Rat Model Of Asthma Research Articles

Pingchuanning decoction attenuates airway inflammation by suppressing autophagy via phosphatidylinositol 3-kinase/protein kinase B/mammalian target of rapamycin signaling pathway in rat models of asthma.

Pingchuanning decoction is a well-known traditional Chinese medicinefor the treatment of airway inflammatory diseases, including asthma. However, the potential mechanism by which Pingchuanning decoction contributes to the amelioration of airway inflammation remains unknown. A rat model of asthma was well established by inducing ovalbumin. Lipopolysaccharide-stimulated rat tracheal epithelial (RTE) cells were used as cellular model. Lung histopathology and goblet cell hyperplasia were assessed by hematoxylin-eosin (HE) and periodic acid Schiffstaining, respectively. Total inflammatory cells count and RTE cell apoptosis were analyzed by flow cytometry. The autophagic activities were evaluated by immunohistochemical and immunofluorescence analysis and Western blot analysis of autophagy-related proteins. We also detected the effects of Pingchuanning decoction on phosphatidylinositol 3-kinase/protein kinase B/mammalian target of rapamycin (PI3K/Akt/mTOR) and high-mobility group box 1 (HMGB1)-mediated toll-like receptor 4 (TLR4)/NF-κB pathways-related proteins and inflammatory cytokines using the Western blot analysis and enzyme-linked immunosorbentassay. Pingchuanning decoction effectively attenuated pulmonary pathology and autophagy. Treatment with Pingchuanning decoction activated PI3K/Akt/mTOR pathway and inhibited HMGB1/TLR4/NF-κB pathway, which could be overturned by LY294002, a PI3K antagonist, or rapamycin (Rapa), an autophagy inducer. Pingchuanning decoction exerted a therapeutic effect on asthma by inhibiting autophagy via PI3K/Akt /mTOR signaling pathway.

GAS5 promotes airway smooth muscle cell proliferation in asthma via controlling miR-10a/BDNF signaling pathway

AimsTo explore the role of long non-coding RNA (lncRNA) growth arrest-specific transcript 5 (GAS5) in the cell proliferation of airway smooth muscle cells (ASMCs) in asthma. Materials and methodsAn asthma rat model was established by ovalbumin sensitization and challenge. The expression of GAS5, miR-10a and BDNF mRNA and protein was determined with qRT-PCR and western blot, separately. The targeting relationship between GAS5 and miR-10a was examined with RNA immunoprecipitation and RNA pull-down assay; the interaction between miR-10a and BDNF was evaluated by luciferase reporter assay. Cell Proliferation Assay (MTS) was used for ASMC proliferation detection. Knock-down of GAS5 was performed in asthmatic rats to determine the effects of GAS5 in vivo. Key findingsCompared with control group, the inspiratory resistance and expiratory resistance were increased in asthma group; and the expression of GAS5, miR-10a and BDNF was higher, lower and higher, respectively. The expression of GAS5 and miR-10a was elevated and repressed, respectively, by platelet-derived growth factor-BB (PDGF-BB). GAS5 functioned as a bait of miR-10a. GAS5 regulates BDNF expression through miR-10a. PDGF-BB promotes the cell proliferation of ASMCs through miR-10a/BDNF. Knock-down of GAS5 significantly decreased airway hyperresponsiveness in asthmatic rats. SignificanceThe lncRNA GAS5/miR-10a/BDNF regulatory axis played an important role in promoting ASMCs proliferation, thus contributing to asthma.

Influence of Treating Essential Oils of Canarium Tree Resin on The Level Malondialdehyde (MDA), Protease Activity, Bronchi Histopathology Description and Expression of Tumor Necrosis Alpha Factor (TNF-α) on Asthma Rats (Rattus norvegicus)

Essential oils of canarium tree resin ( Canarium indicum L ) have anti-inflammatory and antioxidant activity. Inflammation of the bronchi and airway remodeling is a major factor in the occurrence of asthma. The purpose of this study was to study the potential of essential oils of canarium tree resin on the expression of TNF-α, changes in bronchial epithelial cell features, MDA levels and protease activity from OVA and LPS exposure in a rat model of asthma. This study used four groups of rat, the negative control group, asthma group, therapy group dose 25 mg/kg BB and 50 mg/kg BB. TNF-α expression was calculated using Walter calculations, histopathologic observation of bronchi was observed using Olympus BX51 microscope, MDA level was measured using Thiobarbituric Acid (TBA) method and measurement of protease activity was done by spectrophotometric method, and analyzed by ANOVA. The results showed that the therapy of essential oils of canarium tree resin at 25 mg/kg BB and 50 mg/kg BB significantly (P<0.05), after treatment for seven days decreased, MDA 44%, Protease activity 46%, improved bronchial epithelium and TNF-α expression by 51%. This study proves that essential oils of canarium tree resin can be effectively used as therapy in asthma model rats.

Expression and pathological significance of CC chemokine receptor 7 and its ligands in the airway of asthmatic rats exposed to cigarette smoke

Cigarette smoking aggravates the symptoms of asthma, leading to the rapid decline of lung function. Dendritic cells (DCs) and lymphocytes are considered initiating and promoting factors for the airway inflammation reactions of asthma. In addition, activation of CC chemokine receptor 7 (CCR7) by chemokine (C-C motif) ligand (CCL) 19 and 21 promotes DCs and T cells migration to lymphoid tissues during inflammation. We aimed to examine how cigarette smoke affects the expression of CCR7 in the lungs of asthmatic rats and explore the signaling mechanism linking CCR7 expression to exacerbation of symptoms. Forty Wistar rats were randomized to four groups: control, asthma, smoke exposure, and asthma with smoke exposure groups. A rat asthma model was established by intraperitoneal ovalbumin injection. CCR7 expression was examined with immunohistochemistry and western blotting. The number of airway DCs was determined by OX62 immunohistochemistry. Interferon (INF)-γ, interleukin (IL)-4, CCL19, and CCL21 expression levels in blood and bronchioalveolar lavage fluid (BALF) were determined by enzyme-linked immunosorbent assays (ELISAs). Tissue CCR7 expression, peripheral blood and BALF CCL19 and CCL21 concentrations, and the number of airway DCs were significantly higher in the asthma with smoke exposure group than the asthma group (P<0.01). In addition, INF-γ expression was decreased and IL-4 increased in the asthma and asthma with smoke exposure groups compared with the control group (P<0.01), and in the asthma with smoke exposure group compared with the asthma group (P<0.01). Expression of CCR7 correlated negatively with INF-γ expression in peripheral blood and BALF (P<0.01), and positively with the airway DCs and IL-4 expression in the peripheral blood and BALF (P<0.01). Cigarette smoking may aggravate asthma symptoms by attenuating immunity, possibly through CCR7-mediated DCs aggregation in lung tissue.

Systemic Transplantation of Mesenchymal Stem Cells Modulates Endothelial Cell Adhesion Molecules Induced by Ovalbumin in Rat Model of Asthma.

Achieving the optimal clinical outcome of mesenchymal stem cells (MSCs) is particularly dependent on fundamental understanding of therapeutic mechanisms. The current study was focused on the possible mechanisms by which rat bone marrow-derived mesenchymal stem cells (rBMMSCs) and/or conditioned media (CM) display broad immunomodulatory properties for ameliorating of asthma-related pathological changes. Male rats were divided equally into four experimental groups (n = 6): healthy rats received 50μl PBS intravenously (group C), sensitized rats received 50μl PBS intravenously (group OVA), sensitized rats received 50μl CM intravenously (group OVA + CM), and sensitized rats received 50μl PBS intravenously containing 2 × 106 rBMMSCs (group OVA + MSCs). After 2weeks, the expression of interleukin (IL)-5, IL-12 and INF-γ, ICAM-1, and VCAM-1; pathological injuries; and the homing of MSCs into the lung tissues were assessed. Our results showed that systemic delivery of rBMMSCs, but not CM, returned the expression of IL-5, IL-12 and INF-γ, ICAM-1, and VCAM-1 and pathological injuries in the lung tissues of asthmatic groups to the near level of control group (p < 0.001 to p < 0.05). Moreover, rBMMSCs had potential to successfully recall to asthmatic niche in cell-administrated rats. However, no regulatory function was observed by MSC-CM. Collectively, our data notified the potency of MSCs in ameliorating OVA-mediated airway inflammation in a rat model of asthma presumably by regulating endothelial expression of leukocyte-selective cell adhesion molecules in lung tissue.

Vitamin D supplementation decreases the expression of TGF-β1 in rats with asthma and thereby suppressing airway remodeling

Objective To investigate the preventive and therapeutic effects of 1, 25-(OH)2D3 on airway remodeling in asthmatic rats, and to explore the effect of 1, 25-(OH)2D3 on the expression of transforming growth factor-β1 (TGF-β1) and the related mechanism between them. Methods Seventy male Sprague Dawley (SD) rats were randomly divided into seven groups: normal control group (group A, n=10), asthmatic group (group B, n=10), dexamethasone group (group C, n=10), 1, 25-(OH)2D3 2 μg/(kg·d) group (group D, n=10), 1, 25-(OH)2D3 4 μg/(kg·d) group (group E, n=10), 1, 25-(OH)2D3 8 μg/(kg·d) group (group F, n=10), 1, 25(OH)2D3 16 μg/(kg·d) group (group G, n=10). Rats were sensitized and challenged with ovalbumin (OVA) to establish the asthmatic model in B, C, D, E, F, G group respectively. Rats in group B and group C were fed with normal saline 10 ml/(kg·d) and dexamethasone 2 mg/(kg·d) before atomization. While group D-G was 1, 25- (OH)2D3 intervention group, rats were fed with vitamin D 2, 4, 8, 16 μg/(kg·d) before atomization. The number of total and different cells of the bronchoalveolar lavage fluid (BALF) from the 7 groups was counted for analysis; The change of the thickness, the area of airway wall and the number of ASMC nucleus and pulmonary tissue changes were observed by microscope. The protein and mRNA expression of TGF-β1 in the lung tissue was measured by immunochemistry and real-time polymerase chain reaction (RT-PCR). Results ⑴ The airway remodeling and pulmonary inflammatory exudation in the B group were significantly heavier than those in the A, C and G groups (P<0.01); and the difference between groups of different doses of vitamin D [D group (minimum dose) and G group(the maximum dose) ] was statistically significant (P<0.01). ⑵ The results of TGF-β1 mRNA and protein levels in rats of each group showed that the expression level of TGF-β1 mRNA and integrated option density (IOD) value in A group were significantly lower than those in other groups (P<0.01); the expression level of TGF-β1 mRNA and IOD value in B group was higher than the other groups (P<0.01); Compared with the B group, the expression level of TGF-β1 mRNA and IOD value in G group (large dose vitamin D group) was decreased, with statistically difference. Conclusions In the rat model of asthma, 1, 25-(OH)2D3 may alleviate airway remodeling by regulating the expression of TGF- beta 1 and play its opposite biological effect in the prevention and treatment of asthma. Key words: Asthma; Rats; Transforming growth factor beta1; Vitamin D; Airway remodeling

Mahuang decoction mitigates airway inflammation and regulates IL-21/STAT3 signaling pathway in rat asthma model

Ethnopharmacological relevanceNowadays, bronchial asthma is still a severe disease threatening human health, and it is incumbent upon us to seek effective therapeutic drugs. Mahuang decoction (MHD), a classic famous Chinese prescription, has been used for thousands of years to prevent phlegm from forming, stop coughing and relieve asthma, but the relevant mechanism has not been thoroughly clarified. This study aims to investigate the anti-airway inflammation effect of MHD and the possible molecular mechanism underlying IL21/STAT3 signaling pathway, so as to provide guidance for the treatment of MHD on bronchial asthma. Materials and methodsSpecific pathogen free SD rats were randomly divided into 6 groups: normal control group, model group, positive group (Compound methoxyphenamine), MHD-treated groups at doses of 10 ml/kg, 5 ml/kg and 2.5 ml/kg, 10 rats in each group. Except for the normal control group, rats in other groups were sensitized with ovalbumin via introperitoneal injection and challenged with ovalbumin inhalation to trigger asthma model. At 24 h after the last excitation, bronchoalveolar lavage fluid (BALF) of every rat was drawn and the number of inflammatory cells was analyzed using cell counting method. ELISA method was performed to determine the concentrations of TXB2, 6-keto-PGF1α, MMP-9, TIMP-1, IL-2, IL-4, IL-5 and TNF-α in rat serum. The protein expressions of IL-21, IL-21R, STAT3 and p-STAT3 in murine pulmonary tissues were assessed with western blotting analysis. ResultsCompared with the control group, the airway wall and airway smooth muscle of murine pulmonary tissues significantly thickened and massive inflammatory cells infiltration occurred around the bronchus in the model group, and the cell counts of WBC and EOS in BALF were also apparently increased, which indicated the rat asthma model was successfully established. MHD or Compound methoxyphenamine not only alleviated the pulmonary inflammatory pathological damages, but also down- regulated the numbers of WBC and EOS in BALF. What's more, the levels of TXB2, MMP-9, TIMP-1, ILs-(2, 4, 5) and TNF-α in rat serum were lessened by the treatment of MHD. In western blotting analysis, treatment with 10 ml/kg or 5 ml/kg MHD markedly declined the increased protein expressions of IL-21, IL-21R, STAT3 and p-STAT3 in lung tissues of asthmatic rats to normal level. ConclusionMHD intervention demonstrated a strong inhibitory action on the secretion of inflammatory mediators as well as the inflammatory cell infiltration in pulmonary tissues of asthmatic rats, and also depressed the protein expressions of IL-21, IL-21R, STAT3 and p-STAT3 in pulmonary tissues. MHD effectively mitigates airway inflammation and regulates the IL-21/STAT3 signaling pathway in rat asthma model.

Variable ventilation decreases airway responsiveness and improves ventilation efficiency in a rat model of asthma

The optimal ventilation strategy in patients receiving mechanical ventilation for severe asthma remains unclear. The effect of conventional ventilation (with constant tidal volume and respiratory rate) and variable ventilation (with the same average but variable tidal volume and respiratory rate) on peak airway pressure and airway exacerbation induced by increasing doses of methacholine was compared in a rat model of asthma. The respiratory rate and tidal volume data were obtained from a spontaneously breathing intact rat during immobility using a whole-body plethysmograph. Peak airway pressure and airway responsiveness to cumulative doses of methacholine were significantly affected by ventilation mode and they were lower in variable ventilation group than in the conventional ventilation group. Also, variable ventilation improved oxygen saturation compared to conventional ventilation. Our results indicate that variable ventilation decreases airway responsiveness and enhances ventilation efficiency in a rat model of asthma. We suggest further investigations on beneficial effects of variable ventilation strategy in mechanically ventilated patients with severe asthma.

Ameliorating effects of Nigella sativa oil on aggravation of inflammation, oxidative stress and cytotoxicity induced by smokeless tobacco extract in an allergic asthma model in Wistar rats

BackgroundThe comparison of smokeless tobacco (ST) exposure versus Ovalbumin (Ova) sensitized rats or asthmatic patients has hardly been studied in the literature. Thus, the present study aims to investigate the aggravation of inflammation, exacerbation of asthma, oxidative stress and cytotoxicity induced by ST. MethodsST was given at the dose of 40mg/kg in an allergic asthma model in Wistar rats. Furthermore, the effects of oral administration of Nigella sativa oil (NSO), at a dose of 4mL/kg/day, were investigated. ResultsThe obtained results showed that ST clearly enhanced lung inflammation through interleukin-4 (IL-4) and Nitric oxide (NO) increased production. Actually, ST was found to intensify the oxidative stress state induced by Ova-challenge in rats, which was proven not only by augmenting lipid peroxidation and protein oxidation, but also by altering the non-enzymatic and enzymatic antioxidant status. Furthermore, the aggravation of inflammation and oxidative stress was obviously demonstrated by the histopathological changes observed in lung. In contrast, NSO administration has shown anti-inflammatory effects by reducing IL-4 and NO production, restoring the antioxidant status, reducing lipid peroxidation and improving the histopathological alterations by both protein oxidation and NSO treatment. ConclusionsOur data have proven that severe concurrent exposure to allergen and ST increases airway inflammation and oxidative stress in previously sensitized rats. They also suggest that the oral NSO treatment could be a promising treatment for asthma.

Cyclosporine A/porous quaternized chitosan microspheres as a novel pulmonary drug delivery system

N-[(2-Hydroxyl)-propyl-3-trimethyl ammonium] chitosan chloride (HTCC), a hydrosoluble chitosan derivative, has been extensively investigated as a class of drug delivery vehicles because of its unique features. However the studies on HTCC for pulmonary delivery systems have been rarely conducted. This study aimed to design porous microspheres (MS) containing cyclosporine A (CsA) using HTCC as the carrier. The physicochemical properties and biocompatibility of the MS were evaluated. The in vivo efficacy of MS was evaluated in an asthmatic rat model after pulmonary administration. The results showed that porous MS suitable for inhalation could be readily produced by spray drying method. Optimized porous MS in this study exhibited to be biocompatible and safe to use in the lung, and they were effective in suppression of inflammation in the asthmatic rat model. Above all, our results suggested that HTCC porous MS are promising drug carriers for pulmonary drug delivery.

Curcumin affects tracheal responsiveness and lung pathology in asthmatic rats.

Curcumin has shown various pharmacological effects such as anti-inflammatory activities. In this study, the effects of curcumin on tracheal responsiveness and lung pathological features were evaluated in a rat model of asthma. Tracheal responsiveness and lung pathological features were evaluated in control rats (C), ovalbumin (OVA)-sensitized rats (as an animal model of asthma; A), A rats treated with curcumin (Cu, 0.15, 0.30, and 0.60mg/ml) and dexamethasone (D, 1.25μg/ml), (n=8 in curcumin-treated groups and n=6 in other groups). Curcumin and dexamethasone were added to animals' drinking water during the sensitization period. Asthmatic group showed increased lung pathological score and tracheal responsiveness to methacholine and OVA compared to control group (p<0.01 to p<0.001). Pathological features including interstitial inflammation, interstitial fibrosis, bleeding, and emphysema as well as tracheal responsiveness to methacholine and OVA, were significantly decreased in treated groups with dexamethasone and all concentrations of curcumin compared to group A (p<0.05 to p<0.001). Epithelial damage was also significantly decreased in treated groups with the two higher concentrations of curcumin (p<0.05 to p<0.001). Curcumin showed preventive effects on tracheal responsiveness and lung pathological features in asthmatic rats.

Human placenta mesenchymal stem cells suppress airway inflammation in asthmatic rats by modulating Notch signaling.

Neurogenic locus notch homolog protein (Notch) signaling mediates intracellular communication and may regulate cell fate decisions, including cell proliferation, differentiation, and apoptosis. Mesenchymal stem cells (MSCs) possess immunomodulatory properties and the potential for use in stem cell replacement treatments. The aim of the present study was to evaluate the therapeutic effects of human placenta‑deviated MSCs (hPMSCs) in asthma and to investigate the mechanisms of Notch signaling mediated by transplanted MSCs. A Sprague‑Dawley rat ovalbumin (OVA)‑sensitized acute asthma model was established and challenged. MSCs derived from human placenta (hPMSCs) were transplanted into the asthmatic rats. Transplantation resulted in reduced Notch‑1, Notch‑2 and jagged‑1, and increased Notch‑3, Notch‑4 and delta‑like ligand (delta)‑4 expression in lung, blood, and lymph samples. Notch‑1, Notch‑2, and jagged‑1 expression in OVA‑treated rats was significantly decreased compared with controls and hPMSC‑treated rats; however, Notch‑3, Notch‑4 and delta‑4 expression was significantly increased. Serum interferon‑γ significantly increased after hPMSCs transplantation, whereas interleukin‑4 and immunoglobulin E decreased. In OVA‑treated rats, Notch‑1, Notch‑2 and jagged‑1 levels were increased in the lymph compared with the blood, although Notch‑4 and delta‑4 levels were decreased. Peribronchial infiltration of cells and goblet cell hyperplasia were markedly decreased in the OVA + hPMSCs group compared with those in the OVA‑treated and control groups. Alterations in Notch signaling pathway expression were accompanied by decreased inflammatory cell infiltration, goblet cell hyperplasia and mucus production in lung tissues. The results of the present study are consistent with hPMSC suppression of asthma symptoms and inflammation by regulating the Notch signaling pathway in the rat asthma model.

Jinkui Shenqi Pills Ameliorate Asthma with "Kidney Yang Deficiency" by Enhancing the Function of the Hypothalamic-Pituitary-Adrenal Axis to Regulate T Helper 1/2 Imbalance.

The aim of the study was to investigate the effects and underlying mechanism of JKSQP in a rat model of asthma with kidney-yang deficiency (KYD). Materials and Methods. Hydrocortisone (HYD) was used to establish the rat model of KYD; rats were then sensitized and challenged with ovalbumin (OVA). JKSQP was administered to OVA-challenged rats, and the changes in signs and symptoms of KYD were observed. The leukocyte number and subpopulations in bronchoalveolar lavage fluid (BALF) were counted and the cells were stained with Wright–Giemsa dye. Serum adrenocorticotropic hormone (ACTH), corticosterone (CORT), corticotropin-releasing hormone (CRH), total immunoglobulin E (IgE), and OVA-specific IgE levels were determined using relevant enzyme-linked immunosorbent assays (ELISA) kits. Results. JKSQP not only reversed the phenomenon of KYD but also significantly inhibited the number of leukocyte and eosinophils in the BALF, increasing the level of interferon (IFN)-γ and decreasing the levels of interleukin-4 (IL-4) and IgE in the serum compared with the OVA-challenged groups. Conclusions. Taken together, the antiasthma effects of JKSQP were likely mediated by the enhancement of the function of the hypothalamic-pituitary-adrenal axis and the reversal of T helper 1/2 imbalance.

Effect of airway remodeling and hyperresponsiveness on complexity of breathing pattern in rat

The complexity of respiratory dynamics is decreased, in association with disease severity, in patients with asthma. However, the pathophysiological basis of decreased complexity of breathing pattern in asthma is not clear. In the present study, we investigated the effect of airway remodeling and hyperresponsiveness induced by repeated bronchoconstriction (using methacholine) on breathing pattern in rats with or without allergen-induced sensitization. Entropy analysis of respiratory variability showed decreased irregularity (less complexity) of respiratory rhythm in this rat model of asthma. Airway remodeling and hyperresponsiveness induced by repeated bronchoconstriction also led to increased regularity of respiratory dynamics in sensitized rats. However, these airway alterations had no significant effect on the complexity of breathing pattern in non-sensitized rats. Our results indicate that mechanical respiratory alterations cannot per se attenuate the complexity of respiratory dynamics, unless there is an underlying inflammation. We suggest further studies on underlying mechanisms of breathing variability with focus on respiratory control alterations due to airway inflammation.

Inhibition of airway remodeling and inflammation by isoforskolin in PDGF-induced rat ASMCs and OVA-induced rat asthma model

Isoforskolin (ISOF) has been reported to play an important role in many illnesses including respiratory, cardiovascular and ophthalmologic diseases. In our study, we aimed to investigate how ISOF regulates airway remodeling and inflammation in asthma. Based on SO2-stimulated mouse cough model, we assessed the role of ISOF in cough and secretion of phlegm. Afterwards, platelet derived growth factor (PDGF)-induced primary rat airway smooth muscle cell (ASMC) model and ovalbumin (OVA)-induced rat asthma model were used to continue our following research. Our results showed that ISOF could prolong the cough latent period, reduce the cough times in two minutes, and increase the excretion of red phenol, which suggested the antitussive and expectorant effects of ISOF. Besides, ISOF pretreatment reversed the hypotonicity and cytoskeleton remodeling in PDGF-induced ASMCs, and reduced mucus hypersecretion and collagen overdeposition in OVA-induced rat asthma model, which indicated its inhibition on airway remodeling in vitro and in vivo. Moreover, ISOF reduced the invasion of inflammatory cells into bronchoalveolar lavage fluid (BALF) and lungs, which revealed its inhibitory role in airway inflammation. The down-regulation of transforming growth factor β1 (TGF-β1) and interleukin-1β (IL-1β) upon ISOF treatment might be responsible for its anti-remodeling and anti-inflammation roles. In conclusion, ISOF can reduce cough and sputum, as well as inhibit airway remodeling and inflammation by regulating the expression of TGF-β1 and IL-1β. These data indicate the potency of ISOF in treating asthma and also provide insights into the development of new anti-asthma agent.

Discovery of a novel series of α-terpineol derivatives as promising anti-asthmatic agents: Their design, synthesis, and biological evaluation

A series of novel α-terpineol derivatives were designed and synthesized through structural derivatization of the tertiary hydroxyl moiety or reduction of the double bond. Of the resulting compounds, eight compounds enhanced relaxation of airway smooth muscle (ASM) compared to the α-terpineol precursor, and four compounds (4a, 4d, 4e, and 4i)were superior or comparable to aminophylline at a concentration of 0.75 mmol/L. Assays for 3′-5′-Cyclic adenosine monophpsphate (cAMP) activation revealed that some representative α-terpineol derivatives in this series were capable of upregulating the level of cAMP in ASM cells. Further in vivo investigation using the asthmatic rat model, illustrated that treatment with the compounds 4a and 4e resulted in significantly lowered lung resistance (RL) and enhanced dynamic lung compliance (Cldyn), two important parameters for lung fuction. Moreover, treatment with 4e downregulated the levels of both IL-4 and IL-17. Due to its several favorable physiological functions, including ASM relaxation activity, cAMP activation capability, and in vivo anti-asthmatic efficacy, 4e is a promising remedy for bronchial asthma, meriting extensive development.

Effects of Aspergillus fumigatus on glucocorticoid receptor and β2-adrenergic receptor expression in a rat model of asthma

ABSTRACTPurpose: Conventional inhaled corticosteroids or β2-adrenergic receptor agonists do not work well in some asthmatic populations while empirical antifungal therapy has obvious impact on those patients. The study was designed to investigate whether short-term exposure to Aspergillus fumigatus (A. fumigatus) could decrease glucocorticoid receptor (GCR) and β2-adrenergic receptor (ADRB2) expression in lung tissue of asthmatic rats. Materials and Methods: A rat model of chronic asthma was first established by ovalbumin sensitization and challenge. Rats with chronic asthma were then exposed to short-term application of A. fumigatus spores. Airway hyper-responsiveness, eosinophil ratio in bronchoalveolar lavage (BAL) fluid and total IgE in serum were counted in these experimental animals. GCR and ADRB2 expression in the lung were detected and analyzed. Furthermore, the levels of toll-like receptors (TLRs) 2, 3 and 4 in lung tissue were measured. Results: Short-term exposure to A. fumigatus could down-regulate the expression of GCR, aggravate airway hyper-responsiveness and increase the level of TLR2 in rats with asthma. There were no obvious changes in the levels of ADRB2 expression, recruited eosinophils, total IgE, TLR3 and TLR4 after application of A. fumigatus in asthmatic rats. Conclusions: These findings indicate that A. fumigatus exposure may be involved in glucocorticoids unresponsiveness by down-regulating the expression of GCR in asthmatics. The possibility of A. fumigatus colonization or infection should not be ignored in patients of steroid-resistant asthma.

Anti‐inflammatory, antioxidant, and immunomodulatory effects of curcumin in ovalbumin‐sensitized rat

Anti-inflammatory and antioxidant properties of curcumin have been shown. In this study, anti-inflammatory, antioxidant, and immunomodulatory effects of curcumin in sensitized rat were evaluated. Six groups of rats including control (C), ovalbumin-sensitized (as a rat model of asthma, S), S groups treated with curcumin (Cu 0.15, 0.30, and 0.60 mg/mL), and 1.25 μg/mL dexamethasone (S + D) were studied. Curcumin and dexamethasone were given in animals' drinking water during sensitization period. Total and differential WBC count, PLA2, TP, IFN-γ, IL-4, IgE, oxidant, and antioxidant biomarker levels in bronchoalveolar lavage fluid (BALF) were examined. Total WBC, neutrophil and eosinophil counts, levels of PLA2, TP, IgE, IL-4, NO2 , NO3 , and MDA in BALF were increased but lymphocyte percentage, SOD, CAT, thiol, and IFN-γ levels and IFN-γ/IL-4 ratio decreased in S animals compared to controls (P < 0.001 for all cases). Treatment with all concentrations of curcumin significantly improved total WBC, PLA2, TP, IgE, IL-4, IFN-γ, IFN-γ/IL-4 ratio, SOD, thiol, NO2 , and NO3 compared to S group (P < 0.01 to P < 0.001). Two higher concentrations of curcumin significantly decreased neutrophil and eosinophil counts and MDA level but increased IFN-γ, CAT and lymphocyte values compared to S group (P < 0.001 for all cases). Dexamethasone treatment also significantly improved most of the measured parameters (P < 0.05 to P < 0.001) but it did not change IL-4 and IFN-γ levels and IFN-γ/IL-4 ratio. Anti-inflammatory, antioxidant, and immunomodulatory effects of curcumin with more specific immunomodulatory effect on Th1/Th2 balance compared to dexamethasone in sensitized rats was shown. © 2017 BioFactors, 43(4):567-576, 2017.

Regulation of acupuncture on expression of AKT protein in lung tissues of asthma rats

To explore the effects of acupuncture on the expression of protein kinase B (PKB/AKT) in lung tissues of asthma rats. Forty SPF male SD rats were randomly divided into a blank group, a model group, an acupuncture group and a blocker group, 10 rats in each one. The rat model of asthma was established by egg albumin stimulation in the model group, acupuncture group and blocker group. Since the establishment of rat model, the rats in the acupuncture group were treated with acupuncture at "Dazhui" (GV 14), "Feishu" (BL 13) and "Fengmen" (BL 12) before atomization; the rats in the blocker group were treated with intervention of blocker LY294002, once every two days, for 7 times. There was no treatment in the blank group and model group. HE staining was applied to observe the morphologic changes of lung tissues; the immunohistochemical method was applied to test the protein expression of AKT in lung tissue. HE staining indicated the infiltration and aggregation of a variety of inflammatory cells around airways, as well as bronchial smooth muscle spasm and confined lumen in the model group; in the acupuncture group and blocker group the inflammatory cells were less and confined lumen was relieved. Compared with the blank group, the protein expression of AKT was higher in the model group (P<0.05); compared with the model group, the protein expression of AKT in the acupuncture group and blocker group was reduced (both P<0.05); the differences between the acupuncture group and blank group, blocker group were not significant (both P>0.05). Acupuncture could reduce the protein expression of AKT in lung tissue in asthma rats, leading to relieved inflammation reaction and airway remodeling.

The effect of hydro-ethanolic extract of Curcuma longa rhizome and curcumin on total and differential WBC and serum oxidant, antioxidant biomarkers in rat model of asthma.

Objective(s):The effects of Curcuma longa (C. longa) and curcumin on total and differential WBC count and oxidant, antioxidant biomarkers, in rat model of asthma were evaluated.Materials and Methods:Total and differential WBC count in the blood, NO2, NO3, MDA, SOD, CAT and thiol levels in serum were examined in control, asthma, Asthmatic rats treated with C. longa (0.75, 1.50, and 3.00 mg/ml), curcumin (0.15, 0.30, and 0.60 mg/ml), and dexamethasone (1.25 μg/ml) rats.Results:Total and most differential WBC count, NO2, NO3 and MDA were increased but lymphocytes, SOD, CAT and thiol were decreased in asthmatic animals compared to controls (P<0.001). Total WBC, NO2 and NO3 were significantly reduced in treated groups with dexamethasone and all concentrations of C. longa and curcumin compared to asthmatic group (P<0.001 for all cases). MDA was significantly decreased, but SOD, CAT and thiol increased in treated asthma animals with dexamethasone and two higher concentrations of C. longa and curcumin (P<0.01 to P<0.001). There were significant improvement in eosinophil percentage due to treatment of highest concentration of the extract and curcumin, neutrophil and monocyte due to highest concentration of curcumin and lymphocyte due to highest concentration of the extract and two higher concentrations of curcumin compared to asthmatic group (P<0.01 to P<0.001). Dexamethasone treatment improved monocyte (P<0.001) and lymphocyte (P<0.01) percentages.Conclusion:Antioxidant and anti-inflammatory effects of C. longa extract and its constituent curcumin in animal model of asthma was observed which suggest a therapeutic potential for the plant and its constituent on asthma.