[Therapeutic effects of Bacille Calmette-Guerin vaccine on asthma airway remodeling in rats and its mechanism].

OBJECTIVE: To explore the therapeutic effects and mechanism of Bacillus Calmette-Guerin (BCG) vaccine on airway remodeling in rats. METHODS: Forty male Wistar rats were randomly divided into 5 groups of control, asthma,BCG vaccine, dexamethasone and BCG vaccine plus dexamethasone (n = 8 each). The animals were then sensitized and challenged by ovalbum in to establish the asthmatic model. A subcutaneous injection of BCG vaccine 0.025 mg was administered for the BCG vaccine group and an intraperitoneal injection of dexamethasone 0.5 mg/kg for the dexamethasone group.In BCG vaccine plus dexamethasone group, the rats received a subcutaneous injection of BCG vaccine (0.025 mg) plus an intraperitoneal injection of dexamethasone (0.25 mg/kg). All treatments were offered at half an hour pre-atomization. The control rats received an aerosol inhalation of normal saline instead of ovalbum. The parameters of airway morphological changes and the degree of airway remodeling were analyzed with computer graphics. The levels of transforming growth factor beta 1 (TGF-ß1) in bronchoalveolar lavage fluid (BALF) and the expressions of E-cadherin, α-smooth muscle actin (α-SMA) and fibronectin in lung tissue and sera were detected. RESULTS: In asthmatic rats, the thickness of airway wall and smooth muscle were more significant than those of the control group ((95.01 ± 0.48), (43.86 ± 0.51) vs (25.96 ± 0.42), (15.14 ± 0.18) µm). Compared with the control group, the levels of TGF-ß1 in BALF and sera were significantly higher ((10.05 ± 0.26), (75.67 ± 1.17) vs (1.53 ± 0.18), (22.24 ± 0.35) µg/L), the expression of E-cadherin significantly decreased (0.26 ± 0.03 vs 0.45 ± 0.04), while α-SMA and fibronectin significantly increased (0.54 ± 0.06,0.56 ± 0.06 vs 0.32 ± 0.04, 0.35 ± 0.06) (all P < 0.01); Notably, compared with the asthmatic group, the thickness of airway wall and smooth muscle ((58.46 ± 2.43),(49.51 ± 1.44), (49.63 ± 1.42) and (25.84 ± 0.54), (25.44 ± 0.40), (25.62 ± 1.17) µm) significantly decreased by the treatments of BCG vaccine, dexamethasone or BCG vaccine plus dexamethasone, the levels of TGF-ß1 in BALF and sera ((3.42 ± 0.18), (3.27 ± 0.34), (3.39 ± 0.26) and (37.61 ± 0.22), (35.65 ± 0.49), (36.22 ± 0.71) µg/L) significantly decreased, the expressions of E-cadherin (0.29 ± 0.04, 0.32 ± 0.04, 0.31 ± 0.03) significantly increased and α-SMA and fibronectin (0.40 ± 0.06, 0.35 ± 0.06, 0.40 ± 0.05 and 0.47 ± 0.03, 0.43 ± 0.06, 0.47 ± 0.04) significantly declined (all P < 0.01). Western blot showed the similar results. CONCLUSIONS: BCG vaccine alleviates airway epithelial cell injury and epithelial mesenchymal transition induced by TGF-ß1 through immunoregulation. It also reduces asthmatic airway remodeling with a combination of dexamethasone.

Baicalin inhibits PDGF-induced proliferation and migration of airway smooth muscle cells.

Airway smooth muscle (ASM) cell proliferation and migration play important roles in airway remodeling in asthma. In vitro platelet-derived growth factor (PDGF) induced ASM cell proliferation and migration. Baicalin is one of flavonoid extracts from Scutellaria baicalensis, which has an anti-asthma effect. However, little is known about its role in PDGF-induced proliferation and migration in rat ASM (RASM) cells. In this study, we aimed to investigate the effects of baicalin on PDGF-induced RASM cell proliferation and migration. We also identified the signaling pathway by which baicalin influences RASM cell proliferation and migration. In the current study, we demonstrated that baicalin suppressed PDGF-induced RASM cell proliferation, arrested PDGF-induced cell-cycle progression. It also suppressed PDGF-induced RASM cell migration. Furthermore, baicalin suppressed PDGF-induced expression of phosphorylated p38, ERK1/2 and JNK in RASM cells. In summary, our study is the first to show that baicalin pretreatment can significantly inhibit PDGF-induced RASM cell proliferation and migration by suppressing the MAPK signaling pathway, and baicalin may be a useful chemotherapeutic agent for asthma.

Inhibition of allergic airway inflammation by antisense-induced blockade of STAT6 expression.

BACKGROUND: The signal transducer and activator of transcription 6 (STAT6) expression in lung epithelial cells plays a pivotal role in asthma pathogenesis. Activation of STAT6 expression results in T helper cell type 2 (Th2) cell differentiation leading to Th2-mediated IgE production, development of allergic airway inflammation and hyperreactivity. Therefore, antagonizing the expression and/or the function of STAT6 could be used as a mode of therapy for allergic airway inflammation. METHODS: In this study, we synthesized a 20-mer phosphorothioate antisense oligonucleotide (ASODN) overlapping the translation starting site of STAT6 and constructed STAT6 antisense RNA (pANTI-STAT6), then transfected them into murine spleen lymphocytes and analyzed the effects of antagonizing STAT6 function in vitro and in a murine model of asthma. RESULTS: In vitro, we showed suppression of STAT6 expression and interleukin (IL)-4 production of lymphocytes by STAT6 ASODN. This effect was more prominent when cells were cultured with pANTI-STAT6. In a murine model of asthma associated with allergic pulmonary inflammation in ovalbumin (OVA)-sensitized mice, local intranasal administration of fluorescein isothiocyanate (FITC)-labeled STAT6 ASODN to DNA uptake in lung cells was accompanied by a reduction of intracellular STAT6 expression. Such intrapulmonary blockade of STAT6 expression abrogated signs of lung inflammation, infiltration of eosinophils and Th2 cytokine production. CONCLUSION: These data suggest a critical role of STAT6 in the pathogenesis of asthma and the use of local delivery of STAT6 ASODN as a novel approach for the treatment of allergic airway inflammation such as in asthma.