- Email: [email protected]
Molecular and Cellular Inflammatory Mechanisms in the Development of Postoperative Ileus
Molecular and Cellular Inflammatory Mechanisms in the Development of Postoperative Ileus Beverley A. Moore,* Jörg C. Kalff,† and Anthony J. Bauer* Iatrogenic postoperative ileus occurs almost inevitably following abdominal surgery. Various pathogenic mechanisms have been investigated and the pathophysiology appears to be multifactorial with neurogenic, inflammatory, and pharmacological mechanisms all contributing to this clinical conundrum. In fact, recent data suggest a synergistic interplay between the various mechanisms. Early manifestations of postoperative ileus most likely have a strong neurogenic component, but the prolonged clinical phenomenon is probably primarily caused by the generation of a local molecular and cellular inflammatory response within the immunologically active muscularis externa of the surgically manipulated gastrointestinal tract. Also, important in understanding this disorder is delineating the natural anti-inflammatory pathways that restore the bowel to normal function and the therapeutic potential of preemptively modulating this pathway. Semin Colon Rectal Surg 16:184-187 © 2005 Elsevier Inc. All rights reserved. KEYWORDS postoperative ileus, inflammation, motility, macrophage, muscularis externa
A
s early as 1906,1 iatrogenic postoperative ileus was observed to occur almost inevitably following abdominal surgery. Postoperative ileus, the temporary impairment of coordinated gastrointestinal motility following surgery, is characterized by delayed gastric emptying, dilation of the small bowel and colon, loss of normal propulsive contractile patterns, and the inability to evacuate gas or stool. In both humans and animals, there is evidence that different regions of the gastrointestinal tract exhibit different sensitivities to the development of postoperative ileus. Indeed, the colon appears to be particularly sensitive to disturbances within the abdominal cavity, exhibiting recovery times twice that of the stomach and three times that of the small bowel, even when not directly involved in the surgical procedure.2,3 Despite the common occurrence of postoperative ileus, its potential to
*Department of Medicine, Division of Gastroenterology, Hepatology and Nutrition, University of Pittsburgh, Pittsburgh, Pennsylvania. †Klinik und Poliklinik für Allgemein-, Viszeral-, Thorax- und Gefäßchirurgie, Rheinische Friedrich-Wilhelms-Universität Bonn, Bonn, Germany. Supported by grants from the National Institutes of Health (R01-GM58241, R01-DK068610, and P50-GM53789), Deutsche Forschungsgemeinschaft (DFG) KFO-115/1⫹2, and BONFOR grant N-012.0029. Address reprint requests to Anthony J. Bauer, PhD, Department of Medicine, Division of Gastroenterology, Hepatology and Nutrition, University of Pittsburgh, S-849 Scaife Hall, 3550 Terrace Street, Pittsburgh, PA 15261. E-mail: [email protected]
184
1043-1489/06/$-see front matter © 2005 Elsevier Inc. All rights reserved. doi:10.1053/j.scrs.2006.01.003
increase morbidity and mortality, and its economic impact, no adequate regimens are available for the prevention, treatment, or management of postoperative ileus, although “fasttrack surgery” is showing particular promise.4 Multiple causes of postoperative ileus have been suggested, including the involvement of sympathetic reflexes, inhibitory humoral agents, norepinephrine release from the bowel wall, anesthetic and analgesic agents, and inflammation.5,6 It is becoming apparent from both human and rodent studies that at least two major mechanisms are involved in manipulation-induced postoperative dysmotility—neurogenic and inflammatory mechanisms. In our view, these two mechanisms are not seen to be exclusive of one another, but rather work “cooperatively” in the development of ileus. However, the contributing strategic importance of each mechanism may vary over time, with considerable overlap and potential for interaction. Early manifestations of postoperative ileus most likely have a strong neurogenic component, but the prolonged clinical phenomenon is probably caused primarily by the generation of a local molecular and cellular inflammatory response within the immunologically active muscularis externa of the surgically manipulated gastrointestinal tract. And, of recent particular interest have been the molecular mechanisms, which resolve this proinflammatory response within the intestinal muscularis.
Inflammatory mechanisms
Inflammatory Mechanisms Underlying Postoperative Ileus Human surgical tissue7 and rodent models of postoperative ileus have demonstrated that the muscularis externa is a highly immunologically active compartment. Normally resident within the muscularis externa is an impressive array of common leukocytes.8,9 Most common of these are resident macrophages, which form an extensive network of cells from the esophagus to the rectum. Evidence suggests that the resident macrophages act as “gladiators of the gut,” poised to defend and heal the gastrointestinal tract following insult. The origination of the inflammatory hypothesis of ileus emerged from a rediscovery and realization of the importance of this dense network of muscularis macrophages, as first described by Taxi in 196510 and further characterized by Mikkelsen and Rumessen11 and Kalff and coworkers.8 Classically, macrophages function as protean-like sentinel cells that secrete an abundance of substances, including cytokines, chemokines, nitric oxide (NO), prostaglandins, reactive oxygen intermediates, and so on, most typically in response to bacterial invasion. However, when these phagocytes are iatrogenically activated, a simple and intuitively pleasing hypothesis of postoperative ileus unfolds by intellectually putting these leukocytes in the context of the innervated smooth muscle syncytium of the gut wall (Fig. 1). It is clear, now, that surgical manipulation of the intestine activates the resident macrophage network, initiating an immediate local molecular inflammatory response within the muscularis, which is followed by a complex leukocytic cellular infiltration that together results in the suppression of the neuromuscular apparatus.12-16 Early molecular responses include the activation of classic inflammatory transcription factors (NF-B, NF-IL6, STATs, and EGR-1), which is followed by the transcriptional upregulation of numerous inflammatory cytokines (IL-6, IL-1, and TNF␣) and chemokines (MCP-1).17 The generation of this local muscularis inflammatory milieu leads to the expression of adhesion molecules (ICAM-1, P-selectin) on the vascular endothelium and recruitment of monocytes, neutrophils, and mast cells from the systemic circulation.12-16 The resident and infiltrating leukocytes release smooth muscle kinetically active substances, proteases, and reactive oxygen intermediates that contribute to neuromuscular dysfunction.18,19 Central to the development of postoperative dysmotility is that both the resident macrophages and infiltrating leukocytes synthesize and release prostaglandins (derived from the induction of cyclooxygenase, COX-2) and nitric oxide (NO; derived from the inducible form of nitric oxide synthase, iNOS), agents that have potent inhibitory effects on the intestinal neuromuscular apparatus.14,20-22 The important role of the kinetically active mediators NO and prostaglandins in the manifestations of inflammatory ileus has been confirmed by using both pharmacologic (selective inhibitors) and genetic (iNOS and COX-2 knockout) approaches.14,23 Studies using pharmacologic intervention also served to identify differences in the relative importance of these two inflammatory components
185 in mediating postoperative ileus of the small bowel and colon. A selective COX-2 inhibitor was found in animal studies to be protective in the small intestine,14 but had only a marginal effect in the colon.15 Conversely, a selective iNOS inhibitor exhibited moderate efficacy in the small bowel, but its protective effect was proportionally greater in the colon15 These findings underscore the need for considering regional differences in inflammatory mechanisms when designing interventions for gastrointestinal inflammation. Recent findings have suggested that the local molecular and cellular inflammatory responses within the muscularis may be compounded by additional factors, such as the enteric transference of luminal substances. We have shown that surgical manipulation of the small bowel or colon results in a transient increase in mucosal permeability, permitting escape of luminal substances from the intestine.24 In these studies, fluorescence-labeled beads or lipopolysaccharide introduced into the colonic lumen crossed the postsurgical colonic mucosa and was found to traffic through the lymphatics and then label leukocytes within the colonic and jejunal muscularis causing inflammation and dysmotility in both regions of the gut. Due to the presence of large numbers of bacteria and their associated by-products within the colonic lumen, disturbances to colonic barrier function have particular significance in terms of systemic inflammatory responses.
Immunogenic Modulation of Neurogenic Mechanisms of Postoperative Ileus There is now growing evidence that interactions between the inflammatory milieu and neural reflex mechanisms occur. As noted above, prostaglandins secreted through increased COX-2 expression are known to participate in the pathogenesis of inflammatory postoperative ileus.14 Kreiss and coworkers25 demonstrated that COX-2 generated prostaglandins within the postoperatively inflamed gut wall could sensitize extrinsic primary afferent neurons, as measured by increased c-fos immunoreactivity in neuronal cell bodies in the L5-S1 spinal cord, and that this elevated expression persisted for at least 24 hours postoperatively. Pretreatment with the selective COX-2 inhibitor (5-dimethyl-3-(3-fluorophenyl)-4-(4-methylsulfonyl)-2(5H)-furanon) or using the genetic COX-2 knockout mouse attenuated the physical manifestations of postoperative ileus, and significantly reduced both the leukocytic infiltrate and the number of spinal neurons expressing c-fos. It was proposed in this study that release of prostaglandins within the intestinal muscularis activated spinal afferent neurons, which in turn activated efferent inhibitory motor reflexes to the gut, suppressing intestinal contractility. More recently, it was hypothesized that noradrenaline released from efferent neurons can potentiate the release of inflammatory mediators from infiltrating leukocytes, thus contributing to postoperative intestinal dysfunction. In support of this hypothesis, Kreiss and coworkers26 demonstrated that adrenergic alpha-2 receptor expression could be found on leukocytes invading the intestinal muscu-
B.A. Moore, J.C. Kalff, and A.J. Bauer
186
Figure 1 Inflammatory pathways of postoperative ileus and their bidirection interactions with the nervous system. (Color version of figure is available online.)
laris 24 hours after surgical manipulation of the small bowel, and that the application of alpha-2 receptor antagonists could inhibit NO synthesis and attenuate, although not completely prevent, intestinal dysmotility associated with postoperative ileus. Recently, the Tracey laboratory has discovered that cholinergic neurons can inhibit acute inflammation by vagal activation of nicotinic alpha-7 acetylcholine receptors on macrophages. Hence, giving the nervous system the capability to reflexively regulate the inflammatory response in real time.27,28 De Jonge and coworkers29 have applied this principle to a postoperative ileus model, also demonstrating the existence of a vagal, anti-inflammatory pathway that acts on macrophages via alpha-7 receptor activation through the Jak2-STAT3 signaling cascade. Such findings underscore the potential for neuroimmune and immunoneural interactions during intestinal inflammation (Fig. 1).
Anti-Inflammatory Mechanisms of Postoperative Ileus Previous efforts to develop strategies for management of postoperative ileus have focused on modulating neuronal mechanisms, disrupting proinflammatory mechanisms, or using specific mediators that alter the functional properties of intestinal smooth muscle. Our recent thoughts have led us to begin to delineate the natural endogenous anti-inflammatory pathways that physiologically are important in the natural resolution of ileus, with the therapeutic purpose of preemptively targeting the early activation of the anti-inflammatory mechanisms, which would attenuate subsequent iatrogeni-
cally-induced proinflammatory processes. We have focused specifically on inducible heme oxygenase (HO-1) activity and its end products (carbon monoxide and biliverdin). Analyses of HO-1 null mice, as well as the first reported HO-1-deficient human, show that both species have a phenotype exhibiting a hyperinflammatory state,30,31 thus underscoring the importance of this molecule in host defense against oxidative stress and inflammation. We hypothesized that a preemptive exploitation of the cytoprotective and antiinflammatory effects of the heme oxygenase pathway through its upregulation and the direct application of its biologically active end products could provide a novel means for preemptively suppressing the proinflammatory pathways that are associated with postoperative ileus. Indeed this approach appears to be very successful in preventing many of the intestinal inflammatory sequelae associated with postoperative ileus.32,33 Although more work needs to be done, considerable progress has been achieved in our basic understanding of postoperative ileus. It now is imperative that these basic science findings be implemented for the development of more effective prevention, treatment, and management of this clinical conundrum.
References 1. Cannon WB, Murphy FT: The movement of the stomach and intestine in some surgical conditions. Ann Surg 43:512-536, 1906 2. Graber JN, Schulte WJ, Condon RE, Cowles VE: Relationship of duration of postoperative ileus to extent and site of operative dissection. Surgery 92:87-92, 1982 3. Waldhausen JH, Shaffrey ME, Skenderis BS, et al: Gastrointestinal myo-
Inflammatory mechanisms
4. 5. 6.
7.
8.
9. 10. 11.
12.
13.
14.
15. 16.
17.
18. 19.
electric and clinical patterns of recovery after laparotomy. Ann Surg 211:777-784, 1990 Kehlet H, Wilmore DW: Fast-track surgery. Br J Surg 92:3-4, 2005 Livingston EH, Passaro EP Jr: Postoperative ileus. Dig Dis Sci 35:121132, 1990 Bueno L, Ferre JP, Ruckebusch Y: Effects of anesthesia and surgical procedures on intestinal myoelectric activity in rats. Am J Dig Dis 23:690-695, 1978 Kalff JC, Türler A, Schwarz NT, et al: Intra-abdominal activation of a local inflammatory response within the human muscularis externa during laparotomy. Ann Surg 237:301-315, 2003 Kalff JC, Schwarz NT, Walgenbach KJ, et al: Leukocytes of the intestinal muscularis externa: their phenotype and isolation. J Leukoc Biol 63: 683-691, 1998 Mikkelsen, HB: Macrophages in the external muscle layers of mammalian intestines[review]. Histol Histopathol 10:719-36, 1995 Taxi J: Contribution a letude des connexions des neurones moteurs du sytemc nerveux autonome. Ann Sci Nat Zool 7:413-674, 1995 Mikkelsen HB, Rumessen JJ: Characterization of macrophage like cells in the external layers of human small and large intestine. Cell Tissue Res 270:273-279, 1992 Kalff C, Schraut WH, Simmons R, Bauer AJ: Surgical manipulation of the gut elicits an intestinal muscularis inflammatory response resulting in postoperative ileus. Ann Surg 228:652-663, 1998 Kalff JC, Eskandari MK, Hierholzer C, et al: Biphasic response to gut manipulation and temporal correlation of cellular infiltrates and muscle dysfunction in rat. Surgery 126:498-509, 1999 Schwarz NT, Kalff JC, Türler A, et al: Prostanoid production via COX-2 as a causative mechanism of rodent postoperative ileus. Gastroenterology 121:1354-1371, 2001 Turler A, Moore BA, Pezzone MA, et al: Colonic postoperative inflammatory ileus in the rat. Ann Surg 236:56-66, 2002 Schwarz NT, Kalff JC, Turler A, et al: Selective jejunal manipulation causes postoperative pan-enteric inflammation and dysmotility. Gastroenterology 126:159-169, 2004 Wehner S, Schwarz NT, Hundsdoerfer R, et al: Induction of IL-6 within the rodent intestinal muscularis after intestinal surgical stress. Surgery 137:436-446, 2005 Bielefeldt K, Conklin JL: Intestinal motility during hypoxia and reoxygenation in vitro. Dig Dis Sci 42:878-884, 1997 von Ritter C, Be R, Granger DN: Neutrophilic proteases: mediators of formyl-methionyl-leucyl-phenylalanine-induced ileitis in rats. Gastroenterology 97:605-609, 1989
187 20. Kalff JC, Carlos TM, Schraut WH, et al: Surgically induced leukocytic infiltrates within the rat intestinal muscularis mediate postoperative ileus. Gastroenterology 117:378-387, 1999 21. Josephs MD, Cheng G, Ksontini R, et al: Products of cyclooxygenase-2 catalysis regulate postoperative bowel motility. J Surg Res 86:50-54, 1999 22. Collins SM, Hurst SM, Main C, et al: Effect of inflammation of enteric nerves. Cytokine-induced changes in neurotransmitter content and release. Ann N Y Acad Sci 664:415-424, 1992 23. Kalff JC, Schraut WH, Billiar TR, et al: Role of inducible nitric oxide synthase in postoperative intestinal smooth muscle dysfunction in rodents. Gastroenterology 118:316-327, 2002 24. Schwarz NT, Beer-Stolz D, Simmons RL, Bauer AJ: Pathogenesis of paralytic ileus: intestinal manipulation opens a transient pathway between the intestinal lumen and the leukocytic infiltrate of the jejunal muscularis. Ann Surg 235:31-40, 2001 25. Kreiss C, Birder LA, Kiss S, et al: COX-2 dependent inflammation increases spinal Fos expression during rodent postoperative ileus. Gut 52:527-534, 2003 26. Kreiss C, Toegel S, Bauer AJ: Alpha2-adrenergic regulation of NO production alters postoperative intestinal smooth muscle dysfunction in rodents. Am J Physiol Gastrointest Liver Physiol 287:G658-G666, 2004 27. Pavlov VA, Wang H, Czura CJ, et al: The cholinergic anti-inflammatory pathway: a missing link in neuroimmunomodulation. Mol Med 9:125134, 2003 28. Wang H, Yu M, Ochani M, et al: Nicotinic acetylcholine receptor alpha7 subunit is an essential regulator of inflammation. Nature 421: 384-388, 2003 29. de Jonge WJ, van der Zanden EP, The FO, et al: Stimulation of the vagus nerve attenuates macrophage activation by activating the Jak2-STAT3 signaling pathway [see comment]. Nat Immunol 6:844-851, 2005 30. Poss KD, Tonegawa S: Reduced stress defense in heme oxygenase 1-deficient cells. Proc Natl Acad Sci USA 94:10925-10930, 1997 31. Yachie A, Niida Y, Wada T, et al: Oxidative stress causes enhanced endothelial cell injury in human heme oxygenase-1 deficiency. J Clin Invest 103:129-135, 1999 32. Moore BA, Overhaus M, Whitcomb J, et al: Brief inhalation of low-dose carbon monoxide protects rodents and swine from postoperative ileus. Crit Care Med 33:1317-1326, 2005 33. Moore BA, Otterbein LE, Turler A, et al: Inhaled carbon monoxide suppresses the development of postoperative ileus in the murine small intestine. Gastroenterology 124:377-391, 2003
A
s early as 1906,1 iatrogenic postoperative ileus was observed to occur almost inevitably following abdominal surgery. Postoperative ileus, the temporary impairment of coordinated gastrointestinal motility following surgery, is characterized by delayed gastric emptying, dilation of the small bowel and colon, loss of normal propulsive contractile patterns, and the inability to evacuate gas or stool. In both humans and animals, there is evidence that different regions of the gastrointestinal tract exhibit different sensitivities to the development of postoperative ileus. Indeed, the colon appears to be particularly sensitive to disturbances within the abdominal cavity, exhibiting recovery times twice that of the stomach and three times that of the small bowel, even when not directly involved in the surgical procedure.2,3 Despite the common occurrence of postoperative ileus, its potential to
*Department of Medicine, Division of Gastroenterology, Hepatology and Nutrition, University of Pittsburgh, Pittsburgh, Pennsylvania. †Klinik und Poliklinik für Allgemein-, Viszeral-, Thorax- und Gefäßchirurgie, Rheinische Friedrich-Wilhelms-Universität Bonn, Bonn, Germany. Supported by grants from the National Institutes of Health (R01-GM58241, R01-DK068610, and P50-GM53789), Deutsche Forschungsgemeinschaft (DFG) KFO-115/1⫹2, and BONFOR grant N-012.0029. Address reprint requests to Anthony J. Bauer, PhD, Department of Medicine, Division of Gastroenterology, Hepatology and Nutrition, University of Pittsburgh, S-849 Scaife Hall, 3550 Terrace Street, Pittsburgh, PA 15261. E-mail: [email protected]
184
1043-1489/06/$-see front matter © 2005 Elsevier Inc. All rights reserved. doi:10.1053/j.scrs.2006.01.003
increase morbidity and mortality, and its economic impact, no adequate regimens are available for the prevention, treatment, or management of postoperative ileus, although “fasttrack surgery” is showing particular promise.4 Multiple causes of postoperative ileus have been suggested, including the involvement of sympathetic reflexes, inhibitory humoral agents, norepinephrine release from the bowel wall, anesthetic and analgesic agents, and inflammation.5,6 It is becoming apparent from both human and rodent studies that at least two major mechanisms are involved in manipulation-induced postoperative dysmotility—neurogenic and inflammatory mechanisms. In our view, these two mechanisms are not seen to be exclusive of one another, but rather work “cooperatively” in the development of ileus. However, the contributing strategic importance of each mechanism may vary over time, with considerable overlap and potential for interaction. Early manifestations of postoperative ileus most likely have a strong neurogenic component, but the prolonged clinical phenomenon is probably caused primarily by the generation of a local molecular and cellular inflammatory response within the immunologically active muscularis externa of the surgically manipulated gastrointestinal tract. And, of recent particular interest have been the molecular mechanisms, which resolve this proinflammatory response within the intestinal muscularis.
Inflammatory mechanisms
Inflammatory Mechanisms Underlying Postoperative Ileus Human surgical tissue7 and rodent models of postoperative ileus have demonstrated that the muscularis externa is a highly immunologically active compartment. Normally resident within the muscularis externa is an impressive array of common leukocytes.8,9 Most common of these are resident macrophages, which form an extensive network of cells from the esophagus to the rectum. Evidence suggests that the resident macrophages act as “gladiators of the gut,” poised to defend and heal the gastrointestinal tract following insult. The origination of the inflammatory hypothesis of ileus emerged from a rediscovery and realization of the importance of this dense network of muscularis macrophages, as first described by Taxi in 196510 and further characterized by Mikkelsen and Rumessen11 and Kalff and coworkers.8 Classically, macrophages function as protean-like sentinel cells that secrete an abundance of substances, including cytokines, chemokines, nitric oxide (NO), prostaglandins, reactive oxygen intermediates, and so on, most typically in response to bacterial invasion. However, when these phagocytes are iatrogenically activated, a simple and intuitively pleasing hypothesis of postoperative ileus unfolds by intellectually putting these leukocytes in the context of the innervated smooth muscle syncytium of the gut wall (Fig. 1). It is clear, now, that surgical manipulation of the intestine activates the resident macrophage network, initiating an immediate local molecular inflammatory response within the muscularis, which is followed by a complex leukocytic cellular infiltration that together results in the suppression of the neuromuscular apparatus.12-16 Early molecular responses include the activation of classic inflammatory transcription factors (NF-B, NF-IL6, STATs, and EGR-1), which is followed by the transcriptional upregulation of numerous inflammatory cytokines (IL-6, IL-1, and TNF␣) and chemokines (MCP-1).17 The generation of this local muscularis inflammatory milieu leads to the expression of adhesion molecules (ICAM-1, P-selectin) on the vascular endothelium and recruitment of monocytes, neutrophils, and mast cells from the systemic circulation.12-16 The resident and infiltrating leukocytes release smooth muscle kinetically active substances, proteases, and reactive oxygen intermediates that contribute to neuromuscular dysfunction.18,19 Central to the development of postoperative dysmotility is that both the resident macrophages and infiltrating leukocytes synthesize and release prostaglandins (derived from the induction of cyclooxygenase, COX-2) and nitric oxide (NO; derived from the inducible form of nitric oxide synthase, iNOS), agents that have potent inhibitory effects on the intestinal neuromuscular apparatus.14,20-22 The important role of the kinetically active mediators NO and prostaglandins in the manifestations of inflammatory ileus has been confirmed by using both pharmacologic (selective inhibitors) and genetic (iNOS and COX-2 knockout) approaches.14,23 Studies using pharmacologic intervention also served to identify differences in the relative importance of these two inflammatory components
185 in mediating postoperative ileus of the small bowel and colon. A selective COX-2 inhibitor was found in animal studies to be protective in the small intestine,14 but had only a marginal effect in the colon.15 Conversely, a selective iNOS inhibitor exhibited moderate efficacy in the small bowel, but its protective effect was proportionally greater in the colon15 These findings underscore the need for considering regional differences in inflammatory mechanisms when designing interventions for gastrointestinal inflammation. Recent findings have suggested that the local molecular and cellular inflammatory responses within the muscularis may be compounded by additional factors, such as the enteric transference of luminal substances. We have shown that surgical manipulation of the small bowel or colon results in a transient increase in mucosal permeability, permitting escape of luminal substances from the intestine.24 In these studies, fluorescence-labeled beads or lipopolysaccharide introduced into the colonic lumen crossed the postsurgical colonic mucosa and was found to traffic through the lymphatics and then label leukocytes within the colonic and jejunal muscularis causing inflammation and dysmotility in both regions of the gut. Due to the presence of large numbers of bacteria and their associated by-products within the colonic lumen, disturbances to colonic barrier function have particular significance in terms of systemic inflammatory responses.
Immunogenic Modulation of Neurogenic Mechanisms of Postoperative Ileus There is now growing evidence that interactions between the inflammatory milieu and neural reflex mechanisms occur. As noted above, prostaglandins secreted through increased COX-2 expression are known to participate in the pathogenesis of inflammatory postoperative ileus.14 Kreiss and coworkers25 demonstrated that COX-2 generated prostaglandins within the postoperatively inflamed gut wall could sensitize extrinsic primary afferent neurons, as measured by increased c-fos immunoreactivity in neuronal cell bodies in the L5-S1 spinal cord, and that this elevated expression persisted for at least 24 hours postoperatively. Pretreatment with the selective COX-2 inhibitor (5-dimethyl-3-(3-fluorophenyl)-4-(4-methylsulfonyl)-2(5H)-furanon) or using the genetic COX-2 knockout mouse attenuated the physical manifestations of postoperative ileus, and significantly reduced both the leukocytic infiltrate and the number of spinal neurons expressing c-fos. It was proposed in this study that release of prostaglandins within the intestinal muscularis activated spinal afferent neurons, which in turn activated efferent inhibitory motor reflexes to the gut, suppressing intestinal contractility. More recently, it was hypothesized that noradrenaline released from efferent neurons can potentiate the release of inflammatory mediators from infiltrating leukocytes, thus contributing to postoperative intestinal dysfunction. In support of this hypothesis, Kreiss and coworkers26 demonstrated that adrenergic alpha-2 receptor expression could be found on leukocytes invading the intestinal muscu-
B.A. Moore, J.C. Kalff, and A.J. Bauer
186
Figure 1 Inflammatory pathways of postoperative ileus and their bidirection interactions with the nervous system. (Color version of figure is available online.)
laris 24 hours after surgical manipulation of the small bowel, and that the application of alpha-2 receptor antagonists could inhibit NO synthesis and attenuate, although not completely prevent, intestinal dysmotility associated with postoperative ileus. Recently, the Tracey laboratory has discovered that cholinergic neurons can inhibit acute inflammation by vagal activation of nicotinic alpha-7 acetylcholine receptors on macrophages. Hence, giving the nervous system the capability to reflexively regulate the inflammatory response in real time.27,28 De Jonge and coworkers29 have applied this principle to a postoperative ileus model, also demonstrating the existence of a vagal, anti-inflammatory pathway that acts on macrophages via alpha-7 receptor activation through the Jak2-STAT3 signaling cascade. Such findings underscore the potential for neuroimmune and immunoneural interactions during intestinal inflammation (Fig. 1).
Anti-Inflammatory Mechanisms of Postoperative Ileus Previous efforts to develop strategies for management of postoperative ileus have focused on modulating neuronal mechanisms, disrupting proinflammatory mechanisms, or using specific mediators that alter the functional properties of intestinal smooth muscle. Our recent thoughts have led us to begin to delineate the natural endogenous anti-inflammatory pathways that physiologically are important in the natural resolution of ileus, with the therapeutic purpose of preemptively targeting the early activation of the anti-inflammatory mechanisms, which would attenuate subsequent iatrogeni-
cally-induced proinflammatory processes. We have focused specifically on inducible heme oxygenase (HO-1) activity and its end products (carbon monoxide and biliverdin). Analyses of HO-1 null mice, as well as the first reported HO-1-deficient human, show that both species have a phenotype exhibiting a hyperinflammatory state,30,31 thus underscoring the importance of this molecule in host defense against oxidative stress and inflammation. We hypothesized that a preemptive exploitation of the cytoprotective and antiinflammatory effects of the heme oxygenase pathway through its upregulation and the direct application of its biologically active end products could provide a novel means for preemptively suppressing the proinflammatory pathways that are associated with postoperative ileus. Indeed this approach appears to be very successful in preventing many of the intestinal inflammatory sequelae associated with postoperative ileus.32,33 Although more work needs to be done, considerable progress has been achieved in our basic understanding of postoperative ileus. It now is imperative that these basic science findings be implemented for the development of more effective prevention, treatment, and management of this clinical conundrum.
References 1. Cannon WB, Murphy FT: The movement of the stomach and intestine in some surgical conditions. Ann Surg 43:512-536, 1906 2. Graber JN, Schulte WJ, Condon RE, Cowles VE: Relationship of duration of postoperative ileus to extent and site of operative dissection. Surgery 92:87-92, 1982 3. Waldhausen JH, Shaffrey ME, Skenderis BS, et al: Gastrointestinal myo-
Inflammatory mechanisms
4. 5. 6.
7.
8.
9. 10. 11.
12.
13.
14.
15. 16.
17.
18. 19.
electric and clinical patterns of recovery after laparotomy. Ann Surg 211:777-784, 1990 Kehlet H, Wilmore DW: Fast-track surgery. Br J Surg 92:3-4, 2005 Livingston EH, Passaro EP Jr: Postoperative ileus. Dig Dis Sci 35:121132, 1990 Bueno L, Ferre JP, Ruckebusch Y: Effects of anesthesia and surgical procedures on intestinal myoelectric activity in rats. Am J Dig Dis 23:690-695, 1978 Kalff JC, Türler A, Schwarz NT, et al: Intra-abdominal activation of a local inflammatory response within the human muscularis externa during laparotomy. Ann Surg 237:301-315, 2003 Kalff JC, Schwarz NT, Walgenbach KJ, et al: Leukocytes of the intestinal muscularis externa: their phenotype and isolation. J Leukoc Biol 63: 683-691, 1998 Mikkelsen, HB: Macrophages in the external muscle layers of mammalian intestines[review]. Histol Histopathol 10:719-36, 1995 Taxi J: Contribution a letude des connexions des neurones moteurs du sytemc nerveux autonome. Ann Sci Nat Zool 7:413-674, 1995 Mikkelsen HB, Rumessen JJ: Characterization of macrophage like cells in the external layers of human small and large intestine. Cell Tissue Res 270:273-279, 1992 Kalff C, Schraut WH, Simmons R, Bauer AJ: Surgical manipulation of the gut elicits an intestinal muscularis inflammatory response resulting in postoperative ileus. Ann Surg 228:652-663, 1998 Kalff JC, Eskandari MK, Hierholzer C, et al: Biphasic response to gut manipulation and temporal correlation of cellular infiltrates and muscle dysfunction in rat. Surgery 126:498-509, 1999 Schwarz NT, Kalff JC, Türler A, et al: Prostanoid production via COX-2 as a causative mechanism of rodent postoperative ileus. Gastroenterology 121:1354-1371, 2001 Turler A, Moore BA, Pezzone MA, et al: Colonic postoperative inflammatory ileus in the rat. Ann Surg 236:56-66, 2002 Schwarz NT, Kalff JC, Turler A, et al: Selective jejunal manipulation causes postoperative pan-enteric inflammation and dysmotility. Gastroenterology 126:159-169, 2004 Wehner S, Schwarz NT, Hundsdoerfer R, et al: Induction of IL-6 within the rodent intestinal muscularis after intestinal surgical stress. Surgery 137:436-446, 2005 Bielefeldt K, Conklin JL: Intestinal motility during hypoxia and reoxygenation in vitro. Dig Dis Sci 42:878-884, 1997 von Ritter C, Be R, Granger DN: Neutrophilic proteases: mediators of formyl-methionyl-leucyl-phenylalanine-induced ileitis in rats. Gastroenterology 97:605-609, 1989
187 20. Kalff JC, Carlos TM, Schraut WH, et al: Surgically induced leukocytic infiltrates within the rat intestinal muscularis mediate postoperative ileus. Gastroenterology 117:378-387, 1999 21. Josephs MD, Cheng G, Ksontini R, et al: Products of cyclooxygenase-2 catalysis regulate postoperative bowel motility. J Surg Res 86:50-54, 1999 22. Collins SM, Hurst SM, Main C, et al: Effect of inflammation of enteric nerves. Cytokine-induced changes in neurotransmitter content and release. Ann N Y Acad Sci 664:415-424, 1992 23. Kalff JC, Schraut WH, Billiar TR, et al: Role of inducible nitric oxide synthase in postoperative intestinal smooth muscle dysfunction in rodents. Gastroenterology 118:316-327, 2002 24. Schwarz NT, Beer-Stolz D, Simmons RL, Bauer AJ: Pathogenesis of paralytic ileus: intestinal manipulation opens a transient pathway between the intestinal lumen and the leukocytic infiltrate of the jejunal muscularis. Ann Surg 235:31-40, 2001 25. Kreiss C, Birder LA, Kiss S, et al: COX-2 dependent inflammation increases spinal Fos expression during rodent postoperative ileus. Gut 52:527-534, 2003 26. Kreiss C, Toegel S, Bauer AJ: Alpha2-adrenergic regulation of NO production alters postoperative intestinal smooth muscle dysfunction in rodents. Am J Physiol Gastrointest Liver Physiol 287:G658-G666, 2004 27. Pavlov VA, Wang H, Czura CJ, et al: The cholinergic anti-inflammatory pathway: a missing link in neuroimmunomodulation. Mol Med 9:125134, 2003 28. Wang H, Yu M, Ochani M, et al: Nicotinic acetylcholine receptor alpha7 subunit is an essential regulator of inflammation. Nature 421: 384-388, 2003 29. de Jonge WJ, van der Zanden EP, The FO, et al: Stimulation of the vagus nerve attenuates macrophage activation by activating the Jak2-STAT3 signaling pathway [see comment]. Nat Immunol 6:844-851, 2005 30. Poss KD, Tonegawa S: Reduced stress defense in heme oxygenase 1-deficient cells. Proc Natl Acad Sci USA 94:10925-10930, 1997 31. Yachie A, Niida Y, Wada T, et al: Oxidative stress causes enhanced endothelial cell injury in human heme oxygenase-1 deficiency. J Clin Invest 103:129-135, 1999 32. Moore BA, Overhaus M, Whitcomb J, et al: Brief inhalation of low-dose carbon monoxide protects rodents and swine from postoperative ileus. Crit Care Med 33:1317-1326, 2005 33. Moore BA, Otterbein LE, Turler A, et al: Inhaled carbon monoxide suppresses the development of postoperative ileus in the murine small intestine. Gastroenterology 124:377-391, 2003