Gene expression profiles in mouse lung tissue after administration of two cationic polymers used for nonviral gene delivery.
OBJECTIVE
This study compared gene expression profiles in mouse lungs after administration of the cationic polymers polyethyleneimine (PEI) or chitosan alone or formulated with a luciferase reporter plasmid (PEI-pLuc, chitosan-pLuc).


METHODS
The polymers and formulations were administered intratracheally to Balb/c mice at doses judged to be nontoxic according to intracellular dehydrogenase activity and tissue morphology. RNA was isolated from the lungs 24 or 72 h after administration, and a dedicated stress and toxicology cDNA array was used to monitor the in vivo response to the gene delivery system in the lung tissue.


RESULTS
The gene expression profiles differed between the PEI and chitosan groups with regard to both the total number and the type of expressed genes. Chitosan-pLuc upregulated genes that protect the cell from oxidative stress and inflammation, such as heme oxygenase-1 and catalase, whereas PEI-pLuc upregulated genes involved in inflammatory processes, such as the cyclooxygenases 1 and 2, indicating possible involvement in the development of adverse reactions. However, both polymers activated genes involved in reaction to stress, such as DNA damage repair. Furthermore, in the PEI group, chaperone genes and members of the p38 mitogen-activated protein kinase pathway were also upregulated, suggesting a possible explanation for the better performance of PEI in gene delivery systems.


CONCLUSIONS
The results indicate that gene expression profiling is a useful and sensitive tool for the evaluation of tissue responses after administration of polymers or gene delivery systems. The results also suggest a possible explanation for the differences in gene delivery performance between the two polymers in gene delivery systems.
Regnström
Karin
K
Department of Pharmacy, Uppsala University, Uppsala, Sweden.
Ragnarsson
Eva G E
EG
Fryknäs
Mårten
M
Köping-Höggård
Magnus
M
Artursson
Per
P
D000818:Animals; D002374:Catalase / Q000235:genetics / Q000378:metabolism; D002412:Cations; D048271:Chitosan / Q000737:chemistry / Q000494:pharmacology; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D018014:Gene Transfer Techniques; D006419:Heme Oxygenase (Decyclizing) / Q000235:genetics / Q000378:metabolism; D008168:Lung / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D020411:Oligonucleotide Array Sequence Analysis; D011094:Polyethyleneimine / Q000737:chemistry / Q000494:pharmacology; D011108:Polymers / Q000737:chemistry / Q000494:pharmacology*; D011451:Prostaglandin-Endoperoxide Synthases / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism
D002412:Cations; D011108:Polymers; D012333:RNA, Messenger; D011094:Polyethyleneimine; D048271:Chitosan; D002374:Catalase; D006419:Heme Oxygenase (Decyclizing); D011451:Prostaglandin-Endoperoxide Synthases