Galangin attenuates airway remodelling by inhibiting TGF-β1-mediated ROS generation and MAPK/Akt phosphorylation in asthma.
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ABSTRACT:
SUBMITTER: Liu YN
PROVIDER: S-EPMC4496730 | biostudies-other | 2015
REPOSITORIES: biostudies-other
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Project description:BackgroundThe ischemia-reperfusion (IR) environment during deep hypothermic circulatory arrest (DHCA) cardiovascular surgery is a major cause of acute kidney injury (AKI), which lacks preventive measure and treatment. It was reported that cold inducible RNA-binding protein (CIRP) can be induced under hypoxic and hypothermic stress and may have a protective effect on multiple organs. The purpose of this study was to investigate whether CIRP could exert renoprotective effect during hypothermic IR and the potential mechanisms.MethodsUtilizing RNA-sequencing, we compared the differences in gene expression between Cirp knockout rats and wild-type rats after DHCA and screened the possible mechanisms. Then, we established the hypothermic oxygen-glucose deprivation (OGD) model using HK-2 cells transfected with siRNA to verify the downstream pathways and explore potential pharmacological approach. The effects of CIRP and enarodustat (JTZ-951) on renal IR injury (IRI) were investigated in vivo and in vitro using multiple levels of pathological and molecular biological experiments.ResultsWe discovered that Cirp knockout significantly upregulated rat Phd3 expression, which is the key regulator of HIF-1α, thereby inhibiting HIF-1α after DHCA. In addition, deletion of Cirp in rat model promoted apoptosis and aggravated renal injury by reactive oxygen species (ROS) accumulation and significant activation of the TGF-β1/p38 MAPK inflammatory pathway. Then, based on the HK-2 cell model of hypothermic OGD, we found that CIRP silencing significantly stimulated the expression of the TGF-β1/p38 MAPK inflammatory pathway by activating the PHD3/HIF-1α axis, and induced more severe apoptosis through the mitochondrial cytochrome c-Apaf-1-caspase 9 and FADD-caspase 8 death receptor pathways compared with untransfected cells. However, silencing PHD3 remarkably activated the expression of HIF-1α and alleviated the apoptosis of HK-2 cells in hypothermic OGD. On this basis, by pretreating HK-2 and rats with enarodustat, a novel HIF-1α stabilizer, we found that enarodustat significantly mitigated renal cellular apoptosis under hypothermic IR and reversed the aggravated IRI induced by CIRP defect, both in vitro and in vivo.ConclusionOur findings indicated that CIRP may confer renoprotection against hypothermic IRI by suppressing PHD3/HIF-1α-mediated apoptosis. PHD3 inhibitors and HIF-1α stabilizers may have clinical value in renal IRI.
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Project description:Switching of airway smooth muscle (ASM) cell phenotype from differentiated-contractile to dedifferentiated-proliferative/synthetic state often occurs in asthmatic subjects with airway dysfunction. Evidence has been provided that chloroquine (an agonist of bitter taste receptors) presented benefits to ASM cell function implicated in asthma. However, the underlying mechanism is unclear. House dust mite (HDM)-sensitized mice were administered with chloroquine or dexamethasone before challenge. BALF and lung tissue were obtained for cell counting, histological analysis or ELISA. Primary cultured ASM cells were stimulated with transforming growth factor (TGF)-β1 or H2O2. Cells and supernatant were collected for the detection of ASM phenotype, ROS level, and proinflammatory cytokine production. In HDM-sensitized mice, chloroquine attenuated airway hyperresponsiveness (AHR), inflammation and remodeling with an inhibition of immunoglobulin E, IL-4/-13, and TGF-β1 in BALF. ASM cell proliferation (PCNA), hypertrophy (α-SMA), and parasecretion (MMP-9 and MMP-13) were strongly suppressed by chloroquine, hinting the rebalance of the heterogeneous ASM populations in asthmatic airway. Our data in vitro indicated that chloroquine markedly restrained maladaptive alteration in ASM phenotype in concert with a remission of ROS. Using H2O2 and PI3K inhibitor (LY294002), we found that the inhibition of oxidative stress level and ROS-AKT signal by chloroquine may serve as a potential mechanism that dedicates to the restoration of the phenotypic imbalance in ASM cells. Overall, the present findings suggested that chloroquine improves asthmatic airway function by controlling ASM cell phenotype shift, sketching a novel profile of chloroquine as a new therapeutic candidate for airway remodeling.
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Project description:BackgroundAirway remodelling is the major pathological feature of chronic obstructive pulmonary disease (COPD), and leads to poorly reversible airway obstruction. Current pharmacological interventions are ineffective in controlling airway remodelling. In the present study, we investigated the potential role of artesunate in preventing and treating airway remodelling and the underlying molecular mechanisms in vitro and in vivo.MethodsA COPD rat model was established by cigarette smoke (CS) exposure. After 12 weeks of artesunate treatment, pathological changes in the lung tissues of COPD rats were examined by ELISA and histochemical and immunohistochemical staining. A lung functional experiment was also carried out to elucidate the effects of artesunate. Human bronchial smooth muscle (HBSM) cells were used to clarify the underlying molecular mechanisms.ResultsArtesunate treatment inhibited CS-induced airway inflammation and oxidative stress in a dose-dependent manner and significantly reduced airway remodelling by inhibiting α-smooth muscle actin (α-SMA) and cyclin D1 expression. PPAR-γ was upregulated and TGF-β1/Smad2/3 signalling was inactivated by artesunate treatment in vivo and in vitro. Furthermore, PPAR-γ knockdown by siRNA transfection abolished artesunate-mediated inhibition of HBSM cell proliferation by activiting the TGF-β1/Smad2/3 signalling pathway and downregulating the expression of α-SMA and cyclin D1 in HBSM cells.ConclusionsThese findings suggest that artesunate could be used to treat airway remodelling by regulating PPAR-γ/TGF-β1/Smad signalling in the context of COPD.
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Project description:The anti-inflammatory effects of glycyrrhizic acid (GA) against asthma have previously been reported; however, the underlying molecular mechanism of GA in asthma has not yet been elucidated. Thus, the present study aimed to determine the function and potential molecular mechanism of GA for modulating the transforming growth factor-β1 (TGF-β1)/Smad signaling pathway in asthma-associated airway inflammation and remodeling. In order to study the mechanism of GA on airway inflammation and airway remodeling in asthmatic mice, a mouse model of chronic asthma was constructed. A total of 50 female mice were randomly assigned into five groups (10 mice/group), as follows: Blank group, asthma group, GA group, dexamethasone group and GA + TGF-β1 group. Hematoxylin and eosin, and Masson staining were performed to assess the airway inflammation and remodeling in mice with ovalbumin (OVA)-induced asthma. The serum levels of interleukin (IL)-4, IL-5, IL-13 and IL-17 in mice were assessed via the enzyme-linked immunosorbent assay. Reverse transcription-quantitative PCR and western blot analyses were performed to detect the levels of TGF-β1 and Smads in lung tissues of each group of mice. The results demonstrated that GA and dexamethasone treatment mitigated airway inflammation, inflammatory cell infiltration and airway remolding, with a concomitant decrease in the expression levels of IL-4, IL-5, IL-13 and IL-17, in mice with OVA-induced asthma. In addition, the levels of TGF-β1 and Smad2 notably decreased, while Smad7 expression increased in the GA and dexamethasone groups compared with the asthma group. Furthermore, histopathological morphometry exhibited significantly elevated inflammatory cell infiltration, airway wall and smooth muscle, collagen secretion and inflammatory cytokines in the serum of mice in the GA + TGF-β1 group compared with the GA group. Taken together, the results of the present study suggest that GA ameliorates airway inflammation and remodeling via the TGF-β1/Smad signaling pathway in mice with asthma.
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Project description:BackgroundTGF-β1 can induce epithelial-mesenchymal transition (EMT) in primary airway epithelial cells (AECs). Semaphorin7A (Sema7a) plays a crucial role in regulating immune responses and initiating and maintaining transforming growth factor β1 TGF-β1-induced fibrosis.ObjectiveTo determine the expression of Sema7a, in serum isolated from asthmatics and non-asthmatics, the role of Sema7a in TGF-β1 induced proliferation, migration and airway EMT in human bronchial epithelial cells (HBECs) in vitro.MethodsThe concentrations of Sema7a in serum of asthmatic patients was detected by enzyme-linked immunosorbent assay (ELISA). The expressions of Sema7a and integrin-β1 were examined using conventional western blotting and real-time quantitative PCR (RT-PCR). Interaction between the Sema7a and Integrin-β1 was detected using the Integrin-β1 blocking antibody (GLPG0187). The changes in EMT indicators were performed by western blotting and immunofluorescence, as well as the expression levels of phosphorylated Focal-adhesion kinase (FAK) and Extracellular-signal-regulated kinase1/2 (ERK1/2) were analyzed by western blot and their mRNA expression was determined by RT-PCR.ResultsWe described the first differentially expressed protein of sema7a, in patients with diagnosed bronchial asthma were significantly higher than those of healthy persons (P<0.05). Western blotting and RT-PCR showed that Sema7a and Integrin-β1 expression were significantly increased in lung tissue from the ovalbumin (OVA)-induced asthma model. GLPG0187 inhibited TGF-β1-mediated HBECs EMT, proliferation and migration, which was associated with Focal-adhesion kinase (FAK) and Extracellular-signal-regulated kinase1/2 (ERK1/2) phosphorylation.ConclusionSema7a may play an important role in asthma airway remodeling by inducing EMT. Therefore, new therapeutic approaches for the treatment of chronic asthma, could be aided by the development of agents that target the Sema7a.
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Project description:Background and purpose: Fengshi Gutong capsule (FSGTC), a traditional herbal formula, has been used clinically in China for the treatment of arthritis. However, the mechanism underlying the therapeutic effects of FSGTC on osteoarthritis (OA) has not been elucidated. The present study investigated the function and mechanisms of FSGTC in rat OA model and interleukin (IL)-1β-stimulated synovial cells. Materials and methods: Rat OA model was established by intra-articular injection containing 4% papain. IL-1β-induced SW982 cells were used as an OA cell model. Safranin-O-Fast green (S-O) and hematoxylin-eosin (HE) stainings were used to observe the changes in cartilage morphology. Enzyme-linked immunosorbent assay (ELISA) and real-time quantitative PCR (qPCR) detected the expression of inflammatory cytokines. In addition, molecular mechanisms were analyzed by Western blot in the OA cell model. Results: FSGTC treatment significantly relieved the degeneration of cartilage and reduced the contents of tumor necrosis factor-α (TNF-α) and IL-6 in the serum in papain-induced OA rats. FSGTC also reduced the protein and mRNA levels of IL-6 and IL-8 in IL-1β-stimulated SW982 cells. Moreover, it inhibited the phosphorylation levels of ERK (extracellular signal-related kinase), JNK (c-Jun N-terminal kinase), p38, Akt (protein kinase B), and c-Jun. It also decreased the extent of IκBα degradation and p65 protein translocation into the nucleus. Conclusion: The current data confirmed the protective effects of FSGTC in the rat and OA cell models. The results suggested that FSGTC reduced the production of inflammatory mediators via restraining the activation of mitogen-activated protein kinases (MAPK), nuclear factor kappa B (NF-κB), activator protein-1 (AP-1), and Akt.
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Project description:Eosinophilia is a marker of corticosteroid responsiveness and risk of exacerbation in asthma; although it has been linked to submucosal matrix deposition, its relationship with other features of airway remodelling is less clear.The aim of this study was to investigate the relationship between airway eosinophilia and airway remodelling.Bronchial biopsies from subjects (n = 20 in each group) with mild steroid-naïve asthma, with either low (0-0.45 mm(-2)) ) or high submucosal eosinophil (23.43-46.28 mm(-2) ) counts and healthy controls were assessed for in vivo epithelial damage (using epidermal growth factor receptor staining), mucin expression, airway smooth muscle (ASM) hypertrophy and inflammatory cells within ASM.The proportion of in vivo damaged epithelium was significantly greater (P = 0.02) in the high-eosinophil (27.37%) than the low-eosinophil (4.14%) group. Mucin expression and goblet cell numbers were similar in the two eosinophil groups; however, MUC-2 expression was increased (P = 0.002) in the high-eosinophil group compared with controls. The proportion of submucosa occupied by ASM was higher in both asthma groups (P = 0.021 and P = 0.046) compared with controls. In the ASM, eosinophil and T-lymphocyte numbers were higher (P < 0.05) in the high-eosinophil group than both the low-eosinophil group and the controls, whereas the numbers of mast cells were increased in the high-eosinophil group (P = 0.01) compared with controls.Submucosal eosinophilia is a marker (and possibly a cause) of epithelial damage and is related to infiltration of ASM with eosinophils and T lymphocytes, but is unrelated to mucus metaplasia or smooth muscle hypertrophy.
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