Effects of macrophage-dependent peroxisome proliferator-activated receptor γ signalling on adhesion formation after abdominal surgery in an experimental model.
Hong, G-S; Schwandt, T; Stein, Ket al.
2015 • In British Journal of Surgery, 102 (12), p. 1506 - 1516
[en] [en] BACKGROUND: The pathophysiology of adhesion formation after abdominal and pelvic surgery is still largely unknown. The aim of the study was to investigate the role of macrophage polarization and the effect of peroxisome proliferator-activated receptor (PPAR) γ stimulation on adhesion formation in an animal model.
METHODS: Peritoneal adhesion formation was induced by the creation of ischaemic buttons within the peritoneal wall and the formation of a colonic anastomosis in wild-type, interleukin (IL) 10-deficient (IL-10(-/-) ), IL-4-deficient (IL-4(-/-) ) and CD11b-Cre/PPARγ(fl) (/fl) mice. Adhesions were assessed at regular intervals, and cell preparations were isolated from ischaemic buttons and normal peritoneum. These samples were analysed for macrophage differentiation and its markers, and expression of cytokines by quantitative PCR, fluorescence microscopy, arginase activity and pathological examination. Some animals underwent pioglitazone (PPAR-γ agonist) or vehicle treatment to inhibit adhesion formation. Anastomotic healing was evaluated by bursting pressure measurement and collagen gene expression.
RESULTS: Macrophage M2 marker expression and arginase activity were raised in buttons without adhesions compared with buttons with adhesions. IL-4(-/-) and IL-10(-/-) mice were not affected, whereas CD11b-Cre/PPARγ(fl) (/fl) mice showed decreased arginase activity and increased adhesion formation. Perioperative pioglitazone treatment increased arginase activity and decreased adhesion formation in wild-type but not CD11b-Cre/PPARγ(fl) (/fl) mice. Pioglitazone had no effect on anastomotic healing.
CONCLUSION: Endogenous macrophage-specific PPAR-γ signalling affected arginase activity and macrophage polarization, and counter-regulated peritoneal adhesion manifestation. Pharmacological PPAR-γ agonism induced a shift towards macrophage M2 polarization and ameliorated adhesion formation in a macrophage-dependent manner. Surgical relevance Postoperative adhesion formation is frequently seen after abdominal surgery and occurs in response to peritoneal trauma. The pathogenesis is still unknown but includes an imbalance in fibrinolysis, collagen production and inflammatory mechanisms. Little is known about the role of macrophages during adhesion formation. In an experimental model, macrophage M2 marker expression was associated with reduced peritoneal adhesion formation and involved PPAR-γ-mediated arginase activity. Macrophage-specific PPAR-γ deficiency resulted in reduced arginase activity and aggravated adhesion formation. Pioglitazone, a PPAR-γ agonist, induced M2 polarization and reduced postoperative adhesion formation without compromising anastomotic healing in mice. Pioglitazone ameliorated postoperative adhesion formation without compromising intestinal wound healing. Therefore, perioperative PPAR-γ agonism might be a promising strategy for prevention of adhesion formation after abdominal surgery.
Disciplines :
Neurology
Author, co-author :
Hong, G-S; Department of Surgery, University Hospital of Bonn, Bonn, Germany
Schwandt, T; Department of Surgery, University Hospital of Bonn, Bonn, Germany
Stein, K; Department of Surgery, University Hospital of Bonn, Bonn, Germany
Schneiker, B; Department of Surgery, University Hospital of Bonn, Bonn, Germany
Kummer, M P; Clinical Neurosciences Unit, University Hospital of Bonn, Bonn, Germany
HENEKA, Michael ; Clinical Neurosciences Unit, University Hospital of Bonn, Bonn, Germany
Kitamura, K; Department of Surgery, University Hospital of Bonn, Bonn, Germany ; Graduate School of Medicine, Kyoto University, Kyoto, Japan
Kalff, J C; Department of Surgery, University Hospital of Bonn, Bonn, Germany
Wehner, S; Department of Surgery, University Hospital of Bonn, Bonn, Germany ; Tytgat Institute for Liver and Intestinal Research, Academic Medical Centre, Amsterdam, The Netherlands
External co-authors :
yes
Language :
English
Title :
Effects of macrophage-dependent peroxisome proliferator-activated receptor γ signalling on adhesion formation after abdominal surgery in an experimental model.
Publication date :
November 2015
Journal title :
British Journal of Surgery
ISSN :
0007-1323
eISSN :
1365-2168
Publisher :
John Wiley and Sons Ltd, Chichester, West Sussex, England
Ellis H, Moran BJ, Thompson JN, Parker MC, Wilson MS, Menzies D, et al. Adhesion-related hospital readmissions after abdominal and pelvic surgery: a retrospective cohort study. Lancet 1999; 353: 1476-1480.
Ten Broek RP, Issa Y, van Santbrink EJ, Bouvy ND, Kruitwagen RF, Jeekel J, et al. Burden of adhesions in abdominal and pelvic surgery: systematic review and meta-analysis. BMJ 2013; 347: f5588.
Xu X, Rivkind A, Pappo O, Pikarsky A, Levi-Schaffer F,. Role of mast cells and myofibroblasts in human peritoneal adhesion formation. Ann Surg 2002; 236: 593-601.
Ohashi K, Yoshimoto T, Kosaka H, Hirano T, Iimuro Y, Nakanishi K, et al. Interferon gamma and plasminogen activator inhibitor 1 regulate adhesion formation after partial hepatectomy. Br J Surg 2014; 101: 398-407.
Burnett SH, Beus BJ, Avdiushko R, Qualls J, Kaplan AM, Cohen DA,. Development of peritoneal adhesions in macrophage depleted mice. J Surg Res 2006; 131: 296-301.
Gordon S, Martinez FO,. Alternative activation of macrophages: mechanism and functions. Immunity 2010; 32: 593-604.
ten Broek RP, Stommel MW, Strik C, van Laarhoven CJ, Keus F, van Goor H,. Benefits and harms of adhesion barriers for abdominal surgery: a systematic review and meta-analysis. Lancet 2014; 383: 48-59.
Nagy L, Szanto A, Szatmari I, Szeles L,. Nuclear hormone receptors enable macrophages and dendritic cells to sense their lipid environment and shape their immune response. Physiol Rev 2012; 92: 739-789.
Sindrilaru A, Scharffetter-Kochanek K,. Disclosure of the culprits: macrophages-versatile regulators of wound healing. Adv Wound Care (New Rochelle) 2013; 2: 357-368.
El Kasmi KC, Qualls JE, Pesce JT, Smith AM, Thompson RW, Henao-Tamayo M, et al. Toll-like receptor-induced arginase 1 in macrophages thwarts effective immunity against intracellular pathogens. Nat Immunol 2008; 9: 1399-1406.
Stein M, Keshav S, Harris N, Gordon S,. Interleukin 4 potently enhances murine macrophage mannose receptor activity: a marker of alternative immunologic macrophage activation. J Exp Med 1992; 176: 287-292.
Wynn TA, Ramalingam TR,. Mechanisms of fibrosis: therapeutic translation for fibrotic disease. Nat Med 2012; 18: 1028-1040.
Morán-Salvador E, , Titos E, , Rius B, , González-Périz A, , García-Alonso V, , Lõpez-Vicario C, et al. Cell-specific PPARγ deficiency establishes anti-inflammatory and anti-fibrogenic properties for this nuclear receptor in non-parenchymal liver cells. J Hepatol 2013; 59: 1045-1053.
Reed KL, Fruin AB, Bishop-Bartolomei KK, Gower AC, Nicolaou M, Stucchi AF, et al. Neurokinin-1 receptor and substance P messenger RNA levels increase during intraabdominal adhesion formation. J Surg Res 2002; 108: 165-172.
Pantelis D, Beissel A, Kahl P, Vilz TO, Stoffels B, Wehner S, et al. Colonic anastomotic healing in the context of altered macrophage function and endotoxemia. Int J Colorectal Dis 2011; 26: 737-746.
Sikkink CJ, de Man B, Bleichrodt RP, van Goor H,. Auto-cross-linked hyaluronic acid gel does not reduce intra-abdominal adhesions or abscess formation in a rat model of peritonitis. J Surg Res 2006; 136: 255-259.
Zühlke HV, Lorenz EM, Straub EM, Savvas V,. [ Pathophysiology and classification of adhesions.] Langenbecks Arch Chir Suppl II Verh Dtsch Ges Chir 1990; 1009-1016.
Corraliza IM, Campo ML, Soler G, Modolell M,. Determination of arginase activity in macrophages: a micromethod. J Immunol Methods 1994; 174: 231-235.
Schürmann C, Seitz O, Sader R, Pfeilschifter J, Goren I, Frank S,. Role of wound macrophages in skin flap loss or survival in an experimental diabetes model. Br J Surg 2010; 97: 1437-1451.
Rath M, Müller I, Kropf P, Closs EI, Munder M,. Metabolism via arginase or nitric oxide synthase: two competing arginine pathways in macrophages. Front Immunol 2014; 5: 532.
Manuelpillai U, Lourensz D, Vaghjiani V, Tchongue J, Lacey D, Tee JY, et al. Human amniotic epithelial cell transplantation induces markers of alternative macrophage activation and reduces established hepatic fibrosis. PLoS One 2012; 7: e38631.
Pesce JT, Ramalingam TR, Mentink-Kane MM, Wilson MS, El Kasmi KC, Smith AM, et al. Arginase-1-expressing macrophages suppress Th2 cytokine-driven inflammation and fibrosis. PLoS Pathog 2009; 5: e1000371.
Odegaard JI, Ricardo-Gonzalez RR, Goforth MH, Morel CR, Subramanian V, Mukundan L, et al. Macrophage-specific PPARgamma controls alternative activation and improves insulin resistance. Nature 2007; 447: 1116-1120.
Gallardo-Soler A, Gõmez-Nieto C, Campo ML, Marathe C, Tontonoz P, Castrillo A, et al. Arginase I induction by modified lipoproteins in macrophages: a peroxisome proliferator-activated receptor-gamma/delta-mediated effect that links lipid metabolism and immunity. Mol Endocrinol 2008; 22: 1394-1402.
Freeman HC, Hugill A, Dear NT, Ashcroft FM, Cox RD,. Deletion of nicotinamide nucleotide transhydrogenase: a new quantitive trait locus accounting for glucose intolerance in C57BL/6 J mice. Diabetes 2006; 55: 2153-2156.
Greer N, Foman NA, MacDonald R, Dorrian J, Fitzgerald P, Rutks I, et al. Advanced wound care therapies for nonhealing diabetic, venous, and arterial ulcers: a systematic review. Ann Intern Med 2013; 159: 532-542.
Campbell L, Saville CR, Murray PJ, Cruickshank SM, Hardman MJ,. Local arginase 1 activity is required for cutaneous wound healing. J Invest Dermatol 2013; 133: 2461-2470.
Kavalukas SL, Uzgare AR, Bivalacqua TJ, Barbul A,. Arginase inhibition promotes wound healing in mice. Surgery 2012; 151: 287-295.
Witte MB, Vogt N, Stuelten C, Gotoh T, Mori M, Becker HD,. Arginase acts as an alternative pathway of l -arginine metabolism in experimental colon anastomosis. J Gastrointest Surg 2003; 7: 378-385.
Beck DE, Cohen Z, Fleshman JW, Kaufman HS, van Goor H, Wolff BG,. A prospective, randomized, multicenter, controlled study of the safety of Seprafilm adhesion barrier in abdominopelvic surgery of the intestine. Dis Colon Rectum 2003; 46: 1310-1319.
