16-16-dimethylprostaglandin-e2 and Ischemia

We have previously shown that PGE(2) and PGI(2) induce recovery of transepithelial resistance (TER) in ischemia-injured porcine ileal mucosa, associated with initial increases in Cl(-) secretion. We believe that the latter generates an osmotic gradient that stimulates resealing of tight junctions. Because of evidence implicating phosphatidylinositol 3-kinase (PI3K) in regulating tight junction assembly, we postulated that this signaling pathway is involved in PG-induced mucosal recovery. Porcine ileum was subjected to 45 min of ischemia, after which TER was monitored for a 180-min recovery period. Endogenous PG production was inhibited with indomethacin (5 microM). PGE(2) (1 microM) and PGI(2) (1 microM) stimulated recovery of TER, which was inhibited by serosal application of the osmotic agent urea (300 mosmol/kgH(2)O). The PI3K inhibitor wortmannin (10 nM) blocked recovery of TER in response to PGs or mucosal urea. Immunofluorescence imaging of recovering epithelium revealed that PGs restored occludin and zonula occludens-1 distribution to interepithelial junctions, and this pattern was disrupted by pretreatment with wortmannin. These experiments suggest that PGs stimulate recovery of paracellular resistance via a mechanism involving transepithelial osmotic gradients and PI3K-dependent restoration of tight junction protein distribution.

Topics: 16,16-Dimethylprostaglandin E2; Animals; Anti-Ulcer Agents; Electric Impedance; Epoprostenol; Female; Humans; Ileum; Intestinal Mucosa; Ischemia; Male; Membrane Proteins; Microscopy, Electron; Occludin; Osmotic Pressure; Phosphatidylinositol 3-Kinases; Phosphoproteins; Platelet Aggregation Inhibitors; Recovery of Function; Signal Transduction; Swine; Tight Junctions; Urea; Zonula Occludens-1 Protein

Cytoprotective effect of 16,16-dimethyl prostaglandin E2 (PGE2) was studied on splanchnic ischemia in rats. The superior mesenteric artery or the vascular pedicle to the isolated right hepatic lobe was occluded for 30 min, respectively, 1 or 2 h. Groups of rats were pretreated with PGE2 in a dose of 5 micrograms/kg b.w. 30 min before induction of ischemia. Ischemic damage was assessed by release of the lysosomal enzyme beta-glucuronidase and ALAT into circulation, the enzyme content in ischemic bowel and histology. Small bowel ischemia induced a marked enzyme release, a decrease of enzyme and protein content in the ischemic mucosa and typical histologic alterations. These findings were abolished in rats pretreated with PGE2. Occlusion of the vascular pedicle of the right hepatic lobe also caused enzyme release and histologic changes, but these were not affected by pretreatment with PGE2. PGE2 has a protective effect on small bowel ischemia and the observations support the concept that PGE2 may act by stabilization of cellular cytomembranes. No effect was observed on ischemic liver cell injury and this type of cell injury may be caused by other disturbances of cell function besides altered membrane function.

Topics: 16,16-Dimethylprostaglandin E2; Animals; Glucuronidase; Intestinal Mucosa; Intestine, Small; Ischemia; Liver; Male; Prostaglandins E, Synthetic; Rats; Rats, Inbred Strains; Spleen

Focal ischemia is postulated to contribute to gastric mucosal stress ulceration. This study evaluated directly whether or not mucosal ulceration during hemorrhagic shock is preceded by focal gastric mucosal blood flow changes, and whether or not topical Dm-PGE2 (16,16-dimethyl prostaglandin E2) affects focal gastric mucosal blood flow during hemorrhagic shock. Twelve anesthetized miniature swine had pyloric ligation and intragastric infusion of 5 ml/kg autogenous bile in 140 mM HCl. Gastric mucosal blood flow was documented by radiolabeled microspheres during normotension, initial hemorrhagic shock (50 mm Hg), and hemorrhagic shock + 50 micrograms topical Dm-PGE2. Stable shock was then maintained for 3 hr. During this time ulceration developed, shedding radiolabeled microsphere-bearing mucosa into the lumen. Intact gastric mucosa and luminal contents were collected, weighed, and gamma counted. Blood flow to intact mucosa was calculated by standard techniques. The weight of shed tissue, as well as the blood flow to shed tissue, was calculated from luminal microspheres.. gastric mucosal blood flow was decreased 35% with hemorrhagic shock (28.8 +/- 4.0 vs 18.7 +/- 2.7 ml/100 g/min, P less than 0.05). Blood flow to tissue which was subsequently shed averaged 6.4 +/- 3.1 ml/100 g/min at the same time period (P less than 0.05 vs surrounding tissue). Addition of Dm-PGE2 increased blood flow to shed tissue from 29 +/- 8% to 48 +/- 10% of blood flow to intact tissue (P less than 0.05).. (1) gastric mucosal ulceration is preceded by focal decreases in gastric mucosal blood flow, and (2) topical Dm-PGE2 reverses focal mucosal ischemia during hemorrhagic shock. Dm-PGE2's ability to reverse focal ischemia suggests a mechanism for prostaglandin-mediated cytoprotection.

Topics: 16,16-Dimethylprostaglandin E2; Administration, Topical; Animals; Gastric Mucosa; Ischemia; Prostaglandins E, Synthetic; Regional Blood Flow; Shock, Hemorrhagic; Stomach Ulcer; Stress, Physiological; Swine; Swine, Miniature; Time Factors