Airway Challenge Research Articles

Capability of hypertonic saline cough provocation test to predict the response to inhaled corticosteroids in chronic cough: a prospective, open-label study

BackgroundMany patients with chronic cough respond to treatment with inhaled corticosteroids but it is difficult to predict which patients are likely to respond. The primary aim of the present study was to define the capability of hypertonic saline cough provocation test to predict the responsiveness to inhaled corticosteroids in chronic cough. The secondary aim was to assess the ability of the saline test to monitor the healing of cough during corticosteroid treatment.MethodsForty-three patients with chronic cough were recruited. Before therapy, spirometry, ambulatory peak flow monitoring, nitric oxide measurement, histamine airway challenge, and saline test were performed. Those responding to the first saline test repeated it and the nitric oxide measurement during the subsequent visits. The patients used inhaled budesonide, 400 ug twice daily, for twelve weeks. The treatment response was assessed by Leicester Cough Questionnaire at baseline, and at one, four, and twelve weeks.ResultsSeventy-seven % of the patients demonstrated the minimal important difference in the Leicester Cough Questionnaire indicating a symptomatic response. Neither the response magnitude nor the speed was predicted by the saline test. Histamine challenge showed the strongest predictive ability: The maximal improvement in Leicester Cough Questionnaire total score was 5.08 (3.76 – 6.40) points in the histamine positive and 2.78 (1.55 – 4.01) points in the histamine negative subjects (p = 0.006). Baseline nitric oxide level also associated with the improvement in Leicester Cough Questionnaire total score (p = 0.02). During the treatment, the cough sensitivity to saline gradually decreased among the budesonide responders but not in the non-responders. Nitric oxide levels decreased very rapidly among the responders.ConclusionsSaline test cannot predict the responsiveness to inhaled corticosteroids in chronic cough but it may be utilized to monitor the effect of this treatment.Trial registrationThe study was registered in ClinicalTrials.gov database (KUH5801112). ClinicalTrials.gov Identifier: NCT00859274

Obesity: Changing Asthma in the 21st Century

Obesity: Changing Asthma in the 21st Century

Skin thymic stromal lymphopoietin promotes airway sensitization to inhalant house dust mites leading to allergic asthma in mice

Asthma is often preceded by atopic dermatitis (AD), a phenomenon known as 'atopic march'. It has been suggested that sensitization to common inhalant allergens, which is developed in a majority of patients with AD and often during the course of AD, may play a critical role in triggering the atopic march. Yet, what signal(s) delivered by AD skin could promote sensitization to inhalant allergens remains elusive. Here, by employing an experimental mouse asthma protocol, which is induced by airway sensitization and challenge to inhalant house dust mite (HDM), we demonstrate that the overproduction of cytokine thymic stromal lymphopoietin (TSLP) by AD skin promotes airway sensitization to HDM, thereby triggering subsequently an allergic asthma. Together, this study provides, for the first time, the experimental proof that TSLP represents an AD skin-delivered signal to promote sensitization to inhalant aeroallergen, which may account for one mechanism underlying the 'atopic march'.

Foxp3+ Cells Control Th2 Responses in a Murine Model of Atopic Dermatitis

The role of Foxp3+ regulatory T (Treg) cells in atopic dermatitis (AD) is still unclear. In a murine AD model, the number of Foxp3+ cells increased in the allergen-exposed skin area and in the secondary lymphoid organs. Both Foxp3+ and Foxp3- IL-10+ T cells accumulated at the site of allergen exposure, and CD103+ effector/memory Foxp3+ Treg cells expanded gradually in the lymph nodes throughout the sensitization protocol. The depletion of Foxp3+ Treg cells led to significantly exacerbated skin inflammation, including increased recruitment of inflammatory cells and expression of T helper type 2 cytokines, as well as elevated serum IgE levels. The effect of depleting Treg cells during epicutaneous sensitization was mirrored off by a stronger inflammatory response also in the lungs following airway challenge. Thus, Treg cells have an important role in controlling AD-like inflammation and the transfer of allergic skin inflammation to the lungs.

Volumetric capnography curves as lung function test to confirm bronchoconstriction after carbachol challenge in sedated dogs

This study investigated volumetric capnography (VC) in detecting airway responsiveness following airway challenge using carbachol in seven sedated dogs via face mask. Nebulised saline was administered, followed by increasing concentrations of nebulised carbachol until airflow limitation occurred (EP). Dead space (DS) variables and shape indices of the VC curve were calculated automatically after entering arterial carbon dioxide tension. Airway DS, airway DS to tidal volume (VT) ratio and the intercept of slope 2 of the VC curve decreased significantly at EP by 10%, 13% and 16%, respectively, minute ventilation, VT and alveolar DS increased significantly at EP by 49%, 22% and 200%, respectively. We conclude that VC and derived indices may be used to verify a reaction to airway challenge caused by carbachol in sedated dogs.

MicroRNA-181a, -146a and -146b in spleen CD4+ T lymphocytes play proinflammatory roles in a murine model of asthma

CD4+ T lymphocytes can be primarily polarized to differentiate into Th2 cells, and are heavily involved in the Th2 inflammation of asthma. Little is known about the correlation between microRNAs and Th2 inflammation in asthma, therefore we explore the roles of five microRNAs (microRNA-181a, -155, -150, -146a and -146b) in Th2 inflammation of asthma by tracking their expression levels in splenic CD4+ T lymphocytes under different conditions. Using quantitative real-time polymerase chain reaction (qPCR), the dynamic changes of these microRNAs in murine models of acute asthma (i.e. the OVA group) were analyzed, in comparison to a control group. The effects of dexamethasone on the miRNA expression levels were also investigated. The results showed that the expression levels of microRNA-181a, -150, -146a and -146b were higher in the OVA group compared to the control group in the beginning of the disease, and after 5days dropped to control group levels because there was no new airway challenge. Moreover, the miRNA-146a expression was down-regulated by treatment with dexamethasone. MicroRNA-181a had a positive linear correlation with the numbers of inflammatory cells (i.e. the numbers of total cells or of the eosinophils in the BALF) by Spearman correlation analysis, so did miRNA-146a and miRNA-146b. These observations suggest that microRNA-181a, -146a and -146b are proinflammatory factors in asthma, and that down-regulation of miRNA-146a may partially account for the anti-inflammatory effect of dexamethasone.

Skin TSLP and “atopic march”: What do we learn from mouse models?

Thymic stromal lymphopoietin (TSLP) is a cytokine expressed mainly in epithelial cells, including skin, lung and gut. Employing mouse genetic approaches, our previous work has suggested that keratinocyte-derived TSLP, which was found over-expressed in skin lesions of atopic dermatitis (AD) patients, plays a key role in triggering AD pathogenesis. Moreover, we found that overproduction of keratinocytic TSLP led to aggravation of an experimental mouse asthma induced by ovalbumin intraperitoneal sensitization and airway challenge, suggesting that keratinocyte-produced TSLP may represent an important factor in the progression from AD to asthma, a phenomenon known as the “atopic march”. More recently, we established novel experimental allergic asthma mouse models to more faithfully mimic human “atopic march”. Employing these models, we investigated the role of keratinocytic TSLP in allergen sensitization occurring in skin and airways. We discuss briefly here what we learn from these mouse models on the crucial role of TSLP produced by keratinocytes in allergen sensitization through skin or airways during the onset of “atopic march”.

Early Life Interventions to Prevent Allergy in the Offspring: The Role of Maternal Immunization and Postnatal Mucosal Allergen Exposure

Background: Childhood allergy is influenced by maternal factors and allergen exposure in early life, but the factors that determine the development of allergy and tolerance are unknown. Therefore, we compared the effects of two early life interventions, i.e. maternal allergen immunization and postnatal intranasal allergen exposure, as well as a combination of both treatments on allergic responses in the offspring. Methods: Female mice were immunized with ovalbumin (OVA) or vehicle during pregnancy. After birth, half the offspring from each group were exposed intranasally to low doses of OVA or vehicle weekly for 5 weeks before intraperitoneal immunization with OVA. Results: Maternal immunization reduced OVA-specific IgE and IgG1, but increased IgG2a and T_H2 cytokine responses in the offspring after immunization. Postnatal intranasal OVA exposure similarly reduced both IgE and IgG1, but also spleen cell numbers and cytokine secretion. Following airway challenges of the offspring, IgE and airway inflammation were suppressed only by intranasal exposure, but not by maternal immunization, the effect of which also waned with age. Differential gene expression in the spleen of offspring supported that IgE suppression by the two interventions was caused by different mechanisms. Despite this, tolerance development after mucosal exposure was obtained in the offspring of immunized dams. Conclusions: The study suggests that prevention of allergy is possible if initiated in early life, and early mucosal allergen exposure may play a protective role independent of the maternal immune responses.

62 Keratinocytic Thymic Stromal Lymphopoietin Plays an Important Role in Epicutaneous Sensitization and the Atopic March

BackgroundAtopic dermatitis (AD or eczema) often precedes the development of asthma and allergic rhinitis in atopic subjects, a phenomenon known as atopic march. An important role of epicutaneous (e.c.) sensitization has been recognized in the atopic march; however, the factors involved in e.c. sensitization remain poorly understood. Our previous studies using mouse models have shown that induced overexpression of Thymic Stromal Lymphopoietin (TSLP) in keratinocytes not only triggers an AD [Li, M. et al. Proc Natl Acad Sci U S A. 2006;103:11736–11741] but also aggravates experimental asthma induced by systemic sensitization and airway challenge of ovalbumin (OVA) [Zhang Z, et al. Proc Natl Acad Sci U S A. 2009;106:1536–1541], suggesting that TSLP represents an important factor linking AD to asthma. However, whether keratinocytic TSLP is essentially required for developing e.c. sensitization and triggering the atopic march remained to be determined.MethodsWe develop a mouse model in which e.c. sensitization of OVA through tape-stripped skin is followed by intranasal challenge to induce an allergic asthma. TSLPep−/−mice (in which TSLP is selectively ablated in epidermal keratinocytes at adult stage) or TSLPover mice (in which keratinocytic TSLP overexpression is induced by topical application of MC903, a low-calcemic vitamin D analog) are subjected to this mouse model.ResultsUpon OVA e.c. treatment, TSLPep−/− mice develop a defective allergen sensitization evidenced by decreased production of OVA-specific IgE and IgG1 and a reduction of the secretion of Th2 and Th17 (but not Th1) cytokines by in vitro OVA stimulated splenocytes. TSLPep−/− mice also exhibit a decreased OVA-induced skin inflammation. Finally, upon intranasal challenge, TSLPep−/− mice develop a less severe airway allergic inflammation and a reduced airway hyperresponsiveness. In contrast, overproduction of keratinocytic TSLP boosts the e.c. sensitization and triggers an aggravated asthma.ConclusionsOur results demonstrate an important role of keratinocytic TSLP in developing epicutaneous sensitization, generating allergic skin inflammation and triggering the atopic march. Thus, blocking the expression or activity of keratinocytic TSLP could be helpful to limit epicutaneous sensitization and prevent the atopic march.

125 The Association between Mast Cells and Remodelling of the Small Airways in Chronic Asthma

BackgroundRepeated airway challenges with House Dust Mite (HDM) allergen results in marked remodelling and mast cell hyperplasia in the small airways of allergic sheep. We now examine mast cell activation and its association with small airway function and remodelling in these sheep using a novel segmental allergen challenge approach.MethodsEight allergic sheep received weekly intra-lung challenges of HDM to the left caudal lung for 24 weeks. Eight separate sheep were used as controls. Baseline lung function was assessed in the left caudal segments of all sheep throughout the challenge regime using a wedged-bronchoscope technique. Airway tissue was collected from challenged segments from all sheep, 7 days following the final intra-lung challenge. The airway tissues were immunohistochemically labelled for chymase-mast cells and eosinophils. Collagen and airway smooth muscle content were assessed on Masson's Trichrome stained sections.ResultsResting lung function in the left caudal segment is elevated in 4 out of 8 sheep at the end of the repeated allergen challenge regime. Chymase mast cell density was significantly increased in the small bronchial walls of the HDM-challenged group compared to the control group (52 ± 8 vs 8 ± 4; P < 0.01). There were significant increases in bronchial collagen deposition in HDM-exposed segments compared to control segments (0.17 ± 0.02 vs 0.11 ± 0.02 mm2/BM, P < 0.05). A correlation analysis of individual sheep data showed that there was a trend for a direct association between the increases in bronchial collagen deposition and the density of chymase-labelled mast cells (rs = 0.71, P = 0.088). Eosinophil density in the small bronchial walls of HDM-challenged segments was also significantly increased compared to controls (65 ± 19 vs 11 ± 3 cells/mm2, P < 0.001), but not associated with collagen content. The bronchial smooth muscle content was not different between HDM-challenged and unexposed control segments.ConclusionsThe results show that repeated exposure to allergen results in significant increases in density of chymase-labelled mast cells, together with increased levels of collagen content in the small airways. The segmental challenge protocol allows for a novel approach to characterise the progressive remodelling events occurring in the small airways in chronic asthma.

Vitamin D3 deficiency enhances allergen‐induced lymphocyte responses in a mouse model of allergic airway disease

There is debate as to whether vitamin D deficiency contributes towards the extent of the asthma epidemic. In this study, using a mouse model, we determined whether vitamin D deficiency in utero and during early life modulated the severity of asthma. Using dietary restriction, vitamin D(3) -replete and vitamin D(3) -deficient colonies of BALB/c mice were established. Utilizing the allergic airway disease model of asthma with the experimental allergen ovalbumin (OVA), we examined asthma-like responses 24 h after airway challenge with OVA in adult offspring born to vitamin D(3) -replete and vitamin D(3) -deficient mothers. The ability of airway-draining lymph node cells to proliferate and secrete cytokines in response to OVA ex vivo was significantly enhanced by vitamin D(3) deficiency. However, other aspects of allergic disease, including the numbers and proportions of inflammatory cells and cytokines in the lungs and the quantity of OVA-specific IgE in serum, were not modified. These results suggest that vitamin D(3) deficiency modulates the capacity of lymphocytes to respond to allergens.

Cutting Edge: Persistence of Increased Mast Cell Numbers in Tissues Links Dermatitis to Enhanced Airway Disease in a Mouse Model of Atopy

The development of chronic allergic dermatitis in early life has been associated with increased onset and severity of allergic asthma later in life. However, the mechanisms linking these two diseases are poorly understood. In this study, we report that the development of oxazolone-induced chronic allergic dermatitis, in a mouse model, caused enhanced OVA-induced allergic asthma after the resolution of the former disease. Our findings show that oxazolone-induced dermatitis caused a marked increase in tissue mast cells, which persisted long after the resolution of this disease. Subsequent OVA sensitization and airway challenge of mice that had recovered from dermatitis resulted in increased allergic airway hyperreactivity. The findings demonstrate that the accumulation of mast cells during dermatitis has the detrimental effect of increasing allergic airway hypersensitivity. Importantly, our findings also show that exposure to a given allergen can modify the immune response to an unrelated allergen.

Increased hypoxia-inducible factor 1α expression in lung cells of horses with recurrent airway obstruction

BackgroundRecurrent airway obstruction (RAO, also known as equine heaves) is an inflammatory condition caused by exposure of susceptible horses to organic dusts in hay. The immunological processes responsible for the development and the persistence of airway inflammation are still largely unknown. Hypoxia-inducible factor (Hif) is mainly known as a major regulator of energy homeostasis and cellular adaptation to hypoxia. More recently however, Hif also emerged as an essential regulator of innate immune responses. Here, we aimed at investigating the potential involvement of Hif1-α in myeloid cells in horse with recurrent airway obstruction.ResultsIn vitro, we observed that Hif is expressed in equine myeloid cells after hay dust stimulation and regulates genes such as tumor necrosis factor alpha (TNF-α), interleukin-8 (IL-8) and vascular endothelial growth factor A (VEGF-A). We further showed in vivo that airway challenge with hay dust upregulated Hif1-α mRNA expression in myeloid cells from the bronchoalveolar lavage fluid (BALF) of healthy and RAO-affected horses, with a more pronounced effect in cells from RAO-affected horses. Finally, Hif1-α mRNA expression in BALF cells from challenged horses correlated positively with lung dysfunction.ConclusionTaken together, our results suggest an important role for Hif1-α in myeloid cells during hay dust-induced inflammation in horses with RAO. We therefore propose that future research aiming at functional inactivation of Hif1 in lung myeloid cells could open new therapeutic perspectives for RAO.

Airway challenges in critical care

Airway challenges in critical care

Anesthetic challenges in managing a case of type III laryngo-tracheo-esophageal cleft

Laryngo-tracheo-esophageal cleft (LTEC) is a rare congenital anomaly characterized by failure of fusion of the cricoid cartilage posteriorly and incomplete development of the tracheo-esophageal septum. Securing the airway during anesthesia in patients with LTEC, especially in the severe forms is a challenge. We describe the anesthetic management and the airway challenges in a neonate with type III LTEC who underwent bronchoscopy and repair of LTEC.

Airway challenges in critical care

Airway challenges in critical care

Airway responsiveness to psychological processes in asthma and health

Psychosocial factors have been found to impact airway pathophysiology in respiratory disease with considerable consistency. Influences on airway mechanics have been studied particularly well. The goal of this article is to review the literature on airway responses to psychological stimulation, discuss potential pathways of influence, and present a well-established emotion-induction paradigm to study airway obstruction elicited by unpleasant stimuli. Observational studies have found systematic associations between lung function and daily mood changes. The laboratory-based paradigm of bronchoconstrictive suggestion has been used successfully to elicit airway obstruction in a substantial proportion of asthmatic individuals. Other studies have demonstrated modulation of airway responses to standard airway challenges with exercise, allergens, or pharmacological agents by psychological factors. Standardized emotion-induction techniques have consistently shown airway constriction during unpleasant stimulation, with surgery, blood, and injury stimuli being particularly powerful. Findings with various forms of stress induction have been more mixed. A number of methodological factors may account for variability across studies, such as choice of measurement technique, temporal association between stimulation and measurement, and the specific quality and intensity of the stimulus material, in particular the extent of implied action-orientation. Research has also begun to elucidate physiological processes associated with psychologically induced airway responses, with vagal excitation and ventilatory influences being the most likely candidate pathways, whereas the role of specific central nervous system pathways and inflammatory processes has been less studied. The technique of emotion-induction using films has the potential to become a standardized challenge paradigm for the further exploration of airway hyperresponsiveness mediated by central nervous system processes.

Post-burn facial contractures in pediatric patients: Challenging aspects of difficult airway management

Pediatric burn injuries are the most challenging to handle especially when they involve the face as the airway compromise invariably occurs due to edema and inflammation of the soft tissues of pharynx and larynx. The healing of the facial burns causes development of contractures and deformities after survival from the initial insults. Such patients when presented for surgery of the affected area or for that matter any surgery under general anesthesia, poses unique challenges to the attending anesthesiologists. Not only there are technical difficulties, but the socio-behavioral aspects related to pediatric age group and the various side-effects of anesthetic drugs are the main concerns for the anesthesiologist during the entire operative intervention. We are presenting a case of an infant who was brought to our institute by his parents for the cosmetic correction of the contractures and deformities of the lower face and the neck and in whom we faced extensive airway challenges because of the nature of the surgery.

Carinal injury: An airway challenge for anesthesiologists

Tracheobronchial disruption is a potentially life-threatening airway challenge for all the anesthesiologists. Carinal rents, although rare, if not timely managed can be catastrophic. We describe a patient with carinal rent being managed successfully by prompt diagnosis, use of low pressure ventilation, and bronchoscopic sealing using tissue glue.

Dianthus superbus fructus suppresses airway inflammation by downregulating of inducible nitric oxide synthase in an ovalbumin-induced murine model of asthma

BackgroundDianthus superbus has long been used as a herbal medicine in Asia and as an anti-inflammatory agent. In this study, we evaluated the anti-inflammatory effects of Dianthus superbus fructus ethanolic extract (DSE) on Th2-type cytokines, eosinophil infiltration, and other factors in an ovalbumin (OVA)-induced murine asthma model. To study the possible mechanism of the anti-inflammatory effect of DSE, we also evaluated the expression of inducible nitric oxide synthase (iNOS) in the respiratory tract.MethodsMice were sensitized on days 0 and 14 by intraperitoneal injection of OVA. On days 21, 22 and 23 after initial sensitization, mice received an airway challenge with OVA for 1 h using an ultrasonic nebulizer. DSE was applied 1 h prior to OVA challenge. Mice were administered DSE orally at doses of 100 mg/kg or 200 mg/kg once daily from day 18 to 23. Bronchoalveolar lavage fluid (BALF) was collected 48 h after the final OVA challenge. Levels of interleukin (IL)-4, IL-13 and eotaxin in BALF were measured using enzyme-linked immunosorbent assays (ELISAs). Lung tissue sections were stained with hematoxylin and eosin for assessment of cell infiltration and mucus production with periodic acid shift staining, in conjunction with ELISA and western blot analyses for iNOS expression.ResultsDSE significantly reduced the levels of IL-4, IL-13, eotaxin, and immunoglobulin (Ig) E, number of inflammatory cells in BALF, and inflammatory cell infiltration and mucus production in the respiratory tract. DSE also attenuated the overexpression of iNOS protein induced by OVA challenge.ConclusionOur results suggest that DSE effectively protects against allergic airway inflammation by downregulating of iNOS expression and that DSE has potential as a therapeutic agent for allergic asthma.