Research
Macroscopic inflammation and ulceration of the bowel can be easily diagnosed using endoscopy and results in clear clinical pictures, mostly characterized by pain and blood loss.
However, a large number of patients suffer from gastrointestinal symptoms, such as irritable bowel syndrome (IBS), where no abnormalities can be identified upon endoscopy. More sophisticated investigation has shown that, in such patients, symptoms are related to a drastically changed movement (or motility) of the bowel and an increased sensitivity to pain.
To date, the etiology of these phenomena remains an enigma, and by consequence, treatment success rate is rather disappointing.
In the current project, we hypothesize that microscopic inflammation (invisible at endoscopic investigation) is responsible for the altered motility and sensitivity to pain in the gastro -intestinal tract.
Such an inflammation can account for the symptoms found in 113S, as well as a range of other gastro-intestinal diseases. In the experiments described in this project, we aim to show how this inflarnmation arises, how it alters intestinal function and motility and, especially, how we can therapeutically intervene.
More specifically, we propose that the inflammation, which is of neurogenic origin (neurogenic inflammation)(Fig. 1), is the outcome of a multi-step process (see the scheme in Fig. 2). The first step would be the intense activation of intestinal nerve fibers, either triggered by encountered stress (MS) or by surgical manipulation (post-operative ileus), leading to the release of so-called neuropeptides. These peptides are potent activators of a specific subgroup of immune cells (mast cells), known to lie in close vicinity of nerve fibers.
Once mast cells are activated (step 2), a mixture of substances is released affecting cells in their vicinity, but most importantly, attracting inflammatory cells from the blood stream to the site of activation (step 3). Finally, the neuro-immune interaction of inflammatory cells and nerve endings (step 4), and the local release of soluble inflammatory mediators (cytokines), can subsequently alter motility and sensitivity along the entire gastro-intestinal tract (step 5).
Pilot experiments from our group corroborate the initial hypotheses. To this end, we recently set up experimental animal models for stress-induced IBS and post-operative ileus (lasting intestinal hypomotility observed after surgical manipulation). In these models, motility changes were indeed preluded by the occurrence of local inflammatory sites. Moreover, prevention of this inflammation normalized motility. The aim of the experiments currently proposed is to clarify the interaction between mast cell-mediators and nerve endings, thus identifying the mediators initiating neurogenic inflammation.
Utilization
The project group carries the technical skills and clinical expertise required to accomplish these goals. In this regard it should be mentioned that within our group fundamental research and daily clinical practice are closely inter-woven. The proposed fusion of fundamental research, clinical practice, and pharmaceutical industry will thoroughly accelerate implementation of the findings obtained in our animal models. The preliminary contribution of C 100,000 by our 'user'(Janssen Pharmaceutics, JP) already reflects the commitment of all those involved.
The current project plan is, after close consultation with JP, aimed at identifying new therapeutical targets in every step in the cascade of events that characterizes neurogenic inflammation. All events: manipulation-, or stress-induced release of neuropeptides by afferent nerves (step 1), mast cell degranulation (step 2), recruitment of inflammatory cells (step 3), interaction between inflammatory cells (step 3), interaction between inflammatory cells and neurons (step 4), and projection of this
interaction towards motility changes (step 5) (overview in Fig. 2), will be monitored separately in our in vivo and in vitro systems, as further described in this research proposal.
The user (JP), has a long-standing expertise concerning the development, chemical synthesis,and optimalization of potent pharmaca, especially those influencing gastro-intestinal motility.
Regular meetings of our project group with JP has revealed that a large number of newly developed pharmaca awaits testing in experimental animal models of gastro-Intestinal diseases. Employing the animal models described here will allow adequate tests of in vivo potency of pharmaca on a large scale.
Risks and Rewards
In this project, we hypothesize that a central mechanism (degranulation of mast cells and neurogenic inflammation) elicits several intestinal diseases, of which post-operative ileus and IBS are studied in most detail.
Although the separate steps in the proposed sequence of mast cell degranulation and neurogenic inflammation are described in other organ systems, like intestine and skin (see elsewhere), the proposed central role for mast cells innovative. Obviously, in eliciting aberrant intestinal motility and pain-perception is highly following this hypothesis carries risks for the outcome of the experiments. However, as already mentioned, pilot studies in our experimental animal models confirm our primary hypothesis of the involvement of neurogenic inflammation in motility changes in 113S and post-operative ileus.
Moreover, we anticipate that the mechanistic insights that will be obtained most probably are also
applicable to other clinical features, like functional dyspepsia (upper abdominal symptoms), and Crohn's disease. On the other hand, drugs currently in use like in fliximab, or remicade to treat Crohn's disease, and antagonists against the receptor for the stress hormone corticotrophin releasing hormone (CRH) to treat major depression, may also be applicable in 113S and ileus. Generating new targets to pharmacologically treat these very common intestinal diseases will, regarding the huge number of patients worldwide, undoubtedly have an enormous impact on health care.