Anti-TIM1 suppresses airway inflammation and hyperresponsiveness via the STAT6 /STAT1 pathways in mice with allergic asthma.

T cell immunoglobulin and mucin domain-1 (TIM-1) is a transmembrane glycoprotein and has been reported as an molecular mechanism of allergic diseases. This study aimed to explore the effects of anti-TIM-1 monoclonal antibodies (anti-TIM1) on the development of allergic asthma. Female C57BL/6 mice were induced and challenged with ovalbumin (OVA) and received subsequent intranasal administration of anti-TIM1. The airway resistance of all mice was evaluated using a Buxco PFT system. Flow cytometry was used to detect the expression of TIM-1 in peripheral blood mononuclear cells. The level of cytokine production in the bronchial alveolar lavage fluid and serum was determined using ELISA. Mucous cells were observed using Alcian blue and periodic acid-Schiff staining. In addition, B-cell lymphoma gene 2(BCL2), T-box transcription factor (T-bet), GATA binding protein-3(GATA3), signal transducer and activator of transcription (STAT) 1, STAT6 were analyzed by western blot analysis. Their corresponding mRNA expression levels were determined by quantitative PCR. The mRNA expression level of Mucin 5AC in the lung tissues was also detected using quantitative RT-PCR. The results showed that the intranasal administration of anti-TIM1 ameliorated airway inflammation and hyperresponsiveness in an acute model of asthma. Following administration of anti-TIM1, both the mRNA and protein levels of T-bet were upregulated, while those of BCL2 and GATA3 were downregulated. Moreover, the phosphorylation levels of STAT1 and STAT6 were increased. Taken together, these findings demonstrated that intranasal administration of anti-TIM1 ameliorated allergic lung inflammation and remodeling in mouse models of asthma by repairing both the STAT1 and STAT6 pathways.

YKL-40 mediates airway remodeling in asthma via activating FAK and MAPK signaling pathway.

YKL-40 is a chitinase-like protein which was significantly elevated in asthma patients and related closely to asthma severity and airway remodeling. Airway remodeling in asthma involves complicated physical and pathological processes, including increased airway smooth muscle mass due to proliferation, migration of airway smooth muscle cells, epithelial-mesenchymal transition (EMT) and sub-epithelial fibrosis. However, the precise effect and underlying mechanism of YKL-40 in this pathological alteration remained unelucidated. In this study, we demonstrated that YKL-40 could promote asthma airway remodeling by increasing airway smooth muscle mass, inducing EMT and sub-epithelial fibrosis. Furthermore, we identified that FAK and MAPK signaling pathways are activated in the process. Inhibiting FAK or MAPK pathway could significantly ameliorate airway remodeling induced by excessive secretion of YKL-40 in vitro. and in vivo. In conclusion, this study shed light upon the effects of YKL-40 in asthma airway remodeling and provided potential novel targets in asthma patients with high YKL-40 level.

YKL-40 induces IL-8 expression from bronchial epithelium via MAPK (JNK and ERK) and NF-κB pathways, causing bronchial smooth muscle proliferation and migration.

Recently, the serum levels of YKL-40, a chitinase-like glycoprotein, have been shown to be significantly elevated in asthmatics and are associated with asthma severity. Although these studies raise the possibility that YKL-40 may influence asthma, the mechanisms remain unknown. This study firstly investigated the mechanisms involved in YKL-40-mediated inflammation in human bronchial epithelial cells (HBECs) and analyzed the soluble factors secreted by bronchial epithelial cells exposed to YKL-40 that were responsible for increasing proliferation and migration of primary normal human bronchial smooth muscle cells (BSMCs). YKL-40-induced inflammation was assayed in two HBECs (BEAS-2B cell line and primary HBECs). In addition, we treated BEAS-2B cells and HBECs with YKL-40 and added the conditioned culture media to BSMCs. The proliferation and migration of BSMCs were determined by premixed WST-1 cell proliferation reagent (Clontech Laboratories) and QCM chemotaxis migration assay (Millipore), respectively. Bronchial epithelial cells treated with YKL-40 resulted in a significant increase of IL-8 production, which was dependent on MAPK (JNK and ERK) and NF-κB pathways activation. YKL-40-induced IL-8 was found to further stimulate proliferation and migration of BSMCs, and the effects were inhibited after neutralizing IL-8. Through investigating the interaction of airway epithelium and smooth muscle, our findings implicate that YKL-40 may be involved in the inflammation of asthma by induction of IL-8 from epithelium, subsequently contributing to BSMC proliferation and migration. Moreover, inhibition of IL-8 signaling is a potential therapeutic target for YKL-40-induced inflammation and remodeling of asthma.

[A randomized trial of docetaxol plus cisplatin versus gemzar plus cisplatin in treating advanced non-small cell lung cancer].

BACKGROUND & OBJECTIVE: Treating advanced non-small cell lung cancer (NSCLC) is difficult. The response rate (RR) of NSCLC patients to traditional chemotherapy regimen is about 40%. Now the RR has been improved with application of new drugs, such as taxol, docetaxal, and gemzar. This randomized trial was designed to determine treatment efficacies of docetaxol plus cisplatin and gemzar plus cisplatin on advanced NSCLC, and observe their cytotoxicities. METHODS: A total of 43 advanced NSCLC patients were randomized into 2 groups, 22 in TP group (docetaxol plus cisplatin) and 21 in GP group (gemzar plus cisplatin), and received relevant treatments. The RR, time to progression (TTP), mean survival time (MST), and 1- and 2-year survival rates of the patients were analyzed. RESULTS: The RR was 45.4% in TP group with 1 case of complete remission (CR) and 9 cases of partial remission (PR), and 42.9% in GP group with 9 cases of PR. The TTP was 4.6 months in TP group, and 4.7 months in GP group; the MST was 10.6 months in TP group [95% confidence interval (CI), 9.3-11.3 months], and 11.3 months in GP group (95% CI, 6.8-14.8 months). The 1- and 2-year survival rates were 38.1% and 15.3% in TP group, and 34.1% and 11.2% in GP group. The differences of RR and survival rate between the 2 groups were not significant (P=0.71, P=0.89). The major cytotoxicity of TP was leukopeniaû the major cytotoxicities of GP group were fatigue and thrombocytopenia. All adverse reactions were tolerable. CONCLUSION: TP and GP regimens may enhance the remission rate of NSCLC patients with tolerable adverse reaction, and improve the short-term survival rate, but the differences in treatment efficacies of TP and GP groups are not significant.

[A study of interferon-gamma induced airway mucous cell apoptosis and its mechanisms].

OBJECTIVE: To investigate the effect of interferon-gamma (IFN-gamma) on airway mucous cells and its mechanisms. METHODS: (1) Normal human bronchial epithelial cells (NHBEs) were cultured under specific conditions, and treated by IFN-gamma for 3 days. The cells were analyzed with fluorescein isothiocyanate (FITC) and terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) assay. (2) Twenty wild type C57BL/6J mice were immunized and divided into 4 groups, and treated with IFN-gamma (50 ng and 100 ng, respectively), interleukin-13 (IL-13, 5 microg) and saline by nostril instillation. The mice were sacrificed and the airway mucous cells were analyzed by morphometry and TUNEL assay. RESULTS: (1) IFN-gamma induced apoptosis in NHBEs, which showed condensed nuclei, nuclear and DNA fragmentaion, and were positive by TUNEL assay. Bax was upregulated and translocated from cell plasma to mitochondria under the treatment. (2) Airway mucous cell account in 100 ng IFN-gamma instillation immunized mice group (28 +/- 6 mucous cells/mm basal lamina) was significantly decreased as compared to that in saline (58 +/- 12) and IL-13 (59 +/- 6) instillation groups (all < 0.05). There was no difference among the IFN-gamma 50 ng (48 +/- 11), saline (58 +/- 12) and IL-13 (59 +/- 6) instillation groups (all P > 0.05). TUNEL assay was also positive in airway mucous cells from IFN-gamma instillation mice as compared to saline instillation mice. CONCLUSIONS: IFN-gamma leads to airway mucous cell apoptosis by Bax upregulating and translocation into mitochondria. This might be of significance in the new therapies of asthma.