Airway Sensitivity Research Articles

A COMPARATIVE STUDY OF MODIFIED MALLAMPATI CLASSIFICATION WITH NECK CIRCUMFERENCE ALONG WITH UPPER LIP BITE TEST IN MORBIDLY OBESE PATIENTS

INTRODUCTION: Anaesthesia in morbidly obese patients can present many challenges. The overriding concern of most anaesthesiologists is airway management, as obese patients have been thought to be at greater risk of difcult airway and/or difcult intubation, when compared with the general population. The term 'difcult airway' has been dened by the American Society of Anaesthesiologists (ASA) taskforce as the clinical situation in which a conventionally trained anaesthesiologist experiences problems with mask ventilation or tracheal intubation or both. AIMS AND OBJECTIVES- To assess the positive predictive value,sensitivity and specicity of MMPC, NC along with ULBT and compare it with Cormack Lehane grading intraoperatively. MATERIALS AND METHOD- Preoperative airway assessment of 200 patients posted for surgery under general anaesthesia was carried out to evaluate the usefulness of multiple screening tests in predicting the ease or difculty of laryngoscopy in obese patients undergoing laparoscopic bariatric surgery. Modied Mallampati test grade III or IV, Upper Lip Bite test grade III, Neck Circumference >40cm were considered as predictors of difcult laryngoscopy. Laryngoscopy was considered difcult if the view on laryngoscopy was Cormack and Lehane grade III or IV. The results were evaluated on the basis of sensitivity, specicity, positive and negative predictive value and accuracy of these tests. RESULT- Group A (ULBT+MMPC) identied 65% of the patients with difcult intubation (sensitivity of 92.86 % & specicity of 33.3 %), whereas Group B (ULBT+NC) identied 75% of the patients with difcult airway (sensitivity 93.75% & specicity of 25%). Pearson Correlation analysis was applied to know the correlation between the various tests and the Cormack Lehane Classication, both the groups had p value of 0.001 , which was highly signicant. CONCLUSION-When multiple predictors are taken into consideration there was a considerable reduction in false negatives with signicant improvement in accuracy of test and hence prediction of difcult laryngoscopy was made easy. Application of multiple predictors in combination can reduce the frequency of unanticipated difculty and unnecessary interventions related to over prediction of airway difculty.

Viability of cultured human skin cells treated with 1,6-hexamethylene diisocyanate monomer and its oligomer isocyanurate in different culture media

The isocyanate monomer 1,6-hexamethylene diisocyanate (HDI) and one of its trimers, HDI isocyanurate, are airway and skin sensitizers contained in polyurethane paint. The toxic response of cultured skin cells to these compounds was measured by evaluating the isocyanate concentrations at which 50% of the cells die (i.e., lethal concentration 50%, LC50) because the relative toxicity of each form of HDI should be considered when exposure limits of HDI-based paints are set. By using a luminescent ATP-viability assay, we compared the cytotoxic effects of HDI monomer and HDI isocyanurate on cultured human skin cells (keratinocytes, fibroblasts, and melanocytes) after 4-h isocyanate exposures using culture media with varying levels of nutrients in order to also determine the effects of media composition on isocyanate toxicity. Before analysis, experimental wells were normalized to controls containing cells that were cultured with the same vehicle and media. The measured mean LC50 values ranged from 5 to 200 µM across the experimental conditions, in which HDI isocyanurate in protein-devoid media was the most toxic to cells, producing the lowest LC50 values. For HDI monomer, keratinocytes were the most resistant to its toxicity and melanocytes were the most susceptible. However, when exposed to HDI isocyanurate, the opposite was observed, with melanocytes being the most resilient and the keratinocytes and fibroblasts were more susceptible. Depending on the type of skin cells, dose–response data indicated that HDI isocyanurate was 2–6 times more toxic than HDI monomer when using protein-devoid media whereas HDI isocyanurate was 4–13 times more toxic than HDI monomer when protein-rich media was used. Therefore, if the protein-devoid saline medium alone were used for these experiments, then a significant under-estimation of their relative toxicities in protein-rich environments would have resulted. This difference is because HDI monomer toxicity was more attenuated by the presence of protein in the culture media than HDI isocyanurate toxicity. Thus, conclusions based on comparative toxicity studies and consequent inference applied to potential human toxicity can be affected by in vitro culture media conditions. The physiochemical difference in reactivity of the two forms of HDI to biological molecules most likely explains the observed toxicity differences and may have implications for skin penetration, adverse effects like skin sensitization, and systemic responses like asthma. Future studies are warranted to investigate differences in the biological availability, cellular toxicity, and immunologic sensitization mechanisms for HDI monomer and HDI isocyanurate.

Pathophysiological relevance of sputum MUC5AC and MUC5B levels in patients with mild asthma

BackgroundAirway mucus hypersecretion is an important pathophysiological feature of asthma. MUC5AC and MUC5B are the major secreted polymeric mucins in airways, and their compositions affect mucus properties. Despite the increasing appreciation of MUC5AC and MUC5B compositions in asthmatic airways, their pathophysiological relevance remains to be fully understood in humans. MethodsIn this cross-sectional study, we prospectively enrolled newly referred steroid-untreated patients with mild asthma and healthy controls. We compared induced sputum MUC5AC and MUC5B levels between patients and controls. Subsequently, we assessed the correlation between MUC5AC and MUC5B levels and clinical indices in patients. Sputum MUC5AC and MUC5B levels were measured using enzyme-linked immunosorbent assays. ResultsSputum MUC5AC and MUC5B levels were significantly higher in patients (n = 87) than in controls (n = 22) (p = 0.0002 and p = 0.006, respectively). The ratio of sputum MUC5AC to MUC5B tended to be higher in patients than in controls (p = 0.07). Sputum MUC5AC levels significantly and positively correlated with fractional exhaled nitric oxide at expiratory flow of 50 mL/s (Spearman's rho = 0.29, p = 0.006), sputum eosinophil proportion (rho = 0.34, p = 0.0013), and airway sensitivity (rho = 0.39, p = 0.0005). By contrast, sputum MUC5B levels significantly and positively correlated with airway sensitivity (rho = 0.35, p = 0.002) and negatively correlated with airway reactivity (rho = −0.33, p = 0.004). ConclusionsSputum MUC5AC is increased by protein levels and involved in airway type 2/eosinophilic inflammation and airway hyperresponsiveness in steroid-untreated patients with mild asthma.

Epigenetic Markers Are Associated With Differences in Isocyanate Biomarker Levels in Exposed Spray-Painters.

Isocyanates are respiratory and skin sensitizers that are one of the main causes of occupational asthma globally. Genetic and epigenetic markers are associated with isocyanate-induced asthma and, before asthma develops, we have shown that genetic polymorphisms are associated with variation in plasma and urine biomarker levels in exposed workers. Inter-individual epigenetic variance may also have a significant role in the observed biomarker variability following isocyanate exposure. Therefore, we determined the percent methylation for CpG islands from DNA extracted from mononuclear blood cells of 24 male spray-painters exposed to 1,6-hexamethylene diisocyanate (HDI) monomer and HDI isocyanurate. Spray-painters’ personal inhalation and skin exposure to these compounds and the respective biomarker levels of 1,6-diaminohexane (HDA) and trisaminohexyl isocyanurate (TAHI) in their plasma and urine were measured during three repeated industrial hygiene monitoring visits. We controlled for inhalation exposure, skin exposure, age, smoking status, and ethnicity as covariates and performed an epigenome-wide association study (EWAS) using likelihood-ratio statistical modeling. We identified 38 CpG markers associated with differences in isocyanate biomarker levels (Bonferroni < 0.05). Annotations for these markers included 18 genes: ALG1, ANKRD11, C16orf89, CHD7, COL27A, FUZ, FZD9, HMGN1, KRT6A, LEPR, MAPK10, MED25, NOSIP, PKD1, SNX19, UNC13A, UROS, and ZFHX3. We explored the functions of the genes that have been published in the literature and used GeneMANIA to investigate gene ontologies and predicted protein-interaction networks. The protein functions of the predicted networks include keratinocyte migration, cell–cell adhesions, calcium transport, neurotransmitter release, nitric oxide production, and apoptosis regulation. Many of the protein pathway functions overlap with previous findings on genetic markers associated with variability both in isocyanate biomarker levels and asthma susceptibility, which suggests there are overlapping protein pathways that contribute to both isocyanate toxicokinetics and toxicodynamics. These predicted protein networks can inform future research on the mechanism of allergic airway sensitization by isocyanates and aid in the development of mitigation strategies to better protect worker health.

Semaphorin 3E deficiency dysregulates dendritic cell functions: In vitro and in vivo evidence.

Regulation of dendritic cell functions is a complex process in which several mediators play diverse roles as a network in a context-dependent manner. The precise mechanisms underlying dendritic cell functions have remained to be addressed. Semaphorins play crucial roles in regulation of various cell functions. We previously revealed that Semaphorin 3E (Sema3E) contributes to regulation of allergen-induced airway pathology partly mediated by controlling recruitment of conventional dendritic cell subsets in vivo, though the underlying mechanism remained elusive. In this study, we investigate the potential regulatory role of Sema3E in dendritic cells. We demonstrated that bone marrow-derived dendritic cells differentiated from Sema3e-/- progenitors have an enhanced migration capacity both at the baseline and in response to CCL21. The enhanced migration ability of Sema3E dendritic cells was associated with an overexpression of the chemokine receptor (CCR7), elevated Rac1 GTPase activity and F-actin polymerization. Using a mouse model of allergic airway sensitization, we observed that genetic deletion of Sema3E leads to a time dependent upregulation of CCR7 on CD11b+ conventional dendritic cells in the lungs and mediastinal lymph nodes. Furthermore, aeroallergen sensitization of Sema3e-/- mice lead to an enhanced expression of PD-L2 and IRF-4 as well as enhanced allergen uptake in pulmonary CD11b+ DC, compared to wild type littermates. Collectively, these data suggest that Sema3E implicates in regulation of dendritic cell functions which could be considered a basis for novel immunotherapeutic strategies for the diseases associated with defective dendritic cells in the future.

The atopic march and its prevention

The atopic march described the progression from atopic dermatitis (AD) toward asthma and allergic rhinitis,1 variably interpreted initially as AD and later with the onset of wheezing or rhinitis, or as all 3 atopic disorders in the order of AD, then asthma, then rhinitis. A central role for AD barrier dysfunction was implicated by the development of airway sensitization in tape-stripped murine models sensitized epicutaneously. Data-driven assessments, however, suggest a more complex, multimorbidity relationship among these atopic disorders, reflecting their shared pathomechanisms, environmental triggers, and genetic risk factors.

Respiratory allergies: Salicaceae sensitization (Review).

Seasonal allergic rhinitis (SAR) is one of the most frequent chronic conditions of the modern world. Pollen carried by the wind from pollinated trees is a major source of SAR. Betulaceae, Oleaceae and Platanus are the most important sources of airway sensitization with regard to tree pollen and, therefore, they are included in the official recommendations of skin prick testing by different official societies. Salicaceae pollen is a moderate source of pollen sensitization. Conversely, large areas are covered with poplars and willows around the world. A number of studies from many countries showed that in some particular situations (large and compacted areas covered by Salicaceae, weather conditions, air pollution, urban ornamental vegetation), poplar and willow pollens may become of local importance in producing SAR. The aim of this review was to present a synthesis of information regarding Salicaceae pollen allergy showing that, if various unfavorable aspects are brought together, a minor problem (Salicaceae sensitization) can became a public health problem.

Epicutaneous vaccination with protease inhibitor-treated papain prevents papain-induced Th2-mediated airway inflammation without inducing Th17 in mice

Environmental allergen sources such as house dust mites contain proteases, which are frequently allergens themselves. Inhalation with the exogenous proteases, such as a model of protease allergen, papain, to airways evokes release and activation of IL-33, which promotes innate and adaptive allergic airway inflammation and Th2 sensitization in mice. Here, we examine whether epicutaneous (e.c.) vaccination with antigens with and without protease activity shows prophylactic effect on the Th airway sensitization and Th2-medated airway inflammation, which are driven by exogenous or endogenous IL-33. E.c. vaccination with ovalbumin restrained ovalbumin-specific Th2 airway sensitization and/or airway inflammation on subsequent inhalation with ovalbumin plus papain or ovalbumin plus recombinant IL-33. E.c. vaccination with papain or protease inhibitor-treated papain restrained papain-specific Th2 and Th9 airway sensitization, eosinophilia, and infiltration of IL-33-responsive Th2 and group 2 innate lymphoid cells on subsequent inhalation with papain. However, e.c. vaccination with papain but not protease inhibitor-treated papain induced Th17 response in bronchial draining lymph node cells. In conclusions, we demonstrated that e.c. allergen vaccination via intact skin in mice restrained even protease allergen-activated IL-33-driven airway Th2 sensitization to attenuate allergic airway inflammation and that e.c. vaccination with protease allergen attenuated the airway inflammation similar to its derivative lacking the protease activity, although the former but not the latter promoted Th17 development. In addition, the present study suggests that modified allergens, of which Th17-inducing e.c. adjuvant activity such as the protease activity was eliminated, might be preferable for safer clinical applications of the e.c. allergen administration.

Methacholine-Induced Cough in the Absence of Asthma: Insights From Impulse Oscillometry.

IntroductionThe pathophysiologic differences between methacholine-induced cough but normal airway sensitivity (COUGH) and healthy individuals (CONTROL) are incompletely understood and may be due to differences in the bronchodilating effect of deep inspirations (DIs). The purpose of this study is to compare the bronchodilating effect of DIs in individuals with classic asthma (CA), cough variant asthma (CVA), and COUGH with CONTROL and to assess impulse oscillometry (IOS) measures as predictors of the bronchodilating effect of DIs.MethodsA total of 43 adults [18 female; 44.8 ± 12.3 years (mean ± SD); n = 11 CA, n = 10 CVA, n = 7 COUGH, n = 15 CONTROL] underwent modified high-dose methacholine challenge, with IOS and partial/maximal expiratory flow volume (PEFV/MEFV) maneuvers (used to calculate DI Index) to a maximum change (Δ) in FEV1 of 50% from baseline (MAX). Cough count and dyspnea were measured at each dose. The relation between IOS parameters and DI Index was assessed at baseline and MAX using multivariable linear regression analysis.ResultsCough frequency, dyspnea intensity, and baseline peripheral resistance (R5–R20) were significantly greater in COUGH compared with CONTROL (p = 0.006, p = 0.029, and p = 0.035, respectively). At MAX, the DI Index was significantly lower in COUGH (0.01 ± 0.36) compared with CA (0.67 ± 0.97, p = 0.008), CVA (0.51 ± 0.73, p = 0.012), and CONTROL (0.68 ± 0.45, p = 0.005). Fres and R5–R20 were independent IOS predictors of the DI Index.ConclusionThe bronchodilating effect is impaired in COUGH and preserved in mild CA, CVA, and CONTROL. Increased peripheral airway resistance and decreased resonant frequency are associated with a decreased DI Index. COUGH is a clinical phenotype distinct from healthy normals and asthma.

Bronchial Provocation Testing for the Identification of Exercise-Induced Bronchoconstriction

Exercise-induced bronchoconstriction (EIB) occurs in patients with asthma, children, and otherwise healthy athletes. Poor diagnostic accuracy of respiratory symptoms during exercise requires objective assessment of EIB. The standardized tests currently available are based on the assumption that the provoking stimulus to EIB is dehydration of the airway surface fluid due to conditioning large volumes of inhaled air. "Indirect" bronchial provocation tests that use stimuli to cause endogenous release of bronchoconstricting mediators from airway inflammatory cells include dry air hyperpnea (eg, exercise and eucapnic voluntary hyperpnea) and osmotic aerosols (eg, inhaled mannitol). The airway response to different indirect tests is generally similar in patients with asthma and healthy athletes with EIB. Furthermore, the airway sensitivity to these tests is modified by the same pharmacotherapy used to treat asthma. In contrast, pharmacological agents such as methacholine, given by inhalation, act directly on smooth muscle to cause contraction. These "direct" tests have been used traditionally to identify airway hyperresponsiveness in clinical asthma but are less useful to diagnose EIB. The mechanistic differences between indirect and direct tests have helped to elucidate the events leading to airway narrowing in patients with asthma and elite athletes, while improving the clinical utility of these tests to diagnose andmanage EIB.

Secreted Phospholipase A2 Group X Acts as an Adjuvant for Type 2 Inflammation, Leading to an Allergen-Specific Immune Response in the Lung.

Secreted phospholipase A2 (sPLA2) enzymes release free fatty acids, including arachidonic acid, and generate lysophospholipids from phospholipids, including membrane phospholipids from cells and bacteria and surfactant phospholipids. We have shown that an endogenous enzyme sPLA2 group X (sPLA2-X) is elevated in the airways of asthmatics and that mice lacking the sPLA2-X gene (Pla2g10) display attenuated airway hyperresponsiveness, innate and adaptive immune responses, and type 2 cytokine production in a model of airway sensitization and challenge using a complete allergen that induces endogenous adjuvant activity. This complete allergen also induces the expression of sPLA2-X/Pla2g10 In the periphery, an sPLA2 found in bee venom (bee venom PLA2) administered with the incomplete Ag OVA leads to an Ag-specific immune response. In this study, we demonstrate that both bee venom PLA2 and murine sPLA2-X have adjuvant activity, leading to a type 2 immune response in the lung with features of airway hyperresponsiveness and Ag-specific type 2 airway inflammation following peripheral sensitization and subsequent airway challenge with OVA. Further, the adjuvant effects of sPLA2-X that result in the type 2-biased OVA-specific adaptive immune response in the lung were dependent upon the catalytic activity of the enzyme, as a catalytically inactive mutant form of sPLA2-X does not elicit the adaptive component of the immune response, although other components of the immune response were induced by the inactive enzyme, suggesting receptor-mediated effects. Our results demonstrate that exogenous and endogenous sPLA2s play an important role in peripheral sensitization, resulting in airway responses to inhaled Ags.

IL-9 Represses Intestinal Granzyme A Positive CD4 T Cells in Mice with Allergic Airway Inflammation

Abstract Mediated by immune responses in the airways, symptoms of allergic airway diseases include shortness of breath, difficulty breathing, and wheezing. Responses in distant tissues, such as increased lymphocyte proliferation and cytokine secretion, are also exhibited. How airway sensitization mediates these distant effects is unclear. We recently described the development and function of granzyme A-expressing T cells that control intestinal inflammation. Using models of chronic and memory allergic airway inflammation, we now show that a granzyme A expressing CD4 T cell population in the intestine increases during these diseases. This response is amplified in mice that lack IL-9 signaling through a deficiency in IL-9 receptor levels (IL9RKO) or receive an IL-9 antibody blockade. In a chronic intranasal allergen challenge model, we saw elevated levels of granzyme A expressing CD4 T cells in IL9RKO mice when compared to wild-type controls. In a memory internasal allergen model using wild-type mice (chronic allergen exposure, followed by an allergen-free rest period, and an allergen re-exposure), granzyme A expressing cells in the intestine were increased upon IL-9 antibody blockade. Blocking IL-9 or administering IL-9 to naïve mice or cell cultures that generate granzyme A expressing T cells did not affect cell prevalence. Therefore, concurrent allergic airway inflammation seems to be required for the proliferation of these granzyme A expressing T cells. Together, these studies suggest that allergic airway inflammation increases granzyme A expressing CD4 T cells in the intestine and that IL-9 attenuates this effect. Moreover, these results show that allergic airway inflammation impacts immunity at a distant mucosal site.

Early Metabolic Syndrome (MetS) in Chronic Rhesus Macaque Model of Human Allergic Asthma

Human asthma, obesity, MetS, overt Type 2 diabetes, and related sequelae such as cardiovascular diseases, account for much of the mortality and morbidity worldwide. The etiology and complex physiological mechanisms underlying these pathological states intersect within the human body – and within Rhesus macaques. Much like humans, these animals (in captivity) often develop spontaneous, age‐related obesity. Hence, these animals are ideally suited for investigations of obesity and metabolism, as well as chronic allergic asthma.In 2013, twenty animals were sensitized by i.p. injection of house dust mite antigen (HDM) adsorbed to alum; airway sensitization and maintenance were accomplished by exposure to aerosolized HDM (aeroHDM) at ≥ 2‐week intervals, to a dose that induced an acute asthmatic response: ≥ 100% increase in lung resistance, ≥ 40% decrease in dynamic compliance, and/or peripheral oxygen saturation ≤ 70%. Periodically, we assessed the late phase asthmatic response 24 hours after aeroHDM exposure: airway hyperreactivity was assessed by aerosolized methacholine challenge; pulmonary inflammation was assessed by bronchoalveolar lavage. Occasionally animals were also exposed to an experimental asthma therapeutic.In 2018, ten animals had developed obesity and were suspected to harbor other clinical manifestations of MetS. Retrospective analyses confirmed relative hypertension in animals that had robust responsiveness to aeroHDM and were &gt; 16 kg. Using archived frozen serum samples, we reconstructed the biochemical history of adiposity development and glucose metabolism ‐ a story that was evolving coincident with chronic exposures to both Diet A and aeroHDM (Fig. 1). By age 10 years, 4/5 of the largest animals (body weight, 21 ± 2 kg; waist circumference in lateral recumbency, 68 ± 5 cm; BMI using crown‐to‐rump length, 53 ± 3 kg/m2: values are mean ± SD) had insulin resistance (peak HOMA‐IR, 61 ± 29) associated with leptin &gt; 14 ng/ml and total adiponectin &lt; 3.5 μg/ml; 3/5 animals had dyslipidemia (Fig. 2); 1/5 animals had diabetes by age 8 years – 4 to 6 years earlier than would be expected based on non‐human primate literature. Biomarkers of inflammation and oxidative stress are outstanding.In July 2019, six months after switching to lower carbohydrate/higher protein Diet B, and &gt; 12 months since the last aeroHDM exposure: all animals lost weight coincident with larger animals resolving insulin resistance, dyslipidemia, and diabetes. As seen in some obese asthmatic humans, larger animals had higher pulmonary inflammation (especially neutrophilic) and higher airway hyperreactivity to aerosolized methacholine.We concluded that chronic allergic inflammation synergized with inflammation of developing adiposity, accelerating onset of MetS in susceptible animals. We hypothesize that resumption of chronic periodic aeroHDM exposure will trigger more rapid progression/re‐establishment of MetS, IR, and eventually overt Type 2 diabetes if we do not intervene.Historical event timeline.Figure 1Body weight and serum triglycerides of 5 largest animals (mean ± SD: n=3 to 5 for each time point). Gray vertical bar: gradual transition to lower carbohydrate/higher protein Diet B.Figure 2

The Th2 adjuvant activity of indoor dust is dependent upon Dectin-1

Indoor dust (ID) contains environmental agents that promote T helper 2 (Th2) responses to inhaled allergens through a tumor necrosis factor (TNF)-dependent pathway. The main components of ID responsible for inducing Th2 responses are unknown. Here, we investigated if the Th2 adjuvant activity of ID is mediated by ligands for Dectin-1, a C-type lectin receptor that recognizes microbe-derived β-glucans. Using a cell reporter assay, we screened ID samples for bioactive Dectin-1 ligands. Using an ID-mediated asthma model, we compared allergic airway inflammation (airway eosinophilia, serum total IgE levels), TNF levels in bronchoalveolar lavage fluid (BALF), and airway hyperreactivity (AHR) in wild type (WT) and Dectin-1-deficient (Clec7a−/−) mice. ID samples contained bioactive Dectin-1 ligands that activated nuclear factor kappa B signaling. In an ID-mediated asthma model, allergic airway inflammation was diminished in Clec7a−/− mice compared to WT mice, as demonstrated by decreased total airway cells, airway eosinophils and serum total IgE levels following allergen challenge. In contrast, allergen-induced AHR was similar in WT and Clec7a−/− mice. Following acute exposure to ID, Clec7a−/− mice had significantly decreased TNF levels in BALF compared to WT mice. In Clec7a−/− mice, addition of TNF during sensitization with ID and allergen restored airway eosinophilia upon allergen challenge. Dectin-1 signaling is required for the Th2 adjuvant activity of ID, possibly by inducing TNF production during airway sensitization to inhaled allergens. Collectively, these findings suggest that Dectin-1 ligands within the indoor environment may contribute to asthma development by promoting allergic airway sensitization.

Endocrine Disruptor Bisphenol A (BPA) Triggers Systemic Para-Inflammation and is Sufficient to Induce Airway Allergic Sensitization in Mice.

Allergic airway diseases are accompanied by increased permeability and an inflammatory state of epithelial barriers, which are thought to be susceptible to allergen sensitization. Although exogenous drivers (proteases, allergens) of epithelial barrier disruption and sensitization are well studied, endogenous contributors (diet, xenobiotics, hormones, and metabolism) to allergic sensitization are much less understood. Xenoestrogens are synthetic or natural chemical compounds that have the ability to mimic estrogen and are ubiquitous in the food and water supply of developed countries. By interfering with the estrogen produced by the endocrine system, these compounds have the systemic potential to disrupt the homeostasis of multiple tissues. Our study examined the potential of prototypical xenoestrogen bisphenol A (BPA) to disrupt epithelial homeostasis in vitro and promote allergic responses in vivo. We found that BPA exposure in epithelial cultures in vitro significantly inhibited epithelial cell proliferation and wound healing, as well as promoted the expression of the innate alarmin cytokine TSLP in a time-and dose-dependent manner. In vivo, the exposure to BPA through water supply or inhalation induced a systemic para-inflammatory response by promoting the expression of innate inflammatory mediators in the skin, gut, and airway. In a murine tolerogenic antigen challenge model, chronic systemic exposure to BPA was sufficient to induce airway sensitization to innocuous chicken egg ovalbumin in the complete absence of adjuvants. Mechanistic studies are needed to test conclusively whether endocrine disruptors may play an upstream role in allergic sensitization via their ability to promote a para-inflammatory state.

Upregulation of H3K27 Demethylase KDM6 During Respiratory Syncytial Virus Infection Enhances Proinflammatory Responses and Immunopathology.

Severe disease following respiratory syncytial virus (RSV) infection has been linked to enhanced proinflammatory cytokine production that promotes a Th2-type immune environment. Epigenetic regulation in immune cells following viral infection plays a role in the inflammatory response and may result from upregulation of key epigenetic modifiers. In this study, we show that RSV-infected bone marrow-derived dendritic cells (BMDC) as well as pulmonary dendritic cells (DC) from RSV-infected mice upregulated the expression of Kdm6b/Jmjd3 and Kdm6a/Utx, H3K27 demethylases. KDM6-specific chemical inhibition (GSK J4) in BMDC led to decreased production of chemokines and cytokines associated with the inflammatory response during RSV infection (i.e., CCL-2, CCL-3, CCL-5, IL-6) as well as decreased MHC class II and costimulatory marker (CD80/86) expression. RSV-infected BMDC treated with GSK J4 altered coactivation of T cell cytokine production to RSV as well as a primary OVA response. Airway sensitization of naive mice with RSV-infected BMDCs exacerbate a live challenge with RSV infection but was inhibited when BMDCs were treated with GSK J4 prior to sensitization. Finally, in vivo treatment with the KDM6 inhibitor, GSK J4, during RSV infection reduced inflammatory DC in the lungs along with IL-13 levels and overall inflammation. These results suggest that KDM6 expression in DC enhances proinflammatory innate cytokine production to promote an altered Th2 immune response following RSV infection that leads to more severe immunopathology.

Role of chemical composition and redox modification of poorly soluble nanomaterials on their ability to enhance allergic airway sensitisation in mice

BackgroundEngineered nanoparticles (NPs) have been shown to enhance allergic airways disease in mice. However, the influence of the different physicochemical properties of these particles on their adjuvant properties is largely unknown. Here we investigate the effects of chemical composition and redox activity of poorly soluble NPs on their adjuvant potency in a mouse model of airway hypersensitivity.ResultsNPs of roughly similar sizes with different chemical composition and redox activity, including CeO2, Zr-doped CeO2, Co3O4, Fe-doped Co3O4(using Fe2O3 or Fe3O4) and TiO2 NPs, all showed adjuvant activity. OVA induced immune responses following intranasal exposure of BALB/c mice to 0.02% OVA in combination with 200 μg NPs during sensitization (on day 1, 3, 6 and 8) and 0.5% OVA only during challenge (day 22, 23 and 24) were more pronounced compared to the same OVA treatment regime without NPs. Changes in OVA-specific IgE and IgG1 plasma levels, differential cell count and cytokines in bronchoalveolar lavage fluid (BALF), and histopathological detection of mucosa cell metaplasia and eosinophil density in the conducting airways were observed. Adjuvant activity of the CeO2 NPs was primarily mediated via the Th2 response, while that of the Co3O4 NPs was characterised by no or less marked increases in IgE plasma levels, BALF IL-4 and IL-5 concentrations and percentages of eosinophils in BALF and more pronounced increases in BALF IL-6 concentrations and percentages of lymphocytes in BALF. Co-exposure to Co3O4 NPs with OVA and subsequent OVA challenge also induced perivascular and peribronchiolar lymphoid cell accumulation and formation of ectopic lymphoid tissue in lungs. Responses to OVA combined with various NPs were not affected by the amount of doping or redox activity of the NPs.ConclusionsThe findings indicate that chemical composition of NPs influences both the relative potency of NPs to exacerbate allergic airway sensitization and the type of immune response. However, no relation between the acellular redox activity and the observed adjuvant activity of the different NPs was found. Further research is needed to pinpoint the precise physiological properties of NPs and biological mechanisms determining adjuvant activity in order to facilitate a safe-by-design approach to NP development.

Indoor dust acts as an adjuvant to promote sensitization to peanut through the airway

There is growing evidence that environmental peanut exposure through non-oral routes, including the skin and respiratory tract, can result in peanut sensitization. Environmental adjuvants in indoor dust can promote sensitization to inhaled antigens, but whether they contribute to peanut allergy development is unclear. We investigated whether indoor dust promotes airway sensitization to peanut and peanut allergy development in mice. Female and male C57BL/6J mice were exposed via the airways to peanut, indoor dust extract, or both for 2 weeks. Mice were then challenged with peanut and assessed for anaphylaxis. Peanut-specific immunoglobulins, peanut uptake by lung conventional dendritic cells (cDCs), lung innate cytokines, and T cell differentiation in lung-draining lymph nodes were quantified. Innate cytokine production by primary human bronchial epithelial cells exposed to indoor dust was also determined. Inhalational exposure to low levels of peanut in combination with indoor dust, but neither alone, resulted in production of peanut-specific IgE and development of anaphylaxis upon peanut challenge. Indoor dust triggered production of innate cytokines in murine lungs and in primary human bronchial epithelial cells. Additionally, inhaled indoor dust stimulated maturation and migration of peanut-laden lung type 1 cDCs to draining lymph nodes. Inhalational exposure to peanut and indoor dust induced peanut-specific T helper 2 cell differentiation and accumulation of T follicular helper cells in draining lymph nodes, which were associated with increased B cell numbers and peanut-specific immunoglobulin production. Indoor dust promotes airway sensitization to peanut and development of peanut allergy in mice. Our findings suggest that environmental adjuvants in indoor dust may be determinants of peanut allergy development in children.

UTILITY OF CLINICAL AND RADIOLOGICAL SIGNS IN AIRWAY FOREIGNBODIES

Background: Foreign Body Aspiration (FBA) is a grave problem in children and delays in diagnosis and management can be devastating. The history is very often vague, with subtle physical and chest radiograph abnormalities&#x0D; Aim: To assess the diagnostic accuracy of the triad: history of chocking, unilateral reduction in air entry to lungs, unilateral hyperinflation or collapse on chest X-ray.&#x0D; Results: In our study sensitivity of history of chocking in detection of FB was 80.47%, specificity was 20.45%. Sensitivity of examination finding of unilateral decrease in air entry to lungs in detection of FB was 71.59%%, specificity was 4.545%. Sensitivity and specificity of chest radiograph in detection of FB was 54.43% and 47.72% respectively. When the triad of history of chocking, decreased air entry on examination and chest radiograph finding of hyperinflation or collapse was considered in detection of FB in airway sensitivity was 59.76% while specificity was 79.54%.&#x0D; Conclusion: Bronchoscopy is a gold standard in diagnosis of FBA. History, physical examination and radiologic studies have a very low specificity in detection of FBA. The triad of history of chocking, decreased air entry on examination and chest radiograph finding of hyperinflation or collapse has a better specificity in detection of FBA than individual parameters.

Treatment with Paracetamol is not Associated with Increased Airway Sensitivity and Risk of Asthma in Rats.

Some studies have linked the use of paracetamol (PAR) with adverse effects like wheezing, exacerbation of asthma symptoms and other respiratory problems. Other studies are inconclusive or deny this correlation. This makes the association between PAR and airway hypersensitivity very controversial and still under debate. This work investigated if chronic treatment with PAR in rats could directly affect the contraction and relaxation for different stimulus in isolated airways. Rats were treated for 2 weeks with PAR (400 mg/Kg, v.o.). The blood was collected for biochemical analysis (alanine aminotransferase (ALT), aspartate aminotransferase (AST), TBARs reaction and glutathione) and isolated tracheal rings were prepared in organ bath to measure isometric tone after contractile and relaxant stimulus. Hepatic enzymes (ALT, AST) and lipid peroxidation were increased after PAR-treatment, while glutathione was decreased. Rats do not present any alteration in airway myocytes responsiveness, either to contractile or relaxant stimulus (i.e. cholinergic agonist, membrane depolarization, Ca2+ influx across sarcolemma, internal Ca2+ release from sarcoplasmic reticulum, Ca2+ channel blocking, β-agonist and NOmediating relaxation). Despite increased oxidative stress and reduced antioxidant defense, chronic treatment with PAR does not induce airway hypersensitivity or risk of asthma in rats.