Abstract
Nonsteroidal anti-inflammatory drugs (NSAIDs), such as indomethacin, decrease mucosal prostaglandin (PG) E2 content by inhibiting cyclooxygenase (COX) activity and cause damage in the small intestine. The development of these lesions required the inhibition of both COX-1 and COX-2, because inhibition of COX-1 up-regulated COX-2 expression and PGs produced by COX-2 counteracted the deleterious influences of COX-1 inhibition. The intestinal ulcerogenic response to indomethacin (10 mg/kg) was accompanied by decreased Muc2 expression/mucus secretion and increased intestinal motility, enterobacterial invasion, and expression of inducible nitric oxide synthase (iNOS)/NO production. These lesions were prevented by PGE2 mediated by EP3/EP4 receptors, and this action was functionally associated with the stimulation of mucus secretion, inhibition of intestinal hypermotility and enterobacterial invasion, and downregulation of iNOS expression. On the other hand, the healing of these lesions was delayed by repeated administration of low-dose indomethacin (2 mg/kg) as well as the EP4 antagonist after ulceration, and the effects were reversed by co-administration of PGE2 and the EP4 agonist. Mucosal COX-2 and vascular endothelial growth factor (VEGF) expressions were upregulated after ulceration, and changes in VEGF expression paralleled those in mucosal PGE2 content. Indomethacin down-regulated VEGF expression and angiogenesis in the injured mucosa, and the effects were reversed by cotreatment with the EP4 agonist. These data suggest that the presence of EP4 receptors is essential for both the protective and healing-promoting effects of PGE2 on NSAID-induced small intestinal lesions. The former effect is functionally associated with increased Muc2 expression/mucus secretion and inhibition of intestinal hypermotility, both mediated mainly by EP4 receptors, while the latter effect is associated with the stimulation of angiogenesis through the upregulation of VEGF expression via the activation of EP4 receptors.
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