Platelet-activating factor, intestinal epithelial cells, and Chron's disease : An experimental study

Sammanfattning: Platelet-activating factor (PAF-acethcr, 1-0-alky l-2-acetyl-s n- glycero-3- phosphocholine), is a potent inflammatory mediator that can be formed by a variety of cells and tissues. In the present investigation, the content of PAFacether was determined in mucosal biopsies from the ileum and colon of patients with Crohn's disease and control patients. PAF-acether was found in both groups and was raised in patients with Crohn's disease, both in the ileum and colon.Colonic PAF-accther content was raised irrespective of the presence of colonic inflammation as judged macroscopically. The activity of PAF acetylhydrolase in ileal biopsies was lower in patients with Crohn's disease than in controls, and patients with high disease activity had lower PAF acetylhydrolase activity in plasma than patients in clinical remission or healthy subjects. PAF-acether was also found in small intestinal and colonic mucosa of neonatal rats and was found to decrease as the proportion of epithelial cells decreased during early postnatal development. Cultured intestinal epithelial cells (INT 407 cells) produced PAFaccther when stimulated with calcium ionophorc (A23187) or with phospholipase C from Clostridium perfringens, a naturally occurring bacterial toxin in the intestine. Phospholipase C increased the formation of PAF-acether in INT 407 cells, but did not increase the level of lyso PAF-acethcr. The phospholipase A2 inhibitor 4-bromophcnacyl bromide (BPB) had no significant effect on the PAF- and lysoPAF-acether formation, wheras the calmodulin inhibitor trifluoperazine (TEPA), and the protein kinase C inhibitor 1-(5-isoquinolinylsulfonyl)- -methyl-piperazine (H-7), decreased the PAF-acether formation, but not the lysoPAF-acether formation. Tumor necrosis factor-alpha (TNA-alpha) potentiated phospholipase A2-mediated release of arachidonic acid (AA), after stimulation with phospholicpase C, withour affecting the formation of PAF-acether.These findings indicate that intestinal epithelial cells are able to produce and metabolize PAF-acether, and that increased PAF-acether formation in INT-407 can be evoked by phospholipase C from Clostridium perfringens , a naturally occuring bacterial toxin. Moreover, the findings add further support to the impirtance of bioactive lipids in inflammatory bowel bowel disease and suggest a possible role for PAF-acether in Croh's disease