| Background and ObjectivePulmonary sarcoidosis(PS)is a systemic disease,which is characterized by non-caseous necrotizing epithelial granuloma.At present,conventional treatment mainly focuses on the applications of glucocorticoids,but it is easy to relapse after the withdrawal of hormone therapy,and the side effects are obvious.TCM treatment of PS has certain advantages,Tonghua formula(THF)is a basic prescription for the treatment of PS established on the basis of sanjiao "membranous four channels" which is proposed by Professor Liangduo Jiang.In the first part of this study,systematic evaluation method was used to determine the exact efficacy of glucocorticoids in the treatment of PS and its long-term prognosis and recurrence.In the second part,the academic thought of "membranous four channels" of Professor Liangduo Jiang and the important guiding value of this theory in the clinical diagnosis and treatment of PS were summarized.The third part is the clinical study to observe the curative effect of THF in the treatment of PS and to explore the influence on the long-term prognosis through follow-up.The fourth part analyzes the molecular mechanism and effectiveness of THF through network pharmacology.Methods1 A Meta-analysis about glucocorticoids therapy of PS:the first part randomized controlled trials(RCTs)of glucocorticoids in the treatment of PS were retrieved from domestic and foreign databases.Main observation indexes were effective rate of treatment and follow-up,recurrence rate,pulmonary function index and serum angiotensin converting enzyme(SACE)2 The theoretical research on the treatment of PS from the "membranous four channels"of sanjiao:the second part combined with the ancient and modern literature research on sanjiao,summarizing evolution process from its shape,quality,physiological function and syndrome differentiation.Secondly,the theory of "membranous four channels" proposed by Professor Liangduo Jiang was expounded.Finally,the important guiding value of the theory of "membranous four channels" in the clinical diagnosis and treatment of PS was expounded,and THF was established as the basic prescription according to this theory.3 Clinical study of THF in treatment of PS:In the clinical study,a prospective case series study suitable for rare diseases was adopted.Patients with advanced or recurrent of stage II PS were enrolled and treated with THF for a period of 6 months and a follow-up period of 6 months.General data and clinical data were recorded,patients undergoing SACE detection were divided into SACE elevated group and SACE normal group.The differences in chest HRCT,physical and chemical inspection,TCM symptom scores were compared and the correlation were also compared.In the efficacy evaluation,the comprehensive efficacy,chest HRCT,physical and chemical inspection,TCM symptom scores were compared after treatment and follow-up,and the safety of THF was monitored4 Network pharmacological study:The targets of THF were compared with targets of PS,building drug-disease control network to find the key targets.Finally,the gene ontology(GO)function and kyoto encyclopedia of genes and genomes(KEGG)signal pathway enrichment analysis of key targets were conducted to explore the therapeutic mechanism of THF on PS.Results1 The Meta-analysis:In this study,8 RCTs were selected,all of which were published in English.The results showed that the effective rate of the treatment group was higher than that of the control group(P<0.05).During the follow-up,there was no significant difference in the effective rate and recurrence rate between the treatment group and control group(P>0.05).After treatment,FVC and DLCO in the glucocorticoid-treated group were higher than those in the control group(P<0.05),but there were no significant differences in FEV1 and SACE between the two groups(P>0.05).2 The theoretical research:The quality of sanjiao is the focus of debate and the function of sanjiao is mainly focused on gasification and the metabolism of water and liquid in historical periods.Sanjiao syndrome differentiation has far-reaching influence not only in hot and humid diseases,but also in other complex diseases.PS can be diagnosed and treated from the theory of sanjiao membranous four channels.Professor Liangduo Jiang proposed that sanjiao is the capsule,capsule,lymphatic tissue and interstitial tissue of human organs,and is the four tubular channels connecting viscera and striae.Depression and stagnation of sanjiao affect the movement of body fluid and blood,so the phlegm and blood stasis were formed.Phlegm and blood stasis interconnect to form nodules,which flow through the whole body through sanjiao membranous four channels.The treatment should make sanjiao unobstructed.Therefore,on the basis of this theory,my doctor supervisor created THF as the basic prescription for the treatment of PS.3 Clinical study:3.1 General information:A total of 31 patients were enrolled,including 7 males and 24 females.The mean age of the patients was 56.97 ± 1.07 years old,and the mean course of disease was 1.91 ± 0.06 years.The lesions of the extrapulmonary system included subcutaneous nodules,ocular invasion and parotid enlargement.HRCT scores of lung invasion in the upper and middle lung areas were higher than those in the lower lung areas(P<0.05).3.2 Clinical data:A total of 26 patients completed SACE detection,including 12 patients with elevated SACE and 14 patients with normal SACE.Compared with the normal group,the lung infiltration HRCT scores and chest HRCT total scores were higher and lymphocytes were lower in the elevated SACE group(P<0.05).Correlation analysis showed that SACE level was correlated with lung infiltration HRCT scores and chest HRCT total scores.3.3 Clinical efficacy:Comprehensive efficacy:The comprehensive efficacy rate of THF was 66.7%after 6 months of treatment,and 63.6%after 6 months of follow-up.There was no significant decrease during the follow-up(P>0.05).Chest HRCT:After treatment and follow-up,HRCT score of lung infiltration,HRCT score of lymph node enlargement and total score of chest HRCT were significantly decreased(P<0.01).However,there were no statistically significant differences between the follow-up and treatment(P>0.05).After treatment,the effective rate of lymph node enlargement was higher than that of lung infiltration(P<0.05).Types and grades of lung infiltration:Lung infiltration types included pulmonary nodules,ground glass and consolidation,and there was no statistical difference in the proportion of the three types after treatment and follow-up(P>0.05).After treatment,the HRCT scores of nodule and ground glass were lower than those before treatment,(P<0.05 or P<0.01).After follow-up,HRCT score of nodules was lower than that before treatment(P<0.01).The three types all has no significant difference between follow-up and treatment(P>0.05).The HRCT scores of lung infiltration before and after treatment and follow-up were divided into mild group and moderate group,the proportion showed no statistical difference(P>0.05).Laboratory examination:After treatment and follow-up,SACE,erythrocyte sedimentation rate decreased and lymphocytes increased(P<0.05).After follow-up,lymphocytes were lower and monocytes were higher than the treatment of 6months(P<0.05).After treatment and follow-up,there were significant differences in the abnormal proportions of SACE,erythrocyte sedimentation rate and lymphocytes(P<0.05).Lung function:A total of 16 patients completed lung function detection before treatment.The proportion of reduced diffuse function and small airway function was the highest.Efficacy of lung function was not compared after treatment and follow-up.TCM syndrome:The TCM syndromes scores of all patients and patients with the syndrome of depression and stagnation of sanjiao,phlegm and blood stasis obstruction,and deficiency of Qi and Yin were significantly lower after 6 months of treatment and 6 months of follow-up compared with those before and after 1 month of treatment(P<0.01).Compared with before treatment,the TCM syndrome scores of patients with depression and stagnation of sanjiao,phlegm and blood stasis obstruction and damp-heat accumulation in lung were lower after 6 months of treatment and follow-up(P<0.05 or P<0.01).Compared with before treatment,the TCM syndrome scores of patients with depression and stagnation of sanjiao,phlegm and blood stasis obstruction and Yang qi deficiency were lower after 6 months follow-up(P<0.05).TCM efficacy:The TCM effective rate was significantly increased after 1 month treatment,6 months treatment and 6 months follow-up(P<0.01).The effective rate was higher after 6 months of treatment and 6 months of follow-up than after 1 month of treatment(P<0.01).There was no difference in the effective rate between 6 months of follow-up and 6 months of treatment(P>0.05).TCM symptoms:After 1 month of treatment,the scores of symptoms of epigastric distention and tightness decreased(P<0.05).The scores of symptoms of chest tightness,subcutaneous nodules,fatigue,sputum,dry mouth and throat,chilly sensation and the cold limbs,hot flashes and night sweats,diarrhea with loose stools were all decreased after 6 months of treatment and 6 months of follow-up compared with those before treatment(P<0.05).Adverse reactions:During the treatment and follow-up,no serious adverse reactions occurred in the enrolled patients.4 Network pharmacological study:The key targets interleukin 6(IL6),matrix metalloproteinase 9(MMP9),caspase 3(CASP3)and chemokine ligand 2(CC12)were found by constructing THF-PS-targets regulatory network.Hepatitis B,T helper cell(Th17)cell differentiation,tumor necrosis factor(TNF),interleukin 17(IL-17)signaling pathways were found by GO function and KEGG signaling pathway enrichment analysis.IL6,MMP9,CASP3,CCL2 genes,Th17 cell differentiation,TNF signaling pathway,and IL-17 signaling pathway are currently recognized related targets and mechanisms of PS,thus confirming the effectiveness of THF in the treatment of PS.ConclusionGlucocorticoids are effective in the treatment of PS,but have no benefit in the long-term prognosis and recurrence.THF has definite clinical effect for treating PS established on the theory of sanjiao membranous four channels.THF can improve chest HRCT and subcutaneous nodules,reduce the results of laboratory examination related to disease activity and severity,and reduce the TCM syndrome scores.Through follow-up,it is found to have a good long-term prognosis and reduce the recurrence rate.The network pharmacological analysis also confirmed the effectiveness of THF. |
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