Model Of Gut Inflammation Research Articles

Understanding inflammatory bowel disease--the clinician's perspective.

The treatment of patients with ulcerative colitis and Crohn's disease is a huge challenge to the clinician mainly because the etiology of IBD is still completely unknown. Pathogenetic mechanisms, in constrast, have partly been elucidated thanks to immunohistochemical investigation of the tissue in IBD and the study of experimental animal models of gut inflammation. There is extensive evidence that at least in Crohn's disease tolerance for commensal bacteria is lost which leads to uncontrolled inflammation mediated by a T-helper 1 response and to tissue destruction of the gut epithelium with inadequate repair. Genetic factors are probably responsible for increased susceptibility and may define disease phenotypes. These insights have led to a dramatic improvement of our therapeutic means with the development of the chimeric monoclonal antibody to TNF. The pathogenetic mechanisms are less clear in UC. The hypothesis is that UC is a T-helper 2 mediated disease. We have a very attractive way to study the early onset of Crohn's disease in the postoperative Crohn's situation. Newer therapeutic approaches should aim at preventing recurrence of Crohn's lesions in the normal postoperative bowel. Such model is also available for UC since there is increasing evidence that pouchitis is recurrent ulcerative colitis in the small bowel. Cooperation between clinicians and basic scientists is the best way to achieve fast progress in understanding IBD.

Recombinant human interleukin-11 decreases severity of acute necrotizing pancreatitis in mice.

Interleukin (IL)-11 has anti-inflammatory activity in animal models of gut inflammation, endotoxemia, and radiation-induced thoracic injury. The aim of the present study was to investigate the protective role of IL-11 in a model of acute necrotizing pancreatitis in mice. Acute pancreatitis was induced by administration of seven intraperitoneal injections of cerulein (50 microg/kg) at hourly intervals. Lipopolysaccharide (LPS) was injected 5 hours after the first cerulein injection. Treatment with recombinant human IL-11 (rhIL-11) was started 30 minutes before the first cerulein injection and repeated 4 hours later. Serum levels of amylase, lipase, and tumor necrosis factor (TNF)-alpha were measured at the end of the experiments. The severity of pancreatitis was evaluated by histological scoring using a semiquantitative analysis of hematoxylin and eosin-stained sections of the pancreas. Competitive reverse transcription-polymerase chain reaction (RT-PCR) was performed to quantify the intrapancreatic TNF-alpha mRNA levels. Serum amylase and lipase levels progressively increased with a maximum reached between 8 and 11 hours. Treatment with rhIL-11 significantly decreased amylase and lipase levels at 6 and 8 hours. Serum TNF-alpha peaked at 6 hours and rapidly decreased thereafter. The elevation of serum TNF-alpha was markedly inhibited by treatment with rhIL-11. Histologically, treatment of rhIL-11 reduced the severity of pancreatic injury including edema, inflammatory cell infiltration, and hemorrhage at 6 hours. Intrapancreatic TNF-alpha mRNA levels were reduced by >50% in the rhIL-11-treated group at 6 hours. In conclusion, rhIL-11 decreased the severity of experimental pancreatitis early on but not later and inhibited the intrapancreatic TNF mRNA expression in vivo, suggesting that the protective effect of IL-11 during the early stage of acute pancreatitis may be mediated, at least in part, through modulation of TNF production.

T cells in mouse models of gut inflammation.

T cells in mouse models of gut inflammation.

New Biotechnological Therapies for Crohn??s Disease

Recent advances in mucosal immunology have provoked recent interest in the application of biodrugs to Crohn's disease intestinal inflammation. Our understanding of the roles of cytokines, adhesion molecules, cell trafficking and cellular immune mechanisms of disease has lead to a number of recent clinical trials. There has been simultaneous research by a number of groups using several animal models of gut inflammation. Better animal models and in particular, the use of gene knock-outs and transgenics has benefitted our understanding of the inflammatory components of Crohn's. Examples of early cellular biodrugs included anti-CD4 monoclonal antibodies. The recent FDA approval of infliximab was preceded by knowledge that levels of tumour necrosis factor (TNF)-alpha are suppressed in the clinical therapy of Crohn's. A recent study of interleukin (IL)-10 was not as favourably reported. Equivocal data has not supported the use of IL-10 for Crohn's disease therapy at this time. An ongoing multicentre phase III study of antisense to ICAM-1 for Crohn's disease is nearing completion and review. The newer monoclonal antibodies to enter into clinical studies of Crohn's disease therapy include those targeting the adhesion molecules beta7 and alpha4beta7. Numerous other biodrugs are in planning stages or early clinical studies. The coagulation pathway is another target that has been identified. This range of compounds will produce mixed efficacy in clinical studies and winners and losers will result. Moreover, combination therapy using 2 or more of these and other pre-existing compounds may prove clinically beneficial. Tailoring of pharmaceutical use to specific patients may also be expected, as we understand more about the subclasses of Crohn's disease.

Role of inducible nitric oxide synthase expression and peroxynitrite formation in guinea pig ileitis

Background & Aims Inflammatory bowel disease is characterized by increased synthesis of nitric oxide. The aim of this study was to determine if inducible NO synthase (iNOS) was responsible for tissue injury, potentially via peroxynitrite formation, in the guinea pig model of gut inflammation. Methods Inflammation was induced in guinea pig ileum by intraluminal administration of the hapten trinitrobenzene sulfonic acid in 50% ethanol, iNOS gene expression was assessed by reverse-transcriptase polymerase chain reaction and Western blotting, immunohistochemistry was determined by its localization, and activity was inhibited with the specific inhibitor aminoguanidine administered via the drinking water for 7 days. Nitration of tyrosines was assessed by immunohistochemistry. Results In control animals, iNOS gene expression was minimal to absent, whereas, in hapten, inflammation-marked iNOS gene expression was evident from day 1 to 7. Nitrotyrosine and iNOS immunohistochemistry were colocalized, and positive staining was most intense in epithelia and neurons. Inhibition of NO formation prevented nitrotyrosine formation. Aminoguanidine inhibited the inflammatory response and restored morphology. Conclusions The colocalization of tyrosine nitration with iNOS immunoreactivity suggests that iNOS may be responsible for tissue injury and the formation of NO-dependent nitrating species, potentially peroxynitrite. Inhibition of iNOS may afford a new therapeutic approach to the treatment of inflammatory bowel disease.

Inflammatory mediators of experimental colitis in rats

Colonic inflammation was induced in rats by intracolonic administration of 0.25 ml of 50% ethanol containing 30 mg of trinitrobenzene sulfonic acid (TNB). Control rats were treated with 0.25 ml of 50% ethanol or with 30 mg of TNB in 0.25 ml of saline. After 24 h, mucosal ulceration and hemorrhage were observed in TNB/ethanol-, 50% ethanol-, and to a lesser extent, in TNB/saline-treated rats. After 1 wk, mucosal damage was completely resolved in the 50% ethanol and TNB/saline-treated rats but the lesions in the TNB/ethanol-treated rats persisted and progressed to a chronic active inflammatory process after 3 wk. Myeloperoxidase activity was significantly elevated in mucosal scrapings from all treatment groups at all time intervals when macroscopic and microscopic mucosal injury was evident. Interleukin-1 was found to be the most sensitive indicator of mucosal inflammation, and its mucosal values correlated with myeloperoxidase activity. Leukotriene B4 was increased in control rats at 1 wk and in TNB/ethanol-treated rats at all time intervals. The maximal increase in leukotriene B4 was observed at 1 wk. Thromboxane B2 generation was reduced while platelet activating factor generation was not increased in TNB/ethanoltreated rats. These results indicate that in this TNB/ethanol model of gut inflammation, myeloperoxidase activity and interleukin-1 are reliable and sensitive indicators of colonic inflammation, and that thromboxane B2 is not involved in the acute lesions, whereas leukotriene B4 appears in the chronic active inflammatory response.