Anti-asthmatic activity of standardized hydro-ethanolic and aqueous extracts of Stachytarpheta cayennensis (Rich.) Vahl in a murine model.

ETHNOPHARMACOLOGICAL RELEVANCE: Stachytarpheta cayennensis (Verbenaceae) has been used in Brazilian traditional medicine to treat asthma and other respiratory diseases. AIMS OF THE STUDY: To investigate the effects of different doses of standardized hydro-ethanolic (SCH) and aqueous (SCA) extracts of aerial parts of S. cayennensis using a murine ovalbumin (OVA)-induced asthma model. MATERIALS AND METHODS: The major constituents of the plant extracts were identified and standardized by ultra-performance liquid chromatography coupled with mass spectrometry. Balb/c mice were challenged with OVA solution and treated concomitantly by intraperitoneal injection of standardized SCH or SCA extracts at 50, 100, and 200 mg/kg concentrations. OVA-challenged control animals were treated with either dexamethasone (OVA-DEX) or saline solution (OVA-SAL). After challenge, we assessed in vivo bronchial hyperresponsiveness, airway inflammation (number of cells), peribronchial inflammation (histological analysis) and production of OVA-specific IgE and interleukin (IL)-4, IL-5, and IL-13 (ELISA). RESULTS: Acteoside, isoacteoside, and ipolamiide were the major constituents of SCH and SCA. The respective concentrations of acteoside in SCH and SCA were 78 and 98 µg/mL, while those of ipolamiide were 30 and 19 µg/mL. Treatment with 200 mg/kg of SCH or SCA decreased IL-4, IL-5, and IL-13 in lung homogenates. These reductions were accompanied by a lower influx of inflammatory cells (eosinophils, lymphocytes, and macrophages) to the airways and lungs. In addition to the anti-inflammatory effects, administration of SCA, but not SCH, ameliorated the parameters of bronchial hyperresponsiveness and decreased levels of circulating OVA-specific IgE. CONCLUSION: The results presented herein demonstrate for the first time the anti-asthmatic activity of S. cayennensis extracts in a murine model, thereby supporting the ethnopharmacological uses of the plant.

Momordica charantia L. improves airway hyperresponsiveness and suppresses inflammation in a murine model of allergic asthma.

OBJECTIVE: To evaluate the effect of a hydroethanolic extract of Momordica charantia L. ("bitter melon", Cucurbitaceae) leaves (MCHA) on ovalbumin (OVA)-induced asthma model. Balb/c mice were sensitized twice and challenged for 4 alternate days with OVA and then treated with MCHA (500 mg/kg) for 7 consecutive days. METHODS: Control groups received treatment with normal saline or dexamethasone (2 mg/kg) on the same day. We assessed in vivo bronchial hyperresponsiveness and ex-vivo inflammation and mucus production in bronchoalveolar lavage (BAL), lung homogenates, and lung tissue. RESULTS: MCHA significantly improved airway hyperresponsiveness near baseline levels. MCHA administration significantly improved airway and lung inflammation, demonstrated by decreased total and inflammatory cells in BAL, lower levels of IL-5 and IL-13 in lung homogenate, and fewer inflammatory cells in lung tissue. Additionally, MCHA significantly diminished goblet cells in lung tissue. CONCLUSIONS: Administration of a hydroethanolic extract of M. charantia leaves was effective in treating OVA-induced asthma in an animal model.

Cycloastragenol alleviates airway inflammation in asthmatic mice by inhibiting autophagy.

Cycloastragenol (CAG), a secondary metabolite from the roots of Astragalus zahlbruckneri, has been reported to exert anti­inflammatory effects in heart, skin and liver diseases. However, its role in asthma remains unclear. The present study aimed to investigate the effect of CAG on airway inflammation in an ovalbumin (OVA)­induced mouse asthma model. The current study evaluated the lung function and levels of inflammation and autophagy via measurement of airway hyperresponsiveness (AHR), lung histology examination, inflammatory cytokine measurement and western blotting, amongst other techniques. The results demonstrated that CAG attenuated OVA­induced AHR in vivo. In addition, the total number of leukocytes and eosinophils, as well as the secretion of inflammatory cytokines, including interleukin (IL)­5, IL­13 and immunoglobulin E were diminished in bronchoalveolar lavage fluid of the OVA­induced murine asthma model. Histological analysis revealed that CAG suppressed inflammatory cell infiltration and goblet cell secretion. Notably, based on molecular docking simulation, CAG was demonstrated to bind to the active site of autophagy­related gene 4­microtubule­associated proteins light chain 3 complex, which explains the reduced autophagic flux in asthma caused by CAG. The expression levels of proteins associated with autophagy pathways were inhibited following treatment with CAG. Taken together, the results of the present study suggest that CAG exerts an anti­inflammatory effect in asthma, and its role may be associated with the inhibition of autophagy in lung cells.

A Synthetic Curcuminoid Analogue, 2,6-Bis-4-(Hydroxyl-3-Methoxybenzylidine)-Cyclohexanone (BHMC) Ameliorates Acute Airway Inflammation of Allergic Asthma in Ovalbumin-Sensitized Mice.

2,6-Bis-(4-hydroxyl-3-methoxybenzylidine) cyclohexanone (BHMC), a synthetic curcuminoid analogue, has been shown to exhibit anti-inflammatory properties in cellular models of inflammation and improve the survival of mice from lethal sepsis. We further evaluated the therapeutic effect of BHMC on acute airway inflammation in a mouse model of allergic asthma. Mice were sensitized and challenged with ovalbumin (OVA), followed by intraperitoneal administration of 0.1, 1, and 10 mg/kg of BHMC. Bronchoalveolar lavage fluid, blood, and lung samples were collected, and the respiratory function was measured. OVA sensitization and challenge increased airway hyperresponsiveness (AHR) and pulmonary inflammation. All three doses of BHMC (0.1-10 mg/kg) significantly reduced the number of eosinophils, lymphocytes, macrophages, and neutrophils, as well as the levels of Th2 cytokines (IL-4, IL-5 and IL-13) in bronchoalveolar lavage fluid (BALF) as compared to OVA-challenged mice. However, serum level of IgE was not affected. All three doses of BHMC (0.1-10 mg/kg) were effective in suppressing the infiltration of inflammatory cells at the peribronchial and perivascular regions, with the greatest effect observed at 1 mg/kg which was comparable to dexamethasone. Goblet cell hyperplasia was inhibited by 1 and 10 mg/kg of BHMC, while the lowest dose (0.1 mg/kg) had no significant inhibitory effect. These findings demonstrate that BHMC, a synthetic nonsteroidal small molecule, ameliorates acute airway inflammation associated with allergic asthma, primarily by suppressing the release of inflammatory mediators and goblet cell hyperplasia to a lesser extent in acute airway inflammation of allergic asthma.

Aqueous Pyrostegia venusta (Ker Gawl.) Miers extract attenuates allergen-induced asthma in a mouse model via an antioxidant mechanism.

Objective:Pyrostegia venusta (Ker-Gawl.) Miers (Bignoniaceae) is a perennial invasive vine, distributed worldwide. In folk medicine, its parts are used for the treatment of inflammatory respiratory diseases. Extracts of P. venusta have antioxidant, antimicrobial, and antinociceptive properties. The aim of this study was to evaluate the effects of two extracts (aqueous and hydroethanolic) of P. venusta in the treatment of asthma in an animal model.Methods: Balb/c mice were sensitized twice with ovalbumin (OVA) intraperitoneally (ip), one week apart, and after one week, challenged with OVA intranasally on four alternate days. Mice were treated ip with 300 mg/kg of aqueous or hydroethanolic extracts for seven consecutive days. Control groups received saline on the same days. Bronchial hyperresponsiveness, production of Th1 and Th2 cytokines, lung and airway inflammation, and antioxidant activity in lung tissue were assessed.Results: Treatment with aqueous extract significantly decreased bronchial hyperresponsiveness, measured by total and tissue resistance and elastance. The administration of hydroethanolic extract did not reduce bronchial hyperresponsiveness. In addition, both extracts significantly reduced total cell and eosinophil counts in bronchoalveolar lavage. Both extracts did not change significantly IL-4, IL-5, IL-9, IL-13, IFN-gamma, and TGF-beta levels. Of note, only the aqueous extract significantly increased the total antioxidant activity and reduced lung inflammation.Conclusion: Aqueous extract of P. venusta reduced bronchial hyperresponsiveness, lung and airway inflammation, probably via an antioxidant mechanism. These results demonstrate that P. venusta may have potential for asthma treatment.

Anti-Inflammatory Effects of a Cordyceps sinensis Mycelium Culture Extract (Cs-4) on Rodent Models of Allergic Rhinitis and Asthma.

Allergic rhinitis and asthma are common chronic allergic diseases of the respiratory tract, which are accompanied by immunoglobulin E (IgE)-mediated inflammation and the involvement of type 2 T helper cells, mast cells, and eosinophils. Cordyceps sinensis (Berk.) Sacc is a fungal parasite on the larva of Lepidoptera. It has been considered to be a health-promoting food and, also, one of the best-known herbal remedies for the treatment of airway diseases, such as asthma and lung inflammation. In the present study, we demonstrated the antiallergic rhinitis effect of Cs-4, a water extract prepared from the mycelium culture of Cordyceps sinensis (Berk) Sacc, on ovalbumin (OVA)-induced allergic rhinitis in mice and the anti-asthmatic effect of Cs-4 in a rat model of asthma. Treatment with Cs-4 suppressed the nasal symptoms induced in OVA-sensitized and challenged mice. The inhibition was associated with a reduction in IgE/OVA-IgE and interleukin (IL)-4/IL-13 levels in the nasal fluid. Cs-4 treatment also decreased airway responsiveness and ameliorated the scratching behavior in capsaicin-challenged rats. It also reduced plasma IgE levels, as well as IgE and eosinophil peroxidase levels, in the bronchoalveolar fluid. Cs-4 treatment completely suppressed the increases in IL-4, IL-5, and IL-13 levels in rat lung tissue. In conclusion, our results suggest that Cs-4 has the potential to alleviate immune hypersensitivity reactions in allergic rhinitis and asthma.

Curcumin analogs (B2BrBC and C66) supplementation attenuates airway hyperreactivity and promote airway relaxation in neonatal rats exposed to hyperoxia.

BACKGROUND: This study was undertaken to test the hypothesis that the newly synthesized curcuminoids B2BrBC and C66 supplementation will overcome hyperoxia-induced tracheal hyperreactivity and impairment of relaxation of tracheal smooth muscle (TSM). MATERIALS AND METHODS: Rat pups (P5) were exposed to hyperoxia (>95% O2 ) or normoxia for 7 days. At P12, tracheal cylinders were used to study in vitro contractile responses induced by methacholine (10-8 -10-4 M) or relaxation induced by electrical field stimulation (5-60 V) in the presence/absence of B2BrBC or C66, or to study the direct relaxant effects elicited by both analogs. RESULTS: Hyperoxia significantly increased contraction and decreased relaxation of TSM compared to normoxia controls. Presence of B2BrBC or C66 normalized both contractile and relaxant responses altered by hyperoxia. Both, curcuminoids directly induced dose-dependent relaxation of preconstricted TSM. Supplementation of hyperoxic animals with B2BrBC or C66, significantly increased catalase activity. Lung TNF-α was significantly increased in hyperoxia-exposed animals. Both curcumin analogs attenuated increases in TNF-α in hyperoxic animals. CONCLUSION: We show that B2BrBC and C66 provide protection against adverse contractility and relaxant effect of hyperoxia on TSM, and whole lung inflammation. Both analogs induced direct relaxation of TSM. Through restoration of catalase activity in hyperoxia, we speculate that analogs are protective against hyperoxia-induced tracheal hyperreactivity by augmenting H2 O2 catabolism. Neonatal hyperoxia induces increased tracheal contractility, attenuates tracheal relaxation, diminishes lung antioxidant capacity, and increases lung inflammation, while monocarbonyl CUR analogs were protective of these adverse effects of hyperoxia. Analogs may be promising new therapies for neonatal hyperoxic airway and lung disease.

Osthole attenuates ovalbumin­induced lung inflammation via the inhibition of IL­33/ST2 signaling in asthmatic mice.

Asthma is a common chronic inflammatory airway disease. Recent studies have reported that interleukin (IL)­33 is a potential link between the airway epithelium and Th2­type inflammatory responses, which are closely related to the progression of asthma. The IL­33 receptor, ST2, is highly expressed in group 2 innate lymphoid cells (ILC2s), Th2 cells, mast cells, eosinophils and natural killer (NK) cells. Cnidii Fructus is a Chinese herb with a long history of use in the treatment of asthma in China. Osthole is one of the major components of Cnidii Fructus. The present study examined the anti­asthmatic effects of osthole in mice and aimed to elucidate the underlying mechanisms involving the IL­33/ST2 pathway. BALB/c mice were sensitized and challenged with ovalbumin and then treated with an intraperitoneal injection of osthole (25 and 50 mg/kg). Subsequently, the airway hyper­responsiveness (AHR) and inflammation of the lungs were evaluated. The amounts of IL­4, IL­5, IL­13, interferon (IFN)­Î³ and IL­33 in the bronchoalveolar lavage fluid (BALF) were measured by Luminex assay and their mRNA levels in the lungs were measured by reverse transcription­quantitative PCR. The histopathology of the lungs was performed with H&E, PAS and Masson's staining. The expression of ST2 in the lungs was evaluated by immunohistochemistry. The data demonstrated that osthole markedly reduced AHR and decreased the number of eosinophils and lymphocytes in BALF. It was also observed that osthole significantly inhibited the release of Th2­type cytokines (IL­4, IL­5 and IL­13) and upregulated the IFN­Î³ level in BALF. Moreover, osthole significantly attenuated the IL­33 and ST2 expression in the lungs of asthmatic mice. On the whole, osthole attenuated ovalbumin­induced lung inflammation through the inhibition of IL­33/ST2 signaling in an asthmatic mouse model. These results suggest that osthole is a promising target for the development of an asthma medication.

Qingfei oral liquid alleviates airway hyperresponsiveness and mucus hypersecretion via TRPV1 signaling in RSV-infected asthmatic mice.

Pediatric asthma is exacerbated by Respiratory Syncytial Virus (RSV) infection, and Transient Receptor Potential Vanilloid 1 (TRPV1) promotes production of inflammatory cytokines and mucus hypersecretion in the pathology of this disease. Our previous research revealed that Qingfei oral liquid (QF) inhibited airway inflammation and mucus hypersecretion in RSV-infected asthmatic mice models and that this may be associated with the TRPV1-regulation of NF-κB and Mucin 5AC (MUC5AC) expression, but the exact mechanism is unknown. In the present study, LC-MS was used for analyzing the chemicals in QF, ovalbumin (OVA)-induced asthmatic mice inhaled RSV three consecutive times to create an RSV-infected asthmatic model. We found treatment from QF alleviated airway hyperresponsiveness (AHR) and reduced congestion, edema, and infiltration of inflammatory cells into pulmonary tissues. Additionally, QF was found to decrease expression of NF-κB and its downstream inflammatory cytokines IL-1ß, IL-4, IL-5, and IL-13, as well as a decrease in MUC5AC and pro-inflammatory cytokines in PKC via a reduction in Protein Kinase C-dependent signaling. These findings suggest that QF can alleviate AHR and mucus hypersecretion caused by RSV infection in asthmatic mice, and its mechanism may be associated with the regulation of the TRPV1 signaling pathway.

Response to bronchodilator and clinical, pathophysiological features in patients with nonasthmatic eosinophilic bronchitis.

INTRODUCTION: Whether nonasthmatic eosinophilic bronchitis (NAEB) shows response to bronchodilator (RB) remains unclear. OBJECTIVES: To investigate the RB and its relationship with clinical and pathophysiological features in NAEB. METHODS: Fifty-one patients with NAEB were assigned in a 2:1 ratio to receive oral bambuterol hydrochloride (n = 34, 10 mg, once daily, for 3 days) or matched placebo (n = 17) randomly, of whom 48 patients (32 with bronchodilator and 16 with placebo) completed the study. Sputum induction, spirometry and cough reflex sensitivity were measured. RB was considered when cough Visual analogue scale (VAS) score decreased 30% or more after treatment. Cough reflex sensitivity was defined as the lowest concentration of capsaicin inducing five coughings or more (C5), and presented as Log C5. RESULTS: The responsive rate of patients with bronchodilator was significantly higher than that with placebo (34.4% vs 6.3%, P < 0.05). The VAS score decreased significantly in patients with bronchodilator (median: 6.0-3.0, P < 0.01). There was a significantly higher median Log C5 (2.7 vs 1.3, P < 0.05), and a higher trend of decline in FEV1 % predicted and MMEF% predicted after bronchial provocation in patients with RB as compared with patients without RB. No significant differences in baseline percentages of sputum eosinophil were found between patients with RB and that without RB. CONCLUSIONS: One third of patients with NAEB respond well to bronchodilator treatment, which are related with lower cough reflex sensitivity and increased airway responsiveness. The relationship between NAEB and asthma needs to be investigated further.

Petiveria alliacea Suppresses Airway Inflammation and Allergen-Specific Th2 Responses in Ovalbumin-Sensitized Murine Model of Asthma.

OBJECTIVE: To examine the effect of metanol extract of Petiveria alliacea (PM) on airway inflflammation in a murine model of chronic asthma. METHODS: Two-month-old male BALB/c mice (n=6-8/group) were sensitized on days 0 and 14 by intraperitoneal injection of 20 µg ovalbumin (OVA). On day 25, the mice received an airway challenge with OVA (3%, w/v, in phosphate buffered saline). PM was administered orally by oral gavage to mice at doses of 100, 200 and 400 mg/kg body weight once daily from days 18 to 23. Control mice were orally administered phosphate buffered saline (PBS) to induce a model of asthma. At the end of the test, respiratory reactivity was assayed, the total cell number, interleukin-4 (IL-4), IL-5, IL-13, tumor necrosis factor-alpha (TNF-α) and reactive oxygen species (ROS) in the bronchoalveolar lavage fluid (BALF) were determined and the levels of serum IgE, intercellular cell adhesion molecule 1 (ICAM-1) and eotoxin were measured. In addition, lung tissue was used to qualify the IL-4, IL-5, IL-13, TNF-α and transforming growth factor beta 1 (TGF-ß1). Histologic examination was performed to observe inflammatory cellular infiltration. RESULTS: The administration of PM in comparison with the OVA-only treated group signifificantly attenuated the infifiltration of eosinophils and other inflflammatory cells (P<0.01). Airway resistance (RI) in the OVA-only induced group was significantly higher than that of the PBS control group (P<0.01) when methacholine was added. TNF-α, IgE, TGF-ß1 and cytokine levels IL-4, IL-5, IL-13 in the BALF decreased compared to control mice (P<0.01 or P<0.05). PM treatment also inhibited the production of chemokines, eotaxin and ICAM-1 in BALF (P<0.01), which improved lung function. Histopathological examination revealed that the sensitized treated PM groups had significant lower in inflammatory scores similar to dexamethasone treatments and the untreated group. CONCLUSION: Administration of PM could inhibit airway inflammation, regulate cytokines, chemokines and enhance pulmonary conditions in allergic murine model of asthma.

Aqueous extracts from Uncaria tomentosa (Willd. ex Schult.) DC. reduce bronchial hyperresponsiveness and inflammation in a murine model of asthma.

ETHNOPHARMACOLOGICAL RELEVANCE: Uncaria tomentosa (Willd. Ex Schult) DC is used by indigenous tribes in the Amazonian region of Central and South America to treat inflammation, allergies and asthma. The therapeutic properties of U. tomentosa have been attributed to the presence of tetracyclic and pentacyclic oxindole alkaloids and to phenolic acids. AIMS OF THE STUDY: To characterize aqueous bark extracts (ABE) and aqueous leaf extracts (ALE) of U. tomentosa and to compare their anti-inflammatory effects. MATERIALS AND METHODS: Constituents of the extracts were identified by ultra performance liquid chromatography-mass spectrometry. Anti-inflammatory activities were assessed in vitro by exposing lipopolysaccharide-stimulated macrophage cells (RAW264.7-Luc) to ABE, ALE and standard mitraphylline. In vivo assays were performed using a murine model of ovalbumin (OVA)-induced asthma. OVA-sensitized animals were treated with ABE or ALE while controls received dexamethasone or saline solution. Bronchial hyperresponsiveness, production of Th1 and Th2 cytokines, total and differential counts of inflammatory cells in the bronchoalveolar lavage (BAL) and lung tissue were determined. RESULTS: Mitraphylline, isomitraphylline, chlorogenic acid and quinic acid were detected in both extracts, while isorhyncophylline and rutin were detected only in ALE. ABE, ALE and mitraphylline inhibited the transcription of nuclear factor kappa-B in cell cultures, ALE and mitraphylline reduced the production of interleukin (IL)-6, and mitraphylline reduced production of tumor necrosis factor-alpha. Treatment with ABE and ALE at 50 and 200 mg kg-1, respectively, reduced respiratory elastance and tissue damping and elastance. ABE and ALE reduced the number of eosinophils in BAL, while ALE at 200 mg kg-1 reduced the levels of IL-4 and IL-5 in the lung homogenate. Peribronchial inflammation was significantly reduced by treatment with ABE and ALE at 50 and 100 mg kg-1 respectively. CONCLUSION: The results clarify for the first time the anti-inflammatory activity of U. tomentosa in a murine model of asthma. Although ABE and ALE exhibited distinct chemical compositions, both extracts inhibited the production of pro-inflammatory cytokines in vitro. In vivo assays revealed that ABE was more effective in treating asthmatic inflammation while ALE was more successful in controlling respiratory mechanics. Both extracts may have promising applications in the phytotherapy of allergic asthma.

Genipin inhibits allergic responses in ovalbumin-induced asthmatic mice.

Genipin is a natural compound isolated from the fruit of Gardenia jasminoides with various pharmacological effects. In this study, we investigated whether genipin effectively alleviates allergic responses in a murine model of ovalbumin (OVA)-induced asthma. The mice were administered an intraperitoneal injection of OVA on day 0 and 14 to boost the immune response; genipin was then administered from day 18 to 23 by oral gavage. On days 21 to 23, mice were OVA-challenged using am ultrasonic nebulizer, and airway hyperresponsiveness (AHR) was determined on day 24 by plethysmography. Genipin significantly reduced the inflammatory cell count in bronchoalveolar lavage fluids (BALF) and AHR, which were accompanied by lower interleukin-5 (IL-5), IL-13 and OVA-specific immunoglobulin (Ig) E levels in the BALF or serum from OVA-induced asthmatic mice. In histology, genipin significantly decreased airway inflammation and mucus hypersecretion in OVA-induced asthmatic mice. Additionally, genipin inhibited OVA-induced increases in the expression of inducible nitric oxide synthase and cyclooxygenase-2 proteins. Further, genipin reduced the activity and protein levels of matrix metalloproteinase-9 in lung tissue from OVA induced asthmatic mice. Overall, genipin effectively alleviated the asthmatic inflammatory response in an OVA-induced asthmatic model. Therefore, our results suggest that genipin has therapeutic potential for treating asthma.

Bronchoprotective tolerance with indacaterol is not modified by concomitant tiotropium in persistent asthma.

BACKGROUND: Tiotropium is a long acting muscarinic antagonist (LAMA), licensed as triple therapy with inhaled corticosteroid and long-acting beta-agonist (ICS/LABA). There may be a synergistic benefit between LAMA and LABA as a consequence of receptor cross-talk, which in turn could modify beta-2 receptor downregulation and associated tolerance induced by LABA. OBJECTIVE: We hypothesize this mechanism may result in a reduction of airway hyperresponsiveness (AHR) when using triple therapy. METHODS: We evaluated 14 non-smoking asthmatics using an open-label, randomized crossover design. ICS with Indacaterol and Tiotropium (IND/TIO) vs ICS with Indacaterol (IND) over 4 weeks with challenge performed after first and last doses at trough. RESULTS: We found no significant difference in mannitol sensitivity, expressed as the provocative dose of mannitol required to reach a 15% drop in FEV1 , or mannitol reactivity, expressed as the response dose ratio (RDR: max % fall in FEV1 /cumulative dose), when comparing ICS/IND/TIO to ICS/IND. Geometric mean fold differences for RDR comparing single and chronic dosing were 3.26-fold (95% CI 1.46-7.29) and 2.51-fold (95% CI 1.32-4.79) for IND and IND/TIO, respectively. Furthermore, salbutamol recovery post-challenge was significantly blunted after chronic compared to single dosing with either ICS/IND (P<.005) or ICS/IND/TIO (P<.05). CONCLUSION AND CLINICAL RELEVANCE: Our data suggest that concomitant tiotropium does not modify the bronchoprotective tolerance induced by Indacaterol, in turn suggesting that cross-talk may not be clinically relevant when using triple therapy. This study was registered on clinicaltrials.gov as NCT02039011.

A CASE OF BRONCHIAL ASTHMA WITH HYPEREOSINOPHILIA WITH EFFECTIVE SAIBOKUTOU THERAPY.

A 42 year old woman visited on our hospital because of cough, sputum, pruritus and erythema. She showed peripheral blood eosinophilia, high level of FENO, bronchial hyperresponsiveness. Diagnosis of bronchial asthma and atopic dermatitis was made, but she rejected therapy except for Saibokutou, a Kampo herbal medicine. After 1 year, her symptoms and her laboratory data were improved.

Mandevilla longiflora (Desf.) Pichon improves airway inflammation in a murine model of allergic asthma.

ETHNOPHARMACOLOGICAL RELEVANCE: Mandevilla longiflora, popularly known as "velame" in central Brazil, is a subshrub widely distributed in South America. Its xylopodium is used in the form of a decoction or infusion to treat inflammation and other ailments. AIM OF THE STUDY: This study aimed to evaluate the anti-inflammatory potential of M. longiflora in an in vivo model of ovalbumin-induced immediate hypersensitivity, identifying its effects on leukocyte infiltration, IgE and LTB4 levels, and Th2 cytokine production. In addition, HPLC fingerprint of the extract was performed. MATERIAL AND METHODS: The hydroethanolic extract 70% of M. longiflora (HEMI) was obtained by maceration of the plant xylopodium. Swiss mice were sensitized by i.p. injection OVA-aluminium hydroxide on days 1 and 10. Nine days after the last sensitisation animals were challenged for 6 consecutive days with OVA solution for 20min daily in a closed chamber under continuous flow of aerosol. The animals were treated with HEMl (20, 50 and 200mg/kg p.o.), 2 times per day, and euthanized 24h later. Animals treated with vehicle (2% Tween-20) or dexamethasone were used as negative and positive controls, respectively. The recruitment of inflammatory cells into the pulmonary cavity was evaluated by counting cells present in broncho-alveolar lavage fluid (BALF). Lung tissue was also collected for histopathology and infiltration analysis. Quantification of IL-4, IL-5 and IL-13 from the BALF, and IgE, and LTB4 from plasma, were conducted by immunoassay. RESULTS AND CONCLUSIONS: The HEMl attenuated leukocyte migration into the airways, which was evidenced by a decrease in eosinophils, neutrophils and mononuclear cells, both in BALF quantification and by histopathological analysis, as well as decreasing the concentrations of IL-4, IL-5, IL-13, IgE and LTB4. All of these events are typical of air-mucosa inflammatory disease. These findings scientifically evidence for the first time the ethnopharmacological use of M. longiflora to treat chronic inflammatory events, such as asthma, and suggest a potential therapeutic use or complementary therapy for this plant extract.

A standardized methanol extract of Eclipta prostrata (L.) L. (Asteraceae) reduces bronchial hyperresponsiveness and production of Th2 cytokines in a murine model of asthma.

ETHNOPHARMACOLOGICAL RELEVANCE: Eclipta prostrata (L.) L. (Asteraceae) has been used in Brazilian traditional medicine to treat asthma and other respiratory illnesses. AIMS OF THE STUDY: To investigate the effects of different doses of a standardized extract of E. prostrata using a murine model of allergen induced asthma. MATERIALS AND METHODS: Balb/c mice were sensitized twice with ovalbumin (OVA) administered intraperitoneally and challenged over four alternate days with nasal instillations of OVA solution. The standardized methanol extract of E. prostrata was administered in doses of 100, 250 and 500mgkg-1 concomitantly with nasal instillation over seven consecutive days. Control animals were treated with dexamethasone or saline solution. Bronchial hyperresponsiveness, production of Th1 and Th2 cytokines, allergen sensitization, airway and lung inflammation, mucous secretion and airway remodeling were assessed. RESULTS: The concentrations of chemical markers in the standardized methanol extract were 0.02% oroboside, 1.69% demethylwedelolactone and 1.71% wedelolactone. Treatment with 250mgkg-1 of extract, which provided 0.745, 4.22 and 4.30mgkg-1day-1 of oroboside, demethylwedelolactone and wedelolactone, respectively, significantly reduced (P<0.05) respiratory resistance and elastance. Such effects were comparable with those produced by dexamethasone. The total number of inflammatory cells and eosinophils in the bronchoalveolar lavage and the concentrations of interleukin (IL)-4, IL-5 and IL-13 in lung homogenate were significantly reduced (P<0.05) by the methanol extract of E. prostrata. CONCLUSION: The results presented herein demonstrate for the first time the anti-inflammatory activity of E. prostrata in a murine model of asthma, thereby supporting the ethnopharmacological uses of the plant.

Hypoxia-induced pulmonary arterial hypertension augments lung injury and airway reactivity caused by ozone exposure.

Ozone (O3)-related cardiorespiratory effects are a growing public health concern. Ground level O3 can exacerbate pre-existing respiratory conditions; however, research regarding therapeutic interventions to reduce O3-induced lung injury is limited. In patients with chronic obstructive pulmonary disease, hypoxia-associated pulmonary hypertension (HPH) is a frequent comorbidity that is difficult to treat clinically, yet associated with increased mortality and frequency of exacerbations. In this study, we hypothesized that established HPH would confer vulnerability to acute O3 pulmonary toxicity. Additionally, we tested whether improvement of pulmonary endothelial barrier integrity via rho-kinase inhibition could mitigate pulmonary inflammation and injury. To determine if O3 exacerbated HPH, male C57BL/6 mice were subject to either 3 weeks continuous normoxia (20.9% O2) or hypoxia (10.0% O2), followed by a 4-h exposure to either 1ppm O3 or filtered air (FA). As an additional experimental intervention fasudil (20mg/kg) was administered intraperitoneally prior to and after O3 exposures. As expected, hypoxia significantly increased right ventricular pressure and hypertrophy. O3 exposure in normoxic mice caused lung inflammation but not injury, as indicated by increased cellularity and edema in the lung. However, in hypoxic mice, O3 exposure led to increased inflammation and edema, along with a profound increase in airway hyperresponsiveness to methacholine. Fasudil administration resulted in reduced O3-induced lung injury via the enhancement of pulmonary endothelial barrier integrity. These results indicate that increased pulmonary vascular pressure may enhance lung injury, inflammation and edema when exposed to pollutants, and that enhancement of pulmonary endothelial barrier integrity may alleviate such vulnerability.

Abietic acid attenuates allergic airway inflammation in a mouse allergic asthma model.

Abietic acid (AA), one of the terpenoids isolated from Pimenta racemosa var. grissea, has been reported to have anti-inflammatory and immunomodulatory effects. However, the anti-allergic effects of AA remain unclear. The aim of this study was to investigate the anti-allergic effects of AA in an ovalbumin (OVA)-induced asthma murine model. The model of mouse asthma was established by induction of OVA. AA (10, 20, 40mg/kg) was administered by oral gavage 1h after the OVA treatment on days 21 to 23. At 24h after the last challenge, bronchoalveolar lavage fluid (BALF) and lung tissues were collected to assess pathological changes, cytokines production, and NF-κB expression. The results showed that AA attenuated lung histopathologic changes, inflammatory cells infiltration, and bronchial hyper-responsiveness. AA also inhibited OVA-induced the nitric oxide (NO), IL-4, IL-5, IL-13, and OVA-specific IgE production, as well as NF-κB activation. In conclusion, the current study demonstrated that AA exhibited protective effects against OVA-induced allergic asthma in mice and the possible mechanism was involved in inhibiting NF-κB activation.

Pheretima aspergillum decoction suppresses inflammation and relieves asthma in a mouse model of bronchial asthma by NF-κB inhibition.

ETHNOPHARMACOLOGICAL RELEVANCE AND AIM OF THE STUDY: Guang-Pheretima, the live form of the earthworm Pheretima aspergillum, is a traditional Chinese medicine commonly used for the treatment of asthma, cough, stroke, epilepsy and other diseases due to its anti-inflammatory, anti-asthmatic, anti-seizure, thrombolytic and diuretic properties. Although Guang-Pheretima is effective in the relief of asthma, its pharmacological activity and the underlying molecular mechanisms are not fully understood. Hence, we investigated the effects of a Pheretima aspergillum decoction (PAD) against inflammation in a model of ovalbumin (OVA)-induced asthma in BALB/c mice, as well as the nuclear factor-κB (NF-κB) pathway involved in this process. MATERIALS AND METHODS: OVA was used to sensitize and challenge the airway of the mice, and PAD was administrated by gavage. We measured airway hyperresponsiveness (AHR) in the mice 24h following a final methacholine challenge with whole-body plethysmography. The bronchoalveolar lavage fluid (BALF), serum and pulmonary tissues were collected 48h after the last challenge. The levels of inflammatory factors and the related mRNAs were determined by enzyme-linked immunosorbent assay (ELISA) and real-time polymerase chain reaction (RT-PCR), respectively. The number of differential inflammatory cells in the BALF was counted. Serum total and OVA-specific IgE levels were measured with ELISA. The activation of NF-κB signaling in the lung was detected by western blotting. In addition, the lung tissues were stained with hematoxylin and eosin or periodic acid Schiff stain for histopathological examination. RESULTS: PAD treatment significantly alleviated AHR in the asthmatic mice, decreased the mRNA and protein levels of IL-4, IL-5 and IL-13 and downregulated IgE. In addition, PAD treatment attenuated mucus secretion and infiltration of inflammatory cells in the lung while inhibiting the activation of NF-κB signaling. CONCLUSIONS: PAD effectively inhibited the activation of NF-κB signaling in the lungs of mice with OVA-induced asthma, and mitigated AHR and Th2 type inflammatory reactions. Therefore, PAD may serve as a drug candidate for asthma treatment.