Mesenchymal stem cell transplantation for severe acute pancreatitis-associated lung injury: A meta-analysis of animal studies

Table 1 Search strategies for an English database (PubMed) and a Chinese database (CNKI)

	ID: Query
Search strategy for PubMed	#1 “Pancreatitis”[Mesh]
	#2 ((((((((Edematous Pancreatitis, Acute) OR (Acute Edematous Pancreatitis)) OR (Edematous Pancreatitis, Acute)) OR (Pancreatic Parenchymal Edema)) OR (Acute Pancreatitis)) OR (Peripancreatic Fat Necrosis)) OR (Parenchymal Edema, Pancreatic)) OR (Necrosis, Peripancreatic Fat)) OR (Pancreatitis, Acute)
	#3 “Pancreatitis, Acute Necrotizing”[Mesh]
	#4 ((((((Necrotizing Pancreatitis, Acute) OR (Pancreatitis Necrotising)) OR (Acute Necrotizing Pancreatitis)) OR (Pancreatic Necrosis)) OR (Hemorrhagic Necrotic Pancreatitis)) OR (Necrotic Pancreatitis, Hemorrhagic)) OR (Pancreatitis, Hemorrhagic Necrotic)
	#5 #1 OR #2 OR #3 OR #4
	#6 “Stem Cells”[Mesh]
	#7 ((((((((((((((Cell, Stem) OR (Cells, Stem)) OR (Stem Cell)) OR (Progenitor Cells)) OR (Cell, Progenitor)) OR (Cells, Progenitor)) OR (Progenitor Cell)) OR (Mother Cells)) OR (Cell, Mother)) OR (Cells, Mother)) OR (Mother Cell)) OR (Colony-Forming Unit)) OR (Colony Forming Unit)) OR (Colony-Forming Units)) OR (Colony Forming Units)
	#8 “Mesenchymal Stem Cells”[Mesh]
	#9 (((((((((((Stem Cell, Mesenchymal) OR (Bone Marrow Mesenchymal Stem Cells)) OR (Bone Marrow Stromal Cells)) OR (Multipotent Bone Marrow Stromal Cell)) OR (Adipose-Derived Mesenchymal Stem Cells)) OR (Mesenchymal Stem Cells, Adipose-Derived)) OR (Adipose Tissue Derived Mesenchymal Stem Cells)) OR (Adipose Tissue Derived Mesenchymal Stem Cells)) OR (Mesenchymal stem Cells)) OR (Multipotent Mesenchymal stem Cells)) OR (Progenitor Cell, Mesenchymal)) OR (Wharton Jelly Cells)
	#10 #6 OR #7 OR #8 OR #9
	#11 “Lung Injury”[Mesh]
	#12 ((Injuries, Lung) OR (Injuries, Pulmonary)) OR (Pulmonary Injuries)
	#13 “Acute Lung Injury”[Mesh]
	#14 ((Acute Lung Injuries) OR (Lung Injuries, Acute)) OR (Lung Injury, Acute)
	#15 #11 OR #12 OR #13 OR #14
	#16 #5 AND #10 AND #15
Search strategy for CNKI	#1 “acute pancreatitis”[MeSH Terms]
	#2 “severe acute pancreatitis”[MeSH Terms]
	#3 #1 OR #1
	#4 “stem cells”[MeSH Terms]
	#5 “mesenchymal stem cells”[MeSH Terms]
	#6 #4 OR #5
	#7 “lung injury”[MeSH Terms]
	#8 “acute lung injury”[MeSH Terms]
	#9 #7 OR #8
	#10 #3 AND #6 AND #9

Table 2 General characteristics of the included studies

Ref.	Country	Animals	SAP modeling	Sample size (T/C)	Type of stem cells	Route of transplantation	Number of stem cells transplanted	Control protocol	Duration of transplantation	Follow-up duration	Outcome measures
Yu and Song[7], 2022	China	SD rats (200 g)	Injection of 3% sodium taurocholate (1 mL/kg) into the biliopancreatic duct	6/6	BMSCs	Tail vein	1 × 107/rat	PBS	6 hours	72 hours	a, b, e, h, k
Li et al[31], 2020	China	SD rats (200-240 g)	Injection of 4% sodium taurocholate (1 mL/kg) into the biliopancreatic duct	12/12	PMSCs	Tail vein	1 × 107/kg	PBS	6 hours	12 hours, 24 hours	a, b, c, d, e, g, h, j, k
Song et al[32], 2019	China	SD rats (150-200 g)	Injection of 3% sodium taurocholate (1 mL/kg) into the biliopancreatic duct	6/6	BMSCs	Tail vein	1 × 107/kg	PBS	12 hours	72 hours	a, b, d, f, i, k
Yu et al[33], 2017	China	SD rats (180-220 g)	Injection of 1.5% sodium deoxycholate (1 mL/kg) into the biliopancreatic duct	10/10	BMSCs	Tail vein	3 × 106/kg	Blank	0	7 days	c
Chen et al[34], 2016	China	SD rats (200-250 g)	Injection of 4% sodium taurocholate (1 mL/kg) into the biliopancreatic duct	10/10	BMSCs	Tail vein	NR	NS	24 hours	24 hours	a, b, e, g, j
Zhao et al[35], 2016	China	SD rats (200-250 g)	Injection of 3% sodium taurocholate (1 mL/kg) into the biliopancreatic duct	10/10	BMSCs	Tail vein	(5-7) × 107/rat	PBS	24 hours	72 hours	a, g, j
Yang et al[36], 2013	China	SD rats (250-280 g)	Injection of 5% sodium taurocholate (1 mL/kg) into the biliopancreatic duct	12/12	UCMSCs	Tail vein	5 × 106/kg	NS	0, 1 hour, 6 hours, 12 hours	48 hours	a, b, e, k
Sheng et al[37], 2012	China	SD rats (200-250 g)	Injection of 5% sodium taurocholate (1 mL/kg) into the biliopancreatic duct	36/32	BMSCs	Tail vein	1 × 107/kg	NS	1 hours	3 hours, 6 hours, 12 hours, 24 hours	b, c, e, h, k
Wu et al[26], 2012	China	SD rats (200-230 g)	Injection of 5% sodium taurocholate (1 mL/kg) into the biliopancreatic duct	20/20	BMSCs	Femoral vein	(0.5-1) × 104/kg	Medium	1 hour	6 hours, 12 hours	a, b, c, e, h, k
Wang et al[12], 2012	China	SD rats (250-300 g)	Injection of 5% sodium taurocholate (1 mL/kg) into the biliopancreatic duct	25/25	BMSCs	Tail vein	1 × 106/rat	Medium	2 hours	1 hour, 3 hours, 6 hours, 12 hours, 24 hours	c, d, g, k
Li et al[38], 2011	China	SD rats (260-280 g)	Injection of 5% sodium taurocholate (1 mL/kg) into the biliopancreatic duct	20/20	BMSCs	Tail vein	2 × 105/kg	NS	0	12 hours	b, c, e, g
Li et al[39], 2011	China	SD rats (180-200 g)	Injection of 5% sodium taurocholate (1 mL/kg) into the biliopancreatic duct	30/30	BMSCs	Tail vein	1 × 107/kg	NS	0	3 hours, 6 hours, 12 hours	b, c, f, k
Lu et al[40], 2011	China	SD rats	Two intraperitoneal injections of L-arginine (2 g/kg)	48/48	BMSCs	Femoral vein	NR	Blank	6 hours	12 hours, 24 hours, 48 hours, 72 hours	d

a: Pancreatic histopathological score; b: Lung histopathological score; c: Lung wet/dry weight ratio; d: Lung myeloperoxidase level; e: Serum tumor necrosis factor-α (TNF-α) level; f: Lung TNF-α level; g: Lung TNF-α mRNA expression; h: Serum interleukin (IL)-1β level; i: Lung IL-1β level; j: Lung IL-1β mRNA expression; k: Serum amylase level. SAP: Severe acute pancreatitis; T: Treatment group; C: Control group; BMSCs: Bone marrow mesenchymal stem cells; PBS: Phosphate buffered saline; PMSCs: Placenta mesenchymal stem cells; NR: Not reported; NS: Normal saline; UCMSCs: Umbilical cord mesenchymal stem cells.

Table 3 Results of risk of bias assessment in the included studies

Ref.	Generation of random sequences	Baseline characteristics	Allocation concealment	Randomized animal allocation	Blinding of animal caretakers and investigators	Assessment of random outcomes	Blinding of outcome assessors	Incomplete data reporting	Selective reporting of outcome	Other bias
Yu and Song[7], 2022	Yes	Yes	Unclear	Unclear	No	Unclear	No	No	No	Unclear
Li et al[31], 2020	Yes	Yes	Unclear	Unclear	No	Unclear	No	No	No	Unclear
Song et al[32], 2019	Unclear	Yes	Unclear	Unclear	No	Unclear	No	No	No	Unclear
Yu et al[33], 2017	Unclear	Yes	Unclear	Unclear	No	Unclear	No	No	No	Unclear
Chen et al[34], 2016	Unclear	Yes	Unclear	Unclear	No	Unclear	No	No	No	Unclear
Zhao et al[35], 2016	Unclear	Yes	Unclear	Unclear	No	Unclear	No	No	No	Unclear
Yang et al[36], 2013	Unclear	Yes	Unclear	Unclear	No	Unclear	No	No	No	Unclear
Sheng et al[37], 2012	Unclear	Yes	Unclear	Unclear	No	Unclear	No	No	No	Unclear
Wu et al[26], 2012	Unclear	Yes	Unclear	Unclear	No	Unclear	No	No	No	Unclear
Wang et al[12], 2012	Unclear	Yes	Unclear	Unclear	No	Unclear	No	No	No	Unclear
Li et al[38], 2011	Unclear	Yes	Unclear	Unclear	No	Unclear	No	No	No	Unclear
Li et al[39], 2011	Unclear	Yes	Unclear	Unclear	No	Unclear	No	No	No	Unclear
Lu et al[40], 2011	Unclear	Yes	Unclear	Unclear	No	Unclear	No	No	No	Unclear

Table 4 Subgroup analysis

Subgroup	Number of studies included	Test for heterogeneity		Effect model	SMD/WMD (95%CI)	P value
		I2 (%)	P value
Lung histopathology score
Stem cell type
BMSCs	13	86	< 0.001	Random	-2.95 (-3.96 to -1.93)	< 0.001
Non-BMSCs	6	89	< 0.001	Random	-2.87 (-4.46 to -1.29)	< 0.001
Transplantation route
Tail vein	17	83	< 0.001	Random	-2.37 (-3.12 to -1.62)	< 0.001
Femoral vein	2	79	0.03	Random	-8.09 (-12.90 to -3.28)	0.001
Transplantation duration
< 6 hours	12	89	< 0.001	Random	-3.34 (-4.50 to -2.18)	< 0.001
≥ 6 hours	7	79	< 0.001	Random	-2.15 (-3.29 to -1.00)	< 0.001
Follow-up duration
< 24 hours	10	88	< 0.001	Random	-3.21 (-4.46 to -1.95)	< 0.001
≥ 24 hours	9	86	< 0.001	Random	-2.62 (-3.79 to -1.46)	< 0.001
Lung MPO activity
Stem cell type
BMSCs	10	79	< 0.001	Random	-3.03 (-4.22 to -1.85)	< 0.001
Non-BMSCs	2	39	0.2	Random	-2.56 (-4.15 to -0.97)	0.002
Transplantation route
Tail vein	8	78	< 0.001	Random	-4.39 (-6.35 to -2.43)	< 0.001
Femoral vein	4	69	0.02	Random	-2.00 (-2.93 to -1.07)	< 0.001
Transplantation duration
< 6 hours	5	87	< 0.001	Random	-7.32 (-12.13 to -2.51)	0.003
≥ 6 hours	7	58	0.03	Random	-2.24 (-2.98 to -1.50)	< 0.001
Follow-up duration
< 24 hours	6	81	< 0.001	Random	-3.07 (-4.91 to -1.22)	0.001
≥ 24 hours	6	79	< 0.001	Random	-4.47 (-6.82 to -2.12)	< 0.001
Lung wet/dry weight ratio
Stem cell type
BMSCs	16	89	< 0.001	Random	-0.46 (-0.61 to -0.32)	< 0.001
Non-BMSCs	2	0	0.33	Random	-0.87 (-1.13 to -0.61)	< 0.001
Transplantation route
Tail vein	16	88	< 0.001	Random	-0.50 (-0.66 to -0.34)	< 0.001
Femoral vein	2	95	< 0.001	Random	-0.54 (-1.02 to -0.06)	0.03
Transplantation duration
< 6 hours	16	89	< 0.001	Random	-0.46 (-0.61 to -0.32)	< 0.001
≥ 6 hours	2	0	0.33	Random	-0.87 (-1.13 to -0.61)	< 0.001
Follow-up duration
< 24 hours	14	84	< 0.001	Random	-0.46 (-0.59 to -0.33)	< 0.001
≥ 24 hours	4	94	< 0.001	Random	-0.62 (-1.11 to -0.13)	0.01

SMD: Standardized mean difference; WMD: Weighted mean difference; CI: Confidence interval; BMSCs: Bone marrow mesenchymal stem cells; MPO: Myeloperoxidase.