Traditional Chinese medicine composition based on different pathological stages of idiopathic pulmonary fibrosis and preparation method and application thereof

Abstract

The application belongs to the technical field of traditional Chinese medicine, and relates to a traditional Chinese medicine composition based on different pathological stages of idiopathic pulmonary fibrosis (IPF) and a preparation method and application thereof. The traditional Chinese medicine composition comprises a tonifying and defibering composition and a collateral-dredging and defibering composition. The tonifying and defibering composition comprises Astragalus, Lily, Codonopsis, Chinese yam, Ophiopogon, Wolfberry, Salvia miltiorrhiza, Zhejiang fritillary, Whitehead, Apricot kernel and Licorice. The collateral-dredging and defibering composition comprises Zhejiang fritillary, Salvia miltiorrhiza, Whitehead, Poria cocos, Safflower, Angelica, Astragalus, Chinese yam, Lily, Apricot kernel and Licorice. The application formulates corresponding traditional Chinese medicine compositions according to the characteristics of IPF pathological stages and emphasizes on treatment methods, restores M1 / M2 polarization balance through regulation of the IFN-gamma / IL-4-JAKs / STATs pathway, realizes precise intervention at different stages and improves the treatment effect.

Description

Technical Field

[0001] This invention belongs to the field of traditional Chinese medicine technology, specifically relating to traditional Chinese medicine compositions based on different pathological stages of idiopathic pulmonary fibrosis, their preparation methods, and applications. Background Technology

[0002] Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive fibrotic interstitial lung disease, clinically characterized by progressive dyspnea and significantly reduced lung compliance. The histological, pathological, and chest HRCT features of IPF are similar to those of common interstitial pneumonia, ultimately leading to gradual fibrosis of the pulmonary interstitium and progressive respiratory failure. Epidemiological studies show that the incidence of IPF is increasing annually, with 2-30 new cases per 100,000 people per year, and is more prevalent in people over 65 years of age. The median survival from diagnosis to death for IPF is 3-5 years, with a poor prognosis. Currently, guidelines only recommend pirfenidone and nintedanib for the treatment of this disease, but their clinical use in China is limited due to numerous adverse reactions and high cost. Lung transplantation is the main treatment for end-stage IPF, but the survival rate remains low, and chronic immune rejection is a concern.

[0003] IPF is characterized by diffuse alveolitis, massive proliferation and activation of pulmonary fibroblasts and myofibroblasts, and extensive deposition of extracellular matrix (ECM). While its pathological progression is continuous, it is generally characterized by alveolitis in the early stages and fibrosis in the middle and late stages. Alveolar macrophages are inherent immune cells in lung tissue; those distributed in the airways are called alveolar macrophages (AM). AM can be divided into two types based on phenotype and function: classically activated macrophages (M1) and alternatively activated macrophages (M2). During the alveolitis phase, AM shifts towards the M1 subtype; in the middle and late stages, i.e., the fibrosis repair phase, it shifts towards the M2 subtype, making them the core cells regulating pulmonary fibrosis. Under abnormal polarization, M1 may synergistically induce an inflammatory cascade response with other immune cells; during the damage repair process, M2 may contribute to the development and progression of pulmonary fibrosis. The interferon-γ (IFN-γ) / interleukin-4 (IL-4)-Janus kinases / signal transducer and activator of transcription (JAKs / STATs) pathway is a key pathway for regulating M1 / M2 polarization, and targeting this pathway is expected to achieve precise staged regulation.

[0004] Currently, several traditional Chinese medicine (TCM) formulas for treating IPF are undergoing basic and clinical research. However, their fixed drug composition and dosage cannot fully adapt to the different TCM pathogenesis of IPF at different basic pathological stages. For example, patent CN116350732B discloses a TCM formula (Shenlong Decoction) for treating IPF, but it uses a fixed prescription for intervention throughout the entire course of the disease and does not dynamically adjust the formula according to the different pathological characteristics of early and late stages of IPF. Therefore, there is an urgent need for TCM compositions based on the pathological stages of IPF. Summary of the Invention

[0005] In view of the aforementioned technical problems, this invention proposes a traditional Chinese medicine composition based on different pathological stages of idiopathic pulmonary fibrosis (IPF), its preparation method, and its application. This invention formulates corresponding traditional Chinese medicine compositions according to the characteristics of IPF pathological stages and emphasizes specific treatment methods. By regulating the IFN-γ / IL-4-JAKs / STATs pathway to restore the M1 / M2 polarization balance, it achieves precise intervention based on stage and improves treatment efficacy.

[0006] To achieve the above objectives, the present invention adopts the following technical solution.

[0007] Traditional Chinese medicine compositions based on different pathological stages of idiopathic pulmonary fibrosis include: Fuzheng Huaxian Formula and Tongluo Huaxian Formula. The Fuzheng Huaxian Formula composition is used in the early stage of idiopathic pulmonary fibrosis and is made from the following raw materials in parts by weight: Astragalus membranaceus 15-20 parts, Lilium brownii 15-20 parts, Codonopsis pilosula 10-15 parts, Dioscorea opposita 15-20 parts, Ophiopogon japonicus 10-15 parts, Lycium barbarum 10-15 parts, Salvia miltiorrhiza 5-10 parts, Fritillaria thunbergii 5-10 parts, Cynanchum paniculatum 5-10 parts, Prunus armeniaca 5-10 parts, and Glycyrrhiza uralensis 10-15 parts. The Tongluo Huaxian Formula composition is used for the middle and late stages of idiopathic pulmonary fibrosis. It is made from the following raw materials in parts by weight: Fritillaria thunbergii 10-15 parts, Salvia miltiorrhiza 10-15 parts, Cynanchum paniculatum 10-15 parts, Poria cocos 10-15 parts, Carthamus tinctorius 5-10 parts, Angelica sinensis 10-15 parts, Astragalus membranaceus 10-15 parts, Dioscorea opposita 10-15 parts, Lilium brownii 10-15 parts, Prunus armeniaca 5-10 parts, and Glycyrrhiza uralensis 10-15 parts.

[0008] Furthermore, the TCM syndrome corresponding to the early stage of idiopathic pulmonary fibrosis is Qi and Yin deficiency combined with phlegm and blood stasis obstructing the collaterals; the TCM syndrome corresponding to the middle and late stages of idiopathic pulmonary fibrosis is phlegm and blood stasis obstructing the collaterals combined with Qi and Yin deficiency.

[0009] The preparation method of traditional Chinese medicine compositions based on different pathologies of idiopathic pulmonary fibrosis includes the following steps: Weigh out eleven Chinese medicinal herbs according to the specified ratio, mix them, add water and decoct them multiple times. Filter and combine the decoctions, concentrate them, add soluble starch, make them into granules, and dry them to obtain the final product.

[0010] Furthermore, the decoction is performed three times, with each addition of water equal to eight times the total mass of the medicinal herbs, and each decoction lasting one hour.

[0011] The above-mentioned traditional Chinese medicine composition is prepared in the form of decoction, granules, oral liquid, pills or capsules.

[0012] Furthermore, in the early stage of idiopathic pulmonary fibrosis, the Fuzheng Huaxian formula composition is used; in the middle and late stages of idiopathic pulmonary fibrosis, the Tongluo Huaxian formula composition is used.

[0013] Furthermore, the early stage is the alveolitis stage, and the middle and late stages are the pulmonary fibrosis stage; the polarization balance of alveolar macrophages M1 / M2 is regulated by intervening in the IFN-γ / IL-4-JAKs / STATs signaling pathway.

[0014] The pharmacological effects and efficacy of each active pharmaceutical ingredient are as follows: Astragali Radix: sweet in flavor, slightly warm in nature. It acts on the spleen and lung meridians, with the effects of invigorating qi and elevating yang, consolidating the exterior and stopping sweating, inducing diuresis to reduce edema, promoting fluid production and nourishing blood, and activating stagnation to unblock bi. Its main active ingredients include astragaloside IV, astragalus polysaccharide, etc., and it has pharmacological effects such as anti-inflammation, resisting oxidative stress, inhibiting fibroblast activation and collagen deposition, and reducing extracellular matrix deposition.

[0015] Lilii Bulbus: sweet in flavor, cold in nature. It acts on the heart and lung meridians, with the effects of nourishing yin and moistening the lung, and clearing heart fire and calming the mind. Its main active ingredient is lily polysaccharide, etc., and it has pharmacological effects such as anti-inflammation, regulating the balance of matrix metalloproteinases, reducing lung coefficient and hydroxyproline level, and alleviating collagen deposition.

[0016] Dioscoreae Rhizoma: sweet in flavor, neutral in nature. It acts on the spleen, lung and kidney meridians, with the effects of tonifying and nourishing the spleen, promoting fluid production and benefiting the lung, and tonifying the kidney and astringing essence. Its main active ingredients include dioscorea saponin, dioscorea polysaccharide, etc., and it has pharmacological effects such as anti-inflammation, resisting oxidative stress, down-regulating the expression of inflammatory factors, and alleviating inflammatory injury of lung tissue.

[0017] Salviae Miltiorrhizae Radix et Rhizoma: bitter in flavor, slightly cold in nature. It acts on the heart and liver meridians, with the effects of activating blood circulation to dissipate blood stasis, unblocking meridians and relieving pain, and clearing heart fire and eliminating restlessness. Its main active ingredients include danshensu, total salvianolic acids, tanshinone, etc., and it has pharmacological effects such as reducing lung index, alleviating alveolitis and pulmonary fibrosis injury, and exerting anti-inflammatory and anti-fibrosis effects.

[0018] Fritillariae Thunbergii Bulbus: bitter in flavor, cold in nature. It acts on the lung and heart meridians, with the effects of clearing heat, resolving phlegm and relieving cough, and detoxifying, resolving stagnation and dissipating carbuncle. Its main active ingredients are alkaloids such as peimine, and it has pharmacological effects such as anti-inflammation, relieving cough and eliminating phlegm, anti-oxidation, inhibiting abnormal proliferation and activation of fibroblasts, and reducing collagen accumulation in pulmonary interstitium.

[0019] Cynanchi Stauntonii Rhizoma et Radix: pungent and bitter in flavor, slightly warm in nature. It acts on the lung meridian, with the effects of descending qi, resolving phlegm and relieving cough. Its main active ingredients are C21 steroidal saponins, etc., and it has pharmacological effects such as inhibiting the production of inflammatory mediators, down-regulating the expression of nitric oxide synthase, and exerting anti-inflammatory effect.

[0020] Armeniacae Semen Amarum: bitter in flavor, slightly warm in nature, with slight toxicity. It acts on the lung and large intestine meridians, with the effects of descending qi, relieving cough and asthma, and moistening intestine for defecation. Its main active ingredient is amygdalin, etc., and it has pharmacological effects such as inhibiting epithelial-mesenchymal transition, reducing collagen fiber production, down-regulating inflammatory factors, regulating the balance of type 1 T helper cells / type 2 T helper cells, relieving cough and asthma, and resisting oxidative damage.

[0021] Glycyrrhizae Radix et Rhizoma: sweet in flavor, neutral in nature. It acts on the heart, lung, spleen and stomach meridians, with the effects of tonifying spleen and benefiting qi, clearing heat and removing toxicity, eliminating phlegm and relieving cough, relieving spasm and pain, and harmonizing the properties of other medicinals. Its main active ingredients include glycyrrhizic acid, glycyrrhetinic acid, etc., and it has pharmacological effects such as anti-inflammation, anti-oxidation and anti-fibrosis.

[0022] Unique herbal ingredients of Fuzheng Huaxian Prescription Codonopsis pilosula: Sweet and neutral in nature. It enters the spleen and lung meridians, and has the effects of strengthening the spleen and lungs, nourishing blood and promoting body fluid production. Its main active ingredients are Codonopsis pilosula polysaccharides, etc., which have pharmacological effects such as downregulating the release of inflammatory factors and anti-inflammatory effects.

[0023] Ophiopogon japonicus: sweet, slightly bitter, and slightly cold. It enters the heart, lung, and stomach meridians, and has the effects of nourishing yin and promoting body fluid production, moistening the lungs and clearing the heart. Its main active ingredients are ophiopogonin D, etc., which have pharmacological effects such as reducing pulmonary consolidation and collagen deposition, reducing α-smooth muscle actin expression, inhibiting inflammasome activation, downregulating inflammatory factors, inhibiting fibroblast activation, and reducing extracellular matrix accumulation.

[0024] Goji berries: sweet, neutral in nature. They enter the liver and kidney meridians, and have the effects of nourishing the liver and kidneys, benefiting essence and improving eyesight. The main active ingredients are goji polysaccharides, which have pharmacological effects such as anti-oxidative stress, anti-inflammation, downregulating type I collagen and α-smooth muscle actin expression, reducing lung coefficient and hydroxyproline content, inhibiting collagen synthesis, and alleviating pulmonary fibrosis damage.

[0025] The unique medicinal flavor of the Tongluo Huaxian formula Poria cocos: sweet, bland, and neutral in nature. It enters the heart, lung, spleen, and kidney meridians, and has the effects of promoting diuresis and eliminating dampness, strengthening the spleen, and calming the mind. Its main active ingredients include poria cocos triterpenoids and poria cocos polysaccharides, which have pharmacological effects such as anti-inflammatory, anti-oxidative stress, inhibition of inflammatory mediator release, bidirectional regulation of macrophage and T cell immune homeostasis, and reduction of inflammatory infiltration and collagen deposition.

[0026] Safflower: pungent and warm in nature. It enters the heart and liver meridians, and has the effects of promoting blood circulation, regulating menstruation, dispersing blood stasis, and relieving pain. Its main active ingredients are hydroxysafflower yellow A, etc., which have pharmacological effects such as antagonizing transforming growth factor-β-mediated cell damage and delaying the progression of pulmonary fibrosis.

[0027] Angelica sinensis: sweet, pungent, and warm. It enters the liver, heart, and spleen meridians, and has the effects of nourishing blood, promoting blood circulation, regulating menstruation, and relieving pain. Its main active ingredients are angelica polysaccharides, which have pharmacological effects such as inhibiting alveolar epithelial-mesenchymal transition, increasing antioxidant enzyme activity, reducing malondialdehyde content, alleviating oxidative stress damage, and anti-pulmonary fibrosis through multiple pathways.

[0028] The Fuzheng Huaxian formula is used in the early stage of IPF (alveolar inflammation) to mainly replenish qi and nourish yin, while also resolving phlegm, promoting blood circulation, and clearing the meridians. Astragalus and lily are the principal herbs, focusing on replenishing qi and nourishing yin to moisten the lung meridians. Codonopsis, yam, ophiopogon, and wolfberry are the assistant herbs, which strengthen the spleen and nourish the kidneys, and help the principal herbs to enhance their qi-replenishing and yin-nourishing effects. Salvia miltiorrhiza, fritillaria thunbergii, cynanchum paniculatum, and apricot kernel are the adjuvant herbs, which promote blood circulation, resolve phlegm, relieve asthma and cough, and eliminate pathogens without harming the body's vital energy. Licorice is the guiding herb, which harmonizes the effects of all the herbs.

[0029] The Tongluo Huaxian Formula is used in the middle and late stages of IPF (fibrosis stage). The formula mainly focuses on resolving phlegm, promoting blood circulation, and clearing the meridians, while also tonifying qi and nourishing yin. Fritillaria thunbergii and Salvia miltiorrhiza are the principal herbs, which focus on resolving phlegm, dispersing nodules, promoting blood circulation, and clearing the meridians. Cynanchum paniculatum, Poria cocos, Carthamus tinctorius, and Angelica sinensis are the assistant herbs, which resolve phlegm, promote blood circulation, and help the principal herbs to clear the blocked lung meridians. Astragalus membranaceus, Dioscorea opposita, Lilium brownii, and Prunus armeniaca are the adjuvant herbs, which tonify qi, nourish yin, and support the body's resistance, while preventing the blood-activating and meridian-clearing herbs from depleting qi and yin. Glycyrrhiza uralensis is the guiding herb, which harmonizes the effects of the other herbs.

[0030] Compared with the prior art, the beneficial effects of the present invention are as follows.

[0031] (1) This invention proposes a TCM treatment strategy based on different pathological stages of IPF, realizing precise syndrome differentiation and treatment by "changing the prescription according to the syndrome".

[0032] (2) Animal experimental results of the present invention show that the treatment with Fuzheng Huaxian Formula in the early stage of IPF (alveolar inflammation stage) and the treatment with Tongluo Huaxian Formula in the middle and late stage (pulmonary fibrosis stage) have better effects on improving lung function, blood gas analysis and histopathology than the Shenlong Decoction group.

[0033] (3) In vitro and in vivo experiments of the present invention have confirmed that the present invention can achieve therapeutic effects by intervening in the IFN-γ / IL-4-JAKs / STATs pathway and regulating AM polarization imbalance.

[0034] (4) In addition to the above-mentioned granules, the composition of the present invention can also be made into decoctions, oral liquids, pills and other dosage forms. Only the formulation excipients need to be adjusted, and the core medicinal material ratio and the staged administration logic remain unchanged, so that the purpose of staged treatment of IPF can be achieved.

[0035] (5) Those skilled in the art can reasonably adjust the dosage of each raw material within the weight range described in this technical solution according to the actual condition. As long as the compatibility principle of Fuzheng Huaxian Fang is mainly based on Qi-tonifying and Yin-nourishing drugs and Tongluo Huaxian Fang is mainly based on phlegm-resolving and blood-activating drugs, the staged treatment purpose of this invention can be achieved. Attached Figure Description

[0036] Figure 1 HE and Masson staining results of rat lung tissue (28 days). Detailed Implementation

[0037] The present invention will be further described in detail below with reference to embodiments. However, it should not be construed that the scope of the above-described subject matter of the present invention is limited to the following embodiments, and all technologies implemented based on the content of the present invention fall within the scope of the present invention.

[0038] Example 1.

[0039] Formula for Strengthening the Body and Reducing Fiber: Astragalus membranaceus 20g, Lilium brownii 20g, Codonopsis pilosula 15g, Dioscorea opposita 20g, Ophiopogon japonicus 15g, Lycium barbarum 15g, Salvia miltiorrhiza 10g, Fritillaria thunbergii 10g, Cynanchum paniculatum 10g, Prunus armeniaca 10g, Glycyrrhiza uralensis 10g.

[0040] Formula for clearing the meridians and dissolving fibrosis: Fritillaria thunbergii 15g, Salvia miltiorrhiza 15g, Cynanchum paniculatum 15g, Poria cocos 15g, Carthamus tinctorius 10g, Angelica sinensis 15g, Astragalus membranaceus 15g, Dioscorea opposita 15g, Lilium brownii 15g, Prunus armeniaca 10g, Glycyrrhiza uralensis 10g.

[0041] Preparation method: Weigh out eleven Chinese medicinal herbs according to the specified ratio, add water and decoct three times, each time adding water at a ratio of 8 times the total weight of the medicinal herbs. Decoction for 1 hour, filter, combine the filtrates, concentrate to a relative density of 1.15-1.25 (50℃), add an appropriate amount of soluble starch, granulate, dry, and package to obtain the final product. The preparation methods for the Fuzheng Huaxian Formula and the Tongluo Huaxian Formula are the same; prepare them before use.

[0042] Example 2.

[0043] 2.1 Animal Experiments 2.1.1 Modeling and Drug Administration One hundred and twenty male Wistar rats were randomly divided into five groups: blank control group, model group, Western medicine group, traditional Chinese medicine group, and traditional Chinese medicine staged group, with 24 rats in each group. A rat model of pulmonary fibrosis was established by intratracheal instillation of bleomycin. The traditional Chinese medicine group used the traditional Chinese medicine preparation, Shenlong Decoction, as described in the invention patent (CN116350732B).

[0044] Rats were administered gavage once daily for 28 consecutive days, starting the day after model establishment. The Western medicine group received pirfenidone (60 mg / kg / day); the traditional Chinese medicine group received Shenlong decoction (11.35 g / kg / day); the traditional Chinese medicine staged treatment group received Fuzheng Huaxian formula (16.15 g / kg / day) from days 1-7 and Tongluo Huaxian formula (15.63 g / kg / day) from days 8-28; the blank control group and the model group received the same volume of physiological saline. Three rats were randomly selected from each group on days 7, 14, 21, and 28 for testing.

[0045] The first 1-7 days after modeling are the early stage of IPF, with alveolitis mediated by M1 hyperpolarization as the main pathological change; in the middle and late stages, fibrosis mediated by M2 hyperpolarization gradually becomes the main pathological change. Therefore, the 7th day is the time point for switching drugs.

[0046] 2.1.2 Detection Indicators and Methods (1) Lung function: The forced vital capacity (FVC), peak expiratory flow (PEF), inspiratory resistance (RI) and dynamic lung compliance (Cdyn) of rats were measured using a small animal lung function testing system.

[0047] (2) Blood gas analysis: The partial pressure of oxygen in arterial blood (PaO2), partial pressure of carbon dioxide (PaCO2), and oxygen saturation (SaO2) of rats were measured using a blood gas analyzer.

[0048] (3) Lung tissue pathology: Hematoxylin and eosin staining (HE) and Masson Trichrome staining (Masson) were used to observe the pathological changes in rat lung tissue and to score alveolitis and fibrosis.

[0049] (4) Hydroxyproline (HYP) content in lung tissue: The HYP content in lung tissue was detected according to the steps of the HYP detection kit.

[0050] (5) Expression of lung tissue-related proteins: Immunofluorescence was used to detect the expression of inducible nitric oxide synthase (iNOS), hemoglobin clearance receptor (Cluster of Differentiation 163, CD163), IFN-γ and IL-4 proteins in lung tissue.

[0051] (6) Lung tissue protein gene expression: The expression of IFN-γ and IL-4 mRNA was detected by quantitative real-time polymerase chain reaction (qPCR).

[0052] 2.1.3 Statistical Analysis Statistical analysis was performed using GraphPad Prism 10.6 software. Quantitative data were presented as follows: This indicates that one-way ANOVA was used for comparisons among multiple groups. P <0.05 indicates a statistically significant difference.

[0053] 2.1.4 Main Results (1) Lung function: Compared with the blank group, the model group showed significantly reduced FVC, PEF and Cdyn, and significantly increased RI; compared with the model group, each drug administration group showed improvement at each time point; compared with the traditional Chinese medicine group, the traditional Chinese medicine staged group showed more prominent improvement in lung function (as shown in Table 1).

[0054] Table 1. Statistical results of lung function in rats of each group ( (n=3) Note: Comparison between the model group and the blank group:** P <0.01; Comparison of Western medicine group, traditional Chinese medicine group, traditional Chinese medicine staged group and model group: # P <0.05, ## P <0.01.

[0055] (2) Blood gas analysis: Compared with the blank group, PaO2 and SaO2 of rats in the model group were significantly reduced and PaCO2 was significantly increased at each detection time point. Compared with the model group at the same time point, each drug administration group could significantly regulate blood gas-related indicators and improve the damage of lung ventilation and gas exchange function in rats. Under the same intervention conditions, the improvement effect of the traditional Chinese medicine staged group on blood gas indicators was significantly better than that of the traditional Chinese medicine group, and the improvement effect was more prominent (as shown in Table 2).

[0056] Table 2 Statistical results of blood gas analysis of lung tissue ( (n=3) Note: Comparison between the Western medicine group, the traditional Chinese medicine group, the traditional Chinese medicine staged group, and the model group: # P <0.05, ## P <0.01; Comparison between the traditional Chinese medicine staged group and the traditional Chinese medicine group: & P <0.05.

[0057] (3) Pathological staining of lung tissue and HYP content: such as Figure 1 As shown, the alveolar structure of rats in the blank group was intact, with no obvious inflammatory cell infiltration or collagen deposition; the alveolar structure of the model group was severely damaged, with extensive inflammatory cell infiltration, widespread collagen fiber deposition, and significant pulmonary fibrosis; the degree of alveolar damage in the Western medicine group was reduced, inflammatory cell infiltration was decreased, and the area of ​​collagen deposition was significantly reduced; the alveolar damage in the traditional Chinese medicine group was somewhat alleviated, inflammatory cell infiltration was reduced, but collagen fiber accumulation still existed in some areas, and the repair effect was weaker than that in the Western medicine group; the traditional Chinese medicine staged group showed the most significant overall improvement in lung tissue, with mild inflammatory infiltration and the most significant decrease in the degree of collagen deposition.

[0058] Compared with the blank group, the alveolitis score, pulmonary fibrosis score, and HYP content in lung tissue of rats in the model group were significantly increased. Compared with the model group at the same time point, all drug administration groups could significantly reduce the alveolitis score, fibrosis score, and HYP content of rats, and alleviate lung inflammation and fibrosis damage. Under the same intervention conditions, the traditional Chinese medicine staged group had a significantly better downregulation effect on inflammation and fibrosis indicators than the traditional Chinese medicine group at some time points (as shown in Table 3).

[0059] Table 3. Statistical results of lung tissue pathological scores and HYP content ( (n=3) Note: Comparison between the model group and the blank group:** P <0.01; Comparison of Western medicine group, traditional Chinese medicine group, traditional Chinese medicine staged group and model group: # P <0.05, ## P <0.01; Comparison between the traditional Chinese medicine staged group and the traditional Chinese medicine group: & P <0.05, && P <0.01.

[0060] (4) Immunofluorescence staining of lung tissue proteins: Compared with the blank group, the expression of IFN-γ and iNOS in the model group reached its peak on day 7 and then gradually decreased, while the expression of IL-4 and CD163 continued to increase over time until reaching its peak on day 28. Compared with the model group, the expression levels of the above proteins in each drug administration group at each time point were significantly reduced. Compared with the traditional Chinese medicine group, the reduction was more obvious in the traditional Chinese medicine stage group (as shown in Table 4).

[0061] Table 4. Expression results of IFN-γ, iNOS, IL-4, and CD163 in rat lung tissue ( (n=3) Note: Comparison between the model group and the blank group:** P <0.01; Comparison of Western medicine group, traditional Chinese medicine group, traditional Chinese medicine staged group and model group: # P <0.05, ## P <0.01; Comparison between the traditional Chinese medicine staged group and the traditional Chinese medicine group: & P <0.05, && P <0.01.

[0062] (5) mRNA expression of cytokines in lung tissue: compared with the blank group, the mRNA expression of IFN-γ and IL-4 in lung tissue of the model group was significantly increased; compared with the model group, all administration groups showed significant reduction at all time periods; among them, the staged traditional Chinese medicine group had a better inhibitory effect than the traditional Chinese medicine group (as shown in Table 5).

[0063] Table 5 Results of IFN-γ and IL-4 mRNA expression in lung tissue ( , n=3) Note: Comparison between the model group and the blank group: ** P <0.01; comparison between the western medicine group, the traditional Chinese medicine group, and the staged traditional Chinese medicine group with the model group: # P <0.05, ## P <0.01; comparison between the staged traditional Chinese medicine group and the traditional Chinese medicine group: & P <0.05, && P <0.01.

[0064] 2.2 Cell experiment 2.2.1 Establishment of cell model and administration Rat alveolar macrophages (NR8383) were selected for the experiment; 120 male Wistar rats were randomly divided into a blank group, a traditional Chinese medicine group, a Fuzheng Huaxian Recipe group, and a Tongluo Huaxian Recipe group, with 30 rats in each group. The corresponding medicinal liquid was administered by intragastric gavage for 3 consecutive days, the full-day dose was given once on the 4th day, blood was collected from the abdominal aorta 1 hour later, after standing for 2 hours, centrifugation was performed at 3000 r / min at 4°C for 15 min, serum was separated, inactivated at 56°C for 30 min, filtered and sterilized with a 0.22 μm filter membrane to obtain drug-containing serum. The administration concentration of drug-containing serum of Shenlong Decoction, Fuzheng Huaxian Recipe and Tongluo Huaxian Recipe was 20%. NR8383 cells were treated with IFN-γ and lipopolysaccharide (LPS) to induce an M1 polarized cell model; IL-4 was added to induce an M2 polarized cell model. The blank group, M1 group and M2 group were given normal serum; the traditional Chinese medicine group was given Shenlong Decoction drug-containing serum; the staged traditional Chinese medicine group was given Fuzheng Huaxian Recipe drug-containing serum and Tongluo Huaxian Recipe drug-containing serum respectively.

[0065] 2.2.2 Detection indicators and methods (1) Polarization level of M1 and M2: flow cytometry was used to detect the expression of cell markers Cluster of Differentiation 86 (CD86) / Cluster of Differentiation 206 (CD206).

[0066] (2) Detection of cytokine expression levels: The levels of tumor necrosis factor-alpha (TNF-α) and transforming growth factor-beta1 (TGF-β1) in the cell supernatant were detected by ELISA.

[0067] (3) mRNA expression of key proteins in the polarization pathway: qPCR was used to detect the mRNA expression of interferon-γ receptor 1 (IFN-γR1), JAK1, JAK2, STAT1, interleukin-4 receptor alpha (IL-4Ra), JAK3, and STAT6.

[0068] 2.2.3 Statistical Analysis Statistical analysis was performed using GraphPad Prism 10.6 software. Quantitative data were expressed as mean ± standard deviation (mean ± SD). One-way ANOVA was used for comparisons among multiple groups, and P < 0.05 was considered statistically significant.

[0069] 2.2.4 Main Results (1) Polarization levels of M1 and M2: Compared with the blank group, the CD86 expression level of the M1 control group was significantly increased; compared with the M1 control group, the CD86 expression level of the Chinese medicine group and the Chinese medicine stage group was significantly decreased; compared with the Chinese medicine group, the downregulation effect of the Chinese medicine stage group was stronger (as shown in Table 6).

[0070] Compared with the blank control group, the CD206 expression level in the M2 control group was significantly increased; compared with the M2 control group, the CD206 expression level in the traditional Chinese medicine group and the traditional Chinese medicine stage group was significantly decreased; compared with the traditional Chinese medicine group, the traditional Chinese medicine stage group had a stronger downregulation effect (as shown in Table 6).

[0071] Table 6. Statistical results of CD86 and CD206 expression ( (n=3) Note: Comparison of M1 / M2 groups with the control group:** P <0.01; Comparison between the traditional Chinese medicine group, the traditional Chinese medicine stage group, and the M1 / M2 group: ## P <0.01; Comparison between the traditional Chinese medicine staged group and the traditional Chinese medicine group: & P <0.05, && P <0.01.

[0072] (2) Cytokine expression levels: Compared with the blank group, the TNF-α content in the cell supernatant of the M1 control group was significantly increased; compared with the M1 control group, the TNF-α content in the Chinese medicine group and the Chinese medicine stage group was significantly decreased; compared with the Chinese medicine group, the Chinese medicine stage group had a stronger downregulation effect (as shown in Table 7).

[0073] Compared with the blank control group, the TGF-β1 content in the cell supernatant of the M2 control group was significantly increased; compared with the M2 control group, the TGF-β1 content in the traditional Chinese medicine group and the traditional Chinese medicine stage group was significantly decreased; compared with the traditional Chinese medicine group, the traditional Chinese medicine stage group had a stronger downregulation effect (as shown in Table 7).

[0074] Table 7. Results of TNF-α and TGF-β1 content detection ( (n=3) Note: Comparison of M1 / M2 groups with the control group:** P <0.01; Comparison between the traditional Chinese medicine group, the traditional Chinese medicine stage group, and the M1 / M2 group: # P <0.05, ## P <0.01; Comparison between the traditional Chinese medicine staged group and the traditional Chinese medicine group: & P <0.05.

[0075] (3) mRNA expression of key proteins in polarization pathway: Compared with the blank group, the expression of IFN-γR1, JAK1 / 2 and STAT1 mRNA in the M1 control group was significantly increased; compared with the M1 control group, the expression levels of the above key proteins mRNA in the Chinese medicine group and the Chinese medicine stage group were significantly decreased; compared with the Chinese medicine group, the Chinese medicine stage group had a stronger inhibitory effect (as shown in Table 8).

[0076] Compared with the blank control group, the expression of IL-4Ra, JAK1 / 3, and STAT6 mRNA was significantly increased in the M2 control group; compared with the M2 control group, the expression levels of the above key proteins mRNA were significantly decreased in the traditional Chinese medicine group and the traditional Chinese medicine stage group; compared with the traditional Chinese medicine group, the traditional Chinese medicine stage group had a stronger inhibitory effect (as shown in Table 9).

[0077] Table 8. Statistical results of expression of key genes in the IFN-γ-JAKs / STATs pathway ( (n=3) Note: Comparison between group M1 and the control group:** P <0.01; Comparison between the traditional Chinese medicine group, the traditional Chinese medicine stage group, and the M1 group: ## P <0.01; Comparison between the traditional Chinese medicine staged group and the traditional Chinese medicine group: & P<0.05.

[0078] Table 9. Statistical results of expression of key genes in the IL-4-JAKs / STATs pathway ( (n=3) Note: Comparison between M2 group and blank group: * P <0.05,** P <0.01; Comparison between the traditional Chinese medicine group, the traditional Chinese medicine stage group, and the M2 group: # P <0.05, ## P <0.01; Comparison between the traditional Chinese medicine staged group and the traditional Chinese medicine group: & P <0.05, && P <0.01.

[0079] Example 3.

[0080] Case 1.

[0081] Basic information: Wang, male, 56 years old, retired; Chief complaint: Shortness of breath and dry cough after activity for more than 2 months; Present Illness: Two months ago, the patient developed shortness of breath and dry cough after exertion without any obvious cause. A chest CT scan at a local hospital revealed subpleural ground-glass opacities in both lower lobes, with a few fine reticular shadows; Velcro rales were audible in both lower lobes; pulmonary function tests showed FVC% at 78.6% and DLCO% at 63.5%; the 6-minute walking distance was 390m; after ruling out other definite causes, the patient was diagnosed with "idiopathic pulmonary fibrosis". The patient was concerned about the gastrointestinal and skin side effects of pirfenidone and refused Western anti-fibrotic treatment, seeking treatment from a traditional Chinese medicine practitioner. Current Symptoms: Shortness of breath, dry cough, worsening with exertion, occasional sputum production, spontaneous sweating, weak voice, dry mouth and thirst, fatigue, good appetite, good sleep, slightly dry stools, normal urination; pale and dark tongue with a slightly white and greasy coating; thready and hesitant pulse. Traditional Chinese Medicine diagnosis: Pulmonary atrophy (Qi and Yin deficiency, phlegm and blood stasis obstructing the collaterals); Western medicine diagnosis: Idiopathic pulmonary fibrosis (early stage); Prescription: The formula in Example 1, Fuzheng Huaxian Fang, is given once a day, taken with warm water after breakfast and dinner, for a course of 2 months.

[0082] Follow-up: After 3 months of follow-up after taking the medication, the symptoms improved significantly, the 6-minute walking distance increased to 420m, and the re-examination of lung function showed FVC% to be 79.1% and DLCO% to be 66.8%; no significant progression was seen on chest CT.

[0083] Case 2.

[0084] Basic information: Ms. Wu, female, 69 years old, retired; Chief complaint: Dry cough accompanied by chest tightness and shortness of breath for more than half a year; Present Illness: Six months ago, the patient developed a dry cough accompanied by chest tightness and shortness of breath without any obvious cause, which worsened with activity. A chest CT scan at a local hospital revealed subpleural ground-glass opacities in the middle and lower lobes of both lungs, with thickening of the interlobular septa, fine reticular striations, and tractional bronchiectasis. Inspiratory Velcro rales were audible in both lower lung fields. Pulmonary function tests showed an FVC% of 70.8%, a DLCO% of 57.2%, and a 6-minute walking distance of 360 meters. After ruling out other identifiable causes, the patient was diagnosed with "idiopathic pulmonary fibrosis." He had been intermittently taking pirfenidone for anti-fibrotic treatment for 3 months, but his symptoms did not improve significantly. Seeking traditional Chinese medicine treatment, he came to this clinic. Current symptoms include: irritating dry cough with sticky, white, and difficult-to-expectorate sputum; chest tightness and shortness of breath, worsened with activity; fatigue and weakness; sallow complexion; dry mouth and thirst; fair appetite; poor sleep; normal urination; and dry stools. The tongue is red with no coating, and the sublingual veins are obstructed. The pulse is thready and hesitant. Traditional Chinese Medicine diagnosis: Pulmonary atrophy (Qi and Yin deficiency, phlegm and blood stasis obstructing the collaterals); Western medicine diagnosis: Idiopathic pulmonary fibrosis (intermediate stage); Prescription: The formula described in Example 1, "Unblocking Meridians and Resolving Fiber," is prescribed once daily, taken with warm water after breakfast and dinner, for a course of 3 months. Continue oral pirfenidone treatment. Follow-up: After 3 months of follow-up following the course of treatment, symptoms improved significantly; the 6-minute walking distance increased to 375m; repeat pulmonary function tests showed FVC% at 72.5% and DLCO% at 59.7%; chest CT showed no significant progression.

[0085] Case 3.

[0086] Basic information: Liu, male, 78 years old, retired; Chief complaint: Wheezing and coughing for more than 2 years, which has worsened in the past half month; Present Illness: Two years ago, the patient developed wheezing and coughing symptoms without any obvious cause. After being diagnosed with "idiopathic pulmonary fibrosis" at a local hospital, the patient began taking nintedanib for anti-fibrotic treatment. In the past two weeks, the patient's symptoms have worsened without any obvious cause, with chest tightness and shortness of breath occurring even at rest. A chest CT scan at the local hospital showed extensive subpleural reticular striations in both lower lobes, distorted lung structure, and traction bronchiectasis. Pulmonary function tests showed an FVC% of 52.5%, DLCO at 38.8% of predicted value, and a 6-minute walking distance of 260 meters. The patient sought treatment from a traditional Chinese medicine practitioner. Current Symptoms: Shortness of breath, cough, copious white, sticky sputum that is difficult to expectorate, dark lips, weak voice, spontaneous sweating, dry mouth and thirst, poor appetite, poor sleep, dry stools, normal urination. The tongue is purplish-dark with a white, greasy coating, and the pulse is deep, hesitant, and weak. Traditional Chinese Medicine diagnosis: Pulmonary atrophy (phlegm and blood stasis obstructing the collaterals, qi and yin deficiency syndrome); Western medicine diagnosis: Idiopathic pulmonary fibrosis (late stage); Prescription: The Tongluo Huaxian Formula in Example 1 is administered, one dose daily, taken with warm water after breakfast and dinner, with a treatment course of 3 months. Continue oral administration of nintedanib for anti-fibrotic therapy, and receive oxygen inhalation at home every day; Follow-up: After 3 months of follow-up upon administration, the symptoms were significantly improved; the 6-minute walking distance increased to 275 m; reexamination of pulmonary function showed that FVC% was 54.2% and DLCO% was 41.6%; no obvious progression was observed on chest CT.

Claims

1. A traditional Chinese medicine composition based on different pathological stages of idiopathic pulmonary fibrosis, characterized in that, include: Compositions for strengthening the body and promoting blood circulation in chemical fibers; The Fuzheng Huaxian Formula composition is used in the early stage of idiopathic pulmonary fibrosis and is made from the following raw materials in parts by weight: Astragalus membranaceus 15-20 parts, Lilium brownii 15-20 parts, Codonopsis pilosula 10-15 parts, Dioscorea opposita 15-20 parts, Ophiopogon japonicus 10-15 parts, Lycium barbarum 10-15 parts, Salvia miltiorrhiza 5-10 parts, Fritillaria thunbergii 5-10 parts, Cynanchum paniculatum 5-10 parts, Prunus armeniaca 5-10 parts, and Glycyrrhiza uralensis 10-15 parts. The aforementioned Tongluo Huaxian formula composition is used for the middle and late stages of idiopathic pulmonary fibrosis and is made from the following raw materials in parts by weight: Fritillaria thunbergii 10-15 parts, Salvia miltiorrhiza 10-15 parts, Cynanchum paniculatum 10-15 parts, Poria cocos 10-15 parts, Carthamus tinctorius 5-10 parts, Angelica sinensis 10-15 parts, Astragalus membranaceus 10-15 parts, Dioscorea opposita 10-15 parts, Lilium brownii 10-15 parts, Prunus armeniaca 5-10 parts, and Glycyrrhiza uralensis 10-15 parts.

2. The traditional Chinese medicine composition based on different pathological stages of idiopathic pulmonary fibrosis according to claim 1, characterized in that, The TCM syndrome pattern corresponding to the early stage of idiopathic pulmonary fibrosis is Qi and Yin deficiency combined with phlegm and blood stasis obstructing the collaterals; the TCM syndrome pattern corresponding to the middle and late stages of idiopathic pulmonary fibrosis is phlegm and blood stasis obstructing the collaterals combined with Qi and Yin deficiency.

3. The traditional Chinese medicine composition based on different pathological stages of idiopathic pulmonary fibrosis according to claim 1, characterized in that, The preparation form of the traditional Chinese medicine composition is any one of the following: decoction, granules, oral liquid, pills, or capsules.

4. A method for preparing a traditional Chinese medicine composition based on different pathological stages of idiopathic pulmonary fibrosis as described in claim 1, characterized in that, The process includes the following steps: Weigh out eleven Chinese medicinal herbs according to the specified ratio, mix them, add water and decoct them multiple times, filter and combine the decoctions, concentrate them, add soluble starch, make them into granules, and dry them to obtain the final product.

5. A TCM treatment strategy based on different pathological stages of idiopathic pulmonary fibrosis, characterized in that, Includes the following steps: In the early stage of idiopathic pulmonary fibrosis, administer the fibrosis-strengthening and anti-fibrotic formula composition according to any one of claims 1-3; In the middle and late stages of idiopathic pulmonary fibrosis, the fibrosis-clearing and blood-activating formula composition according to any one of claims 1-3 is administered.

6. The treatment strategy according to claim 5, characterized in that, The early stage is the alveolitis stage, and the middle and late stages are the pulmonary fibrosis stage; the treatment strategy regulates the polarization balance of alveolar macrophages M1 / M2 by intervening in the IFN-γ / IL-4-JAKs / STATs signaling pathway.

7. The use of a traditional Chinese medicine composition as described in any one of claims 1-3 or a treatment strategy as described in any one of claims 5-6 in the preparation of a drug for treating idiopathic pulmonary fibrosis.

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