Table 2.

Summary of EMT-targeting therapy studies in COPD

Therapy	Refs	Study description	Main findings
Inhaled corticosteroids (ICS)	[152]	Phase IIa Randomized Controlled Trial. 34 COPD participants were randomized 2∶1 to fluticasone propionate 500 µg bid or placebo bid for 6 months	Treatment inhibited epithelial activation (EGFR expression), “clefts/fragmentation” in the Rbm, and EMT biomarkers (S100A4 and MMP-9)
	[156]	Nine prospective cohort studies included 181,859 COPD patients	ICS was associated with a decreased risk of lung cancer in patients with COPD
N-acetylcysteine (NAC)	[15]	Rat model. Except for the normal group of Rats in the COPD, the group was administered intratracheally lipopolysaccharide and then exposed to smoke for 30 min a day for 28 days	NAC reduced collagen volume fraction, α-SMA level, wall area/total bronchiole area, and the wall thickness/bronchiole diameter in COPD rat
Phosphodiesterase-4 (PDE4) inhibitors	[161]	Mouse model. Mice in the Bleomycin group were anesthetized and administered intratracheally bleomycin. Mice in the control group received an identical volume of intratracheal saline	Roflumilast reduced bleomycin-induced lung alpha(I)collagen transcripts, fibrosis, and vascular remodeling response in mice
	[162]	Mouse model. Chronic exposure mice were exposed to the smoke of three cigarettes/day for 5 days/week for 7 months. Control mice were exposed to room air	Roflumilast ameliorated cigarette smoke-induced lung inflammation and emphysema
	[163]	In vitro. Isolated HBECs from non-smokers, smokers, and COPD patients	RNO inhibited CSE induced the upregulation of α-SMA, vimentin, and collagen type I, and reversed the downregulation of E-cadherin, ZO-1, and KRT5 in HBEC. Moreover, RNO decreased a-SMA, vimentin, and collagen type I yet increased E-cadherin and ZO-1 in HBECs isolated from smokers and COPD patients
PDE4 inhibitors and statins	[121]	In vitro. Isolated HBEC from human lung tissue of patients undergoing surgery for lung cancer	RNO partly alleviates the CSE-induced EMT in WD-HBEC in vitro, and simvastatin increases the ability of RNO to inhibit CSE-induced EMT
uPA and uPAR	[174, 175]	In vitro. Human small airway epithelial cell lines (HSAEpiCs)	uPA and uPAR inhibition could block CSE-induced EMT by reversing E-cadherin and α-catenin expression and retarding the induction of N-cadherin and vimentin
ADSC-CM	[178]	In vitro. A549 cells	ADSC-CM culture could reverse CSE-induced decreased E-cadherin expression, increased vimentin expression, and accelerated cell migration in A549 cells
Ginsenoside Rg1	[108]	Mouse model and Human bronchial epithelial (HBE) cells line. Rats with COPD were exposed to the smoke of 3 cigarettes/day, 6 times per day, 6 days a week, for 12 weeks. The normal control group was exposed to room air	Ginsenoside Rg1 alleviated CS or CSE-induced EMT via blocking the regulation of α-SMA and E-cadherin expression by CS or CSE