Apikal periodontitiste inflamatuar mediatörlerin özü

Abstract

Apikal periodontitis (AP), dişlerin periradiküler dokularının nekrotik pulpa ile kronik inflamatuar reaksiyonunu ifade eder. AP çok faktörlü bir hastalık olarak kabul edilmesine rağmen, enfekte kök kanallarından farklı mikroorganizmalar ve bunların virülans faktörlerinin periradiküler inflamatuar sürecin birincil nedeni olduğu düşünülmektedir. Mikroplar ve konakçı arasındaki etkileşim, bağışıklığın doğuştan gelen ve adaptif bileşenlerinin aktivasyonunu içeren inflamatuar bir olaylar dizisine yol açar. AP'de farklı bağışıklık hücrelerinin aktivasyonuna, inflamasyon aracıları olarak bilinen farklı moleküller aracılık eder. Bu moleküller iltihaplı periapikal bölgede çeşitli ağ ilişkileri kurar ve alveolar kemik emilimini indükler. Bu derleme makalesi, sitokinler, matriks metalloproteinazlar, kemik rezorpsiyon düzenleyicileri ve AP'de alveoler kemik rezorpsiyonunda rol oynayan oksidatif stres bileşenleri dahil olmak üzere bazı inflamatuar mediatörlerle ilgili mevcut bilgileri sunmayı amaçlamaktadır.

Keywords

• periapikal periodontitis
• sitokinler
• oksidatif stres
• matriks metalloproteinazlar
• kemik rezorpsiyonu

Inflammatory mediators’ essence in apical periodontitis

Abstract

Apical periodontitis (AP) represents chronic inflammatory reaction of periradicular tissues of teeth with necrotic pulp. Although AP has been considered as a multifactorial disease, different microorganisms and their virulence factors from infected root canals are considered to be the primary cause of periradicular inflammatory process. The interplay between microbes and host leads to an inflammatory cascade of events that includes activation of innate and adaptive components of immunity. Activation of different immune cells in AP is intermediated by different molecules known as mediators of inflammation. These molecules establish various network interrelationships in the inflamed periapical area and induce alveolar bone resorption. This narrative review aimed to explore and present the current knowledge of selected inflammatory mediators, including cytokines, matrix metalloproteinases, bone resorption regulators and components of oxidative stress involved in the alveolar bone resorption in AP.

Keywords

• periapical periodontitis
• cytokines
• oxidative stress
• matrix metalloproteinases
• bone resorption

References

1. 1. Nair, P.N. On the causes of persistent apical periodontitis: a review. Int Endod J 2006; 39: 249281. google scholar
2. 2. Siqueira JF Jr, Röças IN. Present status and future directions: Microbiology of endodontic infections. Int Endod J 2022; 55: 512-530. google scholar
3. 3. Marton, I.J., Kiss, C. Overlapping protective and destructive regulatory pathways in apical periodontitis. J Endod 2014; 40: 155-163. google scholar
4. 4. Fouad AF. Molecular mediators of pulpal inflammation. In: Franklin RT, Seltzer S, Hargreaves KM, Goodis HE, editors. Seltzer and Bender's Dental Pulp. Chicago: Quintessence Publishing, 2012, p. 241-75. google scholar
5. 5. Liu C, Chu D, Kalantar-Zadeh K, George J, Young HA, Liu G. Cytokines: From Clinical Significance to Quantification. Adv Sci (Weinh) 2021; 8: 2004433. google scholar
6. 6. Lee SK, Lorenzo J. Cytokines regulating osteoclast formation and function. Curr Opin Rheumatol 2006; 18: 411-8. google scholar
7. 7. Idriss HT, Naismith JH. TNF alpha and the TNF receptor superfamily: structure-function relationship(s). Microsc Res Tech 2000; 50: 184-95. google scholar
8. 8. Bradley JR. TNF-mediated inflammatory disease. J Pathol 2008; 214: 149-60. google scholar

9. 9. Gazivoda D, Dzopalic T, Bozic B, Tatomirovic Z, Brkic Z, Colic M. Production of proinflammatory and immunoregulatory cytokines by inflammatory cells from periapical lesions in culture. J Oral Pathol Med 2009; 38: 605-11. google scholar
10. 10. Artese L, Piattelli A, Quaranta M, Colasante A, Musani P. Immunoreactivity for interleukin 1-beta and tumor necrosis factor-alpha and ultrastructural features of monocytes/macrophages in periapical granulomas. J Endod 1991; 17: 483-7. google scholar
11. 11. Graves DT, Oskoui M, Volejnikova S, Naguib G, Cai S, Desta T, Kakouras A, Jiang Y. Tumor necrosis factor modulates fibroblast apoptosis, PMN recruitment, and osteoclast formation in response to P. gingivalis infection. J Dent Res 2001; 80: 1875-9. google scholar
12. 12. Samuel RO, Gomes-Filho JE, Azuma MM, Sumida DH, de Oliveira SHP, Chiba FY, Bomfim SRM, Ciarlini PC, Narciso LG, Cintra LTA. Endodontic infections increase leukocyte and lymphocyte levels in the blood. Clin Oral Investig 2018; 22: 1395-1401. google scholar
13. 13. Safavi KE, Rossomando EF. Tumor necrosis factor identified in periapical tissue exudates of teeth with apical periodontitis. J Endod 1991; 17: 12-4. google scholar
14. 14. Nunez N, Erdogan O, Casey SM, Hernandez R, Tan S, Gibbs JL. Elevated Cytokine Levels in Gingival Crevicular Fluid of Teeth with Apical Periodontitis. J Endod 2023; 49: 657-63. google scholar
15. 15. Pezelj-Ribaric S, Magasic K, Prpic J, Miletic I, Karlovic Z. Tumor necrosis factor-alpha in peripical tissue exudates of teeth with apical periodontitis. Mediators Inflamm 2007; 2007: 69416. google scholar
16. 16. Teixeira-Salum TB, Rodrigues DB, Gervasio AM, Souza CJ, Rodrigues V Jr, Loyola AM. Distinct Th1, Th2 and Treg cytokines balance in chronic periapical granulomas and radicular cysts. J Oral Pathol Med 2010; 39: 250-6. google scholar
17. 17. Ataoglu T, Ungor M, Serpek B, Haliloglu S, Ataoglu H, Ari H. Interleukin-1beta and tumour necrosis factor alpha levels in periapical exudates. Int Endod J 2002; 35: 181-5. google scholar
18. 18. Prso IB, Kocjan W, Simic H et al. Tumor necrosis factor alpha and interleukin 6 in human periapical lesions. Mediators Inflamm 2007; 2007: 38210. google scholar
19. 19. Jakovljevic A, Knezevic A, Karalic D, Soldatovic I, Popovic B, Milasin J, Andric M. Pro-inflammatory cytokine levels in human apical periodontitis: Correlation with clinical and histological findings. Aust Endod J 2015; 41: 72-7. google scholar
20. 20. Palomo J, Dietrich D, Martin P, Palmer G, Gabay C. The interleukin (IL)-1 cytokine family--Balance between agonists and antagonists in inflammatory diseases. Cytokine 2015; 76: 25-37. google scholar
21. 21. Gabay C, Lamacchia C, Palmer G. IL-1 pathways in inflammation and human diseases. Nat Rev Rheumatol 2010; 6: 232-41. google scholar
22. 22. Hamachi T, Anan H, Akamine A, Fujise O, Maeda K. Detection of interleukin-1 beta mRNA in rat periapical lesions. J Endod 1995; 21: 118-21. google scholar
23. 23. Matsumoto A, Anan H, Maeda K. An immunohistochemical study of the behavior of cells expressing interleukin-1 alpha and interleukin-1 beta within experimentally induced periapical lesions in rats. J Endod 1998; 24: 811-6. google scholar
24. 24. Barkhordar RA, Hussain MZ, Hayashi C. Detection of interleukin-1 beta in human periapical lesions. Oral Surg Oral Med Oral Pathol 1992; 73: 334-6. google scholar
25. 25. Kuo ML, Lamster IB, Hasselgren G. Host mediators in endodontic exudates. I. Indicators of inflammation and humoral immunity. J Endod 1998; 24: 598-603. google scholar
26. 26. Lim GC, Torabinejad M, Kettering J, Linkhardt TA, Finkelman RD. Interleukin 1-beta in symptomatic and asymptomatic human periradicular lesions. J Endod 1994; 20: 225-7. google scholar
27. 27. Tazawa K, Azuma Presse MM, Furusho H, Stashenko P, Sasaki H. Revisiting the role of IL-1 signaling in the development of apical periodontitis. Front Dent Med 2022; 3: 985558. google scholar
28. 28. Tanaka T, Narazaki M, Kishimoto T. IL-6 in inflammation, immunity, and disease. Cold Spring Harb Perspect Biol 2014; 6: a016295. google scholar
29. 29. Matsushita K, Tajima T, Tomita K, Abeyama K, Maruyama I, Takada H, Nagaoka S. Inflammatory cytokine production and specific antibody responses against possible causative bacteria in patients with multilesional periapical periodontitis. J Endod 1998; 24: 817-21. google scholar
30. 30. Kawashima N, Stashenko P. Expression of bone-resorptive and regulatory cytokines in murine periapical inflammation. Arch Oral Biol 1999; 44: 55-66. google scholar
31. 31. Huang GT, Do M, Wingard M, Park JS, Chugal N. Effect of interleukin-6 deficiency on the formation of periapical lesions after pulp exposure in mice. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2001; 92: 83-8. google scholar
32. 32. Balto K, Sasaki H, Stashenko P. Interleukin-6 deficiency increases inflammatory bone destruction. Infect Immun 2001; 69: 744-50. google scholar
33. 33. Barkhordar RA, Hayashi C, Hussain MZ. Detection of interleukin-6 in human dental pulp and periapical lesions. Endod Dent Traumatol 1999; 15: 26-7. google scholar
34. 34. Radics T, Kiss C, Tar I, Marton IJ. Interleukin-6 and granulocyte-macrophage colony stimulating factor in apical periodontitis: correlation with clinical and histologic findings of the involved teeth. Oral Microbiol Immunol 2003; 18: 9-13. google scholar
35. 35. Abdolsamadi HR, Vahedi M, Esmaeili F, Nazari S, Abdollahzadeh S. Serum Interleukin-6 as a Serologic Marker of Chronic Periapical Lesions: A Case-control Study. J Dent Res Dent Clin Dent Prospects 2008; 2: 43-7. google scholar
36. 36. Alvarez C, Monasterio G, Cavalla F, Cordova LA, Hernandez M, Heymann D, Garlet GP, Sorsa T, Parnanen P, Lee HM, Golub LM, Vernal R, Kantarci A. Osteoimmunology of Oral and Maxillofacial Diseases: Translational Applications Based on Biological Mechanisms. Front Immunol. 2019; 18: 1664. google scholar
37. 37. Okamoto K, Nakashima T, Shinohara M, Negishi-Koga T, Komatsu N, Terashima A, Sawa S, Nitta T, Takayanagi H. Osteoimmunology: The Conceptual Framework Unifying the Immune and Skeletal Systems. Physiol Rev 2017; 97: 1295-349. google scholar
38. 38. Terashima A, Takayanagi H. Overview of Osteoimmunology. Calcif Tissue Int 2018; 102: 50311. google scholar
39. 39. Zhang X, Peng B. Immunolocalization of receptor activator ofNF kappa B ligand in rat periapical lesions. J Endod 2005; 31: 574-7. google scholar
40. 40. Kawashima N, Suzuki N, Yang G, Ohi C, Okuhara S, Nakano-Kawanishi H, Suda H. Kinetics of RANKL, RANK and OPG expressions in experimentally induced rat periapical lesions. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2007; 103: 707-11. google scholar
41. 41. Chuang FH, Tsai CC, Chen JH, Chen KK, Chen YK, Lin YC. Long-term sequential receptor activator of NF-kB ligand (RANKL) and osteoprotegrin (OPG) expression in lipopolysaccharide-induced rat periapical lesions. J Oral Pathol Med 2012; 41: 186-93. google scholar
42. 42. Tay JY, Bay BH, Yeo JF, Harris M, Meghji S, Dheen ST. Identification of RANKL in osteolytic lesions of the facial skeleton. J Dent Res 2004; 83: 349-53. google scholar
43. 43. Sabeti M, Simon J, Kemani V, Valles Y, Rostein I. Detection of receptor activator of NF-kappa beta ligand in apical periodontitis. J Endod 2005; 31: 17-8. google scholar
44. 44. Fukada SY, Silva TA, Garlet GP, Rosa AL, da Silva JS, Cunha FQ. Factors involved in the T helper type 1 and type 2 cell commitment and osteoclast regulation in inflammatory apical diseases. Oral Microbiol Immunol 2009; 24: 25-31. google scholar
45. 45. Menezes R, Bramante CM, da Silva Paiva KB, Letra A, Carneiro E, Fernando Zambuzzi W, Granjeiro JM. Receptor activator NFkappaB-ligand and osteoprotegerin protein expression in human periapical cysts and granulomas. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2006; 102: 4049. google scholar
46. 46. Salinas-Munoz M, Garrido-Flores M, Baeza M, Huamân-Chipana P, Gartfa-Sesnich J, Bologna R, Vernal R, Hernandez M. Bone resorptive activity in symptomatic and asymptomatic apical lesions of endodontic origin. Clin Oral Investig 2017; 21: 2613-2618. google scholar
47. 47. Duka M, Erakovic M, Dolicanin Z, Stefanovic D, Ğolic M. Production of Soluble Receptor Activator of Nuclear Factor Kappa-B Ligand and Osteoprotegerin by Apical Periodontitis Cells in Culture and Their Modulation by Cytokines. Mediators Inflamm 2019; 18: 8325380. google scholar
48. 48. Nikolic N, Jakovljevic A, Carkic J, Beljic-Ivanovic K, Miletic M, Soldatovic I, Andric M, Ivanovic V, Milasin J. Notch Signaling Pathway in Apical Periodontitis: Correlation with Bone Resorption Regulators and Proinflammatory Cytokines. J Endod 2019; 45: 123-8. google scholar
49. 49. Cabral-Pacheco GA, Garza-Veloz I, Castruita-De la Rosa C, Ramirez-Acuna JM, Perez-Romero BA, Guerrero-Rodriguez JF, et al. The roles of matrix metalloproteinases and their inhibitors in human diseases. Int J Mol Sci 2020; 21: 9739. google scholar
50. 50. Monea M, Pop AM. The use of salivary levels of matrix metalloproteinases as an adjuvant method in the early diagnosis of oral squamous cell carcinoma: A narrative literature review. Curr Issues Mol Biol 2022; 44: 6306-22. google scholar
51. 51. Loffek S, Schilling O, Franzke C-W. Biological role of matrix metalloproteinases: A critical balance. Eur Respir J 2010; 38: 191-208. google scholar
52. 52. Anshida VP, Kumari RA, Murthy CS, Samuel A. Extracellular matrix degradation by host matrix metalloproteinases in restorative dentistry and endodontics: An overview. J Oral Maxillofac Pathol 2020; 24: 352-60. google scholar
53. 53. Hannas AR, Pereira JC, Granjeiro JM, Tjaderhane L. The role of matrix metalloproteinases in the oral environment. Acta Odontol Scand 2007; 65: 1-13. google scholar
54. 54. Sorsa T, Tjaderhane L, Salo T. Matrix metalloproteinases (MMPs) in oral diseases. Oral Dis 2004; 10: 311-8. google scholar
55. 55. Panagakos FS, O'Boskey JF Jr, Rodriguez E. Regulation of pulp cell matrix metalloproteinase production by cytokines and lipopolysaccharides. J Endod 1996; 22: 358-61. google scholar
56. 56. O'Boskey FJ Jr, Panagakos FS. Cytokines stimulate matrix metalloproteinase production by human pulp cells during long-term culture. J Endod 1998; 24: 7-10. google scholar
57. 57. Wang G, Fan WT, Zhang Z, Huang SG. Expression of matrix metalloproteinase-8 and matrix metalloproteinase-13 in mast cells of human periapical lesions. Int J Clin Exp Pathol 2018; 11: 25306. google scholar
58. 58. Corotti MV, Willian Fernando Zambuzzi, Paiva S, Menezes R, Pinto LC, Vanessa Soares Lara, et al. Immunolocalization of matrix metalloproteinases-2 and -9 during apical periodontitis development. Arch Oral Biol 2009; 54: 764-71. google scholar
59. 59. Wan CY, Li L, Liu LS, Jiang CM, Zhang HZ, Wang JX. Expression of Matrix Metalloproteinases and Tissue Inhibitor of Matrix Metalloproteinases during Apical Periodontitis Development. J Endod 2021; 47: 1118-25. google scholar
60. 60. Shin SJ, Lee JI, Baek SH, Lim SS. Tissue levels of matrix metalloproteinases in pulps and periapical lesions. J Endod 2002; 28: 313-5. google scholar
61. 61. Leonardi R, Caltabiano R, Loreto C. Collagenase-3 (MMP-13) is expressed in periapical lesions: an immunohistochemical study. Int Endod J 2005; 38: 297-301. google scholar
62. 62. Martinho FC, Teixeira FF, Cardoso FG, Ferreira NS, Nascimento GG, Carvalho CA, Valera MC. Clinical Investigation of Matrix Metalloproteinases, Tissue Inhibitors of Matrix Metalloproteinases, and Matrix Metalloproteinase/Tissue Inhibitors of Matrix Metalloproteinase Complexes and Their Networks in Apical Periodontitis. J Endod 2016; 42: 1082-8. google scholar
63. 63. Letra A, Ghaneh G, Zhao M, Ray H Jr, Francisconi CF, Garlet GP, Silva RM. MMP-7 and TIMP-1, new targets in predicting poor wound healing in apical periodontitis. J Endod 2013; 39: 1141-6. google scholar
64. 64. Hadziabdic N, Kurtovic-Kozaric A, Pojskic N, Sulejmanagic N, Todorovic L. Gene-expression analysis of matrix metalloproteinases 1 and 2 and their tissue inhibitors in chronic periapical inflammatory lesions. J Oral Pathol Med 2016; 45: 224-30. google scholar
65. 65. Pereira Faustino IS, Azevedo RS, Takahama A Jr. Metalloproteinases 2 and 9 Immunoexpression in Periapical Lesions from Primary Endodontic Infection: Possible Relationship with the Histopathological Diagnosis and the Presence of Pain. J Endod 2016; 42: 547-51. google scholar
66. 66. Georgiou AC, Cornejo Ulloa P, Van Kessel GMH, Crielaard W, Van der Waal SV. Reactive oxygen species can be traced locally and systemically in apical periodontitis: A systematic review. Arch Oral Biol 2021; 129: 105167. google scholar
67. 67. Xiang M, Fan J, Fan J. Association of Toll-like receptor signaling and reactive oxygen species: a potential therapeutic target for posttrauma acute lung injury. Mediators Inflamm 2010; 2010: 916425. google scholar
68. 68. Chapple IL. Reactive oxygen species and antioxidants in inflammatory diseases. J Clin Periodontol 1997; 24: 287-96. google scholar
69. 69. Trivedi S, Lal N. Antioxidant enzymes in periodontitis. J Oral Biol Craniofac Res 2017; 7: 5457. google scholar
70. 70. Biswas SK. Does the Interdependence between Oxidative Stress and Inflammation Explain the Antioxidant Paradox? Oxid Med Cell Longev 2016; 2016: 5698931. google scholar
71. 71. Halliwell B, Whiteman M. Measuring reactive species and oxidative damage in vivo and in cell culture: how should you do it and what do the results mean? Br J Pharmacol 2004; 142: 231-55. google scholar
72. 72. Babior BM. The respiratory burst of phagocytes. J Clin Invest 1984; 73: 599-601. google scholar
73. 73. Halliwell B. Reactive oxygen species in living systems: source, biochemistry, and role in human disease. Am J Med 1991; 91: 14-22. google scholar
74. 74. Hernândez-Rios P, Pussinen PJ, Vernal R, Hernândez M. Oxidative Stress in the Local and Systemic Events of Apical Periodontitis. Front Physiol 2017; 8: 869. google scholar
75. 75. Frazâo DR, Santos Mendes PF, Baia-da-Silva DC, Mendonça de Moura JD, Neves Dos Santos VR, Matos-Sousa JM, de Souza Balbinot G, Guimarâes DM, Collares FM, Lima RR. Modulation of blood redox status by the progression of induced apical periodontitis in rats. Front Physiol 2023; 14: 1214990. google scholar
76. 76. Prieto AKC, Gomes-Filho JE, Azuma MM, Sivieri-Araujo G, Narciso LG, Souza JC, Ciarlini PC, Cintra LTA. Influence of Apical Periodontitis on Stress Oxidative Parameters in Diabetic Rats. J Endod 2017; 43: 1651-56. google scholar
77. 77. Milojevic Samanovic A, Jakovljevic V, Vasovic M, Mitrovic S, Rankovic M, Mihajlovic K, Bolevich S, Zivkovic V. Cardiac, biochemical and histopathological analysis reveals impaired heart function in hypertensive rats with apical periodontitis. Int Endod J 2021; 54: 1581-96. google scholar
78. 78. Tsosura TVS, Dos Santos RM, Chaves Neto AH, Chiba FY, Carnevali ACN, Mattera MSLC, Belardi BE, Cintra LTÂ, da Silva Machado NE, Matsushita DH. Maternal Apical Periodontitis Increases Insulin Resistance and Modulates the Antioxidant Defense System in the Gastrocnemius Muscle of Adult Offspring. J Endod 2021; 47: 1126-31. google scholar
79. 79. Cotti E, Zedda A, Deidda M, Piras A, Flore G, Ideo F, Madeddu C, Pau VM, Mercuro G. Endodontic infection and endothelial dysfunction are associated with different mechanisms in men and women. J Endod 2015; 41: 594-600. google scholar
80. 80. Gomes C, Martinho FC, Barbosa DS, Antunes LS, Povoa HCC, Baltus THL, Morelli NR, Vargas HO, Nunes SOV, Anderson G, Maes M. Increased Root Canal Endotoxin Levels are Associated with Chronic Apical Periodontitis, Increased Oxidative and Nitrosative Stress, Major Depression, Severity of Depression, and a Lowered Quality of Life. Mol Neurobiol 2018; 55: 2814-2827. google scholar
81. 81. Inchingolo F, Marrelli M, Annibali S, Cristalli MP, Dipalma G, Inchingolo AD, Palladino A, Inchingolo AM, Gargari M, Tatullo M. Influence of endodontic treatment on systemic oxidative stress. Int J Med Sci 2013; 11: 1-6. google scholar
82. 82. Giebultowicz J, Wroczynski P, Samolczyk-Wanyura D. Comparison of antioxidant enzymes activity and the concentration of uric acid in the saliva of patients with oral cavity cancer, odontogenic cysts and healthy subjects. J Oral Pathol Med 2011; 40: 726-30. google scholar
83. 83. Vengerfeldt V, Mandar R, Saag M, Piir A, Kullisaar T. Oxidative stress in patients with endodontic pathologies. J Pain Res 2017; 10: 2031-40. google scholar
84. 84. Dezerega A, Madrid S, Mundi V, Valenzuela MA, Garrido M, Paredes R, Gartfa-Sesnich J, Ortega AV, Gamonal J, Hernandez M. Pro-oxidant status and matrix metalloproteinases in apical lesions and gingival crevicular fluid as potential biomarkers for asymptomatic apical periodontitis and endodontic treatment response. J Inflamm (Lond) 2012; 9: 8. google scholar
85. 85. Cotti E, Zedda A, Deidda M, Piras A, Flore G, Ideo F, Madeddu C, Pau VM, Mercuro G. Endodontic infection and endothelial dysfunction are associated with different mechanisms in men and women. J Endod 2015; 41: 594-600. google scholar
86. 86. Miller AA, De Silva TM, Jackman KA, Sobey CG. Effect of gender and sex hormones on vascular oxidative stress. Clin Exp Pharmacol Physiol 2007; 34: 1037-43. google scholar
87. 87. Lamster IB, Novak MJ. Host mediators in gingival crevicular fluid: implications for the pathogenesis of periodontal disease. Crit Rev Oral Biol Med 1992; 3: 31-60. google scholar
88. 88. Mody N, Parhami F, Sarafian TA, Demer LL. Oxidative stress modulates osteoblastic differentiation of vascular and bone cells. Free Radic Biol Med 2001; 31: 509-19. google scholar
89. 89. Yoon SO, Park SJ, Yoon SY, Yun CH, Chung AS. Sustained production of H(2)O(2) activates pro-matrix metalloproteinase-2 through receptor tyrosine kinases/phosphatidylinositol 3-kinase/NF-kappa B pathway. J Biol Chem 2002; 277: 30271-82. google scholar
90. 90. Binker MG, Binker-Cosen AA, Gaisano HY, de Cosen RH, Cosen-Binker LI. TGF-Ş1 increases invasiveness of SW1990 cells through Rac1/ROS/NF-KB/IL-6/MMP-2. Biochem Biophys Res Commun 2011; 405: 140-5. google scholar
91. 91. Kakehashi S, Stanley HR, Fitzgerald RJ. The Effects Of Surgical Exposures Of Dental Pulps In Germ-Free And Conventional Laboratory Rats. Oral Surg Oral Med Oral Pathol 1965; 20: 340-9. google scholar
92. 92. Jakovljevic A, Andric M, Nikolic N, Coric V, Krezovic S, Carkic J, Knezevic A, Beljic-Ivanovic K, Pljesa-Ercegovac M, Miletic M, Soldatovic I, Radosavljevic T, Jovanovic T, Simic T, Ivanovic V, Milasin J. Levels of oxidative stress biomarkers and bone resorption regulators in apical periodontitis lesions infected by Epstein-Barr virus. Int Endod J 2018; 51: 593-604. google scholar
93. 93. Huang X, Browngardt CM, Jiang M, Ahn SJ, Burne RA, Nascimento MM. Diversity in Antagonistic Interactions between Commensal Oral Streptococci and Streptococcus mutans. Caries Res 2018; 52: 88-101. google scholar
94. 94. Shetty P, Kumari, S. Serum total anti-oxidants, super oxide dismutase (SOD), myeloperoxidase and vitamin C levels in periapical inflammation-A Original Study. Res J Pharm Biol Chem Sci 2012; 3: 934-9. google scholar
95. 95. Inchingolo F, Marrelli M, Annibali S, Cristalli MP, Dipalma G, Inchingolo AD, Palladino A, Inchingolo AM, Gargari M, Tatullo M. Influence of endodontic treatment on systemic oxidative stress. Int J Med Sci 2013; 11: 1-6. google scholar
96. 96. Guo TZ, Wei T, Huang TT, Kingery WS, Clark JD. Oxidative Stress Contributes to Fracture/Cast-Induced Inflammation and Pain in a Rat Model of Complex Regional Pain Syndrome. J Pain 2018; 19: 1147-1156. google scholar