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Biomedical subjects

F Esteva

Publications and source records attributed to F Esteva.

17 recordsLinked to original sources
PubMed2000

Nitric oxide and superoxide anion in low-grade esophagitis induced by acid and pepsin in rabbits.

It has been suggested that free radicals are involved in esophagitis. To study the role and potential interaction of superoxide anion and nitric oxide (NO) in low-grade esophagitis, we perfused acidified pepsin (30 min every 12 hr) for seven days in rabbits treated with different agents to modulate the generation of these radicals. Measurements included macroscopic and microscopic damage, superoxide anion generation, mucosal nitric oxide synthase activity, and peroxynitrite formation. Low-grade esophagitis was associated with increased nitric oxide synthase mucosal activity and mucosal damage was dose-dependently increased by treatment with the NO synthase inhibitor NG-nitro-L-arginine. Superoxide anion was scarcely generated in the mucosa, but this was not accompanied by any change in the activity of mucosal superoxide dismutase. Treatment with superoxide dismutase did not improve mucosal damage. Generation of peroxynitrites was not detected. In conclusion, nitric oxide is involved in the mucosal defense of the esophagus against acid- and pepsin-induced damage. Superoxide anion generation seems irrelevant in the induction of low-grade esophagitis and not sufficient to interact with nitric oxide to generate measurable mucosal peroxynitrite radicals.

Animals↗
PubMed2000

Omeprazole does not interfere with the antiplatelet effect of low-dose aspirin in man.

BACKGROUND: Experimental studies have shown that omeprazole and other anti-inflammatory agents compromise the therapeutic activity of nonsteroidal anti-inflammatory drugs and aspirin in rats. It is not known whether this effect will occur in humans. Our aim was to determine whether omeprazole affects the antiplatelet effects of low-dose aspirin in humans. METHODS: Platelet lumiaggregation, skin bleeding time, plasma levels of aspirin and salicylic acid, and serum gastrin levels were determined in 14 healthy men before and after the ingestion of 125 mg aspirin with or without previous treatment with 20 mg/day of omeprazole for 4 days before testing. RESULTS: Omeprazole increased serum gastrin levels from 64 (median; range, 52-91) pg/ml to 80.5 (median; range, 56-455) pg/ml (P < 0.05) but did not significantly affect the plasma concentration of aspirin or salicylic acid. Aspirin increased skin bleeding time in all subjects, and the increase was similar with and without previous omeprazole treatment. Aspirin inhibited platelet aggregation in response to both collagen and arachidonic acid regardless of omeprazole treatment. CONCLUSION: A single dose of 20 mg omeprazole daily does not interfere with the biologic activity of 125 mg aspirin on platelets in humans.

Adult↗
PubMed2000

Platelet-derived growth factor and epidermal growth factor play a major role in human colonic fibroblast repair activities.

BACKGROUND AND AIMS: Ulceration is a common feature of inflammatory bowel diseases, where subepithelial cell growth is frequently necessary for resolution. In order to further understand the role of colonic fibroblasts in this process, we have used an in vitro model of wound repair to study the response of human colonic fibroblasts to several growth factors expressed in colonic tissues. METHODS: Proliferation was determined by [(3)H]thymidine incorporation into DNA in subconfluent fibroblast cultures. In vitro wound repair was determined in confluent fibroblast monolayers after mechanical denudation. The presence of growth factors secreted by fibroblasts was studied in conditioned medium by heparin affinity chromatography and immunodetection with specific antibodies. RESULTS: Serum and platelet-derived growth factor (PDGF-BB) induced a dramatic increase in both colonic fibroblast proliferation and closure of wounded cell monolayers. Epidermal growth factor (EGF) stimulated both fibroblast activities, but the effect was less potent. However, colonic fibroblasts did not respond to transforming growth factor-beta(1). Conditioned medium stimulated fibroblast proliferation and wound repair activity, which was reverted by the addition of suramin. Furthermore, a PDGF-like factor was isolated from colonic fibroblast-conditioned medium. CONCLUSIONS: EGF and PDGF-BB promote human colonic fibroblast-dependent wound repair activities. Human colonic fibroblasts may exert an autocrine regulation via the production of growth factors.

Cell Division↗
PubMed1999

Effects of extracellular pH on restitution and proliferation of rabbit oesophageal epithelial cells.

BACKGROUND AND AIMS: Exposure to luminal acid induces mucosal damage in the oesophagus. The extent and degree of interaction of acid with wound repair mechanisms of the oesophagus have not been explored. METHODS: Rabbit oesophageal cells were isolated, cultured and exposed to different extracellular pHs for several periods of time. Cell mortality was studied in both isolated and primary cultures of these cells by cell flow cytometry using fluorochrome propidium iodide and LDH release. Subconfluent cell cultures were used to study proliferative responses determined by [3H]-thymidine incorporation into DNA. Restitution was studied in confluent monolayers wounded by mechanical denudation. RESULTS: Isolated cells were resistant to acid when exposed to pH > 2 for 15 min. Cell proliferation increased with small pH decreases (7-6.5) if the period of exposure was less than 6 h, but was inhibited with lower pHs and/or longer periods of acid exposure. However, restitution was gradually inhibited with further pH decreases (6.5-3) and time of acid exposure (0.5-24 h). CONCLUSIONS: The wound repair activities of oesophageal epithelial cells are deeply affected by even small decreases in pH. These findings may help to explain the need for profound acid inhibition in acid-related reflux oesophagitis.

Animals↗
PubMed1998

In vitro wound repair by human gastric fibroblasts: implications for ulcer healing.

Fibroblasts modulate epithelial biological activities and play a key role in the ulcer healing process. There is no information regarding the biological response of human gastric fibroblasts to regulatory compounds. The aim of this study was to assess the effects of growth factors and prostaglandins on an in vitro model of human gastric fibroblast wound repair. Subconfluent fibroblast cultures were used to study proliferative responses, determined by [3H]thymidine incorporation into DNA. In vitro wound repair was determined in confluent fibroblast monolayers after mechanical denudation. The presence of putative growth factors secreted by fibroblasts was studied in conditioned medium by heparin-affinity chromatography and immunodetection with specific antibodies. Serum and platelet-derived growth factor (PDGF) -BB induced a dramatic increase in both gastric fibroblast proliferation and closure of wounded cell monolayers, whereas these activities were inhibited by both transforming growth factor (TGF) -beta1 and prostaglandin E1. Basal activities in unstimulated gastric fibroblasts were lower than those obtained in skin fibroblasts. Conditioned medium stimulated fibroblast proliferation and wound repair activity, which was inhibited by the addition of suramin, and was partially dependent on the presence of PDGF-like factor. PDGF is a major, autocrine promotor of human gastric fibroblast-dependent wound repair activities, which are inhibited by prostaglandins and TGF-beta. These findings might be important for future therapeutic ulcer healing approaches.

Adult↗
PubMed1998

Effect of growth factors and prostaglandin E2 on restitution and proliferation of rabbit esophageal epithelial cells.

Factors and mechanisms involved in esophageal mucosal injury and repair are not well known. The aim of this study was to assess the effects of growth factors and prostaglandins on esophageal mucosal cell repair activities. Rabbit esophageal cells were isolated, cultured, and exposed to different growth factors and prostaglandin E2. Subconfluent cell cultures were used to study proliferative responses determined by [3H]thymidine incorporation into DNA. Restitution was studied in confluent monolayers wounded by mechanical denudation. Restitution was the main mechanism involved in wound repair within the first 24 hr. HGF, IGF-I, and EGF dose-dependently stimulated cell proliferation but did not affect restitution. TGF-beta1 inhibited both proliferation and restitution while PDGF-BB and prostaglandin E2 had no effect. Esophageal epithelial cell restitution and proliferation are affected by growth factors. HGF, IGF-I, EGF (stimulation), and TGF-beta1 (inhibition) are major growth factors affecting in vitro esophageal wound repair activities, which, unlike those of other areas of the digestive tract, are not affected by prostaglandins.

Animals↗
PubMed1998

Collagen secretion by human gastric and skin fibroblasts: implications for ulcer healing.

Fibroblasts (FIB) play an important role in the wound-healing process. It is not known whether human skin and gastric FIB show different responses to regulatory compounds. In this study, we have examined the collagen production by these FIB after different stimuli. In vitro release of collagen into the medium by steady-state confluent human FIB cultures was assessed over a 24-hour period by 3H-proline incorporation into collageneous protein. Serum and epidermal growth factor increased collagen secretion in both types of FIB, but gastric FIB produced less collagen than skin FIB. Prostaglandin E1 inhibited collagen production in both types of FIB, but nonsteroidal anti-inflammatory drugs and interleukin-1beta, a cytokine involved in the wound-healing process, had opposite effects on gastric and skin FIB. The effects of lipoxygenase metabolites on collagen secretion was small, but different in both types of FIB. We conclude that, when compared to skin FIB, human gastric FIB produce less collagen and show pronounced different responses to different agents, which might be relevant to explain (in part) their clinical effects on ulcer healing. These data provide new insights into the wound-healing process.

Adult↗
PubMed1997

Prostaglandin E2 is the major arachidonic acid metabolite secreted by esophageal mucosal cells in rabbits.

Unlike gastric mucosa, it has been considered that lipoxygenase metabolites protect the esophageal mucosa and that prostaglandins are only secreted in the presence of esophageal inflammation. The aim of this study was to determine the profile of arachidonic acid metabolites and their response to regulatory compounds in rabbit esophageal mucosal cells in culture. Eicosanoids secreted into the medium were extracted and identified by HPLC and RIA. Esophageal mucosal cells in culture metabolized arachidonic acid mainly through the cycloxygenase pathway and PGE2 was the major arachidonic acid metabolite secreted. The addition of IL-1 beta and A23187 (calcium ionophore) stimulated PGE2 synthesis. In basal conditions neither leukotrienes nor HETEs were detected. However, the addition of the NDGA induced the secretion of lipoxygenase metabolites identified as 12-15 HETEs. In conclusion, rabbit esophageal epithelial cells in culture metabolize arachidonic acid via both cycloxygenase and lipoxygenase pathways. In our system, PGE2 was the main arachidonic acid metabolite.

6-Ketoprostaglandin F1 alpha↗
PubMed1997

Evidence of aspirin use in both upper and lower gastrointestinal perforation.

BACKGROUND & AIMS: Current studies lack appropriate data on aspirin and other risk factors for gastrointestinal perforation. The aim of this study was to obtain the best estimate on aspirin and nonaspirin nonsteroidal anti-inflammatory drug (NSAID) use in these patients. METHODS: In 76 consecutive patients with gastrointestinal perforation and 152 matched controls, a detailed clinical history supplemented with an objective test of current aspirin use (platelet cyclooxygenase activity) was obtained. RESULTS: Of the 76 cases, 78.9% were upper and 21% lower gastrointestinal perforations. Evidence of NSAID use was found in 71% of cases (70% upper, 75% lower) vs. 26.9% of controls (odds ratio, 6.64; 95% confidence interval, 3.6-12.2; P < 0.0001). The objective test showed 12.7% more aspirin users than clinical history alone. NSAID use was aspirin (alone or combined) in 66.6% of cases, and 59.25% was nonprescription. Other independent risk factors were smoking, alcohol, and a history of arthritis or peptic ulcer but not a positive Helicobacter pylori serology. Age, but not NSAID use, affected perforation-associated mortality. CONCLUSIONS: NSAID use is strongly associated with an increased risk of both upper and lower gastrointestinal perforation. The high prevalence of aspirin (over-the-counter) use suggests that future introduction of new NSAIDs may not have a major impact on decreasing gastrointestinal complications if other measures are not taken. Concomitant NSAID use, smoking, and alcohol use is a pervasive association.

Aged↗
PubMed1996

Aspirin related gastrointestinal bleeders have an exaggerated bleeding time response due to aspirin use.

BACKGROUND: Gastrointestinal bleeding is related to non-steroidal anti-inflammatory drug (NSAID) use, especially aspirin, but only a small subset of users bleed. AIM: To look for risk factors or mechanisms whereby aspirin may promote gastrointestinal bleeding. PATIENTS: Sixty one patients with previous aspirin related upper gastrointestinal bleeding and 61 matched controls. METHODS: Patients and controls were given 375 mg of aspirin and sequential skin bleeding time and blood aspirin levels were measured. Additional studies included platelet lumiaggregation, von Willebrand factor, Factor VIII, and coagulation studies. RESULTS: Baseline skin bleeding time was similar in bleeders and controls, but bleeders had a more prolonged skin bleeding time after aspirin use. Hyper-response was more frequent in bleeders (30% v 9.3%; p < 0.01) and was associated with more than one previous separate bleeding event and a lower packed cell volume during the preceding bleeding episode. No differences were found in other factors studied. Logistic regression analysis identified prolonged skin bleeding time after aspirin use as an independent factor contributing to aspirin related gastrointestinal bleeding (RR = 5.4; 95% CI: 1.8 to 17.1). CONCLUSIONS: 30% of patients with a history of aspirin related gastrointestinal bleeding have an exaggerated prolongation of skin bleeding time in response to aspirin, which may be a risk factor for bleeding. This intrinsic defect or to subclinical von Willebrand disease or different aspirin metabolism.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed1995

Risk factors associated with refractory peptic ulcers.

BACKGROUND & AIMS: The risk factors associated with refractory peptic ulcers are still undefined. The purpose of this study was to identify these factors in a multivariate context. METHODS: Clinical and endoscopic findings as well as Helicobacter pylori status, gastric secretion analysis, serum gastrin levels, nonsteroidal anti-inflammatory drug (NSAID) use, and objective testing of aspirin use by platelet cyclooxygenase activity were studied in 60 consecutive refractory patients with peptic ulcer and 54 matched nonrefractory controls. RESULTS: Refractory patients had a longer history of symptomatic ulcer, had an earlier onset, had more frequent relapses, and smoked more during the episode of refractoriness. H. pylori status was similar in both groups, but H. pylori eradication in a subset of refractory patients (23 of 26) was highly effective in healing these ulcers (14 of 23). Globally, NSAID-analgesic abuse (including > 1500 mg/day paracetamol) was present in 40% of refractory patients (P < 0.006). Objective testing showed that 43.7% of NSAID use was surreptitious. Multivariate logistic regression analysis identified only NSAID and analgesic abuse and the number of relapses as individually affecting refractoriness. CONCLUSIONS: NSAID and analgesic abuse is the single most important exogenous factor associated with refractoriness. H. pylori infection emerges as an important intrinsic factor, but almost a quarter of refractory patients cannot be linked to either NSAID use or H. pylori infection.

Alcohol Drinking↗
PubMed1995

Aspirin renders the oesophageal mucosa more permeable to acid and pepsin.

OBJECTIVE: To examine the effects of aspirin on the oesophageal mucosa and on acid- and pepsin-induced oesophagitis. DESIGN AND METHODS: The effects both of intraluminal (18 mg/ml) and of parenteral (100 mg/kg per h) aspirin on an in-vivo rabbit model of oesophagitis induced by acidified pepsin (pH 2) were studied. Oesophageal injury was assessed by macroscopic and microscopic scoring including the cell proliferation immunohistochemical parameter mib1. The mucosal barrier function was determined by hydrogen, potassium and haemoglobin flux rates. RESULTS: Acidified saline alone caused no damage, but the addition of aspirin induced mucosal barrier damage (P < 0.05). The exposure of the oesophageal mucosa to acidified aspirin and then acidified pepsin significantly increased mucosal injury and mucosal barrier dysfunction compared with control experiments (exposure to acidified saline and acidified pepsin). This damage was significantly (P < 0.05) reduced (> 40%) by prostaglandin cotherapy (prostaglandin E2) administered before acidified aspirin exposure. Mucosal damage was less severe (P < 0.05) when the oesophageal mucosa was exposed to a pH 6 aspirin solution. Parenterally administered aspirin also increased the oesophageal damage induced by acidified pepsin compared with control experiments, but the damage was 23% lower than that obtained with intraluminal aspirin. Cell proliferation studies showed a significant increase in the number of positive cells in those experiments with a higher degree of damage and in those treated with prostaglandins. CONCLUSION: Aspirin renders the oesophageal mucosa more permeable to acid and pepsin. These effects are in part pH-dependent and might be partially reversed by prostaglandin E2 cotherapy.

Acids↗
PubMed1995

Non-steroidal anti-inflammatory drugs and prostaglandin effects on pepsinogen secretion by dispersed human peptic cells.

The effects of aspirin and ibuprofen on pepsinogen secretion were studied in isolated human peptic cells prepared from endoscopically obtained biopsy specimens after collagenase digestion, mechanical disruption, and percoll gradient centrifugation. Pharmacological concentrations of aspirin and ibuprofen (10(-8)-10(-4) M), potentiated histamine (10(-6)-10(-4)M) and forskolin (10(-5)M) stimulated pepsinogen secretion without affecting basal secretion, acetylcholine (10(-6)M) stimulated pepsinogen secretion or cell vitality. Augmentation of secretagogue stimulated pepsinogen secretion was dependent on extracellular calcium because potentiation was abolished by calcium depletion of the medium. Cimetidine inhibited the potentiation effect on histamine but not on forskolin stimulated pepsinogen secretion, thus suggesting that this augmentation was independent of histamine H2 receptors. Of interest, potentiation was also independent of endogenous prostaglandin inhibition because exogenous addition of prostaglandin E2 and D2 increased both basal and acetylcholine stimulated pepsinogen secretion in a dose dependent way, but they did not modify histamine or histamine plus aspirin or ibuprofen stimulated pepsinogen secretion. In conclusion, aspirin and ibuprofen potentiate secretagogue stimulated pepsinogen secretion by dispersed human peptic cells and this might be an additional mechanism of non-steroidal anti-inflammatory drug (NSAID) induced gastric injury. This potentiation effect is regulated by calcium, independent of endogenous prostaglandin inhibition and seems to act on pepsinogen secretion at a post-receptor site.

Acetylcholine↗
PubMed1995

Increased gastric acid secretion after massive small bowel resection is related to a decrease in enterogastrones.

The reported increase of gastric secretion after small bowel (SB) resection is controversial. To determine the effect of SB resection on gastric acid secretion we studied basal and dose step pentagastrin-stimulated gastric acid secretion as well as basal serum gastrin, secretin, neurotensin and postprandial gastrin levels in 12 dogs, before and after resection of 60% of the intestine representing both proximal (n = 6) and distal (n = 6) SB. Rat bioassay was also performed to rule out the presence of unknown gastric secretagogues in the blood. Proximal SB resection produced a significant increase in basal and low dose (100 ng/kg/h) pentagastrin-stimulated gastric acid secretion (ED50 = 1,110 vs. 720 ng/kg/h after resection). However, no significant changes in gastric secretion were observed after distal SB resections. Neither proximal nor distal SB resection altered basal or postprandial serum gastrin levels. Proximal SB resection reduced serum secretin levels (229 +/- 38 vs. 134 +/- 16 pg/ml, p < 0.05) but did not alter neurotensin levels. Rat bioassay failed to reveal a circulating secretagogue after SB resections. We conclude that proximal but not distal SB resection increases basal and submaximally stimulated gastric acid secretion. Such an effect may be due to the observed decrease in circulating secretin levels.

Animals↗
PubMed1987

[Alpha-adrenergic receptors in the hepatic sinusoid of the rat and its relation to portal pressure].

The presence of alpha-adrenergic receptors in the hepatic sinusoid of the rat, and its relation to portal pressure (PP), by local and systemic infusion of bolus doses of norepinephrine (NE) (1 microgram/100 g) and phentolamine (FA) (25 micrograms/100 g) have been studied. Fifty-five male Wistar rats with intact nerves have been used in 5 experiments. When NE is injected into the portal vein (PV), it provokes an immediate rise in PP, modified subsequently by the systemic effect is induced earlier and more intensely than if injected into PV. If FA is infused into PV, PP decreases and the effect of posterior infusion of NE is less marked. These results suggest the presence of alpha-adrenergic receptors in the hepatic sinusoid of the rat. When they are stimulated PP raises, indicating that basal PP is maintained not only because of hepatic arterial flow, but also through a distinct sympathetic tone.

Animals↗