Neuropeptide receptor expression in inflammatory bowel disease
Beek, W.P. ter
Citation
Beek, W. P. ter. (2008, April 3). Neuropeptide receptor expression in inflammatory bowel disease. Retrieved from https://hdl.handle.net/1887/12667
Version: Corrected Publisher’s Version
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2 Outline and Aims
of this Thesis
- Chapter two 38
Outline and aims of this thesis
Neuropeptides are important biologically active peptides, which are found in abundance in the gastrointestinal tract. They are involved in the regulation of the inflammatory response and gastrointestinal motility. Both processes are disturbed in patients with inflammatory bowel disease (IBD). This has led to the hypothesis that these peptides are involved in the pathology of IBD. The effects of neuropeptides are caused by interaction with specific cell surface receptors. Lately the interest in the receptors for these gastrointestinal neuropeptides has grown considerably as a result of the ongoing increment in the availability of diverse antagonists and agonists for these receptors in patient care. Although knowledge on the expression pattern of these receptors is growing, it is still incomplete, especially with regard to the human situation. A better understanding of the receptor expression pattern in healthy and diseased intestine may lead to the development of new diagnostic and therapeutic approaches.
The aim of this thesis is to establish whether it is worthwhile setting up studies to investigate the use of agonists or antagonists in IBD patients by increasing our knowledge on the expression patterns in control and inflamed human intestine of the receptors for four important gastro-intestinal neuropeptides. These four neuropeptides are substance P, neurotensin, bombesin/gastrin-releasing peptide and motilin. Three complementary techniques were used to describe the receptor expression patterns. First, the active binding sites for the examined neuropeptides were quantified by autoradiography and subsequently identified. Then the precise location of the receptors in the intestinal tissue was shown immunohistochemically.
Thirdly, in addition to the information on the protein expression level gained by autoradiography and immunohistochemistry, information on the mRNA expression levels was obtained using the RT-PCR method.
In the first part of the study (chapter three) substance P receptor expression was investigated. Substance P is one of the most important pro-inflammatory neuropeptides to be described in the gastrointestinal tract. In animal studies the administration of a substance P antagonist reduced the inflammatory response in the intestine. Furthermore, a small number of papers has described the expression pattern of the receptor for substance P in humans, but in none of these studies the
Outline and aims - 39
combination of three techniques was used to investigate the expression pattern of this receptor.
The fourth and fifth chapters describe the expression pattern of the receptor of the neuropeptide neurotensin in the gastrointestinal tract. Firstly, differences in neurotensin binding sites between control and IBD intestine are described (chapter four). Neurotensin is known to exert both a stimulating and inhibiting effect on motility depending on the location and the type of receptor. Chapter five therefore, describes a study on the differences between the three known receptors for neurotensin.
In chapter six the receptors of the bombesin like-peptide family are studied.
Bombesin-like peptides belong to a well-known peptide family in the gastrointestinal field, but their role in the intestine in the inflammatory process and under normal circumstances is not known. Most studies concentrated on its role in gastric secretion and motility.
Finally, in chapter seven a receptor for another well-known gastrointestinal peptide, motilin, is studied. An agonist for this receptor (erythromycin) is already used to treat non-inflammatory diseases affecting motility. This approach opens the field for studying agonists and antagonists in IBD patients. But before administration of agonists or antagonists is warranted, more knowledge is required on the expression of the receptor for this peptide in colons and ilea of both control subjects and patients with IBD.
In the final chapter of this thesis all results of the above mentioned studies are discussed and summarized.
