PM2.5 exposure regulates Th1/Th2/Th17 cytokine production through NF-κB signaling in combined allergic rhinitis and asthma syndrome.

BACKGROUND: Particulate matter (PM) is a major component of air pollution from emissions from anthropogenic and natural sources and is a serious problem worldwide due to its adverse effects on human health. Increased particulate air pollution increases respiratory disease-related mortality and morbidity. However, the impact of PM with an aerodynamic diameter of ≤ 2.5 µm (PM2.5) on combined allergic rhinitis and asthma syndrome (CARAS) remains to be elucidated. Accordingly, in the present study, we investigated the effect of PM2.5 in an ovalbumin (OVA)-induced CARAS mouse model with a focus on NF-κB signaling. METHODOLOGY: We established an OVA-induced mouse model of CARAS to determine the effects of exposure to PM2.5. BALB/c mice were randomly divided into four groups: (1) naive, (2) PM2.5, (3) CARAS, and (4) CARAS/PM2.5. Mice were systemically sensitized with OVA and challenged with inhalation of ultrasonically nebulized 5% OVA three times by intranasal instillation of OVA in each nostril for 7 consecutive days. Mice in the PM2.5 and CARAS/PM2.5 groups were then exposed to PM2.5 by intranasal instillation of PM2.5 for several days. We then examined the impacts of PM2.5 exposure on histopathology and NF-κB signaling in our OVA-induced CARAS mouse model. RESULTS: PM2.5 increased infiltration of eosinophils in bronchoalveolar lavage fluid (BALF) samples and inflammatory cells in lung tissue. It also increased production of GATA3, RORγ, IL-4, IL-5, IL-13, and IL-17 in nasal lavage fluid (NALF) and BALF samples in the CARAS mouse model, but secretion of IL-12 and IFN-γ was suppressed. Exposure to PM2.5 increased OVA-specific IgE and IgG1 levels in serum, inflammatory cell infiltration in the airways, and fibrosis in lung tissue. It also activated the NF-κB signaling pathway, increasing Th2/Th17 cytokine levels while decreasing Th1 cytokine expression, thereby inducing an inflammatory response and promoting inflammatory cell infiltration in nasal and lung tissue. CONCLUSION: Our results demonstrate that PM2.5 can aggravate OVA-induced CARAS.

Fructus Amomi extract attenuates nasal inflammation by restoring Th1/Th2 balance and down-regulation of NF-κB phosphorylation in OVA-induced allergic rhinitis.

Fructus Amomi Cardamomi (FA) is the mature fruit of Amomum villosum Lour (family Zingiberaceae) and is commonly used in Chinese traditional medicine to treat various gastrointestinal disorders. FA's possible benefits as an allergic rhinitis (AR) treatment, however, have not been examined. We used an ovalbumin (OVA)-induced AR mouse model to identify any anti-allergic effects associated with the administration of 200 mg/kg FA or dexamethasone (Dex) 2.5 mg/kg by oral administration. The results of our testing confirm that FA ameliorated nasal symptoms and alleviated nasal epithelium swelling, reduced the goblet cell hyperplasia and eosinophil cell infiltration in the nasal epithelium, and inhibited lung tissue inflammation and Dex as well. Significantly decreased Th2 cytokine (interleukin (IL)-1ß, IL-4, and IL-5) expression, and a correspondingly significant increase in Th1 cytokine (IL-12, interferon (IFN)-γ) production, was observed in nasal lavage fluid (NALF) taken from mice that received FA or Dex treatment. FA also reduced the presence of OVA-specific immunoglobulin (Ig) E, OVA-specific IgG1, and histamine levels in serum, and inhibited mast cell degranulation in vitro. In addition, these effects were involved with the reduction in NF-κB phosphorylation. These results suggest that FA restores Th1/Th2 balance and inhibits NF-κB phosphorylation and mast cell degranulation, thereby achieving a notable anti-inflammatory effect. Accordingly, it has the potential to be used as an efficacious therapeutic treatment for AR.

PM2.5 Exacerbates Oxidative Stress and Inflammatory Response through the Nrf2/NF-κB Signaling Pathway in OVA-Induced Allergic Rhinitis Mouse Model.

Air pollution-related particulate matter (PM) exposure reportedly enhances allergic airway inflammation. Some studies have shown an association between PM exposure and a risk for allergic rhinitis (AR). However, the effect of PM for AR is not fully understood. An AR mouse model was developed by intranasal administration of 100 µg/mouse PM with a less than or equal to 2.5 µm in aerodynamic diameter (PM2.5) solution, and then by intraperitoneal injection of ovalbumin (OVA) with alum and intranasal challenging with 10 mg/mL OVA. The effects of PM2.5 on oxidative stress and inflammatory response via the Nrf2/NF-κB signaling pathway in mice with or without AR indicating by histological, serum, and protein analyses were examined. PM2.5 administration enhanced allergic inflammatory cell expression in the nasal mucosa through increasing the expression of inflammatory cytokine and reducing the release of Treg cytokine in OVA-induced AR mice, although PM2.5 exposure itself induced neither allergic responses nor damage to nasal and lung tissues. Notably, repeated OVA-immunization markedly impaired the nasal mucosa in the septum region. Moreover, AR with PM2.5 exposure reinforced this impairment in OVA-induced AR mice. Long-term PM2.5 exposure strengthened allergic reactions by inducing the oxidative through malondialdehyde production. The present study also provided evidence, for the first time, that activity of the Nrf2 signaling pathway is inhibited in PM2.5 exposed AR mice. Furthermore, PM2.5 exposure increased the histopathological changes of nasal and lung tissues and related the inflammatory cytokine, and clearly enhanced PM2.5 phagocytosis by alveolar macrophages via activating the NF-κB signaling pathway. These obtained results suggest that AR patients may experience exacerbation of allergic responses in areas with prolonged PM2.5 exposure.

Piper Nigrum extract improves OVA-induced nasal epithelial barrier dysfunction via activating Nrf2/HO-1 signaling.

BACKGROUND: Piper nigrum L. (Piperaceae) is commonly used as a spice and traditional medicine in many countries. It has been reported to have anti-oxidant, anti-bacterial, anti-tumor, anti-mutagenic, anti-diabetic, and anti-inflammatory properties. However, the protective role of P. nigrum on epithelial function of upper respiratory tract injury in an allergic rhinitis (AR) mouse model has been unclear. This study aims to investigate the effects of P. nigrum fruit extract (PNE) on the nasal epithelial barrier function of the upper respiratory tract in an ovalbumin (OVA)-induced AR model. METHODS: AR mouse model was established by intraperitoneal injection with 200 µL saline containing 50 µg OVA adsorbed to 1 mg aluminum hydroxide, and intranasal challenge with 20 µL per nostril of 1 mg/ml OVA. Besides, mice were orally administrated once daily with PNE and dexamethasone (Dex) in 13 days. The nasal symptoms, inflammatory cells, OVA-specific immunoglobulins, cytokines, nasal histopathology, and immunohistochemistry were evaluated. RESULTS: The PNE oral administrations inhibited allergic responses via reduction of OVA-specific antibodies levels and mast cells histamine release, accordingly, the nasal symptoms in the early-phase reaction were also clearly ameliorated. In both nasal lavage fluid and nasal tissue, PNE suppressed the inflammatory cells accumulation, specifically with eosinophils. The intravenous Evans blue injection illustrated the epithelial permeability reduction of nasal mucosa layer in PNE-treated mice. Also; PNE treatments protected the epithelium integrity by preventing the epithelial shedding from nasal mucosa; as a result of enhancing the strong expression of the E-cadherin tight junction protein in cell-to-cell junctions, as well as inhibiting the degraded levels of zonula occludens-1 (ZO-1) and occludin into the nasal cavity. Additionally, PNE protected against nasal epithelial barrier dysfunction via enhancing the expression of Nrf2 activated form which led to increasing synthesis of the anti-inflammation enzyme HO-1. CONCLUSIONS: These obtained results suggest that PNE has a promising strategy for epithelial barrier stabilization in allergic rhinitis treatment.

Gallic acid alleviates nasal inflammation via activation of Th1 and inhibition of Th2 and Th17 in a mouse model of allergic rhinitis.

Allergic rhinitis (AR) is an allergic nasal disease characterized by nasal obstruction, rhinorrhea, sneezing, and itching. Type 1 helper T cells (Th1)/type 2 helper T cells (Th2) imbalance has been identified as an important immunological mechanism of AR. In addition, up-regulation of type 17 helper T cells (Th17) also increase the risk of developing AR. Gallic acid (3, 4, 5-trihydroxybenzoic acid, GA), a polyphenol natural product, is obtained from various herbs, red wine, and green tea. It is known to have diverse biological effects such as anti-oxidation, anti-inflammation, anti-microbial and anti-cancer. In the present study, the effect of GA on airway inflammation and expression of Th1, Th2 and Th17 cytokines in an ovalbumin (OVA)-induced AR mouse model were investigated. GA alleviated the nasal allergic symptoms, reduced the thickness of nasal mucosa, attenuated goblet cell hyperplasia and eosinophil cell infiltration in the nasal mucosa, decreased the levels of interleukin (IL)-4, IL-5, IL-13 and IL-17 in nasal lavage fluid (NALF), and diminished the levels of OVA-specific IgE, OVA-specific IgG1 and OVA-specific IgG2a in serum. However, GA increased the expression of interferon-gamma and IL-12 in NALF. Taken together, it suggests that GA may be used as a therapeutic agent for AR.

Anti-Inflammatory Effects of Cold Thermal Therapy on Allergic Skin Inflammation Induced by Trimellitic Anhydride in BALB/c Mice.

Cold and hot thermal therapies are widely used as a traditional therapy in many cultures and are often prescribed in the treatment of various musculoskeletal and neurological conditions which present themselves to primary care physicians. However, there are no reports that investigated either the effects of cold and hot thermal therapies on the skin inflammation of trimellitic anhydride- (TMA-) induced dermatitis-like contact hypersensitivity (CHS) mouse model, or the mechanism of thermal therapy on allergic skin inflammation. Therefore, in this study, to reveal the anti-inflammatory effect of thermal therapy and its mechanism on TMA-induced CHS, we analyzed ear-swelling response (ear edema), vascular permeability, serum IgE levels, histological examination, and histamine and Th2 cytokine levels. Cold thermal therapy reduced the ear-swelling response, the vascular permeability, the serum IgE levels, and the infiltration of eosinophils and mast cells as well as the mast cell degranulation. To determine the mechanism by which cold thermal therapy inhibits allergic skin inflammation, detailed studies were carried out revealing that cold thermal therapy suppressed IL-4 and IL-5 secretion and mast cell activation. These results indicated that cold thermal therapy cures skin inflammation of TMA-induced CHS by decreasing Th2 cytokine release, especially IL-4 and IL-5, and mast cell activation. These data suggest that new insight into the mechanism of robust therapeutic effects of cold thermal therapy against allergic dermatitis, and cold thermal therapy may prove to be a useful therapeutic modality on allergic inflammatory diseases as traditional use as well as Th2- or mast cell-mediated allergic responses.

Preventive Effect of Bupleurum chinense on Nasal Inflammation via Suppressing T Helper Type 2, Eosinophil and Mast Cell Activation.

Bupleurum chinense is distributed in East Asia and has been used as a traditional herbal medicine for more than a thousand years. Though B. chinense has been reported to have immunomodulatory, anti-inflammatory, anti-oxidant, hepato-protective, antipyretic, analgesic and antifibrotic effects, its specific effect on allergic rhinitis disease has not been clarified. In this study, we investigated the anti-allergic and anti-inflammation effects of B. chinense extract (BCE) in an ovalbumin (OVA)-induced allergic rhinitis (AR) mouse model. Oral administration of BCE in a dose-independent manner regulated the balance of Th1/Th2/Treg cell differentiation in AR mice. Accordingly, BCE attenuated the expression of Th2-related cytokines such as IL-4, IL-5 and IL-13 in nasal lavage fluid (NALF) and nasal tissue and up-regulated the secretion of Th1/Treg cells including IL-10, IL-12 and IFN- γ . Also, BCE inhibited the formation and migration of eosinophils to the nasal mucosa and NALF, as well as suppressed CCL24, an eosinophil-specific chemoattractant in NALF. The levels of anti-OVA specific IgE and anti-OVA specific IgG1 were decreased, and as a result, the allergic response was attenuated by BCE via inhibiting mast cells accumulation in nasal mucosa and serum histamine release. The nasal allergy symptoms, nasal mucosal swelling, epithelial barrier disruption and mucus hyperplasia were obviously ameliorated. These results suggest that BCE may have therapeutic potential for treating allergic rhinitis through modulating the accumulation and activation of important leukocytes in the immune system such as Th1, Th2, Treg, eosinophils and mast cells.

Rosae multiflorae fructus extract and its four active components alleviate ovalbumin-induced allergic inflammatory responses via regulation of Th1/Th2 imbalance in BALB/c rhinitis mice.

BACKGROUND: Rosae Multiflorae fructus has potent antioxidative, analgesic, and anti-inflammatory properties. PURPOSE: We investigated the immunomodulatory effect of Rosae Multiflorae fructus extract (RMFE) on allergic inflammation in an allergic rhinitis (AR) mouse model. METHODS: Mice were sensitized and intranasally challenged with ovalbumin (OVA), the Th1/Th2-related cytokines and histopathology were examinated after RMFE treatments. Primary cell culture from spleen and NALT was performed to evaluate RMFE effect on Th1/Th2 responses. Four active components of RMFE were determined using HPLC and then tested the inhibition on Th2 response. RESULTS: Oral administration of RMFE inhibited the accumulation of eosinophils in nasal lavage fluid (NALF) and the nasal mucosa, goblet cells in the nasal epithelium, and mast cells in the respiratory region of the nasal cavity. Thus, the swelling of the nasal epithelium, nasal-associated lymphoid tissue (NALT), and lung tissue were ameliorated. Furthermore, the RMFE suppressed Th2-related cytokines, such as IL-4, IL-5, and IL-13 in NALF, NALT, and splenocytes, whereas the Th1-associated cytokine IL-12 was up-regulated by RMFE. We also revealed the active components of RMFE, such as ellagic acid, hyperoside, isoquercitrin, and miquelianin. They may inhibit IL-4 secretion in allergic responses. CONCLUSION: RMFE may have therapeutic potential for treating AR by modulating the relationships between Th1/Th2 responses.

The protective role of Piper nigrum fruit extract in an ovalbumin-induced allergic rhinitis by targeting of NFκBp65 and STAT3 signalings.

Piper nigrum L. is commonly used as a traditional medicine and food in many countries. It has been reported to have anti-oxidant, anti-bacterial, anti-tumor, anti-mutagenic, anti-diabetic, and anti-inflammatory properties. However, the effect of P. nigrum on allergic rhinitis (AR) has been unclear. In the present study, an OVA-induced AR mice model were established to investigate the anti-allergic, anti-inflammation properties of P. nigrum fruit extract (PNE). Oral administrations of PNE inhibited the allergic nasal symptoms including rubbing and sneezing in the early-phage of AR. In both NALF and nasal tissue, PNE suppressed the inflammatory cells accumulation, specifically with eosinophils in NALF. Additionally, PNE prevented the activation of STAT3 and NFκBp65 signaling in the cytoplasm which led to increasing the synthesis of the anti-inflammatory Th1 cytokines and suppressing the inflammatory Th2, Th17 cytokines. These obtained results suggest that PNE has the promising strategy for immunotherapy in allergic rhinitis disease.