Misoprostol but not antacid prevents endotoxin-induced gastric mucosal injury: role of tumor necrosis factor-alpha.
Many of the complications of septic shock are believed to be a consequence of elevated circulating levels of tumor necrosis factor (TNF), which is an important mediator of tissue injury. Prostaglandins (PGs) of the E series have recently been reported to inhibit TNF production in vitro. We investigated the in vivo effect of misoprostol, a PGE1 analog, on endotoxin-induced gastric mucosal injury and TNF production. For the gastric mucosal injury studies, groups of animals were pretreated with intragastric misoprostol (100 and 200 micrograms/kg) or with antacid (2 ml/animal of Maalox Plus) 30 min prior to a challenge with intravenous E. coli lipopolysaccharide (LPS) at 5.0 mg/kg. Stomachs were examined 3 hr after LPS. Systemic endotoxin alone induced microscopic edema, vascular congestion, and polymorphonuclear (PMN) infiltration of the gastric mucosa. Pretreatment with misoprostol, but not with antacid, significantly and dose-dependently reduced the gastric mucosal injury. For the TNF studies, groups of rats were given either misoprostol (100 or 200 micrograms/kg, intragastric), or saline 1 hr prior to LPS challenge. Serum samples were obtained 1.5 hr after LPS challenge. Misoprostol dose-dependently and significantly (P less than 0.01) inhibited TNF activity. We conclude that misoprostol is a potent inhibitor of TNF systemic production and inhibits the gastric mucosal injury induced by endotoxemia. These studies suggest a potentially important therapeutic role for misoprostol in inflammatory diseases in which TNF exerts a contributory role.
Department of Medicine, Tulane University School of Medicine, New Orleans, Louisiana 70112.
M
M
Mahatma
N
N
Agrawal
E Z
EZ
Dajani
S
S
Nelson
C
C
Nakamura
J
J
Sitton
D000536:Aluminum Hydroxide / Q000494:pharmacology*; D000818:Animals; D000863:Antacids / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004338:Drug Combinations; D005753:Gastric Mucosa / Q000187:drug effects*; D008276:Magnesium Hydroxide / Q000494:pharmacology*; D008297:Male; D016595:Misoprostol / Q000494:pharmacology*; D009504:Neutrophils / Q000187:drug effects; D051381:Rats; D011919:Rats, Inbred Strains; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors* / Q000378:metabolism
D000863:Antacids; D004338:Drug Combinations; D014409:Tumor Necrosis Factor-alpha; D016595:Misoprostol; C013591:aluminum hydroxide, magnesium hydroxide, drug combination; D000536:Aluminum Hydroxide; D008276:Magnesium Hydroxide