dinoprost and Esophagitis

Intraesophageal administration of manganese superoxide dismutase-plasmid/liposome (MnSOD-PL) prior to single fraction radiation has been shown to protect mice from lethal esophagitis. In our study, C3H/HeNsd mice received fractionated radiation in two protocols: (i) 18 Gy daily for four days with MnSOD-PL administration 24 hr prior to the first and third fraction, or (ii) 12 Gy daily for six days with MnSOD-PL 24 hr prior to the first, third, and fifth fraction. Control radiated mice received either no liposomes only or LacZ (bacterial beta-galactosidase gene)-plasmid/liposome (LacZ-PL) by the same schedules. We measured thiol depletion and lipid peroxidation (LP) in whole esophagus and tested the effectiveness of a new plasmid, hemagglutinin (HA) epitope-tagged MnSOD (HA-MnSOD). In fractionation protocols, mice receiving MnSOD-PL, but not LacZ-PL (200 microl of plasmid/liposomes containing 200 microg of plasmid DNA), showed a significant reduction in morbidity, decreased weight loss, and improved survival. Four and seven days after 37 Gy single fraction radiation, the esophagus demonstrated a significant increase in peroxidized lipids and reduction in overall antioxidant levels, reduced thiols, and decreased glutathione (GSH). These reductions were modulated by MnSOD-PL administration. The HA-MnSOD plasmid product was detected in the basal layers of the esophageal epithelium 24 hr after administration and provided significant radiation protection compared to glutathione peroxidase-plasmid/liposome (GPX-PL), or liposomes containing MnSOD protein, vitamin E, co-enzyme Q10, or 21-aminosteroid. Thus, MnSOD-PL administration significantly improved tolerance to fractionated radiation and modulated radiation effects on levels of GSH and lipid peroxidation (LP). These studies provide further support for translation of MnSOD-PL treatment into human esophageal radiation protection.

Topics: Animals; Biomarkers; Cells, Cultured; Chromatography, High Pressure Liquid; Dinoprost; Dose-Response Relationship, Drug; Epitopes; Esophagitis; Fatty Acids, Unsaturated; Female; Hemagglutinins; Lac Operon; Lipid Metabolism; Lipid Peroxidation; Liposomes; Mice; Mice, Inbred C3H; Mice, Inbred C57BL; Plasmids; Radiotherapy; Superoxide Dismutase; Time Factors

The PGE2, PGF2 alpha, PGI2, and TXB2 content in biopsies of healthy esophageal mucosa and inflamed mucosa and from subjects with chronic esophagitis was measured and statistically analyzed. No significant differences were found between the tissue concentrations of prostaglandins in the inflamed and the healthy mucosa, except for elevated PGI2 content in the inflamed esophageal mucosa in comparison to healthy mucosa. The prostaglandin content of jejunal mucosa was unchanged in jejunitis and in atrophy compared to findings in healthy subjects. Regression analysis revealed a significant negative correlation between the PGF2 alpha and PGI2 content in both inflamed esophageal and inflamed jejunal mucosa. In healthy mucosa, no correlation was found between the tissue concentrations of these two prostaglandins, either in the esophagus or in the jejunum. These results suggest the redistribution of cyclic endoperoxide metabolism under certain pathological conditions.

Topics: Analysis of Variance; Biopsy; Chronic Disease; Dinoprost; Dinoprostone; Epoprostenol; Esophagitis; Humans; Intestinal Mucosa; Jejunal Diseases; Linear Models; Mucous Membrane; Prostaglandins; Thromboxane B2