Salidroside inhibits platelet-derived growth factor-induced proliferation and migration of airway smooth muscle cells.

Abnormal proliferation and migration of airway smooth muscle cells (ASMCs) have been found to be important for the airway remodeling during the pathogenesis of asthma. Salidroside a bioactive glucoside that exerts antitumor activity via inhibiting the cell proliferation and migration of cancer cells. The aim of the current study was to evaluate the effects of salidroside on the proliferation and migration of ASMCs. Our results showed that salidroside inhibited the proliferation and migration of ASMCs in response to platelet-derived growth factor (PDGF) stimulation. Salidroside markedly attenuated the PDGF-induced production of matrix metalloproteinase 2 (MMP-2) and MMP-9 in ASMCs. The levels of contractile phenotype markers including smooth muscle α-actin and calponin were reduced in response to PDGF stimulation, which was attenuated by salidroside pretreatment. Salidroside diminished the increase in the expression levels of type I collagen and fibronectin in PDGF-stimulated ASMCs. Furthermore, salidroside blocked the PDGF-induced activation of the nuclear factor-κB (NF-κB) pathway in ASMCs. The results suggested that salidroside functionally regulated the proliferation, migration, phenotype plasticity, and extracellular matrix deposition in PDGF-induced ASMCs and the NF-κB pathway might be implicated in the effects of salidroside on ASMCs induced by PDGF.

Li H ，Yang T ，Wu R ，Chen T ，Sun Z ，Yang L ... -  《-》

ABCA1 inhibits PDGF-induced proliferation and migration of rat airway smooth muscle cell through blocking TLR2/NF-κB/NFATc1 signaling.

Airway remodeling is a key feature of asthma, characterized by abnormal proliferation and migration of airway smooth muscle cells (ASMCs). ABCA1, a member of the ATP-binding cassette family of active transporters, plays an essential role in the progression of lung diseases. However, the contributions of ABCA1 in ASMCs remain to be explored. The purpose of the present study was to investigate the functional role and potential molecular mechanism of ABCA1 in platelet derived growth factor (PDGF)-induced primary rat ASMC proliferation and migration. We observed that PDGF- led to a significant decrease in the expression of ABCA1. Overexpression of ABCA1 strikingly suppressed PDGF-induced ASMC proliferation accompanied by a decrease in the expression of PCAN stimulated by PDGF. Additionally, augmentation of ABCA1 dramatically restrained PDGF-induced migration concomitant with attenuate the accumulation of MMP-2 and MMP-9 in response to PDGF. Furthermore, forced expression of ABCA1 enhanced contractile phenotype markers proteins including α-SMA along with sm-MHC, sm-α-actin, and calponin reduced by PDGF. Meanwhile, introduction of ABCA1 depressed ECM over-deposition induced by PDGF as reflected by a decrease in the expression of ECM protein collagen I and fibronectin. More importantly, addition of ABCA1 effectively suppressed the activity of TLR2/NF-κB signaling as well as diminished the expression of NFATc1 in rat ASMCs after PDGF stimulation. Interestingly, blockage of TLR2/NF-κB signaling effectively inhibited PDGF-induced proliferation and migration, these effects were similar to ABCA1. Taken together, these data implicated that ABCA1 suppressed PDGF-induced proliferation, migration, and contraction in rat ASMCs at least partly through TLR2/NF-κB/NFATc1 signaling, which might offer hope for the future treatment of airway remodeling in asthma.

Cheng W ，Yan K ，Chen Y ，Zhang W ，Ji Z ，Dang C ... -  《-》

Galectin-1 inhibits PDGF-BB-induced proliferation and migration of airway smooth muscle cells through the inactivation of PI3K/Akt signaling pathway.

Childhood asthma is one of the most common chronic childhood diseases. Platelet-derived growth factor BB (PDGF-BB) induced airway smooth muscle cell (ASMC) proliferation and migration are involved in the pathogenesis of asthma. Galectin-1 (Gal-1) is a glycan-binding protein that has been found to be involved in the progression of asthma. However, the mechanism remains unclear. In the current study, we aimed to evaluate the role of Gal-1 in regulating the phenotype switching of ASMCs, which is an important mechanism in the pathogenesis of asthma. Our results showed that Gal-1 was markedly down-regulated in the samples from asthma patients. In vitro study also proved that Gal-1 expression was decreased in PDGF-BB-stimulated ASMCs. In addition, Gal-1 overexpression significantly inhibited PDGF-BB-induced ASMCs proliferation and migration, while Gal-1 knockdown exhibits opposite effects of Gal-1 overexpression. The PDGF-BB-caused reductions in expressions of α-smooth muscle actin (α-SMA), specific muscle myosin heavy chain (SM-MHC), and calponin were elevated by Gal-1 overexpression, but were deteriorated by Gal-1 knockdown in ASMCs. Furthermore, overexpression of Gal-1 inhibited PDGF-BB-stimulated PI3K/Akt activation in ASMCs. Notably, treatment with IGF-1, an activator of PI3K, reversed the effects of Gal-1 on ASMCs proliferation, migration, and phenotype switching. In conclusion, these findings showed that Gal-1 exerted inhibitory effects on PDGF-BB-stimulated proliferation, migration, and phenotype switching of ASMCs via inhibiting the PI3K/Akt signaling pathway. Thus, Gal-1 might be a promising target for the treatment of asthma.

Pang X ，Qiao J 《-》

Esculetin regulates the phenotype switching of airway smooth muscle cells.

Airway remodeling is one important feature of childhood asthma, which is one of the most common chronic childhood diseases. Phenotype switching of airway smooth muscle cells (ASMCs), defined as a reversible switching between contractile and proliferative phenotypes, plays an important role in the process of airway remodeling. Esculetin has shown antiinflammatory action in animal models of asthma; however, the effects of esculetin on ASMC phenotype switching have not been investigated. In the present study, platelet-derived growth factor (PDGF) was used to induce the phenotype modulation of ASMCs. The results demonstrated that esculetin pretreatment mitigated the PDGF-caused inhibitory effects on expressions of contractile phenotype protein markers, including calponin and SM22α. Esculetin also inhibited PDGF-induced migration and proliferation of ASMCs. Besides, the PDGF-induced expressions of extracellular matrix components, collagen I and fibronectin, were attenuated by esculetin pretreatment. Furthermore, PDGF-caused activation of PI3K/Akt pathway in ASMCs was inhibited by esculetin. These findings suggest that esculetin might exert its inhibitory effect on PDGF-induced ASMC phenotype switching through inhibition of PI3K/Akt pathway.

Xie C ，Li Y ，Gao J ，Wang Y ... -  《-》

Shikonin alleviates allergic airway remodeling by inhibiting the ERK-NF-κB signaling pathway.

Shikonin is a naphthoquinone extracted from the root of Lithospermum erythrorhizon, and has been reported to suppress allergic airway inflammation in mice. However, the underlying mechanisms are unclear and need to be further elucidated. In this study, shikonin (0.5, 2 or 4mg/kg) was given intraperitoneally to ovalbumin (OVA)-challenged BALB/c mice. We found that the pathological airway remodeling of asthmatic mice was alleviated by shikonin, and the infiltrated inflammatory cells and collagen deposition in their lungs were reduced. Furthermore, the abnormal activation of extracellular signal-regulated kinase (ERK)/nuclear factor-κB (NF-κB) pathway and the elevation of matrix metalloproteinase 9 (MMP9) in the lung of asthmatic mice were suppressed by shikonin. The inactivation of NF-κB by shikonin was at least in part via inhibiting IκBα activation. In vitro, the treatment of shikonin inhibited the platelet-derived growth factor (PDGF)-induced proliferation of primary airway smooth muscle cells (ASMCs), and induced a G0/G1 arrest in these cells. In addition, ASMCs exposed to PDGF acquired an enhanced migratory ability, and the activities of MMP9 and matrix metalloproteinase 2 (MMP2) and expression of MMP9 of these cells were significantly up-regulated. These PDGF-induced alterations were also inhibited by shikonin. The inhibitory effects of shikonin on the proliferation and migration of ASMCs were comparable to pyrrolidinedithiocarbamate (PDTC), an inhibitor of NF-κB pathway. In conclusion, the present study sheds lights on how shikonin alleviates allergic airway remodeling.

Wang TY ，Zhou QL ，Li M ，Shang YX ... -  《-》