Neuronal COX-2 expression in human myenteric plexus in active inflammatory bowel disease

Abstract

Background-Inflammatory bowel disease (IBD) is associated with changes in colonic motility which may contribute to the pain and diarrhoea associated with exacerbations of this disease. These changes may be mediated by prostaglandins which are increased in this condition. Increased expression of the inducible isoform of cyclo-oxygenase (COX-2) has been found in active IBD although its cellular distribution remains uncertain. Aims-To evaluate the cellular distribution of COX-2 in active IBD. Patients and methods-Using reverse transcription-polymerase chain reaction, in situ hybridisation, and immunohistochemistry, COX-2 expression was evaluated in 12 colectomy specimens from patients with active ulcerative colitis (UC), and six specimens from patients with Crohn's colitis that had failed medical therapy. Histologically normal colon was obtained from 12 patients having resection for colorectal neoplasia and evaluated as above, acting as control specimens. Results-All specimens expressed COX-2 mRNA, with some 6-8-fold increase in inflamed tissues on densitometric analysis (both UC and Crohn's) compared with controls. In situ hybridisation localised this mRNA to myenteric neural cells, surrounding smooth muscle cells, and inflammatory cells of the lamina propria in the IBD specimens, with some weaker labelling seen in the epithelium. No COX-2 labelling was seen in normal tissues.Immunohistochemistry confirmed these sites of COX-2 expression in all inflamed specimens, with absence of immunoreactivity in control tissues. Conclusions-These findings provide the first evidence of COX-2 expression in neural cells of the myenteric plexus in active IBD which, via increased prostaglandin synthesis at this site, may contribute to the dysmotilty seen in this condition. (Gut 2001;48:468-472)

Differential Role of Cyclooxygenase 1 and 2 Isoforms in the Modulation of Colonic Neuromuscular Function in Experimental Inflammation

“…, whereas other authors reported a scarce or absent expression (Roberts et al, 2001;Schwarz et al, 2001).…”

Nitric oxide-induced cellular stress and p53 activation in chronic inflammation

“…In addition, UC samples used in this study did not show detectable p53 serine 46 phosphorylation, a modification involved in p53-mediated apoptosis (40). Because macrophage migration inhibitory factor (MIF) can inhibit p53-mediated apoptosis (41,42), possibly through PGE-2 production by COX-2 (41,43), and levels of MIF are increased in UC when compared with normal colon samples (44,45), free radical-damaged cells could escape apoptosis and clonally expand. In addition, NO can further attenuate apoptosis by directly inhibiting caspases via nitrosylation (46,47).…”

Effects of PGE2 in guinea pig colonic myenteric ganglia

“…Given that much of the morbidity associated with inflammatory bowel disease is caused by disordered gastrointestinal motor function and that colonic smooth muscle function is regulated by the ENS, it is quite possible that alterations in the excitability of the enteric neurons contribute to intestinal dysmotility. A variety of immune-mediated inflammatory disorders exist, including Crohn's disease and ulcerative colitis, and dysmotility, hypersecretion, and enhanced perception of pain are common features (17,22,23,46). It is now clear that cutaneous and visceral inflammations lead to enhanced excitability of extrinsic primary afferent neurons and altered reflex activity (5,8,14,48).…”

“…A common feature of intestinal inflammation is the upregulation of the cyclooxygenase-2 (COX-2) enzyme, leading to increased synthesis of several eicosanoids (16,46,47,50), including prostaglandin E2 (PGE 2 ). Within guinea pig submucosal plexus neurons in the colon, PGE 2 application has been shown to lead to membrane depolarization and increased action potential frequency, as well as increased chloride ion secretion (18).…”