Abstract
Clinical background
In all patients undergoing abdominal surgery, a transient phase of interruption of bowel motility, named postoperative ileus (POI) occurs. POI is often accepted as an unavoidable “physiological” response and a self-limiting complication after surgery although it has a significant impact on patient morbidity with prolonged hospitalization and increased costs. Annual economic burden has been estimated as much as US $1.47 billion in the USA (Iyer et al. in J Manag Care Pharm 15(6):485–494, 2009).
Pathophysiology
The pathophysiology has been elucidated within the last decades, demonstrating that both, neurogenic and inflammatory mechanisms are involved in response to the surgical trauma. It is now generally accepted that POI pathogenesis processes in two phases: a first neurogenic phase is accountable for the immediate postoperative impairment of bowel motility. This is followed by a second immunological phase that can last for days and mainly affects strength and length of POI. More recent findings demonstrate a bidirectional interaction between the nervous and the immune system, and this interaction significantly contributed to our present understanding of POI pathophysiology. Although nerval mechanisms have a significant impact in the early phase of POI, the contribution of the immune system and subsequently its manipulation has risen as the most promising strategy in prevention or treatment of the clinically relevant prolonged form of POI.
Aims
The present manuscript will give an update on the inflammatory responses, the involved cell types, and participating immune mediators in POI.
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Abbreviations
- ACh:
-
Acetylcholine
- DAMP:
-
Danger-associated molecular patterns
- CO:
-
Carbon monoxide
- COX-2:
-
Cyclooxygenase-2
- Egr-1:
-
Early growth response protein-1
- HO-1:
-
Heme oxygenase-1
- iNOS:
-
Inducible nitric oxide synthase
- ME:
-
Muscularis externa
- MCP-1:
-
Monocyte chemoattractant protein-1
- NO:
-
Nitric oxide
- POI:
-
Postoperative ileus
- PPAR:
-
Peroxisome-proliferator-activated receptor
- PUFA:
-
Polyunsaturated fatty acids
- TLR:
-
Toll-like receptors
References
Iyer S, Saunders WB, Stemkowski S (2009) Economic burden of postoperative ileus associated with colectomy in the United States. J Manag Care Pharm 15(6):485–494
Delaney CP (2004) Clinical perspective on postoperative ileus and the effect of opiates. Neurogastroenterol Motil: Off J Eur Gastrointest Motil Soc 16(Suppl 2):61–66. doi:10.1111/j.1743-3150.2004.00559.x
Asgeirsson T, El-Badawi KI, Mahmood A, Barletta J, Luchtefeld M, Senagore AJ (2010) Postoperative ileus: it costs more than you expect. J Am Coll Surg 210(2):228–231. doi:10.1016/j.jamcollsurg.2009.09.028
Catchpole BN (1969) Ileus: use of sympathetic blocking agents in its treatment. Surgery 66(5):811–820
Zittel TT, Rothenhofer I, Meyer JH, Raybould HE (1994) Small intestinal capsaicin-sensitive afferents mediate feedback inhibition of gastric emptying in rats. Am J Physiol 267(6 Pt 1):G1142–G1145
Zittel TT, Reddy SN, Plourde V, Raybould HE (1994) Role of spinal afferents and calcitonin gene-related peptide in the postoperative gastric ileus in anesthetized rats. Ann Surg 219(1):79–87
Plourde V, Wong HC, Walsh JH, Raybould HE, Tache Y (1993) CGRP antagonists and capsaicin on celiac ganglia partly prevent postoperative gastric ileus. Peptides 14(6):1225–1229
Kalff JC, Schraut WH, Simmons RL, Bauer AJ (1998) Surgical manipulation of the gut elicits an intestinal muscularis inflammatory response resulting in postsurgical ileus. Ann Surg 228(5):652–663
Kalff JC, Buchholz B, Eskandari MK, Hierholzer C, Schraut WH, Simmons RL, Bauer AJ (1999) Biphasic response to gut manipulation and temporal correlation of cellular infiltrates and muscle dysfunction in rats. Surgery 126:498–509
Kalff JC, Carlos TM, Schraut WH, Billiar TR, Bauer AJ (1999) Surgically induced leukocytic infiltrates within the rat intestinal muscularis mediate postoperative ileus. Gastroenterology 117:378–387
Kalff JC, Turler A, Schwarz NT, Schraut WH, Lee KK, Tweardy DJ, Billiar TR, Simmons RL, Bauer AJ (2003) Intra-abdominal activation of a local inflammatory response within the human muscularis externa during laparotomy. Ann Surg 237(3):301–315
Bauer AJ, Boeckxstaens GE (2004) Mechanisms of postoperative ileus. Neurogastroenterol Motil 16(Suppl 2):54–60
Boeckxstaens GE, de Jonge WJ (2009) Neuroimmune mechanisms in postoperative ileus. Gut 58(9):1300–1311
Traut U, Brugger L, Kunz R, Pauli-Magnus C, Haug K, Bucher HC, Koller MT (2008) Systemic prokinetic pharmacologic treatment for postoperative adynamic ileus following abdominal surgery in adults. Cochrane database of systematic reviews (Online) (1):CD004930. doi:10.1002/14651858.CD004930.pub3
Delaney CP, Wolff BG, Viscusi ER, Senagore AJ, Fort JG, Du W, Techner L, Wallin B (2007) Alvimopan, for postoperative ileus following bowel resection: a pooled analysis of phase III studies. Ann Surg 245(3):355–363. doi:10.1097/01.sla.0000232538.72458.93
Kalff JC, Schwarz NT, Walgenbach KJ, Schraut WH, Bauer AJ (1998) Leukocytes of the intestinal muscularis: their phenotype and isolation. J Leukoc Biol 63(6):683–691
Kalff JC, Schwarz NT, Walgenbach KJ, Schraut WH, Bauer AJ (1998) Leukocytes of the intestinal muscularis externa: their phenotype and isolation. J Leukoc Biol 63:683–691
Eskandari MK, Kalff JC, Billiar TR, Lee KKW, Bauer AJ (1997) Lipopolysaccharide activates the muscularis macrophage network and suppresses circular smooth muscle activity. Am J Physiol 273(36):G727–G734
Eskandari MK, Kalff JC, Billiar TR, Lee KK, Bauer AJ (1999) LPS-induced muscularis macrophage nitric oxide suppresses rat jejunal circular muscle activity. Am J Physiol 277(2 Pt 1):G478–G486
Mikkelsen HB, Larsen JO, Hadberg H (2008) The macrophage system in the intestinal muscularis externa during inflammation: an immunohistochemical and quantitative study of osteopetrotic mice. Histochem Cell Biol 130(2):363–373. doi:10.1007/s00418-008-0423-x
Mikkelsen HB, Larsen JO, Froh P, Nguyen TH (2011) Quantitative Assessment of Macrophages in the Muscularis Externa of Mouse Intestines. Anat Rec (Hoboken). doi:10.1002/ar.21444
Mikkelsen HB, Garbarsch C, Tranum-Jensen J, Thuneberg L (2004) Macrophages in the small intestinal muscularis externa of embryos, newborn and adult germ-free mice. J Mol Histol 35(4):377–387
Mikkelsen HB, Rumessen JJ (1992) Characterization of macrophage-like cells in the external layers of human small and large intestine. Cell Tissue Res 270:273–279
Wehner S, Behrendt FF, Lyutenski BN, Lysson M, Bauer AJ, Hirner A, Kalff JC (2007) Inhibition of macrophage function prevents intestinal inflammation and postoperative ileus in rodents. Gut 56(2):176–185
Wehner S, Straesser S, Vilz TO, Pantelis D, Sielecki T, de la Cruz VF, Hirner A, Kalff JC (2009) Inhibition of p38 mitogen-activated protein kinase pathway as prophylaxis of postoperative ileus in mice. Gastroenterology 136(2):619–629
Engel DR, Koscielny A, Wehner S, Maurer J, Schiwon M, Franken L, Schumak B, Limmer A, Sparwasser T, Hirner A, Knolle PA, Kalff JC, Kurts C (2010) T helper type 1 memory cells disseminate postoperative ileus over the entire intestinal tract. Nat Med 16(12):1407–1413
Schwarz NT, Kalff JC, Turler A, Speidel N, Grandis JR, Billiar TR, Bauer AJ (2004) Selective jejunal manipulation causes postoperative pan-enteric inflammation and dysmotility. Gastroenterology 126(1):159–169
Mikkelsen HB, Thuneberg L (1999) Op/op mice defective in production of functional colony-stimulating factor-1 lack macrophages in muscularis externa of the small intestine. Cell Tissue Res 295(3):485–493
Grimbaldeston MA, Chen CC, Piliponsky AM, Tsai M, Tam SY, Galli SJ (2005) Mast cell-deficient W-sash c-kit mutant Kit W-sh/W-sh mice as a model for investigating mast cell biology in vivo. Am J Pathol 167(3):835–848. doi:10.1016/S0002-9440(10)62055-X
Bischoff SC, Wedemeyer J, Herrmann A, Meier PN, Trautwein C, Cetin Y, Maschek H, Stolte M, Gebel M, Manns MP (1996) Quantitative assessment of intestinal eosinophils and mast cells in inflammatory bowel disease. Histopathology 28(1):1–13
de Jonge WJ, The FO, van der CD, Bennink RJ, Reitsma PH, van Deventer SJ, van den Wijngaard RM, Boeckxstaens GE (2004) Mast cell degranulation during abdominal surgery initiates postoperative ileus in mice. Gastroenterology 127(2):535–545
The FO, Bennink RJ, Ankum WM, Buist MR, Busch OR, Gouma DJ, van der Heide S, van den Wijngaard RM, de Jonge WJ, Boeckxstaens GE (2008) Intestinal handling-induced mast cell activation and inflammation in human postoperative ileus. Gut 57(1):33–40
Snoek SA, Dhawan S, van Bree SH, Cailotto C, van Diest SA, Duarte JM, Stanisor OI, Hilbers FW, Nijhuis L, Koeman A, van den Wijngaard RM, Zuurbier CJ, Boeckxstaens GE, de Jonge WJ (2011) Mast cells trigger epithelial barrier dysfunction, bacterial translocation and postoperative ileus in a mouse model. Neurogastroenterol Motil: Off J Eur Gastrointest Motil Soc. doi:10.1111/j.1365-2982.2011.01820.x
Hoetzel A, Dolinay T, Vallbracht S, Zhang Y, Kim HP, Ifedigbo E, Alber S, Kaynar AM, Schmidt R, Ryter SW, Choi AM (2008) Carbon monoxide protects against ventilator-induced lung injury via PPAR-gamma and inhibition of Egr-1. Am J Respir Crit Care Med 177(11):1223–1232. doi:10.1164/rccm.200708-1265OC
Marshall JS (2004) Mast-cell responses to pathogens. Nat Rev Immunol 4(10):787–799. doi:10.1038/nri1460
Barajon I, Serrao G, Arnaboldi F, Opizzi E, Ripamonti G, Balsari A, Rumio C (2009) Toll-like receptors 3, 4, and 7 are expressed in the enteric nervous system and dorsal root ganglia. J Histochem Cytochem 57(11):1013–1023
Rumio C, Besusso D, Arnaboldi F, Palazzo M, Selleri S, Gariboldi S, Akira S, Uematsu S, Bignami P, Ceriani V, Menard S, Balsari A (2006) Activation of smooth muscle and myenteric plexus cells of jejunum via Toll-like receptor 4. J Cell Physiol 208(1):47–54
Wehner S, Buchholz BM, Schuchtrup S, Rocke A, Schaefer N, Lysson M, Hirner A, Kalff JC (2010) Mechanical strain and TLR4 synergistically induce cell-specific inflammatory gene expression in intestinal smooth muscle cells and peritoneal macrophages. Am J Physiol Gastrointest Liver Physiol 299(5):G1187–G1197
Schmidt J, Stoffels B, Moore BA, Chanthaphavong RS, Mazie AR, Buchholz BM, Bauer AJ (2008) Proinflammatory role of leukocyte-derived Egr-1 in the development of murine postoperative ileus. Gastroenterology 135(3):926–936. doi:10.1053/j.gastro.2008.05.079, 936 e921-922
The FO, de Jonge WJ, Bennink RJ, van den Wijngaard RM, Boeckxstaens GE (2005) The ICAM-1 antisense oligonucleotide ISIS-3082 prevents the development of postoperative ileus in mice. Br J Pharmacol 146:252–258
Stoffels B, Schmidt J, Nakao A, Nazir A, Chanthaphavong RS, Bauer AJ (2009) Role of interleukin 10 in murine postoperative ileus. Gut 58(5):648–660. doi:10.1136/gut.2008.153288
Wehner S, Schwarz NT, Hundsdoerfer R, Hierholzer C, Tweardy DJ, Billiar TR, Bauer AJ, Kalff JC (2005) Induction of IL-6 within the rodent intestinal muscularis after intestinal surgical stress. Surgery 137(4):436–446
Kalff JC, Schraut WH, Billiar TR, Simmons RL, Bauer AJ (2000) Role of inducible nitric oxide synthase in postoperative intestinal smooth muscle dysfunction in rodents. Gastroenterology 118(2):316–327
Brugger LE, Beldi G, Beck M, Porta F, Bracht H, Candinas D, Takala J, Jakob SM (2010) Splanchnic vasoregulation after major abdominal surgery in pigs. World J Surg 34(9):2057–2063. doi:10.1007/s00268-010-0560-y
Behrendt FF, Tolba RH, Overhaus M, Hirner A, Minor T, Kalff JC (2004) Indocyanine green fluorescence measurement of intestinal transit and gut perfusion after intestinal manipulation. Eur Surg Res 36(4):210–218
Bennett A, Eley KG, Scholes GB (1968) Effect of prostaglandins E1 and E2 on intestinal motility in the guinea-pig and rat. Br J Pharmacol 34(3):639–647
Bennett A, Eley KG, Scholes GB (1968) Effects of prostaglandins E1 and E2 on human, guinea-pig and rat isolated small intestine. Br J Pharmacol 34(3):630–638
Scholes GB, Eley KG, Bennett A (1968) Effect of prostaglandins on intestinal motility. Gut 9(6):726
Wittmann T, Vaxman F, Lambert A, Sanches O, Buliard G, Grenier JF (1990) Difference in the action of prostaglandin E2 (PGE2) on longitudinal circular muscle contractions of the colon. Experimental study in dogs. Ann Chir 44(9):718–724
Schwarz NT, Kalff JC, Turler A, Engel BM, Watkins SC, Billiar TR, Bauer AJ (2001) Prostanoid production via COX-2 as a causative mechanism of rodent postoperative ileus. Gastroenterology 121(6):1354–1371
Levy DE, Lee CK (2002) What does Stat3 do? J Clin Investig 109(9):1143–1148. doi:10.1172/JCI15650
de Jonge WJ, van der Zanden EP, The FO, Bijlsma MF, van Westerloo DJ, Bennink RJ, Berthoud HR, Uematsu S, Akira S, van den Wijngaard RM, Boeckxstaens GE (2005) Stimulation of the vagus nerve attenuates macrophage activation by activating the Jak2-STAT3 signaling pathway. Nat Immunol 6(8):844–851
Dubuquoy L, Rousseaux C, Thuru X, Peyrin-Biroulet L, Romano O, Chavatte P, Chamaillard M, Desreumaux P (2006) PPARgamma as a new therapeutic target in inflammatory bowel diseases. Gut 55(9):1341–1349. doi:10.1136/gut.2006.093484
De Backer O, Elinck E, Priem E, Leybaert L, Lefebvre RA (2009) Peroxisome proliferator-activated receptor gamma activation alleviates postoperative ileus in mice by inhibition of Egr-1 expression and its downstream target genes. J Pharmacol Exp Ther 331(2):496–503. doi:10.1124/jpet.109.155135
Moore BA, Otterbein LE, Turler A, Choi AM, Bauer AJ (2003) Inhaled carbon monoxide suppresses the development of postoperative ileus in the murine small intestine. Gastroenterology 124(2):377–391
Nakao A, Schmidt J, Harada T, Tsung A, Stoffels B, Cruz RJ Jr, Kohmoto J, Peng X, Tomiyama K, Murase N, Bauer AJ, Fink MP (2006) A single intraperitoneal dose of carbon monoxide-saturated ringer’s lactate solution ameliorates postoperative ileus in mice. J Pharmacol Exp Ther 319(3):1265–1275. doi:10.1124/jpet.106.108654
De Backer O, Elinck E, Blanckaert B, Leybaert L, Motterlini R, Lefebvre RA (2009) Water-soluble CO-releasing molecules reduce the development of postoperative ileus via modulation of MAPK/HO-1 signalling and reduction of oxidative stress. Gut 58(3):347–356. doi:10.1136/gut.2008.155481
Moore BA, Overhaus M, Whitcomb J, Ifedigbo E, Choi AM, Otterbein LE, Bauer AJ (2005) Brief inhalation of low-dose carbon monoxide protects rodents and swine from postoperative ileus. Crit Care Med 33(6):1317–1326
Schwarz NT, Beer-Stolz D, Simmons RL, Bauer AJ (2002) 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(1):31–40
Turler A, Schnurr C, Nakao A, Togel S, Moore BA, Murase N, Kalff JC, Bauer AJ (2007) Endogenous endotoxin participates in causing a panenteric inflammatory ileus after colonic surgery. Ann Surg 245(5):734–744
Bianchi ME (2007) DAMPs, PAMPs and alarmins: all we need to know about danger. J Leukoc Biol 81(1):1–5
Yang D, Chen Q, Yang H, Tracey KJ, Bustin M, Oppenheim JJ (2007) High mobility group box-1 protein induces the migration and activation of human dendritic cells and acts as an alarmin. J Leukoc Biol 81(1):59–66. doi:10.1189/jlb.0306180
Foell D, Wittkowski H, Vogl T, Roth J (2007) S100 proteins expressed in phagocytes: a novel group of damage-associated molecular pattern molecules. J Leukoc Biol 81(1):28–37
Moore BA, Manthey CL, Johnson DL, Bauer AJ (2011) Matrix metalloproteinase-9 inhibition reduces inflammation and improves motility in murine models of postoperative ileus. Gastroenterology 141(4):1283–1292. doi:10.1053/j.gastro.2011.06.035, 1292 e1281-1284
Jiang D, Liang J, Fan J, Yu S, Chen S, Luo Y, Prestwich GD, Mascarenhas MM, Garg HG, Quinn DA, Homer RJ, Goldstein DR, Bucala R, Lee PJ, Medzhitov R, Noble PW (2005) Regulation of lung injury and repair by Toll-like receptors and hyaluronan. Nat Med 11(11):1173–1179
Jiang D, Liang J, Noble PW (2011) Hyaluronan as an immune regulator in human diseases. Physiol Rev 91(1):221–264. doi:10.1152/physrev.00052.2009
Martin DK, Bootcov MR, Campbell TJ, French PW, Breit SN (1995) Human macrophages contain a stretch-sensitive potassium channel that is activated by adherence and cytokines. J Membr Biol 147(3):305–315
Wu X, Cheng J, Li P, Yang M, Qiu S, Liu P, Du J (2010) Mechano-sensitive transcriptional factor Egr-1 regulates insulin-like growth factor-1 receptor expression and contributes to neointima formation in vein grafts. Arterioscler Thromb Vasc Biol 30(3):471–476. doi:10.1161/ATVBAHA.109.184259
The FO, Boeckxstaens GE, Snoek SA, Cash JL, Bennink R, Larosa GJ, van den Wijngaard RM, Greaves DR, de Jonge WJ (2007) Activation of the cholinergic anti-inflammatory pathway ameliorates postoperative ileus in mice. Gastroenterology 133(4):1219–1228
Tsuchida Y, Hatao F, Fujisawa M, Murata T, Kaminishi M, Seto Y, Hori M, Ozaki H (2011) Neuronal stimulation with 5-hydroxytryptamine 4 receptor induces anti-inflammatory actions via alpha7nACh receptors on muscularis macrophages associated with postoperative ileus. Gut 60(5):638–647. doi:10.1136/gut.2010.227546
Snoek SA, Verstege MI, van der Zanden EP, Deeks N, Bulmer DC, Skynner M, Lee K, Te Velde AA, Boeckxstaens GE, de Jonge WJ (2010) Selective alpha7 nicotinic acetylcholine receptor agonists worsen disease in experimental colitis. Br J Pharmacol 160(2):322–333. doi:10.1111/j.1476-5381.2010.00699.x
Calder PC (2004) n-3 fatty acids, inflammation, and immunity—relevance to postsurgical and critically ill patients. Lipids 39(12):1147–1161
Calder PC (2006) n-3 polyunsaturated fatty acids, inflammation, and inflammatory diseases. Am J Clin Nutr 83(6 Suppl):1505S–1519S
Senkal M, Geier B, Hannemann M, Deska T, Linseisen J, Wolfram G, Adolph M (2007) Supplementation of omega-3 fatty acids in parenteral nutrition beneficially alters phospholipid fatty acid pattern. JPEN J Parenter Enteral Nutr 31(1):12–17
Senkal M, Haaker R, Linseisen J, Wolfram G, Homann HH, Stehle P (2005) Preoperative oral supplementation with long-chain Omega-3 fatty acids beneficially alters phospholipid fatty acid patterns in liver, gut mucosa, and tumor tissue. JPEN J Parenter Enteral Nutr 29(4):236–240
Wehner S, Meder K, Vilz TO, Alteheld B, Stehle P, Pech T, Kalff JC (2011) Preoperative short-term parenteral administration of polyunsaturated fatty acids ameliorates intestinal inflammation and postoperative ileus in rodents. Langenbeck’s Arch Surg/Deut Ges fur Chirurgie. doi:10.1007/s00423-011-0862-z
Marik PE, Zaloga GP (2010) Immunonutrition in high-risk surgical patients: a systematic review and analysis of the literature. JPEN J Parenter Enter Nutr 34(4):378–386. doi:10.1177/0148607110362692
Beale RJ, Bryg DJ, Bihari DJ (1999) Immunonutrition in the critically ill: a systematic review of clinical outcome. Crit Care Med 27(12):2799–2805
Cerantola Y, Hubner M, Grass F, Demartines N, Schafer M (2011) Immunonutrition in gastrointestinal surgery. Br J Surg 98(1):37–48. doi:10.1002/bjs.7273
Lubbers T, Luyer MD, de Haan JJ, Hadfoune M, Buurman WA, Greve JW (2009) Lipid-rich enteral nutrition reduces postoperative ileus in rats via activation of cholecystokinin-receptors. Ann Surg 249(3):481–487
The FO, Buist MR, Lei A, Bennink RJ, Hofland J, van den Wijngaard RM, de Jonge WJ, Boeckxstaens GE (2009) The role of mast cell stabilization in treatment of postoperative ileus: a pilot study. Am J Gastroenterol 104(9):2257–2266
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Wehner, S., Vilz, T.O., Stoffels, B. et al. Immune mediators of postoperative ileus. Langenbecks Arch Surg 397, 591–601 (2012). https://doi.org/10.1007/s00423-012-0915-y
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DOI: https://doi.org/10.1007/s00423-012-0915-y