. Author manuscript; available in PMC: 2022 Jan 27.

Published in final edited form as: Transplantation. 2021 May 1;105(5):979–985. doi: 10.1097/TP.0000000000003483

Table 2.

Summary of lab-based studies for investigation and treatment of ischemia reperfusion injury on Ex Vivo Lung Perfusion

	Agent/mechanism/modality	Target	Model	Experimental Groups (N)	Key points

*Pharmacologic*

Wang 2020⁴²	3-aminobenzamide	Poly(adp-ribose) polymerase (PARP)	Murine	EVLP+PARP inhibitor (16); EVLP (15); Control (14)	EVLP+ PARP inhibitor has higher compliance; lower pulmonary edema; and lower LDH, IL-6, and IL-10.
Lin 2018⁴⁵	α1-antitrypsin (A1AT)	-	Porcine	EVLP (6);EVLP+A1AT (6)	Reduced pulmonary artery pressure, pulmonary vascular resistance, pulmonary edema, apoptosis and IL-1α & IL-8.
Wang 2018⁴⁸	Sevoflurane	-	Murine	EVLP+ Sevoflurane (6); EVLP (6); Baseline (3)	Reduced LDH, 3-nitrotyrosine, protein carbonyl, TNF-α, pulmonary edema. Increased oxygenation capacity and static pulmonary compliance.
Weathington 2018⁴⁴	BC1215 with Lipopolysaccharide stress test (LPS)	ubiquitin E3 ligase protein- FBXO3	Human	EVLP+LPS+BC1215 (3); EVLP+ LPS(4)	BC1215 is associated with reduced NF-κβ associated transcripts and inflammatory cytokines. Improved oxygenation
Hijiya 2017⁴⁷	Inhaled β 2 agonist	β 2 adrenoreceptor	Canine	EVLP (5); EVLP+ β2 agonist (5)	Lower PVR, higher CAMP and ATP in β2 group
Huerter 2016⁴⁰	Selective A2BR blocker- ATL802	adenosine A2B receptor (A2BR)	Murine	EVLP (9); EVLP+ATL802 (9)	ATL802 associated with reduced cytokine production, neutrophil infiltration, vascular permeability, and edema. Improved pulmonary compliance.
Haam 2015⁴⁹	Inhaled hydrogen	Oxidative pathways	Porcine	EVLP(5); EVLP+hydrogen(5)	Lower levels of IL-1β, IL-6, IL-8, TNF-α in the EVLP +hydrogen group
Shaghaghi 2015⁴³	Ascorbic acid	-	Murine	EVLP + Ascorbic acid (5);EVLP (5)	Total metabolite was signal larger in the ascorbate cohort and oxidative phosphorylation pathway was more active compared to control, suggesting improved mitochondrial function
Stone 2015³⁹	Adenosine 2A receptor agonist	Adenosine 2 A receptor (A2AR)	Murine	Cold static preservation (12); EVLP (12);EVLP+A2AR agonist (12)	Lung edema, cytokines IL-1, IL-8, IL-6, and IL-17) and neutrophil counts significantly lower in EVLP+A2AR compared with EVLP or cold static preservation.

*Gene therapy/diagnostics*

Tan 2020²⁷	Fusion protein (FP) targeted at 8-oxoguanine DNA glycosylase	Mitochronrial DNA	Murine	Native(11); Native+FP(13) ); DCD(7); DCD+FP (10); DCD+FPKO (8)	Higher fraction of intact mitochondrial DNA in DCD+FP group compared with DCD and knockout mice- associated with lower pulmonary edema and lower mitochondrial DAMPs.
Lonati 2018²⁴	Transcription factor analysis in Frozen lung biopsy specimens	-	Murine	Native (5) Pre-EVLP (5) Post-EVLP (5)	EVLP modulates NF-kB,signal transducer and activator of transcription 3, ERK1/2, p38, Akt, and stress-activated protein kinase/JNK signaling pathways. Increased transcription of genes related to inflammation and its regulation, apoptosis/survival, heat shock, and oxidative stress response
Rofia 2018²⁵	Nano LC-MS spectrometry in frozen lung biopsy	-	Murine	Native(5); Pre-EVLP (5); Post-EVLP (5)	Increased expression of super oxide dismutase-1 associated with reduced free radical damage on EVLP
Yeung 2018 ²⁶	Gene expression profiles in frozen lung biopsy specimens	-	Human	n=10	EVLP associated with increased gene expression for endothelial markers of inflammation. Decreased expression of leucocyte-specific genes.
Machuca 2017²⁸	Adenoviral vector(AV) for human IL10 gene delivery	Nuclear transcription machinery	Porcine	Cold ischemia (4); AV control (4); EVLP control (5); EVLP+AV (5)	Lower acute rejection score in EVLP+AV compared with EVLP; better gas exchange at 7 days. No significant difference in Il-1β, IL6, IL8, or IFNγ

Stem cell and immune therapy

Lonati 2019³³	Mesenchymal stem cell derived extracellular vesicles (EV) via perfusate	-	Murine	EVLP+EV (5); EVLP+ saline (5)	EVLP+EV had lower vascular resistance, higher perfusate nitric oxide metabolites, higher pulmonary ATP
Andreasson 2017³¹	-	Cytokine levels and neutrophil adhesion	Human	N= 42	Increased IL1β and TNFα associated with inpatient mortality
Martens 2017³²	Multipotent adult progenitor cells (MAPC) via airway	-	Porcine	EVLP+MAPC (6); EVLP+albumin (6)	No difference in physiological parameters between groups. Lower BAL neutrophils, TNF-α, IL-1β and IFN-γ in MAPC group.
Noda 2017³⁰	Leukofiltration (LF); caspase-1-inhibitor (INH)	Donor leukocytes, Caspase-1	Murine	EVLP (5);EVLP+LF (5); EVLP+ release of filtered; cytokines (5); EVLP+INH (5)	Leukofiltration and caspase inhibitor associated with lower levels of IL6,TNFα and IL1β; 26% percent of filtered cells found to be pyroptotic.
Stone 2016²⁹	EVLP compared with standard lung transplant	Donor leukocytes	Porcine	EVLP (6); Control (6)	EVLP associated with reduced donor leucocyte transfer, allorecognition, T-cell priming and T-cell infiltration of recipient.