Abstract
Background
Previous studies have shown that healing in intestinal wounds is proportionally faster than skin. Cytokines and growth factors play a major role in these coordinated wound-healing events. We hypothesized that this more rapid intestinal healing is due to an early upregulation of proinflammatory cytokines (IL-1β, TNF-α, and IFN-γ), followed by increases in the expression of the anti-inflammatory cytokine IL-10 and growth factor TGF-β.
Methods
Four wounds (skin, fascia, small intestinal, and colonic anastomosis) were created in each of 48 juvenile male Sprague Dawley rats; tissue samples of each site were harvested at 0, 1, 3, 5, 7, and 14 days postoperatively (n = 8/group) and levels of IL-1β, IFN-γ, TNF-α, IL-10 and TGF-β expression from each site were measured using ELISA kits.
Results
IL-1β expression peaked earlier in small-intestinal and colonic wounds when compared to skin or fascia (e.g., small intestine: day 3 and colon day 5, P < 0.05 by ANOVA). Post-wounding levels of TNF-α were elevated in fascial wounds, but decreased in small-intestinal and colonic wounds. IFN-γ levels were not significantly altered in any wounds. IL-10 showed a similar downregulation pattern in all wounds, while TGF-B levels were decreased in colonic and fascial wounds, but relatively unchanged in SI and skin.
Conclusions
An earlier peak in IL-1β levels and a consistent decrease in TNF-α were seen in healing intestinal tissues; but no clear pattern of increased anti-inflammatory or regulatory cytokines was seen, which might explain the earlier healing of intestinal tissues. Additional studies are required to determine the role of individual cytokines, or the intrinsic reactivity of the tissues may explain the site specific differences of healing rates in different tissues.
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References
Vignali A, Fazio VW, Lavery IC, et al. Factors associated with the occurrence of leaks in stapled rectal anastomoses: a review of 1,014 patients. J Am Coll Surg. 1997;185(2):105–113.
Golub R, Golub RW, Cantu R Jr, Stein HD. A multivariate analysis of factors contributing to leakage of intestinal anastomoses. J Am Coll Surg. 1997;184(4):364–372.
Pickleman J, Watson W, Cunningham J, Fisher SG, Gamelli R. The failed gastrointestinal anastomosis: an inevitable catastrophe? J Am Coll Surg. 1999;188(5):473–482.
Dubay DA, Franz MG. Acute wound healing: the biology of acute wound failure. Surg Clin North Am. 2003;83(3):463–481.
Gailit J, Clark RA. Wound repair in the context of extracellular matrix. Curr Opin Cell Biol. 1994;6(5):717–725.
Bennett NT, Schultz GS. Growth factors and wound healing: Part II. Role in normal and chronic wound healing. Am J Surg. 1993;166(1):74–81.
Sauder DN, Kilian PL, McLane JA, et al. Interleukin-1 enhances epidermal wound healing. Lymphokine Res. 1990;9(4):465–473.
Appleton I, Tomlinson A, Colville-Nash PR, Willoughby DA. Temporal and spatial immunolocalization of cytokines in murine chronic granulomatous tissue. Implications for their role in tissue development and repair processes. Lab Invest. 1993;69(4):405–414.
Graves DT, Nooh N, Gillen T, et al. IL-1 plays a critical role in oral, but not dermal, wound healing. J Immunol. 2001;167(9):5316–5320.
Lee RH, Efron DT, Tantry U, et al. Inhibition of tumor necrosis factor-alpha attenuates wound breaking strength in rats. Wound Repair Regen. 2000;8(6):547–553.
Schaffer M, Bongartz M, Hoffmann W, Viebahn R. Regulation of nitric oxide synthesis in wounds by IFN-gamma depends on TNF-alpha. J Invest Surg. 2006;19(6):371–379.
Shao DD, Suresh R, Vakil V, Gomer RH, Pilling D. Pivotal Advance: Th-1 cytokines inhibit, and Th-2 cytokines promote fibrocyte differentiation. J Leukoc Biol. 2008;83(6):1323–1333.
Rogler G, Andus T. Cytokines in inflammatory bowel disease. World J Surg. 1998;22(4):382–389.
Fahey TJIII, Sherry B, Tracey KJ, et al. Cytokine production in a model of wound healing: the appearance of MIP-1, MIP-2, cachectin/TNF and IL-1. Cytokine. 1990;2(2):92–99.
Loppnow H, Bil R, Hirt S, et al. Platelet-derived interleukin-1 induces cytokine production, but not proliferation of human vascular smooth muscle cells. Blood. 1998;91(1):134–141.
Maish GOIII, Shumate ML, Ehrlich HP, Cooney RN. Tumor necrosis factor binding protein improves incisional wound healing in sepsis. J Surg Res. 1998;78(2):108–117.
Rumalla VK, Borah GL. Cytokines, growth factors, and plastic surgery. Plast Reconstr Surg. 2001;108(3):719–733.
Ishida Y, Kondo T, Takayasu T, Iwakura Y, Mukaida N. The essential involvement of cross-talk between IFN-gamma and TGF-beta in the skin wound-healing process. J Immunol. 2004;172(3):1848–1855.
MacDonald TT, Monteleone G, Pender SL. Recent developments in the immunology of inflammatory bowel disease. Scand J Immunol. 2000;51(1):2–9.
Tamai K, Ishikawa H, Mauviel A, Uitto J. Interferon-gamma coordinately upregulates matrix metalloprotease (MMP)-1 and MMP-3, but not tissue inhibitor of metalloproteases (TIMP), expression in cultured keratinocytes. J Invest Dermatol. 1995;104(3):384–390.
Sato Y, Ohshima T, Kondo T. Regulatory role of endogenous interleukin-10 in cutaneous inflammatory response of murine wound healing. Biochem Biophys Res Commun. 1999;265(1):194–199.
Schultz G, Rotatori DS, Clark W. EGF and TGF-alpha in wound healing and repair. J Cell Biochem. 1991;45(4):346–352.
Buckmire MA, Parquet G, Greenway S, Rolandelli RH. Temporal expression of TGF-beta1, EGF, and PDGF-BB in a model of colonic wound healing. J Surg Res. 1998;80(1):52–57.
Wahl SM, Allen JB, Weeks BS, Wong HL, Klotman PE. Transforming growth factor beta enhances integrin expression and type IV collagenase secretion in human monocytes. Proc Natl Acad Sci USA. 1993;90(10):4577–4581.
Shomaf M. Histopathology of human intestinal anastomosis. East Mediterr Health J. 2003;9(3):413–421.
Brasken P. Healing of experimental colon anastomosis. Eur J Surg (Suppl). 1991;157(566):1–51.
Jiborn H, Ahonen J, Zederfeldt B. Healing of experimental colonic anastomoses. III. Collagen metabolism in the colon after left colon resection. Am J Surg. 1980;139(3):398–405.
Schaffer M, Fuchs N, Volker J, Schulz T, Kapischke M, Viebahn R. Differential effect of tacrolimus on dermal and intestinal wound healing. J Invest Surg. 2005;18(2):71–79.
Levenson SM, Geever EF, Crowley LV, Oates JF I, Berard CW, Rosen H. The healing of rat skin wounds. Ann Surg. 1965;161:293–308.
Attard JA, Raval MJ, Martin GR, et al. The effects of systemic hypoxia on colon anastomotic healing: an animal model. Dis Colon Rectum. 2005;48(7):1460–1470.
Lowry OH, Rosebrough NJ, Farr AL, Randall RJ. Protein measurement with the Folin phenol reagent. J Biol Chem. 1951;193(1):265–275.
Shaper KR, Savage FJ, Hembry RM, Boulos PB. Regulation of matrix metalloproteinases in a model of colonic wound healing in a rabbit. Dis Colon Rectum. 2001;44(12):1857–1866.
Baker EA, El Gaddal S, Williams L, Leaper DJ. Profiles of inflammatory cytokines following colorectal surgery: relationship with wound healing and outcome. Wound Repair Regen. 2006;14(5):566–572.
Ishimura K, Moroguchi A, Okano K, Maeba T, Maeta H. Local expression of tumor necrosis factor-alpha and interleukin-10 on wound healing of intestinal anastomosis during endotoxemia in mice. J Surg Res. 2002;108(1):91–97.
Scallon BJ, Moore MA, Trinh H, Knight DM, Ghrayeb J. Chimeric anti-TNF-[alpha] monoclonal antibody cA2 binds recombinant transmembrane TNF-[alpha] and activates immune effector functions. Cytokine. 1995;7(3):251–259.
Ishimura K, Tsubouchi T, Okano K, Maeba T, Maeta H. Wound healing of intestinal anastomosis after digestive surgery under septic conditions: participation of local interleukin-6 expression. World J Surg. 1998;22(10):1069–1075.
Rongione AJ, Kusske AM, Ashley SW, Reber HA, McFadden DW. Interleukin-10 prevents early cytokine release in severe intraabdominal infection and sepsis. J Surg Res. 1997;70(2):107–112.
Sikas N, Imvrios G, Takoudas D, Gakis D, Papanikolaou V. Mycophenolate mofetil impairs the integrity of colonic anastomosis. J Surg Res. 2006;134(2):168–172.
Acknowledgments
Dr. Zubaidi was sponsored by the Saudi Arabian Government Medical Mission in Canada. Dr. Sigalet’s lab received generous support from a research grant from the University of Calgary, and the Alberta Children’s Hospital. Dr. Hart received support from a CIHR Net Grant from the Institute for Gender and Health Studies.
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Zubaidi, A., Buie, W.D., Hart, D.A. et al. Temporal Expression of Cytokines in Rat Cutaneous, Fascial, and Intestinal Wounds: A Comparative Study. Dig Dis Sci 55, 1581–1588 (2010). https://doi.org/10.1007/s10620-009-0931-0
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DOI: https://doi.org/10.1007/s10620-009-0931-0