| 1BackgroundRadiation Pneumonitis (RP) is one of common complications during radiotherapy of thoracic tumors, which occurs at1to3months after radiation therapy. Mild to severe dyspnea and dry cough is the most common symptom. Low-grade transient fevers are present occasionally (<10%cases). Hemoptysis is a rare symptom. In severe radiation pneumonitis, patients may present with respiratory insufficiency and cyanosis leading to pulmonary hypertension and acute cor pulmonale. In general, radiographic abnormalities occur much more frequently than do clinical symptoms. The performance of X-rays for lung irradiation area is filled with flakes, ground-glass shadow. On computed tomography scans, PR shows patchy confluent regions of increased attenuation.At present, the occurrence of radiation pneumonitis is regarded as the result of interactions and mutual constraints of cells, cytokines and enzymes. Ionizing radiation-induced reactive oxygen species damage type I and type II alveolar epithelial cells, alveolar macrophages, endothelial cells, and fibroblasts, resulting in secretion of large amounts of proinflammatory cytokines, chemokines and fibrogenic factors by cells. Then neutrophil, mononuclear macrophage, and precursor cells of fibroblasts in blood circulation accumulate in the damage lung tissue. The activity of extracellular matrix metalloproteinase becomes abnormal. All of this promote the development of pulmonary inflammation. In TCM, radiation is a fire evil, Yang evil. It is easy to cause impairment of body fluid and QI, convulsion and bleeding, leading to QI deficiency, yin deficiency, blood heat, blood stasis.Adrenal cortical hormone is the main effective drug used in treatment of early RP. It plays the anti-inflammatory effect, reducing the damage degree of lung essence cells and microvessel, relieving the exudation and edema of lung tissue, and then alleviate symp toms effectively. Long-term use of hormone drugs can produce drug dependence, and easily lead to local skin atrophy, pigmentation, hirsutism, infection and other side effects. The other treatments include antibiotics, oxygen, expectorant and symptomatic treatment. Experimental treatment aiming at occurrence mechanism has been carried out, which includes antioxidant, changing the matrix metalloproteinases, cytokines and growth factors. But these methods are still in the experimental stage. According to the character of radiation easily leading to impairment of body fluid and QI, convulsion and bleeding in TCM, Clinical treatment principle is heat-clearing and Detoxifying, supplementing qi and nourishing yin, cooling and activating blood, having achieved good effect, highlighting the advantages of TCM in this area. Experimental Study of TCM treatment of RP is underway to explore its action the mechanism.YangYinQingFei Formula is the experience prescription of my supervisor,used for many years, under the guidance of clearing away heat and nourishing yin. It has achieved good efficacy.YangYinQingFei consist of liriope, asparagus root, rhizoma polygonatum, radix rehmanniae, tendrilleaf fritillary bulb powder, almond, heartleaf houtluynia, american ginseng, panax notoginseng powder, glycyrrhiza. Our previous study found that YangYinQingFei Formula can improve the quality of life, relieve symptoms of patients after radiotherapy, but its mechanism has not yet further studied. So we study its efficacy through clinical observation to quantify symptoms. Experimental study explores the mechanism of YangYinQingFei Formula from aspects of cells and cytokines, which provide experimental basis for further development of drugs, and promote the application of TCM in the treatment of radiation pneumonitis.2Research Objective2.1Clinical observation Observed the clinical efficacy of YangYinQingFei Formula in the treatment of radiation pneumonitis, and its effect to alleviate the clinical symptoms and improve patients’ quality of life.2.2Animal experiment Establish the model of raidiation lung injury, then observe the influence of pathological changes of the damaged lung tissue and the expression of cytokines, to discusses the mechanism.3Contents And Methods3.1Clinical observation Using randomized controlled design,60cases of radiation pneumonitis, visiting to Guang An Men Hospital of China Academy of Traditional Chinese Medicine from2010to2012, were randomly divided into treatment group (YangYinQingFei Formula therapy) and control group (hormone therapy).30cases in each group were followed up for2months. Observe the four indicators of the karnofsky score, the RTOG classification changes, Watters score, and clinical symptoms score, before treatment, and1,2months after treatment.3.2Animal experiment Ninety SD male rats were randomly allocated into control group, model group, herb group, hormone group, herb&hormone group. The lungs of all rats except those in the blank group were irradiated by60Co for20Gy dose once. The corresponding drugs were given orally,1time/day, continued to put to death.6rats in the five groups were randomly got to be observed and drawn the specimen at each of the3time points (2nd,4th and6th weeks after irradiation). Their arterial blood was obtained to detect the expression of TGF-β1, TNF-αby ELlSA. The middle of right lungs of rats were dyed with HE staining to observe the pathological changes, and dyed with Immunohistochemical staining to observe the expression of IL-6. SPSS17.0statistical software were used for data analysis.4Results4.1clinical observationAt the end of the trial,2cases in the treatment group were off and3cases in the control group. Finally55cases were brought into,28cases of treatment group,27cases of control group. The baseline data of two groups were comparable. Compared with the control group, Watters score, Karnofsky score, shortness breath, fatigue symptoms of the treatment group were improved more significantly. But the difference of the RTOG grading score and cough symptoms between two groups was not obvious.4.2animal experiment4.2.1General condition of rats The rats in radiation groups were listlessness and their hair became matt, dry, erect, about at the5th day after the irradiation. At each time point, the coat color and spirit of J, Z and X group, were better than the M group. Beginning form the8th-10th days after irradiation, the back hair of rats appears removal, which becomes obvious at the4th-6th weeks. There is no difference between the four groups receiving irradiation.4.2.2The body weight of rats At the2nd,4th and8th weeks after irradiation, the weight gain of M, J, Z, X-group were significantly reduced than that of K group (p<0.05), but the weight of drug groups (J, Z, X-group) increased faster than the M group, with statistically significant difference (P<0.05), the difference between J group and Z group was statistically significant(P>0.05). At the2nd,4th weeks, the weight growth of X group is more than that of J group and Z group, significant difference (P<0.05), and there was no difference (P>0.05) at the8th group.4.2.3Pathological changes At the2nd,4th weeks, the lung tissues of M group showed acute interstitial pneumonitis. The main lesion was infiltrative, and the inflammation was aggravated at the4th week. Lesions was shown as:the lung interval became thick, alveolar walls became wide, alveolar walls capillaries hyperemia, pulmonary intersitital congestion, obvious edema, In the alveolar interval and the part of the alveolar cavity, scattered neutrophils, macrophage infiltrate, and red blood cells and cellulose kind of exudates appered; At the8th weeks after irradiation, performance of inflammation change continued, but relieved. Part of lung form decompensated emphysema, and part of the blood vessel. At three time points, especially the4th weeks, lung tissue of J, Z, X three groups appeared congestion, edema, exudation. The pathology change is significantly slight than the model group, especially traditional Chinese medicine+hormone group (X group).4.2.4Detect TGF-β1content of rats in the serum by enzyme linked immuneosorbent assay The TGF-β1level of Radiation group (M, J, Z, X group) elevated progressively, and reached a peak at the8th week. At each time point, the levels of the four group were higher than the K group (P<0.05). At expression of TGF-β1of J, Z X group were lower than M group (P<0.05), and the X group has the lowest expression. The difference between J group and Z group was statistically significant(P>0.05).4.2.5Detect TNF-a content of rats in the serum by enzyme linked immuneosorbent assay The expression of TNF-a in M, J, Z, X group elevated after irradiation,and reached a peak at the4th week. At each time point, the levels of the four group were higher than the K group (P<0.05). The expression of TNF-a of J, Z X group were lower than M group (P<0.05), and the X group had lower expression than J、Z group. The difference between J group and Z group was no statistically significant (P>0.05).4.2.6Detect the expression of IL-6in the lung tissue by immunohistochemistry The expression of IL-6in radiation group (M, J, Z, X group) elevated,and reached the highest level at the4th week, decreasing at the8th week. At each time point, the levels of the radiaton group were higher than the K group (P<0.05). The expression of IL-6of treatment group (J, Z X group) were lower than M group (P<0.05), and the X group had lower expression than J、Z group. The difference between J group and Z group was no statistically significant (P>0.05).5Conclusion5.1Clinical observation YangYinQingFei Formula can significantly improve patients’ RTOG classification, watters score, and clinical symptoms score, and relieve symptoms effectively, and improve the life quality of patients. In conclusion YangYinQingFei Formula has the remarkable clinical curative effect.5.2Animal experiment YangYinQingFei Formula can improve the life quality of rats, lessen the inflammatory of lung obviously, alleviate pulmonary intersitital congestion, exudation, hemorrhage, edema and damage of alveolar structure, reduce the expression of cytokines in lung tissue and serum. So YangYinQingFei Formula restraint the progress of radiation induced pneumonitis. |
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