百令胶囊对放射性肺损伤防护作用的基础与临床研究
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摘要
目的：
放射性治疗(radioactive therapy,RT)是肺癌、乳腺癌、食管癌等胸部肿瘤患者最主要的治疗手段之一。肺是人体中辐射较为敏感的器官,放射治疗可使靠近肿瘤周围的肺组织受到超过其生物效应阈值的放射线剂量而导致不同程度的细胞损伤。放射性肺损伤(radio-pulmonary lesion,RPI)是胸部肿瘤放射治疗最为常见并发症之一,临床上通常有两种表现形式,早期急性放射性肺炎和后期放射性肺纤维化[1]。放射性肺损伤限制了肿瘤的放疗剂量,也使放疗效果大大降低,其发病机制尚不清楚,且缺乏有效的预测指标,已成为有效治疗胸部肿瘤的一大难题。一旦发生放射性肺损伤,目前临床上最常用的治疗方法是使用肾上腺皮质激素联合抗生素[2]。虽然大剂量激素可暂时有效缓解症状,抑制肺纤维化的发展,但容易产生诸多并发症。放射性肺损伤严格意义上来讲是无菌性炎症[3],其一旦发生往往不可逆转,因此预防比治疗更重要。近年研究表明放射性肺损伤的发生发展是一个有多种细胞参与,多种细胞因子和炎症介质相互作用发生的复杂生物分子过程[4]。由于其病理机制的多环节及复杂性,单一环节或靶向的干预效果尚不理想,临床上仍然缺乏防治放射性肺损伤的特异有效药物。阿米福叮(amifostine,AMSF)是目前公认的世界上唯一比较成熟应用于临床的放射性肺损伤防护剂[5][6]。遗憾的是,阿米福叮价格昂贵,很少患者能够负担,而且可能存在较大毒副作用，临床上难以广泛应用。因此,寻找更为高效、低毒、经济的放射性肺损伤防护剂就显得愈加重要了。中医药是我国的传统瑰宝,中药具有整体调节,多成分与多环节的作用特点,对病理复杂的疾病可发挥综合优势,研究及实践证明中医药在放射性肺损伤具有良好作用与发展前景。大量的临床研究表明，中医药防治放射性肺炎及肺纤维化疗效确切,能有效改善患者的临床症状,提高生活质量,降低死亡率,因此探讨中医药防治放射性肺损伤具有十分重要的现实意义。百令胶囊(Bailing Capsule,BC)是人工培养的冬虫夏草菌丝,经生物工程方法制成的中药制剂,它与天然虫草的化学组成与功效基本一致,几十年来的研究已经证实,百令胶囊在调节机体免疫、抗肿瘤、抗辐射等方面发挥了一定的作用,研究证实,百令胶囊能显著降低纤维化的重要细胞因子转化生长因子β(transforming growth factor-β,TGF-β),对改善肾脏及肝脏纤维化方面有一定疗效。目前尚未发现百令胶囊防治放射性肺损伤的作用机制研究的报道。本课题分两部分,第一部分为观察百令胶囊防治放射性肺损伤大鼠模型的基础研究。首先复制放射性肺损伤的大鼠模型,以促炎症反应细胞因子和促纤维化细胞因子为切入点,从放射性肺炎及肺纤维化的基础证候着手,以百令胶囊作为养阴清肺的基本药方,观察百令胶囊对大鼠肺系数、肺组织病理形态的影响；对大鼠肺组织超氧化物歧化酶(Superoxide Dismutase, SOD)活性、丙二醛(malondialdehyde,MDA)含量的影响；对大鼠肺组织基质金属蛋白酶(Matrix Metalloproteinase-2,MMP-2)及其组织抑制剂(Tissue Inhibitor of Matrix Metalloproteinases-2,TIMP-2)蛋白质表达的影响；尤其是对大鼠血浆促炎症反应细胞因子肿瘤坏死因子a (tumor necrosis factor α,TNF-α)、白介素-6(interleukin-6,IL-6)及促纤维化细胞因子TGF-β1的影响。第二部分为观察百令胶囊对胸部肿瘤患者放射性肺损伤的临床研究。通过观察胸部肿瘤患者的放射性肺炎发生率、临床症状积分、生活质量及血浆TGF-β1水平以评价百令胶囊对放射性肺损伤的防治效果,为进一步寻找防治放射性肺损伤相关靶点,探求其可能的作用机制并为临床使用提供确切可行的科学依据。如果能够证实百令胶囊确实具有放射性肺损伤防护剂之功效,那么对开发适合我国国情的辐射防护剂将具有重要意义,对肿瘤放射治疗学的发展乃至核工业的发展,都将起到积极的推动作用。
方法：
第一部分(基础研究)：将141只6周龄清洁级雄性SD大鼠,随机分为正常对照组(对照组)、单纯放射模型组(模型组)、百令胶囊预防组(百令预防组)、百令胶囊治疗组(百令治疗组)、地塞米松治疗组(地塞米松组),其中正常对照组21只,其它各组均为30只。各组均给予X射线全胸单次照射20Gy,正常对照组除外。百令胶囊用生理盐水溶解成一定浓度混悬液。正常对照组、模型组于造模后第二天起予等容积的生理盐水灌胃,百令治疗组灌服百令胶囊混悬液,地塞米松组予灌服地塞米松混悬液,每日1次。百令预防组则于照射前2周起开始灌服百令胶囊混悬液。每组分别于2、4、6周不同时间点随机处死大鼠,正常对照组每组7只,其它各组均为10只,腹腔注射10%水合氯醛溶液麻醉大鼠,心脏采血5ml,置肝素抗凝管,4℃3000r/min离心10min,分离血浆,置-20℃冰箱保存待用。采集大鼠肺组织,称重,计算肺系数的变化；HE染色、Masson染色光镜下观察大鼠肺组织病理形态学变化,采用黄嘌呤氧化酶法测定SOD活性,采用硫代巴比妥酸化学比色法测定MDA含量,ELISA法检测大鼠血浆TNF-α、IL-6及TGF-β1含量的变化,免疫组化法观察大鼠肺组织MMP-2,TIMP-2蛋白表达的变化。
第二部分(临床研究)：观察了从2012年1月至2012年8月来源于赣南医学院第一附属医院肿瘤科接受胸部肿瘤放射治疗的患者,共观察38例,随机分为两组,百令胶囊组(19例)：放射同时服用百令胶囊,从放疗第一天开始服用,按500mg/kg,口服,分3次/日,连续服至放疗结束后一个月。对照组(19例)：单纯放疗。观察放射性肺炎发生率、中医临床症状积分评定、生活质量及TGF-β1水平等指标。
结果：
第一部分(基础研究)：
(1)在照射后1周至4周各组呈现急性炎症反应,其中10Gy、15Gy、20Gy组大鼠全部存活,25Gy组大鼠在照射后2周内相继死亡。结合观察大鼠的一般状态,以20Gy最为典型,提示能在较短时间内成功复制大鼠放射性肺损伤模型最佳照射剂量为20Gy,为今后研究中医药防治放射性肺损伤的作用机制及防治药物的筛选最佳照射剂量提供了实验基础。
(2)百令胶囊可显著降低放射性肺炎大鼠肺系数(P<0.01)。其中百令预防组作用优于百令治疗组。百令预防组、百令治疗组、地塞米松组各组间比较差异有统计学差异(P<0.05)。肺组织病理学形态观察表明,第2、4、6周,百令预防组、百令治疗组与模型组比较,肺泡充血、渗出、出血及炎性细胞侵润等方面程度较轻；百令治疗组、百令预防组与地塞米松组比较,炎性程度明显较轻；第2周地塞米松组肺泡隔充血,出血与模型组比较无差别,但炎性细胞浸润相对较轻,4、6周差别不明显。
(3)百令预防组、百令治疗组、地塞米松组2、4、6周大鼠肺组织中SOD活性均高于模型组(P<0.01),MDA含量均低于模型组(P<0.01)。其中,百令预防组SOD活性高于百令治疗组、地塞米松治疗组(P<0.01)。百令治疗组高于地塞米松组(P<0.05)。：百令预防组MDA含量低于百令治疗组、地塞米松治疗组(P<0.01),百令治疗组低于地塞米松组(P<0.05)。
(4)百令预防组、百令治疗组、地塞米松组2、4、6周大鼠血浆中TNF-α、IL-6及TGF-β1低于模型组(P<0.01或P<0.05)。其中,百令预防组TNF-α、IL-6及TGF-β1低于百令治疗组、地塞米松组(P<0.01),百令治疗组TNF-α、IL-6及TGF-β1低于地塞米松组(P<0.01)。
(5)百令预防组2、4、6周各时间点大鼠肺组织中MMP-2表达均低于模型组(P<0.01)；百令治疗组均低于模型组(2周P<0.01；4、6周P<0.05)。地塞米松治疗组各时间点与模型组比较差异不明显(P>0.05)。百令预防组大鼠肺组织中MMP-2表达2、4周明显低于百令治疗组(2周P<0.05,4周P<0.01),6周差异不显著(P>0.05)。百令预防组各时间点与地塞米松治疗组比较均有显著差异(2、4周P<0.01,6周P<0.05)。百令治疗组大鼠MMP-2的表达2周低于地塞米松治疗组(P<0.05),但4、6周差异不明显(P>0.05)。百令预防组大鼠肺组织中TIMP-2表达量明显低于模型组(2周P<0.05,4、6周P<0.01)。百令预防组与模型组比较TIMP-2表达2、4周下降不显著(P>0.05)、第6周差异显著(P<0.05)。地塞米松治疗组各时间点与模型组比较均无显著差异(P>0.05)。百令预防组2周与百令治疗组比较差异不明显(P>0.05),4、6周百令预防组明显低于百令治疗组(4周P<0.05,6周P<0.01)。百令预防组2周与地塞米松治疗组比较无明显差异((P>0.05),4、6周明显低于地塞米松治疗组组(P<0.01)。百令治疗组4周与地塞米松治疗组比较无明显差异(P>0.05),6周百令治疗组低于地塞米松治疗组(P<0.05)。
第二部分(临床研究)：
(1)在放射性肺炎发生率方面,胸部肿瘤放疗患者放疗结束6周后,百令组放射性肺炎的总发生率显著低于对照组(P<0.05)。
(2)在中医临床症状积分评定方面,百令组治疗咳嗽、咳痰、痰中带血、胸闷气短、胸痛和五心烦热等症状方面,在治疗后3周和6周后较第1周显著改善,(P<0.05)；百令组在放射后第3周相与对照组比较,在咳嗽、咳痰、痰中带血、胸闷气短、胸痛较其有显著改善(P<0.05)；在放射后第6周相与对照组比较,在咳嗽、咳痰、痰中带血、胸闷气短较其有显著改善(P<0.01)。
(3)在生活质量评定方面,百令组在生活质量的改善、稳定方面均高于对照组,生活质量降低低于对照组,百令组有效率高于对照组,差异有显著性(P<0.05)。
(4)在放疗患者血浆TGF-β1水平比较方面,百令组胸部放疗患者血浆TGF-β1水平显著低于对照组,(P<0.01),放疗6周时血浆TGF-β1水平显著低于对照组,(P<0.01)。
结论：
第一部分(基础研究)：
(1)本实验提示制作肺损伤模型最佳照射剂量为20Gy。
(2)百令胶囊对放射性肺损伤大鼠有一定的防治效果。其防治作用可能通过以下途径实现：a、增强大鼠肺组织SOD的活性,减少MDA含量；b、抑制血浆促炎症因子IL-6、TNF-α及和促纤维化细胞因子TGF-β1的释放；c、降低放射性肺损伤大鼠肺组织MMP-2、 TIMP-2蛋白质表达,调节MMP-2/TIMP-2的平衡。百令胶囊能从不同程度上抑制或减轻肺泡的炎性反应,并能抑制肺纤维化的进程,从多途径有效保护肺组织从而减轻损伤,且预防优于治疗,防治效果优于地塞米松,未发现任何副作用。
第二部分(临床研究)：
百令胶囊对胸部肿瘤患者放射性肺损伤有一定的防治效果。其防治作用主要表现以下方面：a、百令组能降低胸部肿瘤患者放射性肺炎发生率；b、降低TGF-β1水平；c、降低中医临床症状积分评定；d、改善生活质量。
Objective:Radiation therapy (radioactive, therapy, RT) is one of the treatment of chest tumor,such as lung cancer, breast cancer, esophageal cancer.The lung is a radiation sensitive organs in the human body, radiation therapy can make the lung tissue near the tumor take more than the biological effects of radiation dose threshold and cause cell damage in different degree. Radiation-induced lung injury (radio-pulmonary lesion, RPI) is one of the common complications of the chest tumor radiotherapy, patients usually has two kinds of forms, early stage of acute radiation pneumonia and later stage of radiation pulmonary fibrosis. Radiation-induced lung injury limits the dose of radiotherapy of tumor, the radiation effect is greatly reduced, and its pathogenesis is not clear, and the lack of significant predictors.It has become a big problem in the effective treatment of chest tumor. Once the occurrence of radiation-induced lung injury, using adrenal cortical hormone and antibiotic is the most commonly method of clinical treatment. Although a large dose of hormone may temporarily alleviate symptoms, inhibit the development of pulmonary fibrosis, but easily lead to many complications. Radiation-induced lung injury occurs often irreversible, so prevention is more important than treatment. Recent studies show that a variety of cells, cytokines and inflammatory medium interaction occurred in the process and development of radiation-induced lung injury. Because of many links and the complexity of its pathological mechanism, effect of single link or targeting is not ideal, still lack specific clinical drug for prevention of radiation-induced lung injury. Amifostine (AMSF) is now recognized as the world's only more mature in the clinical application of radioactive lung injury protective agent. Unfortunately, amifostine is expensive, few patients can afford, significant side effects, It can not be widely used clinical. Therefore, searching for radiation-induced lung injury protective agent which need low toxicity and high economy, becomes increasingly important. Chinese medicine is the treasure of traditional Chinese medicine in China.It has the characteristics of overall regulation. Chinese medicine has good effect and prospect in radiation-induced lung injury. Many clinical studies show that, the curative effect of Chinese medicine can effectively improve the clinical symptoms, improve the quality of life, reduce the mortality rate, so research of traditional Chinese medicine for treatment of radiation-induced lung injury has a very important practical significance. Bailing capsule is cultured Cordyceps mycelia, traditional Chinese medicine preparation made by biological engineering method, chemical composition and its effects and natural Cordyceps basic consistent, decades of studies have confirmed, Bailing Capsule has played a certain role on immune regulation, anti-tumor, anti radiation. Research confirms that it can significantly reduce the important cytokine fibrosis transforming growth factor β (TGF-β), have certain effects on the improvement of kidney and liver fibrosis. The mechanism of Bailing Capsule for treatment of radiation-induced lung damage has not yet reported. This paper is divided into two parts, the first part is based on observation of Bailing Capsule treatment of radiation-induced lung injury in rat model.
Method
The first part is basic research:141male SD rats of clean degree, were randomly divided into normal control group (control group), simple radiation model group (model group), Bailing Capsule in the prevention group (bailing prevention group), bailing capsule treatment group (100treatment group), dexamethasone treatment group (dexamethasone treatment group), with21rats in the normal control group, other groups were30. Each group were given X ray chest single irradiation20Gy, normal control group except. Bailing Capsule with physiological saline solution into certain concentration suspension. The normal control group, model group after modeling the very next day to equal volume of saline, bailing treatment group were administrated with Bailing capsule suspension, dexamethasone treatment group was treated with oral dexamethasone suspension,1times a day. Bailing prevention group in irradiation for1weeks before beginning gavage of Bailing Capsule suspension. Each group respectively at2,4,6weeks the rats were sacrificed at different time points randomly,7rats in the normal control group, other groups were10, rats were intraperitoneally injected with10%chloral hydrate anesthesia solution, from the heart of5ml, the heparin anticoagulant tubes,4℃3000r/min centrifugal separation of plasma,10min,-20℃refrigerator for save. Acquisition of lung tissue in rats, weighing, changes of lung coefficient; the pathological changes of lung tissue in rats was observed under light microscope by HE staining, ELISA assay was used to detect the changes of rat plasma TNF-α, IL-6and TGF-β1content. Immunohistochemical staining of lung tissue in MMP-2rats, TIMP-2expression, change detection of lung SOD activity, MDA content and chemical colorimetric method. The second part:To observe the clinical study from2012March to2012August from First Affiliated Hospital of Gannan Medical College oncology patients receiving thoracic tumor radiotherapy, a total of38cases, were randomly divided into two groups:bailing capsule group (19cases)--radiation while taking Corbrin capsule, from the first day to start taking radiotherapy, according to500mg/kg, oral,3times per day, continuous service to one month after the end of radiotherapy. The control group (19cases)--radiotherapy. To observe the incidence of radiation pneumonitis, TGF-p1levels, TCM clinical symptom score, quality of life index evaluation.
Result.
The first part:(1) Based on10Gy,15Gy,20Gy group rats survived, the rats in25Gy group at2weeks after irradiation have died, in1to4weeks after irradiation has presented the acute inflammatory response,20Gy is the most typical, combined with the general condition of rats were observed, suggesting that20Gy irradiation agent amount the successful production of radioactive lung injury model of rats in a relatively short period of time, provides the basis for screening mechanism and prevention and treatment of drug research in Chinese medicine in prevention and treatment of radiation-induced lung injury.
(2) Bailing capsule could significantly reduce the lung coefficient of radiation pneumonia rats (P<0.01), bailing prevention group than bailing treatment group, prevention group, bailing bailing treatment group, dexamethasone treatment group differences have statistical difference (P<0.05). Pulmonary histopathology observation shows that, bailing prevention group, bailing treatment group compared with the model group, inflammatory cell infiltration, alveolar congestion, exudation, hemorrhage and to a lesser extent. Septal hyperemia alveolar treatment group at second weeks of dexamethasone, bleeding relatively model group had no significant difference, but the infiltration of inflammatory cells is relatively light,4and6weeks, the difference was not significant. Second,4,6weeks of relatively bailing treatment group, bailing prevention group, inflammatory degree is heavy. Dexamethasone treatment group fourth week abscess, increased sixth weeks of small abscess, consideration is due to decreased immunity induced by dexamethasone, concurrent infection. The normal control group, clear structure, Bronchial Alveoli and alveolar septum organizational structure is normal, without infiltration of neutrophils in the alveolar septum, no congestion, edema and acute and chronic inflammation change. Each time point were no obvious pathological changes.
(3) Compared with the normal control group, SOD activity in lung tissue of rats in model group decreased (P<0.01), the content of MDA increased (P<0.05); compared with the model group, the prevention group,100%in treatment group, dexamethasone treatment of SOD activity was inc reased in lung tissue of rats (P<0.01), the content of MDA reduce (P<0.01). The activity of SOD:bailing prevention group was higher than that of Bailing treatment group, dexamethasone treated group (P<0.01). Bailing treatment group was higher than that of dexamethasone treated group (P<0.05). MDA content:bailing prevention group was lower than that of Bailing treatment group, dexamethasone treated group (P<0.01), bailing in treatment group was lower than the dexamethasone group (P<0.05).
(4) Compared with the normal control group, TNF-α, IL-6β and TGF-in plasma of rats in model group were2,14,6weeks were significantly higher (P<0.01). Compared with the model group, the prevention group,100%in treatment group, dexamethasone treatment of TNF-α, IL-6and TGF-β in rat plasma group1was significantly decreased (P<0.01or P<0.05). Bailing prevention group was lower than that of Bailing treatment group, dexamethasone treated group (P<0.01), bailing in treatment group was lower than the dexamethasone group (P<0.01).
(5) Compared with the normal control group, MMP-2protein, TIMP-22to4weeks of lung tissue in rats of model group (P<0.01) expression were increased, but MMP-2/TIMP-2ratio increases gradually.4weeks later, MMP-2protein in lung tissue of rats in the model group decreased and TIMP-2expression increased gradually, MMP-2/TIMP-2ratio becomes small. Compared with the model group, the prevention group,100%in treatment group MMP-2, TIMP-2protein expression decreased obviously (P<0.01or P<0.05), MMP-2/TIMP-2balance. Bailing prevention group at2,4weeks than bailing treatment group, no significant difference in sixth weeks. Bailing the treatment group was better than dexamethasone treated group (P<0.01). Compared with MMP-2, TIMP-2with the model group, dexamethasone treatment changes group at each time point, no significant difference (P>0.05). Bailing prevention of MMP-2protein in lung tissue of rats, the expression of24weeks than bailing treatment group (P<0.05at2weeks,4weeks,6weeks of P<0.01) is not obvious (P>0.05). Bailing prevention of TIMP-2protein expression in lung tissue of rats for2weeks and Corbrin group there was no significant difference (P>0.05),4,6weeks a preventive group than in treatment group (P<0.05to4weeks,6weeks P<0.01). Bailing prevention of MMP-2protein expression was lower than the lung tissue of rats with dexamethasone treatment group (2P<0.01,4weeks,6weeks, P<0.05) bailing prevention group rats TIMP-2protein expression in lung and dexamethasone treatment group compared with2weeks no significant difference (P>0.05),4,6weeks a prevention group was lower than that of animal treatment group (P<0.01). Bailing treatment of MMP-2protein expression in lung tissue of rats2weeks than dexamethasone treated group (P<0.05),4,6weeks is not obvious (P>0.05). Bailing treated rats TIMP-2protein expression in lung and dexamethasone treatment group compared with2in4weeks, no significant difference (P>0.05),6weeks a treatment group was lower than that of dexamethasone treated group (P<0.05).
(6) Compared with the normal control group, model group, the expression of MMP-2mRNA in lung tissue of rats were increased (P<0.01); compared with the model group, the treatment of pulmonary tissue of rats in each group the expression of MMP-2mRNA was significantly reduced (P<0.01). Bailing prevention group and treatment group was no significant difference of Bailing (P>0.05); bailing the treatment group was better than dexamethasone treated group (2P<0.01,6weeks,4weeks P<0.05).
The second part of clinical research:(1) in the radiation pneumonia incidence, chest tumor radiotherapy6weeks after the end of Bailing group, radiation pneumonia incidence was significantly lower than the control group (P<0.05).
(2) In TCM clinical symptom score evaluation, bailing group treatment of cough, sputum, bloody sputum, chest tightness, shortness of breath, chest pain and dysphoria heat and other symptoms, at3weeks after treatment and6weeks after a first weeks significantly improved,(P<0.05); bailing group in the third week after radiotherapy and the control group comparison, cough, sputum, bloody sputum, chest tightness shortness of breath, chest pain is the improved significantly (P<0.05); in group sixth week after radiation with control, cough, sputum, bloody sputum, chest tightness shortness of breath is the significant improvement (P<0.01).
(3) In the evaluation of life quality, improve, stable in quality of life of Corbrin group were higher than that of control group, reduced quality of life than those in the control group, bailing group was higher than that of the control group, there were significant differences (P<0.05).
(4) In comparison to TGF-β1levels in plasma of patients with radiotherapy, bailing group chest radiotherapy in patients with plasma TGF-β1levels were significantly lower than those in the control group,(P<0.01), radiotherapy for6weeks the serum TGF-β1was significantly lower than that of the control group,(P<0.01).
Conclusion:
The first part:basic research of Bailing Capsule on rats with radiation-induced lung injury has certain effect. The preventive and therapeutic effects may be achieved through the following ways:enhancing the activity of SOD in lung tissue of rats, reduce the content of MDA in plasma; inhibition of proinflammatory cytokines IL-6, TNF-α and profibrotic cytokine release of TGF-β1; reduce the expression of lung tissue in MMP-2rats, TIMP-2protein of radiation-induced lung injury, adjusting the MMP-2/TIMP-2balance. Inflammatory reaction of different extent inhibit or alleviate alveolar, and can inhibit pulmonary fibrosis, the effective ways of protecting the lung tissue so as to reduce the damage, and prevention is better than cure, prevention is better than that of dexamethasone, without any side effect.
The second part:clinical study of Bailing capsule has certain effect on radiation-induced lung injury in patients with chest tumor. The preventive and therapeutic effects of mainly the following aspects:bailing group can reduce the incidence of patients with chest tumor radiation pneumonia, down-regulate TGF-β1levels, reduce the clinical symptoms of integral evaluation, improve the quality of life.
放射性治疗(radioactive therapy,RT)是肺癌、乳腺癌、食管癌等胸部肿瘤患者最主要的治疗手段之一。肺是人体中辐射较为敏感的器官,放射治疗可使靠近肿瘤周围的肺组织受到超过其生物效应阈值的放射线剂量而导致不同程度的细胞损伤。放射性肺损伤(radio-pulmonary lesion,RPI)是胸部肿瘤放射治疗最为常见并发症之一,临床上通常有两种表现形式,早期急性放射性肺炎和后期放射性肺纤维化[1]。放射性肺损伤限制了肿瘤的放疗剂量,也使放疗效果大大降低,其发病机制尚不清楚,且缺乏有效的预测指标,已成为有效治疗胸部肿瘤的一大难题。一旦发生放射性肺损伤,目前临床上最常用的治疗方法是使用肾上腺皮质激素联合抗生素[2]。虽然大剂量激素可暂时有效缓解症状,抑制肺纤维化的发展,但容易产生诸多并发症。放射性肺损伤严格意义上来讲是无菌性炎症[3],其一旦发生往往不可逆转,因此预防比治疗更重要。近年研究表明放射性肺损伤的发生发展是一个有多种细胞参与,多种细胞因子和炎症介质相互作用发生的复杂生物分子过程[4]。由于其病理机制的多环节及复杂性,单一环节或靶向的干预效果尚不理想,临床上仍然缺乏防治放射性肺损伤的特异有效药物。阿米福叮(amifostine,AMSF)是目前公认的世界上唯一比较成熟应用于临床的放射性肺损伤防护剂[5][6]。遗憾的是,阿米福叮价格昂贵,很少患者能够负担,而且可能存在较大毒副作用，临床上难以广泛应用。因此,寻找更为高效、低毒、经济的放射性肺损伤防护剂就显得愈加重要了。中医药是我国的传统瑰宝,中药具有整体调节,多成分与多环节的作用特点,对病理复杂的疾病可发挥综合优势,研究及实践证明中医药在放射性肺损伤具有良好作用与发展前景。大量的临床研究表明，中医药防治放射性肺炎及肺纤维化疗效确切,能有效改善患者的临床症状,提高生活质量,降低死亡率,因此探讨中医药防治放射性肺损伤具有十分重要的现实意义。百令胶囊(Bailing Capsule,BC)是人工培养的冬虫夏草菌丝,经生物工程方法制成的中药制剂,它与天然虫草的化学组成与功效基本一致,几十年来的研究已经证实,百令胶囊在调节机体免疫、抗肿瘤、抗辐射等方面发挥了一定的作用,研究证实,百令胶囊能显著降低纤维化的重要细胞因子转化生长因子β(transforming growth factor-β,TGF-β),对改善肾脏及肝脏纤维化方面有一定疗效。目前尚未发现百令胶囊防治放射性肺损伤的作用机制研究的报道。本课题分两部分,第一部分为观察百令胶囊防治放射性肺损伤大鼠模型的基础研究。首先复制放射性肺损伤的大鼠模型,以促炎症反应细胞因子和促纤维化细胞因子为切入点,从放射性肺炎及肺纤维化的基础证候着手,以百令胶囊作为养阴清肺的基本药方,观察百令胶囊对大鼠肺系数、肺组织病理形态的影响；对大鼠肺组织超氧化物歧化酶(Superoxide Dismutase, SOD)活性、丙二醛(malondialdehyde,MDA)含量的影响；对大鼠肺组织基质金属蛋白酶(Matrix Metalloproteinase-2,MMP-2)及其组织抑制剂(Tissue Inhibitor of Matrix Metalloproteinases-2,TIMP-2)蛋白质表达的影响；尤其是对大鼠血浆促炎症反应细胞因子肿瘤坏死因子a (tumor necrosis factor α,TNF-α)、白介素-6(interleukin-6,IL-6)及促纤维化细胞因子TGF-β1的影响。第二部分为观察百令胶囊对胸部肿瘤患者放射性肺损伤的临床研究。通过观察胸部肿瘤患者的放射性肺炎发生率、临床症状积分、生活质量及血浆TGF-β1水平以评价百令胶囊对放射性肺损伤的防治效果,为进一步寻找防治放射性肺损伤相关靶点,探求其可能的作用机制并为临床使用提供确切可行的科学依据。如果能够证实百令胶囊确实具有放射性肺损伤防护剂之功效,那么对开发适合我国国情的辐射防护剂将具有重要意义,对肿瘤放射治疗学的发展乃至核工业的发展,都将起到积极的推动作用。
方法：
第一部分(基础研究)：将141只6周龄清洁级雄性SD大鼠,随机分为正常对照组(对照组)、单纯放射模型组(模型组)、百令胶囊预防组(百令预防组)、百令胶囊治疗组(百令治疗组)、地塞米松治疗组(地塞米松组),其中正常对照组21只,其它各组均为30只。各组均给予X射线全胸单次照射20Gy,正常对照组除外。百令胶囊用生理盐水溶解成一定浓度混悬液。正常对照组、模型组于造模后第二天起予等容积的生理盐水灌胃,百令治疗组灌服百令胶囊混悬液,地塞米松组予灌服地塞米松混悬液,每日1次。百令预防组则于照射前2周起开始灌服百令胶囊混悬液。每组分别于2、4、6周不同时间点随机处死大鼠,正常对照组每组7只,其它各组均为10只,腹腔注射10%水合氯醛溶液麻醉大鼠,心脏采血5ml,置肝素抗凝管,4℃3000r/min离心10min,分离血浆,置-20℃冰箱保存待用。采集大鼠肺组织,称重,计算肺系数的变化；HE染色、Masson染色光镜下观察大鼠肺组织病理形态学变化,采用黄嘌呤氧化酶法测定SOD活性,采用硫代巴比妥酸化学比色法测定MDA含量,ELISA法检测大鼠血浆TNF-α、IL-6及TGF-β1含量的变化,免疫组化法观察大鼠肺组织MMP-2,TIMP-2蛋白表达的变化。
第二部分(临床研究)：观察了从2012年1月至2012年8月来源于赣南医学院第一附属医院肿瘤科接受胸部肿瘤放射治疗的患者,共观察38例,随机分为两组,百令胶囊组(19例)：放射同时服用百令胶囊,从放疗第一天开始服用,按500mg/kg,口服,分3次/日,连续服至放疗结束后一个月。对照组(19例)：单纯放疗。观察放射性肺炎发生率、中医临床症状积分评定、生活质量及TGF-β1水平等指标。
结果：
第一部分(基础研究)：
(1)在照射后1周至4周各组呈现急性炎症反应,其中10Gy、15Gy、20Gy组大鼠全部存活,25Gy组大鼠在照射后2周内相继死亡。结合观察大鼠的一般状态,以20Gy最为典型,提示能在较短时间内成功复制大鼠放射性肺损伤模型最佳照射剂量为20Gy,为今后研究中医药防治放射性肺损伤的作用机制及防治药物的筛选最佳照射剂量提供了实验基础。
(2)百令胶囊可显著降低放射性肺炎大鼠肺系数(P<0.01)。其中百令预防组作用优于百令治疗组。百令预防组、百令治疗组、地塞米松组各组间比较差异有统计学差异(P<0.05)。肺组织病理学形态观察表明,第2、4、6周,百令预防组、百令治疗组与模型组比较,肺泡充血、渗出、出血及炎性细胞侵润等方面程度较轻；百令治疗组、百令预防组与地塞米松组比较,炎性程度明显较轻；第2周地塞米松组肺泡隔充血,出血与模型组比较无差别,但炎性细胞浸润相对较轻,4、6周差别不明显。
(3)百令预防组、百令治疗组、地塞米松组2、4、6周大鼠肺组织中SOD活性均高于模型组(P<0.01),MDA含量均低于模型组(P<0.01)。其中,百令预防组SOD活性高于百令治疗组、地塞米松治疗组(P<0.01)。百令治疗组高于地塞米松组(P<0.05)。：百令预防组MDA含量低于百令治疗组、地塞米松治疗组(P<0.01),百令治疗组低于地塞米松组(P<0.05)。
(4)百令预防组、百令治疗组、地塞米松组2、4、6周大鼠血浆中TNF-α、IL-6及TGF-β1低于模型组(P<0.01或P<0.05)。其中,百令预防组TNF-α、IL-6及TGF-β1低于百令治疗组、地塞米松组(P<0.01),百令治疗组TNF-α、IL-6及TGF-β1低于地塞米松组(P<0.01)。
(5)百令预防组2、4、6周各时间点大鼠肺组织中MMP-2表达均低于模型组(P<0.01)；百令治疗组均低于模型组(2周P<0.01；4、6周P<0.05)。地塞米松治疗组各时间点与模型组比较差异不明显(P>0.05)。百令预防组大鼠肺组织中MMP-2表达2、4周明显低于百令治疗组(2周P<0.05,4周P<0.01),6周差异不显著(P>0.05)。百令预防组各时间点与地塞米松治疗组比较均有显著差异(2、4周P<0.01,6周P<0.05)。百令治疗组大鼠MMP-2的表达2周低于地塞米松治疗组(P<0.05),但4、6周差异不明显(P>0.05)。百令预防组大鼠肺组织中TIMP-2表达量明显低于模型组(2周P<0.05,4、6周P<0.01)。百令预防组与模型组比较TIMP-2表达2、4周下降不显著(P>0.05)、第6周差异显著(P<0.05)。地塞米松治疗组各时间点与模型组比较均无显著差异(P>0.05)。百令预防组2周与百令治疗组比较差异不明显(P>0.05),4、6周百令预防组明显低于百令治疗组(4周P<0.05,6周P<0.01)。百令预防组2周与地塞米松治疗组比较无明显差异((P>0.05),4、6周明显低于地塞米松治疗组组(P<0.01)。百令治疗组4周与地塞米松治疗组比较无明显差异(P>0.05),6周百令治疗组低于地塞米松治疗组(P<0.05)。
第二部分(临床研究)：
(1)在放射性肺炎发生率方面,胸部肿瘤放疗患者放疗结束6周后,百令组放射性肺炎的总发生率显著低于对照组(P<0.05)。
(2)在中医临床症状积分评定方面,百令组治疗咳嗽、咳痰、痰中带血、胸闷气短、胸痛和五心烦热等症状方面,在治疗后3周和6周后较第1周显著改善,(P<0.05)；百令组在放射后第3周相与对照组比较,在咳嗽、咳痰、痰中带血、胸闷气短、胸痛较其有显著改善(P<0.05)；在放射后第6周相与对照组比较,在咳嗽、咳痰、痰中带血、胸闷气短较其有显著改善(P<0.01)。
(3)在生活质量评定方面,百令组在生活质量的改善、稳定方面均高于对照组,生活质量降低低于对照组,百令组有效率高于对照组,差异有显著性(P<0.05)。
(4)在放疗患者血浆TGF-β1水平比较方面,百令组胸部放疗患者血浆TGF-β1水平显著低于对照组,(P<0.01),放疗6周时血浆TGF-β1水平显著低于对照组,(P<0.01)。
结论：
第一部分(基础研究)：
(1)本实验提示制作肺损伤模型最佳照射剂量为20Gy。
(2)百令胶囊对放射性肺损伤大鼠有一定的防治效果。其防治作用可能通过以下途径实现：a、增强大鼠肺组织SOD的活性,减少MDA含量；b、抑制血浆促炎症因子IL-6、TNF-α及和促纤维化细胞因子TGF-β1的释放；c、降低放射性肺损伤大鼠肺组织MMP-2、 TIMP-2蛋白质表达,调节MMP-2/TIMP-2的平衡。百令胶囊能从不同程度上抑制或减轻肺泡的炎性反应,并能抑制肺纤维化的进程,从多途径有效保护肺组织从而减轻损伤,且预防优于治疗,防治效果优于地塞米松,未发现任何副作用。
第二部分(临床研究)：
百令胶囊对胸部肿瘤患者放射性肺损伤有一定的防治效果。其防治作用主要表现以下方面：a、百令组能降低胸部肿瘤患者放射性肺炎发生率；b、降低TGF-β1水平；c、降低中医临床症状积分评定；d、改善生活质量。
Objective:Radiation therapy (radioactive, therapy, RT) is one of the treatment of chest tumor,such as lung cancer, breast cancer, esophageal cancer.The lung is a radiation sensitive organs in the human body, radiation therapy can make the lung tissue near the tumor take more than the biological effects of radiation dose threshold and cause cell damage in different degree. Radiation-induced lung injury (radio-pulmonary lesion, RPI) is one of the common complications of the chest tumor radiotherapy, patients usually has two kinds of forms, early stage of acute radiation pneumonia and later stage of radiation pulmonary fibrosis. Radiation-induced lung injury limits the dose of radiotherapy of tumor, the radiation effect is greatly reduced, and its pathogenesis is not clear, and the lack of significant predictors.It has become a big problem in the effective treatment of chest tumor. Once the occurrence of radiation-induced lung injury, using adrenal cortical hormone and antibiotic is the most commonly method of clinical treatment. Although a large dose of hormone may temporarily alleviate symptoms, inhibit the development of pulmonary fibrosis, but easily lead to many complications. Radiation-induced lung injury occurs often irreversible, so prevention is more important than treatment. Recent studies show that a variety of cells, cytokines and inflammatory medium interaction occurred in the process and development of radiation-induced lung injury. Because of many links and the complexity of its pathological mechanism, effect of single link or targeting is not ideal, still lack specific clinical drug for prevention of radiation-induced lung injury. Amifostine (AMSF) is now recognized as the world's only more mature in the clinical application of radioactive lung injury protective agent. Unfortunately, amifostine is expensive, few patients can afford, significant side effects, It can not be widely used clinical. Therefore, searching for radiation-induced lung injury protective agent which need low toxicity and high economy, becomes increasingly important. Chinese medicine is the treasure of traditional Chinese medicine in China.It has the characteristics of overall regulation. Chinese medicine has good effect and prospect in radiation-induced lung injury. Many clinical studies show that, the curative effect of Chinese medicine can effectively improve the clinical symptoms, improve the quality of life, reduce the mortality rate, so research of traditional Chinese medicine for treatment of radiation-induced lung injury has a very important practical significance. Bailing capsule is cultured Cordyceps mycelia, traditional Chinese medicine preparation made by biological engineering method, chemical composition and its effects and natural Cordyceps basic consistent, decades of studies have confirmed, Bailing Capsule has played a certain role on immune regulation, anti-tumor, anti radiation. Research confirms that it can significantly reduce the important cytokine fibrosis transforming growth factor β (TGF-β), have certain effects on the improvement of kidney and liver fibrosis. The mechanism of Bailing Capsule for treatment of radiation-induced lung damage has not yet reported. This paper is divided into two parts, the first part is based on observation of Bailing Capsule treatment of radiation-induced lung injury in rat model.
Method
The first part is basic research:141male SD rats of clean degree, were randomly divided into normal control group (control group), simple radiation model group (model group), Bailing Capsule in the prevention group (bailing prevention group), bailing capsule treatment group (100treatment group), dexamethasone treatment group (dexamethasone treatment group), with21rats in the normal control group, other groups were30. Each group were given X ray chest single irradiation20Gy, normal control group except. Bailing Capsule with physiological saline solution into certain concentration suspension. The normal control group, model group after modeling the very next day to equal volume of saline, bailing treatment group were administrated with Bailing capsule suspension, dexamethasone treatment group was treated with oral dexamethasone suspension,1times a day. Bailing prevention group in irradiation for1weeks before beginning gavage of Bailing Capsule suspension. Each group respectively at2,4,6weeks the rats were sacrificed at different time points randomly,7rats in the normal control group, other groups were10, rats were intraperitoneally injected with10%chloral hydrate anesthesia solution, from the heart of5ml, the heparin anticoagulant tubes,4℃3000r/min centrifugal separation of plasma,10min,-20℃refrigerator for save. Acquisition of lung tissue in rats, weighing, changes of lung coefficient; the pathological changes of lung tissue in rats was observed under light microscope by HE staining, ELISA assay was used to detect the changes of rat plasma TNF-α, IL-6and TGF-β1content. Immunohistochemical staining of lung tissue in MMP-2rats, TIMP-2expression, change detection of lung SOD activity, MDA content and chemical colorimetric method. The second part:To observe the clinical study from2012March to2012August from First Affiliated Hospital of Gannan Medical College oncology patients receiving thoracic tumor radiotherapy, a total of38cases, were randomly divided into two groups:bailing capsule group (19cases)--radiation while taking Corbrin capsule, from the first day to start taking radiotherapy, according to500mg/kg, oral,3times per day, continuous service to one month after the end of radiotherapy. The control group (19cases)--radiotherapy. To observe the incidence of radiation pneumonitis, TGF-p1levels, TCM clinical symptom score, quality of life index evaluation.
Result.
The first part:(1) Based on10Gy,15Gy,20Gy group rats survived, the rats in25Gy group at2weeks after irradiation have died, in1to4weeks after irradiation has presented the acute inflammatory response,20Gy is the most typical, combined with the general condition of rats were observed, suggesting that20Gy irradiation agent amount the successful production of radioactive lung injury model of rats in a relatively short period of time, provides the basis for screening mechanism and prevention and treatment of drug research in Chinese medicine in prevention and treatment of radiation-induced lung injury.
(2) Bailing capsule could significantly reduce the lung coefficient of radiation pneumonia rats (P<0.01), bailing prevention group than bailing treatment group, prevention group, bailing bailing treatment group, dexamethasone treatment group differences have statistical difference (P<0.05). Pulmonary histopathology observation shows that, bailing prevention group, bailing treatment group compared with the model group, inflammatory cell infiltration, alveolar congestion, exudation, hemorrhage and to a lesser extent. Septal hyperemia alveolar treatment group at second weeks of dexamethasone, bleeding relatively model group had no significant difference, but the infiltration of inflammatory cells is relatively light,4and6weeks, the difference was not significant. Second,4,6weeks of relatively bailing treatment group, bailing prevention group, inflammatory degree is heavy. Dexamethasone treatment group fourth week abscess, increased sixth weeks of small abscess, consideration is due to decreased immunity induced by dexamethasone, concurrent infection. The normal control group, clear structure, Bronchial Alveoli and alveolar septum organizational structure is normal, without infiltration of neutrophils in the alveolar septum, no congestion, edema and acute and chronic inflammation change. Each time point were no obvious pathological changes.
(3) Compared with the normal control group, SOD activity in lung tissue of rats in model group decreased (P<0.01), the content of MDA increased (P<0.05); compared with the model group, the prevention group,100%in treatment group, dexamethasone treatment of SOD activity was inc reased in lung tissue of rats (P<0.01), the content of MDA reduce (P<0.01). The activity of SOD:bailing prevention group was higher than that of Bailing treatment group, dexamethasone treated group (P<0.01). Bailing treatment group was higher than that of dexamethasone treated group (P<0.05). MDA content:bailing prevention group was lower than that of Bailing treatment group, dexamethasone treated group (P<0.01), bailing in treatment group was lower than the dexamethasone group (P<0.05).
(4) Compared with the normal control group, TNF-α, IL-6β and TGF-in plasma of rats in model group were2,14,6weeks were significantly higher (P<0.01). Compared with the model group, the prevention group,100%in treatment group, dexamethasone treatment of TNF-α, IL-6and TGF-β in rat plasma group1was significantly decreased (P<0.01or P<0.05). Bailing prevention group was lower than that of Bailing treatment group, dexamethasone treated group (P<0.01), bailing in treatment group was lower than the dexamethasone group (P<0.01).
(5) Compared with the normal control group, MMP-2protein, TIMP-22to4weeks of lung tissue in rats of model group (P<0.01) expression were increased, but MMP-2/TIMP-2ratio increases gradually.4weeks later, MMP-2protein in lung tissue of rats in the model group decreased and TIMP-2expression increased gradually, MMP-2/TIMP-2ratio becomes small. Compared with the model group, the prevention group,100%in treatment group MMP-2, TIMP-2protein expression decreased obviously (P<0.01or P<0.05), MMP-2/TIMP-2balance. Bailing prevention group at2,4weeks than bailing treatment group, no significant difference in sixth weeks. Bailing the treatment group was better than dexamethasone treated group (P<0.01). Compared with MMP-2, TIMP-2with the model group, dexamethasone treatment changes group at each time point, no significant difference (P>0.05). Bailing prevention of MMP-2protein in lung tissue of rats, the expression of24weeks than bailing treatment group (P<0.05at2weeks,4weeks,6weeks of P<0.01) is not obvious (P>0.05). Bailing prevention of TIMP-2protein expression in lung tissue of rats for2weeks and Corbrin group there was no significant difference (P>0.05),4,6weeks a preventive group than in treatment group (P<0.05to4weeks,6weeks P<0.01). Bailing prevention of MMP-2protein expression was lower than the lung tissue of rats with dexamethasone treatment group (2P<0.01,4weeks,6weeks, P<0.05) bailing prevention group rats TIMP-2protein expression in lung and dexamethasone treatment group compared with2weeks no significant difference (P>0.05),4,6weeks a prevention group was lower than that of animal treatment group (P<0.01). Bailing treatment of MMP-2protein expression in lung tissue of rats2weeks than dexamethasone treated group (P<0.05),4,6weeks is not obvious (P>0.05). Bailing treated rats TIMP-2protein expression in lung and dexamethasone treatment group compared with2in4weeks, no significant difference (P>0.05),6weeks a treatment group was lower than that of dexamethasone treated group (P<0.05).
(6) Compared with the normal control group, model group, the expression of MMP-2mRNA in lung tissue of rats were increased (P<0.01); compared with the model group, the treatment of pulmonary tissue of rats in each group the expression of MMP-2mRNA was significantly reduced (P<0.01). Bailing prevention group and treatment group was no significant difference of Bailing (P>0.05); bailing the treatment group was better than dexamethasone treated group (2P<0.01,6weeks,4weeks P<0.05).
The second part of clinical research:(1) in the radiation pneumonia incidence, chest tumor radiotherapy6weeks after the end of Bailing group, radiation pneumonia incidence was significantly lower than the control group (P<0.05).
(2) In TCM clinical symptom score evaluation, bailing group treatment of cough, sputum, bloody sputum, chest tightness, shortness of breath, chest pain and dysphoria heat and other symptoms, at3weeks after treatment and6weeks after a first weeks significantly improved,(P<0.05); bailing group in the third week after radiotherapy and the control group comparison, cough, sputum, bloody sputum, chest tightness shortness of breath, chest pain is the improved significantly (P<0.05); in group sixth week after radiation with control, cough, sputum, bloody sputum, chest tightness shortness of breath is the significant improvement (P<0.01).
(3) In the evaluation of life quality, improve, stable in quality of life of Corbrin group were higher than that of control group, reduced quality of life than those in the control group, bailing group was higher than that of the control group, there were significant differences (P<0.05).
(4) In comparison to TGF-β1levels in plasma of patients with radiotherapy, bailing group chest radiotherapy in patients with plasma TGF-β1levels were significantly lower than those in the control group,(P<0.01), radiotherapy for6weeks the serum TGF-β1was significantly lower than that of the control group,(P<0.01).
Conclusion:
The first part:basic research of Bailing Capsule on rats with radiation-induced lung injury has certain effect. The preventive and therapeutic effects may be achieved through the following ways:enhancing the activity of SOD in lung tissue of rats, reduce the content of MDA in plasma; inhibition of proinflammatory cytokines IL-6, TNF-α and profibrotic cytokine release of TGF-β1; reduce the expression of lung tissue in MMP-2rats, TIMP-2protein of radiation-induced lung injury, adjusting the MMP-2/TIMP-2balance. Inflammatory reaction of different extent inhibit or alleviate alveolar, and can inhibit pulmonary fibrosis, the effective ways of protecting the lung tissue so as to reduce the damage, and prevention is better than cure, prevention is better than that of dexamethasone, without any side effect.
The second part:clinical study of Bailing capsule has certain effect on radiation-induced lung injury in patients with chest tumor. The preventive and therapeutic effects of mainly the following aspects:bailing group can reduce the incidence of patients with chest tumor radiation pneumonia, down-regulate TGF-β1levels, reduce the clinical symptoms of integral evaluation, improve the quality of life.
引文
[1]Chen Y, Williams J, Ding I, et al. Radia-tion pneumonitis and early circulatory cyto-kine m arkers. Semin Radiat Oncol,2002,12(1 Suppl 1): 26-33.
[2]蒋国梁.现代肿瘤放射治疗学.第1版.上海：上海科学技术出版社,2003.90-91.
[3]Graham M V, Purdy JA, Emami B, et al. Clinical dose-volume histogram analysis for pneumonitis after 3D treatm ent for non-small cell lung cancer(NSCLC). Int J Ra-diat Oncol Biol Phys,1999,45(2):323-329.
[4]白浪,刘建军,贺伯明.前列腺素El对稀盐酸吸人性急性肺损伤的保护作用.复旦学报,2001,28(2)：103—106.
[5]冯勤付.阿米福汀对单次肺照射的保护作用及TGF-β1活性的影响[J]-中华放射肿瘤学杂志2004(3)
[6]钟惠青.罗球珠.陈伟兰阿米福汀的药理研究进展[J]-基层医学论坛2012(7)
[7]刘纯杰,王德文,高亚兵,等.细胞因子及其受体在放射性肺纤维化发生中的分子病理机制研究.中华放射医学与防护杂志,2000,20(6)：391—394.
[8]Anscher MS, Marks LB, Shafman TD, et al. Using plasma transfor-ruing growth factor beta-1 during radiotheraphy to select patients for dose escalation. J Clin Oncol,201,19(17):3758-3765.
[9]林白桦,蔡晶,许昌韶.C57/BL小鼠在不同照射剂量下TGF及TNF在不同时段下的变动情况与放射性肺损伤关系的研究.苏州大学学报(医学版),2004,24(3)：288—290.
[10]施小燕,沈惠云,洪远,等.脂微球一前列腺素E1治疗创伤后急性呼吸窘迫综合征疗效评价.中华创伤杂志,202,18(10)：589—591.
[11]郭虹,朱妙珍,段建,等.前列腺素E.对输尿管梗阻大鼠肾间质纤维化及转化生长因子131 mRNA表达的影响.中国医师杂志,203,5(3)：359—377.
[12]刘莉,陆海,CE.Ruebe等.人NSCLC细胞系X-线照射后TNF-a水平变化[J].中华放射医学与防护杂志2004,24(4)：313-316.
[13]Rube CE, Uthe D, Schmid KW, et al. Dose-dependent induction of transforminggrowth factor(TGF-B) in the lung tissue of fibrosis-prone mice after thoracic irradiation [J]. Int. J. Radiation Oncology Biol. Phys.2000; 47: 1033-1042
[14]谢丛华,周云峰,彭纲等.百令胶囊调控放射性肺损伤TGF-β1表达水平的研究[J].中华放射医学与防护杂志,2005,25(2)：143-146
[15]Martin M, Lefaix JL, Delanian S. TGF-β1 and radiation fibrosis:A master switch and a specific therapeutic target? [J]. Int. J. Radiation Oncology Biol. Phys.2000; 47:277-290
[16]Aste-Amezaga, M.X.Ma, Sartori A, et al. Molecular mechanisms of the induction of IL-12 and its inhibition by IL-10 [J]. J. Immunol.1998,160:5936.
[17]Schottelius, A. J., Mayo M. W., Sartor RB,et al. Interleukin-10 signaling blocks inhibitor of B kinase activity and nuclear factor B DNA binding [J]. J. Biol.Chem.1999,274:31868
[18]Kontoyiannis D, Kotlyarov A, Carballo E, et al. Interleukin-10 targets p38 MAPK to modulate ARE-dependent TNF mRNA translation and limit intestinal pathology [J]. EMBO J.2001,20:3760
[19]Denys A, Udalova IA, Smith C,et al. Evidence for a Dual Mechanism for IL-10 Suppression of TNF-Production That Does Not Involve Inhibition of p38 Mitogen-Activated Protein Kinase or NF-B in primary human Macrophagesl [J].The Journal of Immunology,2002,168:4837-4845
[20]李柳宁,陈海,刘伟胜.中医药对恶性肿瘤放疗减毒作用的研究[J].现代肿瘤学,2006,14(4)：503-505
[21]马贵香,郭选贤.解毒散结润肺法治疗放射性肺炎29例[J].陕西中医,2001,22：526-527
[22]尹强,黄英昌,陈玉等.生脉注射液减轻放射性肺损伤的临床观察[J].肿瘤防治杂志,2002；9(5)：506-507
[23]15.张红军,王梅,邱文生,青地汤防治肺癌放疗反应效果观察[J].齐鲁医学杂志2003,18(2)：28-130.
[24]勾承鹊,杨彩周.百合固金汤加味治疗放射性肺炎114例[J].四川中医2003,21(12)：38
[25]陈不尤.活血化瘀抗纤维化治疗放射性肺炎的临床研究[J].中国肿瘤临床与康复.2001,8(5)：30-31
[26]吴金平.清燥救肺汤治疗放射性肺炎临床观察[J].辽宁中医杂志；2006,33(11)：1448
[27]殷玉杰,肖映昱.中医健脾祛湿法预防与治疗放射性肺炎的临床研究[J].中医药学刊,2006,24(10)：1872-1873
[28]王刚,周朝娟.参芪扶正注射液辅助治疗放射性肺炎22例[J].中国中西医结合杂志,2005；25(3)：274-275
[29]杨明会,窦永起,刘哲峰.活血化瘀药物防治放射性肺损伤的实验研究[J].中国中西医结合杂志,2005；25(12)：1096-1099
[30]刘莉,丁乾,戴小芳等.参芪扶正注射液对胸部肿瘤放疗患者血浆细胞因子网络调控作用[J].中国中西医结合杂志2007,27(12)：1082-1085
[1]张霆,马胜林,岳建华,等.清燥救肺汤预防肺癌患者放射性肺损伤的临床研究[J].中华放射肿瘤学杂志,2007,16(4)：315～316.
[2]叶江枫,戚好文,范风云,等.透明质酸、层粘连蛋白作为早期放射性肺损伤标志物的实验研究[J].西北国防医学杂志,2004,25(1)：48-50
[3]廖震,胡春申.润肺清热方治疗放射性肺炎60例疗效观察[J].中国中医急症,2008,17(1)：18-19
[4]李绍东,徐凯,程广军,等.大鼠放射性肺损伤模型制作及影像学评价[J].中 国医学影像技术,2004,20(7)：1003-1005
[5]Tucker SL, Liao ZX, Travis EL. Estimation of the sPatial di Stribution, of target cellS for radiation Pneumonitis in mouselung[J]. Int J Radiat oncolBi01Phys,1997,38(5):1055-1066.
[6]曹小飞,陈龙华,刘国龙.大鼠放射性肺损伤模型的动态病理学观察[J].中华肿瘤防治杂志,2010,17(11)：818-822
[7]孔祥鸣,吴稚冰,马胜林,等.痰热清注射液对急性放射性肺炎大鼠血清TGF-β1水平及肺病理学改变的影响[J].实用中西医结合临床,2008,(04)： 30
[8]刘纯杰,王德文,高亚兵,等.放射性肺纤维化大鼠动物模型的建立及其病变规律[J].中国兽医学报,20(6)：576～5788
[9]张海,王炳胜,刘秀芳,等.每周重复照射建立大鼠放射性肺损伤模型的评价[J].临床军医杂志,2009,37(3)：353-355
[10]杜雪梅,柳晓兰,崔玉芳,等.放射性肺损伤小鼠动物模型的建立及其病变规律[J].中国体视学与图像分析,2003,8(4)：203—206.
[11]Travis EL, Liao ZX, Tucker SL. SPatial heterogeneity of the volume effect for radiation Pneumonotis in mouse lung[J]. Int J Radiat Oncol Biol Phys.1997,38(5):1045-1054.
[12]张霆等.解毒疏络法预防放射性肺损伤的临床研究[J].上海中医药杂志,2007,23(5)：89.
[1]傅尚志,张楚毅.放射性肺炎研究进展[J].中国癌症杂志,1999,9(1)：56.
[2]张曼.糖皮质激素在急性呼吸窘迫征的应用进展[J].临床肺科杂志,2002,5(7)：36-38.
[3]房丽,王红阳,刘卫东,等.不同剂量地塞米松防治放射性肺损伤临床疗效观察[J].广东医学,2009,30(10)：1497-1498
[4]Nelson, C.B., J.S. Puskin, and D.J. Pawel, Adjustments to the baselinelung cancer mortality for radon-induced lung cancers in the BEIR VI risk models. Radiat Res,2001.156(2):p.220-221.
[5]陈军,王明智.治疗放射性肺炎的润肺通络法[J].江南大学学报,2002,1(4)： 435.
[6]张伟,姜良铎,张晓梅,等.肺纤方对博莱霉素致肺间质纤维化大鼠肺系数与肺组织病理的影响[J].北京中医药大学学报,2008,31(8)：544～546
[7]Vujaskovic, Z., et al., Radiation-induced hypoxia may perpetuate late normal tissue injury. Int J Radiat Oncol Biol Phys,2001.50(4):p.851-855.
[8]山广志.百令胶囊加味治疗放射性肺炎的临床观察[J].实用中医内科杂志,1996,10(4)：37
[9]Fu, X.L., et al., Predicting the risk of symptomatic radiation-induced lung injury using both the physical and biologic parameters V(30) and transforming growth factor beta. Int J Radiat Oncol Biol Phys,2001.50(4):p.899-908.
[10]曹小飞,陈龙华,刘国龙.大鼠放射性肺损伤模型的动态病理学观察.[J].中华肿瘤防治杂志；2010,17(11)：818-822
[11]Marks, L.B., et al., Radiation-induced pulmonary injury:symptomatic versus subclinical endpoints. Int J Radiat Biol,2000.76(4):p.469-475.
[12]刘纯杰,王德文,等.放射性肺纤维化大鼠动物模型的建立及其病变规律[J].中国兽医学报,2000,20(6)：576-579
[13]Mesurolle, B., et al., Unusual radiologic findings in the thorax after radiation therapy. Radiographics,2000.20(1):p.67-81.
[1]闫卫平.放射性肺炎[J].医师进修杂志,2004,27(2)：7-9.
[2]唐求,王鹏,胡绍.放射性肺炎的发生机制及其应对[J].临床肺科杂志,2005,10(5)：634636.
[3]房丽,荣绍元,王红阳,等.地塞米松防治急性放射性肺损伤疗效观察[J].山东医药.2009,49(4)：49-50.
[4]谭永红,王东,王兴友,等.放射性肺炎激素治疗临床分析[J].中华放射医学与防护杂志.2005,25(3)：260-261.
[5]山广志.百令胶囊加味治疗放射性肺炎的临床观察[J].实用中医内科杂志,1996,10(4)：37.
[6]房丽,王红阳,刘卫东,等.不同剂量地塞米松防治放射性肺损伤临床疗效观察[J].广东医学.2009,30(10)：1497-1498.
[7]陈军,王明智.治疗放射性肺炎的润肺通络法.江南大学学报,2002,1(4)： 435.
[1]Rube CE, Uthe D,W i lfert F, etal. The bronchiolar ePithel ium as a Prominent SOUrCe of Proinflaromatory cytokines after lung irradiat ion[J]. Int JRadiatOnc01BiolPhys,2005,61(5):1482-1492.
[2]王跃珍.放射性肺炎研究进展[J].中国肿瘤,2007,16(1)：35-38.
[3]吴开良,李艳如,蒋国梁.放射性肺损伤[J].实用癌症杂志,2001,16(1)：110-112
[4]陈军,王明智.治疗放射性肺炎的润肺通络法.江南大学学报,2002,1(4)：435.
[5]Chen Y, Wi 11 iams J, Ding I, etal. Radiat ion Pneumoni t is and early circulatory cytokine markers. Semin Radiat Onc01. January 1,2002,12(1 suPPll):26-33.
[6]郑爱青,韩晨光,朱新英,等.IL-1和IL-6在放射性肺损伤发病中的作用[J].武警医学院学报,2009,18(3)：194-196.
[7]BaiYH, WangDW, Wan LP, etal. The role of free radicals in the develoPment of radiat ion interstitial Pneumonits[J]. Envi ron Pathol ToxicolOnco.1993, 12(4):199.
[8]朱茂祥,龚怡芬,葛桂秀,等.大鼠肺吞噬细胞释放自由基在放射性肺炎 发展中的作用.中华放射医学与防护杂志,1996,16(2)：96～99.
[9]Mccord JM, Fridovich I. SuPeroxide dismutase. An enymjc function for erythrocuPrein(hemocuPrein)[J]. JbiolChem.1969,244:6049-6055.
[10]方允中,郑荣梁,主编.自由基生物学的理论与应用[M].北京：北京科学出版社,2002：213—233.
[11]黄莺.叶燕青.孙洁民肺纤维化形成过程中大鼠肺成纤维细胞分泌TGF-β mRNA及HGF mRNA对肺泡II型上皮细胞的影响[J]-重庆医学2010(19)
[12]雷素英.李银生.张彬姜黄素对急性肺损伤小鼠肺组织转化生长因子-p1表达的影响[J]-中华急诊医学杂志2011(9)
[13]魏路清；董彦；谭明旗糖皮质激素对实验性肺纤维化TGF-β,MCP-1的影响[J]-心肺血管病杂志2006(03)
[14]刘纯杰,王德文,高征兵等.细胞因子及其受体在放射性肺纤维化发生中的分子病理机理研究。中华放射医学与防护杂志。2000。20(6)：391.394。
[15]申文江,王绿化.放射治疗损伤：中国医药科学技术出版社,2001：95,103.
[1]刘纯杰,王德文,高亚兵,等.放射性肺纤维化大鼠动物模型的建立及其病变规律[J].中国兽医学报,20(6)：576～5788
[2][2]曹小飞,陈龙华,刘国龙.大鼠放射性肺损伤模型的动态病理学观察[J].中华肿瘤防治杂志,2010,17(11)：818-822
[3][3]孔祥鸣,吴稚冰,马胜林,等.痰热清注射液对急性放射性肺炎大鼠血清TGF-β1水平及肺病理学改变的影响[J].实用中西医结合临床,2008,(04)： 30
[4][4] Travis EL, Liao ZX, Tucker SL. SPatial heterogeneity of the volume effect for radiation Pneumonotis in mouse lung[J]. Int J Radiat Oncol Biol Phys.1997,38(5):1045-1054
[5][5]杜雪梅,柳晓兰,崔玉芳,等.放射性肺损伤小鼠动物模型的建立及其病变规律[J].中国体视学与图像分析,2003,8(4)：203—206.
[6][6]张海,王炳胜,刘秀芳,等.每周重复照射建立大鼠放射性肺损伤模型的评价[J].临床军医杂志,2009,37(3)：353-355.
[7][7]张霆等.解毒疏络法预防放射性肺损伤的临床研究[J].上海中医药杂志,2007,23(5)：89.
[1]Mu E, Liu XJ, Chen S, et al: Changes in factor Ⅶ-activating protease in a bleomycin-induced lung injury rat model and its influence on human pulmonary fibroblasts in vitro. Int J Mol Med 26:549-555,2010.
[2]Vujaskovic Z, Marks LB and Anscher MS:The physical parameters and molecular events associated with radiation-induced lung toxicity. Semin Radiat Oncol 10:296-307,2000.
[3]Noth I and Martinez FJ:Recent advances in idiopathic pulmonary fibrosis. Chest 132:637-650,2007.
[4]Du Bois RM:Idiopathic pulmonary fibrosis. Annu Rev Med 44:441-450, 1993.
[5]Lingos TI, Recht A, Vicini F, Abner A, Silver B and Harris JR:Radiation pneumonitis in breast cancer patients treated with conservative surgery and radiation therapy. Int J Radiat Oncol Biol Phys 21:355-360,1991.
[6]Wagner GR:Asbestosis and silicosis. Lancet 349:1311-1315,1997.
[7]Tyurina YY, Tyurin VA, Kapralova VI, Wasserloos K, et al: Oxidative lipidomics of γ-radiation-induced lung injury:Mass spectrometric characterization of cardiolipin and phosphatidylserine peroxidation. Radiat Res 175:610-621,2011.
[8]Margetts PJ, Bonniaud P, Liu L, et al: Transient over-expression of TGF-β1 induces epithelial mesenchymal transition in the rodent peritoneum. J Am Soc Nephrol 16:425-436,2005.
[9]Martinez Florez S, Gutierrez Fernandez B, Sanchez-Campos S, Gonzalez Gallego J and Tunon MJ:Quercetin attenuates nuclear factor-kappa activation and nitric oxide production in interleukin-1 beta-activated rat hepatocytes. J Nutr 135:1359-1365,2005.
[10]Kang SK, Rabbani ZN, Folz RJ, et al: Overexpression of extracellular superoxide dismutase protects mice from radiation-induced lung injury. Int J Radiat Oncol Biol Phys 57:1056-1066,2003.
[11]Yara S, Kawakami K, Kudeken N, et al: FTS reduces bleomycin-induced cytokine and chemokine production and inhibits pulmonary fibrosis in mice. Clin Exp Immunol 124:77-85,2001.
[12]Liu R, Ahmed KM, Nantajit D, et al: Therapeutic effects of a-lipoic acid on bleomycin induced pulmonary fibrosis in rats. Int J Mol Med 19:865-873, 2007.
[13]Armutcu F, Cabuk M, Gurel A, Atmaca H and Kart L:Caffeic acid phenethyl ester and vitamin E moderates IL-1β and IL-6 in bleomycin-induced pulmonary fibrosis in rats. Pestic Biochem Physiol 88:209-212,2007.
[14]Liu JF, Wang X, Wang F, Teng L and Cao J:Attenuation effects of heparin superoxide dismutase conjugate on bleomycin-induced lung fibrosis in vivo and radiation-induced inflammatory cytokine expression in vitro. Biomed Pharmacother 63:484-491,2009.
[15]Tomita M, Okuyama T, Katsuyama H, et al: Gene expression in rat lungs during early response to paraquat-induced oxidative stress. Int J Mol Med 17: 37-44,2006.
[16]Hagimoto N, Kuwano K, Inoshima I, et al: TGF-beta 1 as an enhancer of Fas-mediated apoptosis of lung epithelial cells. J Immunol 168:6470-6478, 2002.
[17]Dong XC, Li WJ, Liu QF, et al: The influence of carbon ion irradiation on sweet sorghum seeds. Nucl Instrum Methods Phys Res B 266:123-126,2008.
[18]Ritter MA, Cleaver JE and Tobias CA:High-LET radiations induce a large proportion of non-rejoining DNA breaks. Nature 266:653-655,1977.
[19]Sekine E, Okada M, Matsufuji N, Yu D, Furusawa Y and Okayasu R:High LET heavy ion radiation induces lower numbers of initial chromosome breaks with minimal repair than low LET radiation in normal human cells. Mutat Res 652:95-101,2008.
[20]Zhang H, Li S, Wang XH, et al: Results of carbon ion radiotherapy for skin carcinomas in 45 patients. Br J Dermatol 166:1100-1106,2012.
[21]Wu ZH, Zhang H, Wang XY, et al: Protective effects of melatonin against 12C6+beam irradiation-induced oxidative stress and DNA injury in the mouse brain. Adv Space Res 49:196-203,2012.
[22]Zhou G, Kawata T, Furusawa Y, et al: Protective effects of melatonin against low-and high-LET irradiation. J Radiat Res 47:175-181,2006.
[23]Zhang H, Zhao W, Wang Y, et al: Induction of cytogenetic adaptive response in spermatogonia and spermatocytes by pre-exposure of mouse testis to low-dose 12C6+ ions. Mutat Res 653:109-112,2008.
[24]Liu Y, Zhang H, Zhang L, Zhang X, Xie Y and Zhao W:Melatonin modulates acute testicular damage induced by carbon ions in mice. Pharmazie 64: 685-689,2009.
[25]Stone HB, Coleman CN, Anscher MS and McBride WH:Effects of radiation on normal tissue:consequences and mechanisms. Lancet Oncol 4:529-536, 2003.
[26]Finkelstein JN, Johnston CJ, Baggs R and Rubin P:Early alterations in extracellular matrix and transforming growth factor beta gene expression in mouse lung indicative of late radiation fibrosis. Int J Radiat Oncol Biol Phys 28:621-631,1994.
[27]Rodeman HP and Bamberg M:Cellular basis of radiation-induced fibrosis. Radiother Oncol 35:83-90,1995.
[28]Rubin P, Johnston CJ, Williams JP, McDonald S and Finkelstein JN:A perpetual cascade of cytokines post irradiation leads to pulmonary fibrosis. Int J Radiat Oncol Biol Phys 33:99-109,1995.
[29]Anscher MS, Kong FM, Andrews K, et al: Plasma transforming growth factor betal as a predictor of radiation pneumonitis. Int J Radiat Oncol Biol Phys 41: 1029-1035,1998.
[30]Fu XL, Huang H, Bentel G, et al: Predicting the risk of symptomatic radiation-induced lung injury using both the physical and biologic parameters V30 and transforming growth factor β. Int J Radiat Oncol Biol Phys 50: 899-908,2001.
[31]Chen Y, Williams J, Ding I, et al: Radiation pneumonitis and early circulatory cytokine markers. Semin Radiat Oncol 12 (Suppl 1):26-33,2002.
[32]Broekelmann TJ, Limper AH, Colby TV and Mcdonald JA:Transforming growth factor beta 1 is present at sites of extracellular matrix gene expression in human pulmonary fibrosis. Proc Natl Acad Sci USA 88:6642-6646,1991.
[1]Bajwa EK, Ayas NT, Schulzer M, Mak E, Ryu JH, Malhotra A. Interferon-gamma1b therapy in
[2]idiopathic pulmonary fibrosis:a metaanalysis. Chest 2005;128:203-206.
[3]tolerance induction and inflammation. Curr Opin Immunol 2004; 16:709-716.
[4]Qi Z, Atsuchi N, Ooshima A, Takeshita A, Veno H. Blockade of type beta transforming growth factor signaling prevents liver fibrosis and dysfunction in the rat. Proc Nat! Acad Sci VSA 1999;96:
[5]Sakamoto T, Ueno H, Sonoda K, et al. Blockade of TGF-beta by in vivo gene transfer of a soluble
[6]TGF-beta type II receptor in the muscle inhibits corneal opacification, edema and angiogenesis.Gene Ther 2000;7:1915-1924.
[7]Ueno H, Sakamoto T, Nakamura T, et al. A soluble transforming growth factor beta receptor expressed in muscle prevents liver fibrogenesis and dysfunction in rats. Hum Gene Ther 2000; 11:33-42.
[8]Christ M, McCartney-Francis NL, Kulkarni AB, et al. Immune dysregulation in TGF-beta 1-deficient mice. Immunol 1994; 153.1936-1946.
[9]Border WA, Noble NA, Yamamoto T, et al. Natural inhibitor of transforming growth factor-beta protects against scarring in experimental kidney disease. Nature 1992;360:361-364.
[10]Border WA, Okuda S, Languino LR, Sporn MB, Ruoslahti E. Suppression of experimental glomerulonephritis by antiserum against transforming growth factor beta 1. Nature 1990;346:371-374.
[11]Hill C, Flyvbjerg A, Rasch R, Bak M, Logan A. Transforming growth factor-beta2 antibody attenuates fibrosis in the experimental diabetic rat kidney. Endocrinol 2001; 170:647-651.
[12]McCormick LL, Zhang Y, Tootell E, Gilliam AC. Anti-TGF-beta treatment prevents skin and lung fibrosis in murine sclerodermatous graft-versus-host disease:a model for human scleroderma. ImmunoI1999;163:5693-5699.
[13]Denis M. Neutralization of transforming growth factor-beta 1 in a mouse model of immune-induced lung fibrosis. Immunology 1994;82:584-590.
[14]Ruzek MC, Hawes M, Pratt B, et al. Minimal effects on immune parameters following chronic antiTGF-beta monoclonal antibody administration to normal mice. Immunopharmacol Immunotoxicol 2003;25:235-257.
[15]Kolb M, Margetts PI, Sime PI, Gauldie 1. Proteoglycans decorin and biglycan differentially modulate TGF-beta-mediated fibrotic responses in the lung. Am J Physiol Lung Cell Mol Physiol 2001;
[16]Ghosh AK, Yuan W, Mori Y, Chen S, Varga 1.Antagonistic regulation of type I collagen gene expression by interferon-gamma and transforming growth factor-beta. Integration at the level of p300/CBP transcriptional coactivators. J Biol Chern 2001;276:11,041-11,048.
[17]Higashi K, Inagaki Y, Fujimori K, Nakao A, Kaneko H, Nakatsuka I. Interferon-gamma interferes with transforming growth factor-beta signaling through direct interaction ofYB-1 with Smad3. J Biol Chern 2003-278:43,470-43,479.
[18]Chen Y, Chen J, Dong J, Liu W. Antifibrotic effect of interferon gamma in silicosis model of rat.Toxicol Lett 2005-155:353-360.
[19]Gurujeyalakshmi G, Giri SN. Molecular mechanisms of antifibrotic effect of interferon gamma in bleomycin-mouse model of lung fibrosis:downregulation ofTGF-beta and procollagen Ⅰ and Ⅲ gene expression. Exp Lung Res 1995;21:791-808.
[20]Kalra S, Utz JP, Ryu JH. Interferon gamma-1 b therapy for advanced idiopathic pulmonary fibrosis.Mayo Clin Proc 2003-78:1082-1087.
[21]蔡红兵,罗荣城放射性肺损伤的中医药防治方法探讨第一军医大学学报,2003,23,(9)：958—960.
[22]李兰群,急性放射性肺炎中医辨识)附35例临床分析北京中医药大学学报1999,22,(2)：45.
[23]陈军,王明智治疗放射性肺炎的润肺通络法江南大学学报(自然科学版),2002,1,(4)：345—346
[24]王亚平,李伯祥；川芍嗦防治肾间质纤维化作用的实验研究,中国中西医结合肾病杂志,2002,3(2),77—78.
[25]石清照,徐之良等,当归注射液对辐射损伤小鼠造血调控因子及骨髓微环境的影响,中华放射医学与防护杂志,2004,35,(2)：137—139#
[26]谢从华.当归对小鼠放射性肺损伤过程中TNF—a水平的影响,中华放射肿瘤学杂志,2005,14,(1)：59—63.
[2]蒋国梁.现代肿瘤放射治疗学.第1版.上海：上海科学技术出版社,2003.90-91.
[3]Graham M V, Purdy JA, Emami B, et al. Clinical dose-volume histogram analysis for pneumonitis after 3D treatm ent for non-small cell lung cancer(NSCLC). Int J Ra-diat Oncol Biol Phys,1999,45(2):323-329.
[4]白浪,刘建军,贺伯明.前列腺素El对稀盐酸吸人性急性肺损伤的保护作用.复旦学报,2001,28(2)：103—106.
[5]冯勤付.阿米福汀对单次肺照射的保护作用及TGF-β1活性的影响[J]-中华放射肿瘤学杂志2004(3)
[6]钟惠青.罗球珠.陈伟兰阿米福汀的药理研究进展[J]-基层医学论坛2012(7)
[7]刘纯杰,王德文,高亚兵,等.细胞因子及其受体在放射性肺纤维化发生中的分子病理机制研究.中华放射医学与防护杂志,2000,20(6)：391—394.
[8]Anscher MS, Marks LB, Shafman TD, et al. Using plasma transfor-ruing growth factor beta-1 during radiotheraphy to select patients for dose escalation. J Clin Oncol,201,19(17):3758-3765.
[9]林白桦,蔡晶,许昌韶.C57/BL小鼠在不同照射剂量下TGF及TNF在不同时段下的变动情况与放射性肺损伤关系的研究.苏州大学学报(医学版),2004,24(3)：288—290.
[10]施小燕,沈惠云,洪远,等.脂微球一前列腺素E1治疗创伤后急性呼吸窘迫综合征疗效评价.中华创伤杂志,202,18(10)：589—591.
[11]郭虹,朱妙珍,段建,等.前列腺素E.对输尿管梗阻大鼠肾间质纤维化及转化生长因子131 mRNA表达的影响.中国医师杂志,203,5(3)：359—377.
[12]刘莉,陆海,CE.Ruebe等.人NSCLC细胞系X-线照射后TNF-a水平变化[J].中华放射医学与防护杂志2004,24(4)：313-316.
[13]Rube CE, Uthe D, Schmid KW, et al. Dose-dependent induction of transforminggrowth factor(TGF-B) in the lung tissue of fibrosis-prone mice after thoracic irradiation [J]. Int. J. Radiation Oncology Biol. Phys.2000; 47: 1033-1042
[14]谢丛华,周云峰,彭纲等.百令胶囊调控放射性肺损伤TGF-β1表达水平的研究[J].中华放射医学与防护杂志,2005,25(2)：143-146
[15]Martin M, Lefaix JL, Delanian S. TGF-β1 and radiation fibrosis:A master switch and a specific therapeutic target? [J]. Int. J. Radiation Oncology Biol. Phys.2000; 47:277-290
[16]Aste-Amezaga, M.X.Ma, Sartori A, et al. Molecular mechanisms of the induction of IL-12 and its inhibition by IL-10 [J]. J. Immunol.1998,160:5936.
[17]Schottelius, A. J., Mayo M. W., Sartor RB,et al. Interleukin-10 signaling blocks inhibitor of B kinase activity and nuclear factor B DNA binding [J]. J. Biol.Chem.1999,274:31868
[18]Kontoyiannis D, Kotlyarov A, Carballo E, et al. Interleukin-10 targets p38 MAPK to modulate ARE-dependent TNF mRNA translation and limit intestinal pathology [J]. EMBO J.2001,20:3760
[19]Denys A, Udalova IA, Smith C,et al. Evidence for a Dual Mechanism for IL-10 Suppression of TNF-Production That Does Not Involve Inhibition of p38 Mitogen-Activated Protein Kinase or NF-B in primary human Macrophagesl [J].The Journal of Immunology,2002,168:4837-4845
[20]李柳宁,陈海,刘伟胜.中医药对恶性肿瘤放疗减毒作用的研究[J].现代肿瘤学,2006,14(4)：503-505
[21]马贵香,郭选贤.解毒散结润肺法治疗放射性肺炎29例[J].陕西中医,2001,22：526-527
[22]尹强,黄英昌,陈玉等.生脉注射液减轻放射性肺损伤的临床观察[J].肿瘤防治杂志,2002；9(5)：506-507
[23]15.张红军,王梅,邱文生,青地汤防治肺癌放疗反应效果观察[J].齐鲁医学杂志2003,18(2)：28-130.
[24]勾承鹊,杨彩周.百合固金汤加味治疗放射性肺炎114例[J].四川中医2003,21(12)：38
[25]陈不尤.活血化瘀抗纤维化治疗放射性肺炎的临床研究[J].中国肿瘤临床与康复.2001,8(5)：30-31
[26]吴金平.清燥救肺汤治疗放射性肺炎临床观察[J].辽宁中医杂志；2006,33(11)：1448
[27]殷玉杰,肖映昱.中医健脾祛湿法预防与治疗放射性肺炎的临床研究[J].中医药学刊,2006,24(10)：1872-1873
[28]王刚,周朝娟.参芪扶正注射液辅助治疗放射性肺炎22例[J].中国中西医结合杂志,2005；25(3)：274-275
[29]杨明会,窦永起,刘哲峰.活血化瘀药物防治放射性肺损伤的实验研究[J].中国中西医结合杂志,2005；25(12)：1096-1099
[30]刘莉,丁乾,戴小芳等.参芪扶正注射液对胸部肿瘤放疗患者血浆细胞因子网络调控作用[J].中国中西医结合杂志2007,27(12)：1082-1085
[1]张霆,马胜林,岳建华,等.清燥救肺汤预防肺癌患者放射性肺损伤的临床研究[J].中华放射肿瘤学杂志,2007,16(4)：315～316.
[2]叶江枫,戚好文,范风云,等.透明质酸、层粘连蛋白作为早期放射性肺损伤标志物的实验研究[J].西北国防医学杂志,2004,25(1)：48-50
[3]廖震,胡春申.润肺清热方治疗放射性肺炎60例疗效观察[J].中国中医急症,2008,17(1)：18-19
[4]李绍东,徐凯,程广军,等.大鼠放射性肺损伤模型制作及影像学评价[J].中 国医学影像技术,2004,20(7)：1003-1005
[5]Tucker SL, Liao ZX, Travis EL. Estimation of the sPatial di Stribution, of target cellS for radiation Pneumonitis in mouselung[J]. Int J Radiat oncolBi01Phys,1997,38(5):1055-1066.
[6]曹小飞,陈龙华,刘国龙.大鼠放射性肺损伤模型的动态病理学观察[J].中华肿瘤防治杂志,2010,17(11)：818-822
[7]孔祥鸣,吴稚冰,马胜林,等.痰热清注射液对急性放射性肺炎大鼠血清TGF-β1水平及肺病理学改变的影响[J].实用中西医结合临床,2008,(04)： 30
[8]刘纯杰,王德文,高亚兵,等.放射性肺纤维化大鼠动物模型的建立及其病变规律[J].中国兽医学报,20(6)：576～5788
[9]张海,王炳胜,刘秀芳,等.每周重复照射建立大鼠放射性肺损伤模型的评价[J].临床军医杂志,2009,37(3)：353-355
[10]杜雪梅,柳晓兰,崔玉芳,等.放射性肺损伤小鼠动物模型的建立及其病变规律[J].中国体视学与图像分析,2003,8(4)：203—206.
[11]Travis EL, Liao ZX, Tucker SL. SPatial heterogeneity of the volume effect for radiation Pneumonotis in mouse lung[J]. Int J Radiat Oncol Biol Phys.1997,38(5):1045-1054.
[12]张霆等.解毒疏络法预防放射性肺损伤的临床研究[J].上海中医药杂志,2007,23(5)：89.
[1]傅尚志,张楚毅.放射性肺炎研究进展[J].中国癌症杂志,1999,9(1)：56.
[2]张曼.糖皮质激素在急性呼吸窘迫征的应用进展[J].临床肺科杂志,2002,5(7)：36-38.
[3]房丽,王红阳,刘卫东,等.不同剂量地塞米松防治放射性肺损伤临床疗效观察[J].广东医学,2009,30(10)：1497-1498
[4]Nelson, C.B., J.S. Puskin, and D.J. Pawel, Adjustments to the baselinelung cancer mortality for radon-induced lung cancers in the BEIR VI risk models. Radiat Res,2001.156(2):p.220-221.
[5]陈军,王明智.治疗放射性肺炎的润肺通络法[J].江南大学学报,2002,1(4)： 435.
[6]张伟,姜良铎,张晓梅,等.肺纤方对博莱霉素致肺间质纤维化大鼠肺系数与肺组织病理的影响[J].北京中医药大学学报,2008,31(8)：544～546
[7]Vujaskovic, Z., et al., Radiation-induced hypoxia may perpetuate late normal tissue injury. Int J Radiat Oncol Biol Phys,2001.50(4):p.851-855.
[8]山广志.百令胶囊加味治疗放射性肺炎的临床观察[J].实用中医内科杂志,1996,10(4)：37
[9]Fu, X.L., et al., Predicting the risk of symptomatic radiation-induced lung injury using both the physical and biologic parameters V(30) and transforming growth factor beta. Int J Radiat Oncol Biol Phys,2001.50(4):p.899-908.
[10]曹小飞,陈龙华,刘国龙.大鼠放射性肺损伤模型的动态病理学观察.[J].中华肿瘤防治杂志；2010,17(11)：818-822
[11]Marks, L.B., et al., Radiation-induced pulmonary injury:symptomatic versus subclinical endpoints. Int J Radiat Biol,2000.76(4):p.469-475.
[12]刘纯杰,王德文,等.放射性肺纤维化大鼠动物模型的建立及其病变规律[J].中国兽医学报,2000,20(6)：576-579
[13]Mesurolle, B., et al., Unusual radiologic findings in the thorax after radiation therapy. Radiographics,2000.20(1):p.67-81.
[1]闫卫平.放射性肺炎[J].医师进修杂志,2004,27(2)：7-9.
[2]唐求,王鹏,胡绍.放射性肺炎的发生机制及其应对[J].临床肺科杂志,2005,10(5)：634636.
[3]房丽,荣绍元,王红阳,等.地塞米松防治急性放射性肺损伤疗效观察[J].山东医药.2009,49(4)：49-50.
[4]谭永红,王东,王兴友,等.放射性肺炎激素治疗临床分析[J].中华放射医学与防护杂志.2005,25(3)：260-261.
[5]山广志.百令胶囊加味治疗放射性肺炎的临床观察[J].实用中医内科杂志,1996,10(4)：37.
[6]房丽,王红阳,刘卫东,等.不同剂量地塞米松防治放射性肺损伤临床疗效观察[J].广东医学.2009,30(10)：1497-1498.
[7]陈军,王明智.治疗放射性肺炎的润肺通络法.江南大学学报,2002,1(4)： 435.
[1]Rube CE, Uthe D,W i lfert F, etal. The bronchiolar ePithel ium as a Prominent SOUrCe of Proinflaromatory cytokines after lung irradiat ion[J]. Int JRadiatOnc01BiolPhys,2005,61(5):1482-1492.
[2]王跃珍.放射性肺炎研究进展[J].中国肿瘤,2007,16(1)：35-38.
[3]吴开良,李艳如,蒋国梁.放射性肺损伤[J].实用癌症杂志,2001,16(1)：110-112
[4]陈军,王明智.治疗放射性肺炎的润肺通络法.江南大学学报,2002,1(4)：435.
[5]Chen Y, Wi 11 iams J, Ding I, etal. Radiat ion Pneumoni t is and early circulatory cytokine markers. Semin Radiat Onc01. January 1,2002,12(1 suPPll):26-33.
[6]郑爱青,韩晨光,朱新英,等.IL-1和IL-6在放射性肺损伤发病中的作用[J].武警医学院学报,2009,18(3)：194-196.
[7]BaiYH, WangDW, Wan LP, etal. The role of free radicals in the develoPment of radiat ion interstitial Pneumonits[J]. Envi ron Pathol ToxicolOnco.1993, 12(4):199.
[8]朱茂祥,龚怡芬,葛桂秀,等.大鼠肺吞噬细胞释放自由基在放射性肺炎 发展中的作用.中华放射医学与防护杂志,1996,16(2)：96～99.
[9]Mccord JM, Fridovich I. SuPeroxide dismutase. An enymjc function for erythrocuPrein(hemocuPrein)[J]. JbiolChem.1969,244:6049-6055.
[10]方允中,郑荣梁,主编.自由基生物学的理论与应用[M].北京：北京科学出版社,2002：213—233.
[11]黄莺.叶燕青.孙洁民肺纤维化形成过程中大鼠肺成纤维细胞分泌TGF-β mRNA及HGF mRNA对肺泡II型上皮细胞的影响[J]-重庆医学2010(19)
[12]雷素英.李银生.张彬姜黄素对急性肺损伤小鼠肺组织转化生长因子-p1表达的影响[J]-中华急诊医学杂志2011(9)
[13]魏路清；董彦；谭明旗糖皮质激素对实验性肺纤维化TGF-β,MCP-1的影响[J]-心肺血管病杂志2006(03)
[14]刘纯杰,王德文,高征兵等.细胞因子及其受体在放射性肺纤维化发生中的分子病理机理研究。中华放射医学与防护杂志。2000。20(6)：391.394。
[15]申文江,王绿化.放射治疗损伤：中国医药科学技术出版社,2001：95,103.
[1]刘纯杰,王德文,高亚兵,等.放射性肺纤维化大鼠动物模型的建立及其病变规律[J].中国兽医学报,20(6)：576～5788
[2][2]曹小飞,陈龙华,刘国龙.大鼠放射性肺损伤模型的动态病理学观察[J].中华肿瘤防治杂志,2010,17(11)：818-822
[3][3]孔祥鸣,吴稚冰,马胜林,等.痰热清注射液对急性放射性肺炎大鼠血清TGF-β1水平及肺病理学改变的影响[J].实用中西医结合临床,2008,(04)： 30
[4][4] Travis EL, Liao ZX, Tucker SL. SPatial heterogeneity of the volume effect for radiation Pneumonotis in mouse lung[J]. Int J Radiat Oncol Biol Phys.1997,38(5):1045-1054
[5][5]杜雪梅,柳晓兰,崔玉芳,等.放射性肺损伤小鼠动物模型的建立及其病变规律[J].中国体视学与图像分析,2003,8(4)：203—206.
[6][6]张海,王炳胜,刘秀芳,等.每周重复照射建立大鼠放射性肺损伤模型的评价[J].临床军医杂志,2009,37(3)：353-355.
[7][7]张霆等.解毒疏络法预防放射性肺损伤的临床研究[J].上海中医药杂志,2007,23(5)：89.
[1]Mu E, Liu XJ, Chen S, et al: Changes in factor Ⅶ-activating protease in a bleomycin-induced lung injury rat model and its influence on human pulmonary fibroblasts in vitro. Int J Mol Med 26:549-555,2010.
[2]Vujaskovic Z, Marks LB and Anscher MS:The physical parameters and molecular events associated with radiation-induced lung toxicity. Semin Radiat Oncol 10:296-307,2000.
[3]Noth I and Martinez FJ:Recent advances in idiopathic pulmonary fibrosis. Chest 132:637-650,2007.
[4]Du Bois RM:Idiopathic pulmonary fibrosis. Annu Rev Med 44:441-450, 1993.
[5]Lingos TI, Recht A, Vicini F, Abner A, Silver B and Harris JR:Radiation pneumonitis in breast cancer patients treated with conservative surgery and radiation therapy. Int J Radiat Oncol Biol Phys 21:355-360,1991.
[6]Wagner GR:Asbestosis and silicosis. Lancet 349:1311-1315,1997.
[7]Tyurina YY, Tyurin VA, Kapralova VI, Wasserloos K, et al: Oxidative lipidomics of γ-radiation-induced lung injury:Mass spectrometric characterization of cardiolipin and phosphatidylserine peroxidation. Radiat Res 175:610-621,2011.
[8]Margetts PJ, Bonniaud P, Liu L, et al: Transient over-expression of TGF-β1 induces epithelial mesenchymal transition in the rodent peritoneum. J Am Soc Nephrol 16:425-436,2005.
[9]Martinez Florez S, Gutierrez Fernandez B, Sanchez-Campos S, Gonzalez Gallego J and Tunon MJ:Quercetin attenuates nuclear factor-kappa activation and nitric oxide production in interleukin-1 beta-activated rat hepatocytes. J Nutr 135:1359-1365,2005.
[10]Kang SK, Rabbani ZN, Folz RJ, et al: Overexpression of extracellular superoxide dismutase protects mice from radiation-induced lung injury. Int J Radiat Oncol Biol Phys 57:1056-1066,2003.
[11]Yara S, Kawakami K, Kudeken N, et al: FTS reduces bleomycin-induced cytokine and chemokine production and inhibits pulmonary fibrosis in mice. Clin Exp Immunol 124:77-85,2001.
[12]Liu R, Ahmed KM, Nantajit D, et al: Therapeutic effects of a-lipoic acid on bleomycin induced pulmonary fibrosis in rats. Int J Mol Med 19:865-873, 2007.
[13]Armutcu F, Cabuk M, Gurel A, Atmaca H and Kart L:Caffeic acid phenethyl ester and vitamin E moderates IL-1β and IL-6 in bleomycin-induced pulmonary fibrosis in rats. Pestic Biochem Physiol 88:209-212,2007.
[14]Liu JF, Wang X, Wang F, Teng L and Cao J:Attenuation effects of heparin superoxide dismutase conjugate on bleomycin-induced lung fibrosis in vivo and radiation-induced inflammatory cytokine expression in vitro. Biomed Pharmacother 63:484-491,2009.
[15]Tomita M, Okuyama T, Katsuyama H, et al: Gene expression in rat lungs during early response to paraquat-induced oxidative stress. Int J Mol Med 17: 37-44,2006.
[16]Hagimoto N, Kuwano K, Inoshima I, et al: TGF-beta 1 as an enhancer of Fas-mediated apoptosis of lung epithelial cells. J Immunol 168:6470-6478, 2002.
[17]Dong XC, Li WJ, Liu QF, et al: The influence of carbon ion irradiation on sweet sorghum seeds. Nucl Instrum Methods Phys Res B 266:123-126,2008.
[18]Ritter MA, Cleaver JE and Tobias CA:High-LET radiations induce a large proportion of non-rejoining DNA breaks. Nature 266:653-655,1977.
[19]Sekine E, Okada M, Matsufuji N, Yu D, Furusawa Y and Okayasu R:High LET heavy ion radiation induces lower numbers of initial chromosome breaks with minimal repair than low LET radiation in normal human cells. Mutat Res 652:95-101,2008.
[20]Zhang H, Li S, Wang XH, et al: Results of carbon ion radiotherapy for skin carcinomas in 45 patients. Br J Dermatol 166:1100-1106,2012.
[21]Wu ZH, Zhang H, Wang XY, et al: Protective effects of melatonin against 12C6+beam irradiation-induced oxidative stress and DNA injury in the mouse brain. Adv Space Res 49:196-203,2012.
[22]Zhou G, Kawata T, Furusawa Y, et al: Protective effects of melatonin against low-and high-LET irradiation. J Radiat Res 47:175-181,2006.
[23]Zhang H, Zhao W, Wang Y, et al: Induction of cytogenetic adaptive response in spermatogonia and spermatocytes by pre-exposure of mouse testis to low-dose 12C6+ ions. Mutat Res 653:109-112,2008.
[24]Liu Y, Zhang H, Zhang L, Zhang X, Xie Y and Zhao W:Melatonin modulates acute testicular damage induced by carbon ions in mice. Pharmazie 64: 685-689,2009.
[25]Stone HB, Coleman CN, Anscher MS and McBride WH:Effects of radiation on normal tissue:consequences and mechanisms. Lancet Oncol 4:529-536, 2003.
[26]Finkelstein JN, Johnston CJ, Baggs R and Rubin P:Early alterations in extracellular matrix and transforming growth factor beta gene expression in mouse lung indicative of late radiation fibrosis. Int J Radiat Oncol Biol Phys 28:621-631,1994.
[27]Rodeman HP and Bamberg M:Cellular basis of radiation-induced fibrosis. Radiother Oncol 35:83-90,1995.
[28]Rubin P, Johnston CJ, Williams JP, McDonald S and Finkelstein JN:A perpetual cascade of cytokines post irradiation leads to pulmonary fibrosis. Int J Radiat Oncol Biol Phys 33:99-109,1995.
[29]Anscher MS, Kong FM, Andrews K, et al: Plasma transforming growth factor betal as a predictor of radiation pneumonitis. Int J Radiat Oncol Biol Phys 41: 1029-1035,1998.
[30]Fu XL, Huang H, Bentel G, et al: Predicting the risk of symptomatic radiation-induced lung injury using both the physical and biologic parameters V30 and transforming growth factor β. Int J Radiat Oncol Biol Phys 50: 899-908,2001.
[31]Chen Y, Williams J, Ding I, et al: Radiation pneumonitis and early circulatory cytokine markers. Semin Radiat Oncol 12 (Suppl 1):26-33,2002.
[32]Broekelmann TJ, Limper AH, Colby TV and Mcdonald JA:Transforming growth factor beta 1 is present at sites of extracellular matrix gene expression in human pulmonary fibrosis. Proc Natl Acad Sci USA 88:6642-6646,1991.
[1]Bajwa EK, Ayas NT, Schulzer M, Mak E, Ryu JH, Malhotra A. Interferon-gamma1b therapy in
[2]idiopathic pulmonary fibrosis:a metaanalysis. Chest 2005;128:203-206.
[3]tolerance induction and inflammation. Curr Opin Immunol 2004; 16:709-716.
[4]Qi Z, Atsuchi N, Ooshima A, Takeshita A, Veno H. Blockade of type beta transforming growth factor signaling prevents liver fibrosis and dysfunction in the rat. Proc Nat! Acad Sci VSA 1999;96:
[5]Sakamoto T, Ueno H, Sonoda K, et al. Blockade of TGF-beta by in vivo gene transfer of a soluble
[6]TGF-beta type II receptor in the muscle inhibits corneal opacification, edema and angiogenesis.Gene Ther 2000;7:1915-1924.
[7]Ueno H, Sakamoto T, Nakamura T, et al. A soluble transforming growth factor beta receptor expressed in muscle prevents liver fibrogenesis and dysfunction in rats. Hum Gene Ther 2000; 11:33-42.
[8]Christ M, McCartney-Francis NL, Kulkarni AB, et al. Immune dysregulation in TGF-beta 1-deficient mice. Immunol 1994; 153.1936-1946.
[9]Border WA, Noble NA, Yamamoto T, et al. Natural inhibitor of transforming growth factor-beta protects against scarring in experimental kidney disease. Nature 1992;360:361-364.
[10]Border WA, Okuda S, Languino LR, Sporn MB, Ruoslahti E. Suppression of experimental glomerulonephritis by antiserum against transforming growth factor beta 1. Nature 1990;346:371-374.
[11]Hill C, Flyvbjerg A, Rasch R, Bak M, Logan A. Transforming growth factor-beta2 antibody attenuates fibrosis in the experimental diabetic rat kidney. Endocrinol 2001; 170:647-651.
[12]McCormick LL, Zhang Y, Tootell E, Gilliam AC. Anti-TGF-beta treatment prevents skin and lung fibrosis in murine sclerodermatous graft-versus-host disease:a model for human scleroderma. ImmunoI1999;163:5693-5699.
[13]Denis M. Neutralization of transforming growth factor-beta 1 in a mouse model of immune-induced lung fibrosis. Immunology 1994;82:584-590.
[14]Ruzek MC, Hawes M, Pratt B, et al. Minimal effects on immune parameters following chronic antiTGF-beta monoclonal antibody administration to normal mice. Immunopharmacol Immunotoxicol 2003;25:235-257.
[15]Kolb M, Margetts PI, Sime PI, Gauldie 1. Proteoglycans decorin and biglycan differentially modulate TGF-beta-mediated fibrotic responses in the lung. Am J Physiol Lung Cell Mol Physiol 2001;
[16]Ghosh AK, Yuan W, Mori Y, Chen S, Varga 1.Antagonistic regulation of type I collagen gene expression by interferon-gamma and transforming growth factor-beta. Integration at the level of p300/CBP transcriptional coactivators. J Biol Chern 2001;276:11,041-11,048.
[17]Higashi K, Inagaki Y, Fujimori K, Nakao A, Kaneko H, Nakatsuka I. Interferon-gamma interferes with transforming growth factor-beta signaling through direct interaction ofYB-1 with Smad3. J Biol Chern 2003-278:43,470-43,479.
[18]Chen Y, Chen J, Dong J, Liu W. Antifibrotic effect of interferon gamma in silicosis model of rat.Toxicol Lett 2005-155:353-360.
[19]Gurujeyalakshmi G, Giri SN. Molecular mechanisms of antifibrotic effect of interferon gamma in bleomycin-mouse model of lung fibrosis:downregulation ofTGF-beta and procollagen Ⅰ and Ⅲ gene expression. Exp Lung Res 1995;21:791-808.
[20]Kalra S, Utz JP, Ryu JH. Interferon gamma-1 b therapy for advanced idiopathic pulmonary fibrosis.Mayo Clin Proc 2003-78:1082-1087.
[21]蔡红兵,罗荣城放射性肺损伤的中医药防治方法探讨第一军医大学学报,2003,23,(9)：958—960.
[22]李兰群,急性放射性肺炎中医辨识)附35例临床分析北京中医药大学学报1999,22,(2)：45.
[23]陈军,王明智治疗放射性肺炎的润肺通络法江南大学学报(自然科学版),2002,1,(4)：345—346
[24]王亚平,李伯祥；川芍嗦防治肾间质纤维化作用的实验研究,中国中西医结合肾病杂志,2002,3(2),77—78.
[25]石清照,徐之良等,当归注射液对辐射损伤小鼠造血调控因子及骨髓微环境的影响,中华放射医学与防护杂志,2004,35,(2)：137—139#
[26]谢从华.当归对小鼠放射性肺损伤过程中TNF—a水平的影响,中华放射肿瘤学杂志,2005,14,(1)：59—63.