Model Of Allergic Asthma Research Articles

Adjuvant Effect of Lactobacillus paracasei in Sublingual Immunotherapy of Asthmatic Mice

Background: Sublingual immunotherapy (SLIT) has shown promise in mitigating allergic asthma symptoms; nevertheless, its high dose and prolonged duration of treatment raise safety concerns. This study explored the potential of Lactobacillus paracasei (L. paracasei) to enhance the effectiveness of SLIT in a mouse model of allergic asthma. Methods: Allergic asthma was induced in Balb/c mice following sensitization and challenge with a house dust mite (HDM) allergen. Subsequently, the mice were subjected to SLIT (66 and 132 µg) either alone or in combination with L. paracasei supplementation. Asthma-associated parameters, including rubbing frequency, IgE level, cytokine profiles, and histological changes, were evaluated to assess treatment efficacy. Results: mice that received SLIT 132 µg combined with the probiotic (combined 132) demonstrated a significant reduction in allergic symptoms (rubbing). This treatment strategy led to a marked IgE and eosinophil level decrease in serum; an increase in anti-inflammatory cytokines like IFN-γ and IL-10; and a reduction in pro-inflammatory cytokines IL-17 and TNF-α. The combination therapy also mitigated lung inflammation and supported the restoration of the structural integrity of the colon, promoting the recovery of goblet cells and mucus secretion. Probiotic treatment alone also effectively reduced IgE levels, increased IFN-γ, and decreased levels of IL-17 and TNF-α. Conclusions: The adjuvant effect of L. paracasei in enhancing SLIT represents a promising approach for improving asthma treatment efficacy.

Mycophenolate Mofetil, an Inhibitor of Inosine Monophosphate Dehydrogenase, and Tofacitinib, a Janus Kinase Inhibitor, Attenuate Airway Inflammation and Hyperresponsiveness in a Mouse Model of Allergic Asthma.

Treatment-resistant asthma remains an unresolved clinical problem and a challenge for current medical science. Consequently, there is a growing and urgent need to develop novel or alternative therapeutic options for the treatment of asthma. The research problem raised in this study was to assess and compare mycophenolate mofetil (MMF), an inhibitor of inosine monophosphate dehydrogenase, and tofacitinib (TFB), a Janus kinase inhibitor, for anti-asthmatic properties, and consequently to determine whether these agents may have potential as alternative options for treatment of allergic asthma. For this purpose, we assessed the effect of administration of MMF and TFB on the development of a mouse model of allergic airway inflammation (AAI) and accompanying CD4+ (cluster of differentiation 4) T-cell immune response in the lung-draining mediastinal lymph nodes (MLNs) and lungs, i.e., in the inductive and effector sites, respectively, of the immune response underlying the development of allergic asthma. The results from a histopathological scoring system demonstrated that the administration of MMF and TFB did not prevent or abolish ovalbumin-induced AAI, but strongly attenuated its severity. The pulmonary function tests revealed that the treatment with MMF and TFB significantly reduced methacholine-induced bronchoconstriction. These results indicate that the treatment with TFB and MMF attenuated the development of ovalbumin-induced AAI. The magnitude of the anti-asthmatic effect was comparable between both agents. The study revealed that the impairment of the clonal expansion of effector CD4+ T cells in the MLNs is a critical event in the mechanism underlying the anti-asthmatic effect of MMF and TFB. Apart from this, the findings of the study strongly suggest that the suppression of the interleukin-33/suppression of tumorigenicity-2 signaling pathway may constitute an additional mechanism responsible for producing this effect. In turn, the results indicate that the anti-asthmatic action induced by the studied agents is not mediated by the generation of forkhead box protein 3-expressing CD4+ regulatory T cells. Clinical implication of the results: the results suggest that MMF and TFB may exert anti-asthmatic action, and thus they may be considered therapeutic options for the treatment of allergic asthma cases resistant to conventional/existing treatment.

Anti-Inflammatory Effects of SGLT1 Synthetic Ligand in In Vitro and In Vivo Models of Lung Diseases

Background. Several research findings suggest that sodium–glucose co-transporter 1 (SGLT1) is implicated in the progression and control of infections and inflammation processes at the pulmonary level. Moreover, our previous works indicate an engagement of SGLT1 in inhibiting the inflammatory response induced in intestinal epithelial cells by TLR agonists. In this study, we report the anti-inflammatory effects observed in the lung upon engagement of the transporter, and upon the use of glucose and BLF501, a synthetic SGLT1 ligand, for the treatment of animal models of lung inflammation, including a model of allergic asthma. Methods. In vitro experiments were carried out on human pneumocytes stimulated with LPS from Pseudomonas aeruginosa and co-treated with glucose or BLF501, and the production of IL-8 was determined. The anti-inflammatory effect associated with SGLT1 engagement was then assessed in in vivo models of LPS-induced lung injury, as well as in a murine model of ovalbumin (OVA)-induced asthma, treating mice with aerosolized LPS and the synthetic ligand. After the treatments, lung samples were collected and analyzed for morphological alterations by histological examination and immunohistochemical analysis; serum and BALF samples were collected for the determination of several pro- and anti-inflammatory markers. Results. In vitro experiments on human pneumocytes treated with LPS showed significant inhibition of IL-8 production. The results of two in vivo experimental models, mice exposed to aerosolized LPS and OVA-induced asthma, revealed that the engagement of glucose transport protein 1 (SGLT1) induced a significant anti-inflammatory effect in the lungs. In the first model, the acute respiratory distress induced in mice was abrogated by co-treatment with the ligand, with almost complete recovery of the lung morphology and physiology. Similar results were observed in the OVA-induced model of allergic asthma, both with aerosolized and oral BLF501, suggesting an engagement of SGLT1 expressed both in intestinal and alveolar cells. Conclusions. Our results confirmed the engagement of SGLT1 in lung inflammation processes and suggested that BLF501, a non-metabolizable synthetic ligand of the co-transporter, might represent a drug candidate for therapeutic intervention against lung inflammation states.

DES/O microemulsion for solubilizing and delivering curcumin via the nasal administration to treat acute asthma

As a natural small molecule drug derived from turmeric, curcumin is known for its good biosafety and a range of beneficial effects, including anti-inflammatory, anti-spasmodic, antioxidant, antibacterial, anti-tumor, and neuroprotective effects. Even though, its insolubility in water and instability severely limit its bioavailability and clinical applications. The present study developed a deep eutectic solvent (DES) in oil microemulsion (DES/O-ME) system loaded with Cur for intranasal administration, aiming to enhance both the solubility and permeability of Cur to significantly increase its bioavailability. The project first constructed and screened the optimal choline chloride-based DES. Subsequently, the DES/O-ME system was prepared and optimized to achieve uniform particle size and stability using a pseudo-ternary phase diagram and electrical conductivity measurements. The resulting DES/O-ME system was thoroughly evaluated for its solubilization efficacy, permeability, mucosal cytotoxicity, and stability. Additionally, the therapeutic efficacy of the Cur-DES/O-ME was assessed in vivo using a murine model of allergic asthma. This comprehensive evaluation highlights the potential of the DES/O-ME system as a promising intranasal drug delivery platform to overcome the limitations of curcumin’s bioavailability and clinical application.

Hepatic Cyp3a11 upregulation by Nitro-oleic acid mitigates NAFLD progression in a murine model of allergic asthma

Hepatic Cyp3a11 upregulation by Nitro-oleic acid mitigates NAFLD progression in a murine model of allergic asthma

Mechanisms of Mt.b Ag85B-Fc fusion protein against allergic asthma in mice by intranasal immunization.

Ag85B, the primary component of the Ag85 complex and an early secreted protein by Mycobacterium tuberculosis, has shown potential for the treatment of allergic asthma (AA) when used as a Fc-fusion protein. Administered via nasal immunization, Ag85B-Fc fusion protein significantly alleviated airway inflammation and reduced the proportions of some anaphylaxis related cells in lungs, with no significant histopathological injury to major organs in ovalbumin (OVA)-induced AA model mice. To investigate the underlying immune regulatory mechanisms of Ag85B protein, integrated proteomics and transcriptomics analyses were conducted, identifying the complement and coagulation cascades, and phagosomes as the two significantly enriched pathways at both gene and protein levels. Moreover, C3ar1 (C3aR1), Itgam (CD11b), Itgb2 (CD18), fgg (FGG), Cybb (CYBB), and Ncf4 (NCF4) were identified as core target factors that play a central role in allergic and asthmatic responses. Among them, C3aR1 and CR3 consisting of CD11b and CD18, are main complement receptors, indicating that Ag85B alleviated AA by regulating C3aR1- and CR3-mediated signal transduction. The validation results were consistent with the aforementioned findings. Overall, these results provide valuable insight into the application of mucosal immunotherapy in treatment of AA, positioning Ag85B-Fc fusion protein as a safe mucosal immunotherapeutic agent for AA.

Kiss1 receptor knockout exacerbates airway hyperresponsiveness and remodeling in a mouse model of allergic asthma

BackgroundIn asthma, sex-steroids signaling is recognized as a critical regulator of disease pathophysiology. However, the paradoxical role of sex-steroids, especially estrogen, suggests that an upstream mechanism or even independent of estrogen plays an important role in regulating asthma pathophysiology. In this context, in our previous studies, we explored kisspeptin (Kp) and its receptor Kiss1R’s signaling in regulating human airway smooth muscle cell remodeling in vitro and airway hyperresponsiveness (AHR) in vivo in a mouse (wild-type, WT) model of asthma. In this study, we evaluated the effect of endogenous Kp in regulating AHR and remodeling using Kiss1R knockout (Kiss1R−/−) mice.MethodsC57BL/6J WT (Kiss1R+/+) and Kiss1R−/− mice, both male and female, were intranasally challenged with mixed-allergen (MA) and/or phosphate-buffered saline (PBS). We used flexiVent analysis to assess airway resistance (Rrs), elastance (Ers), and compliance (Crs). Following this, broncho-alveolar lavage (BAL) was performed for differential leukocyte count (DLC) and cytokine analysis. Histology staining was performed using hematoxylin and eosin (H&E) for morphological analysis and Masson’s Trichrome (MT) for collagen deposition. Additionally, lung sections were processed for immunofluorescence (IF) of Ki-67, α-smooth muscle actin (α-SMA), and tenascin-c.ResultsInterestingly, the loss of Kiss1R exacerbated lung function and airway contractility in mice challenged with MA, with more profound effects in Kiss1R−/− female mice. MA-challenged Kiss1R−/− mice showed a significant increase in immune cell infiltration and proinflammatory cytokine levels. Importantly, the loss of Kiss1R aggravated Th2/Th17 biased cytokines in MA-challenged mice. Furthermore, histology of lung sections from Kiss1R−/− mice showed increased collagen deposition on airway walls and mucin production in airway cells compared to Kiss1R+/+ mice. In addition, immunofluorescence analysis showed loss of Kiss1R significantly aggravated airway remodeling and subsequently AHR.ConclusionsThese findings demonstrate the importance of inherent Kiss1R signaling in regulating airway inflammation, AHR, and remodeling in the pathophysiology of asthma.

Requirement for Fucosyltransferase 2 in Allergic Airway Hyperreactivity and Mucus Obstruction.

Mucus hypersecretion is an important pathological problem in respiratory diseases. Mucus accumulates in the airways of people with asthma, and it contributes to airflow limitation by forming plugs that occlude airways. Current treatments have minimal effects on mucus or its chief components, the polymeric mucin glycoproteins MUC5AC and MUC5B. This treatment gap reflects a poor molecular understanding of mucins that could be used to determine how they contribute to airway obstruction. Due to the prominence of glycosylation as a defining characteristic of mucins, we investigated characteristics of mucin glycans in asthma and in a mouse model of allergic asthma. Mucin fucosylation was observed in asthma, and in healthy mice it was induced as part of a mucous metaplastic response to allergic inflammation. In allergically inflamed mouse airways, mucin fucosylation was dependent on the enzyme fucosyltransferase 2 (Fut2). Fut2 gene deficient mice were protected from asthma-like airway hyperreactivity and mucus plugging. These findings provide mechanistic and translational links between observations in human asthma and a mouse model that may help improve therapeutic targeting of airway mucus.

Aging, brain-derived neurotrophic factor, and allergen-induced pulmonary responses in mice.

Asthma in the elderly is being recognized as more severe, resistant to standard therapies, and having greater morbidity. Therefore, it comes important to understand the impact of aging-associated airway structure and function changes towards pathogenesis of asthma in the elderly. Here, airway smooth muscle plays important roles in airway hyperreactivity and structural remodeling. The role of smooth muscle in asthma can be modulated by growth factors (including neurotrophins such as brain-derived neurotrophic factor (BDNF)) and pro-inflammatory senescence factors. In this study, we investigated aging effects on airway hyperreactivity, structural remodeling, inflammation, and senescence in a mouse model of allergic asthma. C57BL/6J wildtype mice or smooth muscle-specific BDNF knockout mice at 4, 18 and 24 months of age were intranasally exposed to mixed allergens (ovalbumin, aspergillus, Alternaria, and house dust mite) over 4 weeks. Assessing lung function by FlexiVent, we found that compared with 4 month old mice, 18 and 24 month old C57BL/6J mice showed decreased airway resistance and increased airway compliance after PBS or MA treatment. Deletion of smooth muscle BDNF blunted airway hyperreactivity in aged mice. Lung histology analysis revealed that aging increased bronchial airway thickness and decreased lung inflammation. Multiplex assays showed that aging largely reduced allergen-induced lung expression of proinflammatory chemokines and cytokines. By immunohistochemistry staining, we found that aging increased bronchial airway expression of senescence markers, including p21, phospho-p53 and phospho-gH2A.X. Our data suggest that aging associated increase of airway senescence in the context of allergen exposure may contribute to asthma pathology in the elderly.

MrgprC11+ Jugular Neurons Control Airway Hyperresponsiveness in Allergic Airway Inflammation.

The lung is densely innervated by sensory nerves, the majority of which are derived from the vagal sensory neurons. Vagal ganglia consist of two different ganglia, termed nodose and jugular ganglia, with distinct embryonic origins, innervation patterns, and physiological functions in the periphery. Since nodose neurons constitute the majority of the vagal ganglia, our understanding of the function of jugular nerves in the lung is very limited. This study aims to investigate the role of MrgprC11+ jugular sensory neurons in a mouse allergic asthma model. Our previous study has shown that MrgprC11+ jugular neurons mediate cholinergic bronchoconstriction. In this study, we found that in addition to MrgprC11, several other Mrgpr family members including MrgprA3, MrgprB4, and MrgprD are also specifically expressed in the jugular sensory neurons. MrgprC11+ jugular neurons exhibit dense innervation in the respiratory tract including the larynx, trachea, proximal, and distal bronchus. We also found that receptors for IL-4 and oncostatin M, two critical cytokines promoting allergic airway inflammation, are mainly expressed in jugular sensory neurons. Both IL-4 and oncostatin M can sensitize the neuronal responses of MrgprC11+ jugular neurons. Moreover, ablation of MrgprC11+ neurons significantly inhibited airway hyperresponsiveness in the asthmatic lung, demonstrating the critical role of MrgprC11+ neurons in controlling airway constriction. Our results emphasize the critical role of jugular sensory neurons in respiratory diseases.

Chimeras Derived from a P2Y14 Receptor Antagonist and UDP-Sugar Agonists for Potential Treatment of Inflammation.

Tethered glycoconjugates of a naphthalene- and piperidine-containing antagonist of the P2Y14 receptor (PPTN) were synthesized, and their nM receptor binding affinity was determined using a fluorescent tracer in hP2Y14R-expressing whole CHO cells. The rationale for preparing mono- and disaccharide conjugates of the antagonists was to explore the receptor binding site, which we know recognizes a glucose moiety on the native agonist (UDP-glucose), as well as enhance aqueous solubility and pharmacokinetics, including kidney excretion to potentially counteract sterile inflammation. Glycoconjugates with varied linker length, including PEG chains, were compared in hP2Y14R binding, suggesting that an optimal affinity (IC50, nM) in the piperidine series was achieved for triazolyl N-linked glucose conjugates having one (8a, MRS4872, 3.21) or two (7a, MRS4865, 2.40) methylene spacers. In comparison of different carbohydrate conjugates lacking a piperidine moiety but containing triazole spacers, optimal hP2Y14R affinity (IC50, nM) was achieved with N-linked glycosides of fucose 10f (6.19) and lactose 10h (1.88), and C-linked glucose 11a (5.30). Selected compounds were examined in mouse models of conditions known to be ameliorated by P2Y14R antagonists. Two glycoconjugates that lacked a piperidine moiety, N-linked glucose derivative 10a and the isomeric C-linked glucose derivative 11a, were protective in a mouse model of allergic asthma. Piperidine-containing glucose conjugate 7a of intermediate linker length and corresponding glucuronide 7b (MRS4866) protected against neuropathic pain. Thus, glycoconjugation of a known antagonist scaffold has produced less hydrophobic P2Y14R antagonists having substantial in vitro and in vivo activity.

Interleukin 9 mediates T follicular helper cell activation to promote antibody responses.

Antigen-specific humoral responses are orchestrated through complex interactions among immune cells in lymphoid tissues, including the collaboration between B cells and T follicular helper (Tfh) cells. Accumulating evidence indicates a crucial role for interleukin-9 (IL-9) in the formation of germinal centers (GCs), enhancing the generation of class-switched high-affinity antibodies. However, the exact function of IL-9 in Tfh cell regulation remains unclear. In this study, we examined the humoral immune responses of CD4Cre/+Il9rafl/fl mice, which lack an IL-9-specific receptor in Tfh cells. Upon intraperitoneal immunization with sheep red blood cells (SRBCs), CD4Cre/+Il9rafl/fl mice displayed diminished levels of SRBC-specific IgG antibodies in their sera, along with reduced levels of GC B cells and plasma cells. Notably, Il9ra-deficient Tfh cells in the spleen exhibited decreased expression of their signature molecules such as B-cell lymphoma 6, C-X-C chemokine receptor 5, IL-4, and IL-21 compared to control mice. In models of allergic asthma induced by house dust mite (HDM) inhalation, CD4Cre/+Il9rafl/fl mice failed to elevate serum levels of HDM-specific IgE and IgG. This was accompanied by reductions in Tfh cells, GC B cells, and plasma cells in mediastinal lymph nodes. Furthermore, group 2 innate lymphoid cells (ILC2s) were identified as producers of IL-9 under immunizing conditions, possibly induced by leukotrienes released by activated IgD+ B cells around the T-B border. These observations may indicate the critical role of IL-9 receptor signaling in the activation of Tfh cells, with ILC2s potentially capable of supplying IL-9 in organized lymphoid tissues.

CD226 implicated in Akt-dependent apoptosis of CD4+ T cell contributes to asthmatic pathogenesis.

Asthma is a chronic airway inflammatory disease in which CD4+ T cell dysregulation occurs. Here, we investigated the molecular role and clinical significance of CD226, a costimulatory molecule of T lymphocytes, in the development of allergic asthma. Our results revealed that the expression of CD226 was significantly increased in CD4+ effector T cells, especially in T helper (Th) 2 cells and Th17 cells in patients with asthma. Moreover, CD4+ T cell-specific Cd226-knockout mice were generated and together with littermates were challenged with ovalbumin (OVA) to establish a model of allergic asthma. We found that CD226 deficiency in CD4+ T cells mitigated lung inflammation, IgE production, and eosinophil infiltration and reduced airway remodeling in experimental allergic asthma. However, the impact of CD226 on asthma was independent of Treg cell modulation. Through RNA-seq data analysis, the apoptosis pathway was screened. Mechanistically, CD226 deletion promoted CD4+ T cell late apoptosis via the activation of Caspase-3 in an Akt-dependent manner. Furthermore, blocking CD226 signaling with a recombinant fusion protein attenuated asthma features in mice and achieved a good therapeutic effect. Overall, this study revealed a unique role of CD226 in CD4+ T cell regulation in asthma pathogenesis. Therefore, targeting CD226 may provide new insights into the clinical treatment of asthma.

Baicalin Attenuates Type 2 Immune Responses in a Mouse Allergic Asthma Model through Inhibiting the Production of Thymic Stromal Lymphopoietin

Plain Language SummaryBaicalin is a flavonoid chemical extracted and purified from Scutellaria baicalensis Georgi, which possesses broad pharmacological properties. Our work objected to explore the protective effect of baicalin on allergic asthma and the possible mechanisms on regulating type 2 immune response. Mice were stimulated with OVA and administrated with baicalin. We found that eosinophils infiltrate in BALF were reduced remarkably in baicalin-treated asthmatic mice. Baicalin decreased OVA-induced inflammatory cytokines and serum immunoglobulin E secretion significantly. Moreover, baicalin alleviated the asthmatic pathological changes and substantially suppressed TSLP expression in the lung tissues. Our study indicates that baicalin attenuates OVA-induced allergic asthma in mice effectively by suppressing type 2 immune responses, which may provide a new mechanistic insight into the anti-asthmatic activity of baicalin.

Unveiling the Potent Anti-Inflammatory Effects of Silymarin in a Mouse Model of Allergic Asthma

Unveiling the Potent Anti-Inflammatory Effects of Silymarin in a Mouse Model of Allergic Asthma

Spleen aminopeptides (FUKETUO) elevate the therapeutic effect of house dust mite desensitization on allergic asthma by inducing interleukin-10 positive regulatory T cells (IL-10+ Tregs) expression.

As a novel immunomodulator, spleen aminopeptides (FUKETUO) can correct the imbalance of immune cells and elevate their functions. Spleen aminopeptides have been used in the treatment of respiratory diseases. However, the regulatory mechanism of it on allergic asthma and desensitization has not been reported, further study is critically needed. This study aimed to investigate the effect and mechanism of spleen aminopeptides on allergic asthma and desensitization. We established an allergic asthma model by house dust mite (HDM) with/without desensitization treatment. The allergic asthma mouse model was established with HDM and treated with desensitization and increasing dose of spleen aminopeptides according to different immune phases. Pathological markers such as airway hyper-responsiveness, and cell composition were monitored to determine the effectiveness of treatment. Spleen aminopeptides can promote the proportion of interleukin-10 positive (IL10+) allergen-specific regulatory T cells (Tregs), and further promote interleukin-10 (IL-10) expression in desensitization. They alleviated the allergic symptoms and elevated desensitization, decreased airway hyper-reaction and lung tissue injury, reduced specific immunoglobulin E (IgE) in serum, eosinophil number and interleukin-4 (IL-4) expression in bronchoalveolar lavage fluid (BALF), therefore, being able to control allergic asthma. Our results suggested that spleen aminopeptides (FUKETUO) could elevate the expression of (CD4+CD25+IL10+) Tregs, especially when it co-immunized with desensitization. Thereby, FUKETUO improved the efficacy of desensitization, and inhibited the development of allergic asthma.

Photobiomodulation Mitigates PM2.5-Exacerbated Pathologies in a Mouse Model of Allergic Asthma.

Exposure to particulate matter (PM), especially PM2.5, is known to exacerbate asthma, posing a significant public health risk. This study investigated the asthma-reducing effects of photobiomodulation (PBM) in a mice model mimicking allergic airway inflammation exacerbated by PM2.5 exposure. The mice received sensitization with ovalbumin (OVA) and were subsequently treated with PM2.5 at a dose of 0.1 mg/kg every 3 days, for 9 times over 3 weeks during the challenge. PBM, using a 610 nm wavelength LED, was applied at 1.7 mW/cm2 to the respiratory tract via direct skin contact for 20 min daily for 19 days. Results showed that PBM significantly reduced airway hyperresponsiveness, plasma immunoglobulin E (IgE) and OVA-specific IgE, airway inflammation, T-helper type 2 cytokine, histamine and tryptase in bronchoalveolar lavage fluid (BALF), and goblet cell hyperplasia in PM2.5-exposed asthmatic mice. Moreover, PBM alleviated subepithelial fibrosis by reducing collagen deposition, airway smooth muscle mass, and expression of fibrosis-related genes. It mitigated reactive oxygen species generation, oxidative stress, endoplasmic reticulum stress, apoptotic cell death, ferroptosis, and modulated autophagic signals in the asthmatic mice exposed to PM2.5. These findings suggest that PBM could be a promising intervention for PM2.5-induced respiratory complications in patients with allergic asthma.

Lentinan attenuates allergic airway inflammation and epithelial barrier dysfunction in asthma via inhibition of the PI3K/AKT/NF-κB pathway

BackgroundAllergic asthma has been regarded as an inflammatory disease mediated by type 2 immunity. The treatment of progressive forms of asthma remains unsatisfactory despite substantial progress in drug development. Lentinan (LTN), a specific polysaccharide derived from Lentinus edodes, exhibits anti-inflammatory and immunomodulatory functions. Nevertheless, the effect and underlying mechanisms of Lentinan on asthma remain unclear. PurposeThis research investigated the regulatory role of Lentinan on allergic airway inflammation and epithelial barrier dysfunction in HDM (house dust mite)-induced asthma. Study designHDM-induced C57BL/6 mice received different dosages of Lentinan through intraperitoneal injections, to observe the effect of Lentinan against allergic airway inflammation and epithelial barrier dysfunction in asthma. MethodsMice were intranasally administered HDM extract solution on days 0, 1, 2 and on days 8 to 12, establishing the allergic asthma model. On days 8 to 12, mice were intraperitoneally administered varying doses of Lentinan (5/10/20mg/kg) 1h before HDM challenge. On day 14, samples were harvested for analysis. Cell counting, flow cytometry, ELISA, HE and PAS staining, IF staining, western blotting, RT-PCR, and bioinformatic analysis were conducted to delve into the underlying functions and mechanisms of Lentinan in asthma. ResultsOur study revealed that the treatment of Lentinan significantly ameliorated allergic airway inflammation and improved epithelial barrier dysfunction in experimental mice. Following Lentinan treatment, there was a significant reduction in eosinophil counts, accompanied by a diminished presence of type 2 cytokines. Reversal of epithelial barrier dysfunction after treatment was also observed. The therapeutic mechanism involved suppression of the PI3K/AKT/ NF-κB pathway. ConclusionOur research illuminated the protective role of Lentinan in allergic airway inflammation and impaired epithelial barrier, suggesting LTN could be an innovative and promising candidate for asthma treatment.

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.