Oxygen Radical-Mediated Pulmonary Toxicity Induced by Some Cationic Liposomes
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Purpose. The objectives of this study are to investigate the toxicityassociated with polycationic liposomes and to elucidate the underlyingmechanism. We tested the hypothesis that the positive charge of liposomesis a key determinant of toxicity by testing differently chargedliposomes in mice.
Methods. Differently charged liposomal systems including cationicliposomes, LipofectAMINE and DOTAP, and neutral and negativeliposomes were evaluated for their toxicity after pulmonaryadministration in mice. LDH assay and differential cell counts were performedto measure toxicity and pulmonary inflammation, respectively. Reactiveoxygen intermediates (ROI) were assessed by chemiluminescence.
Results. Instillation of cationic liposomes eliciteddose-dependent toxicity and pulmonary inflammation. This effect was more pronouncedwith the multivalent cationic liposome LipofectAMINE as comparedto the monovalent cationic DOTAP. Neutral and negative liposomes didnot exhibit lung toxicity. Toxicity associated with cationic liposomescorrelated with the oxidative burst induced by the liposomes.LipofectAMINE induced a dose-dependent increase in ROI generation. Thiseffect was less pronounced with DOTAP and absent with neutral andnegative liposomes.
Conclusions. ROI play a key role in cationic lipid-mediated toxicity.Polyvalent cationic liposomes cause a release of ROI which areresponsible for the pulmonary toxicity.
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- 1.X. Gao and L. Huang. Cationic liposome-mediated gene transfer. Gene Ther. 2:710–722 (1995).Google Scholar
- 2.X. Gao and L. Huang. A novel cationic liposome reagent for efficient transfection of mammalian cells. Biochim. Biophys. Res. Commun. 179:280–285 (1991).Google Scholar
- 3.K. L. Brigham, B. Meyrick, B. Christman, M. Magnusson, G. King, and L. Berry. In vivo transfection of expression of murine lungs with a functioning prokaryotic gene using a liposome vehicle. Am. J. Med. Sci. 298:278–281 (1989).Google Scholar
- 4.N. J. Caplen, E. W. Alton, P. G. Middleton, J. R. Dorin, B. J. Stevenson, X. Gao, S. R. Durham, P. K. Jefferey, M. E. Hodson, and C. Coutelle. Liposome-mediated CFTR gene transfer to the nasal epithelium of patients with cystic fibrosis. Nature Med. 1:39–46 (1995).Google Scholar
- 5.G. J. Nabel, E. G. Nabel, Z. Y. Yang, B. A. Fox, G. E. Plautz, X. Gao, L. Huang, S. Shu, D. Gordon, and A. E. Chang. Direct gene transfer with DNA-liposome complexes in melanoma: Expression, biologic activity, and lack of toxicity in humans. Proc. Natl. Acad. Sci. USA 90:11307–11311 (1993).Google Scholar
- 6.R. K. Scheule, J. A. St. George, R. G. Bagley, J. Marshall, J. M. Kaplan, G. Y. Akita, K. X. Wang, E. R. Lee, D. J. Harris, C. Jiang, N. S. Yew, A. E. Smith, and S. H. Cheng. Basis of pulmonary toxicity associated with cationic lipid-mediated gene transfer to the mammalian lung. Human Gene Ther. 8:689–707 (1997).Google Scholar
- 7.B. D. Freimark, H. P. Blezinger, V. J. Florack, J. L. Nordstrom, S. D. Long, D. S. Deshpande, S. Nochumson, and K. L. Petrak. Cationic lipids enhance cytokine and cell influx levels in the lung following administration of plasmid: Cationic lipid complexes. J. Immunol. 160:4580–4586 (1998).Google Scholar
- 8.Y. K. Song, F. Liu, S. Chu, and D. Liu. Characterization of cationic liposome-mediated gene transfer in vivo by intravenous administration. Human Gene Ther. 8:1585–1594 (1997).Google Scholar
- 9.J. P. Vigneron, N. Oudrhiri, M. Fauquet, L. Vergely, J. C. Bradley, M. Basseville, P. Lehn, and J. M. Lehn. Guanidium-cholesterol cationic lipids: efficient vectors for the transfection of eukaryotic cells. Proc. Natl. Acad. Sci. USA 93:9682–9686 (1996).Google Scholar
- 10.R. Bottega and R. M. Epand. Inhibition of protein kinase C by cationic amphiphiles. Biochemistry 31:9025–9030 (1992).Google Scholar
- 11.S. Gossart, C. Cambon, C. Orfila, M. H. Seguelas, J. C. Lepert, J. Rami, and B. Pipy. Reactive oxygen intermediates as regulators of TNF-α production in rat lung inflammation induced by silica. J. Immunol. 156:1550–1548 (1996).Google Scholar
- 12.J. M. Antonini, K. Vandyke, Z. Ye, M. DiMatteo, and M. J. Reasor. Introduction of luminol-dependent chemiluminescence as a method to study silica inflammation in the tissue and phagocytic cells of rat lung. Environ. Health Persp. 102:37–42 (1994).Google Scholar
- 13.P. Hawley-Nelson, V. Ciccarone, G. Gebeyehu, and J. Jessee. Lipofectamine reagent: A new, higher efficiency polycationic liposome transfection reagent. Focus 15:73–79 (1993).Google Scholar
- 14.D. Liu, J. E. Knapp, and Y. K. Song. Mechanism of cationic liposome-mediated transfection of the lung endothelium. In L. Huang, M. C. Hung, and E. Wagner (eds.), Nonviral Vectors for Gene Therapy, Academic Press, New York, 1999, pp. 313–335.Google Scholar
- 15.H. W. Pogrebniak, M. J. Merino, S. M. Hahn, J. B. Mitchell, and H. I. Pass. Spin trap salvage from endotoxemia: the role of cytokine down-regulation. Surgery 112:130–135 (1992).Google Scholar