| Radiotherapy is widely used in the treatment of head and neck malignancies as the primary treatment,adjuvant to surgery or in conjunction with the chemotherapy,or as palliative treatment for advanced and unresectable tumors.However it also brings a series of undesired reactions,such as oral mucositis,xerostomia,trismus,loss of taste,progressive periodontal attachment loss,dental caries,microvascular alteration,and worst of all,osteoradionecrosis of the jaws(ORNJ),being considered the most devastating complication of radiotherapy in the head and neck region and in severe cases even death can occur.ORNJ can lead to intolerable pain,ulcer,fistulae,sequestration of devitalized bone,pathological fracture and facial deformity,seriously affecting the quality of life of patients.ORNJ is notoriously difficult to manage and once happened,it is irreversible.Although the improvement in radiotherapy techniques,increased attention to predisposing factors and the awareness of oral hygiene,there is no reliable evidence indicating that the incidence of ORNJ has decreased.While due to the obscure pathogenesis,there is no effective prevention and treatment measure for ORNJ.The understanding of pathophysiology of ORNJ has been a controversial topic since it was first appeared.Various theories have been formulated and each has led to sequential changes in management.In recent years the radiation-induced fibratrophic(RIF)theory has attracted more and more attentions,suggesting that ORNJ occurs by a radiation-induced fibratrophic mechanism,including inflammation,free radical formations,macrovascular thrombosis,fibrosis and remodeling and finally bone and tissue necrosis.In this process,myofibroblast(MFB)is the key effect cell that is responsible for the accumulation of the interstitial matrix and the consequent structural deformations associated with fibrosis.It is known to all that about 60%-70% of the radiation-induced cellular damage is caused by hydroxyl radicals,which can trigger oxidation of DNA,lipids,aminoacids,saccharides etc,leading to formation of various secondary free radicals and cause cellular damage and even death.Therefore blocking and scavenging of free radicals become our most important protecting strategy.Some anti-fibrotic medicine have been demonstrated dramatic results in the treatment of ORNJ such as pentoxifylline and tocopherol.Molecular hydrogen could potentially selectively reduce hydroxyl radicals and peroxynitrite,exert organ-protective effects through regulating oxidative stress and inflammation.It is proposed that hydrogen-rich saline might have a protective role against detrimental effect of the ORNJ.Although lack of experimental evidence and ambiguous pathogenesis of ORNJ,it is clear that free radicals,especially hydroxyl radicals and peroxynitrite play a major role in the initiation and progression of pathological damage in ORNJ.The purpose of this study is to evaluate the therapeutic and preventable effect of hydrogen-rich saline on the development of ORNJ and further illustrate the RIF mechanism.We established a clinically translational and repeatable animal model of ORNJ and examined the change of the tissues before and after hydrogen treatment in the radiation areas.This study contained the following sections.1 Establishment and evaluation of the ORNJ model in SD ratObjective: To established a clinically translational and repeatable SD rat model of ORNJ.Methods: The male SD rats were divided into 2 groups randomly,one is the control group and the another is the irradiation group.The left mandible of each rat was irradiated with a dose of 7.0 Gy for 5 fractions,which were equivalent to total doses of 70 Gy.The left mandibular molar of all animals were extracted 6 weeks after the irradiation.12 weeks after irradiation rats were sacrificed respectively and a series of examinations were employed including clinical manifestation,micro-CT and histology examination.Results: The group of irradiation accompanying with normal saline showed typical symptoms of ORNJ such as alopecia,acute radio dermatitis,retardation of central incisor growth,malocclusion and necrotic bone formation.These symptoms were not obvious in the group treated by hydrogen-rich saline treatment.Conclusion: The SD rat model of ORNJ was established successfully which could be used for the further studies on the pathogenesis and the treatment of ORNJ.2 Potential radioprotective effects of hydrogen on the bone mesenchymal stem cells(BMSCs)of ratObjective: To observe the protective effect of hydrogen-rich solution on the irradiation damage of BMSCs.Methods: BMSCs were isolated from the mandibles of the rats.A special culture system was established to allow the BMSCs could be irradiated with or without application of hydrogen rich solution.Then we observed the cellular proliferation and differentiation ability after irradiation and the changes of the production of reactive oxygen species and analyzed the protective effect of hydrogen rich solution on the irradiated BMSCs.Results: After irradiation,the ability of proliferation and differentiation of BMSCs decreased gradually,while reactive oxygen species production increased.The application of hydrogen-rich solution before irradiation could increase the ability of cell proliferation and differentiation and decrease the production of reactive oxygen species.Conclusion: Hydrogen might have a radioprotective effect on BMSCs,which indicated it has potential benefits to prevent and treat ORNJ.3 The effects of hydrogen-rich saline on ORNJ in SD ratObjective: To observe the protective effect of hydrogen-rich saline on the irradiation damage of ORNJ in SD rat and the changes of MFB expression in SD rats after treated with hydrogen-rich saline.Methods: The male SD rats were randomly divided into 3 groups: irradiation plus normal saline group and irradiation plus hydrogen-rich saline group,the control group.The left mandible of each rat was irradiated with a dose of 7.0 Gy for 5 fractions,which were equivalent to total doses of 70 Gy.The left mandibular molar of all animals were extracted 6 weeks after the irradiation.12 weeks after irradiation rats were sacrificed respectively and a series of examinations were employed including clinical manifestation,micro-CT and histology examination.Results: The group of irradiation accompanying with normal saline showed typical symptoms of ORNJ such as alopecia,acute radio dermatitis,retardation of central incisor growth,malocclusion and necrotic bone formation.These symptoms were not obvious in the group treated by hydrogen-rich saline treatment.MFB accumulated overwhelmingly in the fibrosis medulla and around the sequestrum in the irradiated group,it was decreased in the irradiation plus hydrogen-rich saline treated group.Conclusion: Hydrogen might have a radioprotective effect on ORNJ,in ORNJ a large number of MFB gathered round the affected tissue with high expression of related molecules of MFB,as same as other fibrotic diseases.After the intervention of hydrogen rich saline,the expression of MFB related molecule was decreased,further suggesting that MFB may be involved in the process of ORNJ and hydrogen can alleviate the symptoms of ORNJ.It is not only provided more evidences for the RIF theory,but also a new idea for the prevention and treatment of ORNJ. |
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