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American Journal of Respiratory Cell... Apr 2024Bronchopulmonary dysplasia (BPD), the chronic lung disease of prematurity, is characterized by impaired lung development with sustained functional abnormalities due to...
Bronchopulmonary dysplasia (BPD), the chronic lung disease of prematurity, is characterized by impaired lung development with sustained functional abnormalities due to alterations of airways and the distal lung. Although clinical studies have shown striking associations between antenatal stress and BPD, little is known about the underlying pathogenetic mechanisms. Whether dysanapsis, the concept of discordant growth of the airways and parenchyma, contributes to late respiratory disease as a result of antenatal stress is unknown. We hypothesized that antenatal endotoxin (ETX) impairs juvenile lung function as a result of altered central airway and distal lung structure, suggesting the presence of dysanapsis in this preclinical BPD model. Fetal rats were exposed to intraamniotic ETX (10 μg) or saline solution (control) 2 days before term. We performed extensive structural and functional evaluation of the proximal airways and distal lung in 2-week-old rats. Distal lung structure was quantified by stereology. Conducting airway diameters were measured using micro-computed tomography. Lung function was assessed during invasive ventilation to quantify baseline mechanics, response to methacholine challenge, and spirometry. ETX-exposed pups exhibited distal lung simplification, decreased alveolar surface area, and decreased parenchyma-airway attachments. ETX-exposed pups exhibited decreased tracheal and second- and third-generation airway diameters. ETX increased respiratory system resistance and decreased lung compliance at baseline. Only Newtonian resistance, specific to large airways, exhibited increased methacholine reactivity in ETX-exposed pups compared with controls. ETX-exposed pups had a decreased ratio of FEV in 0.1 second to FVC and a normal FEV in 0.1 second, paralleling the clinical definition of dysanapsis. Antenatal ETX causes abnormalities of the central airways and distal lung growth, suggesting that dysanapsis contributes to abnormal lung function in juvenile rats.
Topics: Rats; Animals; Female; Pregnancy; Bronchopulmonary Dysplasia; Endotoxins; Methacholine Chloride; X-Ray Microtomography; Rats, Sprague-Dawley; Animals, Newborn; Lung
PubMed: 38207120
DOI: 10.1165/rcmb.2023-0157OC -
Clinical and Experimental Allergy :... May 2020The relationship of airway hyperresponsiveness to airway remodeling and inflammation in infants with wheeze is unclear. (Clinical Trial)
Clinical Trial
BACKGROUND
The relationship of airway hyperresponsiveness to airway remodeling and inflammation in infants with wheeze is unclear.
OBJECTIVE
To investigate airway hyperresponsiveness, remodeling and inflammation in infants with wheeze and troublesome breathing.
METHODS
Inclusion criteria were as follows: full-term, 3-23 months of age; doctor -diagnosed wheeze and persistent recurrent troublesome breathing; without obvious structural defect, suspicion of ciliary dyskinesia, cystic fibrosis, immune deficiency or specified use of corticosteroids. Airway hyperresponsiveness (AHR) was evaluated by performing a methacholine bronchial challenge test combined with whole body plethysmography and rapid thoracoabdominal compression. Endobronchial biopsies were analysed for remodeling (thickness of reticular basement membrane and amount of airway smooth muscle) and for inflammation (numbers of inflammatory cells). Correlation analyses were performed.
RESULTS
Forty-nine infants fulfilled the inclusion criteria for the present study. Median age was 1.06 years (IQR 0.6; 1.5). Lung function was impaired in 39/49 (80%) children, at the median age of 1.1 years. Methacholine challenge was successfully performed in 38/49 children. Impaired baseline lung function was correlated with AHR (P = .047, Spearman). In children with the most sensitive quartile of AHR, the percentage of median bronchial airway smooth muscle % and the number of bronchial mast cells in airway smooth muscle were not significantly higher compared to others (P = .057 and 0.056, respectively). No association was found between AHR and thickness of reticular basement membrane or inflammatory cells. Only a small group of children with both atopy and AHR (the most reactive quartile) had thicker airway smooth muscle area than non-atopics with AHR (P = .031).
CONCLUSIONS AND CLINICAL RELEVANCE
These findings do not support the concept that AHR in very young children with wheeze is determined by eosinophilic inflammation or clear-cut remodeling although it is associated with impaired baseline lung function. The possible association of increased airway smooth muscle area among atopic children with AHR remains to be confirmed.
Topics: Airway Remodeling; Asthma; Eosinophils; Female; Humans; Infant; Inflammation; Male; Methacholine Chloride; Muscle, Smooth; Respiratory Sounds
PubMed: 32159879
DOI: 10.1111/cea.13598 -
Respiratory Medicine Jan 2020Although the methacholine challenge test is useful in the diagnosis of asthma, it is time-consuming in children. While protocols that quadruple methacholine...
RATIONALE
Although the methacholine challenge test is useful in the diagnosis of asthma, it is time-consuming in children. While protocols that quadruple methacholine concentrations are widely used in adults to shorten testing time, this has not been evaluated in children. Studies have not identified predictors associated with the safe use of a quadrupled concentration protocol.
OBJECTIVES
To identify clinical predictors associated with the preclusion of a quadrupled concentration protocol in children.
METHODS
We included subjects <18 years who performed a methacholine challenge tests between April 2016 to February 2017 (derivation cohort) and March 2017 to September 2017 (validation cohort). We determined the eligibility of a subject to omit the 0.5 mg/ml and 2.0 mg/ml concentrations based on their PC20 and identified baseline characteristics that are associated with the preclusion of the quadrupled protocol using bivariate analysis. The derived algorithm was applied to the validation cohort.
RESULTS
We included 399 and 195 patients in the derivation and validation cohorts, respectively. A baseline FEV ≤90% predicted, FEV/FVC ≤0.8, FEF ≤70% predicted, and a decrease in FEV ≥10% with the previous concentration significantly precluded the omission of the 0.5 mg/ml concentration. A baseline FEF ≤70% predicted and a drop in FEV ≥10% with the previous concentration significantly precluded the omission of the 2.0 mg/ml concentration. Applying these 4 criteria to the validation cohort resulted in an overall sensitivity and specificity of 74.0% and 84.6%, respectively.
CONCLUSIONS
We identified objective pulmonary function measures that may personalize and shorten the methacholine challenge protocol in children by quadrupling concentrations.
Topics: Adolescent; Asthma; Child; Cohort Studies; Female; Forced Expiratory Volume; Humans; Male; Methacholine Chloride; Predictive Value of Tests; Retrospective Studies; Time Factors
PubMed: 31756408
DOI: 10.1016/j.rmed.2019.105823 -
Pediatric Pulmonology Jun 2022Lung ultrasound (LUS) has been shown to be a useful clinical tool in pediatrics, but very little is known about the LUS findings of asthma in children.
BACKGROUND
Lung ultrasound (LUS) has been shown to be a useful clinical tool in pediatrics, but very little is known about the LUS findings of asthma in children.
OBJECTIVES
The primary objective was to characterize LUS findings of pediatric patients before and after a chemically induced bronchospasm. The secondary objective was to evaluate the effect of bronchodilators on LUS findings.
METHODS
Eligible children 6-17 years old presenting for a methacholine challenge test (MCT) in a pediatric respiratory clinic were recruited. Patients with viral symptoms were excluded. A six-zone LUS protocol was performed before and after the MCT, and after bronchodilator administration; video recordings were analysed by an expert blinded to the patient characteristics and MCT results.
RESULTS
Forty-four patients were included in the study. Five patients had positive LUS findings at baseline. Nine patients out of 29 (31%) had new-onset positive LUS following a reactive MCT. There was a significant association between having a chemically induced bronchospasm and a positive LUS post-MCT (odds ratio [95% confidence interval]: 5.3 [1.0-27.7]; p = 0.05). Among patients who developed positive LUS findings post-MCT, four out of nine returned to having a negative LUS postbronchodilator administration.
CONCLUSIONS
This is the first known report of an association between LUS findings and bronchospasm in pediatric patients. It is also the first documentation of resolution of LUS findings postbronchodilator administration. Most LUS findings observed were small and limited to a few intercostal spaces. Further research is required to quantify these findings and evaluate the effect of salbutamol on LUS.
Topics: Adolescent; Bronchial Provocation Tests; Bronchial Spasm; Bronchodilator Agents; Child; Humans; Lung; Methacholine Chloride; Pediatrics; Ultrasonography
PubMed: 35355448
DOI: 10.1002/ppul.25907 -
Respiratory Physiology & Neurobiology Jan 2023Clinical case series suggest beneficial effects of low-dose intermittent hypoxia in asthma. We tested cardiopulmonary effects of repetitive acute hypoxic preconditioning...
Clinical case series suggest beneficial effects of low-dose intermittent hypoxia in asthma. We tested cardiopulmonary effects of repetitive acute hypoxic preconditioning (RAHP) during allergic inflammation. Brown Norway rats were sensitized to house dust mites (HDM) and exposed to 4-week RAHP or normoxia (SHAM), concurrent with weekly HDM or saline (SAL) challenges. We assessed methacholine responses and lung HIF-1α expression at endpoint, and weekly blood pressure (BP). RAHP relative to SHAM: 1) in HDM-challenged rats, showed no protection against HDM-induced airway dysfunction and did not significantly impact BP (week 4 mean BP difference = 10.51 mmHg, p = 0.09) or HIF-1α expression; 2) in SAL-challenged rats, attenuated airway responses to methacholine, reduced BP (week 4 mean BP average difference = -8.72 mmHg, p = 0.04) and amplified HIF-1α expression (p = 0.0086). Four weeks of RAHP did not mitigate the allergen-induced lower airway dysfunction and may detrimentally affect BP. However, it elicited beneficial cardiopulmonary responses in SAL-challenged rats, concurrent with increased HIF-1α expression.
Topics: Rats; Animals; Allergens; Methacholine Chloride; Pyroglyphidae; Hypoxia; Lung
PubMed: 36332748
DOI: 10.1016/j.resp.2022.103982 -
American Journal of Physiology. Lung... Dec 2021Increased insulin is associated with obesity-related airway hyperreactivity and asthma. We tested whether the use of metformin, an antidiabetic drug used to reduce...
Increased insulin is associated with obesity-related airway hyperreactivity and asthma. We tested whether the use of metformin, an antidiabetic drug used to reduce insulin resistance, can reduce circulating insulin, thereby preventing airway hyperreactivity in rats with dietary obesity. Male and female rats were fed a high- or low-fat diet for 5 wk. Some male rats were simultaneously treated with metformin (100 mg/kg orally). In separate experiments, after 5 wk of a high-fat diet, some rats were switched to a low-fat diet, whereas others continued a high-fat diet for an additional 5 wk. Bronchoconstriction and bradycardia in response to bilateral electrical vagus nerve stimulation or to inhaled methacholine were measured in anesthetized and vagotomized rats. Body weight, body fat, caloric intake, fasting glucose, and insulin were measured. Vagally induced bronchoconstriction was potentiated only in male rats on a high-fat diet. Males gained more body weight, body fat, and had increased levels of fasting insulin compared with females. Metformin prevented development of vagally induced airway hyperreactivity in male rats on high-fat diet, in addition to inhibiting weight gain, fat gain, and increased insulin. In contrast, switching rats to a low-fat diet for 5 wk reduced body weight and body fat, but it did not reverse fasting glucose, fasting insulin, or potentiation of vagally induced airway hyperreactivity. These data suggest that medications that target insulin may be effective treatment for obesity-related asthma.
Topics: Animals; Asthma; Bronchial Hyperreactivity; Bronchoconstriction; Bronchoconstrictor Agents; Diet, High-Fat; Female; Glucose; Hyperinsulinism; Hypoglycemic Agents; Male; Metformin; Methacholine Chloride; Obesity; Rats; Rats, Sprague-Dawley; Vagus Nerve; Weight Gain
PubMed: 34668415
DOI: 10.1152/ajplung.00202.2021 -
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 -
Scientific Reports Feb 2020Mechanisms mediating the protective effects of molecular hydrogen (H) are not well understood. This study explored the possibility that H exerts its anti-inflammatory... (Observational Study)
Observational Study
Mechanisms mediating the protective effects of molecular hydrogen (H) are not well understood. This study explored the possibility that H exerts its anti-inflammatory effect by modulating energy metabolic pathway switch. Activities of glycolytic and mitochondrial oxidative phosphorylation systems were assessed in asthmatic patients and in mouse model of allergic airway inflammation. The effects of hydrogen treatment on airway inflammation and on changes in activities of these two pathways were evaluated. Monocytes from asthmatic patients and lungs from ovalbumin-sensitized and challenged mice had increased lactate production and glycolytic enzyme activities (enhanced glycolysis), accompanied by decreased ATP production and mitochondrial respiratory chain complex I and III activities (suppressed mitochondrial oxidative phosphorylation), indicating an energy metabolic pathway switch. Treatment of ovalbumin-sensitized and challenged mice with hydrogen reversed the energy metabolic pathway switch, and mitigated airway inflammation. Hydrogen abrogated ovalbumin sensitization and challenge-induced upregulation of glycolytic enzymes and hypoxia-inducible factor-1α, and downregulation of mitochondrial respiratory chain complexes and peroxisome proliferator activated receptor-γ coactivator-1α. Hydrogen abrogated ovalbumin sensitization and challenge-induced sirtuins 1, 3, 5 and 6 downregulation. Our data demonstrates that allergic airway inflammation is associated with an energy metabolic pathway switch from oxidative phosphorylation to aerobic glycolysis. Hydrogen inhibits airway inflammation by reversing this switch. Hydrogen regulates energy metabolic reprogramming by acting at multiple levels in the energy metabolism regulation pathways.
Topics: Animals; Asthma; Bronchoconstrictor Agents; Cells, Cultured; Disease Models, Animal; Female; Glycolysis; Humans; Hydrogen; Lactic Acid; Leukocytes, Mononuclear; Lung; Male; Methacholine Chloride; Mice; Middle Aged; Ovalbumin; Oxidative Phosphorylation; Primary Cell Culture
PubMed: 32029879
DOI: 10.1038/s41598-020-58999-0 -
Respiratory Care Aug 2021The spirometric response to fast-acting bronchodilator is used clinically to diagnose asthma and in clinical research to verify its presence. However, bronchodilator...
BACKGROUND
The spirometric response to fast-acting bronchodilator is used clinically to diagnose asthma and in clinical research to verify its presence. However, bronchodilator responsiveness does not correlate with airway hyper-responsiveness measured with the direct-acting stimulus of methacholine, demonstrating that bronchodilator responsiveness is a problematic method for diagnosing asthma. The relationship between bronchodilator responsiveness and airway hyper-responsiveness assessed with indirect-acting stimuli is not known.
METHODS
Retrospectively, the spirometric responses to inhaled bronchodilator and a eucapnic voluntary hyperpnea challenge (EVH) were compared in 39 non-smoking adult subjects with asthma (26 male, 13 female; mean ± SD age 26.9 ± 7.8 y; mean ± SD body mass index 26.3 ± 4.7 kg/m). All subjects met one or both of 2 criteria: ≥ 12% and 200 mL increase in FEV after inhaled bronchodilator, and ≥ 10% decrease in FEV after an EVH challenge.
RESULTS
Overall, FEV increased by 9.9 ± 7.9% after bronchodilator (3.93 ± 0.97 to 4.28 ± 0.91 L, < .001) and decreased by 23.9 ± 15.0% after the EVH challenge (3.89 ± 0.89 to 2.96 ± 0.88 L, < .001). However, the change in FEV after bronchodilator did not correlate with the change after EVH challenge (r = 0.062, = .71). Significant bronchodilator responsiveness predicted a positive response to EVH challenge in 9 of 33 subjects (sensitivity 27%). Following EVH, the change in FEV strongly correlated with the change in FVC (FEV percent change vs FVC percent change, r = 0.831, < .001; FEV ΔL vs FVC ΔL, r = 0.799, < .001).
CONCLUSIONS
These results extend previous findings that demonstrate a lack of association between bronchodilator responsiveness and methacholine responsiveness. Given the poor concordance between the spirometric response to fast-acting bronchodilator and the EVH challenge, these findings suggest that the airway response to inhaled β-agonist must be interpreted with caution and in the context of its determinants and limitations.
Topics: Adult; Asthma; Bronchial Provocation Tests; Bronchodilator Agents; Female; Forced Expiratory Volume; Humans; Male; Methacholine Chloride; Retrospective Studies; Young Adult
PubMed: 34006592
DOI: 10.4187/respcare.08421 -
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