Editorial: Preventing postoperative ileus with n 3 PUFA
Gastrointestinal ileus is most commonly initiated by direct mechanical disturbances to the bowel during abdominal surgery. These disturbances trigger a classic acute inflammatory response associated with the induction of arachidonic metabolism and the production of prostaglandins and leukotrienes. As outlined in Figure 1, these agents induce a vascular response comprised of increased permeability and endothelial expression of selectins and integrins. Proinflammatory cytokines and chemokines released within the inflamed tissue recruit a predominantly PMN infiltrate. The resulting inflammatory cascade produces mediators that impair neuromuscular communication and have direct inhibitory effects on smooth muscle contractility, leading to the typical symptoms of bowel stasis: abdominal distension, nausea/vomiting, and the inability to pass gas or stool. Whereas the mechanisms that induce ileus are fairly well understood, those that drive recovery are less clear [1] In a recent manuscript, Stein et al. [2] provide evidence that lipid mediators derived from endogenous PUFA metabolism play an active role in the process of resolution. Furthermore, perioperative exposure to exogenous n 3 PUFA was found to attenuate dysmotility in a murine POI model. For many years, resolution of inflammation was considered to be a relatively passive event, occurring as anti inflammatory mediators and antioxidants, such as IL10 and heme oxygenase 1, suppress proinflammatory mediator production. Recovery occurs as the initiators of inflammation wane, and chemoattractants are cleared. With the discovery of naturally occurring lipid mediators that have anti inflammatory and proresolving properties, it has become clear that resolution is an active programmed response [3, 4] Biosynthesized from dietary v 3 essential fatty acids, these lipids are generated as structurally distinct families of signaling molecules called resolvins, protectins, and maresins. Collectively termed SPMs, observations from animal models indicate that SPMs function as agonists, activating biologic pathways that inhibit cellular recruitment and enhance scavenging and clearance of apoptotic PMN by macrophages. With the use of a mouse model of POI, Stein et al. [2] demonstrated that the 3 classes of SPM and their upstream precursors DHA and eicosapentaenoic acid were significantly up regulated within the intestinal muscularis, 24 h following surgical manipulation. The most abundantly expressed SPMs were the DHAderived molecules resolvin D2 and PDX. Both were shown to be produced via the activity of 12/15 lipoxygenase expressed in infiltrating monocytes. Preoperative intravenous infusion of DHA enriched n 3 PUFA emulsion significantly reduced cellular inflammation and prevented POI in this model. PDX, delivered intraperitoneally immediately postoperatively, showed a similar effect. These observations promptly beg the question: can these pathways be harnessed to prevent POI in the clinical setting? As in mice, uncomplicated ileus in humans is generally self limiting, with bowel motility returning in 3 5 d. As such, POI is considered by some to be a normal physiologic response and should be allowed to run its course. Contrary to this premise are observations that induction of ileus is not limited to direct bowel manipulation [5] Circulating mediators arising from injured tissue following major orthopedic surgery or physical trauma readily traffic to the gastrointestinal tract, where they can induce the inflammatory events that cause bowel stasis. To the degree that ileus can induce mucosal barrier break and bacterial translocation, followed by loss of smooth muscle contractility with static and distended loops of gasand fluid filled bowel, this suggests that the tissue is not at rest but rather in distress. Advances in the management of surgical patients through the use of endoscopic techniques, reduced administration of opioid analgesics, and early ambulation and food intake have reduced the incidence of severe ileus, which in the past, plagued many postoperative patients. Nevertheless, even moderate ileus remains a significant source of patient discomfort. Bowel stasis of more than a few days' duration can contribute to cardiovascular and pulmonary system stress, increase the risk of anastomosis leak, and stimulate bacterial overgrowth of the intestine. Particularly vulnerable are the trauma patient, the elderly, and patients with cardiovascular,
Journal of leukocyte biology