calcimycin and Esophageal-Neoplasms

The aim of this study was to evaluate the effect of fat emulsion administration on neutrophil arachidonic acid and leukotriene B4 (LTB4) generation in surgically stressed patients. Total parenteral nutrition was administered to 17 patients for 2 wk after esophagectomy for carcinoma. Eight patients received fat with glucose (fat group, 30% of total calories) and 9 patients received glucose (glucose group) as a non-protein calorie source from the day of the operation to the seventh postoperative day (POD), and they gradually were converted to enteral nutrition during the second postoperative week. The arachidonic acid in the fat group decreased in the serum from POD 4 to 14. and in neutrophils from 12 h after the beginning of surgery to POD 14, compared to preoperative levels. LTB4 production by A23187-stimulated neutrophils was highest 6 h after the beginning of surgery, when neutrophil arachidonic acid concentration was decreasing, and then fell below the preoperative value from POD 4 to 14 in both groups. LTB4 production on POD 14 was lower in the fat group than in the glucose group. Biosynthesis of arachidonic acid from linoleic acid is inhibited in surgically stressed patients receiving fat emulsion, resulting in the diminished synthesis of LTB4 by neutrophils. The decrease in LTB4 may diminish chemotactic and chemokinetic signals to other leukocytes.

Topics: Aged; Arachidonic Acid; Calcimycin; Dietary Fats; Emulsions; Enteral Nutrition; Esophageal Neoplasms; Esophagectomy; Fatty Acids; Female; Glucose; Humans; Leukotriene B4; Male; Middle Aged; Neutrophils; Postoperative Period

Mechanisms whereby acid reflux may accelerate the progression from Barrett's esophagus (BE) to esophageal adenocarcinoma (EA) are not fully understood. Acid and reactive oxygen species (ROS) have been reported to cause DNA damage in Barrett's cells. We have previously shown that NADPH oxidase NOX5-S is responsible for acid-induced H2O2 production in Barrett's cells and in EA cells. In this study we examined the role of intracellular calcium and NADPH oxidase NOX5-S in acid-induced DNA damage in a Barrett's EA cell line FLO and a Barrett's cell line CP-A. We found that pulsed acid treatment significantly increased tail moment in FLO and CP-A cells and histone H2AX phosphorylation in FLO cells. In addition, acid treatment significantly increased intracellular Ca(2+) in FLO cells, an increase that is blocked by Ca(2+)-free medium with EGTA and thapsigargin. Acid-induced increase in tail moment was significantly decreased by NADPH oxidase inhibitor diphenylene iodonium in FLO cells, and by blockade of intracellular Ca(2+) increase or knockdown of NOX5-S with NOX5 small-interfering RNA (siRNA) in FLO and CP-A cells. Acid-induced increase in histone H2AX phosphorylation was significantly decreased by NOX5 siRNA in FLO cells. Conversely, overexpression of NOX5-S significantly increased tail moment and histone H2AX phosphorylation in FLO cells. We conclude that pulsed acid treatment causes DNA damage via increase of intracellular calcium and activation of NOX5-S. It is possible that in BE acid reflux increases intracellular calcium, activates NOX5-S, and increases ROS production, which causes DNA damage, thereby contributing to the progression from BE to EA.

Topics: Acids; Adenocarcinoma; Barrett Esophagus; Calcimycin; Calcium; Calcium Signaling; Cell Line; Cell Line, Tumor; DNA Damage; Esophageal Neoplasms; Gastroesophageal Reflux; Humans; Hydrogen-Ion Concentration; Membrane Proteins; NADPH Oxidase 5; NADPH Oxidases; Onium Compounds; RNA, Small Interfering