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Chronic infection with Schistosoma mansoni parasites is associated with reduced allergic sensitization in humans, while schistosome eggs protects against allergic airway inflammation (AAI) in mice. One of the main secretory/excretory molecules from schistosome eggs is the glycosylated T2-RNAse Omega-1 (ω1). We hypothesized that ω1 induces protection against AAI during infection. Peritoneal administration of ω1 prior to sensitization with Ovalbumin (OVA) reduced airway eosinophilia and pathology, and OVA-specific Th2 responses upon challenge, independent from changes in regulatory T cells. ω1 was taken up by monocyte-derived dendritic cells, mannose receptor (CD206)-positive conventional type 2 dendritic cells (CD206+ cDC2), and by recruited peritoneal macrophages. Additionally, ω1 impaired CCR7, F-actin, and costimulatory molecule expression on myeloid cells and cDC2 migration in and ex vivo, as evidenced by reduced OVA+ CD206+ cDC2 in the draining mediastinal lymph nodes (medLn) and retainment in the peritoneal cavity, while antigen processing and presentation in cDC2 were not affected by ω1 treatment. Importantly, RNAse mutant ω1 was unable to reduce AAI or affect DC migration, indicating that ω1 effects are dependent on its RNAse activity. Altogether, ω1 hampers migration of OVA+ cDC2 to the draining medLn in mice, elucidating how ω1 prevents allergic airway inflammation in the OVA/alum mouse model., Competing Interests: HS receive research grants from the Lung foundation Netherlands and the Dutch Research Council and is a board member of the Netherlands Respiratory Society., (Copyright: © 2024 Patente et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: Allergic respiratory diseases (ARD) are a highly prevalent health problem affecting infants and children in Yemen. Early infant feeding predisposition to the development of ARD has been a controversial question. The aim of this study is to investigate the association between early feeding before 6 months of age and the development of ARD among children attending Childhood and Maternity Public Hospital (CMPH), Ibb, Yemen Republic., Subjects and Methods: The study population included 151 child patients attending the pediatric clinic at CMPH. Upon clinical and laboratory examinations, 72 out of 151 patients had ARD, while the other 79 had diseases other than ARD; all of them were used in risk assessment. Fifteen blood samples from healthy volunteers were used in laboratory investigations as a control. Complete blood count and IgE level were investigated for all participants. Children's parents were requested to give an informed consent and fill questionnaire about demography and history details., Results: Early infant feeding was a significant risk factor for the development of ARD with an odds ratio (OR) of 6.8 and 95% confidence interval (CI) 3.0 to 15.3. Artificial milk particularly was risk factor with an OR of 6.1 and 95% confidence interval 2.7 to 13.5. Artificial milk exhibited more wheezing and asthma attack than others (OR 4.3, 95% CI 1.9 to 9.4 and OR 7.6, 95% CI 3.5 to 16.3, respectively). The risk of wheezing and asthma attack also increase with early feeding generally (OR 3.0, 95% CI 1.3 to 7.2 and OR 4.8, 95% CI 2.2 to 8.1, respectively). The patients had a higher sensitization markers than the control, such as eosinophil count and total serum IgE. The highest levels of IgE ever reported existed among early fed patients with artificial milk., Conclusions: Early infant feeding, particularly with artificial milk, is a risk factor predisposing infants to the development of allergic respiratory disease presented with more clinical features of wheezing and asthma attack., (© 2022. The Author(s).)

Allergic airway disease is the most common chronic airway inflammatory disorder in developed countries. House dust mite, cockroach, and mold are the leading allergens in most tropical and subtropical countries, including Taiwan. As allergen avoidance is difficult for patients allergic to these perennial indoor allergens, allergen-specific immunotherapy (ASIT) is the only available allergen-specific and disease-modifying treatment. However, for patients sensitized to multiple allergens, ASIT using each corresponding allergen is cumbersome. In the present study, we developed a recombinant L. lactis vaccine against the three most common indoor aeroallergens and investigated its effectiveness for preventing respiratory allergy and safety in mice. Three recombinant clones of Der p 2 (mite), Per a 2 (roach), and Cla c 14 (mold) were constructed individually in pNZ8149 vector and then electroporated into host strain L.lactis NZ3900. BALB/c mice were fed with the triple vaccine 5 times per week for 4 weeks prior to sensitization. The effectiveness and safety profile were then determined. Oral administration of the triple vaccine significantly alleviated allergen-induced airway hyper-responsiveness in the vaccinated mice. The allergen-specific IgG2a was upregulated. IL-4 and IL-13 mRNA expressions as well as inflammatory cell infiltration in the lungs decreased significantly in the vaccinated groups. No body weight loss or abnormal findings in the liver and kidneys were found in any of the groups of mice. This is the first report to describe a triple-aeroallergen vaccine using a food-grade lactococcal expression system. We developed a convenient oral delivery system and intend to extend this research to develop a vaccination that can be self-administered at home by patients., Competing Interests: The authors have declared that no competing interests exist.

Waterpipe smoking (WPS) prevalence is increasing globally. Clinical and laboratory investigations reported that WPS triggers impairment of pulmonary function, inflammation, and oxidative stress. However, little is known if smoking cessation (SC) would reverse the adverse pulmonary effects induced by WPS. Therefore, we evaluated the impact of WPS inhalation for 3 mo followed by 3 mo of SC (air exposure) compared with those exposed for either 3 or 6 mo to WPS or air (control) in C57BL/6 mice. To this end, various physiological, biochemical, and histological endpoints were evaluated in the lung tissue. Exposure to WPS caused focal areas of dilated alveolar spaces and foci of widening of interalveolar spaces with peribronchiolar moderate mixed inflammatory cells consisting of lymphocytes, macrophages, and neutrophil polymorphs. The latter effects were mitigated by SC. Likewise, SC reversed the increase of airway resistance and reduced the increase in the levels of myeloperoxidase, matrix metalloproteinase 9, granulocyte-macrophage colony-stimulating factor, tumor necrosis factor-α, interleukin (IL)-6, and IL-1β in lung tissue induced by WPS. In addition, SC attenuated the increase of oxidative stress markers including 8-isoprostane, glutathione, and catalase induced by WPS. Similarly, DNA damage, apoptosis, and the expression of NF-κB in the lung induced by WPS inhalation were alleviated by CS. In conclusion, our data demonstrated, for the first time, to our knowledge, that SC-mitigated WPS inhalation induced an increase in airway resistance, inflammation, oxidative stress, DNA injury, and apoptosis, illustrating the benefits of SC on lung physiology.

Epidemiological studies demonstrate an apparent sex-based difference in the prevalence of asthma, with a higher risk in boys than girls, which is reversed postpuberty, where women become more prone to asthma than men, suggesting a plausible beneficial role for male hormones, especially androgens as a regulator of pathophysiology in asthmatic lungs. Using a murine model of asthma developed with mixed allergen (MA) challenge, we report a significant change in airway hyperresponsiveness (AHR), as demonstrated by increased thickness of epithelial and airway smooth muscle layers and collagen deposition, as well as Th2/Th17-biased inflammation in the airways of non-gonadectomized (non-GDX) and gonadectomized (GDX) male mice. Here, compared with non-GDX mice, MA-induced AHR and inflammatory changes were more prominent in GDX mice. Activation of androgen receptor (AR) using 5α-dihydrotestosterone (5α-DHT, AR agonist) resulted in decreased Th2/Th17 inflammation and remodeling-associated changes, resulting in improved lung function compared with MA alone challenged mice, especially in GDX mice. These changes were not observed with Flutamide (Flut, AR antagonist). Overall, we show that AR exerts a significant and beneficial role in asthma by regulating AHR and inflammation.

The constituents of the gut microbiome are determined by the local habitat, which itself is shaped by immunological pressures, such as mucosal IgA. Using a mouse model of restricted antibody repertoire, we identified a role for antibody-microbe interactions in shaping a community of bacteria with an enhanced capacity to metabolize L-tyrosine. This model led to increased concentrations of p-cresol sulfate (PCS), which protected the host against allergic airway inflammation. PCS selectively reduced CCL20 production by airway epithelial cells due to an uncoupling of epidermal growth factor receptor (EGFR) and Toll-like receptor 4 (TLR4) signaling. Together, these data reveal a gut microbe-derived metabolite pathway that acts distally on the airway epithelium to reduce allergic airway responses, such as those underpinning asthma.

Flavonol kaempferol possesses a broad spectrum of potent pharmacological activities that seem to be effective in the modulation of allergic respiratory diseases. In our study, an experimental animal model of ovalbumin (OVA)-induced allergic airway inflammation in guinea pigs was used to determine the anti-asthmatic potential of kaempferol. The parameters of specific airway resistance (sRaw) and cough reflex response were evaluated in vivo. In vitro, an assessment of tracheal smooth muscle (TSM) contractility and analyses of inflammatory cytokines (IL-4, IL-5, IL-13, GM-CSF, IFN-γ), transforming growth factor (TGF-β1), immune cells count and ciliary beating frequency (CBF) were performed. Both single (6, 20 mg/kg b. w. p. o.) and long-term administered doses of kaempferol (20 mg/kg b. w. p. o., 21 days) suppressed sRaw provoked by histamine in conscious animals. The administration of kaempferol for 21 days attenuated histamine-induced TSM contractility in vitro and ameliorated the progression of chronic airway inflammation by decreasing the levels of IL-5, IL-13, GM-CSF, eosinophil count in bronchoalveolar lavage (BAL) fluid and TGF-β1 protein level in lung tissue. Kaempferol also eliminated the alterations in cough reflex sensitivity invoked by OVA-sensitization, but it did not affect CBF. The results demonstrate that flavonol kaempferol can modulate allergic airway inflammation and associated asthma features (AHR, aberrant stimulation of cough reflex)., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Inflammation, the major hallmark of all chronic respiratory diseases is generally managed by inhaled corticosteroids. However, long term high dose treatment can result in significant side effects. Hence, there is a medical need for non-steroidal anti-inflammatory therapies to address airway inflammation. Phospholipids have been shown to reduce inflammation in several inflammatory conditions; however, their clinical translation has been limited to liposomal formulations traditionally used as drug carriers and their biological activity has not been investigated. Here we report the first application of empty liposomes as an anti-inflammatory treatment in airway inflammation. In the current study, liposomes (UTS-001) were prepared from cholesterol and a synthetic phospholipid (DOPC). The formulation was characterised in terms of size, charge, polydispersity index, morphology and stability as colloidal suspension and freeze-dried nanoparticles. Time-dependant uptake of UTS-001 in airway epithelial cells was observed which was inhibited by nystatin demonstrating that the uptake is via the caveolae pathway. In-vitro, in primary nasal epithelial cells, UTS-001 treatment successfully attenuated IL-6 levels following TNF-α stimulation. Consistent with the in-vitro findings, in-vivo, in the ovalbumin model of allergic airway inflammation, UTS-001 significantly reduced total immune cell counts in bronchoalveolar lavage fluid and reduced airway hyperresponsiveness in response to increasing doses of methacholine challenge. Therefore, our results establish UTS-001 as a potential anti-inflammatory treatment that may be useful as a therapeutic for lung inflammatory diseases., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Despite many hypothesized benefits of dietary isoflavone genistein (GEN) deriving from soy-based products, questions surrounding GEN's developmental effects are increasing. To understand if in utero GEN exposure modulated postnatal respiratory allergies in the middle age, we conducted a time course study in the B6C3F1 offspring (PND 240-330) using a common household allergen (house dust mites: HDM; 10 μg/mouse for PND 240 and 290, and 50 μg/mouse for PND 330, a middle age in mice) following intranasal instillation, a physiological route of allergen exposure. GEN was administered to dams by gavage from gestational day 14 to parturition at a physiologically relevant dose (20 mg/kg body weight). Female and male offspring were sensitized with HDM allergens beginning about one month prior to sacrifice followed by challenges with three weekly dosings of HDM extracts, and they were euthanized at day 3 following the final HDM exposure. In utero exposure to GEN decreased HDM allergen-induced respiratory allergy in male B6C3F1 offspring at PND 330 as reflected by decreases in airway hyperresponsiveness (e.g., Penh value), HDM-specific IgG 1 (a Th2 type Ab) and the activity of eosinophil peroxidase in the lung (an indication of eosinophil recruitment to the lungs). However, in utero exposure to GEN had minimal effects on HDM allergen-induced respiratory allergy in the middle-aged female offspring. Changes in serum total IgE, HDM-specific IgE, and lung histopathology scores in both male and female offspring were not biologically significant. Overall, in utero GEN exposure exerted a protective effect on respiratory allergy in the middle-aged male, but not female, B6C3F1 offspring following later-life HDM exposures., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Regular physical activity is strongly recommended to prevent chronic respiratory diseases, including asthma. On the other hand, vigorous physical training may trigger airway symptoms and bronchoconstriction. The transient airway narrowing occurring because of exercise is named exercise-induced bronchoconstriction (EIB). Despite management according to guidelines, a significant proportion of patients experiences uncontrolled EIB, which thus represents a relevant unmet medical need. In particular, although prevention and treatment of EIB are effectively based on the use of beta-2 bronchodilator drugs, high heterogeneity in individual responses has been reported. Furthermore, even though beta-2 adrenergic drugs remain the mainstay of EIB management, occurrence of tolerance and side effects, as well as doping concerns have been reported with their use. In regard to this, inhaled antimuscarinics could represent an alternative or additional effective and safe bronchodilator therapeutic option for achieving optimal EIB control and minimize adverse events. The present systematic review aims to collect and provide the most updated and evidence-based literature findings on the efficacy and safety of short- and long-acting inhaled anti-muscarinic drugs for the preventive treatment of EIB in both children and adults. Take-Home Message: Anti-muscarinic drugs are effective and safe in preventing EIB, despite response variability is reported. Further studies should focus on long-acting molecules, chronic administration and phenotype-driven effects., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Studies demonstrated that pneumonia can decrease vitamin A productions and vitamin A reduction/deficiency may promote asthma development. Our previous study showed that neonatal Streptococcus pneumoniae (S. pneumoniae) infection promoted asthma development. Whether neonatal S. pneumoniae pneumonia induced asthma was associated with vitamin A levels remains unclear. The aim of this study was to investigate the effects of neonatal S. pneumoniae pneumonia on vitamin A expressions, to explore the effects of vitamin A supplement after neonatal S. pneumoniae pneumonia on adulthood asthma development. Non-lethal S. pneumoniae pneumonia was established by intranasal inoculation of neonatal (1-week-old) female BALB/c mice with D39. S. pneumoniae pneumonia mice were supplemented with or without all-trans retinoic acid 24 hours after infection. Vitamin A concentrations in lung, serum and liver were measured post pneumonia until early adulthood. Four weeks after pneumonia, mice were sensitized and challenged with OVA to induce allergic airway disease (AAD). Twenty-four hours after the final challenge, the lungs and bronchoalveolar lavage fluid (BALF) were collected to assess AAD. We stated that serum vitamin A levels in neonatal S. pneumoniae pneumonia mice were lower than 0.7µmol/L from day 2-7 post infection, while pulmonary vitamin A productions were significantly lower than those in the control mice from day 7-28 post infection. Vitamin A supplement after neonatal S. pneumoniae pneumonia significantly promoted Foxp3 + Treg and Th1 productions, decreased Th2 and Th17 cells expressions, alleviated airway hyperresponsiveness (AHR) and inflammatory cells infiltration during AAD. Our data suggest that neonatal S. pneumoniae pneumonia induce serum vitamin A deficiency and long-time lung vitamin A reduction, vitamin A supplement after neonatal S. pneumoniae pneumonia inhibit the progression of asthma by altering CD4 + T cell subsets.

Human cadavers constitute very useful educational tools to teach anatomy in medical scholarship and related disciplines such as physiology, for example. However, as biological material, human body is subjected to decay. Thanatopraxy cares such as embalming have been developed to slow down and inhibit this decay, but the formula used for the preservation fluids are mainly formaldehyde (FA)-based. Very recently, other formulas were developed in order to replace FA, and to avoid its toxicity leading to important environmental and professional exposure concerns. However, these alternative FA-free fluids are still not validated or commercialized, and their efficiency is still under discussion. In this context, the use of FA-releasing substances, already used in the cosmetics industry, may offer interesting alternatives in order to reduce professional exposures to FA. Simultaneously, the preservation of the body is still guaranteed by FA generated over time from FA-releasers. The aim of this review is to revaluate the use of FA in thanatopraxy cares, to present its benefits and disadvantages, and finally to propose an alternative to reduce FA professional exposure during thanatopraxy cares thanks to FA-releasers use., (© 2019 Anatomical Society.)

Ozone causes airway hyperresponsiveness, a defining feature of asthma, and is an asthma trigger. In mice, ozone-induced airway hyperresponsiveness is greater in males than in females, suggesting a role for sex hormones in the response to ozone. To examine the role of androgens in these sex differences, we castrated 4-week-old mice. Controls underwent sham surgery. At 8 weeks of age, mice were exposed to ozone (2ppm, 3 h) or room air. Twenty-four hours later, mice were anesthetized and measurements of airway responsiveness to inhaled aerosolized methacholine were made. Mice were then euthanized and bronchoalveolar lavage was performed. Castration attenuated ozone-induced airway hyperresponsiveness and reduced bronchoalveolar lavage cells. In intact males, flutamide, an androgen receptor inhibitor, had similar effects to castration. Bronchoalveolar lavage concentrations of several cytokines were reduced by either castration or flutamide treatment, but only IL-1α was reduced by both castration and flutamide. Furthermore, an anti-IL-1α antibody reduced bronchoalveolar lavage neutrophils in intact males, although it did not alter ozone-induced airway hyperresponsiveness. Our data indicate that androgens augment pulmonary responses to ozone and that IL-1α may contribute to the effects of androgens on ozone-induced cellular inflammation but not airway hyperresponsiveness., (© 2019 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of The Physiological Society and the American Physiological Society.)

Orosomucoid-like protein 3 (ORMDL3) is a common mutation in many asthma patients and its effects on the specific pathogenesis of asthma are still unclear. Therefore, in this study, we used a mouse that specifically knockout the mouse ORDML3 gene to further study the mechanism. We used ovalbumin (OVA) to induce asthma in wild-type mice and ORMDL3 knockout mice. Lung ventilation resistance, airway inflammation, mucus hypersecretion, collagen deposition, the levels of inflammatory factors and the expression of ORDML3 and JNK1/2-MMP-9 pathway were detected. The results showed that ORMDL3 gene was highly expressed in clinical asthmatic children and mouse asthma model. Knocking down the ORMDL3 gene in the lung tissue of asthmatic mice can reduce airway hyperresponsiveness, airway inflammation, mucus secretion, and collagen deposition around the airway. After knocking down the lung tissue of mice, the IL-4, IL-5 and IL-13 concentrations in broncho alveolar lavage fluid of asthmatic mice were significantly decreased, and the activation of JNK1/2-MMP-9 pathway was inhibited in mouse lung tissue. Collectively, our results demonstrate that the ORMDL3 gene may aggravate asthma symptoms by activating the JNK1/2-MMP-9 pathway, which indicates that the ORMDL3 gene may be the key molecule for the next step of asthma targeted therapy., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Removal of toxic formaldehyde from environmental waters is crucial to maintain ecosystem sustainability and human health. In this work, MIL-100(Fe) as a heterogeneous Fenton-like photocatalyst was used for the treatment of formaldehyde-contaminated water. The MIL-100(Fe) was synthesized via a facile solvothermal method and fully characterized using different spectroscopic and microscopic techniques. Based on the results, the formation of highly porous, crystalline, and stable visible light-responsive MIL-100(Fe) was confirmed. The Fenton-like photocatalytic efficiency of the MIL-100(Fe) toward the degradation of formaldehyde was then studied under visible light irradiation. For this purpose, the effect of initial concentration of formaldehyde, photocatalyst dose, H 2 O 2 concentration, solution pH, and contact time on the removal efficiency of the MIL-100(Fe) was investigated using central composite design. The obtained results showed that the removal efficiency of the MIL-100(Fe) is significantly affected by the initial concentration of formaldehyde. A second-order model with R 2  = 0.93 was developed for the system that was able to adequately predict the percentage removal of formaldehyde by the MIL-100(Fe) under different experimental conditions. According to the numerical optimization results, by using 1.13 g L -1 photocatalyst and 0.055 mol L -1 H 2 O 2 , 93% of formaldehyde can be removed after 119 min from an aqueous solution containing 700 mg L -1 of formaldehyde at pH 6.54., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Maternal diet during pregnancy plays a likely role in infant immune development through both direct nutrient specific immunomodulatory effects and by modulating the composition and metabolic activity of the maternal gut microbiome. Dietary fibers, as major substrates for microbial fermentation, are of interest in this context. This is the first study to examine maternal intakes of different fiber sub-types and subsequent infant allergic disease. In an observational study of 639 mother-infant pairs (all infants had a family history of allergic disease) we examined maternal intakes of total fiber, soluble fiber, insoluble fiber, resistant starch, and prebiotic fiber, by a semi-quantitative food frequency questionnaire at 36-40 weeks' gestation. Infants attended an allergy clinical assessment at 12 months of age, including skin prick testing to common allergens. Higher maternal dietary intakes of resistant starch were associated with reduced doctor diagnosed infant wheeze, adjusted odds ratio (aOR) 0.68 (95% CI 0.49, 0.95, p = 0.02). However, in contrast, higher maternal intakes of resistant starch were associated with higher risk of parent reported eczema aOR 1.27 (95% CI 1.09, 1.49, p < 0.01) and doctor diagnosed eczema aOR 1.19 (95% CI 1.01, 1.41, p = 0.04). In conclusion, maternal resistant starch consumption was differentially associated with infant phenotypes, with reduced risk of infant wheeze, but increased risk of eczema.

Objective: To investigate the effect of vitamin D supplementation dose on allergic sensitization and allergic diseases in infants, and to evaluate whether vitamin D status in pregnancy and at birth are associated with infant allergy outcomes., Study Design: Altogether, 975 infants participated in a randomized, controlled trial of daily vitamin D supplementation of 10 μg (400 IU) or 30 μg (1200 IU) from the age of 2 weeks. At 12 months of age, food and aeroallergen IgE antibodies were measured, and the occurrence of allergic diseases and wheezing were evaluated., Results: We found no differences between the vitamin D supplementation groups in food (OR, 0.98; 95% CI, 0.66-1.46) or aeroallergen sensitization at 12 months (OR, 0.76; 95% CI,0.34-1.71). Allergic diseases or wheezing did not differ between groups, except for milk allergy which occurred more often in infants administered 30 μg vitamin D compared with the 10 μg dose (OR, 2.23; 95% CI, 1.00-4.96). Infants with high cord blood 25-hydroxyvitamin D (≥100 nmol/L) had a higher risk of food allergen sensitization compared with those with lower 25(OH)D concentration (75-99.9 nmol/L; OR, 2.00; 95% CI, 1.19-3.39)., Conclusions: High-dose vitamin D supplementation did not prevent allergic sensitization, allergic diseases, or wheezing during the first year of life. In contrast, we observed an increased risk of milk allergy in infants randomized to higher vitamin D supplementation, and an increased risk of allergic sensitization in infants with high cord blood vitamin D status, indicating a possible adverse effect of high concentrations of vitamin D., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Increased angiogenesis is a characteristic feature of remodeling in asthmatic airways and stems from the imbalance between pro-angiogenic and anti-angiogenic factors. Surprisingly, the factors regulating this process in allergic asthma are poorly defined. Previously, we showed an important role of semaphorins 3E (Sema3E) in growth factor-induced airway smooth muscle proliferation and migration in vitro, and in down-regulating airway inflammation, T helper 2/T helper 17 cytokine response, mucus cell hyperplasia, and airway hyperresponsiveness in vivo. However, the role of Sema3E in airway angiogenesis is not fully understood. Here, we investigated the role of Sema3E in airway angiogenesis using a house dust mite (HDM) murine model of allergic asthma. Intranasal treatment with recombinant Sema3E significantly reduced the expression of angiogenesis markers within the airways of HDM-challenged mice compared with untreated mice. HDM-induced expression of vascular endothelial growth factor (VEGF) and VEGF receptor 2 protein were diminished substantially on Sema3E treatment. Interestingly, Sema3E-treated mice showed an enhanced expression of the negative regulator of angiogenesis, soluble VEGF receptor 1, compared with the untreated mice. These events were reversed in Sema3E-deficient mice at baseline or on HDM challenge. Taken together, this study provides the first evidence that Sema3E modulates angiogenesis in allergic asthmatic airways via modulating pro- and anti-angiogenic factors., (Copyright © 2019 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)

We have previously shown that high fat diet (HFD) for 2 weeks increases airway hyperresponsiveness (AHR) to methacholine challenge in C57BL/6J mice in association with an increase in IL-1β levels in lung tissue. We hypothesize that obesity increases AHR via the IL-1β mechanism, which can be prevented by caloric restriction and IL-1β blockade. In this study, we fed C57BL/6J mice for 8 weeks with several hypercaloric diets, including HFD, HFD supplemented with fructose, high trans-fat diet (HTFD) supplemented with fructose, either ad libitum or restricting their food intake to match body weight to the mice on a chow diet (CD). We also assessed the effect of the IL-1β receptor blocker anakinra. All mice showed the same total respiratory resistance at baseline. All obese mice showed higher AHR at 30 mg/ml of methacholine compared to CD and food restricted groups, regardless of the diet. Obese mice showed significant increases in lung IL-1 β mRNA expression, but not the protein, compared to CD and food restricted mice. Anakinra abolished an increase in AHR. We conclude that obesity leads to the airway hyperresponsiveness preventable by caloric restriction and IL-1β blockade.

The practice of human and veterinary medicine is based on the science of anatomy and dissection courses are still irreplaceable in the teaching of anatomy. Embalming is required to preserve body donors, for which process formaldehyde (FA) is the most frequently used and well characterized biocidal substance. Since January 2016, a new occupational exposure limit (OEL) for FA of 0.37mg/m 3 issued by the European Committee on Hazardous Substances is obligatory since FA has been classified as a human 1B carcinogen. The anatomical institutes in the German-speaking region are called upon to consolidate efforts to reduce use of FA in anatomical curricula and body donations. As a result, the Anatomische Gesellschaft (AG) has formed a "Working Group for Reduction of Formaldehyde Exposure in Dissection Courses" tasked with discussion and recommendation of measures to reduce FA. Based on the assessment of the Working Group, the AG has issued an official opinion to the effect that, at this point in time, embalming of body donors without FA completely is not feasible. Therefore, a combination of approaches are to be used to reduce FA exposure, including technical and structural (architectural) adaptations, modification of protocols for fixation and preservation as well as organizational measures. One structural measure considered unavoidable is the integration of air supply and exhaust of individual dissecting tables into the ventilation system of the anatomy building. To embalm human body donors, intra-arterial perfusion fixation with up to 4% FA and a total fluid volume of 150mL/kg body weight will suffice. For animals where body weights and biology of bodies vary widely (i.e. special needs of fixation for ruminants, large animals as horses) perfusion fixation with up to 4% FA and a quantity of fixative solution of 10-15% of the body weight may be required. Preservation of body donors in storage (immersion) can be done with 40% ethanol or in a full bath preservation containing up to 2% FA. Corpse humidification in the dissecting room is possible with 2% phenoxyethanol, in each case without FA. In veterinary anatomy, microbiological burden is often higher and therefore might lead to a need of FA in long-time storage. Compliance with the current OEL in all institutes would appear to be feasible in combination with various organizational measures., (Copyright © 2018 Elsevier GmbH. All rights reserved.)

Toluene diisocyanate (TDI) is a major cause of chemical-induced occupational asthma, which contributes about 15% of global asthma burden. Resistance and compounded side effects associated with the use of corticosteroid in asthma necessitate the search for alternative drugs. Andrographolide (AGP), a naturally occurring diterpene lactone is known to exhibit various bioactivities. Its ability to ameliorate cardinal features of allergic asthma was previously suggested in an eosinophilic asthma endotype. However, its potential antiasthma activity and mechanism of action in a neutrophilic occupational asthma model, as well as its effect on epithelial dysfunction remain unknown. BALB/c mice were dermally sensitised with 0.3% TDI or acetone olive oil (AOO) vehicle on day 1 and 8, followed by 0.1% TDI intranasal challenge on days 15, 18 and 21. Endpoints were evaluated via bronchoalveolar lavage fluid (BALF) cell analysis, 2',7'-dichlorofluorescein diacetate (DCFDA) assays, immunoblotting, immunohistochemistry and methacholine challenge test. Decreases in total and differential leukocyte counts of BALF were recorded in AGP-treated animals. The compound dose-dependently reduced intracellular de-esterification of DCFDA, thus suggesting AGP's potential to inhibit intracellular reactive oxygen species (ROS). Mechanistically, the treatment prevented TDI-induced aberrant E-cadherin distribution and restored airway epithelial β-catenin at cell to cell contact site. Furthermore, AGP ameliorated TDI induced pulmonary collagen deposition. In addition, the treatment significantly upregulated pulmonary HO-1, Nrf2 and phospho-p38 levels. Airway hyperresponsiveness was markedly suppressed among AGP-treated animals. Collectively, these findings suggest AGP's protective function against TDI-induced airway epithelial barrier dysfunction and oxidative lung damage possibly through the upregulation of adherence junction proteins and the activation of p38/Nrf2 signalling. This study elucidates the therapeutic potential of AGP in the control and management of chemical-induced allergic asthma. To the best of our knowledge, the potential anti-asthma activity of AGP in TDI-induced occupational asthma has not been reported previously., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Allergic asthma is a major cause of morbidity in both pediatric and adult patients. Recent research has highlighted the role of hyaluronan (HA), an extracellular matrix glycosaminoglycan, in asthma pathogenesis. Experimental allergic airway inflammation and clinical asthma are associated with an increase of shorter fragments of HA (sHA), which complex with inter-α-inhibitor heavy chains (HCs) and induce inflammation and airway hyperresponsiveness (AHR). Importantly, the effects of sHA can be antagonized by the physiological counterpart high molecular weight HA (HMWHA). We used a mouse model of house dust mite-induced allergic airway inflammation and demonstrated that instilled HMWHA ameliorated allergic airway inflammation and AHR, even when given after the establishment of allergic sensitization and after challenge exposures. Furthermore, instilled HMWHA reduced the development of HA-HC complexes and the activation of Rho-associated, coiled-coil containing protein kinase 2. We conclude that airway application of HMWHA is a potential treatment for allergic airway inflammation.

In this study, the protective effect of spirulina on corneal injury after formaldehyde (FA) exposure was assessed. Thirty adult male albino rats were divided into four groups. Group I: 12 rats were divided into two subgroups: I-a (negative control) and I-b (positive control). Group II (spirulina group): six rats received spirulina via an oral gavage feeding needle at a daily dose of 400 mg/kg b.w. Group III (FA exposure group): six rats were subjected to 10% FA inhalation for 2 h per day for 2 weeks (5 days per week). Group IV (FA exposure group treated with spirulina): six rats were exposed to 10% FA as in group III, with co-administration of spirulina as in group II. After 2 weeks, all the rats were sacrificed; the corneas were dissected and processed for paraffin sections. The sections were stained with hematoxylin and eosin (H&E), Masson's trichrome (MTC), or avidin-biotin peroxidase, and examined by light microscopy. The sections of rat cornea exposed to FA (Group III) showed disorganized and compressed epithelium with erosions. Subepithelial mononuclear cell infiltration and invasion of blood vessels were also evident. Stromal collagen fibers were disorganized and widely separated. All these changes were ameliorated by administration of spirulina (Group IV). Corneal thickness was nearly normal in Group IV, statistically significantly less than in Group III. It was concluded that spirulina protects against FA-induced corneal injury in rats. Clin. Anat. 31:830-837, 2018. © 2018 Wiley Periodicals, Inc., (© 2018 Wiley Periodicals, Inc.)

Objective: This study is the first community engagement phase of a project to develop a residential formaldehyde detection system. The objectives were to conduct a feasibility assessment for device use, and identify factors associated with concerns about environmental exposure and community interest in this device., Design and Sample: A cross-sectional, internet-based survey employing community-based participatory research principles was utilized. 147 individuals participated from a focused Waycross, Georgia (58.5%) and broader national sample (41.5%)., Measures: Variables included acceptable cost and number of testing samples, interest in conducting tests, levels of concern over pollutants, health status, housing, and demographics., Results: The majority of participants desired a system with fewer than 10 samples at ≤$15.00 per sample. Statistically significant higher levels of concern over air quality, formaldehyde exposure, and interest in testing formaldehyde were observed for those with overall worse health status and living in the Waycross, Georgia geographic region. Significant differences in formaldehyde testing interest were observed by health status (OR = 0.31, 95% CI = 0.12-0.81 for home testing) and geographic location (OR = 3.16, 95% CI = 1.22-8.14 for home and OR = 4.06, 95% CI = 1.48-11.12 for ambient testing) in multivariate models., Conclusions: Geographic location and poorer general health status were associated with concerns over and interest in formaldehyde testing., (© 2018 Wiley Periodicals, Inc.)

Lumber Liquidators (LL) Chinese-manufactured laminate flooring (CLF) has been installed in >400,000 U.S. homes over the last decade. To characterize potential associated formaldehyde exposures and cancer risks, chamber emissions data were collected from 399 new LL CLF, and from LL CLF installed in 899 homes in which measured aggregate indoor formaldehyde concentrations exceeded 100 μg/m 3 from a total of 17,867 homes screened. Data from both sources were combined to characterize LL CLF flooring-associated formaldehyde emissions from new boards and installed boards. New flooring had an average (±SD) emission rate of 61.3 ± 52.1 μg/m 2 -hour; >one-year installed boards had ∼threefold lower emission rates. Estimated emission rates for the 899 homes and corresponding data from questionnaires were used as inputs to a single-compartment, steady-state mass-balance model to estimate corresponding residence-specific TWA formaldehyde concentrations and potential resident exposures. Only ∼0.7% of those homes had estimated acute formaldehyde concentrations >100 μg/m 3 immediately after LL CLF installation. The TWA daily formaldehyde inhalation exposure within the 899 homes was estimated to be 17 μg/day using California Proposition 65 default methods to extrapolate cancer risk (below the regulation "no significant risk level" of 40 μg/day). Using a U.S. Environmental Protection Agency linear cancer risk model, 50th and 95th percentile values of expected lifetime cancer risk for residents of these homes were estimated to be 0.33 and 1.2 per 100,000 exposed, respectively. Based on more recent data and verified nonlinear cancer risk assessment models, LL CLF formaldehyde emissions pose virtually no cancer risk to affected consumers., (© 2017 Society for Risk Analysis.)

Purpose: Obesity results in decreased lung function and increased inflammation. Moderate aerobic exercise (AE) reduced lung inflammation and remodeling in a variety of respiratory disease models. Therefore, this study investigated whether AE can attenuate a diet-induced obesity respiratory phenotype; including airway hyper-responsiveness (AHR), remodeling and inflammation., Methods: Sixty C57Bl/6 male mice were distributed into four groups: control lean (CL), exercise lean (EL), obese (O) and obese exercise (OE) groups (2 sets of 7 and 8 mice per group; n = 15). A classical model of diet-induced obesity (DIO) over 12 weeks was used. AE was performed 60 min/day, 5 days/week for 5 weeks. Airway hyperresponsiveness (AHR), lung inflammation and remodeling, adipokines and cytokines in bronchoalveolar lavage (BAL) was determined., Results: A high fat diet over 18 weeks significantly increased body weight (p < .0001). Five weeks of AE significantly reduced both AHR and pulmonary inflammation. AHR in obese mice that exercised was reduced at the basal level (p < .05), vehicle (PBS) (p < .05), 6.25 MCh mg/mL (p < .05), 12.5 MCh mg/mL (p < .01), 25 MCh mg/mL (p < .01) and 50 MCh mg/mL (p < .05). Collagen (p < .001) and elastic (p < .001) fiber deposition in airway wall and also smooth muscle thickness (p < .001) were reduced. The number of neutrophils (p < .001), macrophages (p < .001) and lymphocytes (p < .01) were reduced in the peribronchial space as well as in the BAL: lymphocytes (p < .01), macrophages (p < .01), neutrophils (p < .001). AE reduced obesity markers leptin (p < .001), IGF-1 (p < .01) and VEGF (p < .001), while increased adiponectin (p < .01) in BAL. AE also reduced pro-inflammatory cytokines in the BAL: IL-1β (p < .001), IL-12p40 (p < .001), IL-13 (p < .01), IL-17 (p < .001, IL-23 (p < .05) and TNF-alpha (p < .05), and increased anti-inflammatory cytokine IL-10 (p < .05)., Conclusions: Aerobic exercise reduces high fat diet-induced obese lung phenotype (AHR, pulmonary remodeling and inflammation), involving anti-inflammatory cytokine IL-10 and adiponectin., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Background: Early introduction of dietary peanut in high-risk infants with severe eczema, egg allergy, or both prevented peanut allergy at 5 years of age in the Learning Early About Peanut Allergy (LEAP) study. The protective effect persisted after 12 months of avoiding peanuts in the 12-month extension of the LEAP study (LEAP-On). It is unclear whether this benefit is allergen and allergic disease specific., Objective: We sought to assess the effect of early introduction of peanut on the development of allergic disease, food sensitization, and aeroallergen sensitization., Methods: Asthma, eczema, and rhinoconjunctivitis were diagnosed based on clinical assessment. Reported allergic reactions and consumption of tree nuts and sesame were recorded by questionnaire. Sensitization to food allergens and aeroallergens was determined by means of skin prick testing and specific IgE measurement., Results: A high and increasing burden of food allergen and aeroallergen sensitization and allergic disease was noted across study time points; 76% of LEAP participants had at least 1 allergic disease at 60 months of age. There were no differences in allergic disease between LEAP groups. There were small differences in sensitization and reported allergic reactions for select tree nuts, with levels being higher in the LEAP consumption group. Significant resolution of eczema and sensitization to egg and milk occurred in LEAP participants and was not affected by peanut consumption., Conclusion: Early consumption of peanut in infants at high risk of peanut allergy is allergen specific and does not prevent the development of other allergic disease, sensitization to other food allergens and aeroallergens, or reported allergic reactions to tree nuts and sesame. Furthermore, peanut consumption does not hasten the resolution of eczema or egg allergy., (Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.)

Interleukin-33 (IL-33) and its receptor ST2 have been influentially associated with the pathophysiology of asthma. Due to the divergent roles of IL-33 in regulating mast cell functions, there is a need to further characterize IL-33/ST2-dependent mast cell responses and their significance in the context of asthma. This study aimed to investigate how IL-33/ST2-dependent mast cell responses contribute to the development of airway hyperresponsiveness (AHR) and airway inflammation in a mouse model of house dust mite (HDM)-induced asthma. Mast cell-deficient C57BL/6-Kit W-sh (Wsh) mice engrafted with either wild-type (Wsh + MC-WT) or ST2-deficient bone marrow-derived mast cells (Wsh + MC-ST2KO) were exposed to HDM delivered intranasally. An exacerbated development of AHR in response to HDM was seen in Wsh + MC-ST2KO compared with Wsh + MC-WT mice. The contribution of this IL-33/ST2-dependent mast cell response to AHR seems to reside within the smaller airways in the peripheral parts of the lung, as suggested by the isolated yet marked effect on tissue resistance. Considering the absence of a parallel increase in cellular inflammation in bronchoalveolar lavage fluid (BALF) and lung, the aggravated AHR in Wsh + MC-ST2KO mice seems to be independent of cellular inflammation. We observed an association between the elevated AHR and reduced PGE 2 levels in BALF . Due to the protective properties of PGE 2 in airway responses, it is conceivable that IL-33/ST2-dependent mast cell induction of PGE 2 could be responsible for the dampening effect on AHR. In conclusion, we reveal that IL-33/ST2-dependent mast cell responses can have a protective, rather than causative role, in the development of AHR.

Formalin can be added as preservative to fresh foods to prevent spoilage and extend shelf life. Formalin contains 37-40% formaldehyde, which is classified as carcinogenic to humans. To assess the public health risk associated with formaldehyde exposure in freshwater fish in Southern Bangladesh, formaldehyde concentrations (mg/kg) were determined in tilapia, Indian major carp rui, Chinese carp and a minor carp from local market and in laboratory simulations (0.5, 1.0, 2.0 and 4.0% formaldehyde solution for 5, 15, 30 and 60 min) with spectrophotometric and high performance liquid chromatography (HPLC) methods. A food frequency questionnaire was used to collect fish consumption (kg/kg BW. d) data from 400 respondents. A probabilistic exposure assessment was conducted using @Risk ® 7.0 software. Fish treated with formalin at increasing concentrations and exposure time showed increased trends of formaldehyde acquisition irrespective of fish species and analytical methods used (p < .05). Compared to spectrophotometry, the HPLC method was shown to be more sensitive and is therefore the preferred method for formalin quantification. Maximum exposure to formaldehyde (0.28 mg/kg BW. d) was calculated for tilapia using HPLC analysis. Margin of exposure (MoE) provides high priority (<10,000) for tilapia and Indian major carp rui at P99 under spectrophotometric analysis whereas as determined using HPLC, tilapia had MoE values much lower than 10,000 at P99, P95 and P90 (both total population and consumers). Exposure to formaldehyde associated with freshwater fish consumption is a public health concern in Southern Bangladesh and needs further assessment and risk management strategies., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Cyclophosphamide (CP) is a drug used in chemotherapy and management of neoplastic diseases. This study aimed to investigate the prophylactic impacts of venlafaxine against CP-induced lung toxicity in rats. Rats were assigned randomly into 3 groups; control, CP (150 mg/kg) and CP/venlafaxine (50 mg/kg). On the end day, rats were sacrificed then bronchoalveolar fluid (BALF) and lungs were harvested. CP produced significant decrease in animal body weights and significant increase in lung/body weight ratio; levels of LDH, total protein, total and differential cell counts in BALF in comparison with control group. Moreover, significant elevation incontents of MDA, NOx, TNF-α and IL-1β and significant decline in GSH, SOD activities were observed in lung tissues. CP increased the response of tracheal zigzag to ACh. Histopathological results showed that CP increased inflammation and fibrosis in lung tissues. Venlafaxine restored most parameters to the normal levels. This protective effect of venlafaxine could be linked to its ability to reduce oxidative stress and inflammation., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Background: Rosmarinic acid (RA) as an active component of several medicinal plants, has shown anti-inflammatory and anti-oxidant effects. In this study, the effect of RA on tracheal responsiveness (TR), lung inflammatory cells, oxidant biomarkers in sensitized rats were evaluated., Methods: TR to methacholine and ovalbumin (OVA) as well as total and differential white blood cell (WBC) count and levels of nitrogen dioxide, nitrate, malondialdehyde, thiol, superoxide dismutase, and catalase in bronchoalveolar lavage fluid were measured in control (group C) rats, sensitized animals to OVA and given drinking water alone (group S), S groups receiving drinking water containing three concentrations of RA (0.125, 0.250 and 0.500 mg/mL) and dexamethasone (1.25 μg/mL), (n = 6 in each group)., Results: Increased TR to methacholine and OVA, total WBC count, percentages of eosinophils, monocytes, neutrophils and levels of oxidant biomarkers but decreased other measured parameters were observed in group S compared to group C. Percentages of lymphocytes and antioxidant biomarkers were significantly increased but other measured parameters were significantly decreased in S group treated with dexamethasone and in rats treated with the two higher concentrations of RA compared to S group. The effect of RA medium concentration on percentage of eosinophils and RA high concentration on total WBC count and percentages of eosinophils and lymphocytes, were significantly higher than those of dexamethasone., Conclusion: These results showed the concentration-dependent effect of RA on tracheal responses, lung inflammatory cells and oxidant-antioxidant parameters which was comparable to that of dexamethasone at used concentrations in sensitized rats., (Copyright © 2017 Institute of Pharmacology, Polish Academy of Sciences. Published by Elsevier B.V. All rights reserved.)

Progranulin (PGRN) is a growth factor with multiple biological functions and has been suggested as an endogenous inhibitor of Tumor necrosis factor-α (TNF-α)-mediated signaling. TNF-α is believed to be one of the important mediators of the pathogenesis of asthma, including airway hyperresponsiveness (AHR). In the present study, effects of recombinant PGRN on TNF-α-mediated signaling and antigen-induced hypercontractility were examined in bronchial smooth muscles (BSMs) both in vitro and in vivo. Cultured human BSM cells (hBSMCs) and male BALB/c mice were used. The mice were sensitized and repeatedly challenged with ovalbumin antigen. Animals also received intranasal administrations of recombinant PGRN into the airways 1 h before each antigen inhalation. In hBSMCs, PGRN inhibited both the degradation of IκB-α (an index of NF-κB activation) and the upregulation of RhoA (a contractile machinery-associated protein that contributes to the BSM hyperresponsiveness) induced by TNF-α, indicating that PGRN has an ability to inhibit TNF-α-mediated signaling also in the BSM cells. In BSMs of the repeatedly antigen-challenged mice, an augmented contractile responsiveness to acetylcholine with an upregulation of RhoA was observed: both the events were ameliorated by pretreatments with PGRN intranasally. Interestingly, a significant decrease in PGRN expression was found in the airways of the repeatedly antigen-challenged mice rather than those of control animals. In conclusion, exogenously applied PGRN into the airways ameliorated the antigen-induced BSM hyperresponsiveness, probably by blocking TNF-α-mediated response. Increasing PGRN levels might be a promising therapeutic for AHR in allergic asthma.

Background: Previous studies have shown that dietary pattern is associated with allergy prevention., Methods: We conducted a prospective cohort study on all primary schools in Omihachiman City, Shiga Prefecture, Japan. Questionnaires regarding allergic symptoms and diet were distributed to the parents of all 759 7-year-old schoolchildren for 4 consecutive years, from 2011 to 2014. Specific immunoglobulin E to inhalant allergens was measured at 10 years of age. Participants were then categorized as low, medium, or high intake during the study period for four food groups (fruits, vegetables, fish, and beans). Logistic regression analysis was performed to estimate odds ratios and 95% confidence intervals., Results: A total of 520 children (68.5%) whose parents responded to the questionnaires all 4 years were included in the analysis. The prevalence of asthma, rhinitis, and any allergic symptoms at age 10 was significantly decreased with increases in fruit intake. In addition, the onset of any allergic symptoms during the study period was significantly decreased with increases in fruit intake (33.3%, 28.3%, and 14.3% in children with low, medium, and high fruit intake, respectively; P for trend =.01). The sensitization rate to ragweed at age 10 was significantly decreased with increases in fruit intake (P for trend =.046). No significant effect was observed for the other three food groups, except for the association between fish intake and new-onset asthma symptoms., Conclusions: These findings suggest that higher intake of fruit can help prevent respiratory allergic symptoms in schoolchildren., (© 2017 EAACI and John Wiley and Sons A/S. Published by John Wiley and Sons Ltd.)

Aging is associated with altered decreased barrier function in the skin, which can lead to different types of immunoglobulin E (IgE)-mediated sensitization to environmental allergens. Yet, allergen-specific respiratory sensitization among the elderly is not well described. The aim of this study was to investigate the effect of aging on allergic pulmonary inflammation induced by epicutaneous sensitization of mechanically irritated skin in mice. For this purpose, 6-week-, 6-month-, and 18-month-old female BALB/c mice, underwent epicutaneous sensitization with ovalbumin (OVA) or phosphate buffered saline (PBS), followed by an inhaled OVA challenge. Blood OVA-specific IgE levels measured after epicutaneous sensitization, as well as, bronchial alveolar lavage fluids (BALF) leucocyte, eosinophil, and cytokine levels measured after OVA inhalation challenge were similar among the 6-week-old (young) and 6-month-old (adult) groups. However, significantly decreased levels of systemic OVA IgE, and BALF leukocyte, eosinophil and T helper cell type 2 cytokine levels, were measured after OVA inhalation challenge in elderly (18-month-old) mice compared to the other groups of mice. In addition, interleukin-10 (IL-10), a regulatory suppressor cytokine, was more abundant in the BALF of the elderly group after epicutaneous sensitization and inhalation challenge. Our results suggest that elderly mice have a reduced allergic response to induced sensitization with OVA, possibly regulated by increased IL-10 levels., (© 2017 John Wiley & Sons Australia, Ltd.)

The original hygiene hypothesis declares "more infections in early childhood protect against later atopy". According to the hygiene hypothesis, the increased incidence of allergic disorders in developed countries is explained by the decrease of infections. Epithelial cells and dendritic cells play key roles in bridging the innate and adaptive immune systems. Among the various pattern-recognition receptor systems of epithelial cells and dendritic cells, including toll-like receptors (TLRs), nucleotide-binding oligomerization domain (NOD)-like receptors (NLRs) and others, TLRs are the key systems of immune response regulation. In humans, TLRs consist of TLR1 to TLR10. They regulate cellular responses through engagement with TLR ligands, e.g., lipopolysaccharides (LPS) acts through TLR4 and dsRNA acts through TLR3, but there are certain common components between these two TLR pathways. dsRNA activates epithelial cells and dendritic cells in different directions, resulting in allergy-related Th2-skewing tendency in epithelial cells, and Th1-skewing tendency in dendritic cells. The Th2-skewing effect by stimulation of dsRNA on epithelial cells could be suppressed by the presence of LPS above some threshold. When LPS level decreases, the Th2-skewing effect increases. It may be via these interrelated networks and related factors that LPS modifies the allergic responses and provides a plausible mechanism of the hygiene hypothesis. Several hygiene hypothesis-related phenomena, seemingly conflicting, are also discussed in this review, along with their proposed mechanisms., Competing Interests: The authors declare no competing financial interests.

Chronic schistosome infections protect against allergic airway inflammation (AAI) via the induction of IL-10-producing splenic regulatory B (Breg) cells. Previous experiments have demonstrated that schistosome-induced pulmonary B cells can also reduce AAI, but act independently of IL-10. We have now further characterized the phenotype and inhibitory activity of these protective pulmonary B cells. We excluded a role for regulatory T (Treg) cell induction as putative AAI-protective mechanisms. Schistosome-induced B cells showed increased CD86 expression and reduced cytokine expression in response to Toll-like receptor (TLR) ligands compared with control B cells. To investigate the consequences for T cell activation we cultured ovalbumin (OVA)-pulsed, schistosome-induced B cells with OVA-specific transgenic T cells and observed less Th2 cytokine expression and T cell proliferation compared with control conditions. This suppressive effect was preserved even under optimal T cell stimulation by anti-CD3/28. Blocking of the inhibitory cytokines IL-10 or TGF-β only marginally restored Th2 cytokine induction. These data suggest that schistosome-induced pulmonary B cells are impaired in their capacity to produce cytokines to TLR ligands and to induce Th2 cytokine responses independent of their antigen-presenting function. These findings underline the presence of distinct B cell subsets with different stimulatory or inhibitory properties even if induced by the same type of helminth., (Copyright © 2017 Australian Society for Parasitology. Published by Elsevier Ltd. All rights reserved.)

Over 89% of asthmatic children in underdeveloped countries demonstrate sensitivity to house dust mites (HDMs). The allergic response to HDMs is partially mediated by epithelial cell-derived cytokines that activate group 2 innate lymphoid cells, induce migration and activation of dendritic cells, and promote effector differentiation of HDM-specific TH2 cells. However, the contribution of innate receptor engagement on epithelial or dendritic cells by HDMs that ultimately mediates said innate and adaptive allergic responses is poorly understood. We and other investigators have demonstrated that HDMs express phosphorylcholine (PC) moieties. The major PC receptors involved in immune responses include CD36 and platelet-activating factor receptor (PAFR). Because CD36 and PAFR are expressed by epithelial cells and dendritic cells, and expression of these receptors is higher in human asthmatics, we determined whether engagement of CD36 or PAFR on epithelial or dendritic cells contributes to HDM allergy development. Testing bone marrow chimeric mice revealed that CD36 engagement on radioresistant cells and PAFR engagement on radioresistant and radiosensitive cells in the lung promote allergic responses to HDMs. Additionally, passive anti-PC IgM Abs administered intratracheally with HDMs decreased allergen uptake by epithelial cells and APCs in the lungs of C57BL/6 mice but not CD36 -/- or PAFR -/- mice. These results show that CD36 and PAFR are important mediators of HDM allergy development and that inhibiting HDM engagement with PC receptors in the lung protects against allergic airway disease., (Copyright © 2017 by The American Association of Immunologists, Inc.)

Objective: To investigate the effect of a swimming break on airway hyperresponsiveness (AHR) and to evaluate perception of bronchoconstriction-related symptoms after methacholine challenge testing (MCT)., Design: Observational, controlled study., Setting: University department., Participants: Overall, 25 healthy, elite, competitive swimmers aged ≥14 years from the local Olympic training center and 25 healthy control subjects., Independent Variable: Duration of water abstinence., Main Outcome Measures: Primary outcome measures were a positive MCT with a provocation dose (PD) and the perception score of bronchoconstriction-related symptoms at visit 1 (V1, training period) and visit 2 (V2, after swimming break)., Results: In the study, 13 swimmers (52%) and 10 control subjects (40%) showed AHR. The PD did not differ significantly between V1 and V2 in the swimmers (P = 0.81) or in the control subjects (P = 0.74). No correlation of fraction of exhaled nitric oxide with the PD could be established in both the groups (swimmers: P = 0.97; controls: P = 0.99). The majority of swimmers with AHR were asymptomatic, and only minimal differences in perception of bronchoconstriction-related symptoms between swimmers and control subjects were observed (P = 0.23)., Conclusions: A swimming break of 25 ± 8 days does not seem sufficient to significantly reduce AHR in elite swimmers. Thus, relevant and systematic effects of short-term water abstinence on AHR seem unlikely. Because the majority of swimmers remain asymptomatic, AHR may escape routine screening examinations. The impact of AHR on athletic performance and the long-term clinical consequences remain to be clarified.

Background and Objective: The prevalence of asthma has increased in communities that adopt a Western lifestyle and become more urbanized. Probiotics may be effective in the prevention of allergic diseases, such as asthma. The aim of the current study was to examine the effects of Saccharomyces cerevisiae UFMG A-905 in an allergic model of asthma., Methods: Balb/c mice were sensitized twice with ovalbumin (OVA) intraperitoneally, 1 week apart and challenged with OVA intranasally for 3 days. Mice were daily treated with S. cerevisiae UFMG A-905 via gavaging needle 10 days before OVA sensitization and during challenges. After challenge, in vivo lung function was measured, and bronchoalveolar lavage (BAL) and lung inflammation were assessed., Results: Oral treatment with S. cerevisiae UFMG A-905 significantly decreased airway hyperresponsiveness, total cell number and the influx of eosinophils to the airway, inflammatory cell in the lung, mucus expression in epithelial cells and the levels of IL-4, IL-5 and IL-13. Additionally, S. cerevisiae UFMG A-905 restored the levels of IL-10 and interferon (IFN)-gamma, and increased the levels of IL-17A., Conclusion: Oral administration of S. cerevisiae UFMG A-905 prevented the development of major asthma-like characteristics in a mouse model., (© 2017 Asian Pacific Society of Respirology.)

Semaphorins are an essential family of guidance cues ubiquitously expressed in various organs, which play diverse developmental, homeostatic, and pathological roles. Semaphorin 3E (Sema3E), initially identified as a neuronal chemorepellent, is involved in the regulation of cell migration, proliferation, and angiogenesis. However, expression and function of Sema3E in allergic asthma has not been extensively investigated. We determined the expression of Sema3E in the airways and its effect on airway inflammation, hyperresponsiveness, and remodeling as pathological features of allergic asthma provoked by house dust mite in vivo. Our data indicate that exposure to house dust mite markedly reduces Sema3E expression in mouse airways. More important, replenishment of Sema3E by intranasal administration of exogenous Sema3E protects mice from allergic asthma by reducing eosinophilic inflammation, serum IgE level, and T helper cell 2/T helper cell 17 cytokine response. The regulatory effect of Sema3E on cytokine response was sustained on allergen recall response in the lymph nodes and spleen. Furthermore, goblet cell hyperplasia, collagen deposition, and airway hyperresponsiveness were significantly diminished on Sema3E treatment. The inhibitory effect of Sema3E was associated with a reduction of pulmonary CD11b + conventional dendritic cells and regulation of CD4 + T-cell cytokine response. Collectively, our data represent a novel approach to treating allergic asthma via regulation of immune response to house dust mite., (Copyright © 2017 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)

Airway hyperresponsiveness (AHR) is a major clinical problem in allergic asthma mainly caused by the hypercontractility of airway smooth muscles (ASM). S100A8 is an important member of the S100 calcium-binding protein family with a potential to regulate cell contractility. Here, we analyze the potential of S100A8 to regulate allergen-induced AHR and ASM contraction. Treatment with recombinant S100A8 (rS100A8) diminished airway hyperresponsiveness in OVA-sensitized rats. ASM contraction assays showed that rS100A8 reduced hypercontractility in both isolated tracheal rings and primary ASM cells treated by acetylcholine. rS100A8 markedly rescued the phosphorylation level of myosin light chain induced by acetylcholine in ASM cells. These results show that rS100A8 plays a protective role in regulating AHR in asthma by inhibiting ASM contraction. These results support S100A8 as a novel therapeutic target to control ASM contraction in asthma., (Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.)

DW2008 is an anhydrous ethanol extract of Justicia procumbens produced by Dong-Wha Pharmaceutical, Inc., Co. as a candidate anti-asthmatic drug. In this study, DW2008 selectively reduced T helper 2 (Th2) cytokines in mouse splenocytes and ameliorated ovalbumin-induced airway inflammation by downregulating pulmonary infiltration of differential inflammatory cells and Th2 cytokines more than a decoction or ethanol extract of J. procumbens did in a mouse asthma model. DW2008 also significantly inhibited airway hyperresponsiveness and reduced the thickness of the airway epithelium. HPLC analysis showed that the major peaks (justicidin A and B) of DW2008 were higher than those of the other extracts. Justicidin A and B significantly suppressed Th2 cytokine levels in mouse spleen cells and exhibited a protective effect in ovalbumin-induced airway inflammation. Our findings indicate that DW2008 effectively inhibits allergic airway inflammatory reactions and airway hyperresponsiveness in a mouse model of asthma, suggesting its potential as an anti-asthmatic agent.

The presence of congenitally impaired skin barrier followed by atopic dermatitis (AD) is an initial step in the atopic march. The maintenance of acidic pH in the stratum corneum (SC) has been suggested as a therapeutic or preventive strategy for barrier impairment caused by skin inflammation. To determine whether an AD murine model, flaky tail mice, with inherited filaggrin deficiency could develop airway inflammation by repeated topical application followed by nasal inhalation of house dust mite (HDM) antigen (defined as a novel "atopic march animal model"), and whether maintenance of an acidic SC environment by continuous application of acidic cream could interrupt the following atopic march. During the course of HDM treatment, acidic cream (pH2.8) or neutral cream (pH7.4) was applied to flaky tail mice twice daily. Repeated applications and inhalations of HDM to flaky tail mice induced AD skin lesions followed by respiratory allergies. Maintenance of SC acidity inhibited the occurrence of respiratory allergic inflammation as well as AD-like skin lesions. Collectively, a novel atopic march model could be developed by repeated epicutaneous and nasal applications of HDM to flaky tail mice, and that the acidification of SC could prevent the atopic march from AD to respiratory allergy., (© 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

VLA-1 (very late antigen-1) is implicated in recruitment, retention and activation of leukocytes and its blockade has been referred as a potential target of new drug discovery to address unmet medical needs in inflammatory disease area. In the present study, we investigate the effects of an anti-murine CD49a (integrin α subunit of VLA-1) monoclonal antibody (Ha31/8) on various experimental models of inflammatory diseases in mice. Pretreatment with Ha31/8 at an intraperitoneal dose of 250 µg significantly (P<0.01) reduced arthritic symptoms and joint tissue damage in mice with type II collagen-induced arthritis. In addition, Ha31/8 at an intraperitoneal dose of 100 µg significantly (P<0.01) inhibited airway inflammatory cell infiltration induced by repeated exposure to cigarette smoke. In contrast, Ha31/8 failed to inhibit oxazolone-induced chronic dermatitis and OVA-induced airway hyperresponsiveness at an intraperitoneal dose of 100 µg. These results show that VLA-1 is involved, at least partly, in the pathogenesis of type II collagen-induced arthritis and cigarette smoke-induced airway inflammatory cell infiltration in mice, indicating the therapeutic potential of VLA-1 blockade against rheumatoid arthritis and chronic occlusive pulmonary disease.

Trypsin and chymotrypsin are proteolytic pancreatic enzymes that are secreted as the inactive precursors trypsinogen and chymotrypsinogen, respectively. They have several pharmacological as well as laboratory applications, especially in protein chemistry. Exposure to enzyme dusts has long been known to cause immediate occupational hypersensitivities of the airways. Also trypsin and chymotrypsin are potential inhalable sensitizers, and clear cases of specific airway sensitization caused by trypsin- and chymotrypsin-containing products have been reported by several studies. Positive skin prick and challenge tests as well as specific IgE antibodies have been described. These results and the clinical symptoms usually matched well, suggesting an immunological mechanism of action. Immediate urticarial reactions of the skin due to contact with these enzymes are possible, but there is no clear evidence of allergic cell-mediated delayed eczematous skin reactions., (© Georg Thieme Verlag KG Stuttgart · New York.)

Background: Exposure to non-pathogenic Streptococcus pneumoniae and vaccination are inversely associated with asthma. Studies in animal models demonstrate that airway administration of S. pneumoniae (live or killed), or its vaccines or components, suppresses the characteristic features of asthma in mouse models of allergic airway disease (AAD). These components could be developed into immunoregulatory therapies. S. pneumoniae components are recognized by Toll-like receptors (TLR) 2 and TLR4, and both induce inflammatory cell responses through the adaptor protein myeloid differentiation primary response gene 88 (MyD88). The involvement of TLR2, TLR4 and MyD88 in the pathogenesis of AAD and asthma is incompletely understood, and has not been studied in S. pneumoniae-mediated suppression of AAD. We investigated the role of TLR2, TLR4 and MyD88 in the development of AAD and S. pneumoniae-mediated suppression of AAD., Methods and Findings: OVA-induced AAD and killed S. pneumoniae-mediated suppression of AAD were assessed in wild-type, TLR2-/-, TLR4-/-, TLR2/4-/- and MyD88-/- BALB/c mice. During OVA-induced AAD, TLR2, TLR4 and MyD88 were variously involved in promoting eosinophil accumulation in bronchoalveolar lavage fluid and blood, and T-helper type (Th)2 cytokine release from mediastinal lymph node T cells and splenocytes. However, all were required for the induction of airways hyperresponsiveness (AHR). In S. pneumoniae-mediated suppression of AAD, TLR2, TLR4 and MyD88 were variously involved in the suppression of eosinophilic and splenocyte Th2 responses but all were required for the reduction in AHR., Conclusions: These results highlight important but complex roles for TLR2, TLR4 and MyD88 in promoting the development of OVA-induced AAD, but conversely in the S. pneumoniae-mediated suppression of AAD, with consistent and major contributions in both the induction and suppression of AHR. Thus, TLR signaling is likely required for both the development of asthma and the suppression of asthma by S. pneumoniae, and potentially other immunoregulatory therapies.