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Biomedical subjects

B J Baum

Publications and source records attributed to B J Baum.

At least 73 records · Page 4Linked to original sources
PubMed1998

Systemic action of human growth hormone following adenovirus-mediated gene transfer to rat submandibular glands.

We have previously suggested that although salivary glands function in an exocrine manner they might none the less offer a useful way to deliver therapeutic proteins systemically. As a direct functional test of this hypothesis, we constructed a recombinant adenovirus (AdCMVhGH) encoding human growth hormone (hGH) and then studied the biological action of hGH produced following transfer of the hGH gene to rat submandibular glands. At 48 h following infusion of AdCMVhGH into these glands via cannulation of the main excretory duct, serum levels of hGH were approximately 16 ng/ml and rat insulin-like growth factor-1 was elevated approximately 25%. Moreover, serum chemistry profiles of rats subjected to in vivo gene transfer displayed alterations in the BUN:creatinine ratio and triglyceride levels presumably reflecting the anabolic actions of the hGH. These results provide the first demonstration of systemic biological action from a transgene product secreted in an endocrine fashion from the salivary glands.

Adenoviridae↗
PubMed1998

Safety of salivary gland-administered replication-deficient recombinant adenovirus in rats.

We have examined the safety of a replication-deficient recombinant adenovirus administered at a single, high dose intraductally to rat submandibular glands or systemically via the femoral vein. The virus used directed the synthesis of human aquaporin-1, a water channel protein, and is termed AdhAQP1. Comparisons were made 1 and 9 days post-infection with animals administered either a similar virus encoding no transgene or the viral suspension buffer. Animals were specifically not given anti-inflammatory drugs to impede the well-known immunopathologic response to recombinant adenoviral administration. Serum chemistries and hematological parameters were monitored. Rats were subjected to complete gross necropsy and selected tissues were evaluated by histopathology. Most clinical chemistry and hematology values were within normal ranges; however, evidence of inflammation (e.g., elevated lactic dehydrogenase, total leukocyte count) was seen. Gross pathology was normal, as was histopathology, excepting rare focal areas of necrosis. The results show that intrasalivary gland or intravenous AdhAQP1 administration leads to low levels of toxicity in rats.

Adenoviridae↗
PubMed1998

Sjögren's syndrome: a model for dental care in the 21st century.

The diagnosis and treatment of Sjögren's syndrome, which poses many severe complications, should be of critical interest to dentists, who are often the first practitioners to detect symptoms. Dentistry is an integral part of health care delivery for patients with this condition. Management of Sjögren's syndrome can be seen as a model for the expanded scope of dental care in the future.

Autoimmune Diseases↗
PubMed1998

The mouth is a gateway to the body: gene therapy in 21st-century dental practice.

Gene therapy may become an integral tool in dental practice early in the 21st century. It and other biological therapies are expected to be applied to oral diseases and disorders during the midpractice lifetime of today's dental students. If the applications of oral gene transfer are expanded to systemic diseases, oral health care providers in the future could routinely be "gene therapists" with therapeutic targets well outside the oral cavity.

Animals↗
PubMed1998

Preclinical and biological studies using recombinant adenoviruses encoding aquaporins 1 and 5.

In this report, we have reviewed several of our recent studies using replication-deficient recombinant adenoviruses encoding either aquaporin 1 or 5. The aquaporins are a relatively recently described family of water channels that mediate osmotically-driven transmembrane water permeability. Recombinant adenoviruses are highly efficient gene transfer vectors and readily result in significant levels of transgene expression. These aggregate studies provide examples of how such "tools" can be used in a novel way to address problems of both clinical and biological significance.

Adenoviridae↗
PubMed1997

Increased fluid secretion after adenoviral-mediated transfer of the aquaporin-1 cDNA to irradiated rat salivary glands.

A replication-deficient, recombinant adenovirus encoding human aquaporin-1 (hAQP1), the archetypal water channel, was constructed. This virus, AdhAQP1, directed hAQP1 expression in several epithelial cell lines in vitro. In polarized MDCK cell monolayers, hAQP1 was localized in the apical and basolateral plasma membranes. Fluid movement across monolayers infected by AdhAQP1 in response to an osmotic gradient was approximately 4-fold that seen with uninfected monolayers or monolayers infected by a control virus. When AdhAQP1 was administered to rat submandibular glands by retrograde ductal instillation, significant hAQP1 expression was observed by Western blot analysis in crude plasma membranes and by immunohistochemical staining in both acinar and ductal cells. Three or four months after exposure to a single radiation dose (17.5 or 21 Gy, respectively), AdhAQP1 administration to rat submandibular glands led to a two- to threefold increase in salivary secretion compared with secretion from glands administered a control virus. These results suggest that hAQP1 gene transfer may have potential as an unique approach for the treatment of postradiation salivary hypofunction.

Adenoviridae↗
PubMed1997

Modulation of MMP-2 (gelatinase A) and MMP-9 (gelatinase B) by interferon-gamma in a human salivary gland cell line.

Gelatinases have been shown to be regulated by many cytokines and growth factors, and have been implicated in the pathogenesis of certain autoimmune diseases via tissue destruction. High levels of several cytokines, including IFN-gamma and TNF-alpha, have been demonstrated in the salivary gland microenvironment of patients with Sjogren's syndrome (SS). How these cytokines may be contributing to the pathogenesis of this disease is not well understood. We hypothesized that IFN-gamma with or without (+/-) TNF-alpha could be playing a role in the pathogenesis of SS via the regulation of matrix metalloproteinase (MMP) levels. This study examined the role of IFN-gamma and (+) TNF-alpha in the regulation of the matrix metalloproteinases, MMP-2 (72 kD gelatinase A) and MMP-9 (92 kD gelatinase B). A human salivary gland cell line (HSG) has been used as a possible in vitro model to study the role of IFN-gamma + TNF-alpha in the pathogenesis of SS. The HSG cell line, in the presence of IFN +/- TNF-alpha, displays increased MMP-2 and MMP-9 gelatinolytic activity, protein and RNA levels. The increase in MMP activity was partially blocked with an antibody against the IFN-gamma receptor, and this was associated with a complete inhibition of the previously described IFN-gamma +/- TNF-alpha antiproliferative effect. However, incubation of IFN-gamma treated HSG cells with the synthetic MMP inhibitor BB94 did not alleviate this antiproliferative effect. In addition, we demonstrate that there are very high levels of MMP-9 in the saliva of patients with SS when compared to healthy control subjects. These data suggest that cytokines could be regulating MMP production by salivary epithelial cells and thus indicate a potential role for these cells in the pathogenesis of SS.

Animals↗
PubMed1997

Interferon-gamma-induced JAK2 and STAT1 signalling in a human salivary gland cell line.

We have used a human salivary gland cell line (HSG) as a possible in vitro model to evaluate the effects of IFN-gamma on human salivary gland epithelium (Wu et al., 1994, 1996, 1997). In the present study, we examined the JAK-STAT signal-transduction pathway in IFN-gamma-treated HSG cells. We demonstrate that JAK2 and Stat1 are phosphorylated at tyrosine residues in a time- and concentration-dependent manner following exposure to IFN-gamma. In addition, we show that activation of this signalling pathway is decreased by the addition of a blocking antibody to the IFN-gamma receptor. The same maneuver is also able to reduce by approximately 50-70% the surface expression of two IFN-gamma-induced immunoregulatory molecules: HLA-DR and ICAM-1. These results demonstrate that the JAK2 and Stat1 signalling pathway is active in salivary-derived epithelial cells and may contribute to their immunopathologic destruction.

Antibodies↗
PubMed1997

Polarized distribution of key membrane transport proteins in the rat submandibular gland.

Immunofluorescence labelling and confocal microscopy were employed to examine the polarized distribution of several membrane transport proteins believed to be essential for salivary secretion in the rat submandibular gland. The Na+/K+-ATPase, Na+/H+ exchanger isoform 1 (NHE1), and the secretory Na+/K+/2Cl- cotransporter isoform were all found in the basolateral membranes of acinar and intralobular duct cells. Anion exchanger isoform 2 (AE2) was found only in the basolateral membranes of acinar cells, while AE1 was absent from glandular epithelial cells. Aquaporin 5 was detected in the apical membranes of acinar cells, while the cystic fibrosis transmembrane conductance regulator was found only in apical membranes of intralobular duct cells. NHEs 2 and 3 were found in the apical membranes of both acinar and intralobular duct cells. Our results are generally consistent with the expected distribution of most transporters based on previous physiological and pharmacological experiments. However, the apical localization of NHEs 2 and 3, and the presence of the secretory isoform of the Na+/K+/2Cl- cotransporter in intralobular duct cells were not predicted.

Animals↗
PubMed1997

Triplex-forming oligonucleotides can modulate aquaporin-5 gene expression in epithelial cells.

Triplex-forming oligonucleotides (TFOs) may provide a useful approach to decrease gene transcription in vivo. We have identified two sequences in the rat aquaporin 5 (rAQP5) cDNA that are capable of forming a DNA triple helix. We designed four TFOs based on these sequences (a purine and a pyrimidine TFO per sequence). All four TFOs were able to bind to the rAQP5 cDNA at varying efficiencies in vitro as measured by using gel mobility shift assays. The TFOs were delivered to intact MDCK epithelial cells via adenovirus-polylysine complexes. Experiments with fluorescein-isothiocyanate-labeled oligonucleotides delivered in this way showed primarily a nuclear localization. Three of the four TFOs internalized by adenovirus-polylysine complexes were capable of decreasing rAQP5 expression in intact MDCK cells infected with a recombinant adenovirus encoding rAQP5. These data show that adenovirus-polylysine-TFO complexes can result in TFO delivery to the nucleus in intact epithelial cells and that TFOs may provide a useful way to selectively modulate rAQP5 gene expression.

Animals↗
PubMed1997

Irradiation-induced damage to the salivary glands: the role of redox-active iron and copper.

The mechanism of irradiation-induced hypofunction of the salivary glands is a process that is not fully understood. Here we examine the hypothesis that intracellular and redox-active ions of iron and copper, which are associated with the secretion granules, play a catalytic role in the irradiation-induced damage. Rats were subjected to head and neck irradiation (15 Gy X rays) and allowed to recover for 2 months. The function of the parotid and submandibular glands was then determined by pilocarpine-stimulated salivary secretion. A 45% decrease in the function of both glands was obtained when compared to nonirradiated controls. Treatment prior to irradiation (90 min) with cyclocytidine (200 mg/kg) led to a massive degranulation of the parotid gland and yielded nearly complete protection from radiation-induced damage. In contrast, pilocarpine stimulation prior to irradiation led to a marginal degranulation of the parotid gland and yielded only 13% protection. Neither agent caused degranulation of the submandibular gland mucous cells or yielded functional protection of this gland. Treatment with both agents yielded a marked increase in iron, copper and manganese levels in the parotid gland saliva. An analogous marked increase in the redox activity of iron and copper ions was recorded for the parotid saliva stimulated by pilocarpine and cyclocytidine. Pilocarpine-stimulated submandibular gland saliva contained metal levels similar to those of the parotid gland saliva. However, no redox activity and no increase in metal mobilization could be demonstrated in the submandibular gland saliva stimulated by both agents. The correlation between the patterns of gland degranulation, mobilization of redoxactive metals and the protection of gland function, for both parotid and submandibular glands, focuses attention on the catalytic roles played by transition metal ions in promoting free radical reactions, which likely participate in the process of injury to the tissue.

Ancitabine↗
PubMed1997

Relationship between the cellular distribution of the alpha(v)beta3/5 integrins and adenoviral infection in salivary glands.

This study compared the localization of the alpha(v)beta3/5 integrins in the different cell types of the rat submandibular gland with the susceptibility of these cells to infection by an intraductally administered replication-deficient recombinant type 5 adenovirus coding for rat aquaporin 5 (termed AdrAQP5). We used a panel of antibodies and immunohistochemical procedures to determine the luminal membrane distribution of the integrins. The alpha(v)beta3/5 integrin subunits were present in luminal membranes of all ductal cell types and acini; however, the alpha(v) subunit was found to a lesser extent in the acini. After AdrAQP5 infection, the expression of AQP5 exhibited a similar, though not identical, cellular localization to that seen for alpha(v)beta3/5 integrins. AdrAQP5 infected all cell types in these glands, except excretory ducts, after intraductal administration, directing the transient expression of AQP5. In addition, the localization of alpha(v)beta3/5 integrins was examined in rabbit, monkey, and human submandibular and parotid glands. Although there were some interspecies differences, glands generally displayed the presence of these integrin subunits on luminal membranes of ductal cells and most acinar cells. These findings show that the presence of alpha(v)beta3/5 integrins on the luminal membranes of rat salivary epithelial cells is associated with the susceptibility of these cells to act as targets for adenoviral-mediated gene transfer. However, the abundance of alpha(v)beta3/5 integrin expression was not necessarily predictive of the extent of transgene expression in a particular cell type. Furthermore, because the salivary glands of rabbits, monkeys, and humans show a similar luminal membrane distribution of these integrins, it is likely that recombinant type 5 adenoviruses may be able to mediate in vivo gene transfer to salivary glands in these species.

Adenoviridae↗
PubMed1996

Transfer of a gene encoding the anticandidal protein histatin 3 to salivary glands.

Mucosal candidiasis, the most common opportunistic fungal infection in human immunodeficiency virus (HIV)-infected patients, is an early sign of clinically overt acquired immunodeficiency syndrome (AIDS) and an important cause of morbidity, particularly in HIV-infected children. The appearance of azole-resistant strains of Candida albicans had made clinical management of candidiasis increasingly difficult. We propose a novel approach to the management of candidal infections that involves the use of naturally occurring antifungal proteins, such as the histatins. Histatins are a family of small proteins that are secreted in human saliva. We have constructed recombinant adenovirus vectors that contain the histatin 3 cDNA. These vectors are capable of directing the expression of histatin 3 in the saliva of rats at up to 1,045 micrograms/ml, well above the levels found in normal human saliva. The adenovirus-directed histatin demonstrated a 90% candidacidal effect in the timed-kill assay against both fluconazole-susceptible and fluconazole-resistant strains of C. albicans and inhibited germination by 45% in the same strains. These studies suggest that a gene transfer approach to overexpress naturally occurring antifungal proteins may be useful in the management of mucosal candidiasis.

Adenoviridae↗