TABLE 4.

Strategies for improving the therapeutic efficacy of MSCs in ARDS/ALI preclinical models.

Preconditioning strategy		ARDS/ALI preclinical model	Effects	References
Hypoxia		Endotoxin	↓ Neutrophil influx ↓ TNF-α ↑ IL-10 level	Li et al., 2015
		Bleomycin	↑ Anti-apoptotic factors (HGF and Bcl-2) ↑ Antioxidative factors (catalase and HO-1) ↑ Proangiogenic factors (VEGF)	Lan et al., 2015
Cytokines	IFN-γ	E. coli	↑ Macrophages phagocytosis ↑ Capillary endothelial barrier function	Varkouhi et al., 2019
TLR ligands	TLR4	E. coli	↑ Survival ↓ Lung damage ↑ Bacterial clearance ↓ Influx of inflammatory cells in BALF ↓ MIP-2 in BALF ↓ Total level of protein in BALF	Gupta et al., 2018
	TLR3	E. coli	↑ Bacterial clearance ↑ Phagocytic activity	Monsel et al., 2015
		E. coli	↓ Lung protein permeability	Park et al., 2019
Genetic engineering	CXCR4	Endotoxin	↑ MSC homing to injured lung tissue ↓ Lung protein permeability ↓ TNF-α levels ↑ IL-10 levels ↓ Lung pathology score ↓ Wet/dry ratio ↓ Total protein content in BALF	Yang et al., 2015
	IL-10	E. coli	↓ Infiltrated neutrophils ↑ Phagocytic capacity ↓ Markers of structural lung injury	Jerkic et al., 2019
		HCl	↓ TGF-β1, FN and fibrinogen in BALF ↓ Inflammation scores and Ashcroft scores	Islam et al., 2019
	sST2	Endotoxin	↓ Lung airspace inflammation and vascular leakage ↑ Alveolar architecture	Martinez-Gonzalez et al., 2013
	HGF	I/R	↑ Oxygen saturation ↓ Lung edema	Chen et al., 2017
		HCl	↓ TGF-β1, FN and fibrinogen in BALF ↓ Inflammation scores and Ashcroft scores	Islam et al., 2019
		Radiation	↓ TNF-α, IFN-γ, IL-6 and intercellular adhesion molecule-1 level ↑ IL-10 level ↓ Fibrosis progress	Wang et al., 2013
	Ang-1	Endotoxin	↑ Anti-inflammatory effects ↓ Capillary endothelial barrier function	Mei et al., 2007; Xu et al., 2008
	PGE receptor 2	Endotoxin	↑ MSC homing to injured lung tissue ↓ Alveolar-capillary barrier permeability ↓ TNF-α and IL-1β level	Han et al., 2016
	HO-1	Endotoxin	↑ Survival ↓ Alveolar-capillary barrier permeability ↓ Inflammatory markers ↑ HGF, KGF and IL-10 levels in serum and lungs	Chen et al., 2019
	P130/E2F4	Endotoxin	↑ MSC homing to injured lung tissue ↑ Differentiation into AECs II ↓ Alveolar-capillary barrier permeability	Zhang X. et al., 2019
	microRNA-30b-3p	Endotoxin	↓ Histopathology ↓ Alveolar-capillary barrier permeability ↓ Neutrophil infiltration ↓ MPO activity ↓ Alveolar inflammation	Yi et al., 2019
	miR-22-3p	Endotoxin	↓ Lung inflammation and oxidative stress ↓ Epithelial and endothelial apoptosis	Zheng et al., 2021

AEC, alveolar epithelial cell; ALI, acute lung injury; Ang-1, angiopoetin-1; ARDS, acute respiratory distress syndrome; BALF, bronchoalveolar lavage fluid; Bcl-2, B-cell lymphoma 2; CXCR, CXC chemokine receptor; FN, fibronectin; HGF, hepatocyte growth factor; HO-1, heme oxygenase-1; IFN-γ, interferon gamma; IL, interleukin; KGF, keratinocyte growth factor; MIP-2, macrophage inflammatory protein 2; MPO, myeloperoxidase; MSC, mesenchymal stem cell; PGE, prostaglandin E; sST2, soluble IL-1 receptor-like-1; TGF-β, transforming growth factor β; TLR, toll-like receptor; TNF-α, tumor necrosis factor α; VEGF, vascular endothelial growth factor.