*Purpose: Donor Brain death (BD) induces acute lung injury (BD-ALI), characterized by the breakdown of endo/epithelial barrier functions. These injuries are further exacerbated by ischemia reperfusion injury (IRI), which together adversely affect post-transplant outcomes. We have developed and characterized a novel small molecule gap/tight junction stabilizer, aCT1, which we have shown to improve endothelial integrity. Herein we explored the use of aCT1 as a pretreatment therapeutic to protect donor lungs from the effects of BD-ALI.

*Methods: A mouse model of BD and orthotopic left lung transplant (LTx) were utilized to examine the effects of aCT1 on barrier function stabilization in BD and its impact on post-LTx IRI. Following BD induction Balb/c donors were nebulized with aCT1 or vehicle and ventilated for 3 hrs. Lungs were then removed, flushed with Perfadex, and stored at 4°C for 18 hrs. After which the right lung was processed for histological analysis, and the left lung transplanted into B6 recipients. 6 hrs post LTx, lung function was assessed by measuring PaO₂ levels and lungs were subsequently harvested for histological assessment of graft injury or broncho-alveolar lavage (BAL) to assess cell infiltrates.

*Results: After 3 hrs of BD induction and 18 hrs cold ischemia, lungs had BD-ALI features which included significant increases in immune cell infiltration, edema, and endothelial activation. Treatment with aCT1 had no impact on these BD-ALI features. 6 hrs post-Tx lungs from BD donors had significantly increased IRI as compared to LD controls, as determined by increased immune cell infiltration and pathological assessment of injury. However, treatment of BD donors with aCT1 significantly reduced this BD injury profile, with pathological injury not dissimilar to that seen in LD controls (BD+aCT1 3 vs. BD 8.25, BD+aCT1 3 vs. LD 3, respectively. p<0.001). This reduction in peri-transplant inflammation was further corroborated by reduced neutrophil counts in the BAL fluids of BD vs BD + aCT1 (p<0.001). This decrease in injury and inflammation correlated with significant improvement in lung function as determined by PaO₂ levels (BD 76.67 mmHg vs BD + aCT1 143.0 mmHg, p<0.006).

*Conclusions: These data support gap junction stabilization with aCT1 as a viable option for protecting donor lungs against BD-ALI exacerbated ischemia reperfusion injury.

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