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Biomedical subjects

A H Soll

Publications and source records attributed to A H Soll.

At least 19 recordsLinked to original sources
PubMed1999

Effects of growth factors and trefoil peptides on migration and replication in primary oxyntic cultures.

Restitution, the lateral migration of cells over an intact basement membrane, maintains mucosal integrity. We studied the regulation of migration and proliferation of enzyme-dispersed canine oxyntic mucosa cells in primary culture. Confluent monolayers were wounded and cultured in serum-free medium, and cells migrating into the wound were counted. [3H]thymidine incorporation into DNA was studied using subconfluent cultures. Considerable migration occurred in untreated monolayers; however, epidermal growth factor (EGF), transforming growth factor (TGF)-alpha, basic fibroblast growth factor (bFGF), insulin-like growth factor I (IGF-I), two trefoil peptides, and interleukin (IL)-1beta further enhanced migration. The specific EGF receptor (EGFR) monoclonal antibody, MAb-528, inhibited both basal and TGF-alpha- or IL-1beta-stimulated migration, but not the response to trefoil peptide, bFGF, or IGF-I. Exogenous TGF-beta inhibited cell proliferation but did not alter migration. Immunoneutralization with anti-TGF-beta blocked the response to exogenous TGF-beta and produced a small enhancement of basal thymidine incorporation but did not attenuate basal or TGF-alpha-stimulated migration. In conclusion, endogenous EGFR ligands regulate proliferation and migration. TGF-beta inhibits mitogenesis; it did not upregulate migration in these cultures. Although bFGF, IGF-I, and IL-1beta enhance gastric epithelial migration, only IL-1beta acted in a TGF-alpha-dependent fashion.

Animals↗
PubMed1998

H. pylori stimulates gastrin release from canine antral cells in primary culture.

Patients chronically infected with Helicobacter pylori are known to have hypergastrinemia. Previous studies have demonstrated the stimulation of gastrin from isolated G cells by monocytes and cytokines. The aim of this study was to determine if H. pylori can directly stimulate gastrin secretion. The secretion of gastrin from canine G cells in 48-h primary cultures was investigated using either live H. pylori bacteria or various bacterial extracts from three well-characterized strains. Whole bacterial sonic extracts and water-extracted surface proteins, but not PBS extracts, from strains 43579 (CagA+/VacA+), 60190 (CagA+/VacA+), and 60190:v1 (CagA+/VacA-) significantly stimulated gastrin release. Controls demonstrated that gastrin stimulation by the sonic extracts was not due to a direct toxic effect on G cells. We conclude that H. pylori produces a soluble factor(s), which can directly stimulate gastrin release in enriched canine G cell cultures. This stimulatory effect may play an important role in the H. pylori-associated hypergastrinemia and subsequent development of peptic ulcer disease.

Animals↗
PubMed1997

Management strategies for Helicobacter pylori-seropositive patients with dyspepsia: clinical and economic consequences.

BACKGROUND: Noninvasive testing for Helicobacter pylori is widely available and has been considered as an initial management strategy for uninvestigated dyspepsia. However, data to guide clinicians in the management of patients with dyspepsia who are seropositive for H. pylori are lacking. OBJECTIVE: To examine the economic, clinical, and policy implications of alternative initial management strategies for patients with uninvestigated dyspepsia who are seropositive for H. pylori. DESIGN: Decision analysis comparing the costs and outcomes of initial anti-H. pylori therapy and initial endoscopy. PATIENTS: Helicobacter pylori-seropositive patients with dyspepsia. MEASUREMENTS: Cost estimates were obtained from the Medicare reimbursement schedule and a health maintenance organization pharmacy. Probability estimates were derived from the medical literature. RESULTS: Initial endoscopy costs an average of $1276 per patient, whereas initial anti-H, pylori therapy costs $820 per patient; the average saving is $456 per patient treated. The financial effect of a 252% increase in the use of antibiotics for initial H. pylori therapy is more than offset by reducing the endoscopy workload by 53%. Endoscopy-related costs must be reduced by 96% before the two strategies become equally cost-effective. In patients with nonulcer dyspepsia, the financial benefits of initial anti-H. pylori therapy are not substantially affected by varying the rates of H. pylori eradication, the complications of antibiotics, or the response of symptoms to cure of H. pylori infection. CONCLUSIONS: In H. pylori-seropositive patients with dyspepsia, initial anti-H. pylori therapy is the most cost, effective management strategy. Randomized studies of these strategies that evaluate outcomes and patient preferences are needed to optimize management decisions. In the meantime, unless physicians are concerned about resistance to antimicrobial agents or the lack of proven benefit of anti-H. pylori therapy in nonucler dyspepsia, the strategy outlined in this analysis can be used as a basis for management and policy decisions about H. pylori-seropositive patients with dyspepsia.

Age Factors↗
PubMed1996

Consensus conference. Medical treatment of peptic ulcer disease. Practice guidelines. Practice Parameters Committee of the American College of Gastroenterology.

OBJECTIVE: To integrate the realization that peptic ulcer most commonly reflects infection with Helicobacter pylori or use of aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs) into a disease management approach. PARTICIPANTS: Guidelines were outlined by the author and presented for review to the American College of Gastroenterology (ACG) Practice Parameters Committee, selected by the president of the ACG, and a panel of experts in peptic ulcer, selected by the committee. EVIDENCE AND CONSENSUS PROCESS: These guidelines were formulated following extensive review of the literature obtained by MEDLINE search and presented for detailed review and revision to unpublicized committee meetings on three occasions and to experts by mail. These recommendations are an official statement of the ACG and have been approved by the American Gastroenterological Association and the American Society for Gastroenterological Endoscopy. Firm recommendations are discriminated from reasonable suppositions pending definitive data. CONCLUSIONS: Since cure of H. pylori infection decreases recurrence rates and facilitates healing, antibiotic therapy is indicated for all H. pylori-infected ulcer patients. No optimal, simple antibiotic regimen has yet emerged. Simultaneous conventional ulcer therapy is recommended to facilitate symptom relief and healing. For refractory ulcers, only maximal acid inhibition offers advantage over continued conventional therapy; cure of H. pylori infection is likely to facilitate healing of refractory ulcers. Only with complicated or refractory ulcers should conventional maintenance therapy be continued, at least until successful H. pylori eradication is confirmed. A search for NSAID use is indicated for all ulcer patients. For NSAID-associated ulcers these drugs should be discontinued if possible and H. pylori, if present, should be cured.

Antacids↗
PubMed1996

Mononuclear cells and cytokines stimulate gastrin release from canine antral cells in primary culture.

Patients with Helicobacter pylori-associated gastritis have an increased release of gastrin. The mechanisms by which H. pylori affects the endocrine cells are unclear. We have used primary cultures containing canine antral G cells to examine the effects of human blood mononuclear cells, purified monocytes and lymphocytes, recombinant cytokines, and NH4Cl on gastrin release. Mononuclear cells and purified monocytes in direct contact with G cells stimulated gastrin release dose dependently. Separating mononuclear cells from G cells by Transwell filters with 0.4-micron pore size still produced a significant increase of gastrin release. Three human recombinant cytokines, interferon-gamma, tumor necrosis factor-alpha, and interleukin-2, but not interleukin-6 and interleukin-1 beta, each produced dose-dependent increases of gastrin stimulation. NH4Cl did not stimulate gastrin release. We conclude that mononuclear cells and purified monocytes prepared from human blood, as well as several cytokines, stimulate gastrin release from antral G cells. These factors may play an important role in the pathogenesis of H. pylori-associated hypergastrinemia.

Animals↗
PubMed1995

Different effects of indomethacin and nabumetone on prostaglandin-mediated gastric responses to central vagal activation in rats.

Intracisternal injection of a stable thyrotropin-releasing hormone (TRH) analog increases gastric prostaglandins release and mucosal resistance to injury through central vagal pathways. The effects of two nonsteroidal anti-inflammatory drugs, indomethacin (INDO) and nabumetone on intracisternal injection of various doses of TRH-induced gastric acid secretion and changes in mucosal resistance were investigated in urethane-anesthetized rats. Doses of INDO (5 mg/kg) and nabumetone (13.75 mg/kg) producing similar acute anti-inflammatory response in the carrageenin-induced paw edema were injected i.p. in all studies. INDO potentiated the acid secretion induced by intracisternal injection of TRH at 25, 50 and 200 ng by 5.1-, 1.9- and 1.4-fold, respectively, whereas nabumetone did not modify the secretory response to TRH. Moderate erosions were observed in 100% of rats treated with the combination of INDO and TRH (200 ng) whereas no erosions were observed when TRH or INDO were given alone or TRH in combination with nabumetone. TRH at 7 ng reduced mucosal damage induced by intragastric administration of ethanol (60%, 1 ml/kg) by 63%. The mucosal protective action of TRH was abolished by INDO but not altered by nabumetone pretreatment. These data indicate that at comparable anti-inflammatory doses, nabumetone, unlike INDO, neither blocks the protection against ethanol injury induced by low doses of TRH injected intracisternally nor potentiates the gastric acid secretion or lesions induced by higher dose of TRH. We speculate that these differences reflect reduced inhibition of gastric prostaglandins by nabumetone.

Animals↗
PubMed1994

Somatostatin is released in response to cholecystokinin by activation of type A CCK receptors.

Cholecystokinin is a principal mediator of intestinal fat-induced inhibition of gastric acid secretion, indicating that it is an important physiological enterogastrone. Cholecystokinin has been shown to inhibit acid secretion by activation of type A CCK receptors and through a mechanism involving somatostatin. In the present study, we investigated the possibility that these two mechanisms are directly related such that activation of type A CCK receptors by CCK causes the release of somatostatin. We tested this hypothesis in vivo in a study of CCK-stimulated release of somatostatin in dogs and in vitro in a study of CCK-stimulated release of somatostatin from an enriched culture of canine fundic D cells. In dogs, IV infusion of CCK (50 pmol/kg/h, IV) significantly increased circulating somatostatin concentrations above basal. Further, systemic administration of somatostatin MAb F(ab)1 fragments of a somatostatin monoclonal antibody prevented most of CCK-induced inhibition of meal-stimulated acid secretion. In canine fundic D cells in culture, CCK-stimulated somatostatin release was blocked in a dose-dependent fashion by application of a type A CCK receptor antagonist. This study indicates that CCK activates type A CCK receptors to release somatostatin from canine fundic mucosal D cells, and accounts for somatostatin-dependent CCK-induced inhibition of acid secretion.

Acids↗
PubMed1994

Effects of prostaglandins on gastrin release from canine antral mucosal cells in primary culture.

Evidence in vivo indicates that endogenous and exogenous prostaglandins can alter gastrin secretion. We have used primary cultures containing canine antral G-cells to study the cellular actions of prostaglandins on gastrin secretion, comparing the effects of prostaglandin E2 (PGE2) and its synthetic analogue enprostil. Enprostil (10(-10)-10(-6) M) inhibited gastrin secretion in response to bombesin, carbachol, and forskolin, the latter a receptor-independent activator of adenylate cyclase. This inhibition by enprostil was reversed by treatment with pertussis toxin (200 ng/ml, 8 h). However, enprostil did not inhibit the postreceptor stimuli 8-bromoadenosine 3',5'-cyclic monophosphate (10(-3) M), calcium ionophore A-23187 (10(-7) M), or 4 beta-phorbol 12-myristate 13-acetate (10(-8) M). In contrast, whereas PGE2 inhibited forskolin-stimulated gastrin release, PGE2 did not inhibit the response to carbachol or bombesin in control cultures. However, in pertussis toxin-treated cultures, PGE2 inhibition was reversed and, in contrast, the responses to bombesin, carbachol, and possibly forskolin were augmented. Indomethacin at a dose of 10(-5) M did not alter basal or bombesin-stimulated gastrin secretion. However, the somatostatin antibody CURE-S6 enhanced the response to forskolin and enhanced inhibition by PGE2, suggesting that endogenous somatostatin produced an inhibitory tone in these cultures and excluding the possibility that PGE2 acted via release of endogenous somatostatin. Our data suggest that in cultured antral cells gastrin release is regulated by inhibitory and stimulatory prostaglandin mechanisms.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenylate Cyclase Toxin↗
PubMed1994

Apical acidification induces paracellular injury in canine gastric mucosal monolayers.

We used primary monolayer cultures of enzyme-dispersed canine oxyntic mucosal cells mounted in Ussing chambers to characterize the apical barrier to H+. [3H]mannitol flux (MF) and [14C]inulin flux (IF) were used as size probes for tight junctions. Apical H+ produced a three-phase effect. In phase 1, as the apical pH was decreased from 7 to about 2.5, resistance (R) increased, but short-circuit current (Isc) did not change. In phase 2, an increased paracellular permeability developed at pH below 2.5-1.7, evidenced by decreased R and increased MF but not IF. Size sieving and monolayer integrity were preserved, and this paracellular leak was either fully reversed or stabilized by apical neutralization, depending on the duration of the paracellular leak. In phase 3, after sustained exposure to an apical pH below approximately 2, transepithelial integrity was lost; R decreased to fluid R, and both MF and IF increased. Basolateral acidification below pH 5.5 produced rapid monolayer disruption. Low concentrations of cytochalasin D (CD) decreased R and increased MF but not IF; apical acidification to pH 4 after CD increased R and decreased the MF, indicating reduced paracellular permeability by apical H+. Apical amiloride did not alter Isc; however, after 48 h of treatment with hydrocortisone and insulin, an amiloride-sensitive Isc component became evident. Our data indicate that the increase in R observed with apical acidification reflects decreased paracellular permeability and that the earliest injury with apical acidification is a selective paracellular leak.

Animals↗
PubMed1994

Future directions for reductionistic research in gastric secretion and defense.

Our theme centers on the complex processes that constitute and regulate the function of the gastric mucosa. Although some investigators promote the critical importance of a given element, such as acid, blood flow, or mucus, it is clear that both gastric secretory function and mucosal defense and repair mechanisms are multifactorial and are regulated by redundant control circuits. While it is true that critical studies can be performed in vivo with intact mucosa, at the same time it is frequently difficult, using these methods, to define the specific cellular elements involved in the regulation of secretion, defense, and repair. We now recognize that ulcer disease does not occur simply when this balance is thrown off. To the contrary, ulcer disease commonly occurs when the normal mucosal mechanisms are perturbed by Helicobacter pylori-associated gastro-duodenitis or nonsteroidal anti-inflammatory drugs. In the absence of such perturbation, the redundancy of the regulatory mechanisms underlying gastric secretion and the multiple lines of defense and healing would render ulcer disease rare indeed.

Epithelium↗
PubMed1994

Multiple pathways controlling acid secretion.

A simple balance exists between factors that promote ulcer disease (e.g., acid and pepsin secretion) and factors that protect the stomach from ulcer disease (e.g., mucosal defense mechanisms). These factors are regulated and control the integrity of the gastric mucosa. Some of the newest discoveries in the area of regulation of acid secretion are related to the cellular localization of physiologically relevant receptors for acid secretagogues and acid inhibitors. The ability to isolate and culture histamine-containing ECL cells and somatostatin-containing "D" cells, and the ability to clone genes encoding for specific receptors has greatly enhanced our understanding of the physiological role and the regulation of various cell types within the gastric mucosa.

Cells, Cultured↗
PubMed1993

Paracrine control of gastric epithelial cell growth in culture by transforming growth factor-alpha.

Studying primary cultures of replicating canine oxyntic mucosal cells, we found evidence for modulation of cell growth by endogenous factors. [3H]thymidine incorporation into DNA was rapid with cells cultured in medium free of serum or added growth factors, and growth rates of these cultures were markedly dependent on plating density, indicating mitogenic control by soluble endogenous growth factors. Data indicated that endogenous transforming growth factor-alpha (TGF-alpha) exerted mitogenic control under the following conditions. 1) TGF-alpha was detected in the cultured cells by radioimmunoassay and immunohistochemistry. 2) TGF-alpha-like immunoreactivity and receptor reactivity were present in the medium in concentrations sufficient to exert mitogenic control. 3) Receptors for TGF-alpha and epidermal growth factor (EGF) were present in the cultures. 4) Immunoabsorption by a TGF-alpha-specific antisera reduced [3H]thymidine incorporation. TGF-alpha was localized to parietal cells by immunohistochemistry and cell separation. In contrast, combined [3H]thymidine autoradiography and immunohistochemistry with anti-TGF-alpha did not detect TGF-alpha in dividing cells. We conclude that parietal cell TGF-alpha exerts paracrine control of mucosal cell growth in vitro, and we speculate that this is an important paracrine mechanism in vivo.

Cell Count↗
PubMed1993

Endogenous somatostatin inhibits histamine release from canine gastric mucosal cells in primary culture.

The effects of somatostatin on histamine release were studied using primary cultures of canine oxyntic mucosal cells in which mast cell content was reduced by density gradient. The S6 monoclonal antibody to somatostatin, but not control antibodies, enhanced gastrin-stimulated histamine release. In the presence of S6, the somatostatin analogue SMS-201-995 (10(-7) M) inhibited gastrin-stimulated histamine release by 95%. The dose producing 50% inhibition for this inhibition was approximately 3 x 10(-10) M and was completely reversed by pertussis toxin treatment. In contrast to somatostatin, epinephrine failed to inhibit this gastrin stimulation. However, the lectin concanavalin A (ConA) also stimulated histamine release from these cultures, and this response was inhibited by epinephrine but not by somatostatin. Thus somatostatin selectively inhibited the gastrin-responsive histamine pool, which presumably is stored in oxyntic mucosal endocrine cells. In contrast, epinephrine selectively inhibits histamine release from the ConA-sensitive pool, which is presumably stored in mast cells. Furthermore, enhancement of gastrin-stimulated histamine release by immunoneutralization of somatostatin indicates an important role for endogenous somatostatin as a paracrine inhibitor of non-mast cell histamine release.

Animals↗
PubMed1992

Gastrin induction of histamine release from primary cultures of canine oxyntic mucosal cells.

Using enzyme-dispersed canine oxyntic mucosal cells, we studied regulation of histamine release from fractions in which mast cells were largely removed by density gradient. Histamine-like immunoreactivity was demonstrated using peroxidase-anti-peroxidase immunohistochemistry. Histamine-containing cells in the small cell elutriator fractions (SCEF) were further separated by albumin step density gradients. Approximately 2.5% of cells in the low density fraction (LDF) contained histamine-like immunoreactivity; this fraction was largely depleted of the more dense mast cells (0.5%). These two fractions were cultured for 48-64 h on a Matrigel substrate. The cell content of histamine and release into the medium were measured by radioenzymatic assay. Gastrin, carbachol, and forskolin increased histamine release from the LDF. The induction of histamine release by gastrin was evident within 5 min and was sustained for at least 60 min. The response to gastrin was dose dependent between concentrations of 10(-11) and 10(-8) M. In contrast, in the mast cell-enriched SCEF, basal release was higher and gastrin was without effect; however, concanavalin A stimulated and epinephrine inhibited histamine release indicating that histamine-release mechanisms were intact in this fraction. Our methods provide a preparation of low density oxyntic mucosal histamine cells that demonstrate gastrin-responsive histamine release; we speculate that enterochromaffin-like cells account for this gastrin response.

Animals↗
PubMed1991

Nonsteroidal anti-inflammatory drugs and peptic ulcer disease.

Evidence has accumulated that nonsteroidal anti-inflammatory drugs (NSAIDs) cause clinically important gastroduodenal ulcers. The pathogenesis, which involves the impairment of mucosal resistance to injury in an acid-peptic environment, is multifactorial and controversial. Ulcers caused by NSAIDs can occur either in mucosa inflamed because of infection with Helicobacter pylori or in histologically normal mucosa. The use of these drugs has been linked to an unexpectedly high incidence of ulcer complications, and a history of peptic ulcer disease is common in such cases. Nonsteroidal anti-inflammatory drugs thus appear both to exacerbate an underlying peptic diathesis and to cause de novo ulcers. The association between the use of these drugs and ulcer complications is supported by ulcer prevalence data from cross-sectional studies, and by data from case-controlled and cohort studies, and from randomized, experimental trials. Drug-induced gastric ulcers have been prevented by misoprostol, but not by H2 blocker therapy. Several therapies have been reported to promote ulcer healing despite continued use of NSAIDs, but adequate controlled trials have not been done. Small gastric and duodenal ulcers readily heal, whereas larger gastric ulcers require vigorous and prolonged therapy. The relative efficacies of various therapies in preventing ulcers, healing ulcers, or preventing complications remain to be established.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed1991

Mitogenic response of canine fundic epithelial cells in short-term culture to transforming growth factor alpha and insulinlike growth factor I.

We report methods allowing the culture of rapidly dividing gastric epithelial cells to investigate the regulation of mucosal cell replication. Cells from canine fundic mucosa were dispersed by enzyme treatment, enriched by filtration and elutriation, and cultured on collagen gel in DMEM/F12 medium. After 48 h, greater than 95% of the cells displayed immunoreactivity with antibody to cytokeratin, an epithelial marker. The cells formed confluent monolayers by 72 h with a transmembrane resistance of 1,600 ohm.cm2 when mounted in a Ussing chamber indicating retention of epithelial cell characteristics. Calf serum (0.1-2%) produced a dose-dependent mitogenic effect evident by increases in [3H]-thymidine incorporation into acid-precipitated material and in cell number. After an 18-24-h incubation with [3H]-thymidine, approximately 55% of the cells cultured in 2% serum showed evidence of DNA synthesis by autoradiography and all of the replicating cells were cytokeratin positive. Using comparable culture conditions, a similar proportion of cells incubated for 18-24 h with bromodeoxyuridine displayed nuclear anti-bromodeoxyuridine immunoreactivity, thus indicating that over half of the cells in these cultures synthesized DNA during this period. As with serum, epidermal growth factor and transforming growth factor alpha (TGF alpha) (10 pM to 1 nM), insulin (10 nM to 1 microM) and insulinlike growth factor-I (IGF-I, 1-100 nM) increased [3H]-thymidine uptake. The greater potency of IGF-I, compared to insulin, suggests the presence of IGF-I receptors. We conclude that this culture preparation is composed of fundic mucosal epithelial cells and contains a predominance of dividing epithelial cells. EGF/TGF alpha and IGF-I are potential factors directly regulating proliferation of fundic mucosal cells.

Animals↗
PubMed1991

Gastrin-histamine interactions: direct and paracrine elements.

The receptors mediating the physiologic actions of gastrin on acid secretion and growth have thus far not been localized to specific cells or fully characterized. Studies in canine fundic mucosa indicate that gastrin receptors are present on several cell types, including parietal cells and somatostatin cells. There is also increasing evidence for a gastrin-inducible pool of histamine in the fundic mucosa which is presumably stored in histamine-enterochromaffin-like cells. From the vantage point of studies in the canine fundic mucosa, the issue is no longer which cell type has the gastrin receptor but to sort out the mechanisms by which the effects of the gastrin receptors on endocrine/paracrine (histamine and somatostatin) cells and exocrine (parietal) cells are integrated to regulate secretory function and mucosal growth and differentiation.

Animals↗