*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 1^st liter of Perfadex effluent, but not the 2^nd. 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.

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