Progress of Radix Astragali and Radix Angelicae Sinensis in the treatment of idiopathic pulmonary fibrosis

Hui-Zhe Zhang ,Cong Wang ,Yu-Feng Zhang*

1Department of Respiratory Medicine,Yancheng Hospital Affiliated to Nanjing University of Chinese Medicine,Yancheng 224005,China.2Department of Pulmonary and Critical Care Medicine,Jiangyin Hospital Affiliated to Nanjing University of Chinese Medicine,Jiangyin 214400,China.

Abstract Idiopathic pulmonary fibrosis (IPF) is a chronic,progressive,fibrotic interstitial lung disease.Current treatment options for IPF are limited.Radix Astragali (RA) and Radix Angelicae Sinensis (RAS),according to 5:1 ratio composed of Danggui Buxue decoction(DGBXD),which have played an essential role in the treatment of IPF.This article reviewed the experimental research,clinical research,and progress of RA and RAS (DGBXD) treating IPF to provide a deeper scientific basis for the future experimental research and clinical research.

Keywords: idiopathic pulmonary fibrosis;Radix Astragali;Radix Angelicae Sinensis;Danggui Buxue decoction

Background

IPF is a chronic,progressive,fibrotic interstitial lung disease,with clinical manifestations of dyspnea,restrictive ventilation dysfunction and gas exchange dysfunction,hypoxemia,and even progressive aggravating respiratory failure[1].Usual interstitial pneumonia is the characteristic manifestation of IPF [2,3].IPF is a rare disease that mostly occurs in the elderly [4].The incidence of IPF in Europe and North America is about 2.8 to 9.3 per 100,000 people,with few epidemiological data in China,but the incidence has significantly increased in recent years [5-7].The prognosis of IPF remains poor,with a median survival time after diagnosis of around 2 to 3 years[8].

Current treatment options for IPF are limited,and the aim of the treatment is still to delay the progression of the disease,improve the quality of life and prolong the survival [9].Traditional Chinese medicine (TCM) compound prescriptions play a role in the treatment of IPF with the superiorities of multiple targets and multiple components,small side effects,and easy acceptance to patients.Many studies have shown that IPF patients can achieve certain clinical efficacy using TCM [10-13].Radix Astragali (RA;huangqi in Chinese)and Radix Angelicae Sinensis(RAS;danggui in Chinese)have played a very important role in the treatment of IPF.

Cognition of IPF in TCM

IPF is a modern medical name,without definition in TCM.According to the symptoms of cough,asthma,shortness of breath,chest tightness,chest pain and fatigue in IPF patients,similar diseases such as “pulmonary arthralgia”,“pulmonary fistula”,“cough”,“dyspnea”,“shortness of breath”,“pulmonary distension”and“collateral disease”are widely recorded in the ancient medical literatures.Among them,IPF is more commonly belonged to the category of “pulmonary arthralgia” and “pulmonary fistula”.In the early phase,due to external evil invasion,lung qi deficiency and other pulmonary obstruction，the disease develops into “pulmonary arthralgia”.Later,due to long lung obstruction and lung nourishment loss,the disease finally develops into a “pulmonary fistula” [14,15].“Pulmonary arthralgia” often focuses on qi and blood,and lung collaterals obstruction;“pulmonary fistula” generally emphasizes the qi and blood deficiency and lung collaterals deficiency.

“Pulmonary arthralgia” refers to the external evil,internal injury of diet and mood,obstruction lung of evil qi,lung qi deficiency,affecting the operation of lung qi and blood,smooth of lung meridians in TCM.Patients often show symptoms such as cold,fever,cough and sputum,chest tightness,shortness of breath,chest pain and restlessness,qi and blood stagnation of the body and lung meridians,chronic delay,and finally form “pulmonary arthralgia”.For example,“Su Wen” records that “dyspnea and deficiency,called pulmonary arthralgia,cold and hot,drunk and make the inside”,“disease in the lung,called pulmonary arthralgia,cough on qi”.According to modern medical research,the heart and lung blood vessels are rich,and qi and blood exchange is completed through breathing.During IPF,lung qi and blood exchange function is disordered,while the number of local capillaries in lung tissue is reduced,and blood stasis is formed.These pathological changes are similar to the TCM“pulmonary arthralgia”of lung qi and blood deficiency,blood stasis and qi stagnation.At this time,IPF complies with the category of “pulmonary arthralgia” [16,17].

“Pulmonary fistula”in TCM refers to the loss of lungs in caring,lung withered,lung qi deficiency,cough,shortness of breath,long-term cough,and vomiting white foam sputum as the main clinical characteristics,with modern medicine chronic bronchitis,chronic obstructive pulmonary disease,chronic cor pulmonale,and other chronic lung deficiency diseases.In Zhang Zhongjing’s,it is recorded that“fistula is also wilt,such as the wilt and failure of plants and trees”.In the course of IPF,cough and vomit white foam sputum,dyspnea and chest tightness recurrent attack,and the disease position is from lung and spleen kidney,lung spleen kidney deficiency.According to its clinical syndrome and pulmonary pathological changes,IPF is in line with the category of “pulmonary fistula”[18-20].

Cognition of RA and RAS treating IPF

RA and RAS according to 5:1 ratio composed of DGBXD.DGBXD was first recorded in(),created by Li Dongyuan in the Jin and Yuan Dynasties,which has a history of about 800 years.It is the ancient classic and famous prescription of TCM [21-23].DGBXD was included in the Catalogue of Ancient Classic and Famous Prescriptions (First Batch) formulated by the National Administration of TCM in 2018,which provides better opportunities for the research,inheritance,innovation,and high-quality development of DGBXD (RA and RAS) [24].DGBXD is commonly used in the clinical treatment of leukopenia,dysfunctional uterine bleeding,diabetic nephropathy,nephrotic syndrome,liver fibrosis,and other diseases and has achieved a certain curative effect[25-29].

At present,RA and RAS also have some application in the treatment of pulmonary fibrosis.Some animal experiments have shown that RA and RAS can improve the degree of pulmonary fibrosis in animal models of bleomycin-induced IPF [30-32].Based on literature,association studies show that RA and RAS are the most commonly used herbals for the treatment of pulmonary fibrosis [33,34].RA,slightly warm,belongs to spleen and lung meridian,has the function of supplementing qi and rising yang,benefiting health and consolidating exterior,benefiting yang but not hurting yin,and benefiting qi and regulating qi.RAS,warm,sweet and pungent,belongs to liver,heart and spleen,has the function of promoting blood circulation without hurting blood,replenishing qi and generating blood,removing blood stasis and passing collaterals,and relieving dyspnea.Comprehensive view of the whole prescription,the compatibility of RA and RAS complement each other,which can improve the IPF lung spleen kidney deficiency,and strengthen the blood stasis to remove blood stasis.Thus,RA and RAS in the treatment of IPF is accord with the important rule of TCM “benefiting qi and nourishing blood,promoting blood circulation and removing meridian obstruction” [35].

Experimental research of RA and RAS treating IPF

Peng YF established a bleomycin-induced rat IPF model to investigate the pharmacodynamic mechanism of RA and RAS on IPF [35].It indicated that intervention to transforming growth factor-β1(TGF-β1)/Smad signaling pathway by inhibiting microRNA-21(miR-21) and improving the expression of miR-326 and miR-29b could reduce the extracellular matrix (ECM) deposit and improve pulmonary fibrosis in rats.Zhao HZ first proved the correlation of pulmonary fibrosis and “pulmonary fistula” to explore the treatment mechanism of lung fibrosis through literature research [30].Experiment research showed that RA and RAS extract might promote macrophages to M1 macrophages differentiation and inhibit macrophages to M2 macrophages differentiation,reducing the degree of pulmonary fibrosis.Geng QX et al.replicated mouse pulmonary fibrosis model by endotracheal injection of bleomycin and showed that RA aqueous extract and RAS alcohol extract could reduce the content of hydroxyproline in the lung and inhibit the expression level of TGF-β and vascular endothelial growth factor (VEGF) to improve the degree of lung fibrosis in mice [36,37].Li LJ et al.intervened in an IPF mouse model and verified that high dose of RA and RAS with 5:1 ratio could inhibit the expression level of VEGF mRNA,promote the expression level of the c-kit proto-oncogene and fibroblast growth factor 2 (FGF2) mRNA,inhibit the expression level of key genes for T helper cell 17 (Th17) differentiation,such as TGF-β,interleukin 6(IL-6),and RORγt mRNA,promote regulatory T cell (Treg)differentiation gene forkhead box P3 (Foxp3) mRNA expression and improve the quality of survival of the mice[31,32,38,39].Bao HY et al.used bleomycin airway injection method to replicate the experimental rat pulmonary fibrosis model [40].By the dynamic evaluation of morphometric method and hydroxyproline content in lung tissue,it was pointed out that both RA and RAS alcohol extract and aqueous extract could slow down the process of pulmonary interstitial fibrosis in rats and have some therapeutic effects on pulmonary interstitial fibrosis.Liu Y et al.replicated the rat lung interstitial fibrosis model using endotracheal intubation with pingyangmycin,and pointed out that total glycosides of DGBXD could regulate the free radical levels in lung fibrosis,reduce oxidative damage to lung tissue structure,reduce serum TGF-β1 level,reduce the expression of TGF-β1 mRNA,and prevent lung fibrosis in rats[41,42].Gao J et al.constructed experimental pulmonary fibrosis rat model [43] .Through experiment,it was concluded that DGBXD total glycosides could inhibite bleomycin-induced pulmonary fibrosis,and its mechanism of action was related to the ability of DGBXD total glycosides to inhibit ECM synthesis and balance matrix metalloprotein(MMP)/tissue inhibitor of metalloproteinases 1 (TIMP-1) system.Gao Jian constructed a model of bleomycin-induced rat pulmonary fibrosis,and found that DGBXD total glycosides could reduce alveolar inflammatory edema,maintain alveolar structure,inhibit fibrosis formation and significantly reduce the generation of ECM in pulmonary fibrosis rats [44].It was related to reduce the elevated TGF-β1 levels in serum and promote collagen type I (COL I)degradation.The regulation of ECM remodeling realized by regulating the expression of MMP1 and MMP9/TIMP1.DGBXD total glycosides could downregulate Smad3 and P-Smad3 expression through the TGF-β1,reduce the COL I expression,and reduce the ECM deposition to play an antifibrotic effect.Lu CX et al.observed the rat model of bleomycin replicating IPF,showed that DGBXD could regulate the angiogenic status of IPF rats by downregulating hypoxia-inducible factor-1 (HIF-1) expression and upregulating endostatin expression,and delay the course of IPF disease [45].Liu Na et al.observed bleomycin induced pulmonary fibrosis model rats,found that DGBXD could improve the antioxidant capacity by regulating protein kinase D1 (PKD1)/nuclear factor-kB (NF-kB)/manganese superoxide dismutase (MnSOD) mitochondrial nuclear antioxidant pathway,and then alleviate lung fibrosis [46].Wang JP et al.induced pulmonary fibrosis rat model by bleomycin endotracheal injection [47].Experimental observation was that DGBXD could improve qi deficiency and blood stasis status in pulmonary fibrosis rats by regulating blood rheological indicators.Wang J et al.constructed a bleomycin-induced rat pulmonary fibrosis model,and observed that DGBXD improved pulmonary fibrosis by inhibiting Toll-like receptor 4(TLR4)/NOD-like receptor protein 3 (NLRP3) signaling [48].Wang J et al.showed that DGBXD could improve lung fibrosis,and the mechanism of action might involve the inhibition of lung inflammation,inhibiting lung inflammation and collagen deposition by inhibiting TGF-β1/Smad3/plasminogen activator inhibitor-1(PAI-1) signaling pathway [49].Zhao P et al.observed the rat model of bleomycin-induced pulmonary fibrosis and showed that DGBXD total glycosides alleviated pulmonary fibrosis by regulating oxidative stress by inhibiting NADPH oxidase 4 (NOX4) [50].Li SC et al.pointed out that the treatment of DGBXD total glycosides combined with hirudo in the rat model of bleomycin-induced pulmonary fibrosis could improve pulmonary fibrosis by reducing the expression level of TGF-β1,PAI-1 and hydroxyproline content in lung tissue[51].

Clinical research of RA and RAS treating IPF

Peng YF collected IPF patients with pulmonary qi deficiency and internal stasis [35].IPF patients were randomly divided into control group and observation group.The control group was treated with conventional treatment and the observation group was treated with RA and RAS combined with conventional treatment.The total effective rate of the observation group was 84%,which was significantly higher than that of the control group.The improvement of TCM syndrome points and quality of life points in the observation group was significantly better than that in the control group.Six-minute walk test in the observation group was significantly better than that in the control group.Improvement of diffusion capacity of the lung for carbon monoxide was better than that of the control group.Tumor necrosis factor-α and TGF-β1 in the observation group decreased better than that in the control group.It is suggested that the addition of RA and RAS can treat IPF well,effectively improve clinical symptoms,improve exercise tolerance and quality of life,and reduce the level of inflammatory factors in patients.The curative effect is better than that of the control group,and has a positive effect on delaying the progression of the disease.There are few clinical studies on only RA and RAS treating IPF or DGBXD treating IPF.However,many clinical studies of Chinese herbal prescriptions,including RA and RAS for IPF patients have also achieved good results.Sun XS carried out a clinical observation study on Qihong decoction in the treatment of pulmonary interstitial fibrosis,which was divided into TCM group and hormone control group [52].The TCM group applied Qihong decoction,including 30 g of RA,15 g of RAS,10 g of Flos Carthami (honghua),15 g of Radix Curcumae (yujin),15 g of Flos Inulae (xuanfuhua),15 g of Semen Coicis (yiyiren),and 6 g of Radix Platycodi(jiegeng).It was found that the TCM group was significantly better than the control group in improving symptoms,improving pulmonary function,and arterial oxygen partial pressure.The number of pulmonary reinfections in the TCM group during the treatment was significantly lower than that in the control group.Wei GS et al.observed the clinical efficacy of promoting blood circulation,removing phlegm and opening the inhibited lung-energy of TCM prescription,including RA 30 g,RAS,Semen Lepidii(tinglizi),Fructus Aurantii (zhike) 12 g each,Flos Lonicerae (jinyinhua),Radix Salviae Miltiorrhizae (danshen),Poria (fuling),Semen Coicis (yiyiren) 15 g each,Semen Persicae(taoren),Flos Inulae(xuanfuhua),Flos Carthami(honghua) 10 g each for IPF [53].It was found that significant improvements in clinical symptoms,arterial oxygen partial pressure and pulmonary function.Sun ZT et al.performed a clinical research[54].Comparing with single western medicine control group,TCM prescription of tonifying qi,activating blood and dispersing accumulation,which included RA 20 g,RAS 15 g,Rhizoma Curcumae(ezhu) 10 g,Radix Salviae Miltiorrhizae (danshen) 20 g,Bulbus Fritillariae Cirrhosae (chuanbeimu) 10 g,Radix Scutellariae(huangqin) 10 g,Radix Curcumae (yujin) 10 g could significantly relieve clinical symptoms,improve lung function,reduce adverse drug reactions,improve the quality of life.Nowadays,there are many such clinical research reported.Obviously,the effect of other herbs will have a certain impact on the results,but RA and RAS as main components of benefiting qi and activating blood circulation are still of great significance,such clinical research is still worth further mining analysis,in order to find reliable evidence-based modern scientific basis.Recently,Zhang YF et al.have performed a meta-analysis and revealed that RA and RAS were effective and safe in the treatment of IPF,which was beneficial to pulmonary function and exercise tolerance of these patients [55].

Other progress of RA and RAS treating IPF

The existing basic research and clinical research provide a basis for the further research and development of the treatment of IPF,but there are still short comings.The components of TCM are diverse and complex.Currently,the basic research on RA and RAS mostly explains the action mechanism of a certain target gene and a certain pathway,and lacks the overall view and syndrome differentiation of TCM for the research on multi-component,multi-target and multi-pathway.Zhang YF et al.used the systems bioinformatic tactic of microarray dataset analysis and network pharmacology,found the characteristics of RA and RAS treating IPF were multi-component,multi-target and multi-pathway,revealed the relationships among the active compounds of RA and RAS and their target genes,proteins,and pathways in IPF,created gene-pathway network,achieved preliminary molecular docking,which could prove beneficial in future studies on their mechanisms of action for the treatment of IPF[56,57].Zhao C et al.used network pharmacology to explore the mechanism of DGBXD in the treatment of IPF,explained the role of DGBXD in the treatment of multi-component,multi-target and multi-channel pulmonary fibrosis,and carried out experimental verification of the active ingredients,which provided a research basis for further exploring the pharmacological mechanism of DGBXD[58].Zhang H et al.revealed a potential mechanism of involvement of microRNA (miRNA) and messenger RNA (mRNA) modulatory axes in the pathogenic mechanisms of IPF,which developed a putative IPF-related miRNA-mRNA regulatory network through which DGBXD ameliorated IPF [59].

The composition of RA and RAS is complex,and the modern scientific connotation of the action mechanism of RA and RAS on the treatment of IPF needs to be further deepened,making it a more modern scientific connotation in line with the internationalization of TCM research.It is urgent to carry out a comprehensive and systematic evaluation of the clinical efficacy of RA and RAS in the treatment of IPF,find preliminary evidence-based medical evidence,make the clinical application of RA and RAS in the treatment of IPF more modern scientific connotation,and provide a basis for further scientific research.

Conclusion

Therefore,we have reviewed the experimental research,clinical research and progress of RA and RAS (DGBXD) treating IPF.It is necessary to systematically study the modern scientific connotation of RA and RAS in the treatment of IPF from multiple angles.Exploring the modern scientific connotation of the curative effect and action mechanism of RA and RAS treating IPF from the overall perspective and making the basic mechanism research from surface to point more scientific connotation,will provide a deeper scientific basis for the future experimental research and clinical research.