
Topics: Animals; Rabbits; Cough; Methacholine Chloride; Bronchial Hyperreactivity; Dust; Farms; Ovalbumin; Inflammation; Bronchi; Immunoglobulin E; Endotoxins; Bronchoalveolar Lavage Fluid
PubMed: 36706084
DOI: 10.1371/journal.pone.0279498 -
International Journal of Medical... 2023Although adjuvant tamoxifen therapy is beneficial to estrogen receptor-positive (ER) breast cancer patients, a significant number of patients still develop metastasis or...
Although adjuvant tamoxifen therapy is beneficial to estrogen receptor-positive (ER) breast cancer patients, a significant number of patients still develop metastasis or undergo recurrence. Therefore, identifying novel diagnostic and prognostic biomarkers for these patients is urgently needed. Predictive markers and therapeutic strategies for tamoxifen-resistant ER breast cancer are not clear, and micro (mi)RNAs have recently become a focal research point in cancer studies owing to their regulation of gene expressions, metabolism, and many other physiological processes. Therefore, systematic investigation is required to understand the modulation of gene expression in tamoxifen-resistant patients. High-throughput technology uses a holistic approach to observe differences among expression profiles of thousands of genes, which provides a comprehensive level to extensively investigate functional genomics and biological processes. Through a bioinformatics analysis, we revealed that glutamine synthetase/glutamate-ammonia ligase () might play essential roles in the recurrence of tamoxifen-resistant ER patients. increases intracellular glutamine usage via glutaminolysis, and further active metabolism-related downstream molecules in cancer cell. However, how regulates the tumor microenvironment for tamoxifen-resistant ER breast cancer remains unexplored. Analysis of MetaCore pathway database demonstrated that is involved in the cell cycle, immune response, interleukin (IL)-4-induced regulators of cell growth, differentiation, and metabolism-related pathways. Experimental data also confirmed that the knockdown of in breast cancer cell lines decreased cell proliferation and influenced expressions of specific downstream molecules. Through a Connectivity Map (CMap) analysis, we revealed that certain drugs/molecules, including omeprazole, methacholine chloride, ioversol, fulvestrant, difenidol, cycloserine, and MK-801, may serve as potential treatments for tamoxifen-resistant breast cancer patients. These drugs may be tested in combination with current therapies in tamoxifen-resistant breast cancer patients. Collectively, our study demonstrated the crucial roles of , which provide new targets for the treatment of tamoxifen-resistant breast cancer patients.
Topics: Female; Humans; Breast Neoplasms; Cell Line, Tumor; Drug Resistance, Neoplasm; Fulvestrant; Gene Expression Regulation, Neoplastic; Glutamate-Ammonia Ligase; MicroRNAs; Tamoxifen; Tumor Microenvironment
PubMed: 36619229
DOI: 10.7150/ijms.75625 -
Chest Apr 2023The purpose of this study was to investigate physiological phenotypes of asthma in obesity.
BACKGROUND
The purpose of this study was to investigate physiological phenotypes of asthma in obesity.
RESEARCH QUESTION
Do physiological responses during bronchoconstriction distinguish different groups of asthma in people with obesity, and also differentiate from responses simply related to obesity?
STUDY DESIGN AND METHODS
Cross-sectional study of people with obesity (31 with asthma and 22 without lung disease). Participants underwent methacholine challenge testing with measurement of spirometry and respiratory system impedance by oscillometry.
RESULTS
Participants had class III obesity (BMI, 46.7 ± 6.6 kg/m in control subjects and 47.2 ± 8.2 kg/m in people with asthma). Most participants had significant changes in peripheral airway impedance in response to methacholine: in control subjects, resistance at 5 Hz measured by oscillometry increased by 45% ± 27% and area under the reactance curve (AX) by 268% ± 236% in response to 16 mg/mL methacholine; in people with asthma, resistance at 5 Hz measured by oscillometry increased by 52% ± 38% and AX by 361% ± 295% in response to provocation concentration producing a 20% fall in FEV dose of methacholine. These responses suggest that obesity predisposes to peripheral airway reactivity. Two distinct groups of asthma emerged based on respiratory system impedance: one with lower reactance (baseline AX, 11.8; interquartile range, 9.9-23.4 cm HO/L) and more concordant bronchoconstriction in central and peripheral airways; the other with high reactance (baseline AX, 46.7; interquartile range, 23.2-53.7 cm HO/L) and discordant bronchoconstriction responses in central and peripheral airways. The high reactance asthma group included only women, and reported significantly more gastroesophageal reflux disease, worse chest tightness, more wheeze, and more asthma exacerbations than the low reactance group.
INTERPRETATION
Peripheral airway reactivity detected by oscillometry is common in obese control subjects and obese people with asthma. There is a subgroup of obese asthma characterized by significant peripheral airway dysfunction by oscillometry out of proportion to spirometric airway dysfunction. This peripheral dysfunction represents clinically significant respiratory disease not readily assessed by spirometry.
Topics: Female; Humans; Methacholine Chloride; Cross-Sectional Studies; Asthma; Respiratory System; Spirometry; Bronchial Provocation Tests; Obesity; Airway Resistance; Forced Expiratory Volume
PubMed: 36610669
DOI: 10.1016/j.chest.2022.12.030 -
Biology of Sex Differences Jan 2023Asthma is a chronic airway condition that occurs more often in women than men during reproductive years. Population studies have collectively shown that long-term use of...
RATIONALE
Asthma is a chronic airway condition that occurs more often in women than men during reproductive years. Population studies have collectively shown that long-term use of oral contraceptives decreased the onset of asthma in women of reproductive age. In the current study, we hypothesized that steady-state levels of estrogen would reduce airway inflammation and airway hyperresponsiveness to methacholine challenge.
METHODS
Ovariectomized BALB/c mice (Ovx) were implanted with subcutaneous hormone pellets (estrogen, OVX-E2) that deliver consistent levels of estrogen [68 ± 2 pg/mL], or placebo pellets (OVX-Placebo), followed by ovalbumin sensitization and challenge. In conjunction with methacholine challenge, immune phenotyping was performed to correlate inflammatory proteins and immune populations with better or worse pulmonary outcomes measured by invasive pulmonary mechanics techniques.
RESULTS
Histologic analysis showed an increase in total cell infiltration and mucus staining around the airways leading to an increased inflammatory score in ovarectomized (OVX) animals with steady-state estrogen pellets (OVX-E2-OVA) as compared to other groups including female-sham operated (F-INTACT-OVA) and OVX implanted with a placebo pellet (OVX-Pl-OVA). Airway resistance (Rrs) and lung elastance (Ers) were increased in OVX-E2-OVA in comparison to F-INTACT-OVA following aerosolized intratracheal methacholine challenges. Immune phenotyping revealed that steady-state estrogen reduced CD3+ T cells, CD19+ B cells, ILC2 and eosinophils in the BAL across all experiments. While these commonly described allergic cells were reduced in the BAL, or airways, we found no changes in neutrophils, CD3+ T cells or CD19+ B cells in the remaining lung tissue. Similarly, inflammatory cytokines (IL-5 and IL-13) were also decreased in OVX-E2-OVA-treated animals in comparison to Female-INTACT-OVA mice in the BAL, but in the lung tissue IL-5, IL-13 and IL-33 were comparable in OVX-E2-OVA and F-INTACT OVA mice. ILC2 were sorted from the lungs and stimulated with exogenous IL-33. These ILC2 had reduced cytokine and chemokine expression when they were isolated from OVX-E2-OVA animals, indicating that steady-state estrogen suppresses IL-33-mediated activation of ILC2.
CONCLUSIONS
Therapeutically targeting estrogen receptors may have a limiting effect on eosinophils, ILC2 and potentially other immune populations that may improve asthma symptoms in those females that experience perimenstrual worsening of asthma, with the caveat, that long-term use of estrogens or hormone receptor modulators may be detrimental to the lung microenvironment over time.
Topics: Female; Animals; Mice; Interleukin-33; Estradiol; Immunity, Innate; Interleukin-13; Methacholine Chloride; Allergens; Airway Resistance; Interleukin-5; Bronchoalveolar Lavage Fluid; Lymphocytes; Lung; Asthma; Cytokines; Estrogens
PubMed: 36609358
DOI: 10.1186/s13293-022-00483-7 -
Pulmonary Pharmacology & Therapeutics Feb 2023Allergic asthma is a heterogeneous disease involving a variety of inflammatory cells. Immune imbalance or changes in the immune microenvironment are the essential causes...
Allergic asthma is a heterogeneous disease involving a variety of inflammatory cells. Immune imbalance or changes in the immune microenvironment are the essential causes that promote inflammation in allergic asthma. Tetraspanin CD81 can be used as a platform for receptor clustering and signal transmission owing to its special transmembrane structure and is known to participate in the physiological processes of cell proliferation, differentiation, adhesion, and migration. Previous studies have shown that CD81-targeting peptidomimetics exhibit anti-allergic lung inflammation. However, due to the low metabolic stability of peptide drugs, their druggability is limited. Here, we aimed to generate a metabolically stable anti-CD81 peptide, evaluate its anti-inflammatory action and establish its mechanism of action. Based on previous reports, we applied retro-inverse peptide modification to obtain a new compound, PD00 (NH2-D-Gly-D-Ser-D-Thr-D-Tyr-D-Thr-D-Gln-D-Gly-COOH), with high metabolic stability. Enhanced ultraperformance liquid chromatography-tandem mass spectrometry was used to investigate the in vitro and in vivo metabolic stabilities of PD00. The affinities of PD00 and CD81 were studied using molecular docking and surface plasmon resonance techniques. An ovalbumin (OVA)-induced asthma model was used to evaluate the effects of PD00 in vivo. Mice were treated with different concentrations of PD00 (175 and 350 μg/kg) for 10 days. Airway hyperresponsiveness (AHR) to acetyl-β-methacholine (Mch), inflammatory cell counts in the bronchoalveolar lavage fluid, and serum OVA-specific IgE levels were detected in the mice at the end of the experiment. Lung tissues were collected for haematoxylin and eosin staining, untargeted metabolomic analysis, and single-cell transcriptome sequencing. PD00 has a high affinity for CD81; therefore, administration of PD00 markedly ameliorated AHR and airway inflammation in mice after OVA sensitisation and exposure. Serum OVA-specific IgE levels decreased considerably. In addition, PD00 treatment increased glycerophospholipid and purine metabolism in immune cells. Collectively, PD00 may regulate the glycerophospholipid and purine metabolism pathways to ameliorate the pathophysiological features of asthma. These findings suggest that PD00 is a potential compound for the treatment of asthma.
Topics: Animals; Mice; Ovalbumin; Molecular Docking Simulation; Asthma; Lung; Bronchoalveolar Lavage Fluid; Methacholine Chloride; Inflammation; Immunoglobulin E; Purines; Disease Models, Animal; Mice, Inbred BALB C; Cytokines
PubMed: 36563740
DOI: 10.1016/j.pupt.2022.102185 -
Validation of the clinical utility of sGaw as a response variable in methacholine challenge testing.Respirology (Carlton, Vic.) May 2023Airway hyperresponsiveness (AHR) is commonly assessed by a methacholine challenge test (MCT), during which a provocative concentration causing a 20% reduction in forced...
BACKGROUND AND OBJECTIVE
Airway hyperresponsiveness (AHR) is commonly assessed by a methacholine challenge test (MCT), during which a provocative concentration causing a 20% reduction in forced expiratory volume in 1 second (FEV ) (PC ) < 8 mg/ml is considered a positive response. However, a fall in specific airway conductance (sGaw) may also have clinical significance. The purpose of this study was to assess whether AHR determined by a provocative concentration causing a 40% reduction in sGaw (PC ) < 8 mg/ml corresponds to a clinical diagnosis of asthma.
METHODS
We analysed the changes in spirometry, lung volumes and sGaw during MCT in 211 randomly selected patients being evaluated for AHR to support a clinical diagnosis of asthma.
RESULTS
The mean (SD) age of the group was 53 (15) years, with 141 women (67%). Overall lung function was normal, with FEV = 92 (15) % predicted, total lung capacity = 97 (13) % predicted and sGaw = 0.19 (0.15-0.23) L/s/cm H O/L, (median, 25-75 IQR). There were many more patients who responded by PC only (n = 120) than who responded by PC (n = 52). There was no significant difference in asthma diagnosis between the PC (98%) and PC (93%) groups, and we estimate 34% of patients with a diagnosis of asthma would have been classified as having no AHR if only the FEV criterion was used.
CONCLUSION
Changes in sGaw during MCT indicate clinically significant AHR in support of a clinical diagnosis of asthma among patients being evaluated for asthma.
Topics: Humans; Female; Middle Aged; Methacholine Chloride; Bronchoconstrictor Agents; Asthma; Bronchial Provocation Tests; Respiratory Hypersensitivity; Forced Expiratory Volume
PubMed: 36478621
DOI: 10.1111/resp.14431 -
Respirology (Carlton, Vic.) Mar 2023
Topics: Humans; Methacholine Chloride; Asthma; Bronchial Provocation Tests
PubMed: 36411237
DOI: 10.1111/resp.14416 -
Scientific Reports Oct 2022Cholinergic urticaria (CholU) is classified into several subtypes: (1) conventional sweat allergy-type CholU (conventional SAT-CholU), (2) CholU with palpebral...
Cholinergic urticaria (CholU) is classified into several subtypes: (1) conventional sweat allergy-type CholU (conventional SAT-CholU), (2) CholU with palpebral angioedema (CholU-PA), 3) CholU with acquired anhidrosis and/or hypohidrosis (CholU-Anhd); 1) and 2) include SAT based on pathogenesis. There have been no studies on differences in the prevalence of bronchial asthma among the subtypes. We analyzed bronchial responsiveness using the methacholine dose indicator D, respiratory symptoms, and exhaled nitric oxide (FeNO). Median log10 D (interquartile range) of patients with conventional SAT-CholU (n = 11), CholU-PA (n = 11), and CholU-Anhd (n = 11) was 0.381 (- 0.829, 1.079), 0.717 (0.249, 0.787), and 1.318 (0.121, 1.699), respectively (p = 0.516). Respiratory symptoms were less frequently observed in CholU-Anhd than in conventional SAT-CholU or CholU-PA. FeNO of patients with conventional SAT-CholU, CholU-PA, and CholU-Anhd was 23 (18.5, 65.0), 39 (32.0, 59.5), and 25 (19.0, 33.0) ppb, respectively (p = 0.237). Nine% of conventional SAT-CholU patients and more than half of CholU-PA patients required treatment for asthma. Log D tended to be lower in patients with SAT-CholU than in those with CholU-Anhd. CholU-PA might be associated with asthma.
Topics: Humans; Cross-Sectional Studies; Bronchial Hyperreactivity; Methacholine Chloride; Urticaria; Asthma; Nitric Oxide; Cholinergic Agents
PubMed: 36302805
DOI: 10.1038/s41598-022-22655-6 -
American Journal of Physiology.... Dec 2022Interleukin (IL)-11, a multifunctional cytokine, contributes to numerous biological processes, including adipogenesis, hematopoiesis, and inflammation. Asthma, a...
Interleukin (IL)-11, a multifunctional cytokine, contributes to numerous biological processes, including adipogenesis, hematopoiesis, and inflammation. Asthma, a respiratory disease, is notably characterized by reversible airway obstruction, persistent lung inflammation, and airway hyperresponsiveness (AHR). Nasal insufflation of IL-11 causes AHR in wild-type mice while lung inflammation induced by antigen sensitization and challenge, which mimics features of atopic asthma in humans, is attenuated in mice genetically deficient in IL-11 receptor subunit α-1 (IL-11Rα1-deficient mice), a transmembrane receptor that is required conjointly with glycoprotein 130 to transduce IL-11 signaling. Nevertheless, the contribution of IL-11Rα1 to characteristics of nonatopic asthma is unknown. Thus, based on the aforementioned observations, we hypothesized that genetic deficiency of IL-11Rα1 attenuates lung inflammation and increases airway responsiveness after acute inhalation exposure to ozone (O), a criteria pollutant and nonatopic asthma stimulus. Accordingly, 4 and/or 24 h after cessation of exposure to filtered room air or O, we assessed lung inflammation and airway responsiveness in wild-type and IL-11Rα1-deficient mice. With the exception of bronchoalveolar lavage macrophages and adiponectin, which were significantly increased and decreased, respectively, in O-exposed IL-11Rα1-deficient as compared with O-exposed wild-type mice, no other genotype-related differences in lung inflammation indices that we quantified were observed in O-exposed mice. However, airway responsiveness to acetyl-β-methylcholine chloride (methacholine) was significantly diminished in IL-11Rα1-deficient as compared with wild-type mice after O exposure. In conclusion, these results demonstrate that IL-11Rα1 minimally contributes to lung inflammation but is required for maximal airway responsiveness to methacholine in a mouse model of nonatopic asthma.
Topics: Humans; Mice; Animals; Methacholine Chloride; Ozone; Interleukin-11; Asthma; Pneumonia; Receptors, Interleukin-11; Bronchoalveolar Lavage Fluid
PubMed: 36283092
DOI: 10.1152/ajpregu.00213.2022