The Impact of Perfusate Oxygenation During Ex Vivo Lung Perfusion on Post-transplant Outcomes: Deoxygenated vs. Fully-Oxygenated

AbstractThe endothelial glycocalyx (eGC) is considered a key regulator of several mechanisms that prevent vascular injury and disease. Degradation of this macromolecular layer may be associated with post-transplant graft dysfunction. In this study, we aimed to demonstrate the benefits of eGC protection via heparanase inhibition on graft quality. We established rat models of lung grafts with damaged or preserved eGC using ischemic insult and transplanted the grafts into recipients. Lung grafts were also subjected to normothermic ex vivo lung perfusion for detailed assessment under isolated conditions. Physiologic parameters and eGC-associated cellular events were assessed in grafts before and after reperfusion. Structurally degraded eGC and highly activated heparanase were confirmed in lungs with ischemic insult. After transplant, lungs with damaged eGC exhibited impaired graft function, inflammation, edema, and inflammatory cell migration. Increased eGC shedding was evident in the lungs after reperfusion both in vivo and ex vivo. These reperfusion-related deficiencies were significantly attenuated in lungs with preserved eGC following heparanase inhibition. Our studies demonstrated that eGC plays a key role in maintaining lung graft quality and function. Heparanase inhibition may serve as a potential therapeutic to preserve eGC integrity, leading to improved post-transplant outcomes.

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Nicotinamide Adenine Dinucleotide (NAD+) improves lung function in rat lung ex-vivo lung perfusion model

British Journal of Surgery ◽

10.1093/bjs/znab202.079 ◽

2021 ◽

Vol 108 (Supplement_4) ◽

Author(s):

J P Ehrsam ◽

S Arni ◽

J Chen ◽

H Rodriguez Cetina Biefer ◽

I Opitz ◽

...

Keyword(s):

Lung Function ◽

Ex Vivo ◽

Lung Perfusion ◽

Male Rats ◽

Interleukin 12 ◽

Large Animal ◽

Ex Vivo Lung Perfusion ◽

Long Term Outcome ◽

Anti Inflammatory ◽

The Impact

Abstract Objective Ischemia-reperfusion injury compromises short- and long-term outcome after lung transplantation. The scarce existing data on the natural co-enzyme NAD+ suggest an antagonistic effect on hypoxia induced vasoconstriction, removal capacity on reactive oxygen species, and anti-inflammatory effects. We therefore investigated the impact of NAD+ on ischemic rat lungs during ex-vivo lung perfusion (EVLP). Methods Lungs were retrieved from 12 outbred Sprague Dawley male rats and exposed to 14 hours of cold ischemic storage. All lungs were then perfused in a rat EVLP system for 4 hours. Lung grafts were injected after 1, 2 and 3 hours with 2000 uM NAD + (N = 6) or placebo (N = 6) in the perfusate in proximity of the pulmonary artery. EVLP physiology and biochemistry were monitored. Results During the 4 hours of EVLP, the lung function increased significantly in the NAD+ group when compared to the placebo group. We monitored a higher vascular flow (p = 0.018), a lower mean pulmonary pressure (p = 0.007) and increased oxygenation capacity (p = 0.003). Lung compliance and weight were comparable. Tissue inflammation measured by myeloperoxidase was significantly lower in the NAD+ group (p = 0.015). In the perfusate, we observed in the NAD+ group significantly lower levels of pro-inflammatory interleukin-18 (p = 0.033) and a trend towards high levels of anti-inflammatory interleukin-10 (p = 0.080) and low levels of pro-inflammatory interleukin-12 (p = 0.146). Conclusion Findings from this preliminary study demonstrated that NAD+ is a promising agent with both anti-inflammatory properties and the ability to improve ischemic lung function. This observation should be validated in a large animal model.

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