A systematic review of the research progress of traditional Chinese medicine against pulmonary fibrosis: from a pharmacological perspective

Abstract

Pulmonary fibrosis is a chronic progressive interstitial lung disease caused by a variety of etiologies. The disease can eventually lead to irreversible damage to the lung tissue structure, severely affecting respiratory function and posing a serious threat to human health. Currently, glucocorticoids and immunosuppressants are the main drugs used in the clinical treatment of pulmonary fibrosis, but their efficacy is limited and they can cause serious adverse effects. Traditional Chinese medicines have important research value and potential for clinical application in anti-pulmonary fibrosis. In recent years, more and more scientific researches have been conducted on the use of traditional Chinese medicine to improve or reduce pulmonary fibrosis, and some important breakthroughs have been made. This review paper systematically summarized the research progress of pharmacological mechanism of traditional Chinese medicines and their active compounds in improving or reducing pulmonary fibrosis. We conducted a systematic search in several main scientific databases, including PubMed, Web of Science, and Google Scholar, using keywords such as idiopathic pulmonary fibrosis, pulmonary fibrosis, interstitial pneumonia, natural products, herbal medicine, and therapeutic methods. Ultimately, 252 articles were included and systematically evaluated in this analysis. The anti-fibrotic mechanisms of these traditional Chinese medicine studies can be roughly categorized into 5 main aspects, including inhibition of epithelial-mesenchymal transition, anti-inflammatory and antioxidant effects, improvement of extracellular matrix deposition, mediation of apoptosis and autophagy, and inhibition of endoplasmic reticulum stress. The purpose of this article is to provide pharmaceutical researchers with information on the progress of scientific research on improving or reducing Pulmonary fibrosis with traditional Chinese medicine, and to provide reference for further pharmacological research.

Introduction

Pulmonary fibrosis (abbreviated as PF) is a chronic, progressive, irreversible interstitial lung disease commonly caused by multiple etiologies and characterized by the accumulation of inflammatory cells such as macrophages, neutrophils and lymphocytes in the alveoli, the proliferation and differentiation of fibroblasts, and the development of fibrous connective tissue. Ultimately, it leads to structural changes in the patient's normal lung tissue [1, 2]. In the late stages of many pulmonary diseases, PF is a common pathological manifestation. In modern medicine, interstitial lung disease is divided into two types: secondary interstitial lung disease and idiopathic interstitial lung disease. The former has a relatively clear etiology, including silicosis, pneumoconiosis, asbestosis, radiation-induced PF, and drug-induced interstitial lung disease. In contrast, the etiology of the latter is unknown, including idiopathic pulmonary fibrosis (abbreviated as IPF), cystic fibrosis, and interstitial pneumonia with autoimmune features, among which IPF is the most important [1, 3]. Due to IPF's wide involvement, long course, high mortality rate, and other characteristics, it is also known as a tumor-like disease [2]. Unfortunately, the prognosis for patients with IPF is often unfavorable, as they typically suffer from significant lung function impairment and a reduced quality of life during recovery [4, 5]. Epidemiological surveys have shown that the prevalence and incidence of IPF is increasing year by year and is more prevalent in the elderly. The mortality rate of IPF is high, and more than half of patients with IPF who were hospitalized for acute exacerbations will die during their hospitalization, and their average survival period after diagnosis is 2 to 4 years [6,7,8]. Notably, following the outbreak of COVID-19 in 2019, clinical observations have identified fibrosis in the lungs of patients with COVID-19 [9,10,11]. If PF is not controlled promptly and effectively, it will lead to a decline in lung function and seriously affect the quality of life and life expectancy of patients [12]. At present, glucocorticoids and Immunosuppressive drug, such as pirfenidone and nifanyl, are the main clinical treatments for PF, but their clinical efficacy is not satisfactory, and these drugs are also expensive and have many side effects [13,14,15]. In recent years, traditional Chinese medicines (abbreviated as TCM) has made great progress in improving or reducing of PF, and has become one of the alternative therapies for clinical treatment of IPF due to its significant efficacy and few side effects [16,17,18]. Of particular interest is that in the battle against COVID-19, TCM has shown the advantages of high efficiency and low toxicity in lung injury caused by the novel coronavirus and in the prognosis of rehabilitation, playing an important role in blocking the progression of PF and promoting the recovery of patients [19,20,21]. In this review article, we focus on the research progress of TCM in improving PF from a pharmacological perspective. Firstly, we summarized the research progress on the pharmacological mechanisms related to PF. Secondly, we systematically summarized the potential active compounds in TCM that can be used to improve PF, and classified the targets of these compounds. Finally, future research directions were envisioned. The following search terms were used: IPF, PF, interstitial pneumonia, natural product, herbs. The time limit is from June 2017 to June 2023. We did a systematic search of several major scientific databases, including PubMed, Web of Science, and Google Scholar. A total of 252 articles were retrieved. At that time, the focus was on screening original experimental articles that matched the theme, totaling 184 articles. We evaluated these literature and systematically reviewed the research progress of TCM in improving PF in the past five years.

Pathogenesis of pulmonary fibrosis

The pathogenesis of PF is not yet fully elucidated, but it is known to be caused by a variety of factors: for example, PF due to silica inhalation [22], PF induced by chemicals, such as bleomycin, paraquat [23, 24], and induced by different primary diseases [25].

Modern medicine generally agrees that fibrosis can be described as an irrational form of injury repair [26, 27]. Repeated microdamage to the alveolar epithelium is the first driving factor that induces an abnormal repair process in which persistent alveolar epithelial cell damage and repair abnormalities, proliferation of fibroblasts, and accumulation of extracellular matrix (abbreviated as ECM) lead to structural disorders in the lung and the formation of fibrosis [28,29,30]. In the early stages of PF, there are different influencing factors, but in the later stages of fibrosis, there are the same mechanisms of action [31, 32]. The pathogenesis of PF can be roughly divided into three stages: injury, inflammation, repair. The first stage: the lung is damaged or otherwise noxiously stimulated and fibroblasts are activated and begin to secrete ECM. This phase is disease-specific and it consists mainly of lymphocyte activation and differentiation, autoimmune and immune-mediated conditions of excessive immune response, and chronic granulomatous inflammation. This is due to the persistence of identified or unidentified antigens, or other exposures. These multiple environmental risk factors, such as smoking, occupational exposure, air pollution, toxic compounds, viral infections, can repeatedly damage alveolar cells [2, 33, 34]. The second stage: mitogen-activated protein kinase (abbreviated as MAPK) and nuclear factor kappa B (abbreviated as NF-κB) pathways are activated to promote the production of a large number of cytokines [35]. Activated fibroblasts undergo structural and phenotypic changes and produce a large amount of ECM [36]. Through paracrine, inflammatory cells, including macrophages, move to the stimulated site. T cells are activated to secrete fibrogenic growth factors, such as interleukin and tumor necrosis factor alpha (abbreviated as TNF-α) [37]. Macrophages promote the proliferation and differentiation of fibroblasts and secrete a variety of cytokines, including transforming growth factor beta (abbreviated as TGF-β) and Interleukins-1 (abbreviated as IL-1) [38]. The third phase: the injury factors persisted, resulting in repeating damage of alveolar epithelial cells. Fibroblasts continue to be activated to produce more ECM [39,40,41]. Cytokines continue to cause tissue inflammation and collagen overexpression, ECM deposition, the beginning of a vicious circle, and finally lead to the gradual formation of PF, the loss of lung function at the idiopathic site [42,43,44].

Pulmonary fibrosis-related signaling pathways

TGF-β/Smad

Transforming growth factor-β/Smad (TGF-β/Smad) is a pleiotropic signaling pathway that plays a key role in inflammation, wound healing, fibrosis processes such as epithelial injury, myofibroblast fibroblast proliferation and differentiation and ECM production [45, 46]. TGF-β exerts its biological activity through activation of Smad-dependent and non-dependent pathways. The Smad protein family can be divided into three categories: receptor-activated (R-Smads, including Smads 1, 2, 3, 5, and 8), general-purpose (Co-Smad, including Smad 4), and inhibitory (I-Smads, including Smad 6 and 7) [47]. The TGF-β receptor is a receptor that belongs to the group with endogenous Ser/Thr kinase activity and binds to its type I and type II receptors to form a complex that leads to phosphorylation of Smad2 and Smad3 [48]. The phosphorylated Smad2 and Smad3 then further form a complex with Smad4, which undergoes nuclear translocation, activating the expression of transcription factors downstream of Epithelial-mesenchymal transition (EMT) and promoting EMT [49]. TGF-β1 also activates MAPK, phosphoinositide 3-kinase/protein kinase B pathway, and Rho pathways, induces EMT, increases the expression of collagen, fibronectin, and tissue inhibitor of matrix metalloproteinases (TIMPs), and promotes PF. Recent studies have shown that numerous active substances of natural products can improve PF through the TGF-β/Smad signaling pathway [50].

Nrf2/ARE

When the organism is damaged by external oxidative and chemical stimuli and other stresses, it generates corresponding self-defense responses and induces a series of protective proteins. The Nuclear Factor erythroid 2-Related Factor 2/antioxidant response element (Nrf2/ARE) pathway is a classical defensive transduction pathway that can reduce the oxidative stress damage occurring in cells [51]. Nrf2 is a key factor in the cellular oxidative stress response, with antioxidant, anti-inflammatory response and cytoprotective effects [52]. Nrf2 is a key transcription factor that is essentially expressed in oxidative stress and is present in multiple organs throughout the body, and its deletion or impaired activation directly causes changes in cellular sensitivity to stressors changes in the sensitivity of cells to stressors [53, 54]. The Nrf2/ARE pathway in the lung mainly regulates the expression of antioxidant genes, thus providing protection to lung tissue [55]. When cells are attacked by reactive oxygen species or other electrophile reagents in a state of oxidative stress, Nrf2 is uncoupled from keap1 and translocated across the membrane into the nucleus. By regulating ARE activity, it further initiates the transcription of downstream regulatory antioxidant proteins and phase II detoxification enzymes, and regulates the expression of various antioxidant genes, thereby increasing the production of antioxidant substances, reducing cellular oxidative damage and maintaining intracellular redox homeostasis, thus playing an antioxidant and anti-fibrotic role [55]. By activating the Nrf2/ARE signaling pathway, the synthesis of antioxidant proteins can be increased, and thus the body’s enhanced antioxidant capacity can be achieved to delay the progression of PF [56]. The Nrf2/ARE pathway can also mediate a variety of antioxidant enzymes and phase II detoxification enzymes to protect tissues.

PI3K/AKT

The phosphoinositide 3-kinase/protein kinase B pathway (PI3K/AKT) is one of the central intracellular signaling pathways regulating cell growth, proliferation, motility, metabolism and survival [57, 58]. PI3K is a signal transduction enzyme that phosphorylates PI (4,5) P2 to form PI (3,4,5) P3, which is activated by tyrosine kinase receptors, G protein-coupled receptors/cytokine receptors and Ras protein-associated GD Pase receptors to promote cell proliferation, survival, adhesion, differentiation, cytoskeleton organization, etc. [59, 60]. Protein kinase B (AKT) is a serine/threonine kinase downstream of PI3k, and AKT binds to PI(3,4,5) P3 near the cell membrane to form a complex. The binding of the complex to 3-phosphoinositide-dependent protein kinase 1 promotes the phosphorylation of the PH domain at the amino acid terminus of AKT, which activates downstream factors such as hypoxia-inducible factor-1 and mammalian target of rapamycin (mTOR) to participate in cell proliferation and differentiation [59, 60]. AKT is a direct target protein downstream of PI3K, which can participate in regulating cell proliferation and metabolism, promoting fibrosis-related gene transcription and protein synthesis, and activated AKT can participate in PF by activating mTOR [61]. AKT2-deficient mice can counteract bleomycin (BLM)-induced PF and inflammation, suggesting that PI3K/AKT signaling plays an important role in IPF development [62]. In addition, activation of PI3K/AKT can be involved in the development of PF by regulating its downstream genes such as mTOR, hypoxia-inducible factor-1 and Fox family [63]. It is due to the important role of PI3K/AKT in regulating receptor-mediated signaling that targeting PI3K/AKT has become a promising strategy for the treatment of IPF.

Wnt/β-catenin

Wnt signaling pathway can be divided into classical Wnt signaling pathway (i.e. Wnt/β-catenin signaling pathway) and non-classical Wnt signaling pathway. Among them, β-catenin is the key molecule that mediates classical Wnt signaling. Wnt proteins are a group of secreted glycoproteins expressed in a variety of tissue cells, involved in a variety of signaling pathways, and play a key role in cell differentiation, cell migration, organogenesis, stem cell self-renewal and maintenance of tissue homeostasis. β-catenin is a cytoskeletal protein that, together with E-cadherin and α-catenin, is involved in the construction of cell junctions and intercellular adhesion mechanisms, and plays an important role in maintaining the stability of the intracellular environment and signaling into the nucleus [64, 65].

The Wnt/β-catenin signaling pathway plays an important role in many pathological processes in the lung and is one of the major regulatory pathways in PF [66]. In pulmonary endothelial cells Wnt/β-catenin signaling causes a shift from perivascular fibroblasts to myofibroblast-like cells, leading to ECM accumulation and increased tissue stiffness, further promoting PF [67]. Downregulation of the Wnt signaling pathway also inhibited myofibroblast differentiation, thereby ameliorating PF lesions [68]. The Wnt/β-catenin signaling pathway was significantly activated in the IPF animal model [69], and blockade of the Wnt/β-catenin pathway was also effective in attenuating lung fibrosis in mice [70].

It has been shown that Wnt/β-catenin signaling is involved in the induction of EMT during the development of fibrosis [71]. Wnt1, Wnt3A, Wnt7B, Wnt10B, Fzd2, Fzd3 and β-catenin expression were significantly increased in lung tissues of IPF patients [72]. Wnt5A and Wnt5B ligands have been reported to exert effects on pulmonary fibroblast differentiation via TGF-β [73]. The Wnt/β-catenin pathway also interacts with the TGF-β/Smad, PI3K/AKT signaling pathway and plays an important role in the pathogenesis of IPF, and inhibition of this pathway can reduce or reverse PF [74].

NF-κB

NF-κB is one of the major nuclear transcription factors that regulate inflammatory and immune responses, as well as a signaling pathway that is present in many cell types and closely associated with intracellular biological functions and inflammatory responses [75, 76]. In addition, NF-κB binds to fixed nucleotide sequences in the promoter regions of many genes to initiate gene transcription, which plays a crucial role in the inflammatory response, the regulation of the immune system, and cell growth [77, 78]. Five transcription factors comprise the NF-κB family: NF-κB1 (p50), NF-κB2 (p52), Rel A (p65), Rel B, and c-Rel [79]. NF-κB proteins function as dimers that bind to the κB site and affect the transcription of target genes [80]. The phosphorylation of NF-κB is responsible for activating the NF-κB signaling pathway [81]. Inflammation is now believed to be one of the factors contributing to fibrosis [82,83,84], and during PF, NF-κB is activated, which promotes the release of large amounts of inflammatory factors such as TNF-α, IL-1β, IL-8 and TGF-β1 [85], stimulating the proliferation of fibroblasts and the deposition of collagen fibers, thereby promoting the development of organ fibrosis [86]. Several studies [87, 88] have elucidated the crucial role of the NF-κB signaling pathway in regulating acute lung injury-induced PF. NF-κB also plays a key role in the secretion of pro-fibrotic cytokines during the progression of PF [89]. In addition to inflammation, cellular senescence is an important factor leading to fibrosis that can promote the development of IPF through a variety of mechanisms, such as senescence associated secretory phenotype (SASP), telomere dysfunction, etc. [90, 91]. The NF-κB signaling pathway is a key regulator of SASP, according to [92]. SASP has been shown to be inhibited by the inhibition or knockdown of multiple components that regulate NF-κB signaling [93].

Cytokines related to pulmonary fibrosis

Transforming growth factor β

Transforming Growth Factor β (TGF-β) has been implicated as a central factor in the development of PF [94,95,96]. TGF-β has several biological roles, such as promoting wound repair by increasing ECM deposition, inflammatory cell recruitment and fibroblast differentiation [97, 98]. TGF-β1 is currently recognized as the most critical fibrogenic factor and the most potent promoter of ECM deposition ever identified. It has been shown in the literatures that the TGF-β1/Smad signaling pathway is activated during PF [99, 100], prompting the conversion of fibroblasts to myofibroblasts and alveolar epithelial and endothelial cells to mesenchymal cells. In addition, activation of the TGF-β1/Smad signaling pathway reduces the secretion and inhibits the activity of matrix protein metallases, while increasing the synthesis and secretion of matrix metalloproteinase tissue inhibitory factor, which inhibits myofibroblast apoptosis and leads to the production of large amounts of ECM and its failure to degrade properly, allowing it to accumulate in the lung and cause PF [36, 101].

Platelet-derived growth factor

Platelet-derived growth factor (PDGF) is a peptide-like regulatory factor stored mainly in platelets, and when PF occurs, epithelial cells, alveolar macrophages and activated platelets will secrete large amounts of PDGF [102]. PDGF is closely related to the proliferation and differentiation of lung fibroblasts [103]. PDGF promotes the formation and development of PF by promoting the proliferation, migration and aggregation of lung fibroblasts, as well as regulating the synthesis and deposition of ECM. Therefore, PDGF is known as an energizing factor for fibroblast proliferation [104, 105]. In the process of PF, PDGF is mainly produced at the site of lung tissue injury, and TGF-β1 and TNF can regulate the expression of PDGF. On the one hand, PDGF can cross the cell membrane barrier through the damaged lung epithelial cells into the alveolar mesenchyme and chemotactic mesenchymal cells; On the other hand, similar to the function of TGF-β1, it can also induce fibroblast proliferation and differentiation and stimulate fibroblasts to secrete collagen, but the mechanism of action may be different from that of TGF-β1 [106]. It has been found that increased release of PDGF is observed in the lungs of IPF patients and that blocking PDGF receptor signaling in animal models of IPF attenuates the extent of PF [107].

Interleukins

Interleukins (IL) are a class of cytokines produced mainly by lymphocytes, monocytes or macrophages and act on a variety of cells. They are complex in structure and function and play an important role in a range of processes including immune regulation and inflammation in lung tissue [108, 109]. Thirty-eight species have been named, of which approximately one third are involved in the development of PF. During PF, IL-1, IL-4, IL-6, IL-11, and IL-13 play important roles in promoting proliferation and aggregation of pulmonary fibroblasts, ECM deposition, collagen synthesis, and lung tissue remodeling [110, 111]. Among them, IL-13 has a significant effect on tissue fibrosis. It has been shown that IL-4 and IL-13 can synergistically exert activation effects on M2 type macrophages, and the activated M2 type macrophages secrete pro-fibroblastic cytokines thereby promoting the development of fibrosis [112]. IL-7, IL-10, IL-12, and IL-18 reduce PF by inhibiting inflammatory factors and modulating immunity [113,114,115,116,117]. Among them, IL-10 may activate macrophages through the CCL2/CCR2 axis, causing fibroblast accumulation and eventually causing fibrous degeneration [118].

Tumor necrosis factor-α

Tumor necrosis factor-α (TNF-α) is a multi-temporal, cellular immune defense factor produced by mononuclear macrophages. TNF-α is highly expressed in the pathological process of lung injury and can participate in the local injury and inflammatory response, leading to the aggregation of inflammatory cells, which in turn stimulates massive proliferation of lung fibroblasts and secretion of collagen. Therefore, TNF-α is one of the important indicators for clinical testing of PF. On the one hand, TNF-α is involved in the process of acute inflammatory response and inhibits the repair of lung injury by promoting apoptosis of type II alveolar cells [119]. On the other hand, TNF-α promotes the differentiation of lung resident mesenchymal stem cells into myofibroblasts [120]. In the early stages of PF, macrophages aggregate, synthesize and release large amounts of TNF-α. TNF-α stimulates a massive increase in chemotactic and adhesion molecules, creating an inflammatory cell infiltrate. Therefore, TNF-α is also known as an early response factor [121]. In addition, TNF-α can act synergistically with IL-1 to promote neutrophil activation and aggregation and regulate the inflammatory response in the early stages of PF [122]. TNF-α acts mainly through the NF-κB pathway, and its mechanism may be related to the Wnt/β-catenin signaling pathway. There are NF-κB binding sites on the transcriptional promoter region or enhancer of the TNF-α gene, and the two promote each other and jointly regulate the development of PF [123].

Pharmacological mechanism of TCM in improving pulmonary fibrosis

TCM has demonstrated significant clinical efficacy and unique advantages in improving IPF. PF is closely related with TCM terminologies such as ‘lung obstruction’, ‘lung atrophy’, and ‘lung abscess'. TCM mainly employs a dialectical treatment approach from the perspectives of tonifying the lung and kidney, invigorating the spleen and lung, and promoting blood circulation and removing blood stasis. In recent years, research on TCM therapy for PF has been increasing, and significant progress has been made in some aspects. In this section, we reviewed recent literatures and summarized that the mechanisms by which TCM improving PF can be roughly divided into five categories: inhibiting EMT, anti-inflammatory and anti-oxidative stress, improving ECM deposition, mediating cell apoptosis and autophagy, and inhibiting endoplasmic reticulum stress (ERS), a simple classification information was shown in Fig. 1.

Fig. 1

Schematic diagram of the main intervention targets of traditional Chinese medicine against pulmonary fibrosis

Inhibition of epithelial cell-mesenchymal transformation

EMT is the process by which epithelial cells lose cellular activity through a specific procedure and are then transformed into mesenchymal cells. EMT is the main source of fibroblasts and myofibroblasts in IPF [124, 125]. It has been shown that approximately 33% of myofibroblasts in the lung can be traced to cells undergoing EMT in a bleomycin-induced lung fibrosis model [126]. EMT is mainly divided into 3 types: type I EMT is mainly related to normal physiological activities of cells; type II EMT is mainly related to injury repair, tissue regeneration and organ fibrosis; type III EMT is related to tumor metastasis [127, 128]. Among them, type II EMT is mainly caused by persistent inflammation and injury, regulated by a variety of signaling factors and signaling pathways, and is an important mechanism for the occurrence and development of PF, which can be treated by inhibiting EMT progression. There is growing evidence that EMT is closely associated with fibroblast activation and PF, characterized by increased expression of α-SMA and vimentin and decreased expression of the intercellular adhesion molecule E-cadherin. Therefore, inhibition of EMT is an important way to treat PF. At present, the signaling pathways involved in EMT inhibition by TCM mainly include TGF-β/Smad, NF-κB, PI3K-Akt, and so on.

Andrographolide, a diterpenoid compound isolated from andrographis paniculata, it has pharmacological effects such as anti-inflammatory, antioxidant, and participation in regulating EMT [129, 130]. Sachin Karkale's research team found that Andrographolide can effectively reduce the expression of mesenchymal markers in PF mice and increase the expression of epithelial markers [131]. This study revealed for the first time that andrographolide could shown good anti-fibrosis activity by inhibiting inflammation and targeting EMT, which provided a new idea for the study of TCM to improve silicon induced PF. In addition to silicon induced occupational PF, andrographolide also has a certain inhibitory effect on bleomycin induced IPF. The research results of Li Jingpei's team shown that andrographolide could improve BLM induced PF in rats, and explore its mechanism from different perspectives. First, andrographolide could improve PF by inhibiting the proliferation of fibroblasts and the differentiation of myofibroblasts. This process is affected by TGF-β1 mediated regulation of Smad dependent and non dependent pathways [132]. Secondly, andrographide could inhibit TGF β1 in alveolar epithelial cells (AEC) by regulating the Smad2/3 and Erk1/2 signaling pathways [132]. Then, andrographolide could inhibit EMT in lung epithelial cells through AKT/mTOR signaling pathway, thereby reducing BLM induced PF [134]. These results shown that andrographis paniculata could improve PF through multiple ways and targets, which has great development potential and is worth our in-depth study.

Emodin is an anthraquinone compound with multiple biological activities isolated and purified from rhubarb. Zhou's team research shown that emodin could inhibit NE induced EMT in RLE-6TN and A549 cells, and its mechanism of action was related to NE induced Notch1 lysis [135]. This study preliminarily revealed the mechanism of emodin inhibiting EMT at the cellular level, which has certain reference value for further understanding the pharmacological effect of emodin in improving PF. Emodin can also regulated NF-κB and TGF- β1/Smad3 signaling pathway inhibits EMT and improves silica induced PF [136]. Rhapontin is another important compound in rhubarb, and Tao's team found in vitro experiments that rhapontin could activate AMPK and inhibit TGF- β/Smad pathway reversal of ECM [137]. This experiment confirmed the anti-PF activity of rhapontin for the first time. On the whole, rhubarb has important medicinal value in improving PF, but its pharmacology and toxicology still need further experimental and clinical research.

Salvia miltiorrhiza is a commonly used herbal medicine to treat cardiovascular and pulmonary diseases. Salvianolic acid B is a bioactive component extracted from Salvia miltiorrhiza, which has strong anti-inflammatory and antioxidant effects. Liu's team first confirmed the anti fibrotic activity of salvianolic acid B through a cell model, and further found in animal models that salvianolic acid B inhibits the transdifferentiation of lung fibroblasts by activating Nrf2 signaling [138]. Cryptotanshinone is a diterpenoid compound with antioxidant, anti-inflammatory, and antibacterial activities. Research has shown that CPT exhibits good anti-fibrotic effects in both in vitro and in vivo, inhibiting various cell proliferation and TGF-β induced EMT [139]. Although these research results suggest that Salvia miltiorrhiza may be a potential drug for improving IPF, these studies have only been conducted on animal or cell models and further clinical research is still needed.

In addition to the above-mentioned TCM that can improve PF, the detailed information of other TCM studies in the past five years that can improve PF by inhibiting EMT were summarized and presented in Table 1. It should be noted that the traditional efficacy of most Chinese medicines in the table is related to clearing away heat and detoxification, promoting blood circulation to remove blood stasis, relieving cough and resolving phlegm, which may suggest that the traditional efficacy is a reference factor that cannot be ignored when we are looking for natural drugs with anti PF activity.

Table 1 Details about some traditional Chinese medicines improving pulmonary fibrosis by inhibiting epithelial cell-mesenchymal transformation

Anti-inflammation and anti-oxidation

Oxidative stress is a pathological state in which the body undergoes some kind of stimulation resulting in excessive production of reactive nitrogen radicals and reactive oxygen radicals, leading to an oxidative/antioxidative imbalance. Oxidative stress is a major cellular stressor that can act directly or indirectly on cells, leading to structural necrosis, apoptosis and tissue inflammation [212]. The imbalance between oxidants and antioxidants plays a role in the pathophysiology of IPF, and NADPH oxidase (NOX), which generates reactive oxygen species (ROS), is the primary cause of IPF [213]. Excessive ROS and free radical production can cause lung damage [214]. The level of systemic oxidative stress and disease severity in IPF patients are significantly correlated with dyspnea, as shown by numerous studies [215]. Therefore, anti-oxidative stress is essential for the successful treatment of PF [216]. The inflammatory response is a defense mechanism of the body, and the inflammatory response of the body to different degrees of injury is one of the important factors against lung injury [217, 218]. The pathogenesis of PF may be due to damage to lung epithelial cells by fibrotic stimuli. Therefore, lung inflammation plays an important role in the development of PF. And inflammation is controlled by a variety of cells and cytokines [212, 219] Pro-inflammatory cytokines control tissue differentiation and morphogenesis through adhesion molecules and promote fibrotic responses in lung tissue [220]. Currently, many anti-inflammatory and antioxidant agents have shown effective antifibrotic effects in BLM-induced PF models. Therefore, the imbalance between oxidative stress, oxidants and antioxidants, and inflammation in the development of PF deserve further attention [221, 222].

Emodin is an anthraquinone compound extracted from rhubarb, which has antiviral, anti-cancer, anti-inflammatory and other pharmacological effects [223, 224]. Tian's team found that emodin can significantly reduce the increase of proinflammatory cytokines and oxidative damage caused by BLM [225]. Further experiments found that the anti-inflammatory and antioxidant activities of emodin may be through regulating NF-κB and Nrf2 signal pathways. This study preliminarily revealed the anti-inflammatory and antioxidant activities of emodin in improving PF, and preliminarily explored the possible signal pathways involved. However, the mechanism by which emodin exerts its biological activity still needs to be further explored in order to better play its potential in the treatment of PF. Qi's team found the protective effect and potential mechanism of chrysophanol in IPF through research [226]. The research results shown that chrysophanol can effectively reduce ECM deposition and inflammatory cytokine levels in PF model mice, and chrysophanol can also inhibit Wnt/β-catenin signaling pathway and inhibition of lung fibroblast proliferation to alleviate BLM induced mouse PF. This study demonstrates that chrysophanol has anti-inflammatory biological activity, but further experimental verification is needed. In addition to emodin and chrysophanol, rhubarb also contains many active ingredients with anti-inflammatory and antioxidant effects. The improvement of PF by these active ingredients deserves further research.

Studies have shown that ethyl acetate extract of Salvia miltiorrhiza can reduce the degree of active oxygen-related PF by targeting Nrf2-NOX4 REDOX equilibrium [227, 238]. Tanshinone IIA is a bioactive ingredient extracted from Salvia miltiorrhiza with anti-inflammatory, antioxidant and anti-fibrotic properties. Feng's research team studied the protective effect of Tanshinone IIA on silica-induced PF and its potential mechanism [229], and the results showed that tanshinone IIA could down-regulate the level of oxidative stress markers in silicosis rats and attenuate pulmonary inflammatory response. In addition, Tanshinone IIA may protect the lung from silica damage by inhibiting TGF-β1/Smad signaling, inhibiting NOX4 expression, and activating the Nrf2/ARE pathway. An’s team found a similar phenomenon in mice with bleomycin-induced PF treated with tanshinone IIA [152]. The study found that tanshinone IIA can inhibit PF by activating Nrf2, regulating REDOX homeostasis and glutamine breakdown. Liu's study showed that salvianolic acid B can reduce experimental lung inflammation by protecting endothelial cells from oxidative stress [230], further demonstrating that the anti-inflammatory effects of Salvianolic acid B may be mediated through MAPK and NF-κB signaling pathways. Notably, Salvianolic acid B and Tanshinone IIA sulfonates reduce PF by affecting the inflammatory system and controlling the TGF-β1 pathway, which may be the result of a synergistic effect between the two drugs [153]. In summary, many active compounds in salvia miltiorrhiza have pharmacological effects on improving PF, and the synergistic effect between these compounds is worthy of further study. In addition to the above-mentioned TCM that can improve PF, the detailed information of other TCM studies in the past five years that can improve PF through anti-inflammation and anti-oxidation were summarized and presented in Table 2.

Table 2 Details about some traditional Chinese medicines improving pulmonary fibrosis by anti-inflammation and anti-oxidation effects

Improve extracellular matrix deposition

ECM is a three-dimensional network of non-cellular macromolecules, made primarily of collagen, non-collagenous proteins, and glycoproteins, among others [297]. A pathological characteristic of PF is the massive buildup of ECM in the interstitium. Excessive ECM deposition promotes alveolar structural loss, which generates or aggravates PF. Initial damage to alveolar epithelial cells stimulates the production of multiple pro-fibrotic cytokines that induce fibroblast proliferation, aggregation, and transdifferentiation, generating myofibroblasts that secrete stronger ECM, releasing high levels of ECM, and promoting the development of PF [298]. Under pathological situations, excessive deposition of ECM in the interstitial lung can stimulate ECM synthesis and alter the regulatory function of matrix metalloproteinases (MMPs)/TIMPs [299, 300]. Under pathological situations, excessive deposition of ECM in the interstitial lung can stimulate ECM synthesis and alter the regulatory function of matrix metalloproteinases (MMPs)/TIMPs [301]. The majority of animal investigations have concentrated on the independent detection of TGF-β1, Smads, and MMPs/TIMPs, and the precise mechanism of action is still unknown. Furthermore, Smads, MMPs, and TIMPs comprise several family members whose activities and mutual effects have yet to be thoroughly investigated [45].

In addition to its anti-inflammatory and antioxidant properties, Salvia miltiorrhiza can also play an anti PF role by inhibiting ECM deposition. Feng’s research suggests that tanshinone IIA inhibits TGF-β1/Smad signaling pathway to reduce silica induced PF [302]. Further research found that tanshinone IIA may improve silicosis fibrosis by inhibiting the EMT phase. Cryptotanshinone is a lipophilicity compound derived from salvia miltiorrhiza, which has antioxidant, anti-inflammatory and anti-angiogenesis properties [303]. Zhang research team found that cryptotanshinone improved the lung function of the rat model of bleomycin induced PF, alleviated pathological changes and inhibited ECM precipitation [304]. This experiment found that cryptotanshinone may prevent PF by inhibiting Smad and STAT3 signaling pathways through cell experiments. In conclusion, many active compounds in Salvia miltiorrhiza have good anti PF effects in terms of anti inflammation, anti-oxidation, inhibition of EMT and inhibition of ECM precipitation.

Astragalus membranaceus is a TCM with various pharmacological effects such as enhancing immune function, protecting lung function, and reducing oxidative stress. Astragaloside IV is one of the most important active ingredients in astragalus membranaceus. Some studies have shown that astragaloside IV not only improves the secretion of collagen induced by bleomycin, but also reduces the level of type III collagen, serum laminin and hyaluronic acid in lung homogenate [305]. These findings indicated that astragaloside IV can effectively inhibit ECM deposition in PF mice, providing experimental data support for its use as a candidate compound for the treatment of PF. Li’s team also studied the anti PF effect of astragaloside IV [306]. The difference is that this experiment uses the silicon induced PF model. The experiment shown that astragaloside IV can effectively inhibit the formation of silicosis fibrosis. Further cell experiments have found that astragaloside IV can inhibit ECM precipitation in fibroblasts, and its mechanism of action may be related to TGF-β1/Smad signaling pathway is involved. These results suggest that astragalus may have the potential to improve PF by inhibiting ECM precipitation in a variety of disease induced PF. In addition to the above-mentioned TCM that can improve PF, the detailed information of other TCM studies in the past five years that can improve PF through inhibition of ECM deposition were summarized and presented in Table 3.

Table 3 Details about some traditional Chinese medicines improving pulmonary fibrosis by inhibiting extracellular matrix deposition

Mediate apoptosis and autophagy

Autophagy is the degradation of intracytoplasmic foreign bodies, damaged, and senescent cells by the cell's own structures via lysosomes, which helps maintain a homeostatic equilibrium between degradation and recirculation [319]. Cellular autophagy can promote PF by promoting fibroblast activation, myofibroblast differentiation, and ECM deposition, indicating that autophagy may be one of the key mechanisms in the pathogenesis of PF [320, 321]. The expression of cellular autophagy is typically deficient in all IPF lung tissues, which appears to be one of the risk factors for IPF, as suggested by the current study [322]. When autophagy is inhibited, lung fibroblast epithelial senescence and myofibroblast differentiation can be accelerated. Numerous studies have demonstrated that herbal medicine regulates cellular autophagy primarily via mTOR-dependent and -independent pathways. Apoptosis is a form of programmed cell death characterized primarily by cell shrinkage and the formation of apoptotic vesicles [323]. Excessive apoptosis of alveolar epithelial cells induces aberrant secretion of numerous cytokines, including TGF-β1, and accelerates the progression of PF [324]. Inadequate apoptosis of lung fibroblasts results in their massive transformation into myofibroblasts, which promotes ECM deposition and lung fibrosis [325]. There are multiple signaling pathways involved in the role of apoptosis in lung fibrosis. It has been hypothesized that the MAPK/NF-κB signaling pathway plays a crucial role in this.Autophagy and apoptosis are complex mechanisms that control cell growth and death under physiological and pathological conditions. It has been suggested that the two processes, reduced autophagic activity and apoptotic resistance, may be interrelated in IPF fibroblasts [326]. When mTOR activity is inhibited, autophagy increases, apoptosis increases, and resistance to apoptosis decreases. Enhanced autophagy is accompanied by increased apoptosis. Consequently, insufficient autophagy can result in insufficient apoptosis in fibroblastic cells and excessive apoptosis in alveolar epithelial cells, which, through a cascade of biological responses, leads to IPF.

Various components in the peel of citrus reticulata blanco have anti-inflammatory and antioxidant activities [327]. Wu’s experimental team extracted primary lung fibroblasts from normal mice and bleomycin induced PF mice for experiments. The results indicate that citrus alkaloid extract can effectively induce apoptosis in mouse lung fibroblasts, and its mechanism of action may be related to the p38/COX-2/Fas signaling pathway regulated by oxidative stress [328]. In addition, the experimental team explored the intervention effect of citrus alkaline extract on bleomycin induced PF in mice and its mechanism [329]. The experiment shows that citrine extract can effectively delay the degree of PF mice, and its mechanism may be through inhibiting NF-κB/p38-mediated signaling pathway inhibits cell apoptosis. In addition, studies have shown that citrus alkaloid extracts can activate COX-2 and β-Catenin/P53 pathway inhibits cellular senescence and reduces PF [330, 331]. To sum up, citrus extract can mediate cell apoptosis through multiple signaling pathways, but the specific pharmacodynamic substances in the extract that play a role in improving PF are still unclear, and further experimental research is needed.

Quercetin is a flavonol compound in TCM [332], which has anti-inflammatory, antioxidant, immunomodulatory and anti-tumor activities [333]. Literature studies have shown that quercetin alone cannot promote apoptosis, but quercetin can eliminate fibroblast resistance to apoptosis [334]. Further studies suggest that quercetin may enhance the susceptibility of aging fibroblasts to apoptosis by regulating the expression of caveolin-1 and Fas and activating AKT. In addition, Xiao found that quercetin not only promotes autophagy activity, but also improves fibrosis by inhibiting pro-fibrotic factors and AKT/mTOR signaling pathway [335]. These studies demonstrate quercetin's potential to combat PF by mediating apoptosis, adding to therapeutic strategies for IPF and other fibrotic diseases. However, these studies have only been conducted in vitro or in animals, and further clinical studies are still needed. In addition to the above-mentioned TCM that can improve PF, the detailed information of other TCM studies in the past five years that can improve PF through mediate apoptosis and autophagy were summarized and presented in Table 4.

Table 4 Details about some traditional Chinese medicine improving pulmonary fibrosis by mediating apoptosis and autophagy

Inhibition of endoplasmic reticulum stress

The endoplasmic reticulum (ER) is an organelle responsible for maintaining protein homeostasis in cells. The accumulation of misfolded proteins in the ER is referred to as ERS. Existing literature suggests that ERS is a key mechanism mediating PF in AEC [345, 346]. For example, ER stress promotes inflammation, induces EMT, and activates pro-apoptotic pathways, leading to the generation of PF [345]. In order to maintain homeostasis, cells rely on protective mechanisms to help them cope with ER stress, collectively known as the unfolded protein response (UPR). When the UPR mechanism fails or is over-activated, it can lead to cell apoptosis [347].

ERS can be triggered by various factors, including genetics, environmental exposure, viral infections, and cellular aging. Studies have demonstrated that ERS induced by genetic mutations, such as those found in surfactant protein C (SFTPC), plays a significant role in the development of PF [348, 349]. Additionally, environmental factors can also induce ERS, which is a critical factor in the pathogenesis of PF. For example, research has shown that environmental factors like silica and cigarette smoke can trigger ERS, and airborne particulate matter can activate signaling pathways like PERK and ATF, inducing ERS in cells [350]. Cigarette smoke can cause ERS in bronchial epithelial cells, leading to cell apoptosis in both in vitro and in vivo settings [351, 352]. Viral infections may contribute to fibrosis development by inducing ERS and activating UPR. Research has demonstrated that aging mice infected with herpes virus may develop PF through mechanisms related to ERS [353]. Additionally, aging can impair normal ER function in organisms [354, 355], which is in line with clinical observations indicating that PF is more prevalent in older individuals. In conclusion, enhancing protein processing and mitigating downstream effects of ERS may be an effective strategy to treat fibrosis resulting from ERS.

Citrus reticulata Blanco peel is used to treat lung diseases in Chinese Traditional medicine. Recently, Wang's team carried out a study on citrus extract to improve PF [336]. The results shown that citrus extract could reduce collagen deposition in PF mice and inhibit the increase of endoplasmic reticulum stress biomarkers. Further cell experiments shown that citrus extract regulated ERS through PERK and ATF3/PINK1 pathways. However, it is unclear whether citrus alkaline extract can improve PF by regulating ERS, which still needs further experiments. This study provides an important reference for the mechanism of citrus extract in improving PF.

Chlorogenic acid is the main active ingredient of many TCMs, which has antibacterial, antiviral, and free radical scavenging pharmacological effects. Wang's team evaluated the effect of chlorogenic acid on improving PF related markers through mice and cell models [356]. The results shown that chlorogenic acid can effectively regulate the expression of PF related pathological markers, and reduce the degree of PF by inhibiting the ERS pathway. At the same time, chlorogenic acid plays a certain role in regulating apoptosis involved in PF. Although this study did not deeply explore the signal pathway involved in chlorogenic acid inhibiting ERS, it provided a new experimental reference for chlorogenic acid to improve PF.

Isorhamnetin is a flavonoid active compound in hippophae fructus, which has pharmacological effects such as antioxidant, anti-inflammatory, and anti-tumor. Recent research literature suggests that isorhamnetin can effectively inhibit bleomycin induced collagen deposition and reduce type I collagen and α-SMA [194]. In addition, they further demonstrated that isorhamnetin can improve the degree of PF by inhibiting EMT and ERS. Although more studies are needed to clarify the mechanism of Isorhamnetin in improving PF, this study shown for the first time the potential important value of isorhamnetin in improving PF.

In recent years, the research of citrus alkaline extracts, isorhamnetin and chlorogenic acid to improve PF has made great progress. These studies have explored the activity and pharmacological mechanism of these compounds to improve PF in animal or cell experiments, making these compounds possible candidates for new drugs to treat PF. However, it should be pointed out that these studies have failed to delve into the association between ERS and inflammatory response, EMT, and cell apoptosis, and also lack in-depth research on signaling pathways and molecular mechanisms. Therefore, future research should pay more attention to exploring the molecular mechanism and signal pathway of TCM in improving PF, so as to better understand the pharmacology and toxicology of these candidate compounds. In addition to the above-mentioned TCM that can improve PF, the detailed information of other TCM studies in the past five years that can improve PF through inhibition of endoplasmic reticulum stress were summarized and presented in Table 5.

Table 5 Details about some traditional Chinese medicines improving pulmonary fibrosis by inhibiting endoplasmic reticulum stress

Conclusion

PF is a prevalent lung disease, the prevalence and incidence of IPF increasing annually [6, 7]. If PF is not promptly and effectively treated, it will lead to a decline in lung function, which will have a negative impact on patients' quality of life and life expectancy [12]. In the last decade, glucocorticoids and immunosuppressants are commonly used in the treatment of PF, such as pirfenidone and nintedanib, but their efficacy is not ideal, they have many side effects, and they are expensive [14, 15]. Finding some reliable drugs from natural plants is becoming a research hotspot. TCM has been widely concerned because of its remarkable efficacy in treating or improving PF, mild side effects and low price. In the last five years, the scientific research on the improvement of PF by TCMs are increasing and has made great progress. Systematic and comprehensive summary of these research advances will help pharmaceutical researchers to understand the current research progress more quickly [16,17,18].

This article systematically reviews the progress in improving or reversing PF using traditional Chinese medicine in the last 5 years, and analyzes the major signaling pathways involved from a pharmacological perspective. Overall, the mechanism of improving PF mainly includes inhibiting EMT, anti-inflammatory and antioxidant, improving ECM deposition, mediating apoptosis and inhibiting ERS. The involved signaling pathways include TGF-β1/Smad, Nrf2/ARE, PI3K/AKT, NF-κB, etc. It is worth noting that the same Chinese medicine often involves multiple signaling pathways to improve pulmonary fibrosis, suggesting that these Chinese medicines have multi-target effects.

Although the experimental research of improving or treating PF with TCM has made some important progress, there are still some shortcomings. First, these experiments are mostly based on animal or cellular models and lack clinical trial validation. Secondly, most experiments often study only one or a few signaling pathways, lacking overall and comprehensive research. Third, because the pathogenesis of PF has not been fully elucidated, it also limits the depth of corresponding research in TCM, especially the toxicology research needs to be strengthened. What is most worth thinking about is how current pharmacological research can support the transformation of these TCM into new drugs.

On the basis of the existing known mechanisms of drug action, research methods based on artificial intelligence and big data computing are becoming the mainstream of drug development. The combination of computer aided drug design, drug molecular-target interaction, signaling pathway and pharmacological network, these new technologies will provide more than traditional research approaches to decrypt TCM treatment of PF, which will become a research hotspot in the near future.