Immune Abnormalities and Endotoxemia in Patients with Ulcerative Colitis and in Their First Degree Relatives: Attempts at Neutralizing Endotoxin- Mediated Effects

Abstract

Proinflammatory cytokines released from monocytes/macrophages, in particular tumor necrosis factor (TNF)-alpha, interleukin (IL)-1, IL-6, and IL-8 seem to play an important role in Inflammatory Bowel Disease (ulcerative colitis and Crohn's disease). Endotoxins or lipopolysaccharides, derived from the outer membrane of Gram-negative bacteria interact with CD14 on surface membrane of macrophages, thus triggering a signal cascade, which leads to the production and release of proinflammatory cytokines, particularly TNF-alpha. Therefore, in IBD, lipopolysaccharides could play a pathogenic role. In this respect, plasma endotoxins have been demonstrated in a not negligible percentage of patients with ulcerative colitis and in their unaffected relatives. The presence of circulating endotoxins could be due, at least in part, to the impaired natural immunity in either patients with ulcerative colitis or in their first degree unaffected relatives. Lactoferrin is an iron-binding glycoprotein, which binds to the lipid A region of lipopolysaccharide with a high affinity and this interaction prevents the binding of lipopolysaccharide to CD14, thus inhibiting the release of proinflammatory cytokines. Therefore, based on the possible pathogenic role exerted by endotoxins in ulcerative colitis, lactoferrin may deserve attention as a possible therapeutical agent in experimental models of Inflammatory Bowel Disease.

Inflammatory bowel disease in rats: Bacterial and chemical interaction

“…This observation provides further support to the notion that the inflammation persisted in the combined treatment group regardless of continued or discontinued injections. Once again, these findings are in line with the findings of chronic UC in humans [35,36] . Further characterization of our animal model was carried out at the molecular level in order to evaluate the expression of inflammatory signaling.…”

“…These changes were less pronounced in the iodoacetamide groups and were minimal or absent in the B-treated and MC-treated control groups (Figure 4). Therefore, changes in the microscopic structure of the combined treatment subgroups mimicked the changes commonly encountered in severe UC in humans [30,35,36] . These include extensive hyperemia and loss of epithelial lining, ulceration of the mucosa, severe depletion of goblet cells, loss of crypts, crypt abscesses, cryptitis, with dense inflammatory cell infiltration, severe dilatation of several blood vessels, loss or thinning of muscularis mucosa, and invasion by lymphoid cells [3,17,19] .…”

Lipopolysaccharide Induces Cell Death in Cultured Porcine Myenteric Neurons

“…Bacterial lipopolysaccharide (LPS) is found in plasma of IBD patients (4) and acts, via tolllike receptor 4 activation, as an important trigger of myeloid cells that drive the Th1-type intestinal inflammatory process (5). Experimental studies have shown that LPS causes delayed gastric emptying (6,7), intestinal dysmotility (7,8) and sphincteric dysfunction (9), thus unravelling its interaction with enteric nerves.…”

Exogenous alkaline phosphatase for the treatment of patients with moderate to severe ulcerative colitis

“…21,22 In ulcerative colitis (UC), damaged intestinal mucosa facilitates the influx of LPS or bacterial gut translocation, resulting in activation or worsening of intestinal inflammation. [23][24][25] Additionally, circulating levels of LPS have been documented in patients with UC, 23,24 with increased local activity of intestinal AP also occurring in these patients, 18 while locally available intestinal AP has been shown to protect mice intestinal tissue from inflammatory injury in a chronic colitis model. 26,27 The aim of the present open-label exploratory trial was to assess the safety and preliminary efficacy of exogenous intestinal AP enzyme administered intraduodenally to patients with UC and thus provide a basis for future studies of AP as a potential biologic approach in the treatment of inflammatory bowel disease (IBD).…”