A study on the rule of Chinese medicine use for airway remodeling based on data mining

Xin-Yu Wang ,Guo-Cheng Zhang ,Yu-Qiang Lu ,Yu-Qi Hao ,Hui Ding ,Zhao-Lin Shi ,Hai-Bo Lin,Kang-Xiong Zhao

1Shaanxi University of Chinese Medicine,Xianyang 712046,China.2The Second Affiliated Hospital of Shaanxi University of Chinese Medicine,Xianyang 712046,China.

Abstract Objective:Use data mining techniques to explore the rule of Chinese medicine used for airway remodeling.Methods:Search the literature on Chinese medicine use for airway remodeling in the past 20 years.With the help of WPS Office Excel 11.1,IBM SPSS Statistics 23.0 and SPSS Modeler 18.0 software,prescriptions were analyzed for the frequency of drug use,the four natures,the five flavours and the channel tropism,cluster analysis and association analysis of high-frequency drugs.Results:There were 58 Chinese medicine prescriptions for airway remodeling be found,involving 105 Chinese medicines,the most frequent channel tropism were spleen,stomach,lung,large intestine,liver and gallbladder,the most frequent use of the five flavors was sour,sweet and pungent,the highest frequency of the four natures was cold and hot,cluster analysis yielded eight drug aggregation groups,and association rule analysis yielded five groups of high-frequency drug pairs.Conclusion:The main TCM treatments for airway remodeling are expelling phlegm,relieving cough,asthma calming,expelling blood stasis and deficiency tonifying.The results of this study can provide ideas for compounding and drug selection for subsequent studies.

Keywords:data mining;airway remodeling;medication rules;association analysis;cluster analysis

Introduction

Airway remodeling is the irreversible destruction and remodeling of the physiological structure of the airway wall after suffering from repeated airway inflammation and epithelial tissue injury [1–2].The main pathological changes of airway remodeling are:airway epithelial cell changes,inflammatory cell infiltration,goblet cell proliferation,airway smooth muscle cell (ASMC) proliferation and migration,increased number of fibroblasts,extracellular matrix (ECM)deposition,airway wall thickening and vascularization [3–4].Airway remodeling can cause the airway wall to become less elastic and the bronchial smooth muscle to become thicker,resulting in an increasingly narrow airway diameter.

There is no record of“airway remodeling”in ancient Chinese medical texts,but there are records of other diseases with similar mechanisms to airway remodeling.According to TCM,this disease is similar to“pulmonary distension”in etiology and pathogenesis.In the late stage of“pulmonary distension”,there is the deficiency of lung qi,qi-movement’s ascending and descending was got into chaos,and accumulation of phlegm and blood stasis in the lungs and throat,causing organic changes and severely hampering respiratory function[5].

Chinese medicine has the advantages of multi-target,multi-path and multi-link in the treatment of diseases,which can effectively improve respiratory function and improve the quality of life of patients [6].In this paper,we collected and organized the relevant literature on Chinese medicine for the treatment of airway remodeling in the past 20 years,analyzed their prescription selection and medication rules by adopting the methods of frequency analysis,cluster analysis and association rules,in order to provide effective combinations of drug pairs and new grouping ideas for the Chinese medicine treatment of airway remodeling.

Material and Methods

Literature retrieval

Using“airway remodeling”and“traditional Chinese medicine”as the search theme words,we searched the relevant literature of Chinese databases such as CNKI,Wanfang and Cqvip in the past 20 years.

Inclusion criteria

The type of study was a randomized controlled experimental study,constructed the model of“airway remodeling”in rats,let traditional Chinese medicine as the main treatment method.To study the literature which takes the Chinese medicine group as the experimental object and has been proved to have a practical curative effect.Literature on repeated use of the same prescription is included only once.

Exclusion criteria

(1) Repeatedly published literature.(2) Literature in which Chinese medicine prescriptions were not explicitly given.(3) Literature in which Chinese medicine is an adjunctive therapy.(4) Literature on non-pharmacological treatments such as acupuncture,moxibustion and microwave.(5) Literature on Chinese herbal medicine combined with Western medical treatment.(6) Literature on reviews,theoretical discussions,etc.(7) Literature on the use of Tibetan medicine,Mongolian medicine and other minority medicines.

Data specification

In order to facilitate subsequent statistics and research,the names of the included Chinese medicines were standardized with reference toThe Chinese Pharmacopoeia 2020 Editionand the“Thirteenth Five-Year Plan”textbook of the National Institute of Higher Traditional Chinese MedicineTraditional Chinese Medicine[7–8].

Data Analysis

After standardizing the names of Chinese medicines,we entered them into WPS Office Excel 11.1,and counted the frequency of the channel tropism,the frequency of the five flavors,the frequency of the four natures,the frequency of medication and the high-frequency drugs.Then a new table was created,and the above Chinese medicines were binarized,with“1”indicating the occurrence of the medicine and“0”indicating the absence of the medicine,and imported into SPSS Modeler 18.0 and IBM SPSS Statistics 23.0 for systematic cluster analysis and association rule analysis.

Results

Retrieved literature

A total of 403 documents were retrieved according to the subject terms,and according to the exclusion criteria,70 documents were finally selected,with 58 effective prescriptions containing 105 Chinese medicines and 265 total occurrences of drugs.

Frequency statistics of drug use

The frequency analysis of 105 Chinese medicines was conducted,and the specific frequencies of 41 Chinese medicines with frequency greater than 2 are shown in Table 1.

Statistics on the frequency of medication use of the four natures

There are five types of herbal medicines,also known as“four natures”,namely“flat”,“hot”,“cool”,“warm”and“cold”.Each Chinese medicine only corresponds to one medicinal property.“extreme hot”is classified as“hot”,“slightly cold”classified as“cold”,and“slightly warm”classified as“warm”.The specific frequencies and percentages of the four natures are shown in Table 2.

Statistics on the frequency of medication use of five flavours

There are seven categories of Chinese medicine flavors:“sour”,“pungent”,“salty”,“bitter”,“sweet”,“tasteless”,and“astringent”,also known as "five flavors",each herbal medicine can have more than one flavor at the same time.The total frequency was calculated to be 175 times,with sour medicines being the most applied with a frequency of 55 times and a percentage of 31.4%,followed by sweet and pungent medicines,both with a frequency of 50 and a percentage of 28.6%.The specific frequencies and percentages of the five flavours are shown in Table 3.

Statistics on the frequency of medication use of channel tropism

The meridians are“l(fā)ung”,“stomach”,“small intestine”,“bladder”,“gall bladder”,“pericardium”,“kidney”,“l(fā)arge intestine”and“heart”.“gallbladder”,“pericardium”,“kidney”,“l(fā)arge intestine”,“heart”,“sanjiao”,“spleen”and“l(fā)iver”12 places,each medicine can be attributed to multiple internal organs or multiple meridians.The most frequent ones were“spleen”,with 72 occurrences,percentage 26.2%,and those with more than 25 occurrences were:“stomach”,40 occurrences,percentage 14.5%;“l(fā)ung”,37 occurrences,percentage13.5%;“l(fā)arge intestine”,34 occurrences,percentage 12.4%;“l(fā)iver”,29 occurrences,percentage 10.5%,and“gallbladder”,27 occurrences,percentage 9.8%.The specific frequencies and percentages of the channel tropism are shown in Table 4.

Cluster analysis

Systematic cluster analysis of 41 high-frequency drugs was carried out using the IBM SPSS Statistics 23.0 program and the results are shown in the tree diagram.After analysis it was concluded that the clustering effect was divided into eight classes:Class 1:Notoginseng Radix Et Rhizoma,Fritillariae Thunbergii Bulbus,Sinapis Semen,Saposhnikoviae Radix;Class 2:Dioscoreae Rhizoma.Pseudostellariae Radix,Lepidii Semen;Class 3:Ginkgo Semen,Persicae Semen,Paeoniae Radix Rubra,Rehmanniae Radix,Psoraleae Fructus;Class 4:Uncariae Ramulus Cum Uncis,Ginseng Radix Et Rhizoma,Cicadae Periostracum;Class 5:Bupleuri Radix,Platycodonis Radix,Zanthoxylum Nitidum;Class 6:Paeoniae Radix Alba,Angelicae Sinensis Radix,Rehmanniae Radix Praeparata;Class 7:Farfarae Flos,Asteris Radix Et Rhizoma,Belamcandae Rhizoma;Class 8:Citri Reticulatae Pericarpium,Poria.These contents were listed in Figure 1.

Analysis of association rules

Association rule analysis of high-frequency drugs with the help of IBM SPSS Modeler 18.0 program yielded five drug association combinations as Angelicae Sinensis Radix→Paeoniae Radix Alba;Ephedrae Herba→Farfarae Flos;Glycyrrhizae Radix Et Rhizoma→Poria;Glycyrrhizae Radix Et Rhizoma→Citri Reticulatae Pericarpium;Glycyrrhizae Radix Et Rhizoma→Armeniacae Semen Amarum.These contents were listed in Table 5.The IBM SPSS Modeler 18.0 software was used to analyze the listed Chinese medicines to obtain a mesh diagram of association rules for Chinese medicines.These contents were listed in Figure 2.

Figure 1 Systematic cluster analysis mesh diagram

Figure 2 Mesh diagram of association rules for high-frequency Chinese medicine network

Table 1 The 41 most frequently used Chinese medicines

Table 2 Frequency and percentage of four gases

Table 3 Frequency and percentage of five flavors

Table 4 Frequency and percentage of channel tropism

Table 5 Analysis of association rules for high-frequency Chinese medicine

Discussions

Chinese medicine classifies“airway remodeling”as a late stage of“l(fā)ung distension”,and the pathogenesis is a deficiency of the lung,spleen,kidney and retention of blood stasis and phlegm [9].In the book namedTreatise on Exogenous Febrile Disease,it is said that“coughing with the reversed flow of lung qi is called lung distention”.Lung disease would lead to“the failure of lung qi in dispersion and depurative descending”and decreased respiratory function.According to the theory of“mutual generation of five phases”,the deficiency of the lung qi would cause the deficiency of the kidney qi and spleen qi.The final result is the deficit of three zang-fu viscera.Lung governing the regulation of water passages，if the lung is deficient and unable to transport fluid,the fluid will be transformed into phlegm and fluid retention then accumulate in the lung;the pectoral qi includes two parts,one part comes from food qi and drink qi which be digested in spleen and stomach,the other one comes from the respiratory qi of the lung.The pectoral qi is the embodiment of“l(fā)ung connecting all vessels”,it could assist respiration,run qi and blood,tonifying primordial qi.Currently,the most commonly used drugs for airway remodeling are anti-inflammatory drugs,but their therapeutic effects on airway remodeling vary greatly among individuals and are prone to adverse effects with long-term application [10].The clinical treatment of TCM adheres to the principles of“creating both manifestation and the root cause of disease”,“strengthening vital qi to eliminate pathogenic factor”and“treating deficiency syndrome with tonifying method and treating excess syndrome with purgative method”,and applies to supplement drug,phlegm-expelling drug and blood-activating drug for treatment.

From the frequency statistics,it can be seen that the most frequently used drugs have the function of benefiting qi,removing phlegm,arresting cough and relieving asthma,which corresponds to the above-mentioned treatment principles.

The analysis of the four natures of drugs shows that the most widely used drugs are those of cold and hot nature.TheJifeng Puji Fang -Coughrecorded that:The ancients said that lung disease is difficult to heal and easily leads to death.The lung is a delicate zang-fu viscera,being averse to cold and heat,so it is easy to be hurt by pathogenic qi and hard to be cured [11].It can be seen that both cold pathogen and heat pathogen can injure the lung.According to the treatment principle of Chinese medicine:“treating cold syndrome with hot-natured drugs”and“treating heat syndrome with cold-natured drugs”.It is most appropriate to apply cold drugs to“remove heat-phlegm”,“clear heat and purge lung”,“nourish lung yin”;and hot drugs to“warmingly resolve cold-phlegm”,“warm lung and dispel cold”,“warming yang and benefiting qi”.

From the analysis of the five tastes of drugs,it can be seen that the three flavours of“sour”,“sweet”and“pungent”are applied far more frequently than the other four.The Medical Classic of Yellow Emperorsays:“To restrain the Lung,serve the patient with drugs of sour taste urgently.Drugs of sour taste can be used to replenish the lung and drugs of pungent taste can be used to purge the pathological condition.”The main physiological function of the lung is diffusion,purification and descending,the two are opposite and promote each other.Pungency can disperse and sourness can astringing,which corresponds to the function of the lung to diffusing,purify and descend.Sweet medicine corresponds to the internal zang-fu viscera of the spleen,to the five phases of earth,earth generates metal and can also restrict water,generate metal than the lung qi can be supplemented,restrict water then phlegm and fluid retention can be removed.

From the analysis of the drug's channel tropism,we can see that the drugs belonging to the spleen,stomach,lung and large intestine are the most numerous.The Medical Classic of Yellow Emperorsays:“If the lung coughing a long time,the large intestine would suffer from it”.It can be seen that there is a special relationship between the lung and the large intestine,and according to the theory that“l(fā)ung being connected with large intestine”,drugs belonging to the large intestine meridian can have a special effect on lung-related diseases [12].According to the five phases theory,the spleen and stomach are belonged to the earth while the lung belongs to metal,so the spleen and stomach are the lung’s mother,airway remodeling usually occurs when the lung disease is prolonged,and the pathogenesis of this disease is mostly the deficit of lung.According to the theory that“reinforcing mother viscera for treating a deficiency of child viscera”,using the drugs that channel tropism in the stomach or spleen could get a good curative effect.

Five pairs of commonly used drugs can be derived from the association rule analysis.The first pair is Angelicae Sinensis Radix→ Paeoniae Radix Alba.Angelicae Sinensis Radix can nourish blood and activate blood circulation,while Paeoniae Radix Alba can nourish blood and yin.Angelicae Sinensis Radix is sweet,pungent and warm while Paeoniae Radix Alba is sour,bitter and cold.Pungent can let lung qi diffuse while bitter can let lung qi descend so they are accord with lung’s physiological function,and the combination of cold and warm would let the formula in a balance between cold and hot,conform to the physiological property that“l(fā)ung is a fragile zang-fu viscera”.Ephedrae Herba→Farfarae Flos,Ephedrae Herba is light and clear in odor,which can diffuse the lung qi and alleviate asthma while Farfarae Flos can arrest cough and remove phlegm.These two medicines,one ascending and the other descending,one diffusing and the other descending,restore the diffusing and descending function of the lung.The third pair is Glycyrrhizae Radix Et Rhizoma→Poria,both of them are sweet in flavour and both can benefit the spleen.Glycyrrhizae Radix Et Rhizoma expectorant to arrest cough,and Peria can eliminate dampness and diuresis,the combination of them can nourish earth to generate metal and remove phlegm and fluid retention.

The fourth pair is Glycyrrhizae Radix Et Rhizoma→Citri Reticulatae Pericarpium，Citri Reticulatae Pericarpium is bitter and pungent,could strengthen the spleen and remove phlegm.Be combined with Glycyrrhizae Radix Et Rhizoma,the function of nourishing spleen,arresting cough,descending qi and removing phlegm will be strengthened.The fifth pair is Glycyrrhizae Radix Et Rhizoma→Armeniacae Semen Amarum.Armeniacae Semen Amarum has the function of arresting cough,relieving asthma and moistening the intestine,reflecting the principle of“treating the lung and large intestine together”,which is accord with Glycyrrhizae Radix Et Rhizoma's effect of expectorant and relieving cough.

Cluster analysis can get eight-core drug classes.Class 1:Notoginseng Radix Et Rhizoma,Fritillariae Thunbergii Bulbus,Sinapis Semen,Saposhnikoviae Radix.Fritillariae Thunbergii Bulbus can clear heat,remove phlegm and arrest cough.Sinapis Semen can warmingly resolve cold-phlegm,Saposhnikoviae Radix can dispel pathogenic wind and remove dampness,the combination of the three can resolve phlegm and dampness,then together with Notoginseng Radix Et Rhizoma,which can remove blood stasis,can eliminate pathogenic factor retention in the lungs,Wang ZQ et al.confirmed through their study that Sinapis Semen can reduce airway reactivity [13].Class 2:Dioscoreae Rhizoma,Pseudostellariae Radix,Lepidii Semen.Lepidii Semen eliminates the lung’s pathogenic factor and alleviates asthma,expel water retention and detumescence,Pseudostellariae Radix and Dioscoreae Rhizoma can tonifying the lung,spleen and kidneys.They can protect the three zang-fu viscera so that Lepidii Semen,which is bitter and cold,does not damage the middle qi.Liu Danli's study confirmed that Dioscoreae Rhizoma has the effect of enhancing human cellular and humoral immunity and anti-inflammatory [14].Class 3:Ginkgo Semen,Persicae Semen,Paeoniae Radix Rubra,Rehmanniae Radix,Psoraleae Fructus,Ginkgo Semen can astringe lung qi and alleviate asthma,Psoraleae Fructus can respire qi and alleviate asthma,warmly invigorate spleen yang and kidney yang,tonifies the son and the mother of the lung to strengthens the lung,combined with Persicae Semen,Paeoniae Radix Rubra,Rehmanniae Radix can clear heat,resolve blood stasis,arrest cough and alleviate asthma,Xu Zengmei et al.confirmed that the active ingredient paeoniflorin in Paeoniae Radix Rubra can be sedative,anti-inflammatory and analgesic [15].Class 4:Cicadae Periostracum,Uncariae Ramulus Cum Uncis,Ginseng Radix Et Rhizoma.Cicadae Periostracum can resolve wind-heat,relieve sore throat and produce sound,combined with Uncariae Ramulus Cum Uncis can clear liver-heat,remove the lung’s restraining.Ginseng Radix Et Rhizoma tonifies the spleen and benefits the lung,strengthening the earth to generate metal.Modern pharmacology suggests that Uncariae Ramulus Cum Uncis can reduce tracheal spasm and inhibit asthma caused by histamine [15],Ginseng Radix Et Rhizoma contains Ginseng Radix Et Rhizoma saponin Rh2 restrains the proliferation of smooth muscle and airway epithelial cells [16].Class 5:Bupleuri Radix,Platycodonis Radix,Zanthoxylum nitidum.Platycodonis Radix can diffuse lung qi,relieve sore throat and expel phlegm.Zanthoxylum Nitidum can induce diuresis for removing edema,descending lung qi and relieving asthma.These two medicines,one can diffuse qi and the other can descend qi,compatibility of them can relieve asthma and remove phlegm and dampness.Bupleuri Radix can disperse stagnated liver qi for relieving qi stagnation,then prevent liver qi counter-restrict lung qi.Zhang Junya et al.confirmed through their study that Bupleuri Radix can relieve bronchial wall spasm,inhibit its proliferation and has the effect of improving lung function [17].Class 6:Paeoniae Radix Alba,Rehmanniae Radix Praeparata,Angelicae Sinensis Radix.They can remove stasis and generate new blood,Angelicae Sinensis Radix is bitter,sweet and warm,vest in the heart and spleen meridian and can promote the production of blood,Rehmanniae Radix Praeparata is sweet and warm,vest in the heart and kidney meridian to nourish blood;Paeoniae Radix Alba is sour and cold,vest in liver and spleen to nourish yin.Paeoniae Radix Alba can resist inflammation and regulate immunity,change capillary permeability,reduce inflammatory exudation,and enhance the body's autoimmune function [18].Class 7:Farfarae Flos,Asteris Radix Et Rhizoma,Belamcandae Rhizoma,Belamcandae Rhizoma is multi-nodular,with the same shape as the lung tube,and the leaves are flattened and open horizontally,while its nature is especially specialized in dispelling dampness,making it belong to the lung meridian,and removing phlegm from two sides.Farfarae Flos come into bud in winter,ascend and dredge yang qi from the great cold,combined with Asteris Radix Et Rhizoma,which is soft and moist,can nourish the yin and yang of the lung,and the three together can benefit the yin and yang of the lung and dispel phlegm [19].Modern pharmacology holds that the total sesquiterpenes of Farfara Flos contained in Farfarae Flos can improve airway remodeling in asthma [20].Class 8:Citri Reticulatae Pericarpium,Poria.The book namedEvidence and Treatment Huizi Tonic -Phlegm Evidencesays:“The spleen is the source of phlegm production and the lung is the reservoir of phlegm”[21].Phlegm is stagnant due to stagnant qi,and when qi movement is smooth,phlegm would self-disappear,so Citri Reticulatae Pericarpium is used to regulate qi-flowing;phlegm is generated by dampness,and when dampness is removed,phlegm is eliminated,so Poria is used to eliminate dampness.Poria and Citri Reticulatae Pericarpium can eliminate dampness and strengthen the spleen,eliminating phlegm and dampness from its source.

Conclusions

In conclusion,this paper summarized the medication rules of Chinese medicine for airway remodeling by data mining method,and the main methods of Chinese medicine treatment are expelling phlegm,arresting cough,relieving asthma,eliminating blood stasis and tonifying deficiency,and the results of this study can provide formulation ideas and medication selection for subsequent studies,but the number of literature included in this study is small,and the results still have some limitations.