The effect of Tumor Necrosis Factor alpha inhibitor on wound healing of oral mucosa in induced diabetic rats
AbstractBackground and objective: Impaired wound healing is a major complication of diabetes mellitus. This study was carried out to determine the healing process of oral mucosa in diabetic rats and the role of systemic tumor necrosis factor alpha inhibitor (infliximab). Methods: Thirty eight male rats were divided into two groups, the normoglycemic group (11 rats), and diabetic group (27 rats) that were rendered diabetic by alloxan injection. Two months later, wound was created in the lateral side of the tongue for both groups. The diabetic group was then subdivided into two subgroups, 14 rats received 5mg/kg infliximab subcutaneous injection at the day of wound creation while the other 13 rats received saline injection. After 7 days, biopsies of the tongue were collected and subjected to histological and histochemical procedure. Results: Histological examinations showed delayed healing in the diabetic group with persistence of epithelial discontinuity, large amount of granulation tissue and destruction of the underlying muscle fibers. In the subgroup injected with infliximab, reepitheliazation of the wound was demonstrated with well arranged underlying collagen fibers. Using PAS stain, diabetic group revealed a dramatically high amount of PAS positive precipitants in the lamina properia, especially in the wall of the blood vessels, while with infliximab injection, the PAS+ve precipitants were more prominent than normoglycemic group but less than diabetic group without infliximab. Conclusion: These findings suggest that infliximab accelerated mucosal wound healing in the diabetic rats with the formation of well organized connective tissue.
Li M, and Ikehara S. “Stem cell treatment for type 1 diabetes”. Front Cell Dev Biol. 2014; 20:2-9.
Graves DT, Liu R, Alikhani M, Al-Mashat H, Trackman PC. “Diabetes-enhanced inflammation and apoptosis--impact on periodontal pathology”. J Dent Res 2006; 85:15-21.
Blakytny R, Jude E. “The molecular biology of chronic wounds and delayed healing in diabetes”. Diabet Med 2006; 23:594-608.
Firat ET, Dağ A, Günay A, Kaya B, Karadede MI, Kanay BE,et.al. “The effects of low-level laser therapy on palatal mucoperiosteal wound healing and oxidative stress status in experimental diabetic rats”. Photomed Laser Surg 2013;31: 315-21.
Ahmed N. “Advanced glycation endproducts--role in pathology of diabetic complications”. Diabetes Res Clin Pract 2005; 67 :3-21.
Gurtner GC, Werner S, Barrandon Y, Longaker M. “Wound repair and regeneration”. Nature.2008;15:314-21.
Barrientos S, Stojadinovic O, Golinko M, Brem H, Tomic-Canic M. “Growth factors and cytokines in wound healing,” Wound Repair and Regen 2008; 16:585–601.
Wen Y, Gu J, Li SL, Reddy MA, Natarajan R, Nadler JL. “Elevated glucose and diabetes promote interleukin-12 cytokine gene expression in mouse macrophages”. Endocrinology 2006; 147: 2518–25.
John D, Lyons TE, Wu S, Gnardellis C, Dinh T, Veves A. “Microvascular reactivity and inflammatory cytokines in painful and painless peripheral diabetic neuropathy”. J Clin Endocrinol Metab 2009; 94: 2157–63.
Hart J. “Inflammation 2: its role in the healing of chronic wounds”. J Wound Care 2002; 11: 245-9.
Chatzigeorgiou A, Harokopos V, Mylona-Karagianni C, Tsouvalas E, Aidinis V, Kamper E. “The pattern of inflammatory/anti-inflammatory cytokines and chemokines in type 1 diabetic patients over time”. Ann Med 2010; 42:426–38.
Khanna S, Biswas S, Shang Y, Collard E, Azad A. “Macrophage dysfunction impairs resolution of inflammation in the wounds of diabetic mice”. PLoS one 2010; 5:e9539.
Siqueira MF, Li J, Chehab L, Desta T, Chino T, Krothpali N, et al. “Impaired wound healing in mouse models of diabetes is mediated by TNF- dysregulation and associated with enhanced activation of forkhead box O1 (FOXO1),” Diabetologia; 2010; 53:378–88.
Ring BD, Scully S, Corrine CR, Baker MB, Cullen MJ, Pelleymounter MA, et al. “Systemically and topically administered leptin both accelerate wound healing in diabetic ob/ob mice”. Endocrinol 2000; 141:446-9.
Varani J, Warner RL, Gharaee-Kermani M, Phan SH, Kang S, Chung JH, et al. “Vitamin A antagonizes decreased cell growth and elevated collagen-degrading matrix metalloproteinases and stimulates collagen accumulation in naturally aged human skin”. J Invest Dermatol. 2000; 114:480-6.
Liu R, Bal HS, Desta T, Behl Y, Graves DT. Tumor necrosis factor- α mediates diabetes enhanced apoptosis of matrix-producing cells and impairs diabetic healing. Am J Pathol 2006;168:757-64
Fedyker F, Jones D, Critchely HO, Phipps RP, Blieden TM, Springer TA. “Expression of stromal-derived factor-1 is decreased by IL-1 and TNF in dermal wound healing”. J Immunol 2001; 166: 5749–54.
Miehsler W1, Novacek G, Wenzl H, Vogelsang H, Knoflach P, Kaser A, et al. “A decade of infliximab: The Austrian evidence based consensus on the safe use of infliximab in inflammatory bowel disease; Austrian Society of Gastroenterology and Hepatology”. J Crohns Colitis 2010; 4:221-56.
Horiuchi T, Mitoma H, Harashima S, Tsukamoto H, Shimoda T. “ Transmembrane TNF-alpha: structure, function and interaction with anti-TNF agents. Rheumatology 2010 ; 49:1215-28.
Ibrahim RS.“Effect of low energy laser irradiation on bone healing around intra osseous titanium implant in experimentally diabetic rabbits” 2003. PhD thesis in Oral histology and biology. University of Baghdad, college of dentistry.
Westhovens R; Houssiau F; Joly J. “A phase I study assessing the safety, clinical response, and pharmacokinetics of an experimental infliximab formulation for subcutaneous or intramuscular administration in patients with rheumatoid arthritis”. J Rheumatol 2006; 33: 5-11.
McLaughlin PJ, Immonen JA, Zagon IS. “Topical naltrexone accelerates full-thickness wound closure in type 1 diabetic rats by stimulating angiogenesis”. Exp Biol Med 2013;238:733-43.
Talwar HS, Griffiths CE, Fisher GJ, Hamilton TA, Voorhees JJ. “Reduced type I and type III procollagens in photodamaged adult human skin”. J Invest Dermtol. 1995 ;105:285-90.
Armendariz-Borunda J; Katayama K; and Seyer JM. “Transcriptional mechanisms of type I collagen gene expression are differentially regulated by interleukin-1 beta, tumor necrosis factor alpha, and transforming growth factor beta in Ito cells”. J. Biol. Chem. 1992; 267: 14316-21.
-Buck M, Houglum K, Chojkier M “Tumor necrosis factor inhibits collagen 1 gene expression and wound healing in a murine model of cachexia”. Am J Pathol 1996 ; 149:195-204.
Suragimath G, Krishnaprasad KR, Moogla S, Sridhara SU, Raju S. “ Effect of carbonated drink on excisional palatal wound healing: a study on Wistar rats”. Indian J Dent Res 2010;21:330-3.
Lee SK, Lee SS, Song IS, Kim YS, Park YW, Joo JY, et.al. “Paradoxical effects of elastase inhibitor guamerin on the tissue repair of two different wound models: sealed cutaneous and exposed tongue wounds”. Exp Mol Med 2004; 36:259-67.
Kuroki SH, Yokoo S, Terashi H, Hasegawa M, and Komori T. “Epithelialization in Oral Mucous Wound Healing in Terms of Energy Metabolism”. Kobe J Med Sci 2009; 55:5-15.
Candek M, Lefaucheur L, Ecolan P. “Determination of glycogen in single muscle fibers by computerized image analysis. Application to the quantification of glycogen according to fiber type in two muscles and three pig genotypes”. Res rep1999; 36: 57-66.
Haihong L, Xiaobing F, Lei Z, Qingjun H, Zhigu W, Tongzhu S. “Gels on the Wound Healing of Diabetic Rats and Its Pharmacodynamics”. J Surg Res 2008 ; 145: 41–8.
Velander PE, Theopold C, Raphael G, Oliver B, Yao F, ,Elof E. “Autologous cultured keratinocytes suspensions accelerate re-epithelialization in the diabetic pig”. J Am Col Sur 2004; 199:58-63.
Gottrup F1,Agren MS,Karlsmark T. “Models for use in wound healing research: a survey focusing on invitro & invivo adult soft tissue”. Wound Repair Regen. 2000;8:83-96.
Park JY, Lee J, Jeong M, Min S, Kim SY, Lee H,
et al. “Effect Hominis Placenta on cutaneous wound healing in normal and diabetic mice”. Nutr Res Pract. 2014;8:404-9
Gallucci R. , Simeonova P, Toriumi W, and Luster M. “TNF-a Regulates Transforming Growth Factor-a Expression in Regenerating Murine Liver and Isolated Hepatocytes” J Immunol 2000; 164:872-8.
Desta T, Li J, Chino T, and Graves D. “Altered fibroblast proliferation and apoptosis in diabetic gingival wounds”. J Dent Res 2010; 89: 609–14.
Lamers M. L, Almeida ME, Vicente-Manzanares M. , Horwitz A, and. Santos M. “High glucose-mediated oxidative stress impairs cell migration”. PLoS ONE 2011; 6: e22865
Mann KG. “Thrombin Generation in Hemorrhage Control and Vascular Occlusion”.Circulation. 2011;124: 225–35.
Baby GG, and Padiyath SH. “Gingival Vascular Basement Membrane Changes In Diabetes Mellitus”. OMPJ 2010; 1.ISSN 0976-1225
Goren I; Muller E; and Schiefelbein D. “Systemic anti TNF-alpha treatment restores diabetes-impaired skin repair in ob/ob mice by inactivation of macrophages”. J Invest Dermatol 2007; 127:2259-67.
Lügering A, Lebiedz P, Koch S, Kucharzik T. “Apoptosis as a therapeutic tool in IBD?” Ann N Y Acad Sci. 2006 ;1072:62-77
-Shen C, Assche GV, Colpaert S, Maerten P, Geboes K, Rutgeerst P, et al. “Adalumimab induces apoptosis of human monocytes: a comparative study with infliximab and etanercept”. Aliment Pharmacol Ther 2005; 1:251–8
Rutella S, Fiorino G, Vetrano S., Correale C, Spinelli A, Pagano N, et al., “Infliximab therapy inhibits inflammation-induced angiogenesis in the mucosa of patients with crohn’s disease,” Am. J. Gastroenterol. .2011;106:762–70,
Izquierdo E, Ca˜nete J. D., Celis R Santiago B, Usategui A, Sanmartí R, et al., “Immature blood vessels in rheumatoid synovium are selectively depleted in response to anti-TNF therapy”. PLoS one. 2009; 2;4:e8131.
Goren I, Mu¨ ller E, Pfeilschifter J, Frank S. “Severely impaired insulin signaling in chronic wounds of diabetic ob/ob mice. A potential role of tumor necrosis factor- α”. Am J Pathol. 2006; 168:765–77.
This work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License.
The copyright on any article published in Zanco J Med Sci is retained by the author(s) in agreement with the Creative Commons Attribution Non-Commercial ShareAlike License (CC BY-NC-SA 4.0).