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Exaggerated airway constriction triggered by repeated exposure to allergen, also called hyperreactivity, is a hallmark of asthma. Whereas vagal sensory neurons are known to function in allergen-induced hyperreactivity1-3, the identity of downstream nodes remains poorly understood. Here we mapped a full allergen circuit from the lung to the brainstem and back to the lung. Repeated exposure of mice to inhaled allergen activated the nuclei of solitary tract (nTS) neurons in a mast cell-, interleukin-4 (IL-4)- and vagal nerve-dependent manner. Single-nucleus RNA sequencing, followed by RNAscope assay at baseline and allergen challenges, showed that a Dbh+ nTS population is preferentially activated. Ablation or chemogenetic inactivation of Dbh+ nTS neurons blunted hyperreactivity whereas chemogenetic activation promoted it. Viral tracing indicated that Dbh+ nTS neurons project to the nucleus ambiguus (NA) and that NA neurons are necessary and sufficient to relay allergen signals to postganglionic neurons that directly drive airway constriction. Delivery of noradrenaline antagonists to the NA blunted hyperreactivity, suggesting noradrenaline as the transmitter between Dbh+ nTS and NA. Together, these findings provide molecular, anatomical and functional definitions of key nodes of a canonical allergen response circuit. This knowledge informs how neural modulation could be used to control allergen-induced airway hyperreactivity.

Asthma is one of the most prevalent chronic respiratory diseases in childhood and adolescence. It is characterized by inflammation and bronchial hyperreactivity, which trigger bronchoconstriction and airway obstructions. This condition represents a significant public health issue due to its impact on emergency services, hospitalizations, and school absenteeism. In Ecuador, previous studies have revealed a prevalence of asthma symptoms in adolescents but a low rate of diagnosis, suggesting possible underdiagnosis and insufficient control of the condition. Exercise-induced bronchoconstriction (EIB) is a common manifestation in patients with uncontrolled asthma and can be assessed through provocation tests, such as the Exercise-Induced Bronchial Provocation Test (EIBPT). This study aims to evaluate the bronchial response to the EIBPT in Ecuadorian children and adolescents to contribute to a better understanding of asthma in this population. This nonexperimental, descriptive, observational study was conducted on 25 students aged 8 to 17 years without a prior asthma diagnosis. Participants underwent the EIBPT on a treadmill. The criterion for a positive result was set at a decrease in VEF1 %, observed in only 4% of the 25 participants. The low prevalence of EIB in this sample suggests that, in Ecuadorian children and adolescents without a prior asthma diagnosis, exercise does not induce significant bronchoconstriction, ruling out the existence of an asthma underdiagnosis. [ABSTRACT FROM AUTHOR]

Objective: To compare the thermographic pattern of regions of interest (ROI) of respiratory muscles in young asthmatics with and without bronchospasm induced by eucapnic voluntary hyperpnea (EVH). Materials and Methods: Cross‐sectional study carried out with 55 young (55% male and 45% females) aged 12.5 ± 3.3 years, divided in nine nonasthmatics, 22 asthmatics without exercise‐induced bronchospasm compatible response (EIB‐cr) and 24 asthmatics with EIB‐cr. The diagnosis of EIB was given to subjects with a fall in forced expiratory volume in the first second (FEV1) ≥ 10% compared to baseline. Thermographic recordings of respiratory muscles were delimited in ROI of the sternocleidomastoid (SCM), pectoral, and rectus abdominis intention area. Thermal captures and FEV1 were taken before and 5, 10, 15 and 30 min after EVH. Results: Twenty‐four (52.1%) of asthmatics had EIB‐cr. There was a decrease in temperature at 10 min after EVH test in the SCM, pectoral and rectus abdominis ROIs in all groups (both with p < 0.05). There was a decrease in temperature (% basal) in asthmatic with EIB‐cr compared to nonasthmatics in the rectus abdominis area (p < 0.05). Conclusion: There was a decrease in temperature in the ROIs of different muscle groups, especially in asthmatics. The greater drop in FEV1 observed in individuals with EIB‐cr was initially associated with a decrease in skin temperature, with a difference between the nonasthmatics in the abdominal muscle area. It is likely that this decrease in temperature occurred due to a temporary displacement of blood flow to the most used muscle groups, with a decrease in the region of the skin evaluated in the thermography. [ABSTRACT FROM AUTHOR]

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Introduction: The multiple forced expiratory maneuvers that must be performed during methacholine test require a high degree of collaboration and can lead to fatigue. However, impulse oscillometry (IOS) is a noninvasive test, quick and easy to perform, that does not require effort-dependent maneuvers. Objectives: The primary endpoint was to evaluate the relationship between IOS and spirometry during the methacholine test. The secondary endpoint was to study the predictive value of baseline IOS in the development of bronchial hyperreactivity. Methods: Observational, prospective, cross-sectional study, with recruitment of consecutive patients from the pulmonology department with clinical suspicion of bronchial asthma with negative bronchodilator test and normal FeNO. Results: Twenty-five patients were included, with a mean age of 49 ± 18 years. Thirteen patients (52%) had a positive methacholine test. The correlation between IOS indices and FEV1 was significant (p < 0.05) in all cases. The indices with the highest predictive power were R5-20 and AX. The optimal cutoff points were an increase of greater than 32.96% in R5, greater than 120.83% for X5, an increase of 30.30 [kPa l-1s-1] in R5-20, and an increase of 1.01 [kPa l−1] for AX. Baseline oscillometry demonstrated a strong predictive value in the development of bronchial hyperreactivity, with a sensitivity of 61.5% and a specificity of 91.7%, using the cut-off point of 160.0% for R5. Conclusions: IOS may be a valuable alternative to forced spirometry in detecting bronchial hyperreactivity during the methacholine test, showing a good correlation between both tests. [ABSTRACT FROM AUTHOR]

OBJECTIVE: In this research, we aimed to elucidate the effect of obstructive sleep apnea syndrome (OSAS) and obesity on pulmonary volumes and bronchial hyperreactivity, and particularly the effect of supine position on pulmonary volume and functions. PATIENTS AND METHODS: This was a prospective, cross-sectional study with a total of 96 patients (age range, 20-65 years). Based on the body mass index (BMI) and Apnea-Hypopnea Index (AHI) scores, the patients were divided into four groups: Group 1: AHI=15/h, BMI=30 kg/m2 (n=24), G roup 2: A HI=15/h, B MI<30 k g/m2 (n=24), Group 3: AHI<15/h, BMI=30 kg/m2 (n=24), and Group 4: AHI<15/h, BMI<30 kg/m2 (n=24). All patients first had static and dynamic pulmonary function tests and carbon monoxide diffusion tests (TLco and Kco) in the sitting and supine positions. A bronchial provocation test with methacholine was applied to all patients in the sitting position one day later. Analysis of variance (ANOVA) and multivariate linear regression was used in the statistical analysis. RESULTS: Airway responsiveness was observed in 4 of the patients included in the study, and there was no statistically significant difference between the groups. A statistically significant decrease was observed in forced vital capacity (FVC), forced expiratory volume in one second (FEV1), peak expiratory flow (PEF), total lung capacity (TLC) and functional residual capacity (FRC), especially in Group 1 in sitting position compared to Group 4 (p=0.001, p=0.001, p=0.025, p=0.043, and p=0.001, respectively). Changes in pulmonary functions in the transition from sitting to a supine position did not show any significant difference in the study groups (p<0.05). We observed no difference in the diffusion capacity in the sitting and supine positions among the groups (p<0.05). CONCLUSIONS: The severity of AHI and BMI particularly affect the lower airway, but changes in the position did not show any significant difference in the study groups. [ABSTRACT FROM AUTHOR]

Asthma currently affects more than 339 million people worldwide. In the present preliminary study, we examined the efficacy of a new, inhalable soluble epoxide hydrolase inhibitor (sEHI), 1-trifluoromethoxyphenyl-3-(1-propionylpiperidin-4-yl) urea (TPPU), to attenuate airway inflammation, mucin secretion, and hyper-responsiveness (AHR) in an ovalbumin (OVA)-sensitized murine model. Male BALB/c mice were divided into phosphate-buffered saline (PBS), OVA, and OVA+TPPU (2- or 6-h) exposure groups. On days 0 and 14, the mice were administered PBS or sensitized to OVA in PBS. From days 26-38, seven challenge exposures were performed with 30 min inhalation of filtered air or OVA alone. In the OVA+TPPU groups, a 2- or 6-h TPPU inhalation preceded each 30-min OVA exposure. On day 39, pulmonary function tests (PFTs) were performed, and biological samples were collected. Lung tissues were used to semi-quantitatively evaluate the severity of inflammation and airway constriction and the volume of stored intracellular mucosubstances. Bronchoalveolar lavage (BAL) and blood samples were used to analyze regulatory lipid mediator profiles. Significantly (p < 0.05) attenuated alveolar, bronchiolar, and pleural inflammation; airway resistance and constriction; mucosubstance volume; and inflammatory lipid mediator levels were observed with OVA+TPPU relative to OVA alone. Cumulative findings indicated TPPU inhalation effectively inhibited inflammation, suppressed AHR, and prevented mucosubstance accumulation in the murine asthmatic model. Future studies should determine the pharmacokinetics (i.e., absorption, distribution, metabolism, and excretion) and pharmacodynamics (i.e., concentration/dose responses) of inhaled TPPU to explore its potential as an asthma-preventative or -rescue treatment.

Objective: to determine the distribution of genotypes of genetic polymorphism of manganese superoxide dismutase and to assess the ventilation lung capacity in children& residents of radioactively contaminated areas and children exposed to stressful life events during the war period. Materials and methods. The study involved school&age children - residents of radioactively contaminated areas (RCA) and children exposed to stressful life events during wartime. All those examined had no clinical signs of res& piratory pathology. Genotypes for the SOD2 Val16Ala genetic variant were determined using the polymerase chain reaction (PCR) method. The study of the ventilation lung capacity was assessed by the method of computer spirom& etry based on the flow&volume loop analysis data. Results and conclusions. When studying the genotypes and alleles of the polymorphic marker Superoxide Dismutase 2 Gene Val1 Alain children of group I and II, no significant differences were found between the frequency distribution indicators of genotypes and alleles compared with the reference values of the those of the control group, which consisted of practically healthy residents of the Middle East. Also, no significant differences in the fre& quency distribution of the C and T alleles of the polymorphic marker Superoxide Dismutase 2 Gene Val16Ala were found in the children of both examined groups compared to other representatives of the Caucasian race (Lithua& nians, Finns, Germans). Among children in groups I and II, there was a tendency toward a decrease in the frequen& cy of occurrence of homozygotes with the CC genotype and an increase in the frequency of occurrence of heterozy& gotes with the CT genotype. Among children of both examined groups, in heterozygotes with the CT genotype of the Superoxide Dismutase 2 Gene Val16Ala polymorphism, a tendency towards an increase in the frequency of bronchial hyperreactivity was observed compared to CC homozygotes. Analysis of the variant allele frequency distribution of SOD2 Val16Ala polymorphism in children of both examined groups determined that in the presence of bronchial hyper& reactivity there was a tendency toward an increase in the prevalence of the T allele and a decrease in the prevalence of the C allele. [ABSTRACT FROM AUTHOR]

Background. Considering the features of basic therapy for chronic inflammatory bronchopulmonary process in cystic fibrosis (CF), which includes almost daily inhalation of pharmacological drugs (mucolytics, hypertonic saline (HS), antibiotics), evaluation of their tolerability is relevant in practice. The purpose of the study is to create a prognostic scale convenient for use in practical medicine, which would predict development of bronchial hyperreactivity syndrome in children with CF, based on clinical and anamnestic data, the results of molecular genetic research and inhalation tests with increasing concentrations of HS to prescribe personalized treatment. Materials and methods. The results of clinical and anamnestic, microbiological, biochemical, molecular and genetic studies and inhalation tests with increasing concentrations of HS were analyzed in 40 children with CF. The creation of the predictive algorithm was based on the application of correlation analysis, receiver operating characteristic analysis, binary logistic regression, Wald and Kullback method. Results. Two prognostic models have been created that can be used at different stages of providing medical care. Model 1 was built for the ambulatory stage of providing medical care to patients with CF, considering clinical and anamnestic data, molecular genetic predictors, as well as clinical symptoms during inhalation tests with increasing concentrations of HS. This model also can be used in young children who cannot perform spirometry to assess their external breathing function. For the highly specialized medical care, model 2 was created, which considers indicators of spirometric data of inhalation tests with increasing concentrations of HS and the level of exhaled nitric oxide. Conclusions. The developed models make it possible to calculate with high probability the risk of developing bronchial hyperreactivity to perform a personalized selection of HS and choose preventive brocholytic therapy as needed.

Background: Ultra-processed Food (UPF) consumption can play a role in the pathogenesis and progression of asthma. The aim of this study was to evaluate the association between the consumption of UPF and asthma. Methods: This cross-sectional study included 1857 adults aged 23–25 years from the Ribeirão Preto-SP birth cohort (1978/1979). The exposure variable was the consumption of UPF (expressed as their percentage contribution to energy intake—% total caloric value [%TCV] and their percentage contribution to the amount of food ingested—%grams), which was assessed with a food frequency questionnaire. Asthma was the outcome and was defined based on a positive methacholine challenge test and the presence of wheezing, chest tightness, or shortness of breath over the last 12 months. Poisson regression with robust variance was used to estimate the association between these variables. Unadjusted analyses and analyses adjusted for sex, age, household income, smoking, and physical activity level were performed. Results: The prevalence of asthma in the sample was 13.2%. The mean total consumption of UPF was 37.9 ± 11.2% TCV (corresponding to 35.1 ± 15.1% grams). There was no association between the consumption of UPF and asthma in adults. Conclusion: This study provides no evidence for an association between the consumption of UPF and asthma in young adults. [ABSTRACT FROM AUTHOR]

Asthma is a chronic inflammatory disease of the airways with contributions from genes, environmental exposures, and their interactions. While genome-wide association studies (GWAS) in humans have identified ~200 susceptibility loci, the genetic factors that modulate risk of asthma through gene-environment (GxE) interactions remain poorly understood. Using the Hybrid Mouse Diversity Panel (HMDP), we sought to identify the genetic determinants of airway hyperreactivity (AHR) in response to diesel exhaust particles (DEP), a model traffic-related air pollutant. As measured by invasive plethysmography, AHR under control and DEP-exposed conditions varied 3-4-fold in over 100 inbred strains from the HMDP. A GWAS with linear mixed models mapped two loci significantly associated with lung resistance under control exposure to chromosomes 2 (p = 3.0x10-6) and 19 (p = 5.6x10-7). The chromosome 19 locus harbors Il33 and is syntenic to asthma association signals observed at the IL33 locus in humans. A GxE GWAS for post-DEP exposure lung resistance identified a significantly associated locus on chromosome 3 (p = 2.5x10-6). Among the genes at this locus is Dapp1, an adaptor molecule expressed in immune-related and mucosal tissues, including the lung. Dapp1-deficient mice exhibited significantly lower AHR than control mice but only after DEP exposure, thus functionally validating Dapp1 as one of the genes underlying the GxE association at this locus. In summary, our results indicate that some of the genetic determinants for asthma-related phenotypes may be shared between mice and humans, as well as the existence of GxE interactions in mice that modulate lung function in response to air pollution exposures relevant to humans.

Epidemiologic studies link organophosphorus pesticides (OPs) to increased incidence of asthma. In guinea pigs, OP-induced airway hyperreactivity requires macrophages and TNF-α. Here, we determined whether OPs interact directly with macrophages to alter cytokine expression or release. Human THP1 cells were differentiated into macrophages and then exposed to parathion, chlorpyrifos, or diazinon, or their oxon, phosphate, or phosphorothioate metabolites for 24 hours in the absence or presence of reagents that block cholinergic receptors. TNF-α, IL-1β, platelet-derived growth factor, and transforming growth factor-β mRNA and protein were quantified by qPCR and ELISA, respectively. The effects of OPs on NF-κB, acetylcholinesterase, and intracellular calcium were also measured. Parent OPs and their oxon metabolites upregulated cytokine mRNA and stimulated cytokine release. TNF-α release, which was the most robust response, was triggered by parent, but not oxon, compounds. Cytokine expression was also increased by diethyl dithiophosphate but not diethyl thiophosphate or diethyl phosphate metabolites. Parent OPs, but not oxon metabolites, activated NF-κB. Parent and oxon metabolites decreased acetylcholinesterase activity, but comparable acetylcholinesterase inhibition by eserine did not mimic OP effects on cytokines. Consistent with the noncholinergic mechanisms of OP effects on macrophages, pharmacologic antagonism of muscarinic or nicotinic receptors did not prevent OP-induced cytokine expression or release. These data indicate that phosphorothioate OP compounds directly stimulate macrophages to release TNF-α, potentially via activation of NF-κB, and suggest that therapies that target NF-κB may prevent OP-induced airway hyperreactivity.

BackgroundAllergic asthma causes morbidity in many subjects, and novel precision-directed treatments would be valuable.ObjectiveWe sought to examine the role of a novel innate molecule, repulsive guidance molecule b (RGMb), in murine models of allergic asthma.MethodsIn models of allergic asthma using ovalbumin or cockroach allergen, mice were treated with anti-RGMb or control mAb and examined for airway inflammation and airway hyperreactivity (AHR), a cardinal feature of asthma. The mechanisms by which RGMb causes airways disease were also examined.ResultsWe found that blockade of RGMb by treatment with anti-RGMb mAb effectively blocked the development of airway inflammation and AHR. Importantly, blockade of RGMb completely blocked the development of airway inflammation and AHR, even if treatment occurred only during the challenge (effector) phase. IL-25 played an important role in these models of asthma because IL-25 receptor-deficient mice did not develop disease after sensitization and challenge with allergen. RGMb was expressed primarily by innate cells in the lungs, including bronchial epithelial cells (known producers of IL-25), activated eosinophils, and interstitial macrophages, which in the inflamed lung expressed the IL-25 receptor and produced IL-5 and IL-13. We also found that neogenin, the canonical receptor for RGMb, was expressed by interstitial macrophages and bronchial epithelial cells in the inflamed lung, suggesting that an innate RGMb-neogenin axis might modulate allergic asthma.ConclusionsThese results demonstrate an important role for a novel innate pathway in regulating type 2 inflammation in patients with allergic asthma involving RGMb and RGMb-expressing cells, such as interstitial macrophages and bronchial epithelial cells. Moreover, targeting this previously unappreciated innate pathway might provide an important treatment option for allergic asthma.

Previous studies have suggested a role for Tet1 in the pathogenesis of childhood asthma. However, how Tet1 contributes to asthma remains unknown. Here we used mice deficient for Tet1 in a well-established model of allergic airway inflammation and demonstrated that loss of Tet1 increased disease severity including airway hyperresponsiveness and lung eosinophilia. Increased expression of Muc5ac, Il13, Il33, Il17a, Egfr, and Tff2 were observed in HDM-challenged Tet1-deficient mice compared to Tet1+/+ littermates. Further, transcriptomic analysis of lung RNA followed by pathway and protein network analysis showed that the IFN signaling pathway was significantly upregulated and the aryl hydrocarbon receptor (AhR) pathway was significantly downregulated in HDM-challenged Tet1-/- mice. This transcriptional regulation of the IFN and AhR pathways by Tet1 was also present in human bronchial epithelial cells at base line and following HDM challenges. Genes in these pathways were further associated with changes in DNA methylation, predicted binding of transcriptional factors with relevant functions in their promoters, and the presence of histone marks generated by histone enzymes that are known to interact with Tet1. Collectively, our data suggest that Tet1 inhibits HDM-induced allergic airway inflammation by direct regulation of the IFN and AhR pathways.

Background. Inhaled hypertonic saline solutions (IHSS) are included in the list of mandatory prescriptions in the treatment of cystic fibrosis (CF). However, some patients with CF may develop bronchial hyperreactivity (BHR), which may be the cause of violation of the treatment protocol. The purpose is to study the state of bronchial reactivity to IHSS and its dependence on the clinical, functional and microbiological features of CF course in children. Materials and methods. Forty children with CF were examined. All of them underwent general clinical, molecular genetic, laboratory and microbiological examination. Instrumental methods included spirometry, measurement of fractional exhaled nitric oxide, X-ray and computer tomography of the chest. To determine the individual tolerance of inhalations of hypertonic sodium chloride solution (HSCS), the research protocol proposed by E.P. Dellon et al. was used. Results. According to the results of the research protocol, 17 (42.5 %) patients with CF had BHR to HSCS. The highest frequency of BHR was found in children with a severe CF course. There was no dependence of BHR in CF patients on allergic pathology and a burdened allergic history. Assessment of the tolerance of HSCS before prescribing basic therapy is important. Early functional signs of BHR, which may require the preventive administration of short-acting β2-agonists when using HSCS in children with CF, are as follows: reduction in forced expiratory volume in 1 second by 7 % and maximal expiratory flow at 25 % by 6 % when using 3% HSCS. Conclusions. The presence of BHR in patients with CF may interfere with adequate basic therapy by inhalation. The prescription of IHSS to patients with CF should be personalized with the determination of individual sensitivity of a person to predict a positive therapeutic effect.

Microbial maturation disrupted by early-life dysbiosis has been linked with increased asthma risk and severity; however, the immunological mechanisms underpinning this connection are poorly understood. We sought to understand how delaying microbial maturation drives worsened asthma outcomes later in life and its long-term durability. Drinking water was supplemented with antibiotics on Postnatal Days 10-20. To assess the immediate and long-term effects of delaying microbial maturation on experimental asthma, we initiated house dust mite exposure when bacterial diversity was either at a minimum or had recovered. Airway hyperresponsiveness, histology, pulmonary leukocyte recruitment, flow cytometric analysis of cytokine-producing lymphocytes, and assessment of serum IgG1 (Immunoglobulin G1) and IgE (Immunoglobulin E) concentrations were performed. RT-PCR was used to measure IL-13 (Interleukin 13)-induced gene expression in sequentially sorted mesenchymal, epithelial, endothelial, and leukocyte cell populations from the lung. Delayed microbial maturation increased allergen-driven airway hyperresponsiveness and Th17 frequency compared with allergen-exposed control mice, even when allergen exposure began after bacterial diversity recovered. Blockade of IL-17A (Interleukin 17A) reversed the airway hyperresponsiveness phenotype. In addition, allergen exposure in animals that experienced delayed microbial maturation showed signs of synergistic signaling between IL-13 and IL-17A in the pulmonary mesenchymal compartment. Delaying microbial maturation in neonates promotes the development of more severe asthma by increasing Th17 frequency, even if allergen exposure is initiated weeks after microbial diversity is normalized. In addition, IL-17A-aggravated asthma is associated with increased expression of IL-13-induced genes in mesenchymal, but not epithelial cells. [ABSTRACT FROM AUTHOR]

Numerous epidemiologic studies have identified an association between occupational exposures to organophosphorus pesticides (OPs) and asthma or asthmatic symptoms in adults. Emerging epidemiologic data suggest that environmentally relevant levels of OPs may also be linked to respiratory dysfunction in the general population and that in utero and/or early life exposures to environmental OPs may increase risk for childhood asthma. In support of a causal link between OPs and asthma, experimental evidence demonstrates that occupationally and environmentally relevant OP exposures induce bronchospasm and airway hyperreactivity in preclinical models. Mechanistic studies have identified blockade of autoinhibitory M2 muscarinic receptors on parasympathetic nerves that innervate airway smooth muscle as one mechanism by which OPs induce airway hyperreactivity, but significant questions remain regarding the mechanism(s) by which OPs cause neuronal M2 receptor dysfunction and, more generally, how OPs cause persistent asthma, especially after developmental exposures. The goals of this review are to 1) summarize current understanding of OPs in asthma; 2) discuss mechanisms of OP neurotoxicity and immunotoxicity that warrant consideration in the context of OP-induced airway hyperreactivity and asthma, specifically, inflammatory responses, oxidative stress, neural plasticity, and neurogenic inflammation; and 3) identify critical data gaps that need to be addressed in order to better protect adults and children against the harmful respiratory effects of low-level OP exposures.

Ras, a small GTPase protein, is thought to mediate Th2-dependent eosinophilic inflammation in asthma. Ras requires cell membrane association for its biological activity, and this requires the posttranslational modification of Ras with an isoprenyl group by farnesyltransferase (FTase) or geranylgeranyltransferase (GGTase). We hypothesized that inhibition of FTase using FTase inhibitor (FTI)-277 would attenuate allergic asthma by depleting membrane-associated Ras. We used the OVA mouse model of allergic inflammation and human airway epithelial (HBE1) cells to determine the role of FTase in inflammatory cell recruitment. BALB/c mice were first sensitized then exposed to 1% OVA aerosol or filtered air, and half were injected daily with FTI-277 (20 mg/kg per day). Treatment of mice with FTI-277 had no significant effect on lung membrane-anchored Ras, Ras protein levels, or Ras GTPase activity. In OVA-exposed mice, FTI-277 treatment increased eosinophilic inflammation, goblet cell hyperplasia, and airway hyperreactivity. Human bronchial epithelial (HBE1) cells were pretreated with 5, 10, or 20 μM FTI-277 prior to and during 12 h IL-13 (20 ng/ml) stimulation. In HBE1 cells, FTase inhibition with FTI-277 had no significant effect on IL-13-induced STAT6 phosphorylation, eotaxin-3 peptide secretion, or Ras translocation. However, addition of exogenous FPP unexpectedly augmented IL-13-induced STAT6 phosphorylation and eotaxin-3 secretion from HBE1 cells without affecting Ras translocation. Pharmacological inhibition of FTase exacerbates allergic asthma, suggesting a protective role for FTase or possibly Ras farnesylation. FPP synergistically augments epithelial eotaxin-3 secretion, indicating a novel Ras-independent farnesylation mechanism or direct FPP effect that promotes epithelial eotaxin-3 production in allergic asthma.

Purpose: The incidence of persistent rhinitis in childhood is increasing day by day. Since bronchial hyperreactivity (BHR) and asthma can also be seen in a significant proportion of patients with persistent rhinitis, the use of markers that may indicate the risk of developing asthma in these patients is very important in clinical follow-up. In this study, it was aimed to demonstrate the relationship between persistent rhinitis and asthma in childhood using the bronchial methacoline challenge test (BMCT) and to investigate other factors associated with the risk of developing asthma in patients with persistent rhinitis. Materials and Methods: Patients aged 6-18 years who presented with findings of persistent rhinitis were evaluated with a detailed history, physical examination, and spirometry. Patients with normal examination findings and spirometry findings, and patients whose examination findings and nasal inflammation findings were compatible with moderate-to-severe rhinitis were included in the study, and their atopy status was evaluated by skin prick test, and their BHR was evaluated by BMCT. Results: Seventy-three patients were included in the study. The mean age was 9±2.7years, 45.2% of the patients were male. 63% of the patients were allergic and family history of allergy was present in 45.2% of the patients. 82.2% of the patients had BHR detected with BMCT. The median blood eosinophil count (BEC) was 320/mm3 and the IgE level was 160kU/L. Patients with atopy had statistically significantly higher IgE and BEC values compared with non-allergic patients. Patients with BHR were found to be younger, and had higher median BEC values. In multivariant analysis, it was observed that the patient's age<9 years, BEC values>300/mm3, and IgE levels>250IU/L increased the probability of detecting BHR with BMCT. Conclusion: Care should be taken for every patient with persistent rhinitis because of the risk of BHR and asthma. Atopy examinations should be performed, but the possibility of developing BHR and asthma should not be overlooked even in the patients who are non-allergic. [ABSTRACT FROM AUTHOR]

Objective: to determine the distribution of genotypes of genetic polymorphism of manganese superoxide dismutaseand to assess the ventilation lung capacity in children- residents of radioactively contaminated areas and childrenexposed to stressful life events during the war period., Materials and Methods: The study involved school-age children - residents of radioactively contaminated areas(RCA) and children exposed to stressful life events during wartime. All those examined had no clinical signs of respiratory pathology. Genotypes for the SOD2 Val16Ala genetic variant were determined using the polymerase chainreaction (PCR) method. The study of the ventilation lung capacity was assessed by the method of computer spirometry based on the flow-volume loop analysis data., Results and Conclusions: When studying the genotypes and alleles of the polymorphic marker SuperoxideDismutase 2 Gene Val16Alain children of group I and II, no significant differences were found between the frequencydistribution indicators of genotypes and alleles compared with the reference values of the those of the controlgroup, which consisted of practically healthy residents of the Middle East. Also, no significant differences in the frequency distribution of the C and T alleles of the polymorphic marker Superoxide Dismutase 2 Gene Val16Ala werefound in the children of both examined groups compared to other representatives of the Caucasian race (Lithuanians, Finns, Germans). Among children in groups I and II, there was a tendency toward a decrease in the frequency of occurrence of homozygotes with the CC genotype and an increase in the frequency of occurrence of heterozygotes with the CT genotype. Among children of both examined groups, in heterozygotes with the CT genotype of theSuperoxide Dismutase 2 Gene Val16Ala polymorphism, a tendency towards an increase in the frequency of bronchialhyperreactivity was observed compared to CC homozygotes. Analysis of the variant allele frequency distribution ofSOD2 Val16Ala polymorphism in children of both examined groups determined that in the presence of bronchial hyperreactivity there was a tendency toward an increase in the prevalence of the T allele and a decrease in the prevalence of the C allele., (I. Ye. Kolpakov, V. М. Zigalo, V. H. Kondrashova, V. A. Poznysh, L. O. Leonovych.)

Benefits for vitamin E intake in diseases with inflammatory components have been described and related in part, to endogenously formed metabolites (long-chain metabolites, LCM). Here, we have evaluated the role of LCM in relieving asthma features. To this aim, the endogenous vitamin E metabolite α-13′-carboxychromanol (α-T-13′-COOH) that acts as potent 5-lipoxygenase inhibitor has been administered either intraperitoneally or by oral gavage to BALB/c mice sensitized by subcutaneous injection of ovalbumin (OVA). We also have taken advantage of the metabolically stable α-T-13′-COOH derivative α-amplexichromanol (α-AC). Intraperitoneal treatment with α-T-13'-COOH reduced OVA-induced airway hyperreactivity (AHR) as well as peri-bronchial inflammatory cell infiltration. α-AC was more efficacious than α-T-13'-COOH, as demonstrated by better control of AHR and in reducing subepithelial. Both compounds exerted their protective function by reducing pulmonary leukotriene C4 levels. Beneficial effects of α-AC were coupled to inhibition of the sensitization process, as indicated by a reduction of IgE plasma levels, lung mast cell infiltration and Th2 immune response. Metabololipidomics analysis revealed that α-AC raises the pulmonary levels of prostanoids, their degradation products, and 12/15-lipoxygenase metabolites. Following oral administration, the pharmacodynamically different profile in α-T-13′-COOH and α-AC was abrogated as demonstrated by a similar and improved efficacy in controlling asthma features as well as by metabololipidomics analysis. In conclusion, this study highlights a role for LCM and of vitamin E derivatives as pharmacologically active compounds that ameliorate asthmatic features and defines an important role for endogenous vitamin E metabolites in regulating immune response underlying the sensitization process.

Previous studies have highlighted the importance of lung-draining lymph nodes in the respiratory allergic immune response, whereas the lung parenchymal immune system has been largely neglected. We describe a new in vivo model of respiratory sensitization to Blomia tropicalis, the principal asthma allergen in the tropics, in which the immune response is focused on the lung parenchyma by transfer of Th2 cells from a novel TCR transgenic mouse, specific for the major B. tropicalis allergen Blo t 5, that targets the lung rather than the draining lymph nodes. Transfer of highly polarized transgenic CD4 effector Th2 cells, termed BT-II, followed by repeated inhalation of Blo t 5 expands these cells in the lung >100-fold, and subsequent Blo t 5 challenge induced decreased body temperature, reduction in movement, and a fall in specific lung compliance unseen in conventional mouse asthma models following a physiological allergen challenge. These mice exhibit lung eosinophilia; smooth muscle cell, collagen, and goblet cell hyperplasia; hyper IgE syndrome; mucus plugging; and extensive inducible BALT. In addition, there is a fall in total lung volume and forced expiratory volume at 100 ms. These pathophysiological changes were substantially reduced and, in some cases, completely abolished by administration of neutralizing mAbs specific for IL-4 and IL-13 on weeks 1, 2, and 3. This IL-4/IL-13-dependent inducible BALT model will be useful for investigating the pathophysiological mechanisms that underlie asthma and the development of more effective drugs for treating severe asthma.

Gasdermin B (GSDMB) on chromosome 17q21 demonstrates a strong genetic linkage to asthma, but its function in asthma is unknown. Here we identified that GSDMB is highly expressed in lung bronchial epithelium in human asthma. Overexpression of GSDMB in primary human bronchial epithelium increased expression of genes important to both airway remodeling [TGF-β1, 5-lipoxygenase (5-LO)] and airway-hyperresponsiveness (AHR) (5-LO). Interestingly, hGSDMBZp3-Cre mice expressing increased levels of the human GSDMB transgene showed a significant spontaneous increase in AHR and a significant spontaneous increase in airway remodeling, with increased smooth muscle mass and increased fibrosis in the absence of airway inflammation. In addition, hGSDMBZp3-Cre mice showed increases in the same remodeling and AHR mediators (TGF-β1, 5-LO) observed in vitro in GSDMB-overexpressing epithelial cells. GSDMB induces TGF-β1 expression via induction of 5-LO, because knockdown of 5-LO in epithelial cells overexpressing GSDMB inhibited TGF-β1 expression. These studies demonstrate that GSDMB, a gene highly linked to asthma but whose function in asthma is previously unknown, regulates AHR and airway remodeling without airway inflammation through a previously unrecognized pathway in which GSDMB induces 5-LO to induce TGF-β1 in bronchial epithelium.

High levels of arginine metabolizing enzymes, including inducible nitric oxide synthase (iNOS) and arginase (ARG), are typical in asthmatic airway epithelium; however, little is known about the metabolic effects of enhanced arginine flux in asthma. Here, we demonstrated that increased metabolism sustains arginine availability in asthmatic airway epithelium with consequences for bioenergetics and inflammation. Expression of iNOS, ARG2, arginine synthetic enzymes, and mitochondrial respiratory complexes III and IV was elevated in asthmatic lung samples compared with healthy controls. ARG2 overexpression in a human bronchial epithelial cell line accelerated oxidative bioenergetic pathways and suppressed hypoxia-inducible factors (HIFs) and phosphorylation of the signal transducer for atopic Th2 inflammation STAT6 (pSTAT6), both of which are implicated in asthma etiology. Arg2-deficient mice had lower mitochondrial membrane potential and greater HIF-2α than WT animals. In an allergen-induced asthma model, mice lacking Arg2 had greater Th2 inflammation than WT mice, as indicated by higher levels of pSTAT6, IL-13, IL-17, eotaxin, and eosinophils and more mucus metaplasia. Bone marrow transplants from Arg2-deficient mice did not affect airway inflammation in recipient mice, supporting resident lung cells as the drivers of elevated Th2 inflammation. These data demonstrate that arginine flux preserves cellular respiration and suppresses pathological signaling events that promote inflammation in asthma.

Objective: to assess the presence and degree of bronchial hyperreactivity in convalescents of whooping cough based on the results of bronchial provocation tests.Materials and methods. Using bronchial provocative samples with a 0,02/0,33% histamine solution and 0,33% methacholine solution on a PROVOTEST-2 apparatus from PARI, bronchial hyperreactivity was studied in 12 pertussis convalescents aged 7 to 17 years. The level of endogenous nitrogen monoxide in exhaled air (FeNO) was measured using a portable NObreath electrochemical analyzer (from Bedfont Scientific Ltd.).The results. According to the results of BPP, 6 of 12 convalescents of whooping cough were found to have bronchial hyperreactivity of varying degrees. When conducting a breath test with a histamine solution, bronchial hyperreactivity was recorded in three children, in a sample with methacholine, in five. In 3 out of 6 children with revealed signs of bronchial hyperreactivity, the history of atopy was not burdened, which suggests a connection between the pertussis and the development of bronchial hyperreactivity. A significant increase in the level of endogenous nitric monoxide (above 16 ppb) was observed in 2 out of 10 patients. Follow-up observation showed that the duration of cough with whooping cough ranged from 3 to 6 months, and in patients with positive results of several tests it was maximum. Two out of three children with bronchial asthma showed elevated levels of FeNO and samples with methacholine. Follow-up observation showed that whooping cough aggravated bronchial asthma and demanded correction therapy.Conclusion. A pilot study on the evaluation of bronchial provocative tests suggests that the formation of bronchial hyperreactivity in convalescents of whooping cough is probable, including without a history of atopy, which increases the risk of developing bronchial asthma, however, additional studies are required for a final conclusion.

Summary: Due to the high prevalence of asthma and general airway reactivity, anesthesiologists frequently encounter children with asthma or asthma‐like symptoms. This review focuses on the epidemiology, the underlying pathophysiology, and perioperative management of children with airway reactivity, including controlled and uncontrolled asthma. It spans from preoperative optimization to optimized intraoperative management, airway management, and ventilation strategies. There are three leading causes for bronchospasm (1) mechanical (eg, airway manipulation), (2) non‐immunological anaphylaxis (anaphylactoid reaction), and (3) immunological anaphylaxis. Children with increased airway reactivity may benefit from a premedication with beta‐2 agonists, non‐invasive airway management, and deep removal of airway devices. While desflurane should be avoided in pediatric anesthesia due to an increased risk of bronchospasm, other volatile agents are potent bronchodilators. Propofol is superior in blunting airway reflexes and, therefore, well suited for anesthesia induction in children with increased airway reactivity. [ABSTRACT FROM AUTHOR]

Objective: to determine the association of catalase С-262Т gene polymorphism with the presence of bronchial hyper-reactivity in children living in radioactively contaminated territories. Materials and methods. There were examined school-age children-residents of radioactively contaminated territories (RCT), who did not have clinical signs of respiratory pathology. Catalase (CAT) С-262Т gene deletion polymorphism was studied in the molecular genetic laboratory of the State Institution «Reference Center for Molecular Diagnostic of Public Health Ministry of Ukraine». Determination of the polymorphic variant by the catalase С-262Т gene was performed by Polymerase Chain Reaction (PCR) using specific oligonucleotide primers, followed by Restriction Fragment Length Polymorphism (RFLP) analysis. The CAT С-262Т gene polymorphism in children living in RCT was compared with that in the reference group of practically healthy individuals. Ventilation lung capacity was performed by computer spirometry according to the analysis of the loop «the flow-volume». A pharmacological inhalation test with a bronchodilator that acts on β2-adrenergic receptors of the lungs was used to detect early changes in the ventilatory capacity of the lungs - bronchial hyperreactivity. Results. Comparative analysis showed that in the presence of bronchial hyperreactivity in children living in RCT, the CT genotype was more common than in children without bronchial hyperreactivity, and the frequency of the CC genotype was correspondingly reduced. There was a trend towards a decrease in the frequency of the TT genotype. An analysis of the frequency distribution of allelic variants of the CAT С-262Т gene polymorphism in children living in the RCT revealed a tendency to increase in the frequency of the T-allele and according to the decrease in the frequency of C-allele in the presence of bronchial hyperreactivity. Сonclusions. Thus, among children living in RCT, CT-homozygotes of CAT С-262Т gene polymorphism had bronchial hyperreactivity probably more often than CC-heterozygotes. In the presence of bronchial hyperreactivity, there was a trend towards an increase in the frequency of the T-allele and, accordingly, a decrease in the frequency of the C-allele. [ABSTRACT FROM AUTHOR]

Growing evidence indicates that prenatal exposure to maternal smoking is a risk factor for the development of asthma in children. However, the effects of prenatal environmental tobacco smoke (ETS) exposure on the genome and lung immune cells are unclear. This study aims to determine whether in utero ETS exposure alters DNA methylation patterns and increases airway hyperreactivity (AHR) and inflammation. Pregnant C57BL/6 mice were exposed daily to a concentration of 1.0 mg/m(3) ETS. AHR was determined in the 6-week-old offspring by measurement of airway resistance. Global and gene promoter methylation levels in lung DNA from offspring were analyzed by luminometric methylation and pyrosequencing assays, respectively. Offspring exposed to ETS showed a marked increase in the number of alveolar macrophages in the bronchoalveolar lavage fluid and level of IL-13 in the airways compared with offspring of filtered-air exposed dams (controls). ETS exposure significantly augmented AHR compared with controls. In the methylation analysis, ETS-exposed offspring had a significantly lower level of global DNA methylation than the controls. We observed a significant increase in IFN-γ, and significant decrease in IL-13 methylation levels in the ETS group compared with controls. Collectively, these data suggest that in utero ETS exposure increases the risk of pulmonary inflammation and AHR through altered DNA methylation, but additional studies are needed to fully determine the causal link between changes in methylation and cytokines levels, as well as AHR.

We previously demonstrated that antigen sensitization increases vulnerability to airway hyperreactivity induced by the organophosphorus pesticide (OP) parathion. Sensitization also changes the mechanism of parathion-induced airway hyperreactivity to one that is dependent on IL-5. To determine whether this effect can be generalized to other OPs, and to other classes of pesticides, we measured airway responsiveness to vagal stimulation or intravenous acetylcholine in nonsensitized and ovalbumin-sensitized guinea pigs 24 hours after a single subcutaneous injection of the OPs diazinon or chlorpyrifos, or the pyrethroid permethrin. Sensitization exacerbated the effects of chlorpyrifos on bronchoconstriction in response to vagal stimulation or intravenous acetylcholine. Pretreatment with function-blocking IL-5 antibody prevented chlorpyrifos-induced airway hyperreactivity in sensitized, but not in nonsensitized, guinea pigs. In sensitized guinea pigs, blocking IL-5 decreased eosinophil activation, as measured by decreased eosinophil major basic protein in the trachea. In contrast, sensitization did not alter diazinon-induced airway hyperreactivity, and permethrin did not cause airway hyperreactivity in either nonsensitized or sensitized guinea pigs. None of the pesticides affected inflammatory cells in the bronchoalveolar lavage fluid or blood. We have previously shown that three different OPs cause airway hyperreactivity via loss of neuronal M2 muscarinic receptor function. Similar to parathion, but unlike diazinon, the mechanism of chlorpyrifos-induced airway hyperreactivity is changed by sensitization. Thus, OP-induced airway hyperreactivity is dependent on sensitization status and on the OP used, which may influence therapeutic approaches.

Ambient particulate matter (PM) originates from a range of sources and differs in composition with respect to season, time of day, and particle size. In this study, ambient PM samples in the ultrafine and submicrometer fine range were tested for the potential to exacerbate a murine model of allergic airway inflammation when exposure occurs solely during allergic sensitization, but not during subsequent allergen challenge. Temporally resolved and size-segregated PM samples were used to understand how summer or winter, day or night, and ambient ultrafine and submicrometer fine particle size influence PM's ability to exacerbate allergic inflammation. PM was collected in urban Fresno, CA. BALB/c mice were exposed to PM and house dust mite allergen (HDM) via intranasal aspiration on d 1, 3, and 5. HDM challenge occurred on d 12-14, with inflammation assessed 24 h following final challenge. While season or particle size did not predict allergic inflammation, daytime ultrafine and submicrometer fine particles significantly increased total cellular inflammation, specifically lymphocyte and eosinophil infiltration, compared to allergic controls. Further studies examined PM-mediated changes within the lung during the period where allergen sensitization occurred by measuring direct effects of PM on pulmonary oxidative stress and inflammation. Pulmonary levels of heme oxygenase-1 (HO-1), a biomarker of oxidative stress, but not cellular inflammation, demonstrated a remarkable correlation with the degree of allergic inflammation in animals sensitized to allergen and PM concomitantly, suggesting acute PM-mediated HO-1 levels may serve as a predictive indicator of a particle's ability to exacerbate allergic airway inflammation.