Abstract
The role of the epithelial–mesenchymal transition (EMT) in lung epithelial cells is increasingly being recognized as a key stage in the development of COPD, fibrosis, and lung cancers, which are all highly associated with cigarette smoking and with exposure to second-hand smoke. Using the exposure of human lung cancer epithelial A549 cells and non-cancerous Beas-2B cells to sidestream cigarette smoke extract (CSE) as a model, we studied the protective effects of adipose-derived stem cell-conditioned medium (ADSC-CM) against CSE-induced cell death and EMT. CSE dose-dependently induced cell death, decreased epithelial markers, and increased the expression of mesenchymal markers. Upstream regulator analysis of differentially expressed genes after CSE exposure revealed similar pathways as those observed in typical EMT induced by TGF-β1. CSE-induced cell death was clearly attenuated by ADSC-CM but not by other control media, such as a pass-through fraction of ADSC-CM or A549-CM. ADSC-CM effectively inhibited CSE-induced EMT and was able to reverse the gradual loss of epithelial marker expression associated with TGF-β1 treatment. CSE or TGF-β1 enhanced the speed of A549 migration by 2- to 3-fold, and ADSC-CM was effective in blocking the cell migration induced by either agent. Future work will build on the results of this in vitro study by defining the molecular mechanisms through which ADSC-CM protects lung epithelial cells from EMT induced by toxicants in second-hand smoke.
Highlights
Cigarette smoking is a major risk factor for many lung diseases, including chronic obstructive pulmonary disease (COPD), asthma, fibrotic diseases, and lung cancers [1,2,3].Cigarette smoke extract (CSE), with more than 4000 chemical constituents, is known to cause cell injury, apoptosis, inflammation, and cancer [4,5,6,7,8,9,10,11]
By comparing the results with typical epithelial-tomesenchymal transition (EMT) induced by TGF-β1, we identified signaling pathways that are uniquely induced by CSE and pathways that are involved in TGF-β1 stimulation
Since the roles of TGF-β1 in EMT and the development of COPD and lung cancers have already been discussed previously, we focused on pathways that were activated or inhibited by CSE but that were unchanged by TGF-β1
Summary
Cigarette smoking is a major risk factor for many lung diseases, including chronic obstructive pulmonary disease (COPD), asthma, fibrotic diseases, and lung cancers [1,2,3].Cigarette smoke extract (CSE), with more than 4000 chemical constituents, is known to cause cell injury, apoptosis, inflammation, and cancer [4,5,6,7,8,9,10,11]. EMT has been identified as a key pathological transformation of lung epithelial cells that contributes to the development of COPD, lung fibrosis, and lung cancer [13,14,15,16,17]. Studies have demonstrated that mesenchymal markers, such as vimentin, α-SMA, and S100A4, were increased in the airways of COPD patients and active smokers [18,19]. Among the pathways that have been identified to be involved in EMT, the activation of the TGF-β family and the Wnt/β-catenin signaling pathways have been implicated in EMT associated with COPD or with exposure to CSE collected from mainstream cigarette smoke [16,18,23,26,27]
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