Ex vivo lung perfusion reverses functional impairment from 2-hour warm ischemia in pig lung grafts
Background
The critical shortage of donor lungs for lung transplantation necessitates utilizing grafts from donation after circulatory death (DCD), which often involves extended warm ischemia (WI). While normothermic ex vivo lung perfusion (EVLP) offers a method to assess and rehabilitate these marginal lungs, the safe upper limits of WI duration remain poorly defined. Conflicting preclinical data and varied clinical protocols across countries highlight a crucial gap in understanding lung graft resilience to WI, hindering broader adoption of DCD lungs and potentially limiting transplant opportunities.
Study Design
Researchers used a clinically-relevant pig model comparing paired right (control) and left (WI) lungs from five donors. WI lungs underwent 2-h WI followed by 1-h cold preservation and 6-h EVLP. Control lungs followed the same protocol without WI, serving as a direct comparison. Primary endpoints included functional parameters like compliance and vascular resistance, alongside molecular analyses of oxidative and mitochondrial stress markers, cytokine release, histological injury, edema, and transcriptomic responses via gene expression profiling.
Results
Initial 2-h WI significantly impaired lung function, reducing compliance by 32% and increasing vascular resistance by 25%. However, both parameters showed complete normalization during the subsequent 6-h EVLP period. Crucially, post-EVLP assessment revealed no significant difference between control and WI lungs in markers of oxidative stress, mitochondrial stress, cytokine release, histological injury, or edema. This indicates a robust recovery mechanism.
During EVLP, both control and WI lungs exhibited remarkably similar
transcriptomic responses, with 69 out of 96 analyzed genes showing regulation, and their expression levels converging. This suggests that EVLP effectively mitigated the initial WI-induced damage, leading to functionally and molecularly comparable outcomes between initially compromised and control grafts.
Key Findings
- Initial 2-h warm ischemia reduced lung compliance by 32% and increased vascular resistance by 25%.
- 6-h normothermic ex vivo lung perfusion (EVLP) fully normalized these initial functional impairments.
- No significant differences were found in oxidative stress, mitochondrial stress, cytokine release, or edema between WI and control lungs after EVLP.
- Both WI and control lungs showed similar
transcriptomic responsesduring EVLP, with 69/96 genes regulated.
Why It Matters
This study provides strong evidence that lung grafts can tolerate at least 2 hours of warm ischemia when followed by EVLP, suggesting a potential expansion of the donor pool. For transplant clinicians, this could mean safely accepting lungs previously deemed unsuitable due to extended WI, thereby reducing waitlist mortality and increasing the availability of viable organs. The observed functional and molecular recovery during EVLP highlights its rehabilitative power, potentially informing revised clinical protocols for DCD lung utilization. This finding moves us closer to establishing clearer, evidence-based thresholds for WI duration in lung transplantation, optimizing graft selection and improving patient outcomes.
lung transplantation
warm ischemia
evlp
pig model
graft viability
oxidative stress