CircCDR1as orchestrates the advancement of asthma triggered by PM2.5 through the modulation of ferroptosis.

Exposure to fine particulate matter (PM2.5) in the ambient environment augments susceptibility to respiratory ailments. Circular RNAs, a distinctive subclass of endogenous non-coding RNAs, have been acknowledged as pivotal regulators of pathological conditions. Ferroptosis, an innovative iron-dependent form of cellular demise, has emerged as a consequential participant in numerous maladies. Despite the established association between PM2.5 exposure and the exacerbation of asthma, scant investigations have probed into the implication of circRNAs and ferroptosis in PM2.5-induced asthma. Consequently, this inquiry sought to scrutinize the potential involvement of circCDR1as and ferroptosis in PM2.5-induced asthma. Through the formulation of a PM2.5 exposure model in asthmatic mice and an in vitro cellular model, it was discerned that PM2.5 induced ferroptosis, thereby intensifying asthma progression. Quantitative reverse transcription-polymerase chain reaction (qRT-PCR) revealed an upregulation of circCDR1as in the PM2.5-stimulated asthma cell model. Molecular biology assays demonstrated that diminished circCDR1as expression hindered the onset of ferroptosis in response to PM2.5 exposure. Notably, Ferrostatin-1 (Fer-1), an inhibitor of ferroptosis, manifested the ability to impede the advancement of asthma. Mechanistically, RNA pull-down and molecular biology experiments substantiated that circCDR1as selectively bound to insulin-like growth factor 2 mRNA binding protein 2 (IGF2BP2), thereby modulating the occurrence of ferroptosis. CircCDR1as emerged as a potential orchestrator of asthma progression by regulating ferroptosis under PM2.5 exposure. Additionally, PM2.5 exposure elicited activation of the Wnt/ß-catenin signaling pathway, subsequently influencing the expression of C-myc and Cyclin D1, ultimately exacerbating asthma development. In summation, the interaction between circCDR1as and IGF2BP2 in regulating ferroptosis was identified as a critical facet in the progression of asthma under PM2.5 exposure. This investigation underscores the pivotal roles of circCDR1as and ferroptosis in PM2.5-induced asthma, offering a novel theoretical foundation for the therapeutic and preventive approaches to asthma.

PM2.5 Exposure Inhibits Transepithelial Anion Short-circuit Current by Downregulating P2Y2 Receptor/CFTR Pathway.

Fine particulate matter (PM2.5) can damage airway epithelial barriers. The anion transport system plays a crucial role in airway epithelial barriers. However, the detrimental effect and mechanism of PM2.5 on the anion transport system are still unclear. In this study, airway epithelial cells and ovalbumin (OVA)-induced asthmatic mice were used. In transwell model, the adenosine triphosphate (ATP)-induced transepithelial anion short-circuit current (Isc) and airway surface liquid (ASL) significantly decreased after PM2.5 exposure. In addition, PM2.5 exposure decreased the expression levels of P2Y2R, CFTR and cytoplasmic free-calcium, but ATP can increase the expressions of these proteins. PM2.5 exposure increased the levels of Th2-related cytokines of bronchoalveolar lavage fluid, lung inflammation, collagen deposition and hyperplasisa of goblet cells. Interestingly, the administration of ATP showed an inhibitory effect on lung inflammation induced by PM2.5. Together, our study reveals that PM2.5 impairs the ATP-induced transepithelial anion Isc through downregulating P2Y2R/CFTR pathway, and this process may participate in aggravating airway hyperresponsiveness and airway inflammation. These findings may provide important insights on PM2.5-mediated airway epithelial injury.

Exposure to ambient fine particulate matter components during pregnancy and early childhood and its association with asthma, allergies, and sensitization in school-age children.

BACKGROUND: Exposure to fine particulate matter (PM2.5) has been associated with allergic diseases, including asthma. However, information about the effects of specific PM2.5 components is limited. This study aimed to investigate the relationship of exposure to chemical components of PM2.5 during pregnancy and early childhood with the development of asthma, allergies, and sensitization in school-age children. METHODS: This study included 2,408 children in the second grade of elementary school. Questionnaire surveys of respiratory/allergic symptoms and measurements of serum total IgE and specific IgE levels to house dust mite (HDM) and animal proteins were conducted. Exposures to ambient PM2.5 mass, sulfate (SO42-), nitrate (NO3-), ammonium (NH4+), elemental carbon (EC), and organic carbon (OC) of PM2.5 in participants' residences from conception to age six were estimated using predictive models. Multiple logistic regression analysis was used to analyze the association of respiratory/allergic symptoms and allergen sensitization with estimated exposure concentrations, after adjustment for survey year, sex, season of birth, feeding method during infancy, presence of siblings, history of lower respiratory tract infection, use of childcare facilities, passive smoking, presence of pets, mother's age, history of allergic diseases, smoking during pregnancy, and annual household income. RESULTS: No significant association was found between PM2.5 and its component concentrations and asthma. However, wheezing significantly increased with mean NO3- concentrations during pregnancy (odds ratio of 1.64 [95% confidence interval: 1.10, 2.47] for an interquartile range increase). Significant associations were also found between EC in the second trimester of pregnancy and PM2.5, NO3-, EC, and OC concentrations in early childhood. Higher PM2.5, SO4-, and NH4+ concentrations during the second trimester increased the risk of rhinitis. Sensitizations to HDM and animal proteins were significantly associated with exposure to components such as SO42- and NH4+ during pregnancy but not with postnatal exposure. CONCLUSIONS: Exposures to NO3-, EC, and OC during pregnancy and early childhood were associated with wheezing. SO42- and NH4+ exposures during pregnancy were associated with sensitization to HDM and animal proteins. Asthma was not associated with exposure to PM2.5 and its main components at any period.

C-Phycocyanin Prevents Oxidative Stress, Inflammation, and Lung Remodeling in an Ovalbumin-Induced Rat Asthma Model.

Asthma is a chronic immunological disease related to oxidative stress and chronic inflammation; both processes promote airway remodeling with collagen deposition and matrix thickening, causing pulmonary damage and lost function. This study investigates the immunomodulation of C-phycocyanin (CPC), a natural blue pigment purified from cyanobacteria, as a potential alternative treatment to prevent the remodeling process against asthma. We conducted experiments using ovalbumin (OVA) to induce asthma in Sprague Dawley rats. Animals were divided into five groups: (1) sham + vehicle, (2) sham + CPC, (3) asthma + vehicle, (4) asthma + CPC, and (5) asthma + methylprednisolone (MP). Our findings reveal that asthma promotes hypoxemia, leukocytosis, and pulmonary myeloperoxidase (MPO) activity by increasing lipid peroxidation, reactive oxygen and nitrogen species, inflammation associated with Th2 response, and airway remodeling in the lungs. CPC and MP treatment partially prevented these physiological processes with similar action on the biomarkers evaluated. In conclusion, CPC treatment enhanced the antioxidant defense system, thereby preventing oxidative stress and reducing airway inflammation by regulating pro-inflammatory and anti-inflammatory cytokines, consequently avoiding asthma-induced airway remodeling.

Mechanisms of exacerbation of Th2-mediated eosinophilic allergic asthma induced by plastic pollution derivatives (PPD): A molecular toxicological study involving lung cell ferroptosis and metabolomics.

Polystyrene microplastics (PS-MP) and dibutyl phthalate (DBP) are plastic pollution derivatives (PPDs) commonly found in the natural environment. To investigate the effects of PPD exposure on the risk of allergic asthma, we established a PPD exposure group in a mouse model. The dose administered for PS-MP was 0.1 mg/d and for DBP was 30 mg/kg/d, with a 5-week oral administration period. The pathological changes of airway tissue and the increase of oxidative stress and inflammatory response confirmed that PPD aggravated eosinophilic allergic asthma in mice. The mitochondrial morphological changes and metabolomics of mice confirmed that ferrotosis and oxidative stress played key roles in this process. Treatment with 100 mg/Kg deferoxamine (DFO) provided significant relief, and metabolomic analysis of lung tissue supported the molecular toxicological. Our findings suggest that the increased levels of reactive oxygen species (ROS) in the lungs lead to Th2-mediated eosinophilic inflammation, characterized by elevated IL-4, IL-5, and eosinophils, and reduced INF-γ levels. This inflammatory response is mediated by the NFκB pathway and exacerbates type I hypersensitivity through increased IL-4 production. In this study, the molecular mechanism by which PPD aggravates asthma in mice was elucidated, which helps to improve the understanding of the health effects of PPD and lays a theoretical foundation for addressing the health risks posed by PPD.

The volatile oil of Hyssopus cuspidatus Boriss. (HVO) ameliorates OVA-induced allergic asthma via inhibiting PI3K/Akt/JNK/P38 signaling pathway and maintaining airway barrier integrity.

ETHNOPHARMACOLOGICAL RELEVANCE: Hyssopus cuspidatus Boriss., a classic Uyghur medicine, is used to treat inflammatory lung diseases such as asthma. But the therapeutic effect and mechanism of the volatile oil of Hyssopus cuspidatus Boriss.(HVO) in asthma therapy remain unclear. AIM OF THE STUDY: We aim to characterize the constituents of HVO, investigate the therapeutic effect in OVA-induced allergic asthmatic mice and further explore the molecular mechanism. MATERIALS AND METHODS: In this study, we applied two-dimensional gas chromatography quadrupole time-of-flight mass spectrometry (GC × GC-QTOF MS) to identify the ingredients of HVO. We established OVA-induced asthmatic model to investigate the therapeutic effect of HVO. To further explore the potential molecular pathways, we used network pharmacology approach to perform GO and KEGG pathways enrichment, and then built an ingredient-target-pathway network to identify key molecular pathways. Finally, LPS-induced RAW 264.7 macrophages and OVA-induced asthmatic model were used to validate the potential signaling pathways. RESULTS: GC × GC-QTOF MS analysis revealed the presence of 123 compounds of HVO. The sesquiterpenes and monoterpenes are the main constituents. The in vivo study indicated that HVO suppressed OVA-induced eosinophilic infiltration in lung tissues, inhibited the elevation of IgE, IL-4, IL-5, and IL-13 levels, downregulated the expressions of phosphorylated PI3K, Akt, JNK and P38, and maintained epithelial barrier integrity via reducing the degradation of occludin, Zo-1, Zo-2, and E-cadherin. The in vitro study also revealed an inhibition of NO release and downregulation of phosphorylated PI3K, Akt, JNK and P38 levels. CONCLUSION: HVO alleviates airway inflammation in OVA-induced asthmatic mice by inhibiting PI3K/Akt/JNK/P38 signaling pathway and maintaining airway barrier integrity via reducing the degradation of occludin, Zo-1, Zo-2, and E-cadherin.

Clarithromycin attenuates airway epithelial-mesenchymal transition in ovalbumin-induced asthmatic mice through modulation of Kv1.3 channels and PI3K/Akt signaling.

Airway epithelial-mesenchymal transition (EMT) is the important pathological feature of airway remodeling in asthma. While macrolides are not commonly used to treat asthma, they have been shown to have protective effects on the airways, in which mechanisms are not yet fully understood. This study aims to investigate the impact of clarithromycin on airway EMT in asthma and its potential mechanism. The results revealed an increase in Kv1.3 expression in the airways of ovalbumin (OVA)-induced asthmatic mice, with symptoms and pathological changes being alleviated after treatment with the Kv1.3 inhibitor 5-(4-phenoxybutoxy)psoralen (PAP-1). Clarithromycin was found to attenuate airway epithelial-mesenchymal transition through the inhibition of Kv1.3 and PI3K/Akt signaling. Further experiments in vitro confirmed that PAP-1 could mitigate EMT by modulating the PI3K/Akt signaling in airway epithelial cells undergoing transformation into mesenchymal cells. These findings confirmed that clarithromycin might have a certain protective effect on asthma-related airway remodeling and represent a promising treatment strategy.

Indeno[1,2,3-cd]pyrene enhances the sensitivity of airway epithelial cells to ferroptosis and aggravates asthma.

Particulate matter of aerodynamic diameter ≤2.5 µm (PM2.5) exposure induces oxidative stress in lung tissues. Ferroptosis is a form of regulated cell death based on oxidative damage and lipid peroxidation. Whether PM2.5 exposure-induced oxidative stress can promote ferroptosis to aggravate asthma is not known. To investigate if PM2.5 exposure induces oxidative stress to promote ferroptosis and influence asthma development, a cockroach extract-induced asthma model in mice was used for in vivo studies. Airway epithelial cell (AEC) ferroptosis was detected by assays (CCK8, malonaldehyde, and 4-hydroxynonenal). Molecular mechanisms were investigated by real-time reverse transcription-quantitative polymerase chain reaction, western blotting, flow cytometry, liquid chromatography-tandem mass spectrometry, and chromatin immunoprecipitation. We found that exposure to PM2.5 and Indeno[1,2,3-cd] pyrene (IP; one of the prominent absorbed polycyclic aromatic hydrocarbons in PM2.5) enhanced the sensitivity of AECs to ferroptosis to aggravate asthma, whereas ferroptosis inhibitors and cytosolic phospholipase A2 (cPLA2) inhibitors reversed this augmented inflammatory response in mice suffering from asthma. IP treatment enhanced cPLA2 expression/activation through aryl hydrocarbon receptor (AhR) genomic and non-genomic pathways, resulting in arachidonic-acid release to promote the sensitivity of AECs to ferroptosis. IP exposure enhanced the release of leukotriene-B4 from lung macrophages, resulting in enhanced expression of acyl-coA synthetase long chain family member4 (ACSL4) and the sensitivity of AECs to ferroptosis. This finding suggests that exposure to PM2.5 and IP promote ferroptosis sensitivity in AECs to aggravate asthma, which may provide new targets for the prevention and treatment of asthma.

Genome-Wide DNA methylation profile analysis identifies differentially methylated loci associated with personal PM2.5 exposure in adults with asthma.

Particulate matter with aerodynamic diameters ≤2.5 µm (PM2.5) is a major environmental risk factor for acute asthma exacerbation, and the underlying mechanism is not completely understood. Studies have indicated that DNA methylation is a potential mechanism linking PM2.5 to its health effects. We conducted a panel study involving 24 adult patients with asthma in Beijing,China between 2017 and 2019. PM2.5 and other atmospheric pollutant exposure data were repeatedly measured. Blood samples were collected for genome-wide DNA methylation analysis. A linear mixed-effects (LME) model was conducted to identify differentially methylated probes (DMPs) associated with PM2.5 exposure. After filtering out probes that did not meet the criteria through quality control, 811,001 CpG sites were included in the LME model, and 36 DMPs were strongly associated with personal PM2.5 exposure at false discovery rate (FDR) < 0.05, of which 22 and 14 DMPs negatively and positively correlated with personal PM2.5 exposure, respectively. Functional analysis revealed that DMPs affected smooth muscle cell contraction and development, extracellular matrix synthesis and secretion, T cell activation and differentiation, and inflammatory factor production. This study provides evidence linking personal PM2.5 exposure to genome-wide DNA methylation in adult patients with asthma. Identifying enrichment pathways can provide biological insights into the acute health effects of PM2.5.

Assessment of neuro-pulmonary crosstalk in asthmatic mice: effects of DiNP exposure on cellular respiration, mitochondrial oxidative status and apoptotic signaling.

Human health is becoming concerned about exposure to endocrine disrupting chemicals (EDCs) emanating from plastic, such as phthalates, which are industrially employed as plasticizers in the manufacturing of plastic products. Due to some toxicity concerns, di(2-ethylhexyl) phthalate (DEHP) was replaced by diisononyl phthalate (DiNP). Recent data, however, highlights the potential of DiNP to interfere with the endocrine system and influence allergic responses. Asthma affects brain function through hypoxia, systemic inflammation, oxidative stress, and sleep disturbances and its effective management is crucial for maintaining respiratory and brain health. Therefore, in DiNP-induced asthmatic mice, this study investigated possible crosstalk between the lungs and the brain inducing perturbations in neural mitochondrial antioxidant status, inflammation biomarkers, energy metabolizing enzymes, and apoptotic indicators. To achieve this, twelve (n = 12, 20-30 g) male BALB/c mice were divided into two (2) experimental groups, each with five (6) mice. Mice in group II were subjected to 50 mg/kg body weight (BW) DiNP (Intraperitoneal and intranasal), while group I served as the control group for 24 days. The effects of DiNP on neural energy metabolizing enzymes (Hexokinase, Aldolase, NADase, Lactate dehydrogenase, Complex I, II, II & IV), biomarkers of inflammation (Nitric oxide, Myeloperoxidase), oxidative stress (malondialdehyde), antioxidants (catalase, glutathione-S-transferase, and reduced glutathione), oncogenic and apoptotic factors (p53, K-ras, Bcl, etc.), and brain histopathology were investigated. DiNP-induced asthmatic mice have significantly (p < 0.05) altered neural energy metabolizing capacities due to disruption of activities of enzymes of glycolytic and oxidative phosphorylation. Other responses include significant inflammation, oxidative distress, decreased antioxidant status, altered oncogenic-apoptotic factors level and neural degeneration (as shown in hematoxylin and eosin-stained brain sections) relative to control. Current findings suggest that neural histoarchitecture, energy metabolizing potentials, inflammation, oncogenic and apoptotic factors, and mitochondrial antioxidant status may be impaired and altered in DiNP-induced asthmatic mice suggesting a pivotal crosstalk between the two intricate organs (lungs and brain).

Lung microbiota participated in fibrous microplastics (MPs) aggravating OVA-induced asthma disease in mice.

Environmental pollution is one of the risk factors for asthma. Currently, whether micro-plastics could aggravate asthma, is still unclear. In the air, fibrous MPs are the predominant shape. Since fibrous micro-plastics are reported to be detected in the lower respiratory tract and other body parts, the relationship of fibrous MP and asthma, as well as the potential mechanism is not well investigated. In this study, we produced fibrous MPs, whose lengths and widths were in accordance with the natural environment, and further, investigated the potential adverse effect of which on the asthma in a OVA (ovalbumin)-induced mice model, aiming at exploring the true life hazard of MP to the respiratory system. Following nasal exposure to fibrous MPs, the airway inflammation, mucus hypersecretion and fibrosis were aggravated in asthmatic mice. Fibrous MPs exposure also significantly increased the levels of total IgE, and, cardinal Th2 and Th1 pro-inflammatory cytokines participated in the etiopathogenesis of allergic airway inflammation. In addition, MP fibers exposure induced lung epithelial cells apoptosis, disruption of epithelial barrier integrity and activation of NLRP3 related signaling pathways. Moreover, fibrous MPs significantly altered the bacterial composition at the genus level. Compared to the control group, the relative abundance of Escherichia-Shigella and Uncultured were decreased to 4.47% and 0.15% in OVA group, while Blautia and Prevotella were elevated to 4.96% and 2.94%. For the OVA + MPs group, the relative abundance of Blautia and Uncultured were decreased to 2.27% and 0.006%, while Prevotella was increased to 3.05%. Our study highlights the detrimental effect of fibrous MPs on asthmatic population and facilitates an indication of the latent mechanisms of fibrous MPs induced airway pathology.

Joint associations of air pollutants during pregnancy, infancy, and childhood with childhood persistent asthma: Nationwide database study in Japan.

The joint effect of air pollutants at relatively low levels requires further investigation. Here, a database study was performed to evaluate the effects of exposure to mixtures of air pollutants during pregnancy, infancy, and childhood on childhood persistent asthma. We used the Japan Medical Data Center database, which provides access to family linkages and healthcare provider addresses, and included child-mother dyads in which the child was born between January 2010 and January 2017. The exposure of interest was ground-level air pollutants, and the primary outcome was childhood persistent asthma at 45 years of age, as defined based on outpatient and inpatient asthma disease codes and/or asthma medication dispensing claims. The weighted quantile sum (WQS) regression was used to evaluate the effects of air pollutant mixtures on 52,526 child-mother dyads from 1149 of 1907 municipalities (60.3 %) in Japan. The WQS regression models showed that with every 10th percentile increase in the WQS index, ground-level air pollutants during pregnancy, infancy, and childhood increased the risk of childhood persistent asthma by an odds ratio of 1.04 (95 % CI: 1.02-1.05; p<0.001), 1.02 (95 % CI: 1.01-1.03; p<0.001), and 1.03 (95 % CI: 1.01-1.04; p<0.001), respectively. Moreover, particulate matter with an aerodynamic diameter ≤ 2.5 µm was assigned the highest weight across all three exposure periods. Relatively high weights were assigned to suspended particulate matter and photochemical oxidants during pregnancy, carbon monoxide during infancy, and photochemical oxidants during childhood. Our study showed that a mixture of low-level air pollutants has a detrimental association with childhood persistent asthma.

Health effects of air pollution on respiratory symptoms: A longitudinal study using digital health sensors.

Previous studies of air pollution and respiratory disease often relied on aggregated or lagged acute respiratory disease outcome measures, such as emergency department (ED) visits or hospitalizations, which may lack temporal and spatial resolution. This study investigated the association between daily air pollution exposure and respiratory symptoms among participants with asthma and chronic obstructive pulmonary disease (COPD), using a unique dataset passively collected by digital sensors monitoring inhaled medication use. The aggregated dataset comprised 456,779 short-acting beta-agonist (SABA) puffs across 3,386 people with asthma or COPD, between 2012 and 2019, across the state of California. Each rescue use was assigned space-time air pollution values of nitrogen dioxide (NO2), fine particulate matter with diameter ≤ 2.5 µm (PM2.5) and ozone (O3), derived from highly spatially resolved air pollution surfaces generated for the state of California. Statistical analyses were conducted using linear mixed models and random forest machine learning. Results indicate that daily air pollution exposure is positively associated with an increase in daily SABA use, for individual pollutants and simultaneous exposure to multiple pollutants. The advanced linear mixed model found that a 10-ppb increase in NO2, a 10 µg m-3 increase in PM2.5, and a 30-ppb increase in O3 were respectively associated with incidence rate ratios of SABA use of 1.025 (95 % CI: 1.013-1.038), 1.054 (95 % CI: 1.041-1.068), and 1.161 (95 % CI: 1.127-1.233), equivalent to a respective 2.5 %, 5.4 % and 16 % increase in SABA puffs over the mean. The random forest machine learning approach showed similar results. This study highlights the potential of digital health sensors to provide valuable insights into the daily health impacts of environmental exposures, offering a novel approach to epidemiological research that goes beyond residential address. Further investigation is warranted to explore potential causal relationships and to inform public health strategies for respiratory disease management.

Developmental perfluorooctane sulfonic acid exposure exacerbates house dust mite induced allergic responses in adult mice.

Perfluorooctane sulfonic acid (PFOS) is a long-chain per- and polyfluoroalkyl substance (PFAS), a persistent organic pollutant, which has been used in aqueous film-forming foams. Emerging epidemiological evidence indicates a significant body burden of PFOS is observed in the lungs. Furthermore, developmental PFOS exposure dysregulates lung development and exacerbates eosinophilic inflammation, which are critical risk factors for asthma. However, it is unknown whether PFOS exerts sex-dependent effects on house dust mite (HDM) induced asthmatic progression and allergic inflammation. In this study, timed pregnant Balb/cJ dams were dosed orally via PFOS (1.0 mg/kg/d) spiked or vehicle control mealworms from gestational day (GD) 0.5 to postnatal day (PND) 21. Subsequently, HDM (30 µg/day) was administered starting at PND 77-82 for 10 days, and the mice were sacrificed 48 h after their final treatment. The serum and lung PFOS concentrations were 3.391 ± 0.189 µg/mL and 3.567 ± 0.1676 µg/g in the offspring, respectively. Male mice exposed to PFOS + HDM showed higher total cell counts in bronchoalveolar lavage fluid (BALF), macrophage counts, and eosinophil counts compared to mice exposed to HDM alone. Female mice exposed to PFOS + HDM had increased BALF eosinophil percentage, mucous production, alternatively activated (M2) macrophage polarization, and M2-associated gene expression compared to female mice exposed to HDM alone. PFOS exposure had no significant effect on HDM-induced IL-4, IL-5, or IL-13, but RANTES was further elevated in female mice. Overall, our data suggest that developmental PFOS exposure increased the risk of exacerbated eosinophilic inflammation and M2 polarization, which were more severe in female mice, suggesting sex-dependent developmental effects of PFOS on allergic airway responses.

YiQi GuBen formula alleviates airway inflammation and airway remodeling in OVA-induced asthma mice through TLR4/NF-κB signaling pathway.

BACKGROUND: We aim to investigate the effect of YiQi GuBen formula (YQGB) on airway inflammation and airway remodeling in the ovalbumin (OVA)-induced asthma model to further explore the potential mechanisms of YQGB in treating allergic asthma. METHODS: Mice were divided into five groups randomly (n = 10): the control group, OVA group, OVA + Dex (0.1 mg/kg) group, OVA + low-dose (1.1 g/kg) YQGB group, and OVA + high-dose (2.2 g/kg) YQGB group. Inflammatory cell count and IgE were detected in bronchoalveolar lavage fluid (BALF). Lung tissue histopathology was observed by using H&E, PAS, Masson, and immunohistochemistry staining. qRT-PCR and western blot were applied to analyze key genes and proteins associated with TLR4 and NF-κB signaling pathways. RESULTS: In OVA-induced asthma mice, YQGB decreased eosinophils and IgE in BALF. YQGB alleviated the OVA-induced inflammatory infiltration and declined IL-4, IL-5, IL-13, Eotaxin, ECP, GM-CSF, LTC4, and LTD4. YQGB attenuated the OVA-induced goblet cell metaplasia and mucus hypersecretion. YQGB mitigated the OVA-induced subepithelial fibrosis and lowered TGF-ß1, E-Cadherin, Vimentin, and Fibronectin. YQGB ameliorated the OVA-induced airway smooth muscle thickening and lessened α-SMA and PDGF levels. YQGB reduced the expression of TLR4, MyD88, TRAF6, IκBα, and p65 mRNAs, and IκBα and p-p65 protein levels were also reduced. CONCLUSION: YQGB exhibits the anti-asthma effect by reducing airway inflammation and airway remodeling through suppressing TLR4/NF-κB signaling pathway, and is worth promoting clinically.

Formaldehyde exacerbates inflammation and biases T helper cell lineage commitment through IFN-γ/STAT1/T-bet pathway in asthma.

The correlation between formaldehyde (FA) exposure and prevalence of asthma has been widely reported. However, the underlying mechanism is still not fully understood. FA exposure at 2.0 mg/m3 was found to exacerbate asthma in OVA-induced murine models. IFN-γ, the cytokine produced by T helper 1 (Th1) cells, was significantly induced by FA in serum and bronchoalveolar lavage fluid (BALF) of asthmatic mice, which was different from cytokines secreted by other Th cells. The observation was also confirmed by mRNA levels of Th marker genes in CD4+ T cells isolated from BALF. In addition, increased production of IFN-γ and expression of T-bet in Jurkat T cells primed with phorbol ester and phytohaemagglutinin were also observed with 100 µM FA treatment in vitro. Upregulated STAT1 phosphorylation, T-bet expression and IFN-γ production induced by FA was found to be restrained by STAT1 inhibitor fludarabine, indicating that FA promoted Th1 commitment through the autocrine IFN-γ/STAT1/T-bet pathway in asthma. This work not only revealed that FA could bias Th lineage commitment to exacerbate allergic asthma, but also identified the signaling mechanism of FA-induced Th1 differentiation, which may be utilized as the target for development of interfering strategies against FA-induced immune disorders.

AdipoRon, an adiponectin receptor agonist, modulates AMPK signaling pathway and alleviates ovalbumin-induced airway inflammation in a murine model of asthma.

Asthma is a long-term disease that causes airways swelling and inflammation and in turn airway narrowing. AdipoRonis an orally active synthetic small molecule that acts as a selective agonist at theadiponectin receptor 1 and 2. The aim of the current study is to delineate the protective effect and the potential underlying mechanism ofadipoRon inairway inflammationinduced byovalbumin (OVA) in comparison withdexamethasone. Adult maleSwiss Albino micewere sensitized to OVA on days 0 and 7, then challenged with OVA on days 14, 15 and 16. AdipoRon was administered orally for 6 days starting from the 11th day till the 16th and 1 h prior to OVA in the challenge days. Obtained results from asthmatic control group showed a significant decrease in serum adiponectin concentration, an increase in inflammatory cell counts inthe bronchoalveolar lavage fluid(BALF), CD68 protein expression, inflammatory cytokine concentration and oxidative stress as well. Administration of adipoRon enhanced antioxidant mechanisms limiting oxidative stress by significantly increasing reduced glutathione (GSH) pulmonary content, decreasing serum lactate dehydrogenase (LDH) together with malondialdehyde (MDA) significant reduction in lung tissue. In addition, it modulated the levels of serum immunoglobulin E (IgE), pro-inflammatory cytokines tumor necrosis factor (TNF)-α, interleukin (IL)-4, IL-13, nuclear factor kappa B (NF-κB) and the anti-inflammatory one IL-10 improving lung inflammation as revealed by histopathological evaluation. Furthermore, lung tissue expression of nuclear factor erythroid 2-related factor (Nrf2) and 5'AMP-activated protein kinase (AMPK) were significantly increased adipoRon. Notably, results of adipoRon received group were comparable to those of dexamethasone group. In conclusion, our study demonstrates that adipoRon can positively modulate adiponectin expression with activation of AMPK pathway and subsequent improvement in inflammatory and oxidative signaling.

Mediation of FOXA2/IL-6/IL-6R/STAT3 signaling pathway mediates benzo[a]pyrene-induced airway epithelial mesenchymal transformation in asthma.

Benzo [a]pyrene (BaP), a toxic pollutant, increases the incidence and severity of asthma. However, the molecular mechanisms underlying the effects of BaP in asthma remain unclear. In terms of research methods, we used BaP to intervene in the animal model of asthma and the human bronchial epithelial (16HBE) cells, and the involved mechanisms were found from the injury, inflammation, and airway epithelial to mesenchymal transition (EMT) in asthma. We also constructed small interfering RNAs and overexpression plasmids to knockdown/overexpress IL-6R and FOXA2 in 16HBE cells and a serotype 9 adeno-associated viral vector for lung tissue overexpression of FOXA2 in mice to determine the mechanism of action of BaP-exacerbated asthma airway EMT. We observed that BaP aggravated inflammatory cell infiltration into the lungs, reduced the Penh value, increased collagen fibres in the lung tissue, and increased serum IgE levels in asthmatic mice. After BaP intervention, the expression of FOXA2 in the lung tissue of asthmatic mice decreased, the production and secretion of IL-6 were stimulated, and STAT3 phosphorylation and nuclear translocation increased, leading to changes in EMT markers. However, EMT decreased after increasing FOXA2 expression and decreasing that of IL-6R and was further enhanced after low FOXA2 expression. Our results revealed that BaP exacerbated airway epithelial cell injury and interfered with FOXA2, activating the IL-6/IL-6R/STAT3 signaling pathway to promote airway EMT in asthma. These findings provide toxicological evidence for the mechanism underlying the contribution of BaP to the increased incidence of asthma and its exacerbations.

The association between children's exposure to pesticides and asthma, wheezing, and lower respiratory tract infections. A systematic review and meta-analysis.

Background: Exposure to pesticides is a global public health problem, especially for children. Its association with chronic respiratory disease among children has attracted considerable attention, but the existing evidence remains inconclusive and cannot be certain. Therefore, this systematic review and meta-analysis aim to determine the global pooled effect size of association with pesticide exposure and asthma, wheezing, and respiratory tract infections among children. Methods: A comprehensive search was conducted for relevant literature from electronic databases, including PubMed, Google Scholar, Hinari, Semantic Scholar, and Science Direct. Studies that provided effect size on the association between pesticide exposure and childhood asthma, wheezing, and respiratory tract infections in children were included. The articles were screened, data was extracted, and the quality of each study was assessed with four independent reviewers. Random effects models for significant heterogeneity and fixed effect models for homogeneous studies were conducted to estimate pooled effect sizes with 95% confidence intervals using Comprehensive Meta-Analysis version 3.3.070 and MetaXL version 2. Funnel plot and Higgins I 2 statistics were used to determine the heterogeneity of the included studies. Subgroup analyses were computed based on the types of pesticide exposure, study design, sample size category, and outcome assessment technique. Result: A total of 38 articles with 118,303 children less than 18 years of age were included in this meta-analysis. Pesticide exposure among children increased the risk of asthma by 24%; (OR = 1.24, 95% CI: 1.14-1.35) with extreme heterogeneity (I 2 = 81%, p < 0.001). Exposure to pesticides increased the odds of developing wheezing among children by 34% (OR = 1.34, 95% CI: 1.14-1.57), with high heterogeneity (I 2 = 79%, p < 0.001) and also increased the risk of developing lower respiratory tract infection by 79% (OR = 1.79, 95% CI: 1.45-2.21) with nonsignificant low heterogeneity (I 2 = 30%, p-value = 0.18). Conclusion: This meta-analysis provided valuable evidence supporting the association between childhood asthma, wheezing, and lower respiratory tract infection with pesticide exposure. The findings would contribute to a better understanding of the estimate of the effect of pesticide exposure on respiratory health in children and inform evidence-based preventive strategies and public health interventions.

Inhibition of phosphoinositide 3-kinase activity attenuates neutrophilic airway inflammation and inhibits pyrin domain-containing 3 inflammasome activation in an ovalbumin-lipopolysaccharide-induced asthma murine model.

BACKGROUND: Existing investigations suggest that the blockade of phosphoinositide 3-kinase (PI3K) activity contributes to inflammatory solution in allergic asthma, but whether this inhibition directly attenuates neutrophilic airway inflammation in vivo is still unclear. We explored the pharmacological effects of LY294002, a specific inhibitor of PI3K on the progression of neutrophilic airway inflammation and investigated the underlying mechanism. METHODS AND RESULTS: Female C57BL/6 mice were intranasally sensitized with ovalbumin (OVA) together with lipopolysaccharide (LPS) on days 0 and 6, and challenged with OVA on days 14-17 to establish a neutrophilic airway disease model. In the challenge phase, a subset of mice was treated intratracheally with LY294002. We found that treatment of LY294002 attenuates clinic symptoms of inflammatory mice. Histological studies showed that LY294002 significantly inhibited inflammatory cell infiltration and mucus production. The treatment also significantly inhibited OVA-LPS induced increases in inflammatory cell counts, especially neutrophil counts, and IL-17 levels in bronchoalveolar lavage fluid (BALF). LY294002 treated mice exhibited significantly increased IL-10 levels in BALF compared to the untreated mice. In addition, LY294002 reduced the plasma concentrations of IL-6 and IL-17. The anti-inflammatory effects of LY29402 were correlated with the downregulation of NLRP3 inflammasome. CONCLUSIONS: Our findings suggested that LY294002 as a potential pharmacological target for neutrophilic airway inflammation.