Abnormal adenosine metabolism of neutrophils inhibits airway inflammation and remodeling in asthma model induced by Aspergillus fumigatus.

BACKGROUND: Neutrophils consume a large amount of energy when performing their functions. Compared with other white blood cells, neutrophils contain few mitochondria and mainly rely on glycolysis and gluconeogenesis to produce ATP. The inflammatory site is hypoxic and nutrient poor. Our aim is to study the role of abnormal adenosine metabolism of neutrophils in the asthmatic airway inflammation microenvironment. METHOD: In this study, an asthma model was established by intratracheal instillation of Aspergillus fumigatus extract in Ecto-5'-Nucleotidase (CD73) gene-knockout and wild-type mice. Multiple analyses from bronchoalveolar lavage fluid (BALF) were used to determine the levels of cytokines and chemokines. Immunohistochemistry was used to detect subcutaneous fibrosis and inflammatory cell infiltration. Finally, adenosine 5'-(α, ß-methylene) diphosphate (APCP), a CD73 inhibitor, was pumped subcutaneously before Aspergillus attack to observe the infiltration of inflammatory cells and subcutaneous fibrosis to clarify its therapeutic effect. RESULT: PAS staining showed that CD73 knockout inhibited pulmonary epithelial cell proliferation and bronchial fibrosis induced by Aspergillus extract. The genetic knockdownof CD73 significantly reduced the production of Th2 cytokines, interleukin (IL)-4, IL-6, IL-13, chemokine (C-C motif) ligand 5 (CCL5), eosinophil chemokine, neutrophil IL-17, and granulocyte colony-stimulating factor (G-CSF). In addition, exogenous adenosine supplementation increased airway inflammation. Finally, the CD73 inhibitor APCP was administered to reduce inflammation and subcutaneous fibrosis. CONCLUSION: Elevated adenosine metabolism plays an inflammatory role in asthma, and CD73 could be a potential therapeutic target for asthma.

Herbal Medicines for Asthmatic Inflammation: From Basic Researches to Clinical Applications.

Asthma is one of the most common chronic inflammatory disorders, associated with reversible airflow obstruction, airway hyperresponsiveness, and airway remodeling. This disease has a significant impact on individuals, their families, and society. Standardized therapeutics such as inhaled corticosteroid in combination with long acting ß2 agonist have been applied for asthma control; however, complementary and alternative medicines, especially herbal medicines, are still widely used all over the world. A growing body of literature suggests that various herbals or related products might be effective in inhibiting asthmatic inflammation. In this review, we summarize recent advances about the mechanistic studies of herbal medicines on allergic airway inflammation in animal models and their potential application into clinic for asthma control.

Suhuang antitussive capsule at lower doses attenuates airway hyperresponsiveness, inflammation, and remodeling in a murine model of chronic asthma.

Suhuang antitussive capsule (Suhuang), a traditional Chinese medication, is found effective in treating chronic cough and cough variant asthma (CVA). This study aimed to determine the possible effects and underlying mechanisms of Suhuang on chronic ovalbumin (OVA)-induced airway hyperresponsiveness (AHR), inflammation, and remodeling in mice. Mice were randomly assigned to six experimental groups: control, OVA model with or without Suhuang (low dose: 3.5 g/kg, middle dose: 7.0 g/kg, high dose: 14.0 g/kg), or dexamethasone (2.5 mg/kg). AHR, inflammatory cells, cytokines in bronchoalveolar lavage fluid (BALF), lung pathology, mucus production, and airway remodeling were examined. We found Suhuang treated at lower doses effectively inhibited OVA-induced AHR, airway inflammation, mucus production and collagen deposition around the airway. High dose of Suhuang reduced most of the inflammatory hallmarks while exerted inconsiderable effects on the number of macrophages in BALF and AHR. At all doses, Suhuang significantly reduced the levels of interlukin (IL) -13 and transforming growth factor (TGF)-ß1, but had little effects on IL-4, IL-5, IL-17A and interferon (IFN)-γ. Thus, Suhuang administration alleviates the pathological changes of chronic asthma likely through inhibition of IL-13 and TGF-ß1. Suhuang might be a promising therapy for patients with allergic asthma in the future.

Exogenous interleukin-17A inhibits eosinophil differentiation and alleviates allergic airway inflammation.

IL-17 is known to play important roles in immune and inflammatory disease, such as in asthma, but its functions in allergic airway inflammation are still controversial, and the molecular mechanisms mediating these functions remain unclear. Increased production of eosinophils in bone marrow and their emergence in the airway have been linked to the onset and progression of allergic asthma. In this study, we investigated the effects of exogenous IL-17 on allergic airway inflammation and explored the underlying molecular mechanisms through eosinophil generation. Exogenous IL-17 significantly attenuated the features of allergic inflammation induced by ovalbumin in mice. It inhibited eosinophil differentiation both in vivo and in vitro, accompanied by down-regulated expression of CC chemokine receptor 3, GATA binding protein 1 (GATA-1), and GATA binding protein 2 (GATA-2), as well as reduced formation of common myeloid progenitors and eosinophil progenitors, but without influencing eosinophil apoptosis. IL-17 also significantly decreased the number of eosinophils in IL-5-transgenic mice, although it notably increased the levels of IL-3, IL-5, and granulocyte/macrophage colony-stimulating factor. In addition, IL-17 had little effect on secretion of the inflammatory cytokines by eosinophils. Neutralization of endogenous IL-17 significantly augmented eosinophil recruitment in the airways. Together, these findings suggest that exogenous IL-17 protects against allergic airway inflammation, most likely through inhibition of the eosinophil differentiation in bone marrow.

Prevention of allergic airway hyperresponsiveness and remodeling in mice by Astragaliradix antiasthmatic decoction.

BACKGROUND: Astragali radix Antiasthmatic Decoction (AAD), a traditional Chinese medication, is found effective in treating allergic diseases and chronic cough. The purpose of this study is to determine whether this medication could suppress allergen-induced airway hyperresponsiveness (AHR) and remodeling in mice, and its possible mechanisms. METHODS: A mouse model of chronic asthma was used to investigate the effects of AAD on the airway lesions. Mice were sensitized and challenged with ovalbumin (OVA), and the extent of AHR and airway remodeling were characterized. Cells and cytokines in the bronchoalveolar lavage fluid (BALF) were examined. RESULTS: AAD treatment effectively decreased OVA-induced AHR, eosinophilic airway inflammation, and collagen deposition around the airway. It significantly reduced the levels of IL-13 and TGF-ß1, but exerted inconsiderable effect on INF-γ and IL-10. CONCLUSIONS: AAD greatly improves the symptoms of allergic airway remodeling probably through inhibition of Th2 cytokines and TGF-ß1.

Effect of Astragali-Cordyceps Mixtura on TGF-beta/Smad signal pathway in the lung of asthma airway remodeling.

AIM OF THE STUDY: We try to find out the influence of traditional Chinese Medicine Astragali-Cordyceps Mixtura (ACM) on TGF-beta/Smad signal pathway in the lung of asthma airway remodeling. MATERIALS AND METHODS: Mice were sensitized and challenged by OVA to establish a model of asthma. To assess the effects of ACM on the mice, animals of the ACM groups were treated with ACM. Data were achieved by using techniques as follow: counting cell number of BALF, assaying the amount of collagen deposition by Masson's staining, performing RT-PCR and immunohistochemistry for mRNA and protein expression of TGF-beta1, Smad3 and Smad7. RESULTS: The depositions of collagen in airway wall greatly increased at the model group compared with that of the normal group. In contrast, these decreased at the ACM groups. As compared with the control group, TGF-beta1 expression also decreased at both mRNA and protein level at the ACM-M group versus increased both at the model group. Whereas, Smad7 significantly decreased only at the model group and partly restored at the ACM-M group. CONCLUSIONS: ACM greatly improves the symptoms of asthma airway remodeling by inhibiting the expression of TGF-beta1 and upregulating the amount of Smad7.

Astragalus Membranaceus prevents airway hyperreactivity in mice related to Th2 response inhibition.

AIM OF THE STUDY: Asthma is recognized as a common pulmonary disease throughout the world. To date, there has been a growing interest in herbal products in Traditional Chinese Medicine, which is considered to be effective to treat asthma. A Chinese herb Astragalus Membranaceus (AM) was found useful in treating allergic diseases. The purpose of this study is to determine whether this herbal injection could suppress allergic-induced AHR and mucus hypersecretion in allergic mice. MATERIALS AND METHODS: A mouse model of chronic asthma was used to investigate AM injection on the airway lesions in compared with glucocorticoids. The study was conducted on mice sensitized and challenged with ovalbumin and the whole body plethsmography was performed to assess AHR. The bronchoalveolar lavage (BAL), histopathology were examined. RESULTS: We found 28-day AM administration significantly decreased inflammatory infiltration and mucus secretion in the lung tissues of allergic mice. 28-day AM administration enhanced Ova-induced decreased IFN-gamma, and the Ova-induced elevations of IL-5 and IL-13 in BALF were prevented by 28-day injection. We also showed 28-day AM injection markedly suppressed increased AHR in allergic mice. CONCLUSIONS: Our results indicate Astragalus Membranaceus has a potential role in treating allergic asthma.

[The expression of transforming growth factor beta-1 in rat model of chronic obstructive pulmonary disease and the effects of early drugs intervention].

OBJECTIVE: To evaluate the expression of transforming growth factor beta-1(TGF-beta1) and the effects of early drugs intervention of chronic obstructive pulmonary disease(COPD) in rat model. METHODS: The COPD rat model (group B) was established by intratracheal instillation of lipopolysaccharide twice and daily exposure to cigarette smoking. Drug intervention groups received dongchongxiacao orally daily from the three days before the experiment (group C) and erythromycin by intraperitoneal injection since the third week (group D)and inhalation of budesonide since the forth week (group E). At the end of 10 weeks, all 40 rats including normal control (group A) were assessed for lung resistance (RL) and dynamic lung compliance (Cdyn). The expression of TGF-beta1 gene and protein were also observed by immunohistochemistry and semi-quantitative reverse transcription-polymerase chain reaction (RT-PCR), respectively. RESULTS: The changes of pathology and pathophysiology in rat COPD model were similar to those of human COPD. There was a significant increase in the smooth muscle and collagen thickness in the airway wall of the group B in comparison with that of the group A. RL in group B was significantly higher than that in group A (P<0.01), while it was inhibited by early drugs intervention (P<0.01). Cdyn was decreased in group B as compared with that in group A, which was limited by erythromycin and budesonide intervention (P<0.01). The relative content for TGF-beta1 was significantly increased in the epithelial cells of the bronchi, endothelial cells of the pulmonary small vessel and alveolar macrophages of COPD group as compared with those of normal controls (P<0.01).The relative contents for TGF-beta1 in the epithelial of bronchi in group D and group E were significantly lower than that in group B, but not found in group C. There was no difference between group D and group E. There were statistical positive relationships between the RL and the relative content for TGF-beta1 in the bronchial epithelial cells, between the RL and the mRNA level of TGF-beta1 in the lung tissue (P<0.01 approximately 0.05). CONCLUSION: This rat COPD model could be helpful to obtain more information about airway remodeling. TGF-beta1 may play an important role during the process of airway remodeling, and could be influenced by early drugs intervention such as budesonide and erythromycin, which may imply their potency in the treatment of COPD. But there is not same phenomenon found in dongchongxiacao group.