Session Time: 3:15pm-4:00pm
Presentation Time: 3:30pm-4:00pm
*Purpose: Ex-vivo lung perfusion (EVLP) has been used to evaluate lung function before lung transplant (LT). We used EVLP to expose lungs recovered 6 hours after brain death to COV08-0064, a TLR9 inhibitor, to estimate the impact of TLR9 inhibition during EVLP on lung function and inflammation after LT.
*Methods: Yorkshire cross-bred juvenile pigs (33-54 kg) were used. 2 pigs had lung recovery and EVLP to confirm stable drug levels during EVLP. Donors were anesthetized, intubated, and rendered brain dead by placement of a subdural foley catheter inflated to generate a Cushing response. 6 hours later, lungs were flushed with cold Perfadex and stored cold overnight. EVLP was performed the next morning using the Toronto method (Medtronic circuits) for 4 hours at 37C with or without COV08-0064 (12 μM) in Steen solution (n=6 LT/group). After cooling in the circuit, lungs were flushed with 2 liters cold Perfadex, and had ex-vivo CT scan to assess edema. Left lungs were transplanted into anesthetized recipient pigs, then followed for 6 hours. 2 sham groups (n=3 each) had 6 hours ventilation without brain death. Sham2 (n=3) had EVLP and LT.
*Results: Inflation of the subdural balloon caused hypertension, loss of brain stem reflexes and apnea; donors required inotropic support. After 6 hours brain death or ventilation without brain death (n=6), there was little or no change in BAL protein and cytokines (IL6, IL8, TNFα, IL-1β). However IL6, IL8 and IL-1β increased in lung tissue in all pigs. EVLP caused some pulmonary edema, mostly in the right lungs, and decreased dynamic compliance. Cytokines increased in Steen solution. COV08-0064 had little or no effect on EVLP cytokines, edema during EVLP or BAL cytokines. After EVLP, COV08-0064 was detected in the 1st liter of Perfadex effluent, but not the 2nd. After LTX, flow to the left lung measured by Transonics flow probes was low initially, and improved over 6 hours in all groups. Relative to controls COV08-0064 during EVLP had little or no impact on lung function; NF-kB and MAP kinases were more activated in lung tissue after 30 min reperfusion; and transplanted lungs treated with COV08-0064 had reduced BAL protein and PMNs in lung biopsies, but these treatment effects were not statistically significant.
*Conclusions: EVLP can be used to expose lungs to therapeutic agents. In this model, COV08-0064 administered only during EVLP had little impact on lung function or measures of inflammation after LT.
To cite this abstract in AMA style:Egan TM, Haithcock B, Ali MH, Blackwell JW, Masuodi B, Shipley S, Long T, Akerman A, Montgomery S, Yuan H, Stewart P, Potenziano J, Sekaran C, Fitch R. A Large Animal Model of Ex-Vivo Lung Perfusion as a Platform to Deliver Therapeutic Agents to Lungs Before Lung Transplant [abstract]. Am J Transplant. 2020; 20 (suppl 3). https://atcmeetingabstracts.com/abstract/a-large-animal-model-of-ex-vivo-lung-perfusion-as-a-platform-to-deliver-therapeutic-agents-to-lungs-before-lung-transplant/. Accessed April 23, 2021.
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