POSTOPERATIVE ILEUS INDUCED BY SURGICAL TRAUMA

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DESCRIPTION: (Adapted from the applicant's abstract). Postoperative ileus, the surgically induced temporary impairment of coordinated propulsive intestinal peristalsis, remains a well-documented and almost universal consequence of human abdominal surgery. Despite its frequency and economic impact, accounting for prolonged hospital stays and patient discomfort, little is known for the underlying cellular mechanisms of this surgical conundrum. The investigators have demonstrated that there is, in the normal intestine, an extraordinarily dense and organized network of macrophages within the intestinal muscularis, which can be readily and promptly activated. In addition, they have shown that after macrophage activation, the jejunal circular muscle layer becomes massively infiltrated with numerous leukocyte populations, concurrently associated with a severe impairment in circular muscle function. Based on this data, they hypothesize that simple, mild surgical manipulation of the intestine initiates an inflammatory cascade within the circular smooth muscle layer, which results in the suppression of the intestinal neuromuscular apparatus and ileus. The PI and co-workers have designed a sequential series of experiments, pursuant to their preliminary data, suggesting that postoperative ileus is, at least in part, the end result of a series of molecular and inflammatory events set in motion within the circular smooth muscle of the gut following manipulation. Their preliminary data sketches out a scenario where surgical manipulation of the intestine results in gene induction and the activation of the dense resident muscularis macrophage network. These molecular events, then, lead to the secretion of kinetic substances (nitric oxide and prostaglandins) and the production of pro-inflammatory cytokines. The initial secretions of local macrophage- derived substances cause an initial phase of intestinal muscular dysfunction, which is of a relatively moderate degree and short duration. However, additionally the burst of macrophage cytokine genes causes the up-regulation of adhesion molecules, which then lead to leukocyte emigration and degranulation (nitric oxide, prostaglandins, oxygen radicals, and proteases). This extravasation and release of reactive substances subsequently induces a second phase of muscle and neural dysfunction with is associated with physical damage of a greater degree and duration. The process is most concentrated in the circular muscle; the investigators hypothesize that such a concentration is mechanistically due to the primary role of the endogenous tissue macrophages in this muscle layer.