Dolgor Baatar

Prostaglandin E2 transactivates EGF receptor: A novel mechanism for promoting colon cancer growth and gastrointestinal hypertrophy

Prostaglandins (PGs), bioactive lipid molecules produced by cyclooxygenase enzymes (COX-1 and COX-2), have diverse biological activities, including growth-promoting actions on gastrointestinal mucosa. They are also implicated in the growth of colonic polyps and cancers. However, the precise mechanisms of these trophic actions of PGs remain unclear. As activation of the epidermal growth factor receptor (EGFR) triggers mitogenic signaling in gastrointestinal mucosa, and its expression is also upregulated in colonic cancers and most neoplasms, we investigated whether PGs transactivate EGFR. Here we provide evidence that prostaglandin E2 (PGE2) rapidly phosphorylates EGFR and triggers the extracellular signal-regulated kinase 2 (ERK2)–mitogenic signaling pathway in normal gastric epithelial (RGM1) and colon cancer (Caco-2, LoVo and HT-29) cell lines. Inactivation of EGFR kinase with selective inhibitors significantly reduces PGE2-induced ERK2 activation, c-fos mRNA expression and cell proliferation. Inhibition of matrix metalloproteinases (MMPs), transforming growth factor-α (TGF-α) or c-Src blocked PGE2-mediated EGFR transactivation and downstream signaling indicating that PGE2-induced EGFR transactivation involves signaling transduced via TGF-α, an EGFR ligand, likely released by c-Src-activated MMP(s). Our findings that PGE2 transactivates EGFR reveal a previously unknown mechanism by which PGE2 mediates trophic actions resulting in gastric and intestinal hypertrophy as well as growth of colonic polyps and cancers.

Comparison of pneumoperitoneum and abdominal wall lifting as to hemodynamics and surgical stress response during laparoscopic cholecystectomy

AbstractBackground: Impairments in hemodynamics during pneumoperitoneum (PP) have been noted. This study compared changes in hemodynamics and surgical stress response with PP and abdominal wall lifting (AWL) during laparoscopic cholecystectomy. Methods: Twenty patients with symptomatic cholecystolithiasis were assigned to PP (n= 10) or AWL (n= 10). Cardiac output (CO), stroke volume (SV), and ejection fraction (%EF) were measured by transesophageal echocardiography. Clearances of para-aminohippurate (CPAH) and sodium thiosulfate (CSTS) were determined as measures of renal function. Levels of interleukin-6, C-reactive protein, white cell count, and neutrophil elastase were evaluated as indicators of surgical stress. Results: In the PP group, CO, SV, and %EF were depressed significantly during pneumoperitoneum. Immediately after and 15 min after insufflation, the CPAH and CSTS were decreased by 78.0% and 73.8%, respectively. None of the hemodynamic parameters changed significantly in the AWL group. Surgical stress response was not different significantly between the two groups. Conclusions: In contrast to pneumoperitoneum, AWL did not alter cardiac function or renal hemodynamics. AWL may be useful in patients with cardiovascular or renal disorders.

Selective Cyclooxygenase-2 Blocker Delays Healing of Esophageal Ulcers in Rats and Inhibits Ulceration-Triggered c-Met/Hepatocyte Growth Factor Receptor Induction and Extracellular Signal-Regulated Kinase 2 Activation

Nonsteroidal anti-inflammatory drugs, both nonselective and cyclooxygenase-2 (COX-2) selective, delay gastric ulcer healing. Whether they affect esophageal ulcer healing remains unexplored. We studied the effects of the COX-2 selective inhibitor, celecoxib, on esophageal ulcer healing as well as on the cellular and molecular events involved in the healing process. Esophageal ulcers were induced in rats by focal application of acetic acid. Rats with esophageal ulcers were treated intragastrically with either celecoxib (10 mg/kg, once daily) or vehicle for 2 or 4 days. Esophageal ulceration triggered increases in: esophageal epithelial cell proliferation; expression of COX-2 (but not COX-1); hepatocyte growth factor (HGF) and its receptor, c-Met; and activation of extracellular signal-regulated kinase 2 (ERK2). Treatment with celecoxib significantly delayed esophageal ulcer healing and suppressed ulceration-triggered increases in esophageal epithelial cell proliferation, c-Met mRNA and protein expression, and ERK2 activity. In an ex vivo organ-culture system, exogenous HGF significantly increased ERK2 phosphorylation levels in esophageal mucosa. A structural analog of celecoxib, SC-236, completely prevented this effect. These findings indicate that celecoxib delays esophageal ulcer healing by reducing ulceration-induced esophageal epithelial cell proliferation. These actions are associated with, and likely mediated by, down-regulation of the HGF/c-Met-ERK2 signaling pathway.

Esophageal Ulceration Triggers Expression of Hypoxia-Inducible Factor-1α and Activates Vascular Endothelial Growth Factor Gene: Implications for Angiogenesis and Ulcer Healing

Our previous studies demonstrated that enhanced epithelial cell proliferation is important for healing of experimental esophageal ulcers. However, the roles of angiogenesis, its major mediator, vascular endothelial growth factor (VEGF), and the mechanism(s) regulating VEGF expression during esophageal ulcer healing remain unknown. Esophageal ulcers were induced in rats by focal application of acetic acid. We studied expressions of hypoxia-inducible transcription factor-1 alpha (HIF-1 alpha), an activator of the VEGF gene, and VEGF by reverse transcriptase-polymerase chain reaction, Western blotting, and immunostaining. To determine the efficacy of VEGF gene therapy in esophageal ulcer healing, we studied whether a single local injection of plasmid cDNA encoding recombinant human VEGF(165) affects ulcer healing and angiogenesis. Esophageal ulceration induced HIF-1 alpha protein expression and VEGF gene activation reflected by increased VEGF mRNA (240%) and VEGF protein (310%) levels. HIF-1 alpha protein was expressed in microvessels bordering necrosis where it co-localized with VEGF. Injection of cDNA encoding VEGF(165) significantly enhanced angiogenesis and accelerated esophageal ulcer healing. These results: 1) suggest that HIF-1 alpha may mediate esophageal ulceration-triggered VEGF gene activation, 2) indicate an essential role of VEGF and angiogenesis in esophageal ulcer healing, and 3) demonstrate the feasibility of gene therapy for the treatment of esophageal ulcers.

Laparoscopic resection of a pancreatic mucinous cystadenoma using laparosonic coagulating shears

Abstract. A 71-year-old woman with a solitary mucinous cystic neoplasm of the pancreatic tail complained of back pain. A laproscopic distal pancreatectomy was performed. Laparosonic coagulating shears (LCS) were employed for dissection of the surrounding tissue and transection of the pancreas. The main pancreatic duct was clipped. There was no evidence of bleeding or pancreatic leakage from the transection surface. Pathologic examination showed the tumor to be a mucinous cystadenoma. The postoperative course was uneventful. The LCS was effective in this application.

Activation of hypoxia inducible factor-1alpha in gastric mucosa in response to ethanol injury: a trigger for angiogenesis?

Abstract Gastric mucosal injury triggers angiogenesis and activation of VEGF expression, but the mechanism(s) of VEGF gene activation are not known. In some tissues (e.g. myocardium), hypoxia triggers activation of hypoxia-inducible factor-1α (HIF-1α), a transcription factor known to activate VEGF gene expression. This study was aimed to determine whether hypoxia and/or alcohol injury may induces HIF-1α in gastric mucosa. Normal rat gastric tissue was incubated in organ culture under either hypoxic or normoxic conditions for 6hrs. Rats received, intragastrically, either saline or alcohol and gastric mucosa bordering necrosis was obtained at 1–24hrs. HIF-1α mRNA and protein were determined by RT-PCR and Western-blot analysis. HIF-1α and VEGF proteins were localized by immunostaining. Incubation of normal gastric mucosa under hypoxia caused a significant elevation of HIF-1α mRNA (20±2%, p 300±16%; p

LAPAROSCOPIC ENUCLEATION OF A PANCREATIC INSULINOMA : REPORT OF A CASE

We report herein the case of a 48-year-old Japanese woman in whom a pancreatic insulinoma was successfully treated by laparoscopic enucleation. The patient presented after developing episodic neurohypoglycemic symptoms, and an insulinoma in the pancreatic tail, 1.0 cm in diameter, was diagnosed by the results of biochemical and radiological examinations. A laparoscopic intraoperative ultrasonogram demonstrated a solitary hypoechogenic tumor in the pancreatic tail. After the tail and body of the pancreas with the spleen were mobilized, laparoscopic enucleation was performed without any complications. The total operative time was 225min and the estimated blood loss was 20 ml. Serial blood sugar measurements demonstrated a sharp rise in blood sugar levels at the time of enucleation. The patients postoperative course was uneventful, and she was discharged on the seventh postoperative day. She has remained well for 33 months following surgery without any hypoglycemic symptoms.

LAPAROSCOPIC CHOLECYSTECTOMY IN PATIENTS UNDERGOING ANTICOAGULANT THERAPY

We recently performed a laparoscopic cholecystectomy on three patients receiving preoperative oral anticoagulant therapy. The patients requiring anticoagulants for pre-existing cardiac conditions have the following risks at surgery: thromboembolism, hemorrhage, endocarditis, and cardiopulmonary dysfunction. In patients receiving anticoagulant therapy, one must thus maintain a balanced international normalized ratio of the prothrombin time to prevent thromboembolism or hemorrhage. Warfarin sodium was discontinued preoperatively in all patients. Heparin sodium was individualized according to each patient’s risk of thromboembolism. As a result, these patients all underwent a laparoscopic cholecystectomy without complications. Attention was paid to achieve hemostasis in the operative field and the trocar inserted sites during the procedure. The administration of warfarin sodium was resumed on the first postoperative day in all patients. Restarting warfarin sodium early also helps to simplify postoperative management. A broad spectrum of antibiotic therapy was also used to reduce the risk of endocarditis. Each patient’s cardiopulmonary function was carefully monitored. The minimal invasion experienced during a laparoscopic cholecystectomy may thus facilitate the management of gallstones in patients receiving systemic anticoagulation treatment based on the findings of this limited series.

The role of nitric oxide in the inhibition of gastric epithelial proliferation in portal hypertensive rats

BACKGROUND/AIM Portal hypertension is associated with inhibition of gastric epithelial proliferation and increased gastric nitric oxide synthase activity. Whether the nitric oxide inhibits gastric epithelial proliferation is unclear. METHODS Portal vein ligation was performed to induce portal hypertension in rats. The rats were treated for 7 days with either vehicle or N(G)-nitro-L-arginine methyl ester (L-NAME) at 5 mg/kg or 25 mg/kg doses (gastric gavage, twice a day). Sham-operated rats treated with vehicle served as controls. Hemodynamic parameters were measured using radiolabeled microspheres in anesthetized animals. Gastric epithelial proliferation was assessed by evaluating the proliferative cell nuclear antigen labeling index. RESULTS The cardiac index and gastric fundic blood flow were higher, and the gastric fundic proliferative cell nuclear antigen labeling index was lower in the portal hypertensive rats than in the controls. In portal hypertensive rats, the 5 mg/kg dose of L-NAME decreased the cardiac index and increased the gastric fundic proliferative cell nuclear antigen labeling index to levels similar to those found in the controls, but did not affect gastric fundic blood flow significantly. The 25 mg/kg dose of L-NAME further decreased both the cardiac index and the gastric fundic blood flow, but did not affect the gastric proliferative cell nuclear antigen labeling index significantly. CONCLUSIONS In portal hypertensive rats, the correction of systemic hyperdynamic circulation by NO inhibition is associated with normalization of gastric epithelial proliferation. Excessive nitric oxide may inhibit gastric epithelial proliferation in portal hypertension.

Effects of carbon dioxide pneumoperitoneum on hemodynamics in cirrhotic rats

Background: The aim of our study was to investigate the effect of carbon dioxide pneumoperitoneum on systemic and splanchnic hemodynamics in cirrhotic rats. Methods: Sprague–Dawley rats (n = 80) were used in this study. Liver cirrhosis was induced by thioacetamide administration intraperitoneally (200 mg/kg body weight, twice a week for 16 weeks). The radioactive microsphere method was used to measure systemic and regional hemodynamic parameters before, 1 h after the start, and 1 h after the release of pneumoperitoneum. Results: Splanchnic blood flow and cardiac index were significantly depressed during pneumoperitoneum in liver cirrhosis and control groups, but no significant differences were seen between the two groups. In both groups, portal venous inflow decreased and hepatic arterial blood flow increased significantly during pneumoperitoneum. However, during pneumoperitoneum, total hepatic blood flow as a percentage of its value before pneumoperitoneum was lower in cirrhotic rats (71.0%) than in control rats (91.9%) (p <0.05, Mann–Whitney U-test). Conclusions: Carbon dioxide pneumoperitoneum markedly decreases total hepatic blood flow in cirrhotic rats due to the impaired hepatic arterial buffer response. Liver function should be carefully controlled in cirrhotic patients after laparoscopic surgery with pneumoperitoneum.