Immediate inflammatory responses to adenovirus-mediated gene transfer in rat salivary glands.
Although replication-deficient adenoviruses can efficiently transfer genes to the salivary glands, the current vectors precipitate an immediate, transient decrease in salivary function. To study the cause of this salivary hypofunction, 10(6)-10(10) plaque-forming units (pfu) of the vector AdCMV beta gal were delivered by retrograde ductal infusion to the submandibular glands (SMGs) of rats. Microscopic analysis of infected glands showed a dose-related, rapidly developing inflammatory response, which at the highest amount of virus was characterized by a predominantly neutrophil-containing infiltrate, focal necrosis, and edema. Moreover, the glands of nude rats developed similar morphologic changes to those of immunocompetent rats. After 3 days, the volume of stimulated saliva secreted from SMGs receiving AdCMV beta gal (6.75 x 10(9) pfu) was approximately 20% that of controls. UV-inactivated virus caused a similar decrease in saliva output. We evaluated to what extent the anti-inflammatory glucocorticoid, dexamethasone, could suppress inflammation and preserve salivary function. Three days after infusion with a high dose of AdCMV beta gal (6.75 x 10(9) pfu), the glands from dexamethasone-treated animals showed markedly less inflammation and no necrosis. Furthermore, there was no significant difference in the average amount of saliva secreted from the infected glands (105 +/- 17 microliters) compared to the control glands (123 +/- 18 microliters). In addition, dexamethasone extended the expression of beta-galactosidase in the SMGs. These results suggest that the adenovirus-mediated acute inflammation in rat SMG is responsible for diminished gland function and transgene expression. Furthermore, we demonstrate a useful role for glucocorticoids in controlling acute inflammation during experimental gene transfer with current adenovirus vectors.
Adesanya
M R
MR
Clinical Investigations and Patient Care Branch, National Institute of Dental Research, National Institutes of Health, Bethesda, MD 20892-1190, USA.
Redman
R S
RS
Baum
B J
BJ
O'Connell
B C
BC
D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D003587:Cytomegalovirus / Q000235:genetics; D003907:Dexamethasone / Q000494:pharmacology; D018014:Gene Transfer Techniques; D005822:Genetic Vectors; D005938:Glucocorticoids / Q000494:pharmacology; D007249:Inflammation / Q000209:etiology*; D008297:Male; D051381:Rats; D011923:Rats, Nude; D017208:Rats, Wistar; D012466:Salivary Gland Diseases / Q000209:etiology*; D013997:Time Factors; D014779:Virus Replication / Q000235:genetics*; D001616:beta-Galactosidase / Q000235:genetics / Q000378:metabolism
D005938:Glucocorticoids; D003907:Dexamethasone; D001616:beta-Galactosidase