| Pulmonary fibrosis is caused by a variety of causes,of which the mechanism of lung disease pathogenesis remains unknown.The main pathological changes are diffuse alveolar inflammation in the early period and the occurrence of fibroblast proliferation,transformation,extracellular matrix,and the excessive accumulation of collagen,which results in pulmonary fibrosis.The clinical symptoms of pulmonary fibrosis are dyspnea,dry cough,and shortness of breath.The disease can be incurred by a variety of lung disease.Due to the serious environmental pollution and the high rate of frequent lung infection,the number of PF patients increases rapidly year by year.The disease prognosis is poor,which is listed among refractory diseases by WHO.Modern medicine has not provided effective drugs treating PF,and as regards the treatment of pulmonary fibrosis,traditional Chinese medicine has accumulated abundant prescription and experience for the treatment of PF in the past years.Clinical treatment of PF has displayed its own advantage,but needs the support from further theoretical research,clinical literature data mining of evidence-based medicine and experimental research data."Yangfei Huoxue Prescription" is effective in the clinical treatment of pulmonary fibrosis.And in recent years a number of experimental researches have elaborated on its functional mechanism.On the basis of the review and analysis of ancient and contemporary medical literature on Chinese and western medicine as well as perceiving the specific characteristics of the disease etiology and pathogenesis of TCM,the program has carried on the data mining regarding traditional Chinese medicine in recent 10 years’ medical literature dealing with the clinical treatment of pulmonary fibrosis,explored the basic rule in the clinical treatment of therapeutic method and compatibility of medicines.In addition,relying on the national natural fund project,applying the method of animal and cell experiment,further observation has been made in "Yangfei Huoxue Prescription".Animal model of pulmonary fibrosis and lung fibroblasts in vitro effect of activation(MRC-5),the molecular level of prevention and treatment of pulmonary fibrosis mechanism are discussed and the research result will possess important theoretical guiding significance and clinical practical value.Research Purpose1 Reviewing ancient and modern Chinese medical literature for more in-depth systemic analysis on Pulmonary fibrosis;Clearing the name of disease,and the main etiology and pathogenesis and treatment.2 Exploring Traditional Chinese medicine in recent 10 years literatures in the clinical treatment of pulmonary fibrosis in data mining,analysis;studying its clinical effective treatment,basic rule and characteristics of the principle,clinical recognition and treatment of traditional Chinese medicine for PF clues to provide effective and objective reference for evidence-based medicine.3 Based on vivo animal experiment and in vitro cell experimentfrom somatic cells,surrounding the TLR4/NF-κB signaling pathways,from collagen COL Ⅰ,COL Ⅲ and alpha-SMA expression,inflammation factors,further to explore the clinical prescriptions of "Yangfei Huoxue Prescriptionl" intervention mechanism of action of pulmonary fibrosis.Research Methods1 Theoretical research.On the basis of the review of pulmonary fibrosis relevant ancient and modern medicine literature concerning the name of disease,etiology and pathogenesis,treatment methods in-depth and systematic discussion,from the perspective of modern medicine and analysis the pathogenesis of pulmonary fibrosis.2 Data mining.According to the Chinese medical association respiratory neurology promulgated in 2003 pulmonary fibrosis diagnosis standard,collecting research results from January 2005 to December 2014 of the full-text database(CNKI),Chinese biomedical literature database(CBM)and Chinese medical literature retrieval system database of traditional Chinese medicine(TCM)to treat lung fiber related literature.Conforming to the inclusion criteria of literature and involved in the prescription,using SPSS statistical software for frequency analysis,clustering analysis and association analysis,explore on pulmonary fibrosis therapeutic method and traditional Chinese medicine clinical medicine basic rule and principles of prescription.3.Experimental study3.1 Vivo animal experiment."Yangfei Huoxue Prescription" affecting toxin(BLM)result in PF rats model.Setting blank,model and positive,three control group and "Yangfei Huoxue Prescription" of the low,medium and high three doses,invigorating the circulation of blood group and nourish lung group.Taking western blot protein immunoblot method to detect pulmonary fibrosis rats COL Ⅰ,COL Ⅲ and alpha SMA protein expression,ELISA method to detect pulmonary fibrosis in rats the content of serum IL-13,TGF-beta 1 and IFN-gamma,Western blot protein immunoblot method to detect the activation of TLR4 and nf-kappa B protein expression and TLR4/NF-kappa B signaling pathway,etc.3.2 Cell experiment.Observing the effect of "Yangfei Huoxue Prescription" in TGF beta 1 result in the MRC-5 cells induced by fibrosis model.Like the above set each experimental group,selecting the DAPT as positive medicine contrast group.Taking western blot protein immunoblot method to detect "Yangfei Huoxue Prescription" influence on TGF beta 1-induced MRC-5 cell proliferation,alpha-SMA protein expression and the influence of TLR4/NF-KB signaling pathways.Findings1 Theoretical research results.The pulmonary fibrosis clinical features in chronic cough,sputum,chest tightness,wheezing suppression,such as no pulmonary fibrosis disease in ancient medicine literature,pulmonary fibrosis disease belonging to the traditional Chinese medicine"consumptive lung disease" or "Bi syndrome of lung" category,with the early period"consumptive lung disease",the medium-term "consumptive lung disease" and "Bi syndrome of lung",and the late stage "consumptive lung disease".Lung deficiency caused by such factors as warm disease evil,the deficiency of the lung and stagnation in collateral forming the main pathogenesis of pulmonary fibrosis.Clinically,the commonly used treatment of traditional Chinese medicine is promoting blood circulation to improve blood stasis,nourishing lung,nourishing Yin fluid method,composite therapy,etc.Relevant literature of modern medicine analyzed the main pathogenesis of the disease and claimed lung tissue damage,hyperplasia of fibroblasts and its phenotype transformation into muscle fibroblasts,inflammatory reaction and ECM accumulation led to the occurrence of pulmonary fibrosis.And through transforming growth factor-beta(TGF-beta)cytokines and so on all kinds of cytokines,the TLR4/NF-kappa B signaling pathway and so on all kinds of signaling pathways,in forming a certain network pathways involved in the occurrence and development of PF.2 Data mining research results.2.1 The types of commonly used traditional Chinese medicine.pulmonary fibrosis treatment using high frequency of traditional Chinese medicine for supplementing qi and promoting blood circulation of Chinese traditional medicine.the highest frequency of astragalus traditional Chinese medicine used in supplementing qi(59times),followed by promoting blood circulation to improve blood stasis by salvia miltiorrhiza(42 times).Supplementing qi medicine astragalus,licorice,codonopsis pilosula,used total of 117 times,the medicine for promoting blood circulation salvia miltiorrhiza,angelica sinensis,rhizoma ligustici wallichii,used 107 times.2.2 The basic rule of pharmacy.The prescriptions of TCM clinical treatment of PF is mainly composed of tonic medicine(30.68%),phlegm cough antiasthmatic(20.26%),promoting blood circulation to improve blood stasis medicine(13.47%),antifebrile agents(12.98%),the damp clearing drug(3.83%),flat extinguish wind liver medicine(3.74%),and qi-regulating drug(3.64%),diaphoresis relieving superficies medicine(3.44%),inducing astringency medicine(3.15%),constituting nine kinds medicine.From the basic rule of pharmacy,tonic medicine,phlegm cough antiasthmatic,promoting blood circulation to improve blood stasis medicine and antifebrile medicine are given priority to use,cumulative frequency of 77.38%.2.3 Pathogenesis treatment and therapy.Pulmonary fibrosis features almost in qi deficiency and blood stasis pathogenesis,frequency is 28times(40.58%);Followed by the deficiency of qi and Yin,phlegm and blood stasis(22times),accounting for 31.88%.The disease pathogenesis is the deficiency of qi Yin,sputum and stasis,nourishing lung(supplementing qi and nourishing yin)and promoting blood circulation method as the main therapeutic principle,combined with reduce phlegm relieve a cough.2.4 Formula compatibility of the prescription2.4.1 Formula compatibility are mostly the centralizer invigorate the circulation of medicineMedicine analyzing association rules often found in compatibility of yiqi medicine astragalus membranaceus and angelica sinensis,rhizoma ligustici wallichii,peach kernel,notoginseng,safflower,salvia miltiorrhiza,,etc,like such as these invigorate the circulation of blood medicine.or and invigorate the circulation of blood medicine such as rhizoma zedoariae,leech,embodies the treatment ideas of promoting blood circulation and dredging of collateral.Second,Medicine analyzing association rules also often found in compatibility of yiqi medicine astragalus membranaceus and atractylodes,radix adenophorae that can tonifying spleen and aggrandizing vitality,nourishing lung and stomach medicine,embodies the therapy of tonifying qi and Yin point of view.Medicine group of association rules analysis found in medicine group,yiqi medicine astragalus in salvia miltiorrhiza,rhizoma ligustici wallichii,etc,like such as these invigorate the circulation of blood medicine.at the same time,often compatibility dangshen,Chinese angelica,aggrandizing vitality and blood medicine.That formula compatibility of prescription for the treatment of PF is mostly chosed the centralizer invigorate the circulation of medicine.2.4.2 Give priority to the medicine of tonic and clear heat,invigorate the circulation of blood.In PF efficacy of medicine,high frequency used for the tonic effect medicine(13times),frequency is 16%,among them the most used tonic effect medicine including astragalus root,angelica,atractylodes,radix adenophorae,ginseng,dangshen,etc.,according to the traditional Chinese medicine for the treatment of PF is given priority to the tonic medicine.Secondly frequency be used is clear heat medicine(12times)and the medicine can invigorate the circulation of blood(frequency 10),frequency is over 12,such as clear heat effect of radix rehmanniae,radix glycyrrhizae,invigorate the circulation of efficacy of notoginseng,salvia miltiorrhiza,rhizoma ligustici wallichii,etc.Prompt treatment of PF is given priority to the medicine have tonic and clear heat,invigorate the circulation.2.4.3 Four Qi to compatibility rules often is the lukewarm medicine and Cold property of medicine,tepid medicine.Judging from drug use analysis of four QI,mostly using the lukewarm medicine(12 times),take medicine frequency of about 52%;Cold property of drug(6 times)"Pingxin" medicine(5 times),frequency is 22%.As well as have the warm of radix astragali,rhizoma ligustici wallichii,pinellia,dried orange peel,and the cold of salvia miltiorrhiza,dilong,radix scutellariae,white mulberry root-bark.the prescription fundamental is tonifying qi,promoting blood and qi,combine cold property of drugs and tepid medicine to clearing heat,nourishing Yin,eliminating phlegm,can to treat the main pathogenesis of the disease.2.4.4 Five flavours of herbs to compatibility rules often is the sweetish taste herbs and the bitter herb,acrid herbs.About the five flavours of herbs,sweetish taste medicine and herbs is the highest frequency(14times),frequency is 41%;The second is the bitter herbs and acrid herbs,sour,salty,flat tast herbs frequency is low.sweetish taste herbs,more moist.at the same time of Yiqi method,compatibility with bitter herb,piquancy herbs,so fierce is not easy to hurt Yin,such as radix scutellariae,white mulberry root-bark,pinellia,dried orange peel,Platycodon grandiflorum etc.Sweet herb adjuvant bitter or acrid herbs is conducive to treat lung.2.4.5 On the meridians,lung meridians medicine as the main,and adjuvant with the meridians of liver,spleen and kidney medicine.Treating PF lung and liver meridian of traditional Chinese medicine drug used most frequently(11 frequency),frequent rate is 18%.To treat lung the first choice is lung meridians medicine,lung medicine has Astragalus membranaceus,nansha ginseng,ginseng,lily,radix stemonae,almonds and other lung pulmonary medicine,also have fritillaria,radix scutellariae,white mulberry root-bark,licorice those of clearing lung and so on.Secondly,the liver meridian medicine have angelica sinensis,rhizoma ligustici wallichii,salvia miltiorrhiza,radix paeoniae alba,peach kernel,notoginseng,safflower,rhizoma zedoariae,leech and so on,purpose is to regulate qi and blood,dredging collaterals,and dispersing blood stasis.This is the core to treat liver.In addition,the spleen and the kidney meridian medicine have poria cocos,atractylodes,lily,radix rehmanniae and so on,symptoms usually is lung spleen qi deficiency or lung and kidney qi deficiency,Yin deficiency,and so on,clinical treatment often based on tonifying qi,invigorate the circulation of blood and dredging collaterals.at the same time use the medicine of tonifying kidney and spleen.3.The experimental research results3.1 Animal experimental results show that "Yangfei Huoxue Prescription" induced pulmonary fibrosis in rats model of intervention effects.28weeks after treatment,the lung tissue collagen COL I,COLIII and alpha-SMA show significantly decrease in the model group,among these treatment group which used the high dose of Nourishing Lung and activating blood,the effect is most obvious,and significant difference was found with model group(P<0.05),suggesting "Yangfei Huoxue Prescription" could inhibit the pulmonary fibrosis in rats of ECM deposition,reduce the formation of muscle fibroblasts.Furthermore,it could regulate inflammation factors,improve the inflammatory response in the rat model of pulmonary fibrosis.Embodied in promoting secretion of IFN-gamma,inhibit to generate IL-13 and TGF-betal,"Yangfei Huoxue Prescription" could balance Thl/Th2,inhibit the formation of pulmonary fibrosis.Its mechanism may be involved in regulating lung fiber rats TLR4/nf-kappa B signaling pathway and its activation,by reducing the expression of TLR4 and NF-kappa B protein,inhibiting the activation of signaling pathways of TLR4/NF-kappa B,thus reduce the release of inflammatory transmitters secretion,achieve the purpose of reduce pulmonary fibrosis.3.2 The experimental results show that the cell growth factor(TGF-beta 1)promote cell rights colonization,the number of OD was obviously increase in promoting model group,the number of OD were significantly decrease in "Yangfei Huoxue Prescription" group(P<0.01),used the high,middle dose of Nourishing Lung and activating blood groups could inhibit the cell proliferation,its rate as high as above 50%,explained that the "Yangfei Huoxue Prescription"has inhibitory effect on cell proliferation MRC-5."Yangfei Huoxue Prescription" could significantly reduce the expression of TLR4 and NF-kappa B protein,inhibiting to activate TLR4/NF-κB signaling pathways,and enable to reduce the alpha SMA protein expression,used the high,middle dose of Nourishing Lung and activating blood group have obvious effects(P<0.05),indicating that the prescription could inhibit cell proliferation,inhibit fibroblasts into muscle fibroblasts,thereby affect the occurrence of PF.preliminary illustrates "Yangfei Huoxue Prescription"s intervention mechanism which effect fiber cells on the process of PF development.ConclusionFrom pulmonary fibrosis traditional Chinese medicine in recent 10 years clinical application of the literature analysis,the pathogenesis has the closest relationship with qi deficiency,blood stasis and phlegm.The treatment include tonifying Qi,nourishing Yin,tonifying lung,reduce phlegm,activating blood,dredging collaterals and clearing heat as the main treatment.prescription should choice the herb with function of tonifying Qi and activating blood,tonic and clearing heat medicine.are always be used.Cold and warm character herb used at the same time,sweet herbs used with piquancy and bitter herbs,important of treatment is in the lung meridian,but also should be consider liver,spleen and kidney meridian."Yangfei Huoxue Prescription" could alleviate pulmonary lesion of pulmonary fibrosis in the rat model caused by Bleomycin,could inhibit inflammation,collagen synthesis,regulating activation of the TLR4/NF-kappa B signaling pathway.Also can restrain the proliferation of MRC-5 in vitro,can significantly reduce the expression of TLR4 and NF-kappa B protein,and can reduce protein expression of alpha-SMA.Thus suggests that "Yangfei Huoxue Prescription"could inhibit PF,the mechanism may be related to the intervention of the TLR4/NF-kappa B signaling pathway,inhibit fibroblast proliferation,reduce inflammation and restrain to form collagen secretion,etc. |
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