Model Of Asthma Research Articles

Sensory neurons regulate stimulus-dependent humoral immunity.

Sensory neurons sense pathogenic infiltration, serving to inform immune coordination of host defense. However, sensory neuron-immune interactions have been predominantly shown to drive innate immune responses. Humoral memory, whether protective or destructive, is acquired early in life - as demonstrated by both early exposure to streptococci and allergic disease onset. Our study further defines the role of sensory neuron influence on humoral immunity in the lung. Using a murine model of Streptococcus pneumonia pre-exposure and infection and a model of allergic asthma, we show that sensory neurons are required for B-cell and plasma cell recruitment and antibody production. In response to S. pneumoniae, sensory neuron depletion resulted in a larger bacterial burden, reduced B-cell populations, IgG release and neutrophil stimulation. Conversely, sensory neuron depletion reduced B-cell populations, IgE and asthmatic characteristics during allergen-induced airway inflammation. The sensory neuron neuropeptide released within each model differed. With bacterial infection, vasoactive intestinal polypeptide (VIP) was preferentially released, whereas substance P was released in response to asthma. Administration of VIP into sensory neuron-depleted mice suppressed bacterial burden and increased IgG levels, while VIP1R deficiency increased susceptibility to bacterial infection. Sensory neuron-depleted mice treated with substance P increased IgE and asthma, while substance P genetic ablation resulted in blunted IgE, similar to sensory neuron-depleted asthmatic mice. These data demonstrate that the immunogen differentially stimulates sensory neurons to release specific neuropeptides which specifically target B-cells. Targeting sensory neurons may provide an alternate treatment pathway for diseases involved with insufficient and/or aggravated humoral immunity.

Hypericum perforatum Alleviates Ovalbumin-Induced Asthma through Downregulating TH2 and Upregulating TH1 Related Parameters in BALB/C Mice

Background: Allergic asthma is a chronic and inflammatory disease of the respiratory tract, which is characterized by inflammation, airway obstruction and swelling. Anti-inflammatory compounds can be used to improve the disease severity. Hypericum perforatum (HP)/ St. John’s wort has been used in the treatment of many diseases due to its anti-inflammatory effects. Therefore, this study was performed to investigate the effects of HP on TH1 and TH2 parameters in an animal model of allergic asthma. Methods: Thirty BALB/c mice were sensitized with subcutaneous injection and inhalation of ovalbumin and then administered different doses of HP post-sensitization. Histological analysis of the lungs was performed. The effects of HP on mRNA expression of T-bet and GATA3 (TH1 and TH2 transcription factors, respectively), IFN-γ, IL-4 and IL-10 in the spleen were determined by real-time PCR. The protein levels of IFN-γ, IL-4 and IL-10 cytokines were also determined by ELISA technique in the serum of mice. Results: HP extract (HPE) reduced the clinical severity in asthma-induced mice, and a reduction in the inflammatory cell infiltration in the lung. Furthermore, treatment with HPE inhibited asthma-related mediators as well as increased the anti-inflammatory parameters compared to the control. The study also showed that treatment with HPE significantly increased IFN-γ, IL-10 and T-bet, while decreasing the level of IL-4 and GATA3 in mice treated with HPE. Conclusion: The data indicated that HPE can attenuate allergic asthma autoimmune responses by inhibiting infiltration of immune cell in the lung and TH2-related parameters. It is reasonable to assume that HPE has significant effects in the treatment of allergic asthma.

IL-33 released during challenge phase regulates allergic asthma in an age-dependent way.

Epithelial-derived cytokines, especially type 2 alarmins (TSLP, IL-25, and IL-33), have emerged as critical mediators of type 2 inflammation. IL-33 attracts more interest for its strong association with allergic asthma, especially in childhood asthma. However, the age-dependent role of IL-33 to the development of allergic asthma remains elusive. Here, using OVA-induced allergic asthma model in neonatal and adult mice, we report that IL-33 is the most important alarmin in neonatal lung both at steady state or inflammation. The deficiency of IL-33/ST2 abrogated the development of allergic asthma only in neonates, whereas in adults the effect was limited. Interestingly, the deficiency of IL-33/ST2 equally dampened the ILC2 responses in both neonatal and adult models. However, the effect of IL-33/ST2 deficiency on Th2 responses is age-dependent, which is only blocked in neonates. Furthermore, IL-33/ST2 signaling is dispensable for OVA sensitization. Following OVA challenge in adults, the deficiency of IL-33/ST2 results in compensational more TSLP, which in turn recruits and activates lung DCs and boosts Th2 responses. The enriched γδ T17 cells in IL-33/ST2 deficient neonatal lung suppress the expression of type 2 alarmins, CCL20 and GM-CSF via IL-17A, thus might confer the inhibition of allergic asthma. Finally, on the basis of IL-33 deficiency, the additive protective effects of TSLP blocking is much more pronounced than IL-25 blocking in adults. Our studies demonstrate that the role of IL-33 for ILC2 and Th2 responses varies among ages in OVA models and indicate that the factor of age should be considered for intervention of asthma.

MDM2 Is Essential to Maintain the Homeostasis of Epithelial Cells by Targeting p53.

MDM2 is known as the primary negative regulator of p53, and MDM2 promotes lung cancer fibrosis and lung injury through p53-dependent and p53-independent pathways. However, the mechanism by which MDM2 influences the pathogenesis of asthma is unknown. In this study, we investigated the function of MDM2 in lung epithelial cells in type 2 lung inflammation. We used type II alveolar epithelial cell-specific heterozygous knockout of Mdm2 mice to validate its function. Then papain-induced asthma model was established, and changes in inflammation were observed by measuring immunohistochemistry and flow cytometry analysis. In this study, we knockdown the mouse Mdm2 gene in type 2 alveolar epithelial cells. We demonstrated that heterozygous Mdm2 gene-deleted mice were highly susceptible to protease allergen papain-induced pulmonary inflammation characterized by increased ILC2 numbers, IL-5 and IL-13 cytokine levels, and lung pathology. A mechanistic study showed that following the decreased expression of Mdm2 in lung epithelial cells and A549 cell line, p53 was overactivated, and the expression of its downstream genes p21, Puma, and Noxa was elevated, which resulted in apoptosis. After Mdm2 knockdown, the mRNA expression of inflammation-related gene IL-25, HMGB1, and TNF-α were increased, which further amplified the downstream ILC2 response and lung inflammation. These results indicate that Mdm2 maintains the homeostasis of lung epithelial cells by targeting P53 and regulates the function of lung epithelial cells under type 2 lung inflammation.

In mouse model of mixed granulocytic asthma with corticosteroid refractoriness, Bronchom mitigates airway hyperresponsiveness, inflammation and airway remodeling

BackgroundAsthma is a heterogeneous, inflammatory disease with several phenotypes and endotypes. Severe asthmatics often exhibit mixed granulocytosis with reduced corticosteroid sensitivity. Bronchom is a newly developed Ayurvedic prescription medicine, indicated for the treatment of obstructive airway disorders. The purpose of the present study was to evaluate the in-vivo efficacy of Bronchom in mouse model of mixed granulocytic asthma with steroidal recalcitrance.MethodsHigh-performance thin layer chromatography (HPTLC) and Ultra-high performance liquid chromatography (UHPLC) were employed to identify and quantitate the phytometabolites present in Bronchom. The preclinical effectiveness of Bronchom was assessed in house dust mite (HDM) and Complete Freund’s adjuvant (CFA)-induced mixed granulocytic asthma model in mice. High dose of dexamethasone was tested parallelly. Specific-pathogen-free C57BL/6 mice were immunized with HDM and CFA and nineteen days later, they were intranasally challenged with HDM for four consecutive days. Then the mice were challenged with nebulized methacholine to evaluate airway hyperresponsiveness (AHR). Inflammatory cell influx was enumerated in the bronchoalveolar lavage fluid (BALF) followed by lung histology. Additionally, the concentrations of Th2 and pro-inflammatory cytokines was assessed in the BALF by multiplexed immune assay. The mRNA expression of pro-inflammatory cytokines and Mucin 5AC (MUC5AC) was also evaluated in the lung.ResultsHPTLC fingerprinting and UHPLC quantification of Bronchom revealed the presence of bioactive phytometabolites, namely, rosmarinic acid, gallic acid, methyl gallate, piperine, eugenol and glycyrrhizin. Bronchom effectively reduced AHR driven by HDM-CFA and the influx of total leukocytes, eosinophils and neutrophils in the BALF. In addition, Bronchom inhibited the infiltration of inflammatory cells in the lung as well as goblet cell metaplasia. Further, it also suppressed the elevated levels of Th2 cytokines and pro-inflammatory cytokines in the BALF. Similarly, Bronchom also regulated the mRNA expression of pro-inflammatory cytokines as well as MUC5AC in mice lungs. Reduced effectiveness of a high dose of the steroid, dexamethasone was observed in the model.ConclusionsWe have demonstrated for the first time the robust pharmacological effects of an herbo-mineral medicine in an animal model of mixed granulocytic asthma induced by HDM and CFA. The outcomes suggest the potential utility of Bronchom in severe asthmatics with a mixed granulocytic phenotype.

IL-35 promotes IL-35+IL-10+ Bregs and Conventional LAG3+ Tregs in the lung tissue of OVA-Induced Asthmatic Mice.

This study aimed to investigate the effect of interleukin-35 (IL-35) on inflamed lung tissue in a murine model of asthma. IL-35 was examined for its potential to induce regulatory lymphocytes during ovalbumin (OVA)-induced acute lung injury. Female BALB/c mice sensitized with OVA and were treated with recombinant IL-35 (rIL-35) via intranasal or intraperitoneal routes and were administered 4h before OVA challenge. The effects of rIL-35 treatment on the lung and blood levels of regulatory B cells (Bregs) and regulatory T cells (Tregs), as well as their production of immunosuppressive cytokines, were determined using flow cytometry and enzyme-linked immunosorbent assay (ELISA), respectively. Treatment of OVA-sensitized asthmatic mice with rIL-35, whether administered intranasally or intraperitoneally, resulted in reduced lung inflammation and injury. This reduction was accompanied by an increase in the frequency of IL-35 producing Bregs, IL-35 and IL-10 producing Bregs, and conventional LAG3+ Tregs in the lung tissues and blood. This increase was more pronounced with intranasal rIL-35. Furthermore, there was a positive correlation between the levels of these regulatory cells and lung gene expression of IL-35 and IL-10, and an inverse correlation with both lung gene expression and plasma level of IL-17. The results of this study suggest that IL-35, through its ability to increase Bregs and Tregs, is effective in reversing lung inflammation in the context of asthma. Since the increase was more pronounced with intranasal administration, this highlights the therapeutic potential of its local intrapulmonary application in managing asthma-related inflammation.

CKD-497 inhibits NF-kB signaling and ameliorates inflammation and pulmonary fibrosis in ovalbumin-induced asthma and particulate matter-induced airway inflammatory diseases.

Introduction: Air pollution, allergens, and bacterial infections are major contributors to pathological respiratory disorders worldwide. CKD-497, derived from the rhizome of Atractylodes japonica and the fruits of Schisandra chinensis, is known for its ability to relieve cough and facilitate phlegm expectoration. However, its protective action against allergic asthma and fine dust-induced lung inflammation, along with its underlying mechanisms, have not been thoroughly investigated. Methods: In this study, we established mouse models of ovalbumin (OVA)-induced asthma and particulate matter (PM)-induced pulmonary inflammation to evaluate the effects of CKD-497. Mice were administered CKD-497 orally, and various parameters such as airway inflammation, mucus production, and proinflammatory cytokine levels (IL-1β, IL-6, TNF-α) were measured. Additionally, the macrophage cell line RAW264.7 was pretreated with CKD-497 and stimulated with lipopolysaccharide (LPS) to assess inflammation via the NF-kB signaling pathway. Results: Oral administration of CKD-497 effectively attenuated airway inflammation and mucus production in both OVA-induced asthma and PM-induced lung inflammation models. It also significantly decreased the production of proinflammatory cytokines IL-1β, IL-6, and TNF-α. CKD-497 alleviated leukocyte infiltration, including neutrophils, and reduced fibrillary collagen deposition in PM10-treated mice. In vitro, CKD-497 pretreatment inhibited LPS-induced inflammation in RAW264.7 cells through the suppression of the NF-kB signaling pathway. Discussion: CKD-497 shows potent anti-inflammatory effects in mouse models of asthma and PM-induced lung inflammation, potentially mediated by the inhibition of the NF-kB pathway. These findings suggest that CKD-497 could serve as a functional supplement to protect against respiratory diseases by mitigating pulmonary and airway inflammation induced by allergens and air pollution.

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

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. 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. 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-β1, 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. 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.

Inhibition of MARCKS phosphorylation attenuates of dendritic cell migration in a murine model of acute asthma

BackgroundMARCKS (myristoylated alanine-rich C kinase substrates) serves as a substrate for protein kinase C, residing in the plasma membrane while acts as an actin filament crosslinking protein. This investigation aims to elucidate phosphorylated MARCKS (p-MARCKS) levels and activity in allergic asthma patients and explore the therapeutic potential of peptide inhibitors targeting p-MARCKS in an acute mouse model of allergic asthma. MethodsImmunohistochemistry and histology staining were employed on lung tissue slides to evaluate p-MARCKS expression and allergic asthma symptoms. Airway resistance was measured using invasive whole-body plethysmography. Flow cytometry detected lung dendritic cell migration, and migration/maturation assays were conducted on isolated murine bone marrow-derived dendritic cells (BM-DCs). ResultsElevated p-MARCKS expression was observed in both human asthmatic tissues and animal models immunized with ovalbumin or Alternaria alternata. Remarkably, asthmatic individuals showed elevated high p-MARCKS expression in lung tissues. Intraperitoneal injection of the peptide MPS, targeting the MARCKS phosphorylation site domain, before allergen challenged, effectively suppressed MARCKS phosphorylation in murine lung tissues. MPS inhibited both in vivo and in vitro migration and maturation of dendritic cells (BM-DCs) and reduced Th2-related lymphocyte activation in bronchoalveolar lavage fluid (BALF). MPS pretreatment additionally suppressed all symptoms associated with allergic airway asthma, including a reduction in inflammatory cell influx, airway mucous cell metaplasia, and airway hyperreactivity. ConclusionThese findings suggest that phosphorylated MARCKS occurs in asthmatic lung tissue, and the inhibition of MARCKS phosphorylation by the MPS peptide reduces dendritic cell migration and Th2-related lymphocytes in the lungs in a murine model of acute asthma.

The storage mite Tyrophagus putrescentiae induces greater lung inflammation than house dust mites in mice.

Exposure to storage mite (SM) and house dust mite (HDM) allergens is a risk factor for sensitization and asthma development; however, the related immune responses and their pathology have not been fully investigated. The HDMs Dermatophagoides farinae and Dermatophagoides pteronyssinus and SM Tyrophagus putrescentiae are potent allergens that induce asthma. Most SM-related studies have focused on the allergic reactions of individuals by measuring their immunoglobulin (Ig)E expression. Considering the limited research on this topic, the present study aims to investigate the differences in the immune responses induced by HDMs and SMs and histologically analyze lung tissues in a mouse asthma model to understand the differential effects of HDM and SM. The results revealed that all mite species induced airway inflammation. Mice challenged with T. putrescentiae had the highest airway resistance and total cell, eosinophil, and neutrophil counts in the bronchoalveolar lavage fluid (BALF). The SM-sensitized groups showed more severe lesions and mucus hypersecretions than the HDM-sensitized groups. Although the degree of HDM and SM exposure was the same, the damage to the respiratory lung tissue was more severe in SM-exposed mice, which resulted in excessive mucin secretion and increased fibrosis. Furthermore, these findings suggest that SM sensitization induces a more significant hypersensitivity response in mucosal immunity than HDM sensitization in asthma models.

CircUQCRC2 promotes asthma progression in children by activating the VEGFA/NF-κB pathway by targeting miR-381-3p.

This study targeted to explore circUQCRC2's role and mechanism in childhood asthma. A mouse model of ovalbumin-induced asthma was established to evaluate the effects of circUQCRC2 on childhood asthma in terms of oxidative stress, inflammation, and collagen deposition. The effects of circUQCRC2 on platelet-derived growth factor-BB (PDGF-BB)-induced smooth muscle cells (SMCs) were evaluated, the downstream mRNA of miRNA and its associated pathways were predicted and validated, and their effects on asthmatic mice were evaluated. circUQCRC2 levels were upregulated in bronchoalveolar lavage fluid of asthmatic mice and PDGF-BB-treated SMCs. Depleting circUQCRC2 alleviated tissue damage in asthmatic mice, improved inflammatory levels and oxidative stress in asthmatic mice and PDGF-BB-treated SMC, inhibited malignant proliferation and migration of SMCs, and improved airway remodeling. Mechanistically, circUQCRC2 regulated VEGFA expression through miR-381-3p and activated the NF-κB cascade. circUQCRC2 knockdown inactivated the NF-κB cascade by modulating the miR-381-3p/VEGFA axis. Promoting circUQCRC2 stimulates asthma development by activating the miR-381-3p/VEGFA/NF-κB cascade. Therefore, knocking down circUQCRC2 or overexpressing miR-381-3p offers a new approach to treating childhood asthma.

Cathepsin B-Activatable Bioactive Peptide Nanocarrier for High-Efficiency Immunotherapy of Asthma.

Asthma, a chronic respiratory disease closely associated with inflammation, presents ongoing treatment challenges. IALLIPF (le-Ala-Leu-Leu-Ile-Pro-Phe) is one of millet prolamins peptides (MPP) which shows anti-oxidant bioactivity by reducing the production of reactive oxygen species (ROS). Tryptophan (Trp, W) is an amino acid that has been demonstrated to possess anti-inflammatory effects. We introduce a novel cathepsin B-activatable bioactive peptides nanocarrier, PEG-IALLIPF-GFLG-W (MPP-Trp), designed for immunotherapy of asthma. MPP-Trp is synthesized, purified, and its characteristics are investigated by dynamic light scattering (DLS) and transmission electron microscopy (TEM). The yield of nitric oxide (NO) and pro-inflammatory cytokines (TNF-α, IL-6 and IL-1β) are examined to evaluate anti-inflammatory effects of IALLIPF, Trp and MPP-Trp. The immunomodulatory effects of IALLIPF, Trp and MPP-Trp on Th1/Th2 cell populations and cytokines are investigated by flow cytometry, qRT-PCR and ELISA assays. We explore the therapeutic effect of MPP-Trp in the mouse model of asthma by the analysis of lung histology and ELISA. It is necessary to study the biocompatibility of MPP-Trp by CCK8 assay and histopathologic analysis using hematoxylin and eosin (HE) staining. In asthmatic peripheral blood mononuclear cells (PBMCs), IALLIPF, Trp and MPP-Trp are able to significantly alleviate inflammation by inhibiting the yield of nitric oxide (NO) and pro-inflammatory cytokines (TNF-α, IL-6 and IL-1β), especially MPP-Trp. MPP-Trp significantly upregulates Th1 cell levels while notably reducing Th2 cell levels. Furthermore, MPP-Trp effectively elevates the expression and production of interferon-gamma (IFN-γ), an essential cytokine from Th1 cells. Additionally, MPP-Trp markedly diminishes the mRNA expression and levels of key asthma pathogenesis cytokines, such as interleukin-4 (IL-4), interleukin-13 (IL-13), and interleukin-5 (IL-5), in asthma PBMCs. MPP-Trp ameliorates pulmonary pathological alterations and significantly inhibits OVA-induced inflammation in mice with asthma. It has little influence on the cell viability in Asthma-PBMCs treated with various concentrations or durations of MPP-Trp. No pathological changes, including in the heart, liver, spleen, lung, and kidney tissues, are observed in non-sensitized and non-challenged mice treated with MPP-Trp (20 mg/kg). Our research demonstrates that MPP-Trp has immunomodulatory effects on Th1/Th2 cell populations, essential in managing asthma. It considerably alleviates OVA-induced asthma by shifting the immune response towards a Th1-dominant profile, thereby reducing Th2-driven inflammation. Therefore, this novel bioactive peptide nanocarrier, MPP-Trp, holds promise as a candidate for asthma immunotherapy.

IL-2 family cytokines IL-9 and IL-21 differentially regulate innate and adaptive type 2 immunity in asthma

BackgroundAsthma is often accompanied by type 2 immunity rich in IL-4, IL-5 and IL-13 cytokines produced by TH2 lymphocytes or type 2 innate lymphoid cells (ILC2s). Interleukin-2 family cytokines play a key role in the differentiation, homeostasis and effector function of innate and adaptive lymphocytes. ObjectiveIL-9 and IL-21 boost the activation and proliferation of TH2 and ILC2s, but the relative importance and potential synergism between these γc cytokines is currently unknown. MethodsUsing newly generated antibodies, we inhibited IL-9 and IL-21 alone or in combination, in various murine models of asthma. In a translational approach using segmental allergen challenge, we recently described elevated IL-9 levels in human allergic asthmatics in comparison to non-asthmatic controls. Here, we also measured IL-21 in both groups. ResultsIL-9 played a central role in controlling innate IL-33 induced lung inflammation by promoting proliferation and activation of ILC2s, in an IL-21 independent manner. Conversely, chronic house dust mite induced airway inflammation, mainly driven by adaptive immunity, was solely dependent on IL-21, that controlled TH2 activation, eosinophilia, total serum IgE and formation of tertiary lymphoid structures. In a model of innate on adaptive immunity driven by papain allergen, a clear synergy was found between both pathways, since combined anti-IL-9 or anti-IL-21 blockade was superior in reducing key asthma features. In human bronchoalveolar lavage (BAL) samples we measured elevated IL-21 protein within the allergic asthmatic group, compared with the allergic control group. We also found increased IL21R transcripts and predicted IL-21 ligand activity in various disease-associated cell subsets. ConclusionIL-9 and IL-21 play important and non-redundant roles in allergic asthma by boosting ILC2s and TH2 cells, revealing a dual IL-9 and IL-21 targeting strategy as a new and testable approach.

Soluble E-Cadherin Contributes to Airway Inflammation in Severe Asthma.

Impaired airway epithelial barrier and decreased expression of E-cadherin are key features of severe asthma. As a gatekeeper of the mucosa, E-cadherin can be cleaved from the cell surface and released into the apical lumen as a soluble form (sE-cadherin).This study was aimed to investigate the role of sE-cadherin in severe asthma.Induced sputum was obtained from healthy subjects and patients with asthma. Two murine models of severe asthma were established using either TDI (toluene diisocyanate) or OVA (ovalbumin)/CFA (complete Freund's adjuvants). The role of sE-cadherin in severe asthma was evaluated by intraperitoneal injection of DECMA-1, a neutralizing antibody against sE-cadherin. Mice or THP-1-derived macrophages were treated with recombinant sE-cadherin to explore the pro-inflammatory mechanism of sE-cadherin.Severe asthma patients had a significantly higher sputum sE-cadherin level than the health subjects with mild to moderate asthma, which were positively correlated with sputum HMGB1 level and glucocorticoid dosage required for daily control. Allergen exposure markedly increased sE-cadherin level in the bronchoalveolar lavage fluid in mice. Treatment of DECMA-1 significantly attenuated allergen-induced airway inflammation and hyperresponsivenes in both models of severe asthma. While exposure to recombinant sE-cadherin dramatically up-regulated VEGF expression in THP-1-derived macrophages, and increased neutophlil and eosinophil infiltration into the airway as well as the release of VEGF and IL-6 in mice, both of which can be suppressed by pharmacological inhibition of ERK signaling.Taken together, our data indicated that sE-cadherin contributed to the airway inflammation of severe asthma in an ERK-depedent pathway.

Respiratory conditions and health symptoms associated with air pollution amongst children aged six years and below in Melusi Informal Settlement, Tshwane Metropolitan Municipality, South Africa: a cross-sectional study

BackgroundRespiratory conditions and health symptoms associated with air pollution in children are a major public health concern, as their immune systems and lungs are not yet fully developed. This study aimed to assess self-reported respiratory conditions and health symptoms associated with air pollution sources amongst children aged six years and below in Melusi informal settlement, Tshwane Metropolitan Municipality, South Africa.MethodsWith a quantitative cross-sectional study design, parents/caregivers of children aged six years and below (n = 300) from eight Early Childhood Development Centres were invited to participate in the study. This study employed complete sampling, and data was collected using the modified International Study of Asthma and Allergies in Children. The chi-square and multiple logistic regression models were used to analyze data, with p < 0.05 in the adjusted odds ratios considered as being statistically significant.ResultsThree models were run to examine the predictors of wheezing in the past 12 months, dry cough, and itchy-watery eyes. The model for asthma was excluded, as only seven participants reported having asthma. Wheeze in the past 12 months was associated with participants living in the area for more than three years (OR 2.96 95%CI: 1.011–8.674). Furthermore, having a dog in the house in the past 12 months was associated with wheeze in the past 12 months (OR 5.98 95%CI: 2.107–16.967). There was an association between duration of stay in a residence and dry cough prevalence (OR 5.63 95%CI: 2.175–14.584). Trucks always or frequently passing near homes was associated with itchy-watery eyes (OR 3.27 95%CI: 1.358–7.889). 59% (59%) of participants perceived the indoor air quality in their homes to be good, while 6% perceived it as poor. In contrast, 36% of participants perceived the outdoor air quality to be good, and 19.7% perceived it as poor.ConclusionThe association between perceived air pollution exposure, self-reported respiratory conditions, and health symptoms amongst children is complex. Further research is required to better understand the multifaceted nature of air pollution and its impact on the health of children.

Exploring the In Vitro and In Vivo Therapeutic Efficacy of Juniperus oxycedrus Cade Oil: Antioxidant, Anti-inflammatory, and Anti-asthmatic Effects in an Allergic Asthma Model.

This investigation aimed to explore the antioxidant, anti-inflammatory effects of Cade oil and its efficacy within a Wistar allergic asthma model. The antioxidant activity was assessed through various in vitro tests using chain-breaking antioxidant effects (radical scavenging and reducing abilities assays). In vivo experiments involved Wistar rats categorized into four groups: negative control group, Ovalbumin-sensitised/challenged group, Cade oil-treated group, and Ovalbumin-sensitised/challenged Cade oil-treated group. These experiments aimed to evaluate oxidative stress parameters in the lungs and erythrocytes. The results indicated that the Cade oil exhibited significant antioxidant capabilities, evidenced by its radical scavenging activity against DPPH, ABTS, and Galvinoxyl radicals, with IC50 values ranging from 21.92 to 24.44 µg/mL. Besides, the reducing abilities methods showed A0,5 value ranging from 11.51 to 30.40 µg/mL for reducing power, Cupric ion reducing antioxidant capacity, and O-phenanthroline assays. Additionally, the IC50 value for β-carotene scavenging was found to be (8.2 ± 0.25 µg/ml). Analysis revealed high levels of polyphenols and flavonoids in Cade oil, indicating rich polyphenol (275.21 ± 3.14 mg GAE/g DW) and flavonoid (28.23 ± 1.91 µg QE/mg) content. In vivo findings highlighted Cade oil's efficacy in reducing inflammatory cell recruitment, enhancing antioxidant status, reducing lipid peroxidation, and improving histopathological alterations within the allergic asthma model. These results demonstrated that Cade oil has a potent antioxidant, anti-inflammatory, and anti-asthmatic properties, suggesting its potential therapeutic application in asthma treatment.

Hedgehog signaling pathway regulates Th17 cell differentiation in asthma via IL-6/STAT3 signaling

Asthma is the most prevalent chronic inflammatory disease of the airways in children. The most prevalent phenotype of asthma is eosinophilic asthma, which is driven by a Th2 immune response and can be effectively managed by inhaled corticosteroid therapy. However, there are phenotypes of asthma with Th17 immune response that are insensitive to corticosteroid therapy and manifest a more severe phenotype. The treatment of this corticosteroid-insensitive asthma is currently immature and requires further attention. The objective of this study is to elucidate the regulation of the Hedgehog signaling pathway in Th17 cell differentiation in asthma. The study demonstrated that both Smo and Gli3, key components of the Hedgehog signaling pathway, were upregulated in Th17 polarization in vitro and in a Th17-dominant asthma model in vivo. Inhibiting Smo with a small molecule inhibitor or genetically knocking down Gli3 was found to suppress Th17 polarization. Smo was found to increase in Th1, Th2, Th17 and Treg polarization, while Gli3 specifically increased in Th17 polarization. ChIP-qPCR analyses indicated that Gli3 can directly interact with IL-6 in T cells, inducing STAT3 phosphorylation and promoting Th17 cell differentiation. Furthermore, the study demonstrated a correlation between elevated Gli3 expression and IL-17A and IL-6 expression in children with asthma. In conclusion, the study demonstrated that the Hedgehog signaling pathway plays an important role in the pathogenesis of asthma, as it regulates the differentiation of Th17 cells through the IL-6/STAT3 signaling. This may provide a potential therapeutic target for corticosteroid-insensitive asthma driven by Th17 cells.

Progesterone modulates the immune microenvironment to suppress ovalbumin-induced airway inflammation by inhibiting NETosis

Studies have demonstrated that prior to puberty, girls have a lower incidence and severity of asthma symptoms compared to boys. This study aimed to explore the role of progesterone (P4), a sex hormone, in reducing inflammation and altering the immune microenvironment in a mouse model of allergic asthma induced by OVA. Female BALB/c mice with or without ovariectomy to remove the influence of sex hormones were used for the investigations. Serum, bronchoalveolar lavage fluid (BALF), and lung tissue samples were collected for analysis. The results indicated that P4 treatment was effective in decreasing inflammation and mucus secretion in the lungs of OVA-induced allergic asthma mice. P4 treatment also reduced the influx of inflammatory cells into the BALF and increased the levels of Th1 and Th17 cytokines while decreasing the levels of Th2 and Treg cytokines in both BALF and lung microenvironment CD45+ T cells. Furthermore, P4 inhibited the infiltration of inflammatory cells into the lungs, suppressed NETosis, and reduced the number of pulmonary CD4+ T cells while increasing the number of regulatory T cells. The neutrophil elastase inhibitor GW311616A also suppressed airway inflammation and mucus production and modified the secretion of immune Th1, Th2, Th17, and Treg cytokines in lung CD45+ immune cells. These changes led to an alteration of the immunological milieu with increased Th1 and Th17 cells, accompanied by decreased Th2, Treg, and CD44+ T cells, similar to the effects of P4 treatment. Treatment with P4 inhibited NETosis by suppressing the p38 pathway activation, leading to reduced reactive oxygen species production. Moreover, P4 treatment hindered the release of double-stranded DNA during NETosis, thereby influencing the immune microenvironment in the lungs. These findings suggest that P4 treatment may be beneficial in reducing inflammation associated with allergic asthma by modulating the immune microenvironment. In conclusion, this research indicates the potential of P4 as a therapeutic agent for ameliorating inflammation in OVA-induced allergic asthma mice.

RORγt-dependent antigen-presenting cells direct regulatory T cell-mediated tolerance to food antigen.

The gastrointestinal tract is continuously exposed to foreign antigens in food and commensal microbes with potential to induce adaptive immune responses. Peripherally induced T regulatory (pTreg) cells are essential for mitigating inflammatory responses to these agents1-4. While RORγt+ antigen-presenting cells (RORγt-APCs) were shown to program gut microbiota-specific pTregs5-7, understanding of their characteristics remains incomplete, and the APC subset responsible for food tolerance has remained elusive. Here, we demonstrate that RORγt-APCs are similarly required for differentiation of food antigen-specific pTregs and establishment of oral tolerance. The ability of these cells to direct both food and microbiota-specific pTreg cell differentiation is contingent on expression of RORγt and on a unique cis-regulatory element within the Rorc gene locus (Rorc(t) +7kb). Absent this +7kb element, there was a notable increase in food antigen-specific T helper 2 (Th2) cells in lieu of pTregs, leading to compromised tolerance in a mouse asthma model. By employing single-cell analyses across these models, as well as freshly resected mesenteric lymph nodes from a human organ donor, we identified a rare subset of evolutionarily conserved APCs that are dependent on RORγt, uniquely express the Prdm16 transcription factor, and are endowed with essential mediators for inducing pTreg cell differentiation. Our findings suggest that a better understanding of how RORγt-APCs develop and how they regulate T cell responses to food and microbial antigens could offer new insights into developing therapeutic strategies for autoimmune and allergic diseases as well as organ transplant tolerance.

Novel hypoxia-induced HIF-1αactivation in asthma pathogenesis

BackgroundAsthma’s complexity, marked by airway inflammation and remodeling, is influenced by hypoxic conditions. This study focuses on the role of Hypoxia-Inducible Factor-1 Alpha (HIF-1α) and P53 ubiquitination in asthma exacerbation.MethodsHigh-throughput sequencing and bioinformatics were used to identify genes associated with asthma progression, with an emphasis on GO and KEGG pathway analyses. An asthma mouse model was developed, and airway smooth muscle cells (ASMCs) were isolated to create an in vitro hypoxia model. Cell viability, proliferation, migration, and apoptosis were assessed, along with ELISA and Hematoxylin and Eosin (H&E) staining.ResultsA notable increase in HIF-1α was observed in both in vivo and in vitro asthma models. HIF-1α upregulation enhanced ASMCs’ viability, proliferation, and migration, while reducing apoptosis, primarily via the promotion of P53 ubiquitination through MDM2. In vivo studies showed increased inflammatory cell infiltration and airway structural changes, which were mitigated by the inhibitor IDF-11,774.ConclusionThe study highlights the critical role of the HIF-1α-MDM2-P53 axis in asthma, suggesting its potential as a target for therapeutic interventions. The findings indicate that modulating this pathway could offer new avenues for treating the complex respiratory disorder of asthma.