Ileus and the Macrophage

In this issue, Kalff et al. ¹ report the latest in a series of investigations directed at evaluating local inflammatory responses in intestinal smooth muscle during laparotomy and handling of the bowel. The hypothesis is that ileus results from activation of a network of macrophages that reside in the muscularis: release of proinflammatory agents from the macrophage network in turn causes the sluggish electrical and contractile responses of the muscularis that are the hallmark of paralytic ileus. Pursuit of this hypothesis has potentially far-reaching consequences. In uncomplicated cases, hospital lengths of stay following laparotomy or laparoscopy are determined largely by waiting for return of bowel function. In cases complicated by local or systemic infection or by extensive handling of the bowel, sluggish return of bowel function requires nonenteral approaches to nutritional repletion that are expensive and potentially hazardous. The current economic impact of ileus in the United States may be close to $1 billion. ² A detailed understanding of the pathophysiology of ileus, particularly that of prolonged ileus, is needed so that more rational approaches might be designed for its treatment.

Here the investigators sought full-thickness samples of human small intestine during open abdominal procedures performed to treat real and in some cases acute illness. The strategy for investigation was the evaluation of specimens of small intestine taken early (within 30–60 minutes after skin incision) or late (>3 h after incision). A unique opportunity was afforded the investigators when, in four patients, they were able to retrieve specimens both early and late, thus allowing sequential observations in these patients.

Compared to early-harvest specimens, late-harvest specimens demonstrated activation of macrophages by positive staining with antibody to lymphocyte function-associated antigen-1 (LFA-1), a human CD11-β₂- integrin receptor. LFA-1 is expressed on the surface of all leukocytes, mediating the cell adhesion crucial for normal immune responses and processes by which leukocytes find and enter areas of acute and chronic inflammation. In addition, muscularis extracts from late-harvest specimens demonstrated marked and significant elevations in levels of messenger RNA encoding cytokines such interleukin (IL)-6, the cyclooxygenase isoform COX-2, and inducible nitric oxide synthetase (iNOS). Each of these markers represents a major pathway by which activated leukocytes elicit acute and chronic inflammation. Thus, the immunohistochemical localization studies of IL-6, COX-2, and iNOS in muscularis macrophages provide credible evidence of a generalized activation of an inflammatory process within the muscularis itself. Additional studies indicate that tumor necrosis factor (TNF)-α is stored in this subgroup of macrophages in the unstimulated state and then depleted in macrophages visualized in late-harvest specimens. Also observed in muscularis extracts of late-harvest specimens was activation of the pro-inflammatory pathway transcription factor, Stat-3. Electrical and contractile function of the muscularis, assayed in vitro, appeared to be depressed in late-harvest specimens. TNF-α is a proinflammatory cytokine released during septicemia or local ischemia–reperfusion, and Stat-3 activation is a known effect of exposure to IL-6. Thus, the depletion of TNF-α from macrophages and the activation of Stat3 further support the concept that the macrophage is activated maximally, perhaps exhausted, during prolonged laparotomy.

These findings make a strong case that surgical manipulation of the bowel leads to activation of inflammation pathways within the muscularis of the intestine, independent of systemic anesthesia or manipulations of blood flow to the bowel wall. In conjunction with prior studies in animals, ³ the association of inflammatory cell activation with diminished myoelectrical function makes a strong circumstantial case that ileus results, at least in part, from activation of inflammatory cells within the intestinal muscularis. The authors are to be congratulated for their efforts in first carefully defining the expected results through work in experimental animals ^3–7 and then testing their expectations in human subjects as precisely as circumstances would allow. ^1,8

Over 100 years ago, Bayliss and Starling reported classic experiments in dogs, demonstrating that the gut becomes motionless after manipulation and that this response was prevented by prior splanchnicectomy. ⁹ Over the next several years, Walter Cannon used Roentgen rays to characterize in vivo the movements of the stomach and intestine. ^10,11 Work in Cannon’s laboratory confirmed that intestinal motility is inhibited during laparotomy or following manipulation of extraintestinal viscera such as the testicle. ^12,13 Cannon and others were well aware of the impact of distress and disturbances of innervation on gastrointestinal motility. ¹⁴ It is now well recognized that under controlled conditions, motor activities of the stomach and intestine are enhanced by interruption of the splanchnic nerves or by spinal anesthesia. ¹⁵ Experimental studies have also identified central neural influences that mediate ileus of the upper and lower gastrointestinal tract. ^16–18 Until this series of publications from Bauer et al., the most widely accepted explanation of postoperative ileus was based on the idea that manipulation inhibited motor function through some sort of neurologic reflex response.

The current study is directed at characterizing the role of inflammatory cells in the pathogenesis of intestinal ileus. It is worth pointing out, however, that many factors may lead to ileus, and thus the neurogenic and inflammatory hypotheses of manipulation-induced disturbances of myoelectrical activity are not mutually exclusive. ¹⁹ In addition, recent studies have argued that perioperative fluid and salt intake may be an independent factor that influences recovery of intestinal function following surgery. ²⁰ To fully understand the pathophysiology of ileus and to develop rational approaches to its treatment, it seems likely that future work will have to provide a unifying theory that will take into account diverse contributions from neurologic reflexes, humoral responses to disturbances in homeostasis, and local or regional activation of immune system function.

Under normal circumstances, swallowed air passes from mouth to anus in 30 minutes. ²¹ A bolus of food passes quickly to the esophagus and, following digestion of its contents in the stomach and small intestine, the remnants pass to the colon within several hours. Ileus, then, is the failure of the gastrointestinal tract to provide timely, aboral movements of air and chyme from the esophagus to the anus. Laparotomy and manipulation interfere with these movements. Studies performed in the early 1960s ^22–24 revealed stasis of a barium bolus in the stomach for 18 to 24 hours, whereas peristalsis in the small intestine returned within a few hours after laparotomy. In the colon, postlaparotomy alterations in myoelectrical function and stasis persist for 48 hours or longer. ^25,26 These findings have suggested that the colon (and perhaps the stomach), rather than the small intestine, may be the rate-limiting region of the alimentary tract when it comes to resolution of normal postoperative ileus in humans. In addition, they emphasize that ileus is an integrated response in an intact organism and that it probably has to be defined and evaluated using methods that monitor such integrated responses. ¹⁹ Further work is required to determine whether ileus in the organism, occurring in response to manipulation of the bowel, reflects findings in cells and tissues as described here.

This series of investigations has identified the resident macrophage in the muscularis of the intestine as a target of gentle manipulation as well as of overwhelming systemic stress. As with any good study, this one begs pursuit in a number of directions. One key direction suggested by the reported studies is to understand the mechanisms by which activation of resident macrophages would lead to dysfunction of the neighboring smooth muscle cells. Prior studies ^3,4 indicated that macrophage activation leads to recruitment of neutrophils to the site of activation, leading ultimately to release of their products and perhaps increases in tissue levels of oxygen-derived free radicals. Does this sequence of events lead to disturbances in membrane ion channels (K⁺, Ca²⁺) that regulate myocyte electrical rhythm and contractility? ² Does exposure of the myocyte to the products of macrophage or neutrophil activation lead to altered intracellular (or intercellular) signaling? Another direction would be to determine whether prolonged ileus—so-called adynamic or paralytic ileus—can be attributed at least in part to activation of macrophage networks in individual regions or along the entire length of the gastrointestinal tract. If so, perhaps ileus can be minimized by preventing cross-talk or synergy between macrophages within the network.

One last direction is to determine whether, and under what circumstances, ileus and the macrophage activation to which it has been attributed might perhaps be good for a patient. This set of investigations and other authors have argued that ileus is of no benefit to patients and a nuisance to their insurers. ^2,19 Perhaps here is a need for a more complete understanding of the implications of local or regional macrophage activation, neutrophil recruitment, and motor function for segments of bowel that have been handled. It is possible that wound healing, mucosal function, or other outcomes are benefited by the “rest” that accompanies ileus; it remains an open question whether such outcomes might be compromised by indiscriminate therapeutic strategies that suppress activation of resident macrophages.

These considerations aside, this entire series of studies has provided a different and potentially important perspective on the problem of ileus and the response of intestinal tissue to the surgeon’s hands. If nothing else, such studies should serve to remind us that there is a scientific basis for time-honored emphasis on meticulous technique and gentle handling of tissues in the conduct of any operation.