OVA-induced Airway Hyperresponsiveness Research Articles

Elafibranor PPARα/δ Dual Agonist Ameliorates Ovalbumin-Induced Allergic Asthma.

Asthma is characterized by chronic inflammation and respiratory tract remodeling. Peroxisome proliferator-activated receptors (PPARs) play important roles in the pathogenesis and regulation of chronic inflammatory processes in asthma. The role of PPARγ has been studied using synthetic PPARγ agonists in patients with asthma. However, involvement of PPARα/δ has not been studied in asthma. In the present study, we investigated if elafibranor, a PPARα/δ dual agonist, can modulate ovalbumin (OVA)-induced allergic asthma, which is a potential drug candidate for non-alcoholic fatty liver in obese patients. Elafibranor suppresses antigen-induced degranulation in RBL-2H3 mast cells without inducing cytotoxicity in vitro. In mice with OVA-induced allergic asthma, the administration of elafibranor suppressed OVA-induced airway hyper-responsiveness at a dose of 10 mg/kg. Elafibranor also suppressed the OVA-induced increase in immune cells and pro-inflammatory cytokine production in the bronchoalveolar lavage fluid (BALF). Histological studies suggested that elafibranor suppressed OVA-induced lung inflammation and mucin hyper-production in the bronchial airways. In addition, elafibranor suppressed OVA-induced increases in serum immunoglobulin E and IL-13 levels in BALF. Conversely, the present study suggests that elafibranor has the potential for use in patients with allergic asthma.

Curcumin-Loaded RH60/F127 Mixed Micelles: Characterization, Biopharmaceutical Characters and Anti-Inflammatory Modulation of Airway Inflammation.

Curcumin's ability to impact chronic inflammatory conditions, such as metabolic syndrome and arthritis, has been widely researched; however, its poor bioavailability limits its clinical application. The present study is focused on the development of curcumin-loaded polymeric nanomicelles as a drug delivery system with anti-inflammatory effects. Curcumin was loaded in PEG-60 hydrogenated castor oil and puronic F127 mixed nanomicelles (Cur-RH60/F127-MMs). Cur-RH60/F127-MMs was prepared using the thin film dispersion method. The morphology and releasing characteristics of nanomicelles were evaluated. The uptake and permeability of Cur-RH60/F127-MMs were investigated using RAW264.7 and Caco-2 cells, and their bioavailability and in vivo/vitro anti-inflammatory activity were also evaluated. The results showed that Cur-RH60/F127-MMs have regular sphericity, possess an average diameter smaller than 20 nm, and high encapsulation efficiency for curcumin (89.43%). Cur-RH60/F127-MMs significantly increased the cumulative release of curcumin in vitro and uptake by cells (p < 0.01). The oral bioavailability of Cur-RH60/F127-MMs was much higher than that of curcumin-active pharmaceutical ingredients (Cur-API) (about 9.24-fold). The treatment of cell lines with Cur-RH60/F127-MMs exerted a significantly stronger anti-inflammatory effect compared to Cur-API. In addition, Cur-RH60/F127-MMs significantly reduced OVA-induced airway hyperresponsiveness and inflammation in an in vivo experimental asthma model. In conclusion, this study reveals the possibility of formulating a new drug delivery system for curcumin, in particular nanosized micellar aqueous dispersion, which could be considered a perspective platform for the application of curcumin in inflammatory diseases of the airways.

Effects of chitinase-1 inhibitor in obesity-induced and -aggravated asthma in a murine model

AimsDespite recent investigations on the role of chitinase in asthma, its role in obesity-induced asthma has not been evaluated. Therefore, we investigated the roles of chitin, chitinase-1, and a chitinase-1 inhibitor (compound X, CPX) in a murine model. Main methodsWe assigned C57BL/6 mice to the ovalbumin (OVA) model or obesity model group. In the OVA model, mice received intraperitoneal OVA twice within a 2-week interval and intranasal OVA for 3 consecutive days. Additionally, chitin was intranasally administered for 3 consecutive days, and CPX was intraperitoneally injected three times over 5 days. In the obesity model, a high-fat diet (HFD) was maintained for 13 weeks, and CPX was intraperitoneally injected eight times over 4 weeks. Key findingsIn the OVA model, chitin aggravated OVA-induced airway hyper-responsiveness (AHR), increased bronchoalveolar lavage fluid (BALF) cell proliferation, increased fibrosis, and increased the levels of various inflammatory cytokines (including chitinase-1, TGF-β, TNF-α, IL-1 β, IL-6, IL-4, and IL-13). CPX treatment significantly ameliorated these effects. In the obesity model, HFD significantly increased AHR, BALF cell proliferation, fibrosis, and the levels of various inflammatory cytokines. Particularly, compared to the control group, the mRNA expression of chitinase, chitinase-like molecules, and other molecules associated with inflammation and the immune system was significantly upregulated in the HFD and HFD/OVA groups. Immunofluorescence analysis also showed increased chitinase-1 expression in these groups. CPX significantly ameliorated all these effects in this model. SignificanceThis study showed that CPX can be an effective therapeutic agent in asthma, especially, obesity-induced and -aggravated asthma to protect against the progression to airway remodeling and fibrosis.

Protective Effects of Herba Houttuyniae Aqueous Extract against OVA-Induced Airway Hyperresponsiveness and Inflammation in Asthmatic Mice.

Herba Houttuyniae is the well-knownfood-medicine herb with the special taste and smell. It is also widely used in south China for prevention of various chronic pulmonary inflammatory diseases including asthma. However, the active ingredients and therapeutic mechanism of this herb remain obscure. In this study, network pharmacology technology was employed to investigate the effects of Herba Houttuyniae aqueous extract (HHAE) on OVA-induced airway hyperresponsiveness and inflammation. The results showed that six compounds (isoramanone, kaempferol, 1-methyl-2-nonacosyl-4-quinolone, C09747, spinasterol, and quercetin) were found to be mainly responsible for the therapeutic effects of the herb, which totally regulated the expressions of 168 asthma-related proteins. All those targets involved in the signal transduction of the prolactin signaling pathway, central carbon metabolism in cancer, EGFR tyrosine kinase inhibitor resistance, endocrine resistance, and VEGF signaling pathway. The in vivo experiment also revealed that orally administrated with HHAE alleviated airway hyperresponsiveness and inflammation in OVA-induced asthmatic mice. It significantly decreased the counts of neutrophils, eosinophils, and lymphocytes as well as the levels of IL-1β, IL-4, IL-6, and IL-13 in BALF of asthmatic mice. Mechanically, HHAE downregulated both the mRNA and protein expressions of p38 MAPK, PI3K, AKT, and VEGF in the lung tissues of asthmatic mice. Therefore, HHAE improved OVA-induced airway hyperresponsiveness and inflammation in mice and could be a potential supplement for asthma treatment.

Pharmacological OGG1 inhibition decreases murine allergic airway inflammation.

Background and aim: Allergic asthma is a complex inflammatory disease involving type 2 innate lymphoid cells, type 2T helper cells, macrophages, and eosinophils. The disease is characterized by wheezing, dyspnea, coughing, chest tightness and variable airflow limitation for which there is no cure and is symptomatically treated with inhaled corticosteroids and β2-agonists. Molecular mechanisms underlying its complex pathogenesis are not fully understood. However, 8-oxoguanine DNA glycosylase-1 (OGG1), a DNA repair protein may play a central role, as OGG1 deficiency decreases both innate and allergic inflammation. Methods: Using a murine ovalbumin (OVA) model of allergic airway inflammation we assessed the utility of an inhibitor of OGG1 (TH5487) in this disease context. Cytokines and chemokines, promoting immune cell recruitment were measured using a 23-multiplex assay and Western blotting. Additionally, immune cell recruitment to bronchi was measured using flow cytometry. Histological analyses and immunofluorescent staining were used to confirm immune cell influx and goblet cell hyperplasia of the airways. A PCR array was used to assess asthma-related genes in murine lung tissue following TH5487 treatment. Finally, airway hyperresponsiveness was determined using in vivo lung function measurement. Results: In this study, administration of TH5487 to mice with OVA-induced allergic airway inflammation significantly decreased goblet cell hyperplasia and mucus production. TH5487 treatment also decreased levels of activated NF-κB and expression of proinflammatory cytokines and chemokines resulting in significantly lower recruitment of eosinophils and other immune cells to the lungs. Gene expression profiling of asthma and allergy-related proteins after TH5487 treatment revealed differences in several important regulators, including down regulation of Tnfrsf4, Arg1, Ccl12 and Ccl11, and upregulation of the negative regulator of type 2 inflammation, Bcl6. Furthermore, the gene Clca1 was upregulated following TH5487 treatment, which should be explored further due to its ambiguous role in allergic asthma. In addition, the OVA-induced airway hyperresponsiveness was significantly reduced by TH5487 treatment. Conclusion: Taken together, the data presented in this study suggest OGG1 as a clinically relevant pharmacological target for the treatment of allergic inflammation.

Orally administered solasodine, a steroidal glycoalkaloid, suppresses ovalbumin-induced exaggerated Th2-immune response in rat model of bronchial asthma

Bronchial asthma is a chronic lung disorder, that affects an estimated 262 million people worldwide, thereby, causing a large socio-economic burden. Drug molecules from natural sources have exhibited a good promise in providing an alternative therapy in many chronic ailments. Solasodine, a glycoalkaloid has received an immense interest due to its large pharmacological and industrial value, however, its usefulness in asthma control has not been investigated till date. In this work, solasodine was tested for its ability to reverse several characteristics of bronchial asthma induced by intraperitoneal injection of ovalbumin (OVA) and aluminium hydroxide in experimental rats. Treating asthmatic animals with solasodine (1 mg/kg b.w. or 10 mg/kg b.w.) or dexamethasone (2.5 mg/kg b.w.) reversed OVA-induced airway hyperresponsiveness, infiltration of inflammatory cells and histamine levels in the airways. Furthermore, as compared to OVA-control rats, allergen-induced elevated levels of IgE, nitrites, nitric oxide, and pro-inflammatory mediators, including TNF-α, IL-1β, LTD-4, and Th2-cytokines, particularly, IL-4, IL-5 were remarkably reduced in both bronchoalveolar lavage fluid and blood. These findings are supported by significant protection offered by various treatments against OVA-induced airway inflammation and mast cell degranulation in mesenteric tissues. Further, In-silico molecular docking studies performed to determine inhibitory potential of solasodine at IL-4 and IL-5, demonstrated strong affinity of phytocompound for these receptors than observed with antagonists previously reported. Results of current study imply that solasodine has therapeutic promise in allergic asthma, presumably due to its ability to prevent mast cell degranulation and consequent generation of histamine and Th2-associated cytokines in airways.

Anthocyanins Inhibit Airway Inflammation by Downregulating the NF-κB Pathway via the miR-138-5p/SIRT1 Axis in Asthmatic Mice

Objective: Asthma, caused by chronic inflammation, is a common disease. Anthocyanins are involved in asthma treatment. This study explored the mechanism of anthocyanins on airway inflammation in asthmatic mice by regulating nuclear factor-κB (NF-κB) via the miR-138-5p/sirtuin-1 (SIRT1) axis. Methods: The asthmatic mouse model was established by ovalbumin (OVA) induction and treated with anthocyanins or simultaneously injected with the lentivirus miR-138-5p mimic, followed by the measurement of lung inflammatory injury and IL-4, IL-5, IL-13, and IFN-γ levels in bronchoalveolar lavage fluid. Human bronchial epithelial (HBE) cells 16HBE14o-160 were induced by OVA to establish an asthmatic cell model, treated with anthocyanins and manipulated with miR-138-5p mimic and pcDNA3.1-SIRT1. The releases of inflammatory cytokines, the nuclear translocation of p-p65/p65 in the NF-κB pathway, and the levels of miR-138-5p and SIRT1 mRNA were detected. Results: In vivo experiments showed that anthocyanins could reduce the OVA-induced airway hyperresponsiveness and airway inflammation, improve the inflammatory infiltration and mucus in lung tissues, and diminish the miR-138-5p level in asthmatic mice. Infection with the miR-138-5p mimic averted the remission effect of anthocyanins in asthmatic mice. In vitro experiments showed that in HBE cells exposed to OVA, anthocyanins reduced the miR-138-5p level, increased the SIRT1 level, inhibited the release of inflammatory factors, and reduced the nuclear translocation of NF-κB p65. miR-138-5p targeted SIRT1. miR-138-5p overexpression partially reversed the therapeutic effect of anthocyanins, while SIRT1 overexpression antagonized the effect of miR-138-5p overexpression. Conclusion: Anthocyanins inhibited the NF-κB pathway by regulating the miR-138-5p/SIRT1 axis, thus inhibiting airway inflammation in asthmatic mice.

Differential Regulation of the Asthmatic Phenotype by the Aryl Hydrocarbon Receptor.

The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor that regulates the metabolism of xenobiotics. There is growing evidence that the AhR is implicated in physiological processes such proliferation, differentiation, and immune responses. Recently, a role of the AhR in regulating allergic asthma has been suggested, but whether the AhR also regulates other type of asthma, particularly occupational/irritant-induced asthma, remains unknown. Using AhR-deficient (Ahr−/−) mice, we compared the function of the AhR in the response to ovalbumin (OVA; allergic asthma) vs. chlorine (Cl2; irritant-induced asthma) exposure. Lung inflammation and airway hyperresponsiveness were assessed 24h after exposure to Cl2 or OVA challenge in Ahr−/− and heterozygous (Ahr+/−) mice. After OVA challenge, absence of AhR was associated with significantly enhanced eosinophilia and lymphocyte influx into the airways of Ahr−/− mice. There were also increased levels of interleukin-4 (IL-4) and IL-5 in the airways. However, OVA-induced airway hyperresponsiveness was not affected. In the irritant-induced asthma model caused by exposure to Cl2, the AhR did not regulate the inflammatory response. However, absence of AhR reduced Cl2-induced airway hyperresponsiveness. Collectively, these results support a differential role for the AhR in regulating asthma outcomes in response to diverse etiological agents.

USP4 is pathogenic in allergic airway inflammation by inhibiting regulatory T cell response

AimsAsthma is characterized by chronic inflammation and airway hyperresponsiveness (AHR). It is controllable, but not curable. Ubiquitin-specific peptidase 4 (USP4) has been verified as a regulator of regulatory T (Treg) cells and Th17 cells in vitro. In this study, we aim to investigate whether USP4 could serve as a therapeutic target for asthma. Main methodsAge-matched USP4 wild-type and knockout mice received an intraperitoneal injection of 100 μg ovalbumin (OVA) mixed in 2 mg aluminum hydroxide in 1 × PBS on days 0, 7 and 14. On days 21 to 27, the mice were challenged with aerosolized 1% OVA in 1 × PBS for 30 min. Tissue histology, ELISA and flow cytometry were applied 24 h after the last OVA challenge. Key findingsUSP4 deficiency protected mice from OVA-induced AHR and decreased the production of several inflammatory cytokines in T cells in vivo. Compared to the lung cells isolated from WT mice, Usp4−/− lung cells decreased secretion of IL-4, IL-13 and IL-17A upon stimulation in vitro. Meanwhile, the percentage of CD4+Foxp3+ Treg cells was elevated, with more CCR6+Foxp3+ Treg cells accumulating in the lungs of OVA-challenged USP4 deficient mice than in their wild-type counterparts. Treatment with the USP4 inhibitor, Vialinin A, reduced inflammatory cell infiltration in the lungs of OVA-challenged mice in vivo. SignificanceWe found USP4 deficiency contributes to attenuated airway inflammation and AHR in allergen-induced murine asthma, and Vialinin A treatment alleviates asthma pathogenesis and may serve as a promising therapeutic target for asthma.

Anti-asthmatic effects of tannic acid from Chinese natural gall nuts in a mouse model of allergic asthma

Asthma is a chronic inflammatory disease of the airways, which is characterized by infiltration of inflammatory cells, airway hyperresponsiveness (AHR), and airway remodeling. This study aimed to explore the role and mechanism of tannic acid (TA), a naturally occurring plant-derived polyphenol, in murine asthma model. BALB/c mice were given ovalbumin (OVA) to establish an allergic asthma model. The results revealed that TA treatment significantly decreased OVA-induced AHR, inflammatory cells infiltration, and the expression of various inflammatory mediators (Th2 and Th1 cytokines, eotaxin, and total IgE). Additionally, TA treatment also attenuated increases in mucins (Muc5ac and Muc5b) expression, mucus production in airway goblet cells, mast cells infiltration, and airway remodeling induced by OVA exposure. Furthermore, OVA-induced NF-κB (nuclear factor- kappa B) activation and cell adhesion molecules expression in the lungs was suppressed by TA treatment. In conclusion, TA effectively attenuated AHR, inflammatory response, and airway remodeling in OVA-challenged asthmatic mice. Therefore, TA may be a potential therapeutic option against allergic asthma in clinical settings.

Bacteroides thetaiotaomicron Ameliorates Experimental Allergic Airway Inflammation via Activation of ICOS+Tregs and Inhibition of Th2 Response.

Inhibition of allergic airway diseases (AAD) by immunomodulation of the adaptive immune system through restoration of the enteric dysbiosis is an emerging therapeutic strategy. Patients with allergic rhinitis (n = 6) and healthy controls (n = 6) were enrolled, and gut microbiome composition analysis was performed by 16S rDNA sequencing. We also established an ovalbumin (OVA)-induced allergic airway inflammation murine model. Dysbiosis of the gut flora was observed in both AAD patients and the mice, with the decrease of the biodiversity and the quantity of the Bacteroidetes phylum. Oral application of Bacteroides (B.) thetaiotaomicron ameliorated the symptoms of OVA-induced airway hyperresponsiveness (AHR) and attenuated the airway inflammation in mice. In addition, nasal lavage fluid (NALF) and bronchoalveolar lavage fluid (BALF) from AAD mice orally administered with B. thetaiotaomicron showed reduced numbers of immune cells, and diminished secretion of T helper (Th)-2 cytokines (IL-4, IL-5, and IL-13) compared with the corresponding control mice, whereas the levels of Th1 cytokineIFN-γ was not changed in both the groups. When B. thetaiotaomicron was co-administered with metronidazole in AAD mice, the immunomodulatory effect was weakened and the allergic inflammatory response was aggravated. The ratios of CD4+Foxp3+ cells, CD4+ICOS+ T cells, CD4+ICOS+ Foxp3+ regulatory T cells, and IL-10-expressing CD4+Foxp3+ cells were increased in lymphocytes of spleen, mesenteric, and cervical lymph nodes of AAD mice administrated with B. thetaiotaomicron. Therefore, our data indicate that oral administration of B. thetaiotaomicron effectively inhibited the development of AAD in murine model; inhibition was mediated by the activation of Tregs and inhibition of Th2 response without promoting a Th1 response.

Chitin induces steroid-resistant airway inflammation and airway hyperresponsiveness in mice

BackgroundPrevious reports have shown that pathogen-associated patterns (PAMPs) induce the production of interleukin (IL)-1β in macrophages. Moreover, studies using mouse models also suggest that chitin, which acts as a PAMP, induces adjuvant effects and eosinophilic infiltration in the lung. Thus, we investigated the effects of inhaled chitin in mouse models. MethodsWe developed mouse models of inhaled chitin particle-induced airway inflammation and steroid-resistant ovalbumin (OVA)-induced airway inflammation. Some experimental groups of mice were treated additionally with dexamethasone (DEX). Murine alveolar macrophages (AMs), which were purified from bronchoalveolar lavage (BAL) fluids, were incubated with chitin, and treated with or without DEX. ResultsThe numbers of total cells, AMs, lymphocytes, eosinophils, and neutrophils among BAL-derived cells, as well as the IL-1β levels in BAL fluids and the numbers of IL-1β-positive cells in lung, were significantly increased by chitin stimulation. Airway hyperresponsiveness (AHR) was aggravated in mice of the chitin inflammation model compared to control animals. The production of IL-1β was significantly increased in murine AMs by chitin treatment, but DEX administration did not inhibit this chitin-induced IL-1β production. Furthermore, in mouse models, DEX treatment inhibited the OVA-induced airway inflammation and AHR but not the airway inflammation and AHR induced by chitin or the combination of OVA and chitin. ConclusionsThese results suggest that inhaled chitin induces airway inflammation, AHR, and the production of IL-1β. Furthermore, our findings demonstrate for the first time that inhaled chitin induces steroid-resistant airway inflammation and AHR. Inhaled chitin may contribute to features of steroid-resistant asthma.

Callicarpa japonica Thunb. ameliorates allergic airway inflammation by suppressing NF-κB activation and upregulating HO-1 expression

Ethnopharmacological relevanceCallicarpa japonica Thunb., as an herbal medicine has been used for the treatment of inflammatory diseases in China and Korea. Materials and methodsUltra performance liquid chromatography–photodiode array–quadrupole time–of–flight mass spectrometer (UPLC–PDA–QTof MS) was used to detect the major phenylethanoid glycosides in the C. japonica extract. BALB/c mice were intraperitoneally sensitized by ovalbumin (OVA) (on days 0 and 7) and challenged by OVA aerosol (on days 11–13) to induce airway inflammatory response. The mice were also administered with C. japonica Thunb. (CJT) (20 and 40 mg/kg Per oral) on days 9–13. CJT pretreatment was conducted in lipopolysaccharide (LPS)-stimulated RAW264.7 or phorbol 12-myristate 13-acetate (PMA)-stimulated A549 cells. ResultsCJT administration significantly reduced the secretion of Th2 cytokines, TNF-α, IL-6, immunoglobulin E (IgE) and histamine, and the recruitment of eosinophils in an OVA-exposed mice. In histological analyses, the amelioration of inflammatory cell influx and mucus secretion were observed with CJT. The OVA-induced airway hyperresponsiveness (AHR), iNOS expression and NF-κB activation were effectively suppressed by CJT administration. In addition, CJT led to the upregulation of HO-1 expression. In an in vitro study, CJT pretreatment suppressed the LPS-induced TNF-α secretion in RAW264.7 cells and attenuated the PMA-induced IL-6, IL-8 and MCP-1 secretion in A549 cells. These effects were accompanied by downregulated NF-κB phosphorylation and by upregulated HO-1 expression. ConclusionThese results suggested that CJT has protective activity against OVA-induced airway inflammation via downregulation of NF-κB activation and upregulation of HO-1, suggesting that CJT has preventive potential for the development of allergic asthma.

The IL-17 receptor IL-17RE mediates polyIC-induced exacerbation of experimental allergic asthma

BackgroundThe interleukin 17 receptor E (IL-17RE) is specific for the epithelial cytokine interleukin-17C (IL-17C). Asthma exacerbations are frequently caused by viral infections. Polyinosinic:polycytidylic acid (pIC) mimics viral infections through binding to pattern recognition receptors (e.g. TLR-3). We and others have shown that pIC induces the expression of IL-17C in airway epithelial cells. Using different mouse models, we aimed to investigate the function of IL-17RE in the development of experimental allergic asthma and acute exacerbation thereof.MethodsWild-type (WT) and IL-17RE deficient (Il-17re−/−) mice were sensitized and challenged with OVA to induce allergic airway inflammation. pIC or PBS were applied intranasally when allergic airway inflammation had been established. Pulmonary expression of inflammatory mediators, numbers of inflammatory cells, and airway hyperresponsiveness (AHR) were analyzed.ResultsAblation of IL-17RE did not affect the development of OVA-induced allergic airway inflammation and AHR. pIC induced inflammation independent of IL-17RE in the absence of allergic airway inflammation. Treatment of mice with pIC exacerbated pulmonary inflammation in sensitized and OVA-challenged mice in an IL-17RE-dependent manner. The pIC-induced expression of cytokines (e.g. keratinocyte-derived chemokine (KC), granulocyte-colony stimulating factor (G-CSF)) and recruitment of neutrophils were decreased in Il-17re−/− mice. pIC-exacerbated AHR was partially decreased in Il-17re−/− mice.ConclusionsOur results indicate that IL-17RE mediates virus-triggered exacerbations but does not have a function in the development of allergic lung disease.

Endogenous IL-33 and Its Autoamplification of IL-33/ST2 Pathway Play an Important Role in Asthma

IL-33 and its receptor ST2 are contributing factors to airway inflammation and asthma exacerbation. The IL-33/ST2 signaling pathway is involved in both the onset and the acute exacerbations of asthma. In this study, we address the role of endogenous IL-33 and its autoamplification of the IL-33/ST2 pathway in Ag-dependent and Ag-independent asthma-like models. Wild-type, IL-33 knockout, ST2 knockout mice were either intratracheally administrated with 500 ng of rIL-33 per day for four consecutive days or were sensitized and challenged with OVA over 21 d. In wild-type mice, IL-33 or OVA induced similar airway hyperresponsiveness and eosinophilic airway inflammation. IL-33 induced its own mRNA and ST2L mRNA expression in the lung. IL-33 autoamplified itself and ST2 protein expression in airway epithelial cells. OVA also induced IL-33 and ST2 protein expression. In IL-33 knockout mice, the IL-33- and OVA-induced airway hyperresponsiveness and eosinophilic airway inflammation were both significantly attenuated, whereas IL-33-induced ST2L mRNA expression was preserved, although no autoamplification of IL-33/ST2 pathway was observed. In ST2 knockout mice, IL-33 and OVA induced airway hyperresponsiveness and eosinophilic airway inflammation were both completely diminished, and no IL-33/ST2 autoamplification was observed. These results suggest that endogenous IL-33 and its autoamplification of IL-33/ST2 pathway play an important role in the induction of asthma-like phenotype. Thus an intact IL-33/ST2 pathway is necessary for both Ag-dependent and Ag-independent asthma-like mouse models.

N-acetylcysteine decreases airway inflammation and responsiveness in asthma by modulating claudin 18 expression.

Background/AimsN-acetylcysteine (NAC) affects signaling pathways involved in apoptosis, angiogenesis, cell growth and arrest, redox-regulated gene expression, and the inflammatory response. However, it is not known how the signal mechanism for tight junctional protein claudin (CLDN) 18 is regulated in asthma patients.MethodsTo investigate the effects of NAC on CLDN18 expression in a mouse model of asthma, and to assess plasma levels of CLDN18 in asthma patients. A murine model of asthma induced by ovalbumin (OVA) was established using wild-type BALB/c female mice, and the levels of CLDNs, phosphorylated-pyruvate dehydrogenase kinase 1 (p-PDK1), and protein kinase B (Akt) pathway proteins following NAC treatment were examined by Western blotting and immunohistochemistry. In addition, the plasma levels of CLDN18 were evaluated in asthmatic patients and control subjects.ResultsNAC diminished OVA-induced airway hyper-responsiveness and inflammation. Levels of CLDN18 protein were higher in lung tissue from OVA mice than tissue from control mice, and were increased by treatment with NAC or dexamethasone. Treatment with NAC or dexamethasone decreased the OVA-induced increase in interleukin-1α protein levels. Although treatment with NAC increased OVA-induced p-PDK1 protein levels, it decreased phosphorylated Akt (pAkt)/Akt levels. Soluble CLDN18 levels were lower in patients with asthma than in controls and were correlated with the percentage of neutrophils, forced expiratory volume in 1 second (FEV1)/forced vital capacity % (FVC%) and FEV1%.ConclusionsCLDN18 plays a role in the pathogenesis of asthma and NAC diminishes airway inflammation and responsiveness by modulating CLDN18 expression.

Cordyceps polysaccharide ameliorates airway inflammation in an ovalbumin-induced mouse model of asthma via TGF-β1/Smad signaling pathway

Allergic asthma is a chronic inflammatory disease characterized by airflow obstruction, airway hyperresponsiveness (AHR), airway inflammation, and mucus overproduction. Cordyceps polysaccharide (CPS) is one of the main bioactive compounds of Cordyceps militarisis, a traditional Chinese medicine. In this study, we established a mouse model of asthma using ovalbumin (OVA) challenge and evaluated the potential regulatory effect of CPS (25, 50, and 100 mg/kg) on asthmatic mice. These results showed that the asthmatic mice treated with CPS suppressed the secretion of eotaxin, IL-4, IL-5, IL-13, and IFN-γ in the blood and bronchoalveolar lavage fluid (BALF), and decreased serum IgE levels compared to the vehicle-treated mice. CPS also alleviated inflammatory cell infiltration, goblet cell hyperplasia, and the increases of inflammatory cells in the mouse model of asthma. In addition, OVA-induced AHR was inhibited by CPS treatment. Further analyses of protein expression revealed that CPS inhibited the activation of transforming growth factor β1 (TGF-β1)/Smad pathway in mice with asthma. These findings indicated that CPS might serve as a potential therapeutic agent for the management of allergic asthma.

Baicalein attenuates OVA-induced allergic airway inflammation through the inhibition of the NF-κB signaling pathway.

Asthma is a type of chronic lung inflammation with restrictions in effective therapy. NF-κB pathway activation has been suggested to play an important role in the pathogenesis of asthma. Baicalein, one of the major active flavonoids found in Scutellaria baicalensis, exhibits potent anti-inflammatory properties by inhibiting NF-κB activity. Herein, we report that Baicalein significantly reduces OVA-induced airway hyperresponsiveness (AHR), airway inflammation, serum IgE levels, mucus production, and collagen deposition around the airway. Additionally, western blot analysis and immunofluorescence assay showed that Baicalein attenuates the activation of NF-κB, which was mainly reflected by IκBα phosphorylation and degradation, p65 nuclear translocation and downstream iNOS expression. Furthermore, in human epithelial cells, Baicalein blocked TNF-α-induced NF-κB activation. Our study provides evidence that Baicalein administration alleviates the pathological changes in asthma through inactivating the NF-κB/iNOS pathway. Baicalein might be a promising potential therapy agent for patients with allergic asthma in the future.

Anti-oxidant and Anti-inflammatory Effects of Aquatic Exercise in Allergic Airway Inflammation in Mice.

Oxidative stress and inflammation are key pathways responsible for the pathogenesis of asthma. Aquatic exercise (AE) has been proven to elicit a variety of biological activities such as anti-oxidant and anti-inflammatory effects. However, although proper forms of AE provide beneficial health effects, incorrect forms and types of AE are potentially injurious to health. Several studies have investigated AE, but the relationship between types of AE and asthma has not been fully elucidated. This study evaluated the effects of two types of AE according to resistance on ovalbumin (OVA)-induced allergic airway inflammation in mice. BALB/c mice were subjected to OVA sensitization and challenge, and then to different types of AE including, walking and swimming, in a pool filled with water to a height of 2.5 and 13 cm for 30 min, respectively. AE reduced OVA-induced eosinophilic inflammation, airway hyperresponsiveness, and serum immunoglobulin E level. AE significantly inhibited increases in interleukin (IL)-4, IL-5, IL-13, histamine, leukotriene D4, and tryptase levels in bronchoalveolar lavage fluid (BALF). AE also effectively suppressed mucus formation, lung fibrosis, and hypertrophy of airway smooth muscle within the lung tissues. This exercise markedly reduced the levels of malondialdehyde while increased glutathione and superoxide dismutase (SOD) activity in lung tissues. Furthermore, AE significantly decreased tumor necrosis factor-α, IL-6 levels, and prostaglandin E2 production in BALF. The inhibitory effects of swimming on the levels of biomarkers related to oxidative stress and inflammation were greater than that of walking. These effects may have occurred through upregulation of NF-E2-related factor 2/heme oxygenase-1 signaling and suppression of mitogen-activated protein kinase/nuclear factor-κB pathway. Cumulative results from this study suggest that AE might be beneficial in mitigating the levels of biomarkers related to oxidative stress and inflammation. Thus, this therapy represents a crucial non-pharmacological intervention for treatments of allergic airway inflammation.

Double negative T cells mediate Lag3-dependent antigen-specific protection in allergic asthma

Allergic asthma is an inflammatory disorder of the airway without satisfactory traditional therapies capable of controlling the underlying pathology. New approaches that can overcome the detrimental effects of immune dysregulation are thus desirable. Here we adoptively transfer ovalbumin (OVA) peptide-primed CD4−CD8− double negative T (DNT) cells intravenously into a mouse model of OVA-induced allergic asthma to find that OVA-induced airway hyperresponsiveness, lung inflammation, mucus production and OVA-specific IgG/IgE production are significantly suppressed. The immunosuppressive function of the OVA-specific DNT cells is dependent on the inhibition of CD11b+ dendritic cell function, T follicular helper cell proliferation, and IL-21 production. Mechanistically, Lag3 contributes to MHC-II antigen recognition and trogocytosis, thereby modulating the antigen-specific immune regulation by DNT cells. The effectiveness of ex vivo-generated allergen-specific DNT cells in alleviating airway inflammation thus supports the potential utilization of DNT cell-based therapy for the treatment of allergic asthma.