P210

Donor pretreatment with montelukast and atorvastatin improve physiology and histology in xeno mouse lung perfusion

William Leukhardt¹, Gheorghe Braileanu², Xiangfei Cheng², Agnes Azimzadeh², Carsten Schroeder¹

¹Surgery, Case Western University School of Medicine, Cleveland, OH; ²Surgery, University of Maryland School of Medicine and Baltimore VAMC, Baltimore, MD; United States

Background: Lung injury after xeno-transplantation occurs despite control of α-galactosyl (Gal) antibodies. The mouse lung xeno-perfusion model allows the screening of potential pathways. Atorvastatin (AT), an HMG-CoA reductase inhibitor and montelukast (LTI), a leukotriene inhibitor, have been shown to limit ischemia-reperfusion injury and inflammation in other models. We hypothesized that pre-treatment of the donor with atorvastatin and montelukast could attenuate lung injury.

Methods: Wild type C3H mice were treated with AT (n=6), LTI (n=7), combined AT+LTI (n=5), vehicle control (DMSO, n=6) or left untreated (n=7). After two weeks, the lungs were perfused with fresh human blood and α-Gal inhibitor (NEX1285) using an established mouse lung perfusion model. Lung physiology, histology, blood cell counts and complement and platelet activation were evaluated.

Results: All lungs survived until elective termination at 240min. The early rise in lung pulmonary vascular resistance was significantly decreased in all treated groups until 30min. (p=0.006, Fig.1). After 90min. of perfusion, parameters were equivalent in all groups. Histologic grading revealed highly significant differences in thrombosis between treated groups and controls (p=0.006). AT treated lungs demonstrated significantly diminished thrombosis (p=0.015) and hemorrhage (p=0.016) versus controls (Fig.2). Platelet activation (CD62P expression) at 240min was significantly reduced in the combination of AT+LTI (p<0.05 versus controls). Neutrophil sequestration at 30min. of perfusion was greatest in AT and LTI single treatment experiments. All groups had significant sequestration into the perfused lungs at 120min. except the combination AT+LTI group.

Conclusions: AT and LTI donor pretreatment blunt the physiological and histological phenotype of xenogenic lung injury. Statins as a single treatment seem to have ambivalent effects. The combined treatment of an HMG-CoA reductase and leukotriene inhibitor appears synergistic. Attenuating lung injury and inflammation using atorvastatin and montelukast could impact current human lung transplantation.