What is the central question of this study? Airway angiogenesis occurs in asthma, and airway smooth muscle (ASM) cells have been reported to be capable of promoting airway angiogenesis. What is the potential mechanism by which ASM cells harvested from patients with asthma are capable of promoting airway angiogenesis? What is the main finding and its importance? Endogenous STAT3 mediated the pro-angiogenic ability of ASM cells by directly activating VEGF signalling. These findings contribute to the understanding of airway angiogenesis in pathology and could represent a possible therapeutic target for asthma. Airway angiogenesis indicates the specific vascular structure remodelling that occurs in asthma. Airway smooth muscle (ASM) cells have been reported to be capable of promoting airway angiogenesis; however, the potential mechanism is not yet fully defined. Herein, we investigated the role of signal transducer and activator of transcription 3 (STAT3) in the progress of airway angiogenesis. Western blot analysis showed that STAT3 activation was aberrantly upregulated in ASM tissues of patients with asthma and ASM cells that were exposed to cytokines to imitate the airway conditions in patients with asthma. Compared with the control group, both the inhibition of STAT3 activation and the silencing of endogenous STAT3 in ASM cells significantly reduced the proliferation, migration and tube-forming ability of human lung microvascular endothelial cells induced by the conditioned medium (CM) of ASM cells. The increased proliferation and migration of human aortic vascular smooth muscle cells were also repressed by inhibition of STAT3 in ASM cells. Besides, the increased activity of VEGF signalling was observed in ASM cells and the CM by RT-PCR and Western blotting assay, whereas this increased activity was reduced by STAT3 silencing. Further studies indicated that STAT3 regulated VEGF activation by directly interacting with the binding site on the 5' region of the VEGF gene. The increase in STAT3-induced pro-angiogenic activity of ASM cells was significantly decreased by administration of VEGF neutralizing antibody. In conclusion, we provided evidence that endogenous STAT3 mediates the pro-angiogenic ability of ASM cells by directly activating VEGF signalling, which could represent a possible therapeutic target for asthma.
Chronic obstructive pulmonary disease (COPD) is a chronic airway inflammation and its exacerbation is often accompanied by Aspergillus fumigatus (A. fumigatus) infection. Increasing evidences demonstrated the potent antioxidant and -inflammatory effects of crocin. However, the role of crocin in A. fumigatus-induced inflammation is still unknown. We aimed to evaluate the role of crocin in inflammation response induced by A. fumigatus in human bronchial epithelial cells and the possible mechanisms. BEAS-2B and NHBE cells were pretreated with crocin for 24 h, and then A. fumigatus conidia were added for 24 h. A. fumigatus treatment exhibited a significant higher TNF-α, IL-8, IL-6, and IL-1β level (P < 0.05), whereas crocin pretreatment significantly inhibited A. fumigatus induced the pro-inflammatory cytokines (P < 0.05). NF-κB inhibitor PDTC inhibited pro-inflammatory cytokines release triggered by A. fumigatus (P < 0.05). Furthermore, crocin suppressed A. fumigatus induced NF-κB p65 nuclear translocation, the phosphorylation of IKKα and IκBα, the degradation of IκBα and NF-κB reporter activity. Crocin pretreatment also resulted in an inhibition of A.fumigatus-induced ROS production (P < 0.05). Taken together, these results indicate that crocin may prevent A. fumigatus-induced inflammation through suppressing NF-κB signal pathway.
Claudin-1 (CLDN-1) is one of main tight junction components that play an important role in epithelial-mesenchymal transition (EMT). However, the effects of CLDN-1 on the migration and EMT induced by TGF-β1 in primary normal human bronchial epithelial (NHBE) and BEAS-2B cells have not been clear. The expression of CLDN-1 was quantified by Western blotting in NHBE and BEAS-2B cells. Cell migration and invasion were detected using transwell assays. The expression level of E-cadherin, N-cadherin, α-SMA, and Vimentin was evaluated by quantitative real-time PCR and Western blotting. Here we showed that the protein expression of CLDN-1 was increased exposed to TGF-β1 in a dose- and time-dependent manner. Knockdown of CLDN-1 using small interfering CLDN-1 RNA (siCLDN-1) prevented the migration and invasion in NHBE and BEAS-2B cells. Moreover, depletion of CLDN-1 promoted the E-cadherin expression and decreased the mRNA and protein levels of N-cadherin, α-SMA, and Vimentin induced by TGF-β1. Furthermore, CLDN-1 silencing resulted in the reduction of the Notch intracellular domain (NICD) and hairy enhancer of split-1 (Hes-1) in mRNA and protein level. Jagged-1, an activator of Notch signaling pathway, abrogated the protective function of siCLDN-1 in migration and EMT. In conclusion, CLDN-1 promoted the migration and EMT through the Notch signaling pathway.
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