TABLE 2.

Completed preclinical and clinical trials of mesenchymal stromal cells (MSCs) or MSC-EV treatments in Influenza-associated acute respiratory distress syndrome (ARDS)

	Model disease	Study	MSC			Dose	Frequency	Route	Results	Outcome
Preclinical trial	H1N1	Darwish et al.16	BM-MSC			5 × 105 cells	Once	i.v.	Failed to improve survival, decrease pulmonary inflammation/inflammatory cell counts or prevent acute lung injury (ALI) in influenza virus-infected mice	MSCs failed to improve survival rate in experimental severe influenza
	H1N1	Gotts et al.76	BM-MSC			5 × 105 cells	Once	i.v.	Biologically active MSCs were delivered to the lungs and reduce lung viral load, but MSCs did not improve influenza-induced lung injury	Influenza caused lung injury unresponsive to MSCs in mice
	H1N1	Khatri et al.75	BM-MSC-EV			79 ± 1 μg/100 μl EVs	Once	i.v.	Inhibit HA activity of influenza viruses, virus replication and virus-induced apoptosis, inflammatory cytokines and ALI	MSC-EVs alleviated influenza virus-induced lung lesions in pigs
	H5N1	Chan et al.73	BM-MSC			5 × 105 cells	Once	i.v.	Reduced AFC, proinflammatory cytokine secretion and enhances APP in human alveolar epithelial cells, sodium and chloride transporter protein expression, restore lung injury through angiopoietin 1 (Ang-1) and keratinocyte growth factor (KGF) production	MSCs reduced H5N1-associated ALI injury in mice
	H5N1	Loy et al.74	UC-MSC			5 × 105 cells	Once	i.v.	Reduced H5N1-induced down-regulation of ion transporters, lung proinflammatory responses; restore H5N1-impaired AFC and APP partially through Ang-1 and HGF secretion	UC-MSCs were effective in restoring H5N1-associated ALI than BM-MSCs
	H9N2	Li et al.72	BM-MSC	1 × 105 cells			Once	i.v.	Decreased dry weight ratios, airspace inflammation, ERK and JNK, and expression the chemokine concentration (GM-CSF, MCP-1, KC, MIP-1α, and MIG), PaCO2; improve survival rate, lung histopathology, PaO2, SaO2, PH	MSCs prevented H9N2 avian influenza virus-induced ALI in mice
Clinical trial	H7N9	Chen et al.77	MB-MSCs			1 ×106/kg	4 times	i.v.	Down-regulated the productions of PCT, plasma C reactive protein (CRP), serum creatinine, creatine kinase (CK), prothrombin time (PT), and D-dimer	MSCs improved the survival rate of H7N9-induced ARDS