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Background/hypothesis: Postoperative ileus is a condition of generalized gastrointestinal (GI) hypomotility following every abdominal surgicaI procedure. To date, treatment is limited to conservative management, mainly due ta lack insight in the underlying pathophysiology. Increasing evidence however supports the concept that abdominal surgery activates (Dr sensory) visceral nerves triggering reflex pathways inhibiting motility throughout the gut. These reflexes involve efferent pathways finally activating inhibitory adrenergic and non-adrenergic non-cholinergic (NANC) motor neurons. Using an in vivo rat model, we recently demonstrated that in contrast to laparotomy (resulting in a relaxation of 5-10 minutes ), a more intense stimulus like manipulation of the small intestine followed by caecum resection results in a prolonged inhibition of gastric motility, lasting up to four hours. This etfect was mediated by nerves as it was blocked by hexamethoniurn or by vagotomy combined with blockade of the adrenergic neurotransmissian by guanethidine. Although GI atferents are activated during mechanical stimuli acutely triggering the inhibitory reflexes, it remains unknown which mechanisrns underIie the prolonged inhibition of motility following abdominal surgery (hours in rats, but days in hurnans). When intensely activated, afferents release substance P (SP), a pro-inflammatory neuropeptide, at the site of activation, resulting in so-called 'neuragenic inflammation'. SP stimulates macrophages and mast cells resulting in the release of several pro-inflammatory agents, like prostaglandins, histamine, serotonin (5-HT), interleukin-1 (IL-l ). Many of these substances are potent activators of afferent fibers and thus may be responsible for the persistent triggering of the above described inhibitory reflexes. Therefore, we hypothesize that actvation of inflammatory cells following intense activation of afferents by mechanical stimulation, or 'neurogenic inflarnmation´ is the key mechanism responsible for prolonged GI hypomotility characteristic of postoperarive ileus. Our previous data showing a beneficial effect Dn postoperative ileus of the anti-inflammatory agents indomethacin and ketoro]ac and our preliminary experiments revealing an increased nurnber of inflammatory cel1s and increased myeolperoxidase activity in manipulated small intestine support this hypothesis. Key objectives: I. To identify the inflammatory cells activated and substances released after intense activation of visceral afferents by manipulation of the small intestine. 2. To evaluate the role in vivo of neurogenic inflammation (c.q. of the inflammatory cells and the substances released) in the prolonged inhihition of GI motility observed after manipulation of the small intestine. 3. To identify a mouse model to study the effect of abdominal surgery on GI motility in mice lacking macrophages, mast cells or receptors (f.e. for SP). Experimental approach: 1. Morphological approach: Tissue (stomach, small intestine, colon) obtained from animals which receive manipulation of the small intestine will be compared with sham operared animaIs (laparotomy only) and control animals (only anesthesia). Immuno-histochemistly and histochemical techniques using specific markers will be used to identify celIs and substances involved. The effect of pretreatment with specific SP antagonists and capsaicin (elimination of visceral afferents) on the development of inflammation will be studied. In addition, RNAase protection techniques will be used to specifically identify the Cytokines involved. 2. In vivo approach: Our previously validated rat models will be used to evaluate in vivo the effect of activation of mast celIs and macrophages on GI motility. The effect of specific receptor antagonists to substances (like histamine, 5-hydroxytryptamine, IL-lb, SP) released by the inflammatory cel1s on postoperative ileus wi!I also be evaluated. 3. Development of a mouse model: Finally, we aim to identify a mouse model comparable to the in vivo rat model studying the effect of abdominal surgery on GI motility. This model will allow us to better and more specifically evaluate the exact contribution of the cells and substances involved in postoperative ileus. Originality: The concept of possible interactons between the immune system and the enteric nervous system has on]y recently been introduced. So far , no studies have been reported addressing the issue of possible contribution of inflammation in the rnaintenance of inhibitory reflexes and the pathogenesis of postoperative ileus.
Startdatum: 1 maart 2000
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