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The main results of the present study are as follows: 1) breathing gas mixtures containing 2% or 4% CO2significantly attenuated bronchoconstrictor responses to methacholine, not differently in healthy subjects and subjects with mild asthma, and 2) the causal inhibitory effect of CO2was significantly mediated via an indirect effect of the increment of V̇e in response to intrapulmonary hypercapnia.

The degree of airway responsiveness is generally measured by directly activating the airway smooth muscle (ASM) with incremental doses of inhaled methacholine. In this context, airway hyperresponsiveness (AHR) is defined as an excessive decline in lung function in response to methacholine. Innate or acquired defects in ASM size and/or contractile capacity are often thought to account for AHR. However, many factors lying between inhaled methacholine and the resulting decrease in lung function alter the degree of airway responsiveness. Herein, I review multiple mechanisms whereby an ASM with a normal size and a normal contractile capacity can trigger AHR when it operates in abnormal airways. Cited examples are restricted to studies published from 2018 to 2021.

Wildland firefighters work on wildfire incidents all over the United States and perform arduous work under extreme work conditions, including exposure to smoke. Wildland fire smoke is a mixture of hazardous air pollutants. For assessing wildland firefighter exposure to smoke, most studies measured carbon monoixde (CO) and particulate matter and reported changes in lung health by measured lung function, airway responsiveness, and respiratory symptoms across individual work shifts and single fire seasons. All fire personnel should understand the hazards of smoke and develop ways to mitigate exposure to smoke.

Background Airway obstruction (AO) in asthma is driven by airway smooth muscle (ASM) contraction. AO can be induced extrinsically by direct stimulation of ASM with contractile agonists as histamine, or by indirect provocation with antigens as ovalbumin, while the airway tone is dependent on intrinsic mechanisms. The association of the ASM phenotypes involved in different types of AO and airway tone in guinea pigs was evaluated. Methods Guinea pigs were sensitized to ovalbumin and challenged with antigen. In each challenge, the maximum OA response to ovalbumin was determined, and before the challenges, the tone of the airways. At third challenge, airway responsiveness (AR) to histamine was evaluated and ASM cells from trachea were disaggregated to determinate: (a) by flow cytometry, the percentage of cells that express transforming growth factor-β1 (TGF-β1), interleukin-13 (IL-13) and sarco-endoplasmic Ca2+ ATPase-2b (SERCA2b), (b) by RT-PCR, the SERCA2B gene expression, (c) by ELISA, reduced glutathione (GSH) and, (d) Ca2+ sarcoplasmic reticulum refilling rate by microfluorometry. Control guinea pig group received saline instead ovalbumin. Results Antigenic challenges in sensitized guinea pigs induced indirect AO, AR to histamine and increment in airway tone at third challenge. No relationship was observed between AO induced by antigen and AR to histamine with changes in airway tone. The extent of antigen-induced AO was associated with both, TGF-β1 expression in ASM and AR degree. The magnitude of AR and antigen-induced AO showed an inverse correlation with GSH levels in ASM. The airway tone showed an inverse association with SERCA2b expression. Conclusions Our data suggest that each type of AO and airway tone depends on different ASM phenotypes: direct and indirect AO seems to be sensitive to the level of oxidative stress; indirect obstruction induced by antigen appears to be influenced by the expression of TGF-β1 and the SERCA2b expression level plays a role in the airway tone.

Obesity is a risk factor for asthma, especially nonatopic asthma, and attenuates the efficacy of standard asthma therapeutics. Obesity also augments pulmonary responses to ozone, a nonatopic asthma trigger. The purpose of this study was to determine whether obesity-related alterations in gut microbiota contribute to these augmented responses to ozone. Ozone-induced increases in airway responsiveness, a canonical feature of asthma, were greater in obese db/db mice than in lean wild-type control mice. Depletion of gut microbiota with a cocktail of antibiotics attenuated obesity-related increases in the response to ozone, indicating a role for microbiota. Moreover, ozone-induced airway hyperresponsiveness was greater in germ-free mice that had been reconstituted with colonic contents of db/db than in wild-type mice. In addition, compared with dietary supplementation with the nonfermentable fiber cellulose, dietary supplementation with the fermentable fiber pectin attenuated obesity-related increases in the pulmonary response to ozone, likely by reducing ozone-induced release of IL-17A. Our data indicate a role for microbiota in obesity-related increases in the response to an asthma trigger and suggest that microbiome-based therapies such as prebiotics may provide an alternative therapeutic strategy for obese patients with asthma.

Background Small plateau (SP) on the flow-volume curve was found in parts of patients with suspected asthma or upper airway abnormalities, but it lacks clear scientific proof. Therefore, we aimed to characterize its clinical features. Methods We involved patients by reviewing the bronchoprovocation test (BPT) and bronchodilator test (BDT) completed between October 2017 and October 2020 to assess the characteristics of the sign. Patients who underwent laryngoscopy were assigned to perform spirometry to analyze the relationship of the sign and upper airway abnormalities. SP-Network was developed to recognition of the sign using flow-volume curves. Results Of 13,661 BPTs and 8,168 BDTs completed, we labeled 2,123 (15.5%) and 219 (2.7%) patients with the sign, respectively. Among them, there were 1,782 (83.9%) with the negative-BPT and 194 (88.6%) with the negative-BDT. Patients with SP sign had higher median FVC and FEV1% predicted (both P P = 0.038). SP-Network achieved an accuracy of 95.2% in the task of automatic recognition of the sign. Conclusions SP sign is featured on the flow-volume curve and recognized by the SP-Network model. Patients with the sign are less likely to have airway hyperresponsiveness, automatic visualizing of this sign is helpful for primary care centers where BPT cannot available.

Asthma is an important cause of subacute cough. The concentration of alveolar nitric oxide (CANO) is a sensitive inflammatory indicator in peripheral airways, and it has received much less attention than the fraction of exhaled nitric oxide (FeNO50). The main objective of this study was to explore the correlation between CANO and clinical parameters in asthmatic and non-asthmatic subacute cough, which might promote understanding of the clinical utility of CANO in these special patient populations. 155 patients with subacute cough were included consecutively, of which 25 were diagnosed as asthmatic. Data for demographic characteristics, FeNO50, CANO, baseline spirometry, bronchial provocation test (or bronchodilation test) and response dose ratio (RDR) were collected. Differences between the asthmatic and non-asthmatic groups were analyzed. Spearman’s correlation coefficient (ρ) was used to evaluate the correlation between FeNO50, CANO and other clinical parameters. In patients with subacute cough, baseline CANO values did not differ between asthmatic and non-asthmatic patients (4.4(1.3, 11.4) versus 4.0(2.1, 6.8) ppb, P > 0.05). Besides, CANO exhibited a stronger association with pulmonary function parameters when compared with FeNO50. For asthmatic subacute cough, CANO was inversely correlated with FEV1/FVC (ρ = −0.69, P < 0.01) and small airway parameters including MEF25 (ρ = −0.47, P < 0.05) and MMEF (ρ = −0.45, P < 0.05). For non-asthmatic subacute cough, CANO was inversely correlated with MEF25 (ρ = −0.19, P < 0.05) and RDR (ρ = −0.21, P < 0.05). In subacute cough, asthmatic and non-asthmatic patients had similar values of baseline CANO. In both asthmatic and non-asthmatic subacute cough, CANO exhibited a stronger association with pulmonary function parameters when compared with FeNO50. A low CANO value in non-asthmatic subacute cough corresponded to a higher value of RDR, which implied a stronger tendency towards airway responsiveness.

Background: The mannitol test is widely used for assessment of airway responsiveness in patients with possible asthma, but our knowledge of the value in everyday clinical practice is limited.Object...

We have previously reported that the mouse gut microbiome contributes to pulmonary responses to ozone, a common asthma trigger, and that short-chain fatty acids, end products of bacterial fermentation, likely contribute to this role of the microbiome. A growing body of evidence indicates that there are sex-related differences in gut microbiota and these differences can have important functional consequences. The purpose of this study was to determine whether there are sex-related differences in the impact of the gut microbiota on pulmonary responses to ozone. After acute exposure to ozone, male mice developed greater airway hyperresponsiveness than female mice. This difference was abolished after antibiotic ablation of the gut microbiome. Moreover, weanling female pups housed in cages conditioned by adult male mice developed greater ozone-induced airway hyperresponsiveness than weanling female pups raised in cages conditioned by adult females. Finally, ad libitum oral administration via drinking water of the short-chain fatty acid propionate resulted in augmented ozone-induced airway hyperresponsiveness in male, but not female, mice. Overall, these data are consistent with the hypothesis that the microbiome contributes to sex differences in ozone-induced airway hyperresponsiveness, likely as a result of sex differences in the response to short-chain fatty acids.

Expression of bronchodilatory β2-adrenoceptors and bronchoconstrictive muscarinic M3-receptors alter with airway size. In COPD, (a combination of) β2-agonists and muscarinic M3-antagonists (anticholinergics) are used as bronchodilators. We studied whether differential receptor expression in large and small airways affects the response to β2-agonists and anticholinergics in COPD. Bronchoprotection by indacaterol (β2-agonist) and glycopyrrolate (anticholinergic) against methacholine- and EFS-induced constrictions of large and small airways was measured in guinea pig and human lung slices using video-assisted microscopy. In guinea pig lung slices, glycopyrrolate (1, 3 and 10 nM) concentration-dependently protected against methacholine- and EFS-induced constrictions, with no differences between large and small intrapulmonary airways. Indacaterol (0.01, 0.1, 1 and 10 μM) also provided concentration-dependent protection, which was greater in large airways against methacholine and in small airways against EFS. Indacaterol (10 μM) and glycopyrrolate (10 nM) normalized small airway hyperresponsiveness in COPD lung slices. Synergy of low indacaterol (10 nM) and glycopyrrolate (1 nM) concentrations was greater in LPS-challenged guinea pigs (COPD model) compared to saline-challenged controls. In conclusion, glycopyrrolate similarly protects large and small airways, whereas the protective effect of indacaterol in the small, but not the large, airways depends on the contractile stimulus used. Moreover, findings in a guinea pig model indicate that the synergistic bronchoprotective effect of indacaterol and glycopyrrolate is enhanced in COPD.

Diabetes has been reported to modulate the airway smooth muscle reactivity and lead to attenuation of allergic inflammatory response in the lungs. In this study, we aimed to study the effect of insulin on cell activation and airway responsiveness in patients with diabetes mellitus (DM). The airway contraction in rat model groups including a non‐DM group, a non‐DM+INDUCTION group, a DM+INDUCTION group and a DM+INDUCTION+INSULIN group was measured to observe the effect of insulin on airway responsiveness. Radioenzymatic assay was conducted to measure the levels of histamine, and ELISA assay was conducted to measure bronchial levels of interleukin (IL)‐1b, tumour necrosis factor (TNF)‐a, cytokine‐induced neutrophil chemoattractant (CINC)‐1, P‐selectin and β‐hexosaminidase. The tension in the main and intrapulmonary bronchi of DM+INDUCTION rats was lower than that of the non‐DM+INDUCTION rats, whereas the treatment of insulin partly restored the normal airway responsiveness to OA in DM rats. The release of histamine was remarkably suppressed in DM+INDUCTION rats but was recovered by the insulin treatment. Also, OA significantly increased the levels of IL‐1b, TNF‐a, CINC‐1 and P‐selectin in non‐DM rats, whereas insulin treatment in DM+INDUCTION rats partly restored the normal levels of IL‐1b, TNF‐a, CINC‐1 and P‐selectin in DM rats. Moreover, the expression of IR and IGF1R was evidently suppressed in DM rats, with the methylation of both IR and IGF1R promoters was aggravated in DM rats. Therefore, we demonstrated that DM‐induced hypermethylation inhibited mast cell activation and airway responsiveness, which could be reversed by insulin treatment.

This chapter aims to examine and describe the evidence regarding the efficacy and mechanism(s) of action of some non-pharmacologic approaches that may serve as adjunct therapies for asthma and exercise-induced bronchospasm (EIB). Several non-pharmacologic strategies could contribute to the management of EIB in athletes. Approximately half of individuals with EIB will experience a reduction in airway responsiveness during repeated exercise. High-salt diets can worsen EIB symptoms in main ways: increasing pulmonary capillary blood volume, causing airway compression, and/or increasing osmolarity of the airway surface liquid which stimulates release of pro-inflammatory mediators, causing airway narrowing. The mechanistic pathways by which EIB is attenuated after different dietary interventions are likely to differ, but it remains unknown if the benefits of different interventions are additive. Despite a current lack of mechanistic confirmation, there is growing evidence that prebiotics and probiotics could be a novel nutritional intervention to improve airway health and target EIB in physically active asthmatics.

Background Obesity augments pulmonary responses to ozone. We have reported that IL-33 contributes to these effects of obesity in db/db mice. The purpose of this study was to determine whether IL-33 also contributes to obesity-related changes in the response to ozone in mice with diet-induced obesity. Methods Male wildtype C57BL/6 mice and mice deficient in ST2, the IL-33 receptor, were placed on chow or high fat diets for 12 weeks from weaning. Because the microbiome has been implicated in obesity-related changes in the pulmonary response to ozone, mice were either housed with other mice of the same genotype (same housed) or with mice of the opposite genotype (cohoused). Cohousing transfers the gut microbiome from one mouse to its cagemates. Results Diet-induced increases in body mass were not affected by ST2 deficiency or cohousing. In same housed mice, ST2 deficiency reduced ozone-induced airway hyperresponsiveness and neutrophil recruitment in chow-fed but not HFD-fed mice even though ST2 deficiency reduced bronchoalveolar lavage IL-5 in both diet groups. In chow-fed mice, cohousing abolished ST2-related reductions in ozone-induced airway hyperresponsiveness and neutrophil recruitment, but in HFD-fed mice, no effect of cohousing on these responses to ozone was observed. In chow-fed mice, ST2 deficiency and cohousing caused changes in the gut microbiome. High fat diet-feeding caused marked changes in the gut microbiome and overrode both ST2-related and cohousing-related differences in the gut microbiome observed in chow-fed mice. Conclusion Our data indicate a role for IL-33 in pulmonary responses to ozone in chow-fed but not high fat diet-fed mice and are consistent with the hypothesis that these diet-related differences in the role of IL-33 are the result of changes in the gut microbiome.

Airway epithelial barrier dysfunction is frequently observed in asthma and may have important implications. The physical barrier function of the airway epithelium is tightly interwoven with its immunomodulatory actions, while abnormal epithelial repair responses may contribute to remodelling of the airway wall. We propose that abnormalities in the airway epithelial barrier play a crucial role in the sensitization to allergens and pathogenesis of asthma. Many of the identified susceptibility genes for asthma are expressed in the airway epithelium, supporting the notion that events at the airway epithelial surface are critical for the development of the disease. However, the exact mechanisms by which the expression of epithelial susceptibility genes translates into a functionally altered response to environmental risk factors of asthma are still unknown. Interactions between genetic factors and epigenetic regulatory mechanisms may be crucial for asthma susceptibility. Understanding these mechanisms may lead to identification of novel targets for asthma intervention by targeting the airway epithelium. Moreover, exciting new insights have come from recent studies using single‐cell RNA sequencing (scRNA‐Seq) to study the airway epithelium in asthma. This review focuses on the role of airway epithelial barrier function in the susceptibility to develop asthma and novel insights in the modulation of epithelial cell dysfunction in asthma.

For convenience, many pediatric hospitals are preparing solutions for continuous nebulized albuterol using the 0.5% 20-ml multidose albuterol dropper bottle. This product contains benzalkonium chloride (BAC) that, by itself, produces bronchospasm that is dose dependent and cumulative. The bronchoconstrictive effects of BAC are greater in patients with more severe airway obstruction and increased airway responsiveness. Use of BAC-containing albuterol during severe acute asthma exacerbations may antagonize the bronchodilator response to albuterol, prolong treatment, and increase the risk of albuterol-related systemic adverse effects. Such a deleterious effect of BAC is difficult to detect because some patients improve slowly or may even worsen during treatment. We recommend that only preservative-free albuterol products be used.

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.

Background Diabetes mellitus causes the deterioration of smooth muscle cells and interstitial matrix proteins, including collagen. Collagen and smooth muscle cells are abundant in the lungs, but the effect of diabetes on airway function and viscoelastic respiratory tissue mechanics has not been characterized. This study investigated the impact of diabetes on respiratory function, bronchial responsiveness, and gas exchange parameters. Methods Rats were allocated randomly to three groups: a model of type 1 diabetes that received a high dose of streptozotocin (DM1, n = 13); a model of type 2 diabetes that received a low dose of streptozotocin with a high-fat diet (DM2, n = 14); and a control group with no treatment (C, n = 14). Forced oscillations were applied to assess airway resistance (Raw), respiratory tissue damping (G), and elastance (H). The arterial partial pressure of oxygen to the inspired oxygen fraction (PaO2/FiO2) and intrapulmonary shunt fraction (Qs/Qt) were determined from blood gas samples at positive end-expiratory pressures (PEEPs) of 0, 3, and 6 cmH2O. Lung responsiveness to methacholine was also assessed. Collagen fibers in lung tissue were quantified by histology. Results The rats in groups DM1 and DM2 exhibited elevated Raw, G, H, and Qs/Qt, compromised PaO2/FiO2, and diminished airway responsiveness. The severity of adverse tissue mechanical change correlated with excessive lung collagen expression. Increased PEEP normalized the respiratory mechanics, but the gas exchange abnormalities remained. Conclusions These findings indicate that diabetes reduces airway and lung tissue viscoelasticity, resulting in alveolar collapsibility that can be compensated by increasing PEEP. Diabetes also induces persistent alveolo-capillary dysfunction and abnormal adaptation ability of the airways to exogenous constrictor stimuli.

Background Interleukin-33 is released in the airways following acute ozone exposure and has the ability to cause airway hyperresponsiveness, a defining feature of asthma. Ozone causes greater airway hyperresponsiveness in male than female mice. Moreover, sex differences in the gut microbiome account for sex differences in this response to ozone. The purpose of this study was to determine whether there were sex differences in the role of interleukin-33 in ozone-induced airway hyperresponsiveness and to examine the role of the microbiome in these events. Methods Wildtype mice and mice genetically deficient in ST2, the interleukin-33 receptor, were housed from weaning with either other mice of the same genotype and sex, or with mice of the same sex but opposite genotype. At 15 weeks of age, fecal pellets were harvested for 16S rRNA sequencing and the mice were then exposed to air or ozone. Airway responsiveness was measured and a bronchoalveolar lavage was performed 24 h after exposure. Results In same-housed mice, ozone-induced airway hyperresponsiveness was greater in male than female wildtype mice. ST2 deficiency reduced ozone-induced airway hyperresponsiveness in male but not female mice and abolished sex differences in the response to ozone. However, sex differences in the role of interleukin-33 were unrelated to type 2 cytokine release: ozone-induced increases in bronchoalveolar lavage interleukin-5 were greater in females than males and ST2 deficiency virtually abolished interleukin-5 in both sexes. Since gut microbiota contribute to sex differences in ozone-induced airway hyperresponsiveness, we examined the role of the microbiome in these ST2-dependent sex differences. To do so, we cohoused wildtype and ST2 deficient mice, a situation that allows for transfer of microbiota among cage-mates. Cohousing altered the gut microbial community structure, as indicated by 16S rRNA gene sequencing of fecal DNA and reversed the effect of ST2 deficiency on pulmonary responses to ozone in male mice. Conclusions The data indicate that the interleukin-33 /ST2 pathway contributes to ozone-induced airway hyperresponsiveness in male mice and suggest that the role of interleukin-33 is mediated at the level of the gut microbiome. Electronic supplementary material The online version of this article (10.1186/s12931-019-1168-x) contains supplementary material, which is available to authorized users.

Obesity is a risk factor for incident asthma and worsens pre-existing asthma symptoms. Prior to 2002, investigators using animal models of asthma never considered obesity as a factor that could influence the development of lung inflammation or airway hyperresponsiveness (AHR), two characteristic features of asthma. In 2002, investigators began to use obese mice to comprehend the effects of obesity on lung inflammation and AHR. In response to either atopic or non-atopic stimuli, investigators consistently demonstrated that obesity exacerbates increases in airway responsiveness but had inconsistent effects on lung inflammation. Therefore, to understand the advantages and disadvantages of using obese mice to study asthma associated with obesity, we subsequently discuss results from animal studies relevant to this subset of asthmatics, including potential mechanisms whereby obesity may either cause or worsen asthma. These studies may ultimately prove fruitful in the identification of new therapies to treat obese asthmatics who are often unresponsive to standard asthma medications.

Not all patients with cough variant asthma (CVA) show responsiveness to bronchodilators (RB) in clinic. Whether there are specific clinical and pathophysiological features can indicate RB in patients with CVA needs further investigation. Thus, we aimed to investigate the RB in patients with CVA and associated factors.Forty-two CVA patients were randomized in a 2:1 ratio to receive oral bambuterol hydrochloride (10 mg, once daily, for 3 days) or matched placebo, 36 patients (24 with bronchodilator and 12 with placebo) completed the study eventually. RB was considered when cough visual analogue scale (VAS) score decreased 30% or more after 3 days treatment. The baseline clinical and pathophysiological characteristics between patients with RB and patients without RB were compared. CRS was presented with the lowest concentration of capsaicin inducing at least 5 coughing (C5).The responsive rate of patients with bronchodilator was significantly higher than that with placebo (62.5% vs 16.7%, p 0.01). Patients with RB showed a significant greater mean decline of FEVMore than one-third of patients with CVA do not respond to bronchodilator treatment, indicating that the response to bronchodilator should not be a diagnostic requirement of CVA. CVA patients with higher airway responsiveness will more likely respond to bronchodilator. Cough of CVA might be elicited by different mechanisms, which suggests that CVA could be divided into two phenotypes according to the response to bronchodilators.

Airway responsiveness and inflammatory markers in non-asthmatic adolescents with elevated FeNO

Background: Serum leptin levels reflect the amount of adipose tissue for a given level of BMI. Knowledge of the association between serum leptin and levels of lung function and airway responsiveness may therefore increase our understanding of the effects of adiposity on airway pathophysiology, also in non-obese subjects. Objective: We aimed to explore, in a random population sample of primarily non-obese subjects, if serum leptin levels were associated with FEV1 and airway responsiveness, also after adjusting for BMI. Methods: We examined the cross-sectional associations between serum leptin levels and measurements of lung function including FEV1 and airway responsiveness to methacholine in 163 free-living individuals aged 27-37 who attended the final visit in the Copenhagen Cohort Study, a random sample population study. Results: Fifty-seven percent of subjects were females and 87% were non-obese (BMI Conclusion: In this cross-sectional population study, increased serum leptin was associated with a low level of FEV1 and increased degree of airway responsiveness to methacholine also after adjustment for BMI. This suggests that serum leptin could be a biomarker superior to BMI to use in future studies that explore the effects of adiposity on airway pathophysiology.

Stretching activated strips of airway smooth muscle (ASM) significantly affects both active force and stiffness due to a temporary reduction of the proportion of cycling myosin cross bridges that are bound to their actin binding sites. For the same reason, stretch applied to ASM in situ by a deep inflation (DI) of the lungs is one of the most potent means of reversing bronchoconstriction. When the DI is sufficiently large, however, and is applied while bronchoconstriction is in the process of developing, the subsequent depression in airway resistance is more persistent than can be attributed simply to temporary detachment of ASM cross bridges. In the present study, we use a computational model to demonstrate that this DI-induced ablation of airway responsiveness can be explained by a dose-dependent reduction in the number of cross bridges available to bind to actin when the ASM in the airway wall is stretched above a critical threshold strain and that this disruption of the contractile apparatus recovers over an order of magnitude longer time scale than that of the simple reattachment of unbound cross bridges. NEW & NOTEWORTHY The mechanisms by which deep inflation of the lung reverse bronchoconstriction and affect subsequent airway responsiveness have important potential implications for asthma, yet remain controversial. This study uses computational modeling to posit a mechanism by which sufficiently vigorous inflations applied during active bronchoconstriction not only transiently reverse bronchoconstriction, but also reduce subsequent airways responsiveness for a period of time. Fitting the model to published data in mice supports this notion.

Bronchoprovocation tests are used to assess the propensity of the airways to narrow when challenged with a stimulus that induces airway narrowing. The tendency of the airways to respond too much and too easily to various stimuli that induce airway narrowing is called airway hyperresponsiveness (AHR), which is present in asthma, and can also be present in other airway disorders and individuals who are at risk for asthma. Tests of AHR are useful as diagnostic tests for asthma and can reveal useful information about the underlying basis of airway dysfunction. Bronchoprovocation tests are divided into direct tests that provide an exogenous stimulus for bronchoconstriction and indirect tests that rely on the endogenous release of mediators that cause bronchoconstriction. Because direct tests are sensitive to structural changes in the airways and lung, such tests are sensitive to detect the presence of asthma, but are not specific for a diagnosis of asthma. In contrast, indirect tests may reflect the type of inflammation present in asthma and are thus more specific for asthma and most useful to confirm a diagnosis of asthma and to understand the specific basis of asthma symptoms. Bronchoprovocation tests should be interpreted along with clinical features of asthma and other respiratory disorders.

The Perth Infant Asthma Follow-up (PIAF) study involves a birth cohort of unselected subjects who have undergone longitudinal assessments of airway responsiveness at 1, 6 and 12 months and 6, 11 and 18 years of age. The aim of this study was to determine the relationship between increased airway responsiveness throughout childhood and asthma in early adult life.Airway responsiveness to histamine, assessed as a dose–response slope (DRS), and a respiratory questionnaire were completed at 1, 6 and 12 months and 6, 11 and 18 years of age.253 children were initially recruited and studied. Airway responsiveness was assessed in 203, 174, 147, 103, 176 and 137 children at the above-mentioned time points, respectively (39 participants being assessed on all test occasions). Asthma at 18 years was associated with increased airway responsiveness at 6, 12 and 18 years, but not during infancy (slope 0.24, 95% CI 0.06–0.42; p=0.01; slope 0.25, 95% CI 0.08–0.49; p=0.006; and slope 0.56, 95% CI 0.29–0.83; pIncreased airway responsiveness and its association with asthma at age 18 years is established between infancy and 6 years. We propose that airway responsiveness in early life reflects the initial airway geometry and airway responsiveness later in childhood increasingly reflects immunological responses to environmental influences.

Objective: To evaluate the effect of job exposure on chronic respiratory symptoms, lung function, and bronchial hyperresponsiveness (BHR) in indoor female cleaners, along with the relationship between respiratory symptoms, sensitization to dust allergens and BHR. Methods: A cross-sectional study included 57 indoor female cleaners aged 19-61 years. In addition, 55 female office workers aged 20 to 60 years were examined as a control. Evaluation of examined subjects included completion of a questionnaire on respiratory symptoms, spirometry and histamine challenge (PC20≤8 mg/mL), and skin prick tests (SPT). Results: Prevalence of overall respiratory symptoms was significantly higher in indoor cleaners (35.1% vs 14.5%, P 0.05), whereas significantly higher prevalence was registered for borderline BHR (10.5% vs. 3.6%, P Conclusion: Results suggest significant adverse respiratory effects in indoor cleaners, whose indoor dust exposure is associated with a higher prevalence of chronic respiratory symptoms, lung function impairment, and relatively high sensitization ratios to dust allergens.

The latest methacholine challenge testing (MCT) guidelines published by the European Respiratory Society recommend the characterization of nebulizers before their use in clinics and research. Such investigations are necessary for accurately determining the provocative dose of methacholine causing a 20% fall in FEVSixty mild-to-moderate asthmatics were studied across three research sites in a randomized crossover study. Both methacholine challenges were completed at least 24 hours apart within a 2-week period. Testing with the Wright device was performed as per the 2-minute tidal breathing protocol. The Solo study arm followed the same procedure except for a shorter inhalation time of 1 minute. The provocative concentration of methacholine causing a 20% fall in FEVThe geometric mean methacholine PCThe comparability of PD

Background Bronchodilator response (BDR) is routinely used in asthma management. A new forced oscillation technique (FOT) is able to quickly measure respiratory system resistance (Rrs) and reactance (Xrs) at each tidal breath phase. The present study evaluated bronchial changes by using the new FOT. Methods Respiratory resistance and reactance were measured using FOT in 132 children (age, 10.86±4.78 years; M:F=88:44), including asthmatic ( n =98) and nonasthmatic children ( n =34), pre- and post-bronchodilator inhalation in an asymptomatic state. Whole-breath or within-breath changes in Rrs and Xrs were measured and compared pre- and post-bronchodilator inhalation and between each group. All patients performed spirometry and forced expiratory nitric oxide pre- and post-bronchodilator inhalation. Results Spirometric parameters showed significant positive changes at V 50 and V 25 in both groups; however, these changes were not significantly different between the groups. eNO was significantly higher in the asthmatic group than in the nonasthmatic group; however, there was no significant change pre- and post-inhalation in either group. Rrs in the asthma group was significantly higher in the expiratory phase than in the inspiratory phase. Rrs and Xrs before and after bronchodilator inhalation were significantly different in the asthma group alone, except for the expiratory–inspiratory phase of each of these parameters. Changes in Rrs and Xrs at 5Hz (R5 and X5) in a whole-breath and the inspiratory phase were significantly different between the groups. Conclusions Changes in X5 and R5 reflect bronchial reversibility. The new FOT is useful for asthmatic children.

This article discusses the available literature on refractoriness in exercise-induced bronchoconstriction, namely, a decrease in airway responsiveness with repeated exercise challenges. The mechanisms of this naturally occurring protective feature is unknown. Reviewing previous studies together with findings in more recent studies, the authors propose desensitization of the G protein-coupled cysteinyl leukotriene receptor1 as the mechanism of refractoriness and that this desensitization occurs as a result of interplay between leukotrienes and prostaglandins.

To observe the clinical efficacy and the change of airway responsiveness to Chinese medicine (CM) in treating cough variant asthma (CVA).Ninety-four patients who had confirmed the diagnosis of CVA were selected and randomly assigned to the treatment group and the control group by the blocked randomization method. The ratio of the two groups was 2:1. The treatment group had 63 patients that were treated by CM, lost in 10 cases, 53 patients had finished the trial. The control group had 31 patients that were treated by montelukast tablets and theophylline, lost in 5 cases, 26 patients had finished the trial, two weeks as one therapeutic course. The syndrome efficacy, cough efficacy, symptom score and the airway responsiveness between two groups were observed.The comparison of the syndrome efficacy: the total effective rate of the treatment group was 90.57% and the control group was 76.92%, and the two groups were significantly different (P0.05). The comparison of the cough efficacy: the total effective rate of the treatment group was 98.11% and the control group was 80.77%, and the two groups were also significantly different (P0.05). Syndrome scoring and cough scoring were all significantly lowered, but the airway responsiveness was not significantly lowered.The treatment of CM could ease the cough, improve the syndrome, and shows obvious advantages compared with the control group, which is worthy of extensive clinical application.

Background: Acute ozone (O3) exposure results in greater inflammation and airway hyperresponsiveness (AHR) in obese versus lean mice. Objectives: We examined the hypothesis that these augmented responses to O3 are the result of greater signaling through tumor necrosis factor receptor 2 (TNFR2) and/or interleukin (IL)-13. Methods: We exposed lean wild-type (WT) and TNFR2-deficient (TNFR2–/–) mice, and obese Cpefat and TNFR2-deficient Cpefat mice (Cpefat/TNFR2–/–), to O3 (2 ppm for 3 hr) either with or without treatment with anti–IL-13 or left them unexposed. Results: O3-induced increases in baseline pulmonary mechanics, airway responsiveness, and cellular inflammation were greater in Cpefat than in WT mice. In lean mice, TNFR2 deficiency ablated O3-induced AHR without affecting pulmonary inflammation; whereas in obese mice, TNFR2 deficiency augmented O3-induced AHR but reduced inflammatory cell recruitment. O3 increased pulmonary expression of IL-13 in Cpefat but not WT mice. Flow cytometry analysis of lung cells indicated greater IL-13–expressing CD4+ cells in Cpefat versus WT mice after O3 exposure. In Cpefat mice, anti–IL-13 treatment attenuated O3-induced increases in pulmonary mechanics and inflammatory cell recruitment, but did not affect AHR. These effects of anti–IL-13 treatment were not observed in Cpefat/TNFR2–/– mice. There was no effect of anti–IL-13 treatment in WT mice. Conclusions: Pulmonary responses to O3 are not just greater, but qualitatively different, in obese versus lean mice. In particular, in obese mice, O3 induces IL-13 and IL-13 synergizes with TNF via TNFR2 to exacerbate O3-induced changes in pulmonary mechanics and inflammatory cell recruitment but not AHR.

Remodeling and inflammation together with airway hyperresponsiveness are essential components of asthma but their role in development of the disease is still obscure.Recent data imply that remodeling can occur early in childhood, not necessarily subsequent to but rather, in parallel with inflammation. The assumption of thickening of the reticular basement membrane being a prerequirement for chronic asthma is questioned but development of airway responsiveness is a significant factor. Airway responsiveness is at least partially linked to bronchial inflammation but there are several other genes and pathways regulating airway responsiveness. Increased airway smooth muscle in early childhood is associated with later development of asthma and may be one link between inflammation and airway responsiveness. Novel findings on genetic variation in genes regulating lung growth and remodeling in early childhood shed light on the pathophysiological mechanisms leading to chronic asthma.Even young children with chronic asthma have detectable elements of airway remodeling, inflammation and increased airway responsiveness, which all contribute to impaired lung function.

Introduction Chronic obstructive pulmonary disease (COPD) is a progressive disorder that makes the breathing difficult and is characterized by pathological conditions ranging from chronic inflammation to tissue proteolysis. With regard to ethical issues related to the studies on patients with COPD, the use of animal models of COPD is inevitable. Animal models improve our knowledge about the basic mechanisms underlying COPD physiology, pathophysiology and treatment. Although these models are only able to mimic some of the features of the disease, they are valuable for further investigation of mechanisms involved in human COPD. Material and Methods We searched the literature available in Google Scholar, PubMed and ScienceDirect databases for English articles published until November 2015. For this purpose, we used 5 keywords for COPD, 3 for animal models, 4 for exposure methods, 3 for pathophysiological changes and 3 for biomarkers. One hundred and fifty-one studies were considered eligible for inclusion in this review. Results According to the reviewed articles, animal models of COPD are mainly induced in mice, guinea pigs and rats. In most of the studies, this model was induced by exposure to cigarette smoke (CS), intra-tracheal lipopolysaccharide (LPS) and intranasal elastase. There were variations in time course and dose of inducers used in different studies. The main measured parameters were lung pathological data and lung inflammation (both inflammatory cells and inflammatory mediators) in most of the studies and tracheal responsiveness (TR) in only few studies. Conclusions The present review provides various methods used for induction of animal models of COPD, different animals used (mainly mice, guinea pigs and rats) and measured parameters. The information provided in this review is valuable for choosing appropriate animal, method of induction and selecting parameters to be measured in studies concerning COPD.

The outward tethering forces exerted by the lung parenchyma on the airways embedded within it are potent modulators of the ability of the airway smooth muscle to shorten. Much of our understanding of these tethering forces is based on treating the parenchyma as an elastic continuum; yet, on a small enough scale, the lung parenchyma in two dimensions would seem to be more appropriately described as a discrete spring network. We therefore compared how the forces and displacements in the parenchyma surrounding a contracting airway are predicted to differ depending on whether the parenchyma is modeled as an elastic continuum or as a spring network. When the springs were arranged hexagonally to represent alveolar walls, the predicted parenchymal stresses and displacements propagated substantially farther away from the airway than when the springs were arranged in a triangular pattern or when the parenchyma was modeled as a continuum. Thus, to the extent that the parenchyma in vivo behaves as a hexagonal spring network, our results suggest that the range of interdependence forces due to airway contraction may have a greater influence than was previously thought.

Hydroquinone (HQ) is the main oxidative substance in cigarette smoke and a toxic product of benzene biotransformation. Although the respiratory tract is an inlet pathway of HQ exposure, its effect on airway muscle responsiveness has not been assessed. We thus investigated the effects of low dose in vivo HQ-exposure on tracheal responsiveness to a muscarinic receptor agonist. Male Swiss mice were exposed to aerosolised 5% ethanol/saline solution (HQ vehicle; control) or 0.04 ppm HQ (1 h/day for 5 days) and tracheal rings were collected 1 h after the last exposure. HQ exposure caused tracheal hyperresponsiveness to methacholine (MCh), which was abolished by mechanical removal of the epithelium. This hyperresponsiveness was not dependent on neutrophil infiltration, but on tumour necrosis factor (TNF) secretion by epithelial cells. This conclusion was based on the following data: (1) trachea from HQ-exposed mice presented a higher amount of TNF, which was abrogated following removal of the epithelium; (2) the trachea hyperresponsiveness and TNF levels were attenuated by in vivo chlorpromazine (CPZ) treatment, an inhibitor of TNF synthesis. The involvement of HQ-induced TNF secretion in trachea mast cell degranulation was also demonstrated by the partial reversion of tracheal hyperresponsiveness in sodium cromoglicate-treated animals, and the in vivo HQ-exposure-induced degranulation of trachea connective tissue and mucosal mast cells, which was reversed by CPZ treatment. Our data show that in vivo HQ exposure indirectly exacerbates the parasympathetic-induced contraction of airway smooth muscle cells, mediated by TNF secreted by tracheal epithelial cells, clearly showing the link between environmental HQ exposure and the reactivity of airways.

Summary Background It has been hypothesized that airway hyperresponsiveness (AHR) is characterized by sensitivity (strength of stimulus) and reactivity (responsiveness to stimulus); the latter could be the intrinsic characteristic of AHR. The underlying mechanisms leading to AHR could be 1) airway inflammation, 2) reduction of forces opposing bronchoconstriction, and 3) structural airway changes/geometric factors. Objective Our main objective was to assess the relationships between reactivity in patients with nasal polyposis and these three mechanisms using measurements of 1) bronchial and bronchiolar/alveolar NO, 2) bronchomotor response to deep inspiration, and 3) forced expiratory flows and an index of airway to lung size, i.e. FEF 25–75% /FVC. Methods Patients underwent spirometry, multiple flow measurement of exhaled NO (corrected for axial diffusion), assessment of bronchomotor response to deep inspiration by forced oscillation technique and methacholine challenge allowing the calculation of reactivity (slope of the dose–response curve) and sensitivity (PD 10 ). Results One hundred and thirty-two patients were prospectively enrolled of whom 71 exhibited AHR. Airway reactivity was correlated with alveolar NO concentration (rho = 0.35; p = 0.017), with airflow limitation (FEF 25–75% : rho = −0.40; p = 0.003) and with an index of airway size to lung size (FEF 25–75% /FVC: rho = −0.38; p = 0.005), of which only alveolar NO remained the only independent factor in a stepwise multiple regression analysis (variance 25%). Airway sensitivity was not correlated with any pulmonary function or exhaled NO parameter. Conclusion In patients with nasal polyposis, alveolar NO is associated with airway reactivity, suggesting that bronchiolar/alveolar lung inflammation may constitute one intrinsic characteristic of increased responsiveness.

Summary Background The effect of pro-inflammatory stimuli on bronchoconstrictor-induced air trapping has not been studied. Objective To determine the effect of natural allergen exposure, a pro-inflammatory stimulus, on methacholine- and adenosine 5′-monophospate (AMP)-induced air trapping. Methods Airway responsiveness to methacholine and AMP before and during the pollen season was obtained in 25 subjects with pollen allergy and in 10 healthy controls. The response was expressed by the sensitivity (PC 20 value) and by the slope and intercept of the FVC values recorded at each step of the challenge against the corresponding FEV 1 values. Results The slope and intercept FVC versus FEV 1 values for both methacholine and AMP were significantly higher in subjects with pollen allergy than in healthy controls. In the group with pollen allergy, both methacholine and AMP PC 20 values decreased significantly during the pollen season. However, the mean (95% CI) slope FVC versus FEV 1 values for methacholine were 1.00 (0.84–1.16) before the pollen season and 0.99 (0.86–1.12, P = 0.90) during the pollen season. Similar results were obtained with AMP. Conclusions Although the air trapping induced by both methacholine and AMP is significantly greater in subjects with pollen allergy than in healthy controls, natural allergen exposure is associated with a selective increase in airway sensitivity without concomitant changes in bronchoconstrictor-induced air trapping. These findings suggest that the information provided by the bronchoconstrictor-induced change in FEV 1 and FVC is not equivalent and may be complementary.

In healthy individuals, deep inspiration produces bronchodilation and reduced airway responsiveness, which may be a response of the airway wall to mechanical stretch. The aim of this study was to examine the in vitro response of isolated human airways to the dynamic mechanical stretch associated with normal breathing. Human bronchial segments ( n = 6) were acquired from patients without airflow obstruction undergoing lung resection for pulmonary neoplasms. The side branches were ligated and the airways were mounted in an organ bath chamber. Airway narrowing to cumulative concentrations of acetylcholine (3 × 10−6 M to 3 × 10−3 M) was measured under static conditions and in the presence of “tidal” oscillations with intermittent “deep inspiration.” Respiratory maneuvers were simulated by varying transmural pressure using a motor-controlled syringe pump (tidal 5 to 10 cmH2O at 0.25 Hz, deep inspiration 5 to 30 cmH2O). Airway narrowing was determined from decreases in lumen volume. Tidal oscillation had no effect on airway responses to acetylcholine which was similar to those under static conditions. Deep inspiration in tidally oscillating, acetylcholine-contracted airways produced potent, transient (

Summary Background The methacholine challenge test performed with the tidal breathing method induces a greater fall in FEV 1 than the dosimeter method; however, the effect of the challenge method on methacholine-induced fall in FVC has not been investigated. Objective To determine the influence of the challenge method on methacholine-induced changes in FEV 1 and FVC. Methods Airway responsiveness to methacholine was determined by dosimeter method and tidal breathing method in 37 subjects with suspected asthma. The dosimeter was modified to deliver an identical volume to that obtained with the tidal breathing method and the same nebulizer model was used for the two challenges. The response was expressed by the provocative concentration of methacholine causing a 20% fall in FEV 1 (PC 20 ) and by the percent fall in FVC at the PC 20 value relative to FVC after saline inhalation. Results The PC 20 values obtained with the tidal breathing method and the dosimeter method were similar, with geometric mean values of 3.15 (95%CI, 1.85–5.34 mg/mL) and 2.51 (1.37–4.61 mg/mL, P = 0.092), respectively. The percent fall in FVC at the PC 20 value obtained with the dosimeter was significantly greater than that obtained with the tidal breathing method, with mean values of 11.8 (95%CI, 10.0–13.5%) and 9.4 (95%CI, 8.1–10.8, P = 0.002), respectively. Conclusions Differences in methacholine PC 20 values obtained with the two challenge methods recommended in guidelines may be overcome by introducing some technical modifications in the dosimeter method. However, the technical factors that affect methacholine sensitivity and air trapping are at least partially different.

Correlated survival data analysis techniques were utilize d to determine the efficacy of such techniques to analyze correlated airway responsiveness data. When the survival data are correlated, standard maximum likelihood estimates of the regression coefficients obtained by using the Cox's model ar e consistent, but the estimates of standard errors may not be valid or consistent due to within-subject dependencies and hence give rise to wrong interpretations. We used jackknife, bootstrap and the method proposed by Wei, Lin and Weissfeld (WLW) to obtain robust estimates for the standard errors. The data analyzed in this report were obtained from a longitudinal study conducted to investigate the respiratory health effect s of initial exposure to grain dust among workers commencing employment in the grain industry in the province of Saskatchewan, Canada. Bronchial responsiveness was determined by histamine inhalation test administered at four different time points. The provocation concentration (PC20) of inhaled histamine that produced 20% fall in the lung function parameter forced expired volume in one second (FEV1) was used as an indicator of bronchial responsiveness. Failure was defined as the dose of histamine at which a 20% fall in FEV1 occurred. In provocation tests, censored data may occur due to the failure to reach a determined end point. Censoring occurred when a subject did not have 20% fall in FEV1 with the maximum histamine dose of 8 mg. Significant predicto rs of bronchial responsiveness were FEV1, wheezing and height. The estimates of standard errors were similar for jackknife, bootstrap, and WLW, but different from those obtained using standard maximum likelihood method.

Occupational asthma is common, disabling and costly, and it is often difficult to diagnose. Incidence statistics are consequently unreliable, and there are formidable difficulties in recognizing and managing what should be a preventable illness. The opportunities have largely been missed. The author offers a personal view of what, ideally, should be done--recognizing that at present the ideal is not readily practical. Always consider the possibility of an occupational cause at the time adult-onset asthma is first recognized-the probability of this is of the order 9-15%. Do not prescribe treatment unless this possibility is remote or the asthma is life-threatening. If the possibility is not remote seek immediate advice from a specialized centre, without prescribing masking medication and without curtailing usual work practice. The specialized referral centre should place the accurate measurement of airway responsiveness at the centre of investigatory strategies. A return-to-work study, monitored by serial measurements of airway responsiveness and ventilatory function, provides adequate objective evidence for diagnosis in most cases. When a novel cause is suspected, specific inhalation provocation testing with the particular agent in the specialized centre is desirable. Regular competent surveillance is necessary in high-risk occupational environments; this should include environmental monitoring, the detection of relevant new symptoms, spirometry measurements, serum antibody studies (where available) and a robust protocol for managing inevitable failed attendances.

Summary Background Epidemiological studies suggest that hookworm infection protects against asthma, and therefore that hookworm infection may have a direct or an indirect therapeutic potential in this disease. We now report the first clinical trial of experimental hookworm infection in people with allergic asthma. Objectives To determine the effects of experimental hookworm infection in asthma. Methods Thirty-two individuals with asthma and measurable airway responsiveness to adenosine monophosphate (AMP) were randomized and double blinded to cutaneous administration of either ten Necator americanus larvae, or histamine solution (placebo), and followed for 16 weeks. The primary outcome was the change in provocation dose of inhaled AMP required to reduce forced expiratory volume in 1 s by 20% (PD20AMP) from baseline to week 16. Secondary outcomes included change in several measures of asthma control and allergen skin sensitivity and the occurrence of adverse effects. Results Mean PD20AMP improved in both groups, more in the hookworm [1.49 doubling doses (DD)] than the placebo group (0.98 DD), but the difference between groups was not significant (0.51 DD; 95% confidence interval: −1.79 to 2.80; P=0.65). There were no significant differences between the two groups for other measures of asthma control or allergen skin sensitization. Infection was generally well tolerated. Conclusions Experimental infection with ten hookworm larvae in asthma did not result in significant improvement in bronchial responsiveness or other measures of asthma control in this study. However, infection was well tolerated and resulted in a non-significant improvement in airway responsiveness, indicating that further studies that mimic more closely natural infection are feasible and should be undertaken. Cite this as: J. R. Feary, A. J. Venn, K. Mortimer, A. P Brown, D. Hooi, F. H. Falcone, D. I. Pritchard and J. R. Britton, Clinical & Experimental Allergy, 2010 (40) 299– 306.

Nociceptin/orphanin FQ (N/OFQ), the endogenous ligand for the N/OFQ peptide receptor (NOP), inhibits tachykinin release in the airway of several animal models. The aim of this study was to investigate the role of the N/OFQ-NOP receptor system in bronchoconstriction induced by sensory nerve activation in the isolated mouse lung. We used C57BL/6J NOP(+/+), NOP(-/-), and Balb/C mice sensitized (or not) to ovalbumin. Bronchopulmonary function coupled with measurements of endogenous N/OFQ levels before and after capsaicin-induced bronchoconstriction in the presence or absence of NOP-selective agonists/antagonists are presented. N/OFQ significantly inhibited capsaicin-induced bronchoconstriction in both naive and sensitized mice, these latter animals displaying airway hyperresponsiveness to capsaicin. The inhibitory effect of N/OFQ were not observed in NOP(-/-) mice, and were mimicked/abolished by the selective NOP agonist/antagonist University of Ferrara Peptide (UFP)-112/UFP-101 in NOP(+/+) mice. UFP-101 alone potentiated the effect of capsaicin in naive mice, but not in sensitized mice. Endogenous N/OFQ levels significantly decreased in sensitized mice relative to naive mice. We have demonstrated that a reduction in endogenous N/OFQ, or the lack of its receptor, causes an increase in capsaicin-induced bronchoconstriction, implying a role for the N/OFQ-NOP receptor system in the modulation of capsaicin effects. Moreover, for the first time, we document differential airway responsiveness to capsaicin between naive and sensitized mice due, at least in part, to decreased endogenous N/OFQ levels in sensitized mice.

Background: Asthma is a chronic disease characterized by repeated attacks of breathlessness and wheezing, which occurs principally during night. This is due to circadian changes in ventilation and airway responsiveness. Hence, the chronomodulated therapy is more considering in the treatment of nocturnal asthma. Objective: The objective of the study was to prepare microcapsule‑based chronomodulated drug delivery system of montelukast sodium (MLS) for the treatment of nocturnal asthma. Materials and Methods: Five batches of MLS microcapsules were prepared using pH‑dependent polymer combination of Eudragit® S‑100 with L‑100. The optimized batch microcapsules were enclosed in a capsule to obtain chronomodulated pulsincap systems (CMPSs). In this system, natural gums were used as hydrogel plugs to achieve the required time lag. Microcapsules and CMPSs have been evaluated for their characteristic properties. Results: The developed microcapsules are spherical in shape with smooth surfaces. In vitro release studies predicted that M4 and M5 batches could control the drug release for a period of 12 h. The optimized batch microcapsules (M4) were used in the preparation of CMPSs. The natural hydrogel plugs, i.e. xanthan gum, gum kondagogu, and guargum used in CMPSs showed approximate lag phase of 5, 6, and 5.5 h and drug releases up to 16, 24, and 24 h, respectively. Conclusion: CMPSs containing Eudragit® microcapsules of MLS with programmable lag phase and prolonged drug release were successfully developed using natural gums as hydrogel plugs, which congregates the demands of chronomodulated therapy in asthma.

The mechanism by which deep inspirations protect against increased airway responsiveness in nonasthmatic subjects is not known. The aim was to investigate the role of airway closure and airway narrowing in deep inspiration bronchoprotection. Twelve nonasthmatic and nine asthmatic subjects avoided deep inspirations (DI) for 20 min, then took five DI expired to functional residual capaciy (DI-FRC) or, on a separate day, no DI (no DI) before inhaling a single dose of methacholine. On another day, eight nonasthmatic subjects took five DI expired to residual volume (DI-RV). Peripheral airway function was measured by respiratory system reactance (Xrs), using the forced oscillation technique, and by forced vital capacity (FVC) as an index of airway closure. Respiratory system resistance (Rrs) and forced expiratory volume in 1 s (FEV1)/FVC were measured as indexes of airway narrowing. In nonasthmatic subjects, DI-FRC reduced the response measured by FEV1 ( P = 0.019), Xrs ( P = 0.02), and FVC ( P = 0.0005) but not by Rrs ( P = 0.15) or FEV1/FVC ( P = 0.52) compared with no DI. DI-RV had a less protective effect than DI-FRC on response measured by FEV1 ( P = 0.04) and FVC ( P = 0.016). There was no difference between all protocols when the response was measured by Xrs ( P = 0.20), Rrs ( P = 0.88), or FEV1/FVC ( P = 0.88). DI had no effect on methacholine response in asthmatic subjects. DI protect against airway responsiveness through an effect on peripheral airways involving reduced airway closure. The protective effect of DI on FEV1 and FVC was abolished by expiration to residual volume. We speculate that the reduced airway closure is due to reduced baseline ventilation heterogeneity and/or reduced airway surface tension.