Toxicity of cationic liposome-DNA complex in lung isografts

Background Cationic lipids have been successfully employed as vectors for g ene transfer in lung grafts, yet those lipid vectors have potential toxicit y. Furthermore, the optimal concentration of cationic lipids for gene trans fection to lung grafts has not been determined. We evaluated liposome conce ntration/toxicity relationships in an in vivo rat lung transplantation mode l. Methods. Left lungs were harvested and infused via the pulmonary artery wit h chloramphenicol acetyltransferase (CAT)-DNAnipid 67 (cationic lipid)/diol eoylphosphatidylethanolamine complex (4:1:2 in a final concentration ratio) . Donor lungs were allocated into six groups according to lipid 67 concentr ation: group 1, 0 mu M (control); group 2, 10 mu M; group 3, 50 mu M; group 4, 100 mu M; group 5, 250 mu M; group 6, 500 mu M, Forty-eight hours after orthotopic transplantation, the recipient contralateral right main pulmona ry artery and bronchus were ligated, The graft was ventilated with 100% oxy gen for 5 min. Arterial blood gas analysis (PaO2, PaCO2), peak airway press ure (PAP), and CAT activity of the grafts were measured. Results. Recipient survival, and PaO2, PAP, and CAT levels correlated with the lipid-DNA complex concentration. The grafts in groups 4-6 were more inj ured as evidenced by decreased PaO2 and increased PAP levels in comparison to the control group. CAT level was significantly lower in group 2 than in groups 3-6, Conclusions, The pulmonary toxicity of cationic lipid is dose-dependent. Th e balance between lung graft function and transgene expression is optimal a t a lipid 67 concentration of 50 mu M.