Hindawi BioMed Research International Volume 2019, Article ID 6012473, 7 pages https://doi.org/10.1155/2019/6012473

Research Article Shashen-Maidong Decoction-Mediated IFN-� and IL-4 on the Regulation of Th1/Th2 Imbalance in RP Rats

Yuan Yang1 and Yanping Zhou 2

 Graduate School, Wuhan Sports University, Wuhan, China Hubei University of Chinese Medicine, Wuhan, China

Correspondence should be addressed to Yanping Zhou; [email protected]

Received 31 January 2019; Revised 13 April 2019; Accepted 16 May 2019; Published 24 June 2019

Academic Editor: Frederick D. Quinn

Copyright © 2019 Yuan Yang and Yanping Zhou. Tis is an open access article distributed under the Creative Commons Attribution License, which permits unrestricteduse, distribution, and reproduction in any medium, provided the original work is properly cited.

Objective. Studying correlative changes of T1/T2 (T, Helper T cells) related factor Interferon-� (IFN-�) and Interleukin-4 (IL-4) in the progression of radiation pneumonia (RP) rats and the efcacy of Shashen-Maidong decoction on these indexes to explore the immune mechanism of the decoction on the prevention and treatment of RP. Methods. Male 60 Sprague-Dawley (SD) rats were randomly divided into four groups. In addition to the normal control group taking saline, the other rats were set up RP model treated with Shashen-Maidong decoction or dexamethasone (DXM), respectively. Te IFN-� and IL-4 concentrations in serum nd th and bronchoalveolar lavage fuid (BALF) of rats were tested in the 2 and 4 week afer radiation, and the relative ratio of IFN- �/IL-4 was calculated. Results. (1) Tere was signifcant diference of serum IL-4 concentrations in group B (p<0.01) and extreme th diference in groups C and D (p<0.001) compared with group A in 4 week. Compared with group D, IL-4 concentrations in group nd th B increased signifcantly in both 2 and 4 week (p<0.01). Group B had signifcantly decreased IFN-� concentrations in BALF th (p<0.001) compared with group D in the 4 week. And IFN-� concentrations in BALF in group B were increased compared with th group C in the 4 week (p<0.05). (2) Tere was no diference of the relative ratio of IFN-�/IL-4 at each time in groups B and A for both serum and BALF, while the ratios in groups C and D in 4th week in BALF were increased (p<0.05) compared to group A. Conclusion. Shashen-Maidong decoction can improve the immune function of RP rats by increasing IFN-� concentration and decreasing IL-4 concentration, possibly by increasing the relative ratio of IFN-�/IL-4 to regulate the immune imbalance of T1/T2.

1. Introduction suggested that the immune imbalance pathogenesis of RP can be elaborated and regulated by eliminating pathogen to RP is an acute pulmonary-related disease with early injury support Qi and Yin, which can be used as the theoretical and of aseptic infammation by chest radioactive radiation. Te experimental basis for clinical treatment. damage of collaterals in lung caused by radiation heat-toxicity Traditional Chinese Medicine (TCM) believes radioac- developed from initial symptoms like occasional tachypnea tive radiation, such as X-ray, has the characteristics of high and oppression in chest to parched mouth, cough, and even heat-source property with fast speed and strong penetra- hemoptysis subsequently [1]. Tese symptoms are the lack tion. It can be classifed as the pathogenic factor of heat- of Qi (a generic concept, similar to “function”, especially toxicity in Febrile disease which contains the pathogenic for energy metabolism) and Yin (belonging to Yin-Yang characteristics of external invasion and remarkable thermal theory; here is the implication of immunity) manifesta- property. Tis leads to the damage of Fei-Zang (lung and tions afer the exogenous pathogenic caloradiance invades surrounding tissues) directly by depleting Qi and blood and organisms. In addition, diferent degree of Primordial-Qi fnally defciency of Yin. Shashen-Maidong decoction, the (the most essential Qi in body and the vital foundation of representative prescription of “Yang-Yin Sheng-Jin” method, life, containing the ability of anti-immunity) can also refect nourishing Yin to promote the product of Jin (body fuid, the strength of immune function. Organisms cannot resist whose function is similar to immunity), has good efects exogenous pathogenic factors due to the defciency of Fei- on the clinical treatment of early radiation-induced lung Qi (lung function) which may exacerbate the disease. It is injury [2, 3]. We have carried on a long-term work on the 2 BioMed Research International mechanism of preventive and therapeutic efcacy on RP 3. Methods by Shashen-Maidong decoction [4–6]. Tis study furtherly explored the function of Shashen-Maidong decoction on .. Establishment of RP Rat Model. Rats, weighed before the immune imbalance based on the “Yang-Yin Sheng-Jin” irradiation, were anesthetized by 0.03ml/kg with 10% chloral method. hydrate. 6MV linear accelerator X-ray was used for single At an earlier stage, there was a hot discussion on the rela- chest irradiation (total dose 20Gy). Te model of RP rats was tionship between TCM syndromes and immune cytokines, established in a relatively short time (see previous research which induced the connection of Yin and immunity [7]. protocol [5]). Ultraviolet radiation was used to sterilize the According to a study at present, the mechanism of RP accelerator room before irradiation. Tis process was carried relates to both immune imbalance and defciency of Yin out in the Tumor Radiotherapy Department of the First [8]. As shown in Figure 1, the disorder of proinfammatory Hospital of Wuhan City. Afer modeling, the rats were sent factor and anti-infammatory factor in the development of back to be kept in a routine way. RP will lead to imbalance in cellular immunity, especially .. Grouping and Administration. 60 rats were randomly in the homeostasis of T1/T2. Besides, IFN-� and IL-4 divided into 4 groups: normal control group (group A), are the most typical cytokines of T1 and T2, respec- Shashen-Maidong decoction group (group B), dexametha- tively. Here is a hypothesis that Shashen-Maidong decoction sone treatment group (group C), and modeling control can strengthen Yin and Jin to eliminate pathogenic factor group (group D), with 15 rats each, respectively. Each rat to explore further mechanism of the prescription on the was numbered and marked with picric acid, and then rats immune function of RP rats. Our research aims to provide were grouped into cages. According to the “Methodology a profound analysis for the application of Shashen-Maidong of Pharmacology of TCM” [9], the dosage by intragastric decoction in the treatment of RP. Namely, it can be high- administration was calculated converting from the standard lighted by regulating T1/T2 and getting feedback on cor- of adult physiological weight (the conversion coefcient relations through the concentration change and proportion of rat/200g corresponding to human/70kg was 0.018); we of IFN-� and IL-4 in the Lung and peripheral blood of RP followed and calculated the dosage of Shashen-Maidong rats. decoction as 5.15 ml/kg. Likewise, the dosage of DXM suspension was 5.2 ml/kg. Other groups (A, D) received the 2. Materials same amount of saline. Except group B, which began to take .. Animal. Male 8-week-old SD rats were studied, which Shashen-Maidong decoction for 1 week before irradiation, were bought from the Research Center of Laboratory Animal other groups were given corresponding intragastric admin- in Hubei Province, No. SCXK(e)20080005. Tese 60 rats istration on the second day afer modeling. Te rats were weighing 220±50g were housed individually in stainless weighed once a week during the intervention, and gastric ∘ steel cages in a controlled environment (22±3 C, 40% ∼ perfusion was adjusted once a week according to the body 70% humidity, with a 12-hour light and dark cycle) for 5- weight change: weight gain = current week weigh — weight day acclimation period. All rats were given free diet and before experiment. drinking water during the experiment. We ensured that all .. Specimen Collection. Afer 2 and 4 weeks of intragastric animals were normal so as not to afect the results of the administration, 6 rats in each group were weighed and experiment by keeping the lab clean, checking the equipment anesthetized with 10% chloral hydrate. Each rat toke 10 ml regularly, and observing the rats' diet, defecation, spirit, abdominal aorta blood for further testing. Te lung tissues etc. were isolated, and the lef lung, 3ml × 3 times, was perfused ∘ with BALF. Ten the serum (5000r/min,4 C, 5min) was taken .. Prescription. Shashen-Maidong decoction (purchased from blood and lavage fuid afer centrifugation and stored in from the Chinese Pharmacy of the frst Hospital of Wuhan ∘ -20 C refrigerator. Te results were determined according to City) is composed of Coastal-Glehnia-root (Shashen) 18g, the instructions of rat IFN-� and IL-4 Elisa kit. Phyllostachys ofcinalis (Hou Po) 12g, Ophiopogon japoni- cus (Maidong) 18g, Snake gourd root 9g, Lentils 9g, Mulberry .. Main Determination Methodology leaf 9g, liquorice 6g, and wolferry root-bar 18g. Te original medicine preparation was placed in the rotary evaporator Histopathology Examination. Te lung tissues of rats were (Yarong, Shanghai). Ten we obtained medicine solution fxed with Formaldehyde, pruned and put into the embedding with a concentration of 2g/ml which was concentrated at ∘ ∘ cassettes, dehydrated with alcohol, placed in xylene for 90 C at 0.07mpa and stored at 4 C in a high pressure transparency, and embedded with parafn. Ten we fxed sterilization refrigerator. them to the slicing machine and cut them into a 5 �mthick slices. Afer that they were put into hot water to be smoothed, ∘ .. Instruments and Reagents. 6MV-X linear accelerator afxed to the slide, and dried in 45 C thermostat. Finally, we (Elekta, Sweden); FA2104 Electronic Analytical Balance stained the slides afer dewaxing and watering them. (Shanghai Tianping, China); CS-15R centrifuge (Beckman, Germany); IFN-� and IL-4 Elisa kit (Shenzhen Jingmei IFN-� and IL- ELISA Kit Detection. Te kit was used to Biological Engineering, China); and enzyme-labeled tester assay mouse IFN-� and IL-4 level in the sample. Firstly, solid- (Labsystems, Finland) were used. phase antibody was made by purifying mouse IFN-� and IL-4 BioMed Research International 3

Primordial-qi Fei-qi

Qi Immune imbalance Fei-Zang Yin yang Yin imbalance

Jin

Tachypnea, mouth parched, Radiation pulmonary injury cough, hemoptysis (aseptic infammation)

Figure 1: Relationship between radiation pneumonia and Yin-Yang theory. antibody to coat microtiter plate wells. Ten, IFN-� and IL- .. HE Staining Observation. Te results of HE staining at 4 4 were added to wells, and IFN-� and IL-4 antibody were weeks afer irradiation have shown more obvious diference combined with HRP labeled to became antibody-antigen- than those at 2 weeks afer irradiation in each modeling enzyme-antibody complex. Afer complete washing, TMB group, so we mainly focused on the specifc analysis at 4- substrate solution was added, which turned to blue color week cases. As Figure 2(a) shows, the structure of lung at HRP enzyme-catalyzed reaction. Finally, reaction was tissue was clear, and no obvious pathological changes were terminated by the addition of a sulphuric acid solution, and foundinalveolarandalveolarseptaingroupA.Inthe the color change was measured spectrophotometrically at a other groups, varying degrees of infammatory changes were wavelength of 450 nm. Te concentrations of IFN-� and IL-4 observed mainly with macrophage and lymphocyte infltra- in the samples were then determined by comparing the OD tion (marked with red arrow in the fgure), accompanied by of the samples to the standard curve. alveolar septa enlargement. Specifcally, we can observe from Figure 2(d) that the alveolar septa in group D were slightly .. Statistical Analysis. Te measured data were analyzed wider than others which showed that the interstitial edema and processed by SPSS18.0, GraphPad Prism 5, Image-Pro was more obvious. Te marked places show the infammatory Plus 6.0, and Curve Expert 1.3. T test and ANOVA test cells in groups B, C, and D such as mononuclear macrophages were used to analyze the signifcance of each index among and lymphocytes in the alveolar septa and partial alveolar diferent group samples. Te data analyzed were expressed space. In group B and group C, the alveolar septa were as Mean ± Standard Deviation (M±SD); p<0.05 indicates enlarged and infammatory cells were still infltrated in part statistical diference, p < 0.01 indicates that each data item has of alveolar cavity at the 4th week. However, the infltration signifcant diference, and p<0.001 indicates that each data of infammatory cells and the widening of alveolar septa in item has extreme diference. groups B and C were lighter than those in group D.

4. Results .. IFN-� and IL- Concentrations in Serum and BALF. Figure 3 shows the following: A Tere was no statistical .. Behavior Observation. Comparison between groups afer diference of IFN-� concentrations in serum. B IL-4 con- irradiation: Tere was no obvious abnormality in group A. centrations in serum: Compared with group A, only group D Within 2 weeks afer irradiation, the rats in groups B, C, and decreased signifcantly in 2 weeks (p<0.01); meanwhile, there D showed mild mental depression, decreased food intake, was signifcant diference in group B (p<0.01) and extreme reduced mobility, slow response to stimuli, etc. Some rats diference in groups C and D in 4 weeks (p<0.001). Compared even showed systemic hair loss and other symptoms such with group D, group B increased signifcantly in both 2 weeks as perirhinal hemorrhage and periocular congestion. 2∼4 and 4 weeks (p<0.01). C IFN-� concentrations in BALF: weeks afer irradiation, the spirit, diet, activity, smoothness Compared with group A, group C increased in 4 weeks of hair, and body weight of rats in group B were better than (p<0.05), and group D increased with extreme diference other modeling rats. Several rats in group C had shortness in 4 weeks (p<0.001). Compared with group D, group B of breath apart from the symptoms before. Te spirit of rats decreased signifcantly in 4 weeks (p<0.001), and group C in group D was the worst; in addition to less activity and also decreased in 4 weeks (p<0.01). Compared with group C, continued weight loss, the majority of these rats had eye-side group B increased in 4 weeks (p<0.05). D IL-4 concentrations and paranasal bleeding, increased periocular secretion, and in BALF: Compared with group A, the other three groups all dry stools. decreased signifcantly in 4 weeks (p<0.001). 4 BioMed Research International

(a) (b)

(c) (d)

Figure 2: Pathological changes of lung in each group at the 4th week afer gastric perfusion (HE staining, × 100).

4 IFN- concentrations in serum IL- concentrations in serum 40 100

30 80

60 20 40 4 (pg/ml) IL- IFN-  (pg/ml) 10 20

0 0 A B CD ADB C Groups Groups 2 weeks 2 weeks 4 weeks 4 weeks

IFN- concentrations in BALF IL-4 concentrations in BALF 50 300

40 200 30

20

IL-4 (pg/ml) IL-4 100 IFN-  (pg/ml) 10

0 0 ABCD ABCD Groups Groups 2 weeks 2 weeks 4 weeks 4 weeks Figure 3: Changes of IFN-� and IL-4 concentrations in serum and BALF. BioMed Research International 5

IFN- /IL-4 ratio in Serum and BALF afected T1/T2 immune imbalance by regulating relative concentrations of IFN-� andIL-4.AndhenceShashen- 1.0 Maidong decoction might inhibit the immune hyperactivity of T1 and enhance the immune function of T2 by changing related cytokines, thus regulating the imbalance of T1/T2 immunity and improving the immune function of RP rats. � 0.5 Te results showed that the concentration of IFN- and IL4 in serum was slightly diferent from that in BALF which had /IL-4 ratio IFN-  /IL-4 more obvious changes. It was possible that the infammation factors in blood did not adequately refect the secretion and 0.0 expression of the infammatory cytokines because the more A BCD sensitive target tissue was Fei-Zang afer radiation which Groups might have more intense infammatory response. 4 weeks/Serum 4 weeks/BALF 6. Discussion 2 weeks/Serum 2 weeks/BALF Shashen-Maidong decoction, frstly shown in the book “Wen � Bing Tiao Bian” [10] (a classic medical book which contained Figure 4: IFN- /IL-4 ratio in serum and BALF. detailed analysis of epidemic warm diseases), was put forward by Wu Jutong in Qing Dynasty. Tis efective prescription aimed at the main treatment of “dryness-heat injury of Yin .. e Changes of IFN-�/IL- Ratio. Te ratio of IFN-�/IL-4 from Fei-Zang, being pyretic or causing cough”. Te included was shown in Figure 4. Compared with group A, there was no eight herbs worked together to nourish the Yin and thus diference at each time in group B for both serum and BALF, clear the efect of exogenous evil. In order to cope with the whiletheratioingroupsCandDat4weeksinBALFwas syndrome type of Yin defciency, we analyzed these herbs that increased (p<0.05). could specially act on the lung and related collaterals, such as Coastal-Glehnia-root, Phyllostachys ofcinalis, and Snake 5. Conclusions gourd root. Researches have shown that the main ingredients, such as Shashen polysaccharide [11], Maidong polysaccharide .. Observation. Te general situation of the rats afer irradi- [12], Sangye polysaccharide [13], and Trichosanthin [14], ation refected that the modeling simulated the Yin defciency could regulate the infammatory environment afer radiation. syndrome of “heat-burn with Jin injury and defciency of Qi Meanwhile, Shashen-Maidong decoction was not greasy or and Yin”. We found that the spirit, diet, body weight, and cold with protecting digestion, and the sweet favor could hair removal of the rats with Shashen-Maidong decoction be easier to accept. As we mentioned this prescription had improved more obviously compared with the other modeling been recognized for its good efects which spread widely in groups. Shashen-Maidong decoction could improve series of clinics. Our experiment confrmed the function of its efects symptoms caused by heat-toxic injury and Yin defciency and extended discussion on the mechanism of treatment. of Fei-Zang, and our observation results also confrmed the Besides, this decoction had better target function on Fei-Zang obvious efcacy of this decoction in the treatment of RP. superior to other organs which was in accordance with the Te HE staining results showed that afer 4 weeks of specifc sensitive messenger-induced function of these herbs intragastric administration, the pathological infammatory in the past. changesoflungtissueswithShashen-Maidongdecoction T1 and T2 are two subsets of T cells, and the cytokines intervention were signifcantly reduced compared with the secreted by them can be regulated by cross-talking and model group, which meant Shashen-Maidong decoction maintain the normal immune function in vivo. Lung and could alleviate the infammation of lung tissue in RP rats. In surrounding tissues injury by radiation will directly induce this experiment, however, the improvement of infammation infammation, manifested by T1 mediated hyperactivity of this prescription was not signifcantly diferent from that of humoral immunity and relatively low cellular immu- of dexamethasone intervention. It is suggested that further nity mediated by T2, fnally resulting in RP immunity researches can be done in the follow-up drug administration imbalance and pathological drif of T1/T2. Te balance experiment with diferent length of time. of T1/T2 refers to Yin-Yang theory in TCM. Specifcally, RP is defciency of Fei-Yin (Fei-Qi and Yin syndrome) and .. Analysis of IFN-� and IL- in Serum and BALF. Based on Yang syndrome is relatively hyperactive which corresponds the data above, we found that Shashen-Maidong decoction to the imbalance of immunity. Shashen-Maidong decoction could signifcantly decrease the concentration of IFN-�, can nourish Fei-Yin and help to produce Jin, so that the increase the concentration of IL-4, and then regulate the cells and factors involved in immune response can maintain ratio of IFN-�/IL-4 in radiation modeling rats. Tis moder- the balance of immunity and restore the steady internal ated anti-infammation tendency afer intervention seemed environment. IFN-� is a characteristic T1 type cytokine, to be closer to the control nature rats. It also supported which can be used as an infammatory mediator to promote our hypothesis that Shashen-Maidong decoction possibly the early symptoms of RP [15, 16]. IL-4 can promote the 6 BioMed Research International diferentiation of T2 cells and play an important role in on Immune Function in Rats with Radiation Pneumonia” enhancing cellular immunity and inhibiting humoral immu- (D20132002), Graduate Educational Innovation Program nity [17, 18]. Tus, we can regulate the concentration of T1 Projectin2018(WuhanSportsUniversity). characteristic cytokine IFN-� and T2 related factor IL-4 so as to ameliorate the imbalance of T1/T2 immunity and References alleviate the infammatory injury of lung tissue [19, 20]. Our experiment has shown the regulation of Shashen-Maidong [1] Y. Yuan and Z. Yanping, “TCM prevention and treatment decoction to these two remarks which may be helpful to characteristics of aseptic infammation in RP patients,” Yunnan understand mechanisms that underlie maintenance of steady Journal of traditional Chinese Medicine,vol.36,no.05,pp.108– immunity and termination of aseptic infammation. 110, 2015. Previous studies have showed that changes of INF-� [2] S. Li, X. M. Zhou, and H. P. 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