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W1700 Eosinophils and Their Products Activate Human Esophageal Mesenchymal Cells – Implications for Fibrogenesis in Eosinophilic Esophagitis (EoE)
AGA Abstracts
W1699
in lipopolysaccharide and ventilator-induced lung injury. Previously, we showed that NSAIDs treatments increase GADD45alpha expression In Vitro, in human gastric mucosal epithelial cells in culture, indicating that GADD45alpha plays a role in NSAIDs-induced gastric mucosal injury. In this study, we determined, In Vivo, the importance of GADD45alpha expression in acute gastric mucosal injury by NSAIDs. Methods: C57BL/6 wildtype (WT) and GADD45alpha null mice (-/-) were treated with vehicle only, 15mg/kg indomethacin, or 30mg/kg sulindac via intraperitoneal injections (N=12 mice per treatment condition). 6 hours later, stomachs were removed and the extent of gastric injury was determined by morphometric measurements. Total protein extracts from gastric mucosal scrapings were utilized to determine GADD45alpha protein levels by Western blot analysis. The extent of apoptosis at the site of injury was examined by immunofluorescence staining for active caspase-3. Results: In WT mice: 1) Both indomethacin and sulindac treatments significantly increased Gadd45alpha protein levels (3.90 +/- 0.70 and 2.60 +/- 0.20 fold, respectively; p< 0.05), compared to vehicle only treatment (1.00 +/- 0.02 fold). 2) The treatments also induced extensive gastric mucosal erosion (19.20 +/- 7.30 % and 16.00 +/- 9.70% injury, respectively; p< 0.05), compared to vehicle only treatment (1.81 +/- 1.23 % injury). 3) Active caspase-3 was detected at basal levels in vehicle only treated gastric mucosa, but increased 7 and 5 fold in indomethacin and sulindac treated gastric mucosa, respectively. In -/- mice: 4) Absence of Gadd45alpha protein was confirmed in all vehicle and NSAIDs treated gastric mucosa. 5) Indomethacin and sulindac treatments induced only minimal amounts of gastric mucosal erosion (4.11 + /-3.34 % and 0.75+ 1.49% injury, respectively; p> 0.05), compared to vehicle only treatment (0.97 +/- 1.79 % injury). 6) Active caspase-3 was detected at basal levels in vehicle only treated gastric mucosa, but increased 3 and 2 fold in indomethacin and sulindac treated gastric mucosa, respectively. Conclusion: Induction of the stress signaling response pathway(s) involving Gadd45alpha activation is an important mechanism of NSAIDinduced gastric mucosal injury and apoptosis.
Gene Therapy With Adenovirus Encoding Egr-1 Increased Endogenous Egr-1, VEGF, PDGF and Bfgf Expression and Accelerated Healing of Chronic Duodenal Ulcer in Rats Xiaoming Deng, Longchuan Chen, Tetyana Khomenko, Ximing Xiong, Ganna Tolstanova, Zsuzsa Sandor, Jeffrey Milbrandt, Sandor Szabo We previously demonstrated that gene therapy with naked DNA and adenovirus (AV) of VEGF (vascular endothelial growth factor) or PDGF (platelet-derived growth factor) significantly accelerated chronic duodenal ulcer healing (Deng et al., J Pharmacol Exp Ther 2004; 311:982988). In this study we tested the effect of gene therapy with AV encoding early growth response-1 (egr-1), a gene for Egr-1 transcription factor having promoter sites for angiogenic factors such as VEGF, PDGF and bFGF (basic fibroblast growth factor), on the healing of experimental chronic duodenal ulcer. Methods: Groups of unfasted Sprague-Dawley female rats (180-210g) were given a single dose of cysteamine-HCl (85mg/100g by gavage) to induce duodenal ulcers. The ulcer size was evaluated during laparotomy on the 3rd day after cysteamine and rats with equal severity of duodenal ulcers were randomly divided into the 4 groups which received intraduodenal injection of a single dose (2 x 109 pfu/rat) of AV-Lac Z (control) or AV-egr-1 at laparotomy. The rats were euthanized on the 7th or 14th day after cysteamine administration. To examine whether AV-egr-1 stimulates endogenous egr-1 overexpression, additional groups of rats were given a pretreatment with a single dose (2 x 109 pfu/rat, i.v.) of AV-egr-1 or AV-Lac Z 0.5 hr before cysteamine and euthanized at 0.5, 2, 12, and 24 hr after cysteamine. Healing of the duodenal ulcers was evaluated at autopsy and by histology, and ulcer area was calculated by the ellipsoid formula. Mucosal scrapings of 2 cm proximal duodenum obtained at autopsy were homogenized and tested for gene and protein expression of Egr-1, VEGF, PDGF and bFGF by Real-time PCR and Western blotting. Results: Duodenal ulcer size was significantly reduced in rats treated with AV-egr-1 compared to AV-Lac Z-treated rats both on day 7 (2.6±0.7 vs. 6.5±1.9 mm2) and day 14 (2.1±0.8 vs. 5.6±1.9 mm2). Real-time PCR and Western blots showed that gene and protein expression of egr-1 was markedly increased as early as 0.5 and 2 hr followed by early increased expression of VEGF at 2 hr, and increased levels of PDGF and bFGF at 12, and 24 hr, respectively, after cysteamine. Increased levels (2- to 4-folds) of VEGF, PDGF and bFGF were also seen at days 7 and 14 in the rats with AV-egr-1 gene therapy compared to the controls. Conclusions: 1) Gene therapy with AV-egr-1 significantly accelerated duodenal ulcer healing in rats. 2) Increased levels of Egr-1, VEGF, PDGF and bFGF after AVegr-1 likely play important roles in the duodenal ulcer healing. 3) Thus, AV-egr-1 gene therapy seems to be a new option to achieve a rapid duodenal ulcer healing.
W1702 HLA-DQ Genotype Predicts Severity of the Intestinal Lesion, Chance of Healing on a Gluten-Free Diet After 12 Months and Likelihood of Systemic Complications in Newly Coeliac Disease Sue J. Shepherd, Rebecca Burgell, Patrick Hosking, Peter R. Gibson The relationships of HLA-DQ2 gentoype to clinical phenotype and outcomes are uncertain due to variability of reported results. For example, DQ2 dosage may or may not predict to severity of clinical presentation and the duodenal lesion at diagnosis, but does predict the likelihood of complicating of T-cell lymphoma. However, the majority of studies have been retrospective from tertiary referral hospital cohorts, opening the results to selection bias. Most studies have also been performed in paediatric populations; the applicability of findings in children to patients diagnosed as adults is uncertain. Objective: To examine association of HLA-DQ genotype with: -clinical phenotype in a patients presenting with newly diagnosed celiac disease - healing duodenal lesion after 12 months' diet Methods: HLA typing was performed on 99 consecutive patients presenting for dietary management of newly-diagnosed coeliac disease. Genotype was compared with the severity of gut symptoms, coeliac serology, the nature of the duodenal lesion, anthropometry (BMI, waste-hip ratio), body composition (nitrogen index, potassium index, sarcopenic index), and bone mineral density. The first 53 patients were prospectively studied over 12 months, including assessment of adherence to diet, serology and duodenal histology after 12 months. Results: The mean age (range) of the 99 patients was 39 (18-71) years. 24% were men. 9 different HLA-DQ genotypes were identified. The Table shows some of the phenotypic associations with genotypes divided into those expressing DQ2 in both alleles (“full DQ2”) or in only one (“half DQ2”), or complex heterozygotes (DQ2/DQ8). No significant differences were evident with genotype or of the genotypic groups in relation to the age, sex, anthropometry or severity of gut symptoms and serology (tissue transglutaminase and endomysial antibodies). Conclusions: In this prospectively studied, unselected cohort, HLA genotype predicts the severity of the villous lesion, likelihood of bony complications and ability to heal the duodenal lesion after 12 months' gluten-free diet. HLA-DQ assessment is a potentially important prognostic marker. Phenotype according to HLA-DQ 2 genotype at diagnosis
W1700 Eosinophils and Their Products Activate Human Esophageal Mesenchymal Cells - Implications for Fibrogenesis in Eosinophilic Esophagitis (EoE) Florian Rieder, Ilche T. Nonevski, Zhufeng Ouyang, Gail West, Anja Schirbel, John R. Goldblum, Tracey L. Bonfield, James J. Lee, Gary W. Falk, Claudio Fiocchi BACKGROUND: Organ fibrosis is a serious complication of EoE. We investigated mechanisms of fibrogenesis in EoE by assessing the response of primary human esophageal fibroblasts (HEF) and muscle cells (HEMC) to eosinophil-derived products and eosinophil contact; spontaneous production of fibrogenic cytokines in esophageal biopsies from EoE and control patients was also investigated. METHODS: Production of fibronectin (FN) and collagen I (Col I) by HEF and HEMC in response to selected cytokines, eosinophil products and eosinophil contact was measured by ELISA or RIA. αSMA, and VCAM-1 expression was assessed by flow cytometry and immunocytochemistry. Eosinophil adhesion assays were performed using the human eosinophil cell line AML14.3D10. TGF-β1 and p38MAPK signaling was inhibited by SB431542 and SB203580, respectively. The fibrogenic cytokines IL-4, IL-13, and TGF-β1 were measured in undernatants of biopsy organ cultures by Luminex. RESULTS: Among multiple cytokines secreted by eosinophils (IL-4, IL-5, IL-6, IL-13, eotaxin 1, and TGF-β1) TGF-β1 induced a significant increase in FN and Col I (p<0.001) production by HEF and HEMC, and IL-4 of Col I (p<0.05); IL-4, IL-6, IL-13 and TGF-β1 also increased HEF and HEMC αSMA expression, indicating transformation to a pro-fibrogenic phenotype. Direct physical contact with eosinophils increased production of FN and Col I >2-fold; if eosinophils were pre-activated (IL-3+IL-5+GM-CSF) production increased even further, whereas impeding eosinophil contact (transwell system) inhibited production. Sonicates of pre-activated eosinophils also increased FN and Col I production by HEF and HEMC. Blocking TGF-β1 and p38MAKP signaling reduced FN secretion by 49% and 56%, respectively, and by 62% when combined. Eosinophil binding increased by treating HEF and HEMC with IL4, IL-13, TGF-β1, native eosinophil major basic protein (MBP) or eosinophil sonicates; combined TGF-β1 and p38MAKP blockade reduced sonicate-induced eosinophil adhesion by 45% and completely abrogated the TGF-β1-induced adhesion. IL-4 and IL-13, but not TGF-β1 or eosinophil sonicates, increased VCAM-1 expression. Higher concentrations of IL-13 and TGF-β1, but not IL-4, were present in EoE compared to control esophageal mucosal biopsy cultures. CONCLUSION: Exposure to eosinophil-derived cytokines, degranulation products or eosinophil sonicates increases FN and Col I production by and eosinophil binding to esophageal mesenchymal cells through TGF-β1 and p38MAPK pathways. Thus, the EoE inflammatory milieu, while driving a direct primary fibrogenic response, also promotes eosinophil retention that induces an indirect activation of secondary fibrogenic pathways.
W1703 Survivin is a Key Factor in the Differential Susceptibility of Gastric Endothelial and Epithelial Cells to Alcohol-Induced Injury Michael K. Jones, Oscar R. Padilla BACKGROUND/AIMS: We previously demonstrated that the anti-apoptosis protein, survivin, plays a protective role against alcohol-induced gastric injury. Since the endothelium is a primary target of alcohol-induced gastric damage, we investigated whether survivin expression is a key factor in the greater susceptibility of gastric endothelial vs. epithelial cells to alcohol-induced injury. METHODS: Rat gastric epithelial (RGM1) and rat gastric microvascular endothelial (RGMEC) cells were exposed to either 5% ethanol, to assess overall cell damage, or 3% ethanol to assess apoptosis. siRNA was used to suppress survivin expression while transient transfection was used to elicit survivin overexpression. STUDIES: 1) Survivin protein expression levels by immunoblot analysis; 2) Cell damage by LDH assay; 3) Apoptosis by TUNEL assay. RESULTS: Rat gastric epithelial cells expressed 7.5-fold (P<0.0001) greater survivin protein levels vs. rat gastric endothelial cells. Survivin expression correlated with resistance of gastric epithelial vs. endothelial cells to both alcohol-induced cell damage (20 ± 3% vs. 65 ± 14%, P<0.005) and alcohol-induced apoptosis (12 ± 7% vs. 32 ± 4%,
W1701 Inhibition of Gadd45alpha Expression In Vivo Confers Resistance to Indomethacin and Sulindac Induced Gastric Mucosal Injury Shiun-Kwei Chiou, Amy M. Hodges Background: Regular users of nonsteroidal anti-inflammatory drugs (NSAIDs) such as indomethacin and sulindac experience gastric erosions and ulcers. NSAIDs cause gastric damage via several mechanisms, including apoptosis. Gadd45alpha is an important stress signal response gene involved in regulation of DNA repair and apoptosis, and is recently implicated
AGA Abstracts
S-722
W1699
in lipopolysaccharide and ventilator-induced lung injury. Previously, we showed that NSAIDs treatments increase GADD45alpha expression In Vitro, in human gastric mucosal epithelial cells in culture, indicating that GADD45alpha plays a role in NSAIDs-induced gastric mucosal injury. In this study, we determined, In Vivo, the importance of GADD45alpha expression in acute gastric mucosal injury by NSAIDs. Methods: C57BL/6 wildtype (WT) and GADD45alpha null mice (-/-) were treated with vehicle only, 15mg/kg indomethacin, or 30mg/kg sulindac via intraperitoneal injections (N=12 mice per treatment condition). 6 hours later, stomachs were removed and the extent of gastric injury was determined by morphometric measurements. Total protein extracts from gastric mucosal scrapings were utilized to determine GADD45alpha protein levels by Western blot analysis. The extent of apoptosis at the site of injury was examined by immunofluorescence staining for active caspase-3. Results: In WT mice: 1) Both indomethacin and sulindac treatments significantly increased Gadd45alpha protein levels (3.90 +/- 0.70 and 2.60 +/- 0.20 fold, respectively; p< 0.05), compared to vehicle only treatment (1.00 +/- 0.02 fold). 2) The treatments also induced extensive gastric mucosal erosion (19.20 +/- 7.30 % and 16.00 +/- 9.70% injury, respectively; p< 0.05), compared to vehicle only treatment (1.81 +/- 1.23 % injury). 3) Active caspase-3 was detected at basal levels in vehicle only treated gastric mucosa, but increased 7 and 5 fold in indomethacin and sulindac treated gastric mucosa, respectively. In -/- mice: 4) Absence of Gadd45alpha protein was confirmed in all vehicle and NSAIDs treated gastric mucosa. 5) Indomethacin and sulindac treatments induced only minimal amounts of gastric mucosal erosion (4.11 + /-3.34 % and 0.75+ 1.49% injury, respectively; p> 0.05), compared to vehicle only treatment (0.97 +/- 1.79 % injury). 6) Active caspase-3 was detected at basal levels in vehicle only treated gastric mucosa, but increased 3 and 2 fold in indomethacin and sulindac treated gastric mucosa, respectively. Conclusion: Induction of the stress signaling response pathway(s) involving Gadd45alpha activation is an important mechanism of NSAIDinduced gastric mucosal injury and apoptosis.
Gene Therapy With Adenovirus Encoding Egr-1 Increased Endogenous Egr-1, VEGF, PDGF and Bfgf Expression and Accelerated Healing of Chronic Duodenal Ulcer in Rats Xiaoming Deng, Longchuan Chen, Tetyana Khomenko, Ximing Xiong, Ganna Tolstanova, Zsuzsa Sandor, Jeffrey Milbrandt, Sandor Szabo We previously demonstrated that gene therapy with naked DNA and adenovirus (AV) of VEGF (vascular endothelial growth factor) or PDGF (platelet-derived growth factor) significantly accelerated chronic duodenal ulcer healing (Deng et al., J Pharmacol Exp Ther 2004; 311:982988). In this study we tested the effect of gene therapy with AV encoding early growth response-1 (egr-1), a gene for Egr-1 transcription factor having promoter sites for angiogenic factors such as VEGF, PDGF and bFGF (basic fibroblast growth factor), on the healing of experimental chronic duodenal ulcer. Methods: Groups of unfasted Sprague-Dawley female rats (180-210g) were given a single dose of cysteamine-HCl (85mg/100g by gavage) to induce duodenal ulcers. The ulcer size was evaluated during laparotomy on the 3rd day after cysteamine and rats with equal severity of duodenal ulcers were randomly divided into the 4 groups which received intraduodenal injection of a single dose (2 x 109 pfu/rat) of AV-Lac Z (control) or AV-egr-1 at laparotomy. The rats were euthanized on the 7th or 14th day after cysteamine administration. To examine whether AV-egr-1 stimulates endogenous egr-1 overexpression, additional groups of rats were given a pretreatment with a single dose (2 x 109 pfu/rat, i.v.) of AV-egr-1 or AV-Lac Z 0.5 hr before cysteamine and euthanized at 0.5, 2, 12, and 24 hr after cysteamine. Healing of the duodenal ulcers was evaluated at autopsy and by histology, and ulcer area was calculated by the ellipsoid formula. Mucosal scrapings of 2 cm proximal duodenum obtained at autopsy were homogenized and tested for gene and protein expression of Egr-1, VEGF, PDGF and bFGF by Real-time PCR and Western blotting. Results: Duodenal ulcer size was significantly reduced in rats treated with AV-egr-1 compared to AV-Lac Z-treated rats both on day 7 (2.6±0.7 vs. 6.5±1.9 mm2) and day 14 (2.1±0.8 vs. 5.6±1.9 mm2). Real-time PCR and Western blots showed that gene and protein expression of egr-1 was markedly increased as early as 0.5 and 2 hr followed by early increased expression of VEGF at 2 hr, and increased levels of PDGF and bFGF at 12, and 24 hr, respectively, after cysteamine. Increased levels (2- to 4-folds) of VEGF, PDGF and bFGF were also seen at days 7 and 14 in the rats with AV-egr-1 gene therapy compared to the controls. Conclusions: 1) Gene therapy with AV-egr-1 significantly accelerated duodenal ulcer healing in rats. 2) Increased levels of Egr-1, VEGF, PDGF and bFGF after AVegr-1 likely play important roles in the duodenal ulcer healing. 3) Thus, AV-egr-1 gene therapy seems to be a new option to achieve a rapid duodenal ulcer healing.
W1702 HLA-DQ Genotype Predicts Severity of the Intestinal Lesion, Chance of Healing on a Gluten-Free Diet After 12 Months and Likelihood of Systemic Complications in Newly Coeliac Disease Sue J. Shepherd, Rebecca Burgell, Patrick Hosking, Peter R. Gibson The relationships of HLA-DQ2 gentoype to clinical phenotype and outcomes are uncertain due to variability of reported results. For example, DQ2 dosage may or may not predict to severity of clinical presentation and the duodenal lesion at diagnosis, but does predict the likelihood of complicating of T-cell lymphoma. However, the majority of studies have been retrospective from tertiary referral hospital cohorts, opening the results to selection bias. Most studies have also been performed in paediatric populations; the applicability of findings in children to patients diagnosed as adults is uncertain. Objective: To examine association of HLA-DQ genotype with: -clinical phenotype in a patients presenting with newly diagnosed celiac disease - healing duodenal lesion after 12 months' diet Methods: HLA typing was performed on 99 consecutive patients presenting for dietary management of newly-diagnosed coeliac disease. Genotype was compared with the severity of gut symptoms, coeliac serology, the nature of the duodenal lesion, anthropometry (BMI, waste-hip ratio), body composition (nitrogen index, potassium index, sarcopenic index), and bone mineral density. The first 53 patients were prospectively studied over 12 months, including assessment of adherence to diet, serology and duodenal histology after 12 months. Results: The mean age (range) of the 99 patients was 39 (18-71) years. 24% were men. 9 different HLA-DQ genotypes were identified. The Table shows some of the phenotypic associations with genotypes divided into those expressing DQ2 in both alleles (“full DQ2”) or in only one (“half DQ2”), or complex heterozygotes (DQ2/DQ8). No significant differences were evident with genotype or of the genotypic groups in relation to the age, sex, anthropometry or severity of gut symptoms and serology (tissue transglutaminase and endomysial antibodies). Conclusions: In this prospectively studied, unselected cohort, HLA genotype predicts the severity of the villous lesion, likelihood of bony complications and ability to heal the duodenal lesion after 12 months' gluten-free diet. HLA-DQ assessment is a potentially important prognostic marker. Phenotype according to HLA-DQ 2 genotype at diagnosis
W1700 Eosinophils and Their Products Activate Human Esophageal Mesenchymal Cells - Implications for Fibrogenesis in Eosinophilic Esophagitis (EoE) Florian Rieder, Ilche T. Nonevski, Zhufeng Ouyang, Gail West, Anja Schirbel, John R. Goldblum, Tracey L. Bonfield, James J. Lee, Gary W. Falk, Claudio Fiocchi BACKGROUND: Organ fibrosis is a serious complication of EoE. We investigated mechanisms of fibrogenesis in EoE by assessing the response of primary human esophageal fibroblasts (HEF) and muscle cells (HEMC) to eosinophil-derived products and eosinophil contact; spontaneous production of fibrogenic cytokines in esophageal biopsies from EoE and control patients was also investigated. METHODS: Production of fibronectin (FN) and collagen I (Col I) by HEF and HEMC in response to selected cytokines, eosinophil products and eosinophil contact was measured by ELISA or RIA. αSMA, and VCAM-1 expression was assessed by flow cytometry and immunocytochemistry. Eosinophil adhesion assays were performed using the human eosinophil cell line AML14.3D10. TGF-β1 and p38MAPK signaling was inhibited by SB431542 and SB203580, respectively. The fibrogenic cytokines IL-4, IL-13, and TGF-β1 were measured in undernatants of biopsy organ cultures by Luminex. RESULTS: Among multiple cytokines secreted by eosinophils (IL-4, IL-5, IL-6, IL-13, eotaxin 1, and TGF-β1) TGF-β1 induced a significant increase in FN and Col I (p<0.001) production by HEF and HEMC, and IL-4 of Col I (p<0.05); IL-4, IL-6, IL-13 and TGF-β1 also increased HEF and HEMC αSMA expression, indicating transformation to a pro-fibrogenic phenotype. Direct physical contact with eosinophils increased production of FN and Col I >2-fold; if eosinophils were pre-activated (IL-3+IL-5+GM-CSF) production increased even further, whereas impeding eosinophil contact (transwell system) inhibited production. Sonicates of pre-activated eosinophils also increased FN and Col I production by HEF and HEMC. Blocking TGF-β1 and p38MAKP signaling reduced FN secretion by 49% and 56%, respectively, and by 62% when combined. Eosinophil binding increased by treating HEF and HEMC with IL4, IL-13, TGF-β1, native eosinophil major basic protein (MBP) or eosinophil sonicates; combined TGF-β1 and p38MAKP blockade reduced sonicate-induced eosinophil adhesion by 45% and completely abrogated the TGF-β1-induced adhesion. IL-4 and IL-13, but not TGF-β1 or eosinophil sonicates, increased VCAM-1 expression. Higher concentrations of IL-13 and TGF-β1, but not IL-4, were present in EoE compared to control esophageal mucosal biopsy cultures. CONCLUSION: Exposure to eosinophil-derived cytokines, degranulation products or eosinophil sonicates increases FN and Col I production by and eosinophil binding to esophageal mesenchymal cells through TGF-β1 and p38MAPK pathways. Thus, the EoE inflammatory milieu, while driving a direct primary fibrogenic response, also promotes eosinophil retention that induces an indirect activation of secondary fibrogenic pathways.
W1703 Survivin is a Key Factor in the Differential Susceptibility of Gastric Endothelial and Epithelial Cells to Alcohol-Induced Injury Michael K. Jones, Oscar R. Padilla BACKGROUND/AIMS: We previously demonstrated that the anti-apoptosis protein, survivin, plays a protective role against alcohol-induced gastric injury. Since the endothelium is a primary target of alcohol-induced gastric damage, we investigated whether survivin expression is a key factor in the greater susceptibility of gastric endothelial vs. epithelial cells to alcohol-induced injury. METHODS: Rat gastric epithelial (RGM1) and rat gastric microvascular endothelial (RGMEC) cells were exposed to either 5% ethanol, to assess overall cell damage, or 3% ethanol to assess apoptosis. siRNA was used to suppress survivin expression while transient transfection was used to elicit survivin overexpression. STUDIES: 1) Survivin protein expression levels by immunoblot analysis; 2) Cell damage by LDH assay; 3) Apoptosis by TUNEL assay. RESULTS: Rat gastric epithelial cells expressed 7.5-fold (P<0.0001) greater survivin protein levels vs. rat gastric endothelial cells. Survivin expression correlated with resistance of gastric epithelial vs. endothelial cells to both alcohol-induced cell damage (20 ± 3% vs. 65 ± 14%, P<0.005) and alcohol-induced apoptosis (12 ± 7% vs. 32 ± 4%,
W1701 Inhibition of Gadd45alpha Expression In Vivo Confers Resistance to Indomethacin and Sulindac Induced Gastric Mucosal Injury Shiun-Kwei Chiou, Amy M. Hodges Background: Regular users of nonsteroidal anti-inflammatory drugs (NSAIDs) such as indomethacin and sulindac experience gastric erosions and ulcers. NSAIDs cause gastric damage via several mechanisms, including apoptosis. Gadd45alpha is an important stress signal response gene involved in regulation of DNA repair and apoptosis, and is recently implicated
AGA Abstracts
S-722