ABSTRACT
Bile acid profiles are altered in obese individuals with asthma. Thus, we sought to better understand how obesity-related systemic changes contribute to lung pathophysiology. We also test the therapeutic potential of nitro-oleic acid (NO2-OA), a regulator of metabolic and inflammatory signaling pathways, to mitigate allergen and obesity-induced lung function decline in a murine model of asthma. Bile acids were measured in the plasma of healthy subjects and individuals with asthma and serum and lung tissue of mice with and without allergic airway disease (AAD). Lung function, indices of inflammation and hepatic bile acid enzyme expression were measured in obese mice with house dust mite-induced AAD treated with vehicle or NO2-OA. Serum levels of glycocholic acid and glycoursodeoxycholic acid clinically correlate with body mass index and airway hyperreactivity whereas murine levels of ß-muricholic acid and tauro-ß-muricholic acid were significantly increased and positively correlated with impaired lung function in obese mice with AAD. NO2-OA reduced murine bile acid levels by modulating hepatic expression of bile acid synthesis enzymes, with a concomitant reduction in small airway resistance and tissue elastance. Bile acids correlate to body mass index and lung function decline and the signaling actions of nitroalkenes can limit AAD by modulating bile acid metabolism, revealing a potential pharmacologic approach to improving the current standard of care.
Subject(s)
Asthma/metabolism , Asthma/physiopathology , Bile Acids and Salts/metabolism , Fatty Acids/physiology , Lung/physiopathology , Nitro Compounds/therapeutic use , Obesity/metabolism , Oleic Acids/therapeutic use , Adolescent , Adult , Animals , Anti-Asthmatic Agents/therapeutic use , Antigens, Dermatophagoides/toxicity , Asthma/drug therapy , Asthma/etiology , Diet, High-Fat/adverse effects , Drug Evaluation, Preclinical , Fatty Acids/chemistry , Female , Forced Expiratory Volume , Glycocholic Acid/blood , Humans , Liver/drug effects , Liver/metabolism , Male , Mice , Mice, Inbred C57BL , Middle Aged , Obesity/complications , Obesity/physiopathology , Respiratory Hypersensitivity/chemically induced , Respiratory Hypersensitivity/drug therapy , Respiratory Hypersensitivity/metabolism , Thinness , Ursodeoxycholic Acid/analogs & derivatives , Ursodeoxycholic Acid/blood , Vital Capacity , Young AdultABSTRACT
ETHNOPHARMACOLOGICAL RELEVANCE: Hanchuan Zupa Granule (HCZP), a traditional Chinese ethnodrug, has the functions of supressing a cough, resolving phlegm, warming the lungs, and relieving asthma. In clinical practice employing traditional Chinese medicine (TCM), HCZP is commonly used to treat acute colds, cough and abnormal mucous asthma caused by a cold, or "Nai-Zi-Lai" in the Uygur language. Studies have confirmed the use of HCZP to treat cough variant asthma (CVA) and other respiratory diseases. However, the pharmacological mechanisms of HCZP remain unrevealed. AIM OF THE STUDY: To investigate the anti-tussive and anti-asthmatic effects and the possible pharmacological mechanisms of HCZP in the treatment of CVA. MATERIALS AND METHODS: A guinea pig CVA animal model was established by intraperitoneal injection of ovalbumin (OVA) combined with intraperitoneal injection of aluminium hydroxide adjuvant and atomized OVA. Meanwhile, guinea pigs with CVA received oral HCZP (at dosages of 0.571, 0.285 and 0.143 g/kg bodyweight). The number of coughs induced by aerosol capsaicin was recorded, and the airway hyperresponsiveness (AHR) of CVA guinea pigs was detected with the FinePointe series RC system. H&E staining of lung tissues was performed to observe pathological changes. ELISA was used to detect inflammatory cytokines. qRT-PCR and western blotting analyses were used to detect the expression of Th1-specific transcription factor (T-bet), Th2-specific transcription factor (GATA3), and Toll-like receptor 4 (TLR4) signal transduction elements. These methods were performed to assess the protective effects and the potential mechanisms of HCZP on CVA. RESULTS: Great changes were found in the CVA guinea pig model after HCZP treatment. The number of coughs induced by capsaicin in guinea pigs decreased, the body weights of guinea pigs increased, and inflammation of the eosinophilic airway and AHR were reduced simultaneously. These results indicate that HCZP has a significant protective effect on CVA. A pharmacological study of HCZP showed that the levels of interleukin-4 (IL-4) and IL-5 and tumour necrosis factor-α (TNF-α) in serum decreased. The amount of interferon-γ (IFN-γ) increased, mRNA and protein expression of TLR4 and GATA3 weakened, and mRNA and protein expression of T-bet increased. CONCLUSIONS: HCZP ameliorated the symptoms of guinea pigs with CVA induced by OVA by regulating the Th1/Th2 imbalance and TLR4 receptors.
Subject(s)
Anti-Asthmatic Agents/pharmacology , Antitussive Agents/pharmacology , Asthma/drug therapy , Cough/drug therapy , Drugs, Chinese Herbal/pharmacology , Animals , Anti-Asthmatic Agents/therapeutic use , Antitussive Agents/therapeutic use , Asthma/chemically induced , Body Weight/drug effects , Capsaicin/toxicity , Cough/chemically induced , Cytokines/blood , Disease Models, Animal , Drugs, Chinese Herbal/chemistry , Drugs, Chinese Herbal/therapeutic use , Flavonoids/chemistry , GATA3 Transcription Factor/genetics , GATA3 Transcription Factor/metabolism , Glycyrrhizic Acid/chemistry , Guinea Pigs , Lung/drug effects , Lung/metabolism , Lung/pathology , Medicine, Chinese Traditional , Ovalbumin/toxicity , Respiratory Hypersensitivity/chemically induced , Respiratory Hypersensitivity/drug therapy , T-Box Domain Proteins/genetics , T-Box Domain Proteins/metabolism , Th1 Cells/drug effects , Th2 Cells/drug effects , Toll-Like Receptor 4/genetics , Toll-Like Receptor 4/metabolism , Triterpenes/chemistryABSTRACT
Inflammation, the major hallmark of all chronic respiratory diseases is generally managed by inhaled corticosteroids. However, long term high dose treatment can result in significant side effects. Hence, there is a medical need for non-steroidal anti-inflammatory therapies to address airway inflammation. Phospholipids have been shown to reduce inflammation in several inflammatory conditions; however, their clinical translation has been limited to liposomal formulations traditionally used as drug carriers and their biological activity has not been investigated. Here we report the first application of empty liposomes as an anti-inflammatory treatment in airway inflammation. In the current study, liposomes (UTS-001) were prepared from cholesterol and a synthetic phospholipid (DOPC). The formulation was characterised in terms of size, charge, polydispersity index, morphology and stability as colloidal suspension and freeze-dried nanoparticles. Time-dependant uptake of UTS-001 in airway epithelial cells was observed which was inhibited by nystatin demonstrating that the uptake is via the caveolae pathway. In-vitro, in primary nasal epithelial cells, UTS-001 treatment successfully attenuated IL-6 levels following TNF-α stimulation. Consistent with the in-vitro findings, in-vivo, in the ovalbumin model of allergic airway inflammation, UTS-001 significantly reduced total immune cell counts in bronchoalveolar lavage fluid and reduced airway hyperresponsiveness in response to increasing doses of methacholine challenge. Therefore, our results establish UTS-001 as a potential anti-inflammatory treatment that may be useful as a therapeutic for lung inflammatory diseases.
Subject(s)
Anti-Inflammatory Agents/pharmacology , Cholesterol/pharmacology , Nasal Mucosa/drug effects , Phosphatidylcholines/pharmacology , Pneumonia/prevention & control , Respiratory Hypersensitivity/prevention & control , Animals , Anti-Inflammatory Agents/administration & dosage , Anti-Inflammatory Agents/chemistry , Cell Line , Cholesterol/administration & dosage , Cholesterol/chemistry , Colloids , Disease Models, Animal , Drug Compounding , Female , Humans , Interleukin-6/metabolism , Liposomes , Mice, Inbred C57BL , Nanoparticles , Nasal Mucosa/metabolism , Ovalbumin , Phosphatidylcholines/administration & dosage , Phosphatidylcholines/chemistry , Pneumonia/chemically induced , Pneumonia/metabolism , Respiratory Hypersensitivity/chemically induced , Respiratory Hypersensitivity/metabolism , Tumor Necrosis Factor-alpha/pharmacologyABSTRACT
We investigated the mechanisms involved in the development of airway hyperresponsiveness (AHR) following exposure of mice to halogens. Male mice (C57BL/6; 20-25 g) exposed to either bromine (Br2) or Cl2 (600 or 400 ppm, respectively, for 30 min) developed AHR 24 h after exposure. Nifedipine (5 mg/kg body wt; an L-type calcium channel blocker), administered subcutaneously after Br2 or Cl2 exposure, produced higher AHR compared with Br2 or Cl2 alone. In contrast, diltiazem (5 mg/kg body wt; a nondihydropyridine L-type calcium channel blocker) decreased AHR to control (air) values. Exposure of immortalized human airway smooth muscle cells (hASMC) to Br2 resulted in membrane potential depolarization (Vm Air: 62 ± 3 mV; 3 h post Br2:-45 ± 5 mV; means ± 1 SE; P < 0.001), increased intracellular [Ca2+]i, and increased expression of the calcium-sensing receptor (Ca-SR) protein. Treatment of hASMC with a siRNA against Ca-SR significantly inhibited the Br2 and nifedipine-induced Vm depolarization and [Ca2+]i increase. Intranasal administration of an antagonist to Ca-SR in mice postexposure to Br2 reversed the effects of Br2 and nifedipine on AHR. Incubation of hASMC with low-molecular-weight hyaluronan (LMW-HA), generated by exposing high-molecular-weight hyaluronan (HMW-HA) to Br2, caused Vm depolarization, [Ca2+]i increase, and Ca-SR expression to a similar extent as exposure to Br2 and Cl2. The addition of HMW-HA to cells or mice exposed to Br2, Cl2, or LMW-HA reversed these effects in vitro and improved AHR in vivo. We conclude that detrimental effects of halogen exposure on AHR are mediated via activation of the Ca-SR by LMW-HA.
Subject(s)
Calcium Channel Blockers/pharmacology , Calcium/metabolism , Hyaluronic Acid/pharmacology , Muscle, Smooth/drug effects , Receptors, Calcium-Sensing/metabolism , Respiratory Hypersensitivity/drug therapy , Viscosupplements/pharmacology , Animals , Bromine/toxicity , Cells, Cultured , Chlorides/toxicity , Humans , Male , Mice , Mice, Inbred C57BL , Molecular Weight , Muscle, Smooth/metabolism , Receptors, Calcium-Sensing/antagonists & inhibitors , Receptors, Calcium-Sensing/genetics , Respiratory Hypersensitivity/chemically induced , Respiratory Hypersensitivity/metabolism , Respiratory Hypersensitivity/pathologyABSTRACT
AIM OF THE STUDY: To develop a novel anti-asthma drug. DFSG is a novel herbal cocktail composed of 4 types of herbal medicines. This study explored whether DFSG has the potential to attenuate asthma symptom severity and aimed to determine the immunomodulatory mechanism of DFSG using a chronic asthmatic mouse model induced by repeated challenges with Dermatogoides pteronyssinus (Der p). MATERIALS AND METHODS: BALB/c mice were intratracheally inoculated with Der p (50⯵l, 1â¯mg/ml) once a week for 5 weeks. In addition, 30â¯min before Der p challenge, the mice were orally administered 1x DFSG (1â¯g/kg) or 1/2x DFSG (0.5â¯g/kg). Three days after the final challenge, the mice were sacrificed to evaluate inflammatory cell infiltration, lung histological features, blood total IgE, and cytokine levels in pulmonary alveolar lavage fluid. Furthermore, 30â¯min after the addition of DFSG, caffeic acid, p-coumaric acid or chlorogenic acid to A549 cells, 10â¯ng/ml IL-1ß was added to evaluate the effect of the drug on mucin 5AC (MUC5AC) gene expression after stimulation of A549 cells by IL-1ß. RESULTS: DFSG significantly reduced Der p-induced airway hyperresponsiveness, bronchial inflammatory cell infiltration, and total IgE and IgG1 serum levels. Furthermore, DFSG significantly inhibited TH2 cytokines and increased the expression of TH1 cytokines. In addition, immunohistochemical staining demonstrated that DFSG inhibited MUC5AC expression in the bronchial epithelial cells. DFSG and a mixture of caffeic acid, p-coumaric acid, and chlorogenic acid inhibited MUC5AC gene expression in A549 cells after stimulation with IL-1ß. CONCLUSION: These results suggest that by regulating TH1 and TH2 cytokines and MUC5AC expression, DFSG exhibits anti-airway inflammatory cell infiltration and anti-hyperresponsiveness activity and inhibits specific immunity in a chronic asthmatic mouse model. Therefore, DFSG has potential for development into a drug for chronic asthma treatment.
Subject(s)
Anti-Asthmatic Agents/therapeutic use , Asthma/drug therapy , Asthma/metabolism , Disease Models, Animal , Drugs, Chinese Herbal/therapeutic use , Mucin 5AC/metabolism , A549 Cells , Animals , Anti-Asthmatic Agents/pharmacology , Antigens, Dermatophagoides/toxicity , Asthma/chemically induced , Cell Survival/drug effects , Cell Survival/physiology , Dose-Response Relationship, Drug , Drugs, Chinese Herbal/pharmacology , Humans , Male , Mice , Mice, Inbred BALB C , Mucin 5AC/antagonists & inhibitors , Random Allocation , Respiratory Hypersensitivity/chemically induced , Respiratory Hypersensitivity/drug therapy , Respiratory Hypersensitivity/metabolismABSTRACT
Obesity is a risk factor for asthma, especially nonatopic asthma, and attenuates the efficacy of standard asthma therapeutics. Obesity also augments pulmonary responses to ozone, a nonatopic asthma trigger. The purpose of this study was to determine whether obesity-related alterations in gut microbiota contribute to these augmented responses to ozone. Ozone-induced increases in airway responsiveness, a canonical feature of asthma, were greater in obese db/db mice than in lean wild-type control mice. Depletion of gut microbiota with a cocktail of antibiotics attenuated obesity-related increases in the response to ozone, indicating a role for microbiota. Moreover, ozone-induced airway hyperresponsiveness was greater in germ-free mice that had been reconstituted with colonic contents of db/db than in wild-type mice. In addition, compared with dietary supplementation with the nonfermentable fiber cellulose, dietary supplementation with the fermentable fiber pectin attenuated obesity-related increases in the pulmonary response to ozone, likely by reducing ozone-induced release of IL-17A. Our data indicate a role for microbiota in obesity-related increases in the response to an asthma trigger and suggest that microbiome-based therapies such as prebiotics may provide an alternative therapeutic strategy for obese patients with asthma.
Subject(s)
Gastrointestinal Microbiome/physiology , Obesity/complications , Ozone/toxicity , Respiratory Hypersensitivity/etiology , Airway Resistance , Animals , Anti-Bacterial Agents/pharmacology , Anti-Bacterial Agents/therapeutic use , Asthma/etiology , Asthma/therapy , Cellulose/administration & dosage , Dietary Fiber/administration & dosage , Fecal Microbiota Transplantation , Female , Fermentation , Gastrointestinal Microbiome/drug effects , Germ-Free Life , Mice , Mice, Inbred C57BL , Mice, Obese , Obesity/genetics , Obesity/microbiology , Obesity/physiopathology , Pectins/administration & dosage , Pectins/therapeutic use , Receptors, Leptin/deficiency , Respiratory Hypersensitivity/chemically induced , Respiratory Hypersensitivity/diet therapy , Respiratory Hypersensitivity/microbiologyABSTRACT
BACKGROUND: Siraitia grosvenorii fruits are used in traditional medicine to treat cough, sore throat, bronchitis, and asthma. PURPOSE: This study aimed to investigate the anti-inflammatory and anti-asthmatic effects of S. grosvenorii residual extract (SGRE) on ovalbumin (OVA)-induced asthma in mice. METHODS: Asthma was induced in BALB/c mice by systemic sensitization to OVA, followed by intratracheal, intraperitoneal, and aerosol allergen challenges. SGRE was orally administered for four weeks. We investigated the effects of SGRE on airway hyper-responsiveness, OVA-specific IgE production, histological analysis of lung and trachea, immune cell phenotyping, Th1/Th2 cytokine production in bronchoalveolar lavage fluid (BAL) fluid and splenocytes, and gene expression in the lung. RESULTS: SGRE ameliorated OVA-driven airway hyper-responsiveness, serum IgE production, and histopathological changes in the lung and trachea. SGRE reduced the total number of cells in the lung and BAL, the total number of lymphocytes, neutrophils, monocytes, and eosinophils in the lung and BAL, the absolute number of CD4+/CD69+ T cells in the lung, and the absolute number of CD4+/CD8+ T cells and CD11b+/Gr-1+ granulocytes in the lung and BAL. SGRE also reduced Th2 cytokines (IL-4, IL-5, and IL-13) and increased the Th1 cytokine IFN-γ in the BAL fluid and supernatant of splenocyte cultures. SGRE decreased the OVA-induced increase of IL-13, TARC, MUC5AC, TNF-α, and IL-17 expression in the lung. CONCLUSION: SGRE exerts anti-asthmatic effects via the inhibition of Th2 and Th17 cytokines and the increase of Th1 cytokines, suggesting that SGRE may be a potential therapeutic agent for allergic lung inflammation, such as asthma.
Subject(s)
Anti-Asthmatic Agents/pharmacology , Asthma/drug therapy , Cucurbitaceae/chemistry , Plant Extracts/pharmacology , Pneumonia/drug therapy , Animals , Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Asthma/metabolism , Asthma/pathology , Bronchoalveolar Lavage Fluid/cytology , Bronchoalveolar Lavage Fluid/immunology , Disease Models, Animal , Down-Regulation/drug effects , Eosinophils/immunology , Eosinophils/pathology , Interleukins/genetics , Interleukins/metabolism , Male , Mice, Inbred BALB C , Mucin 5AC/genetics , Mucin 5AC/metabolism , Ovalbumin/immunology , Ovalbumin/toxicity , Pneumonia/chemically induced , Pneumonia/pathology , Respiratory Hypersensitivity/chemically induced , Respiratory Hypersensitivity/drug therapy , Th17 Cells/immunology , Th17 Cells/metabolism , Th17 Cells/pathologyABSTRACT
Epidemiologic studies have demonstrated an association between acetaminophen (APAP) use and the development of asthma symptoms. However, few studies have examined relationships between APAP-induced signaling pathways associated with the development of asthma symptoms. We tested the hypothesis that acute APAP exposure causes airway hyper-responsiveness (AHR) in human airways. Precision cut lung slice (PCLS) airways from humans and mice were used to determine the effects of APAP on airway bronchoconstriction and bronchodilation and to assess APAP metabolism in lungs. APAP did not promote AHR in normal or asthmatic human airways ex vivo. Rather, high concentrations mildly bronchodilated airways pre-constricted with carbachol (CCh), histamine (His), or immunoglobulin E (IgE) cross-linking. Further, the addition of APAP prior to bronchoconstrictors protected the airways from constriction. Similarly, in vivo treatment of mice with APAP (200 mg/kg IP) resulted in reduced bronchoconstrictor responses in PCLS airways ex vivo. Finally, in both mouse and human PCLS airways, exposure to APAP generated only low amounts of APAP-protein adducts, indicating minimal drug metabolic activity in the tissues. These findings indicate that acute exposure to APAP does not initiate AHR, that high-dose APAP is protective against bronchoconstriction, and that APAP is a mild bronchodilator.
Subject(s)
Acetaminophen/pharmacology , Bronchoconstriction/drug effects , Bronchodilator Agents/pharmacology , Lung/drug effects , Acetaminophen/administration & dosage , Acetaminophen/adverse effects , Albuterol/pharmacology , Animals , Asthma/physiopathology , Bronchodilator Agents/adverse effects , Carbachol/pharmacology , Chemical and Drug Induced Liver Injury/etiology , Dose-Response Relationship, Drug , Humans , Lung/physiology , Male , Mice, Inbred C57BL , Mice, Inbred Strains , Middle Aged , Organ Culture Techniques , Oxidative Stress/drug effects , Respiratory Hypersensitivity/chemically inducedABSTRACT
Objectives Folate plays a vital role in biologic functions yet women often do not meet the recommended dietary intake in pregnancy. It has been suggested that high folic acid intake during pregnancy may increase the risk of respiratory diseases in offspring. However, findings from observational studies in human populations are inconclusive. Methods In this population-based study, we collected self-reported folic acid and prenatal vitamin supplement use during pregnancy 3-6 months postpartum from mothers in Los Angeles whose children were born in 2003. Supplement initiation was based on whichever supplement, either folic acid or prenatal supplements, the women initiated first. In a 2006 follow-up survey, approximately 50% of women were re-contacted to gather information on the child's respiratory health, including symptoms and diagnoses, at approximately 3.5 years of age. Results Overall, timing of folic acid supplement initiation was not associated with wheeze or lower respiratory tract infection, even after accounting for preterm births and censoring at follow-up. However, children born to mothers with a history of atopy (hay fever, eczema or asthma) who initiate folic acid supplements in late pregnancy, compared to first trimester initiators, have 1.67 (95% CI 1.12, 2.49) times the risk of wheeze in the first 3 years of life and 1.88 (95% CI 1.05, 3.34) times the risk of wheeze in the past year. No association was found among children of non-atopic mothers. Conclusions These findings suggest that early folic acid or prenatal supplementation among atopic women may be important to prevent wheeze among offspring.
Subject(s)
Dietary Supplements , Folic Acid/administration & dosage , Population Surveillance/methods , Prenatal Care/methods , Prenatal Exposure Delayed Effects/chemically induced , Respiratory Sounds/etiology , Respiratory Tract Infections/epidemiology , Adult , Asthma/chemically induced , Asthma/epidemiology , Child , Child, Preschool , Female , Health Surveys , Humans , Male , Pregnancy , Pregnancy Trimester, First , Respiratory Hypersensitivity/chemically induced , Respiratory Hypersensitivity/epidemiology , Respiratory Tract Infections/chemically induced , United States/epidemiologyABSTRACT
DW2008 is an anhydrous ethanol extract of Justicia procumbens produced by Dong-Wha Pharmaceutical, Inc., Co. as a candidate anti-asthmatic drug. In this study, DW2008 selectively reduced T helper 2 (Th2) cytokines in mouse splenocytes and ameliorated ovalbumin-induced airway inflammation by downregulating pulmonary infiltration of differential inflammatory cells and Th2 cytokines more than a decoction or ethanol extract of J. procumbens did in a mouse asthma model. DW2008 also significantly inhibited airway hyperresponsiveness and reduced the thickness of the airway epithelium. HPLC analysis showed that the major peaks (justicidin A and B) of DW2008 were higher than those of the other extracts. Justicidin A and B significantly suppressed Th2 cytokine levels in mouse spleen cells and exhibited a protective effect in ovalbumin-induced airway inflammation. Our findings indicate that DW2008 effectively inhibits allergic airway inflammatory reactions and airway hyperresponsiveness in a mouse model of asthma, suggesting its potential as an anti-asthmatic agent.
Subject(s)
Anti-Asthmatic Agents/pharmacology , Anti-Inflammatory Agents/pharmacology , Asthma/chemically induced , Asthma/pathology , Cytokines/antagonists & inhibitors , Ovalbumin , Plant Extracts/pharmacology , Plants, Medicinal/chemistry , Spleen/metabolism , Th2 Cells/metabolism , Animals , Cytokines/biosynthesis , Cytokines/metabolism , Down-Regulation/drug effects , Female , Lung/pathology , Mice , Mice, Inbred BALB C , Plant Extracts/chemistry , Respiratory Hypersensitivity/chemically induced , Respiratory Hypersensitivity/prevention & control , Respiratory Mucosa/drug effects , Respiratory Mucosa/pathology , Spleen/cytology , Th2 Cells/drug effectsABSTRACT
D-mannose, a C-2 epimer of glucose, exists naturally in many plants and fruits, and is found in human blood at concentrations less than one-fiftieth of that of glucose. However, although the roles of glucose in T cell metabolism, diabetes and obesity are well characterized, the function of D-mannose in T cell immune responses remains unknown. Here we show that supraphysiological levels of D-mannose safely achievable by drinking-water supplementation suppressed immunopathology in mouse models of autoimmune diabetes and airway inflammation, and increased the proportion of Foxp3+ regulatory T cells (Treg cells) in mice. In vitro, D-mannose stimulated Treg cell differentiation in human and mouse cells by promoting TGF-ß activation, which in turn was mediated by upregulation of integrin αvß8 and reactive oxygen species generated by increased fatty acid oxidation. This previously unrecognized immunoregulatory function of D-mannose may have clinical applications for immunopathology.
Subject(s)
Colitis/immunology , Diabetes Mellitus, Type 1/immunology , Lung Diseases/immunology , Lung/drug effects , Mannose/pharmacology , Pancreas/drug effects , Respiratory Hypersensitivity/immunology , T-Lymphocytes, Regulatory/drug effects , Transforming Growth Factor beta/drug effects , Adoptive Transfer , Animals , Colon/drug effects , Dietary Supplements , Disease Models, Animal , Fatty Acids/metabolism , Flow Cytometry , Forkhead Transcription Factors/metabolism , Humans , In Vitro Techniques , Inflammation , Integrins/drug effects , Integrins/immunology , Lipid Metabolism/drug effects , Lung/immunology , Lung Diseases/chemically induced , Mice , Mice, Inbred C57BL , Mice, Inbred NOD , Ovalbumin/adverse effects , Oxidation-Reduction/drug effects , Pancreas/immunology , Reactive Oxygen Species/metabolism , Real-Time Polymerase Chain Reaction , Respiratory Hypersensitivity/chemically induced , Reverse Transcriptase Polymerase Chain Reaction , Spleen/drug effects , Spleen/immunology , T-Lymphocytes, Regulatory/immunology , T-Lymphocytes, Regulatory/metabolism , Transforming Growth Factor beta/immunology , Up-RegulationABSTRACT
OBJECTIVE: Justicia pectoralis is a plant useful for the treatment of respiratory diseases. Here, we studied the antiasthmatic properties of a standardized extract of J. pectoralis (Jp). METHODS: Ovalbumin (OVA)-sensitized rats were actively challenged with saline or OVA to study airway hyper-responsiveness after oral treatment with saline or Jp. The ability of Jp to inhibit hyper-reactivity was evaluated in isolated trachea mounted in isolated organ bath chamber. KEY FINDINGS: Using KCl or carbachol as contractile agents, tracheal rings of OVA-challenged rats contracted with higher magnitude than trachea of rats challenged with saline. Such hyper-responsive phenotype of OVA-challenged tissues decreased with Jp administration. In Ca+ -free medium, Jp or its major constituent coumarin inhibited preferentially the contractions induced by Ca2+ addition in tissues of OVA-challenged rats stimulated with KCl or acetylcholine. In tissues depleted of their internal Ca+ stores in the presence of thapsigargin, Jp inhibited the contraction induced by capacitative Ca2+ entry. By gavage, Jp abolished the increase caused by challenge with OVA on the levels of IL-1ß and TNF-α in the bronchoalveolar fluid and also impaired the changes in gene expression of canonical transient receptor proteins. CONCLUSIONS: Jp has antiasthmatic properties in an experimental model that reproduces tracheal hyper-reactivity.
Subject(s)
Justicia/chemistry , Plant Extracts/pharmacology , Respiratory Hypersensitivity/drug therapy , Animals , Asthma/chemically induced , Asthma/drug therapy , Asthma/metabolism , Bronchoalveolar Lavage Fluid/chemistry , Calcium/metabolism , Carbachol , Male , Models, Animal , Ovalbumin/pharmacology , Rats , Rats, Wistar , Respiratory Hypersensitivity/chemically induced , Respiratory Hypersensitivity/metabolism , Trachea/drug effects , Trachea/metabolism , Tumor Necrosis Factor-alpha/metabolismABSTRACT
BACKGROUND: Recently, academic studies suggest that global growth of airway allergic disease has a close association with dietary changes including reduced consumption of fiber. Therefore, appropriate dietary fiber supplementation might be potential to prevent airway allergic disease (AAD). OBJECTIVE: We investigated whether dietary fiber intake suppressed the induction of AAD and tried to elucidate the possible underlying mechanisms. METHODS: The control mice and AAD model mice fed with 4% standard-fiber chow, while low-fiber group of mice fed with a 1.75% low-fiber chow. The two fiber-intervened groups including mice, apart from a standard-fiber diet, were also intragastric (i.g.) administrated daily with poorly fermentable cellulose or readily fermentable pectin (0.4% of daily body weight), respectively. All animals except normal mice were sensitized and challenged with ovalbumin (OVA) to induce airway allergic inflammation. Hallmarks of AAD were examined by histological analysis and ELISA. The variation in intestinal bacterial composition was assessed by qualitative analysis of 16S ribosomal DNA (rDNA) content in fecal samples using real-time PCR. RESULTS: Low-fiber diet aggravated inflammatory response in ovalbumin-induced allergic mice, whereas dietary fiber intake significantly suppressed the allergic responses, attenuated allergic symptoms of nasal rubbing and sneezing, decreased the pathology of eosinophil infiltration and goblet cell metaplasia in the nasal mucosa and lung, inhibited serum OVA-specific IgE levels, and lowered the levels of Th2 cytokines in NALF and BALF, but, increased Th1 (IFN-γ) cytokines. Additionally, dietary fiber intake also increased the proportion of Bacteroidetes and Actinobacteria, and decreased Firmicutes and Proteobacteria. Levels of probiotic bacteria, such as Lactobacillus and Bifidobacterium, were upgraded significantly. CONCLUSION: Long-term deficiency of dietary fiber intake increases the susceptibility to AAD, whereas proper fiber supplementation promotes effectively the balance of Th1/Th2 immunity and then attenuates allergic inflammatory responses significantly, as well as optimizes the structure of intestinal microbiota, which suggests potential for novel preventive and therapeutic intervention.
Subject(s)
Dietary Fiber/therapeutic use , Gastrointestinal Microbiome/drug effects , Intestines/drug effects , Respiratory Hypersensitivity/diet therapy , Respiratory Hypersensitivity/immunology , Animals , Bacteroidetes/drug effects , Bacteroidetes/growth & development , Bifidobacterium/drug effects , Bifidobacterium/growth & development , Cellulose/administration & dosage , Disease Models, Animal , Eosinophils/drug effects , Eosinophils/immunology , Feces/microbiology , Female , Gastrointestinal Microbiome/immunology , Goblet Cells/drug effects , Goblet Cells/immunology , Humans , Immunoglobulin E/biosynthesis , Inflammation , Intestines/immunology , Intestines/microbiology , Lactobacillus/drug effects , Lactobacillus/growth & development , Lung/drug effects , Lung/immunology , Mice , Mice, Inbred BALB C , Nasal Mucosa/drug effects , Nasal Mucosa/immunology , Ovalbumin , Pectins/administration & dosage , Proteobacteria/drug effects , Proteobacteria/growth & development , RNA, Ribosomal, 16S/genetics , Respiratory Hypersensitivity/chemically induced , Respiratory Hypersensitivity/microbiology , Th1-Th2 Balance/drug effectsABSTRACT
As a treatment for allergic asthma, inhaled treatments such as bronchodilators that contain ß2-agonists have an immediate effect, which attenuates airway obstructions and decreases airway hypersensitivity. However, bronchodilators only perform on a one off basis, but not consistently. Asthma is defined as a chronic inflammatory disease of the airways accompanying the overproduction of mucus, airway wall remodeling, bronchial hyperreactivity and airway obstruction. Liriope platyphylla radix extract (LPP), a traditional Korean medicine, has been thoroughly studied and found to be an effective anti-inflammatory medicine. Here, we demonstrate that an inhaled treatment of LPP can attenuate airway hyperresponsiveness (AHR) in an ovalbumin-induced asthmatic mouse model, compared to the saline-treated group (p < 0.01). Moreover, LPP decreases inflammatory cytokine levels, such as eotaxin (p < 0.05), IL-5 (p < 0.05), IL-13 (p < 0.001), RANTES (p < 0.01), and TNF-α (p < 0.05) in the bronchoalveolar lavage (BAL) fluid of asthmatic mice. A histopathological study was carried out to determine the effects of LPP inhalation on mice lung tissue. We performed UPLC/ESI-QTOF-MS, LC/MS, and GC/MS analyses to analyze the chemical constituents of LPP, finding that these are ophiopogonin D, spicatoside A, spicatoside B, benzyl alcohol, and 5-hydroxymethylfurfural. This study demonstrates the effect of an inhaled LPP treatment both on airway AHR and on the inflammatory response in an asthmatic mouse model. Hence, LPP holds significant promise as a nasal inhalant for the treatment of asthmatic airway disease.
Subject(s)
Asthma/drug therapy , Liriope Plant , Medicine, Korean Traditional , Phytotherapy , Plant Extracts/administration & dosage , Respiratory Hypersensitivity/drug therapy , Administration, Inhalation , Animals , Asthma/chemically induced , Asthma/metabolism , Bronchoalveolar Lavage Fluid/chemistry , Cytokines/metabolism , Depression, Chemical , Disease Models, Animal , Female , Inflammation Mediators/metabolism , Mice, Inbred BALB C , Ovalbumin , Plant Extracts/pharmacology , Respiratory Hypersensitivity/chemically inducedABSTRACT
Overall asthmatic symptoms can be controlled with diverse therapeutic agents. However, certain symptomatic individuals remain at risk for serious morbidity and mortality, which prompts the identification of novel therapeutic targets and treatment strategies. Thus, using an adjuvant-free T helper type 2 (Th2) murine model, we have deciphered the role of interleukin (IL)-1 signalling during allergic airway inflammation (AAI). Because functional IL-1ß depends on inflammasome activation we first studied asthmatic manifestations in specific inflammasome-deficient [NACHT, LRR and PYD domains-containing protein 3 (NLRP3(-/-) ) and apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC(-/-) )] and IL-1 receptor type 1(-/-) (IL-1R1(-/-) ) mice on the BALB/c background. To verify the onset of disease we assessed cellular infiltration in the bronchial regions, lung pathology, airway hyperresponsiveness and ovalbumin (OVA)-specific immune responses. In the absence of NLRP3 inflammasome-mediated IL-1ß release all symptoms of AAI were reduced, except OVA-specific immunoglobulin levels. To address whether manipulating IL-1 signalling reduced asthmatic development, we administered the IL-1R antagonist anakinra (Kineret®) during critical immunological time-points: sensitization or challenge. Amelioration of asthmatic symptoms was only observed when anakinra was administered during OVA challenge. Our findings indicate that blocking IL-1 signalling could be a potential complementary therapy for allergic airway inflammation.
Subject(s)
Carrier Proteins/metabolism , Inflammasomes/metabolism , Interleukin-1beta/metabolism , Respiratory Hypersensitivity/metabolism , Acute Disease , Animals , Apoptosis Regulatory Proteins/deficiency , CARD Signaling Adaptor Proteins , Carrier Proteins/genetics , Cytokines/metabolism , Disease Models, Animal , Eosinophilia/genetics , Eosinophilia/immunology , Female , Goblet Cells/pathology , Hyperplasia , Interleukin 1 Receptor Antagonist Protein/administration & dosage , Mice , Mice, Knockout , NLR Family, Pyrin Domain-Containing 3 Protein , Ovalbumin/adverse effects , Pneumonia/genetics , Pneumonia/immunology , Pneumonia/metabolism , Pneumonia/pathology , Receptors, Interleukin-1 Type I/deficiency , Respiratory Hypersensitivity/chemically induced , Respiratory Hypersensitivity/drug therapy , Respiratory Hypersensitivity/immunology , T-Lymphocytes, Helper-Inducer/immunology , T-Lymphocytes, Helper-Inducer/metabolismABSTRACT
BACKGROUND: Inhalation of diesel exhaust (DE) at moderate concentrations causes increased airway responsiveness in asthmatics and increased airway resistance in both healthy and asthmatic subjects, but the effect of baseline airway responsiveness and anti-oxidant supplementation on this dynamic is unknown. OBJECTIVES: We aimed to determine if changes in airway responsiveness due to DE are attenuated by thiol anti-oxidant supplementation, particularly in those with underlying airway hyper-responsiveness. METHODS: Participants took N-acetylcysteine (600 mg) or placebo capsules three times daily for 6 days. On the last of these 6 days, participants were exposed for 2 h to either filtered air (FA) or DE (300 µg/m(3) of particulate matter smaller than 2.5 microns). Twenty-six non-smokers were studied under each of three experimental conditions (filtered air with placebo, diesel exhaust with placebo, and diesel exhaust with N-acetylcysteine) using a randomized, double-blind, crossover design, with a 2-week washout between conditions. Methacholine challenge was performed pre-exposure (baseline airway responsiveness) and post-exposure (effect of exposure). RESULTS: Anti-oxidant supplementation reduced baseline airway responsiveness in hyper-responsive individuals by 20% (p = 0.001). In hyper-responsive individuals, airway responsiveness increased 42% following DE compared with FA (p = 0.03) and this increase was abrogated with anti-oxidant supplementation (diesel exhaust with N-acetylcysteine vs. filtered air with placebo, p = 0.85). CONCLUSIONS: Anti-oxidant (N-acetylcysteine) supplementation protects against increased airway responsiveness associated with DE inhalation and reduces need for supplement bronchodilators in those with baseline airway hyper-responsiveness. Individuals with variants in genes of oxidative stress metabolism when exposed to DE are protected from increases in airway responsiveness if taking anti-oxidant supplementation.
Subject(s)
Acetylcysteine/therapeutic use , Antioxidants/therapeutic use , Respiratory Hypersensitivity/chemically induced , Respiratory Hypersensitivity/prevention & control , Vehicle Emissions/toxicity , Acetylcysteine/administration & dosage , Adult , Antioxidants/administration & dosage , Bronchoconstrictor Agents/pharmacology , Cross-Over Studies , Dose-Response Relationship, Drug , Double-Blind Method , Female , Humans , Male , Methacholine Chloride/pharmacology , Middle Aged , Respiratory Function Tests , Young AdultABSTRACT
BACKGROUND: With the increase in production and use of engineered nanoparticles (NP; ≤ 100 nm), safety concerns have risen about the potential health effects of occupational or environmental NP exposure. Results of animal toxicology studies suggest that inhalation of NP may cause pulmonary injury with subsequent acute or chronic inflammation. People with chronic respiratory diseases like asthma or allergic rhinitis may be even more susceptible to toxic effects of inhaled NP. Few studies, however, have investigated adverse effects of inhaled NP that may enhance the development of allergic airway disease. METHODS: We investigated the potential of polyethylene glycol coated amorphous silica NP (SNP; 90 nm diameter) to promote allergic airway disease when co-exposed during sensitization with an allergen. BALB/c mice were sensitized by intranasal instillation with 0.02% ovalbumin (OVA; allergen) or saline (control), and co-exposed to 0, 10, 100, or 400 µg of SNP. OVA-sensitized mice were then challenged intranasally with 0.5% OVA 14 and 15 days after sensitization, and all animals were sacrificed a day after the last OVA challenge. Blood and bronchoalveolar lavage fluid (BALF) were collected, and pulmonary tissue was processed for histopathology and biochemical and molecular analyses. RESULTS: Co-exposure to SNP during OVA sensitization caused a dose-dependent enhancement of allergic airway disease upon challenge with OVA alone. This adjuvant-like effect was manifested by significantly greater OVA-specific serum IgE, airway eosinophil infiltration, mucous cell metaplasia, and Th2 and Th17 cytokine gene and protein expression, as compared to mice that were sensitized to OVA without SNP. In saline controls, SNP exposure did cause a moderate increase in airway neutrophils at the highest doses. CONCLUSIONS: These results suggest that airway exposure to engineered SNP could enhance allergen sensitization and foster greater manifestation of allergic airway disease upon secondary allergen exposures. Whereas SNP caused innate immune responses at high doses in non-allergic mice, the adjuvant effects of SNP were found at lower doses in allergic mice and were Th2/Th17 related. In conclusion, these findings in mice suggest that individuals exposed to SNP might be more prone to manifest allergic airway disease, due to adjuvant-like properties of SNP.
Subject(s)
Lung/drug effects , Nanoparticles/toxicity , Ovalbumin , Respiratory Hypersensitivity/chemically induced , Silicon Dioxide/toxicity , Animals , Bronchoalveolar Lavage Fluid/chemistry , Bronchoalveolar Lavage Fluid/immunology , Cytokines/genetics , Cytokines/metabolism , Disease Models, Animal , Dose-Response Relationship, Drug , Female , Immunoglobulin E/blood , Inflammation Mediators/metabolism , Inhalation Exposure/adverse effects , Lung/immunology , Lung/metabolism , Lymph Nodes/drug effects , Lymph Nodes/immunology , Mice, Inbred BALB C , Neutrophil Infiltration/drug effects , Particle Size , Pulmonary Eosinophilia/blood , Pulmonary Eosinophilia/chemically induced , Pulmonary Eosinophilia/immunology , Respiratory Hypersensitivity/blood , Respiratory Hypersensitivity/genetics , Respiratory Hypersensitivity/immunology , Risk Assessment , Th17 Cells/drug effects , Th17 Cells/immunology , Th17 Cells/metabolism , Th2 Cells/drug effects , Th2 Cells/immunology , Time FactorsABSTRACT
UNLABELLED: ETHNOMEDICAL RELEVANCE: Anti-inflammatory, anti oxidant and effect of Crocus sativus (C. sativus) on Th1/Th2 balance were described previously. AIM OF THE STUDY: The preventive effects of the extract of Crocus sativus on tracheal responsiveness and plasma levels of IL-4, IFN-γ, total NO and nitrite were examined on sensitized guinea pigs. MATERIALS AND METHODS: Five groups of sensitized guinea pigs to ovalbumin (OVA), were given drinking water containing three concentrations of the extract of Crocus sativus, dexamethasone (S+D) or alone (group S). Tracheal responses (TR) of control animals (group C) and sensitized guinea pigs (n=6, for each group) to methacholine, OVA and the levels of IL-4, IFN-γ, total NO and nitrite in serum were examined. RESULTS: The TR to both methacholine and OVA, the levels of serum IL-4, total NO and nitrite in S guinea pigs were significantly increased but that of IFN-γ and IFN-γ/IL-4 ratio (Th1/Th2 balance) were decreased compared to the controls (p<0.05 to p<0.001). In the treated animals with dexamethasone and all concentrations of the extract, TR to both methacholine and OVA, IL-4, total NO and nitrite were significantly decreased but IFN-γ and IFN-γ/IL-4 ratio increased compared to S group (p<0.05 to p<0.001). The effects of the highest concentration of the extract was greater than those of other concentrations and the effect of dexamethasone (p<0.05 to p<0.01). CONCLUSIONS: These results not only showed a preventive effect of C. sativus extract on tracheal responses and serum levels of inflammatory mediators in sensitized guinea pigs but also showed increased Th1/Th2 balance.
Subject(s)
Anti-Inflammatory Agents/pharmacology , Crocus , Plant Extracts/pharmacology , Trachea/drug effects , Allergens/immunology , Allergens/pharmacology , Animals , Bronchoconstrictor Agents/pharmacology , Flowers , Guinea Pigs , Interferon-gamma/blood , Interleukin-4/blood , Methacholine Chloride/pharmacology , Nitric Oxide/blood , Nitrites/blood , Ovalbumin/immunology , Ovalbumin/pharmacology , Respiratory Hypersensitivity/blood , Respiratory Hypersensitivity/chemically induced , Respiratory Hypersensitivity/physiopathology , Trachea/physiopathologyABSTRACT
Protocatechuic acid (PCA) has been isolated from the leaves of ilex chinenses and has numerous pharmacologic effects, including anti-inflammatory and antitumoral activities. This study aims to evaluate the antiasthma activity of PCA and investigate its possible molecular mechanisms. BALB/c mice were sensitized and challenged to ovalbumin (OVA).Then mice were intraperitoneally (i.p.) injected with PCA 1h before OVA challenge. We found that PCA treatment at 15 or 30 mg/kg significantly decreased OVA-induced airway hyper-responsiveness (AHR) to inhaled methacholine. Type 2 helper T cell (Th2) cytokines in bronchoalveolar lavage (BAL) fluid, such as interleukin-4 (IL-4), interleukin 5 (IL-5) and interleukin-13 (IL-13), and serum OVA-specific immunoglobulin E (IgE) levels, were also reduced by PCA. Moreover treatment with PCA markedly decreased the number of inflammatory cells in BALF and attenuated OVA-induced mRNA expression of CCl11, CCR3, Muc5ac, acidic mammalian chitinase (AMCase), chitinase 3-like protein 4 (Ym2) and E-selectin in lung tissues, lung histopathological studies showed that PCA inhibited inflammatory cell infiltration and mucus hypersecretion compared with the OVA-induced mice group. We then investigated the possible molecular mechanisms which might be implicated in PCA activity. Our results suggested that the protective effect of PCA might be mediated by the inhibition of the extracellular signal-regulated protein kinase (ERK), p38 Mitogen-activated protein kinase (MAPK) phosphorylation and the nuclear factor-κB (NF-κB) activation.
Subject(s)
Anti-Asthmatic Agents/therapeutic use , Asthma/drug therapy , Asthma/immunology , Drugs, Chinese Herbal/therapeutic use , Hydroxybenzoates/therapeutic use , Ovalbumin/immunology , Administration, Inhalation , Animals , Anti-Asthmatic Agents/administration & dosage , Anti-Asthmatic Agents/isolation & purification , Asthma/chemically induced , Blotting, Western , Bronchoalveolar Lavage Fluid/chemistry , Bronchoalveolar Lavage Fluid/cytology , Bronchoalveolar Lavage Fluid/immunology , Cytokines/blood , Cytokines/immunology , Dose-Response Relationship, Drug , Drugs, Chinese Herbal/administration & dosage , Drugs, Chinese Herbal/isolation & purification , Female , Hydroxybenzoates/administration & dosage , Hydroxybenzoates/isolation & purification , Immunoglobulin E/blood , Immunoglobulin E/immunology , Lung/drug effects , Lung/immunology , Lung/pathology , Methacholine Chloride/pharmacology , Mice , Mice, Inbred BALB C , Respiratory Hypersensitivity/chemically induced , Respiratory Hypersensitivity/drug therapy , Respiratory Hypersensitivity/immunologyABSTRACT
OBJECTIVE: To review the characteristics and management of hypersensitivity reactions caused by antineoplastic agents. METHOD: We conducted a search in the Pubmed and EMBASE databases for the last 10 years. RESULTS: Almost all chemotherapeutic agents have the potential to cause hypersensitivity reactions, but some groups have been associated with increased risk, such as platinum compounds, taxanes, asparaginase, monoclonal antibodies and epipodophyllotoxins. The clinical manifestations of these reactions are variable and unpredictable, including symptoms affecting the skin and the pulmonary, cardiac and gastrointestinal systems. The mechanism associated with their development is not yet fully understood. Diagnosis is based on patients' signs and symptoms and skin testing. The management of patients who suffer a hypersensitivity reaction to a chemotherapeutic agent varies with the severity of the reaction, the need to continue treatment, and the availability of alternative therapies. CONCLUSIONS: Due to a progressive increase in the use of chemotherapeutic agents an increased incidence of hypersensitivity reactions is to be expected. Desensitisation protocols are a noteworthy alternative that make it possible to re-initiate patients' therapy with the causative agent of the hypersensitivity reaction. Their use should be assessed individually, weighing risks and benefits.