Tissue origin of peptide-responsive eicosanoid production in rabbit intestine

Different layers of rabbit large and small intestine display different peptide sensitivity and different profiles of eicosanoid release. Isolated perfused mesenteric pedicle alone, with muscularis/submucosa or with muscularis and mucosa from normal small bowel, normal colon, or inflamed colon were stimulated with bradykinin (BK) or n-formyl-methionyl-leucyl-phenylalanine (fMLP). Released prostaglandin (PG)E2, thromboxane (Tx)B2, and leukotriene (LT)B4 were assayed using extensively validated radioimmunoassays. In rabbit colon, PGE2 arises primarily from the mesentery, while in small intestine the muscularis/mucosa releases 70-80% of the total PGE2. BK releases no significant thromboxane from healthy colon, although both muscularis/submucosa and mucosa respond in inflamed colon. In contrast, fMLP stimulates thromboxane from muscularis/submucosa and mucosa of even healthy colon, while release is greatly potentiated in inflammation. Lipoxygenase in the colon is regulated differently than cyclooxygenase; it is not stimulated by BK in either healthy or inflamed colon. fMLP releases equal amounts of LTB4 from healthy and inflamed colon, but release was primarily from healthy colonic mucosa, whereas it was distributed throughout mesenteric pedicle, muscularis, and mucosa in inflamed colon. The ability of normal colonic mucosa to release proinflammatory LTB4 in response to a chemotactic factor (fMLP) produced by enteric bacteria suggests a possible role for these compounds as a stimulus for inflammation in some patients with inflammatory bowel disease.