Toxicity of cationic liposome-DNA complex in lung isografts.
BACKGROUND
Cationic lipids have been successfully employed as vectors for gene transfer in lung grafts, yet those lipid vectors have potential toxicity. Furthermore, the optimal concentration of cationic lipids for gene transfection to lung grafts has not been determined. We evaluated liposome concentration/toxicity relationships in an in vivo rat lung transplantation model.


METHODS
Left lungs were harvested and infused via the pulmonary artery with chloramphenicol acetyl-transferase (CAT)-DNA/lipid 67 (cationic lipid)/dioleoylphosphatidylethanolamine complex (4:1:2 in a final concentration ratio). Donor lungs were allocated into six groups according to lipid 67 concentration: group 1, 0 microM (control); group 2, 10 microM; group 3, 50 microM; group 4, 100 microM; group 5, 250 microM; group 6, 500 microM. Forty-eight hours after orthotopic transplantation, the recipient contralateral right main pulmonary artery and bronchus were ligated. The graft was ventilated with 100% oxygen for 5 min. Arterial blood gas analysis (PaO2, PaCO2), peak airway pressure (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 injured 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. The balance between lung graft function and transgene expression is optimal at a lipid 67 concentration of 50 microM.
Nagahiro
I
I
Department of Surgery, Washington University School of Medicine, St. Louis, Missouri, USA.
Mora
B N
BN
Boasquevisque
C H
CH
Scheule
R K
RK
Patterson
G A
GA
D000818:Animals; D004247:DNA / Q000008:administration & dosage*; D004305:Dose-Response Relationship, Drug; D015316:Genetic Therapy; D008081:Liposomes / Q000008:administration & dosage / Q000633:toxicity*; D008168:Lung / Q000187:drug effects; D016040:Lung Transplantation; D008297:Male; D010100:Oxygen / Q000097:blood; D051381:Rats; D011916:Rats, Inbred F344; D019076:Transgenes; D014185:Transplantation, Isogeneic
D008081:Liposomes; D004247:DNA; D010100:Oxygen