Lipopolysaccharide potentiates the effect of hepatocyte growth factor upon replication in lung, thyroid, spleen, and colon in rats in vivo.
Induction of replication may potentiate in vivo gene therapy, as some viral vectors only transduce dividing cells. Hepatocyte growth factor (HGF) increases the percentage of replicating hepatocytes to 18-fold that in normal rats, and lipopolysaccharide (LPS) modestly potentiates this effect. In this study, the effect of iv HGF upon replication in other organs was determined. HGF at 10 mg/kg resulted in replication that was < or =3-fold that of normal rats in alveolar and proximal renal tubular cells. HGF alone had no effect upon replication of epithelial cells from the bronchi, thyroid, pancreas, or colon or upon cells from the muscle, pancreatic islets, spleen, blood vessels, or thymus. HGF and LPS at 5 mg/kg resulted in replication that was 9-fold that of normal rats in alveolar cells, 25-fold in bronchial epithelial cells, 4-fold in thyroid epithelial cells, 1.5-fold in the red pulp of the spleen, and 2-fold in colonic epithelial cells. The synergistic effect may be due to the fact that LPS upregulated the HGF receptor c-met in thyroid, spleen, and colon. We conclude that iv administration of HGF alone is relatively specific for inducing hepatocyte replication and would allow selective gene transfer into the liver.
Gao
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Department of Internal Medicine, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
Kennedy
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Ponder
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D000818:Animals; D001973:Bromodeoxyuridine / Q000378:metabolism; D003106:Colon / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004847:Epithelial Cells / Q000378:metabolism; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods*; D017228:Hepatocyte Growth Factor / Q000494:pharmacology*; D015151:Immunoblotting; D007420:Intestine, Large / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008168:Lung / Q000378:metabolism*; D008297:Male; D008957:Models, Genetic; D009132:Muscles / Q000378:metabolism; D010179:Pancreas / Q000378:metabolism; D019859:Proto-Oncogene Proteins c-met / Q000378:metabolism; D011650:Pulmonary Alveoli / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013154:Spleen / Q000378:metabolism*; D013961:Thyroid Gland / Q000378:metabolism*; D013997:Time Factors
D008070:Lipopolysaccharides; D017228:Hepatocyte Growth Factor; D019859:Proto-Oncogene Proteins c-met; D001973:Bromodeoxyuridine