Administration of Pigment Epithelium-Derived Factor Inhibits Airway Inflammation and Remodeling in Chronic OVA-Induced Mice via VEGF Suppression.

PURPOSE: Pigment epithelium-derived factor (PEDF) is a recently discovered antiangiogenesis protein. PEDF possesses powerful anti-inflammatory, antioxidative, antiangiogenic, and antifibrosis properties. It has been reported that PEDF can regulate vascular endothelial growth factor (VEGF) expression. This study aimed to evaluate whether recombinant PEDF protein could attenuate allergic airway inflammation and airway remodeling via the negative regulation of VEGF using a murine model of chronic ovalbumin (OVA)-induced asthma and BEAS-2B human bronchial epithelial cells. METHODS: In an in vivo experiment, mice sensitized with OVA were chronically airway challenged with aerosolized 1% OVA solution for 8 weeks. Treated mice were given injections of recombinant PEDF protein (50 or 100 µg/kg body weight) via the tail vein. In an in vitro experiment, we investigated the effects of recombinant PEDF protein on VEGF release levels in BEAS-2B cells stimulated with IL-1ß. RESULTS: Recombinant PEDF protein significantly inhibited eosinophilic airway inflammation, airway hyperresponsiveness, and airway remodeling, including goblet cell hyperplasia, subepithelial collagen deposition, and airway smooth muscle hypertrophy. In addition, recombinant PEDF protein suppressed the enhanced expression of VEGF protein in lung tissue and bronchoalveolar lavage fluid (BALF) in OVA-challenged chronically allergic mice. In the in vitro experiment, VEGF expression was increased after IL-1ß stimulation. Pretreatment with 50 and 100 ng/mL of recombinant PEDF protein significantly attenuated the increase in VEGF release levels in a concentration-dependent manner in BEAS-2B cells stimulated by IL-1ß. CONCLUSIONS: These results suggest that recombinant PEDF protein may abolish the development of characteristic features of chronic allergic asthma via VEGF suppression, providing a potential treatment option for chronic airway inflammation diseases such as asthma.

Clinical implications of serum hypoxia inducible factor-1α and vascular endothelial growth factor in lung cancer.

AIMS AND BACKGROUND: Hypoxia inducible factor 1α (HIF-1α) and vascular endothelial growth factor (VEGF) have been deemed as key in angiogenesis of lung cancer. The aim of this study was to investigate diagnostic and prognostic values of HIF-1α and VEGF in patients with lung cancer. METHODS: From May 1, 2011, to April 20, 2014, blood samples and/or pleural effusions were collected from 100 patients with lung cancer, 18 patients with tuberculosis, 47 patients with community-acquired pneumonia, and 29 healthy controls. The pretreatment levels of HIF-1α and VEGF were measured by enzyme-linked immunoassays. Patients with lung cancer were followed up during the period of this study and survival times were recorded for analysis. RESULTS: We detected that the levels of serum and pleural HIF-1α in lung cancer were significantly higher than those in the tuberculosis population, and that the VEGF expressions were not significantly different between malignancy and benign diseases. An area under the curve of pleural HIF-1α (0.877 ± 0.053) showed a high ability to differentiate lung cancer from benign diseases. The significant negative predictors of survival in the univariate analysis were performance status (gt;1), no anticancer therapy, low serum albumin, advanced stage, and serum high level of VEGF (gt;324.17 pg/mL), while in the multivariate Cox regression analysis, only the pretreatment serum level of VEGF, stage, and anticancer therapy were identified as independent prognostic factors. CONCLUSIONS: The overexpression of HIF-1α especially in pleural effusion may be an angiogenic factor for distinguishing malignancy from tuberculosis, and the pretreatment level of serum VEGF may be an independent predictor of survival.

Chrysin attenuates allergic airway inflammation by modulating the transcription factors T-bet and GATA-3 in mice.

Chrysin, a flavonoid obtained from various natural sources, has been reported to possess anti-inflammatory, antitumor, antioxidant and anti-allergic activities. However, its anti-inflammatory and immunoregulatory activities in asthma animal models are poorly understood. In the present study, we examined the effects of chrysin on airway inflammation and the possible mechanisms through which it acts in a murine model of allergic asthma. BALB/c mice sensitized and challenged to ovalbumin (OVA) were administered intragastrically with chrysin at a dose of 50 mg/kg daily. Chrysin significantly suppressed OVA-induced airway hyperresponsiveness (AHR) to acetylcholine chloride (Ach). Chrysin administration significantly inhibited the total inflammatory cell and eosinophil counts in bronchoalveolar lavage fluid (BALF) and total immunoglobulin E (IgE) levels in serum. Histological examination of lung tissue demonstrated that chrysin significantly attenuated allergen-induced lung eosinophilic inflammation and mucus-producing goblet cells in the airway. In addition, chrysin triggered a switch of the immune response to allergens towards a T-helper type 1 (Th1) profile by modulating the transcription factors T-bet and GATA-3 in allergic mice. These data suggest that chrysin exhibits anti-inflammatory and immunoregulatory properties and provides new insights into the immunopharmacological role of chrysin in terms of its effects in a murine model of asthma.

Effects of astragaloside IV on eosinophil activation induced by house dust mite allergen.

Astragaloside IV (AS-IV) has been noted for its reduction of eosinophilic airway inflammation in a murine model of chronic asthma. To gain a better understanding of the mechanisms involved in this anti-inflammatory phenomenon, the effect of AS-IV on human blood eosinophils was studied in vitro. Eosinophils were isolated from the blood of patients with mild atopic asthma, preincubated with AS-IV for 1 h and stimulated in the presence or absence of the house dust mite allergen Dermatophagoides pteronyssinus (Der p) 1 for 4 h. The survival of the eosinophils at 48 h was investigated using trypan blue and the surface expression of CC chemokine receptor 3 (CCR3) and intercellular adhesion molecule-1 (ICAM-1) by the eosinophils was analyzed using flow cytometry. The secretion of cytokines in the supernatants and the chemotaxis of the eosinophils were measured by ELISA and the transwell system, respectively. Der p 1 was found to prolong the survival of the eosinophils. Similarly, the expression of CCR3 and ICAM-1, secretion of interleukin (IL)-1ß, IL-5, tumor necrosis factor (TNF)-α and the granulocyte macrophage colony stimulating factor (GM-CSF) and transmigration of the eosinophils were increased in the presence of Der p 1. However, these inductive effects on the eosinophils were significantly inhibited by AS-IV (50 µg/ml). These findings suggest that AS-IV modulates eosinophil activation and trafficking in response to Der p 1 and may therefore be a useful therapeutic option in eosinophilic asthma.

[Effects of astragaloside IV on the expressions of transforming growth factor-ß1 and thymic stromal lymphopoietin in a murine model of asthma].

OBJECTIVE: To observe the effects of astragaloside IV on the airway remodeling and the expressions of transforming growth factor (TGF)-ß1 and thymic stromal lymphopoietin (TSLP) in a murine model of asthma. METHODS: Forty-eight BALB/c mice were randomly divided into 4 groups, i.e. control group, asthma group, astragaloside IV group and budesonide group (n = 12 each). The BALB/c mice sensitized to ovalbumin (OVA) were chronically challenged with aerosolized OVA for 8 weeks while the mice in the astragaloside IV group were intragastrically administered with astragaloside IV (50 mg/kg) daily for 8 consecutive weeks. Pulmonary functions were measured to evaluate the resistance of expiration. And pulmonary histopathological analysis was performed to observe the infiltration of inflammatory cells, the hyperplasia of airway global cells and the deposition of collagen. The levels of interleukin (IL)-4 and IL-13 in bronchoalveolar lavage fluid (BALF) were measured by ELISA (enzyme linked immunosorbent assay). The pulmonary expression of α-SMA (alpha-smooth muscle actin) was evaluated by immunohistochemistry. The mRNA and protein expressions of TGF-ß1 and TSLP were measured by real-time PCR (polymerase chain reaction) and Western blot respectively. RESULTS: The treatment of astragaloside IV or budesonide led to a sharp decrease in airway resistance compared with the asthma group at a concentration of acetylcholine in 30 µg/kg (P < 0.05). The PAS(+) epithelial/bronchial epithelial cells, the area of collagen staining and α-SMA staining area were significantly elevated in the asthma group compared with the control group (all P < 0.01) while those in the astragaloside and budesonide groups were obviously inhibited compared with the asthma group (all P < 0.05). The BALF levels of IL-4 and IL-13 were markedly elevated in the asthma group versus the control group (P < 0.01) while those markedly decreased in the astragaloside and budesonide groups versus the asthma group (all P < 0.05). The relative expressions of TGF-ß1 and TSLP mRNA (5.23 ± 1.44, 5.70 ± 1.65) were significantly up-regulated in the asthma group versus the control group (1.02 ± 0.21, 1.02 ± 0.25) (P < 0.01) while those in the astragaloside (2.27 ± 0.65, 2.97 ± 1.03) and budesonide groups (2.10 ± 0.57, 3.32 ± 1.11) were obviously down-regulated versus the asthma group (all P < 0.05). The protein levels of TGF-ß1 and TSLP in the asthma group (0.89 ± 0.11, 0.74 ± 0.10) were markedly elevated versus the control (0.39 ± 0.04, 0.44 ± 0.05), the astragaloside (0.51 ± 0.08, 0.59 ± 0.12) and the budesonide groups (0.55 ± 0.08, 0.60 ± 0.08) (all P < 0.05). CONCLUSION: Astragaloside IV can suppress the progression of airway inflammation, airway hyperresponsiveness and remodeling in a murine model of asthma. The above effects may be partially due to the inhibited expressions of TGF-ß1 and TSLP.

Paeonol attenuates airway inflammation and hyperresponsiveness in a murine model of ovalbumin-induced asthma.

Paeonol, the main active component isolated from Moutan Cortex, possesses extensive pharmacological activities such as anti-inflammatory, anti-allergic, and immunoregulatory effects. In the present study, we examined the effects of paeonol on airway inflammation and hyperresponsiveness in a mouse model of allergic asthma. BALB/c mice sensitized and challenged with ovalbumin were administered paeonol intragastrically at a dose of 100 mg/kg daily. Paeonol significantly suppressed ovalbumin-induced airway hyperresponsiveness to acetylcholine chloride. Paeonol administration significantly inhibited the total inflammatory cell and eosinophil count in bronchoalveolar lavage fluid. Treatment with paeonol significantly enhanced IFN-γ levels and decreased interleukin-4 and interleukin-13 levels in bronchoalveolar lavage fluid and total immunoglobulin E levels in serum. Histological examination of lung tissue demonstrated that paeonol significantly attenuated allergen-induced lung eosinophilic inflammation and mucus-producing goblet cells in the airway. These data suggest that paeonol exhibits anti-inflammatory activity in allergic mice and may possess new therapeutic potential for the treatment of allergic bronchial asthma.