Search

In this paper, we aimed to explore the potential mechanism underlying atopic dermatitis (AD) and its association with asthma. The BALB/c mice were randomly assigned to three groups, including the vehicle control (VD) group, the AD group, and the treatment (TR) group. The AD mice model was successfully constructed in the AD and TR group. The dermatitis severity scores and skin lesions were significantly increased in AD mice after DNCB application. Airway responsiveness in the AD group was significantly higher than in the TR group. The number of inflammatory cells was increased in skin lesions and bronchoalveolar lavage fluid (BALF) of AD mice. The levels of IL-4, IL-5, IFN-γ, and OVA-IgE in BALF supernatants of mice in the AD group were higher than those in the VC group. All the changes in AD mice were decreased by tacrolimus. These results indicate that AD may be a significant risk factor for atopic asthma development. [ABSTRACT FROM AUTHOR]

Maternal obesity prior to and during pregnancy has been associated with an increased incidence of childhood asthma. As diets rich in saturated fat are linked to obesity and inflammation, we created a murine model to investigate the effect of maternal high-fat diet (HFD) on adult offspring airway hyperreactivity (AHR), a cardinal feature of asthma. Balb/cByJ dams were fed a HFD (60% fat Calories) or normal-fat diet (NFD) (10% fat Calories) from 8 weeks prior to first breeding through their pregnancies. Pups were weaned to either a HFD or NFD (at 4 weeks of age). AHR was measured in the 10-week-old offspring following inhaled methacholine challenge by end-inflation technique. Bronchial alveolar lavage fluid (BALF) was analyzed for cell count, total protein, and IL-6. Offspring of HFD dams weaned to NFD had increased AHR compared to offspring of NFD dams weaned to NFD. Offspring of HFD dams that remained on HFDs had increased AHR compared to offspring of NFD dams weaned to HFDs. Offspring of HFD dams had higher BALF cell counts, higher neutrophil percentage, greater total protein, and IL-6 in the BALF. These results demonstrate that a maternal diet high in saturated fat through pregnancy and lactation plays a key role in programming adult offspring AHR. [ABSTRACT FROM AUTHOR]

Children born to obese mothers are prone to develop asthma and airway hyperresponsiveness, but the mechanisms behind this are unclear. Here we developed a mouse model of maternal diet-induced obesity that recapitulates metabolic abnormalities seen in humans born to obese mothers. Offspring of dams fed a high-fat diet (HFD) showed increased adiposity, hyperinsulinemia, and insulin resistance at 16 wk of age despite being fed only a regular diet (RD). Bronchoconstriction induced by inhaled 5-hydroxytriptamine was also significantly increased in offspring of HFD-fed versus RD-fed dams. Increased bronchoconstriction was blocked by vagotomy, indicating this reflex was mediated by airway nerves. Three-dimensional (3-D) confocal imaging of tracheas collected from 16-wk-old offspring showed that both epithelial sensory innervation and substance P expression were increased in the offspring of HFD-fed dams compared with offspring of RD-fed dams. For the first time, we show that maternal high-fat diet increases airway sensory innervation in offspring, leading to reflex airway hyperresponsiveness. NEW & NOTEWORTHY Our study reveals a novel potential mechanism, by which maternal high-fat diet increases the risk and severity of asthma in offspring. We found that exposure to maternal high-fat diet in mice leads to hyperinnervation of airway sensory nerves and increased reflex bronchoconstriction in offspring fed a regular diet only. These findings have important clinical implications and provide new insights into the pathophysiology of asthma, highlighting the need for preventive strategies in this patient population.

Therapeutic natural products and medicinal herbs has gained popularity. The anti-antigenic action of the plant alkaloid nordihydroguaiaretic acid (NDGA) was studied in ovalbumin (OA)-sensitized guinea pigs. In one series of experiments conscious, non-sedated guinea pigs were challenged with OA aerosol. Specific airway resistance (SR AW ) was monitored using a two-chambered whole-body plethysmograph. OA aerosol increased SR AW above that produced by vehicle administration. Prior NDGA administration by a 1 min 0.9% aerosol (w/vol) attenuated the increase in SR AW resulting from OA challenge. In the anesthetized guinea pig pretreated with indomethacin, pyrilamine and propranolol, intravenous OA injection increased intra-tracheal pressure above vehicle injection. Intravenous NDGA administration (5 mg/kg) reduced the intra-tracheal pressure increases. In a third series of experiments plasma leukotriene C 4 was measured by radio-immunoassay in 3 groups challenged with OA aerosol: vehicle-treated OA-sensitized, OA-sensitized receiving NDGA and vehicle treated guinea pigs. NDGA pretreatment reduced plasma LTC 4 in response to OA challenge in OA sensitized guinea pigs. This study demonstrates that NDGA is an effective antigenic agent when given by aerosol or intravenous injection in either conscious or anesthetized guinea pigs, respectively. The mechanism of action of NDGA is presumed primarily be due to the blockage of 5-lipoxygenase and therefore the synthesis of leukotrienes. [ABSTRACT FROM AUTHOR]

Asthma is a chronic inflammatory disease of the airway with extensive airway remodeling. The ethical issues associated with the studies in asthmatic patients, required development of animal model of asthma. Animal models of asthma can provide valuable information on several features of asthma pathogenesis and treatment. Although these models cannot carry out all clinical features, they are valuable to understand mechanisms of the disease and curative access. Related articles were searched in different databases from September 1994 to April 2016 using; animal model of asthma, animal sensitization, allergen-induced asthma in animals terms. Although there are several reviews on this topic, in the present article, induction of animal model of asthma in different animals, various methods used for this purpose, measured parameters and research purposes were reviewed, which will help investigators to use the appropriate animal, methods, and evaluating parameters depending on their study design. In this study various method used for induction of animal model of asthma in different animals and measured parameters were described, which will help investigators to use the appropriate animal, method and evaluating parameters depending on their study design. [ABSTRACT FROM AUTHOR]

Physiological differences and similarities in asthma and COPD are documented based on respiratory function testing. (1) The airflow reversibility is usually important for the diagnosis of asthma. However, patients with long disease histories may have poor reversibility. The reversibility test in COPD is useful for predicting the treatment response. (2) In some of the stable asthmatic patients without attack, the concave downslope of flow- volume curve is present. In severe COPD, the flow in the second half of the curve is smaller than that of rest- breathing. (3) Inspiratory capacity (IC) is a good estimator of air trapping and of predicting the exercise capacity in COPD or persistent asthma. (4) Peak expiratory flow (PEF) can be an important aid in both diagnosis and monitoring of asthma. PEF is not used in COPD because the main disorder is in the peripheral airway. (5) Measurements of airway responsiveness may help to a diagnosis of asthma. However, many COPD cases also have it. (6) Impulse oscillation system (IOS) revealed that the predominant airway disorders in asthma and COPD are central and peripheral respiratory resistance, respectively. However, some asthma patients have larger values of peripheral component. (7) Dlco reflects the extent of pathological emphysema and it is useful for the follow-up of COPD, whereas Dlco is not decreased in asthma. (8) The patient with widened A-aDO2 and alveolar hypoventilation may lead to the life threatening hypoxia in severe asthma attack or severe COPD. When PaCO2 overcomes PaO2, the patient should immediately be treated by mechanical ventilation.

Background: Recent studies have suggested that allergic rhinitis is closely related to bronchial asthma, reflecting the "one airway-one disease" hypothesis. It is unclear if the effects of pranlukast, a leukotriene-receptor antagonist, are consistent with this hypothesis. Objective: The goal of the study was to determine if pranlukast has effects on the upper and lower airways through a comparison of the effects of fexofenadine and pranlukast on airway hyperresponsiveness in non-asthmatic patients with cedar pollinosis before the Japanese cedar pollen season and during the peak pollen season. Methods: Patients received fexofenadine hydrochloride plus oral mequitazine (fexofenadine group) or pranlukast hydrate plus oral mequitazine (pranlukast group) as an initial treatment. Subsequent changes in airway responsiveness to acetylcholine were measured. Results: Among patients in whom coughing developed during the peak pollen season, airway responsiveness significantly increased in the fexofenadine group. In the pranlukast group, airway responsiveness did not increase significantly, regardless of the presence or absence of coughing. Conclusions: The results indicate that pranlukast hydrate inhibits airway hyperresponsiveness in non-asthmatic patients with Japanese cedar pollinosis. In turn, this suggests that cysteinyl leukotrienes have a role in increased airway responsiveness.

Background and objective Earlier studies on the levels of physical activity in asthma patients compared with controls have yielded varying results. We have previously reported that high versus moderate levels of physical activity were associated with higher prevalence of wheezing, especially in females. Here we studied the levels of physical activity in young patients with asthma and healthy subjects and their effect on asthma control. Methods Four hundred eight physician-diagnosed patients with asthma and 118 controls (10-34 years) answered questions concerning frequency and/or duration of physical activity and undertook the Asthma Control Test ( ACT), spirometry, methacholine challenges and exhaled nitric oxide measurements. Results Asthma patients were more frequently physically active ( P = 0.01) and for longer durations ( P = 0.002) than controls. Highly versus moderately physically active patients with asthma had a higher prevalence of not well-controlled asthma ( ACT < 20) when physical activity was assessed by frequency (40.6% vs 24.1%, P = 0.001) or duration (39.0% vs 21.7%, P < 0.001). This was only seen in females who had reduced ACT items ( P < 0.05). Frequently versus moderately active females had an odds ratio of 4.81 (2.43, 9.51) to have ACT < 20, while no such effect was found in males ( OR 1.18 (0.61, 2.30)) and this interaction was statistically significantly associated with gender ( P = 0.003). No differences in fraction of exhaled nitric oxide or methacholine reactivity were found between moderately and highly physically active females with asthma. Conclusion Young asthma patients were more active than controls. High levels of physical activity were associated with poor asthma control as judged by the ACT in females, but not in males, and this appears unrelated to airway inflammation or responsiveness. [ABSTRACT FROM AUTHOR]

In this review we discuss the potential of a new procedure, termed Bronchial Thermoplasty to prevent serious consequences resulting from excessive airway narrowing. The most important factor in minimizing an asthmatic attack is limiting the degree of smooth muscle shortening. The premise that airway smooth muscle can be either inactivated or obliterated without any long-term alteration of other lung tissues, and that airway function will remain normal, albeit with reduced bronchoconstriction, has now been demonstrated in dogs, a subset of normal subjects, and mild asthmatics. Bronchial Thermoplasty may thus develop into a useful clinical procedure to effectively impair the ability for airway smooth muscle to reach the levels of pathologic narrowing that characterizes an asthma attack. It may also enable more successful treatment of asthma patients who are unresponsive to more conventional therapies. Whether this will remain stable for the lifetime of the patient still remains to be determined, but at the present time, there are no indications that the smooth muscle contractility will return. This successful preliminary experience showing that Bronchial Thermoplasty could be safely performed in patients with asthma has led to an ongoing clinical trial at a number of sites in Europe and North America designed to examine the effectiveness of this procedure in subjects with moderately severe asthma.

The purpose of this study was to determine if the amount of physical activity influences airway sensitivity and bronchodilation in healthy subjects across a range of physical activity levels. Thirty healthy subjects (age, 21.9 ± 2.6 years; 13 men/17 women) with normal pulmonary function reported to the laboratory on 2 separate occasions where they were randomized to breathe either hypertonic saline (HS) (nebulized hypertonic saline (25%) for 20 min) or HS followed by 5 deep inspirations (DIs), which has been reported to bronchodilate the airways. Pulmonary function tests (PFTs) were performed prior to both conditions and following the HS breathing or 5 DIs. Moderate to vigorous physical activity (MVPA) level was measured via accelerometer worn for 7 days. Following the HS breathing, forced expiratory volume in 1 s (FEV1) and forced vital capacity (FVC) significantly decreased from baseline by -11.8% ± 8.4% and -9.3% ± 6.7%, respectively. A 2-segment linear model determined significant relationships between MVPA and percent change in FEV1 ( r = 0.50) and FVC ( r = 0.55). MVPA above ∼497 and ∼500 min/week for FEV1 and FVC, respectively, resulted in minor additional improvements ( p > 0.05) in PFTs following the HS breathing. Following the DIs, FEV1 and FVC decreased ( p < 0.05) by -7.3% ± 8.6% and -5.7% ± 5.7%, respectively, from baseline, but were not related ( p > 0.05) to MVPA. In conclusion, these data demonstrate that higher MVPA levels attenuated airway sensitivity but not bronchodilation in healthy subjects. [ABSTRACT FROM AUTHOR]

Acute exposure to ozone (O3), an air pollutant, causes pulmonary inflammation, airway epithelial desquamation, and airway hyperresponsiveness (AHR). Pro-inflammatory cytokines--including IL-6 and ligands of chemokine (C-X-C motif) receptor 2 [keratinocyte chemoattractant (KC) and macrophage inflammatory protein (MIP)-2], TNF receptor 1 and 2 (TNF), and type I IL-1 receptor (IL-1α and IL-1β)--promote these sequelae. Human resistin, a pleiotropic hormone and cytokine, induces expression of IL-1α, IL-1β, IL-6, IL-8 (the human ortholog of murine KC and MIP-2), and TNF. Functional differences exist between human and murine resistin; yet given the aforementioned observations, we hypothesized that murine resistin promotes O3-induced lung pathology by inducing expression of the same inflammatory cytokines as human resistin. Consequently, we examined indexes of O3-induced lung pathology in wild-type and resistin-deficient mice following acute exposure to either filtered room air or O3. In wild-type mice, O3 increased bronchoalveolar lavage fluid (BALF) resistin. Furthermore, O3 increased lung tissue or BALF IL-1α, IL-6, KC, TNF, macrophages, neutrophils, and epithelial cells in wild-type and resistin-deficient mice. With the exception of KC, which was significantly greater in resistin-deficient compared with wild-type mice, no genotype-related differences in the other indexes existed following O3 exposure. O3 caused AHR to acetyl-β-methylcholine chloride (methacholine) in wild-type and resistin-deficient mice. However, genotype-related differences in airway responsiveness to methacholine were nonexistent subsequent to O3 exposure. Taken together, these data demonstrate that murine resistin is increased in the lungs of wild-type mice following acute O3 exposure but does not promote O3-induced lung pathology. [ABSTRACT FROM AUTHOR]

Tissue transglutaminase 2 (TG2) is an enzyme with multiple functions, including catalysis of serotonin conjugation to proteins (serotonylation). Previous research indicates that TG2 expression is upregulated in human asthma and in the lung endothelium of ovalbumin (OVA)-challenged mice. It is not known whether endothelial cell TG2 is required for allergic inflammation. Therefore, to determine whether endothelial cell TG2 regulates allergic inflammation, mice with an endothelial cell-specific deletion of TG2 were generated, and these mice were sensitized and challenged in the airways with OVA. Deletion of TG2 in endothelial cells blocked OVA-induced serotonylation in lung endothelial cells, but not lung epithelial cells. Interestingly, deletion of endothelial TG2 reduced allergen-induced increases in respiratory system resistance, number of eosinophils in the bronchoalveolar lavage, and number of eosinophils in the lung tissue. Endothelial cell deletion of TG2 did not alter expression of adhesion molecules, cytokines, or chemokines that regulate leukocyte recruitment, consistent with other studies, demonstrating that deletion of endothelial cell signals does not alter lung cytokines and chemokines during allergic inflammation. Taken together, the data indicate that endothelial cell TG2 is required for allergic inflammation by regulating the recruitment of eosinophils into OVA-challenged lungs. In summary, TG2 functions as a critical signal for allergic lung responses. These data identify potential novel targets for intervention in allergy/asthma. [ABSTRACT FROM AUTHOR]

Toxicity of exhaust from combustion of petroleum diesel (B0), soy-based biodiesel (B100), or a 20% biodiesel/80% petrodiesel mix (B20) was compared in healthy and house dust mite (HDM)-allergic mice. Fuel emissions were diluted to target fine particulate matter (PM2.5) concentrations of 50, 150, or 500 μg/m3. Studies in healthy mice showed greater levels of neutrophils and MIP-2 in bronchoalveolar lavage (BAL) fluid 2 h after a single 4-h exposure to B0 compared with mice exposed to B20 or B100. No consistent differences in BAL cells and biochemistry, or hematological parameters, were observed after 5 d or 4 weeks of exposure to any of the emissions. Air-exposed HDM-allergic mice had significantly increased responsiveness to methacholine aerosol challenge compared with non-allergic mice. Exposure to any of the emissions for 4 weeks did not further increase responsiveness in either non-allergic or HDM-allergic mice, and few parameters of allergic inflammation in BAL fluid were altered. Lung and nasal pathology were not significantly different among B0-, B20-, or B100-exposed groups. In HDM-allergic mice, exposure to B0, but not B20 or B100, significantly increased resting peribronchiolar lymph node cell proliferation and production of TH2 cytokines (IL-4, IL-5, and IL-13) and IL-17 in comparison with air-exposed allergic mice. These results suggest that diesel exhaust at a relatively high concentration (500 μg/m3) can induce inflammation acutely in healthy mice and exacerbate some components of allergic responses, while comparable concentrations of B20 or B100 soy biodiesel fuels did not elicit responses different from those caused by air exposure alone. [ABSTRACT FROM AUTHOR]

The dystrophin-glycoprotein complex (DGC) is an integral part of caveolae microdomains, and its interaction with caveolin-1 is essential for the phenotype and functional properties of airway smooth muscle (ASM). The sarcoglycan complex provides stability to the dystroglycan complex, but its role in ASM contraction and lung physiology in not understood. We tested whether δ-sarcoglycan (δ-SG), through its interaction with the DGC, is a determinant of ASM contraction ex vivo and airway mechanics in vivo. We measured methacholine (MCh)-induced isometric contraction and airway mechanics in δ-SG KO and wild-type mice. Last, we performed immunoblotting and transmission electron microscopy to assess DGC protein expression and the ultrastructural features of tracheal smooth muscle. Our results reveal an age-dependent reduction in the MCh-induced tracheal isometric force and significant reduction in airway resistance at high concentrations of MCh (50.0 mg/mL) in δ-SG KO mice. The changes in contraction and lung function correlated with decreased caveolin-1 and β-dystroglycan abundance, as well as an age-dependent loss of caveolae in the cell membrane of tracheal smooth muscle in δ-SG KO mice. Collectively, these results confirm and extend understanding of a functional role for the DGC in the contractile properties of ASM and demonstrate that this results in altered lung function in vivo. [ABSTRACT FROM AUTHOR]

Copyright of Canadian Journal of Physiology & Pharmacology is the property of Canadian Science Publishing and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Controlled human exposure studies evaluating the effect of inhaled nitrogen dioxide (NO2) on the inherent responsiveness of the airways to challenge by broncho-constricting agents have had mixed results. In general, existing meta-analyses show statistically significant effects of NO2 on the airway responsiveness of individuals with asthma. However, no meta-analysis has provided a comprehensive assessment of the clinical relevance of changes in airway responsiveness, the potential for methodological biases in the original papers, and the distribution of responses. This paper provides analyses showing that a statistically significant fraction (i.e. 70% of individuals with asthma exposed to NO2 at rest) experience increases in airway responsiveness following 30-min exposures to NO2 in the range of 200 to 300 ppb and following 60-min exposures to 100 ppb. The distribution of changes in airway responsiveness is log-normally distributed with a median change of 0.75 (provocative dose following NO2 divided by provocative dose following filtered air exposure) and geometric standard deviation of 1.88. About a quarter of the exposed individuals experience a clinically relevant reduction in their provocative dose due to NO2 relative to air exposure. The fraction experiencing an increase in responsiveness was statistically significant and robust to exclusion of individual studies. Results showed minimal change in airway responsiveness for individuals exposed to NO2 during exercise. [ABSTRACT FROM AUTHOR]

Background: Inhalation of diesel exhaust (DE) at moderate concentrations causes increased airway responsiveness in asthmatics and increased airway resistance in both healthy and asthmatic subjects, but the effect of baseline airway responsiveness and anti-oxidant supplementation on this dynamic is unknown. Objectives: We aimed to determine if changes in airway responsiveness due to DE are attenuated by thiol anti-oxidant supplementation, particularly in those with underlying airway hyper-responsiveness. Methods: Participants took N-acetylcysteine (600 mg) or placebo capsules three times daily for 6 days. On the last of these 6 days, participants were exposed for 2 h to either filtered air (FA) or DE (300 μg/m3 of particulate matter smaller than 2.5 microns). Twenty-six non-smokers were studied under each of three experimental conditions (filtered air with placebo, diesel exhaust with placebo, and diesel exhaust with N-acetylcysteine) using a randomized, double-blind, crossover design, with a 2-week washout between conditions. Methacholine challenge was performed pre-exposure (baseline airway responsiveness) and post-exposure (effect of exposure). Results: Anti-oxidant supplementation reduced baseline airway responsiveness in hyper-responsive individuals by 20% (p = 0.001). In hyper-responsive individuals, airway responsiveness increased 42% following DE compared with FA (p = 0.03) and this increase was abrogated with anti-oxidant supplementation (diesel exhaust with N-acetylcysteine vs. filtered air with placebo, p = 0.85). Conclusions: Anti-oxidant (N-acetylcysteine) supplementation protects against increased airway responsiveness associated with DE inhalation and reduces need for supplement bronchodilators in those with baseline airway hyper-responsiveness. Individuals with variants in genes of oxidative stress metabolism when exposed to DE are protected from increases in airway responsiveness if taking anti-oxidant supplementation. [ABSTRACT FROM PUBLISHER]

Aspergillus fumigatus is often associated in asthmatic patients with the exacerbation of asthma symptoms. The pathomechanism of this phenomenon has not been fully understood. Here, we evaluated the immunological mechanisms and the role of the prostaglandin D2/ Chemoattractant Receptor-Homologous Molecule Expressed on Th2 Cells (CRTH2) pathway in the development of Aspergillus-associated asthma exacerbation. We studied the effects of A. fumigatus on airway inflammation and bronchial hyper-responsiveness in a rat model of chronic asthma. Inhalation delivery of A. fumigatus conidia increased the airway eosinophilia and bronchial hyper-responsiveness in ovalbumin-sensitized, challenged rats. These changes were associated with prostaglandin D2 synthesis and CRTH2 expression in the lungs. Direct inflammation occurred in ovalbumin-sensitized, challenged animals, whereas pre-treatment with an antagonist against CRTH2 nearly completely eliminated the A. fumigatus-induced worsening of airway eosinophilia and bronchial hyper-responsiveness. Our data demonstrate that production of prostaglandin D2 followed by eosinophil recruitment into the airways via a CRTH2 receptor are the major pathogenic factors responsible for the A. fumigatus-induced enhancement of airway inflammation and responsiveness. [ABSTRACT FROM AUTHOR]

Background We recently reported an independent association between Ig E sensitization to food allergens and increased airway inflammation, assessed by fraction of exhaled nitric oxide (Fe NO), in a population-based study ( J Allergy Clin Immunol, 130, 2012, 397). Similar studies have not been performed in populations with asthma. The aim of the present study was to investigate the allergic sensitization profile in asthmatics and examine Fe NO, airway responsiveness and blood eosinophilia in relation to type and degree of Ig E sensitization. Method Fe NO, airway responsiveness, blood eosinophil count ( B- Eos) and Ig E sensitization to food allergens and aeroallergens were determined in 408 subjects with asthma, aged 10-34 years. Results Asthmatics had higher prevalence of Ig E sensitization against all allergens than controls ( P < 0.001). Mite, pollen, furry animal, mould and food sensitizations were each associated with increased Fe NO, airway responsiveness and B- Eos in asthmatics. Ig E sensitization to mould, furry animals and food allergens was independently related to Fe NO (all P < 0.05) after adjustment for age, sex, height, smoking history and medication. Ig E sensitization to mould ( P < 0.001) and furry animals ( P = 0.02) was related to airway responsiveness in a similar model. Finally, Ig E sensitization to mould ( P = 0.001), furry animals ( P < 0.001) and food allergens ( P < 0.001) was independently related to B- Eos. Conclusion Independent effects of Ig E sensitization to aeroallergens (furry animals and mould) and food allergens were found on both local and systemic markers of inflammation in asthma. The finding regarding food Ig E sensitization is novel, and a clinical implication might be that even food sensitization must be assessed to fully understand inflammation patterns in asthma. [ABSTRACT FROM AUTHOR]