Progress of Chinese Herbal Medicines Intervening in Acute Respiratory Distress Syndrome Through Multiple Mechanisms

Abstract

Acute respiratory distress syndrome (ARDS) is a critical pulmonary disorder triggered by multiple factors, with pathological mechanisms involving inflammatory storms, oxidative stress, alveolar-endothelial barrier disruption, and multiple cell death modalities (eg, pyroptosis and ferroptosis). Chinese herbal medicines(CHMs) and their active components have demonstrated their unique potential in the intervention of ARDS through multiple targets and multiple pathways approaches: (1) inhibiting the Wnt/β-catenin signaling pathway to mitigate inflammation; (2) regulating macrophage M1/M2 polarization; (3) activating the Sirtuin-3 (SIRT3) pathway to alleviate oxidative damage; (4) suppressing NLRP3 inflammasome-mediated pyroptosis; (5) improving barrier function via inhibition of the PI3K/AKT signaling pathway;(6) inhibiting ferroptosis through modulation of the Nrf2/SLC7A11/GPX4 axis. In the future, we can start from the pathogenesis of ARDS, and based on the efficacy and results of traditional Chinese medicine and its active components in regulating related signaling pathways to intervene in ARDS, provide references for the research and development of new drugs and clinical applications.

Introduction

Acute Respiratory Distress Syndrome is a critical condition frequently encountered in intensive care units, characterized by hypoxemia and non-cardiogenic pulmonary edema resulting from diverse intrapulmonary (eg, aspiration, pneumonia) or extrapulmonary (eg, sepsis, trauma, acute pancreatitis) etiologies. These pathological changes lead to decreased pulmonary compliance, elevated arteriovenous shunting, and increased physiological dead space, ultimately manifesting as severe hypoxemia.

In May 2023, the American Thoracic Society released a new global definition of ARDS, ¹ further expanding its diagnostic scope to include non-intubated ARDS, intubated ARDS, and ARDS in resource-limited environments. Not only were patients receiving high-flow nasal cannula (HFNC) included, but lung ultrasound was also allowed to replace chest imaging diagnosis. While advancements in respiratory support and anti-inflammatory therapies have improved ARDS management, no pharmacological agents currently demonstrate substantial mortality reduction or quality-of-life enhancement in ARDS patients. ² Epidemiological data from Chinese ICU indicate an ARDS incidence of 3.57%, ³ with a mortality rate reaching 44%. Survivors often experience long-term sequelae, including neurocognitive impairment, muscle atrophy, and pulmonary fibrosis, significantly impacting prognosis. ⁴

ARDS pathogenesis involves multifactorial mechanisms,including dysregulated inflammation (cytokine storm), oxidative stress, alveolar-endothelial barrier dysfunction, and aberrant cell death pathways (eg, pyroptosis, ferroptosis). Studies have found that CHMs have great potential in the prevention and treatment of ARDS, effectively improving ARDS in severe patients providing new ideas and methods for comprehensive prevention and treatment in the future. ⁵ This reviews the research progress of CHMs intervening in ARDS through different mechanisms, providing a reference for the development of new drugs and clinical applications (As shown in Figure 1).

Figure 1.

Multi-Mechanistic Interventions of Chinese Herbal Medicines against Acute Respiratory Distress Syndrome.

Inflammatory Response-Mediated ARDS

The Role of the Inflammatory Response in ARDS

The inflammatory response is a pivotal driver of ARDS pathogenesis. Intrapulmonary (eg, aspiration, pneumonia) or extrapulmonary (eg, sepsis, trauma) insults trigger systemic inflammation, increasing alveolar epithelial and vascular endothelial permeability. This facilitates the influx of inflammatory cells and fluid into alveolar spaces and pulmonary interstitium, ultimately leading to acute respiratory failure. ⁶ Neutrophil accumulation in alveolar and interstitial compartments is clinically and pathologically significant in ARDS progression.

In ARDS patients, neutrophils exhibit enhanced metabolic activity, chemotaxis, delayed apoptosis, and distinct transcriptional profiles.^7,8 Activated neutrophils and platelets form neutrophil extracellular traps (NETs)—chromatin-protein complexes that exacerbate lung injury. ⁹ Alveolar macrophages contribute to both pro-inflammatory and anti-inflammatory responses, modulating epithelial permeability. ¹⁰

CHMs Reduce Inflammatory Response to Improve ARDS

Plumbagin is a common herbal plant widely used in traditional Chinese medicine （TCM）drugs, and its main component, plumbagin, has a variety of pharmacological effects such as anti-inflammatory, antioxidant, antifibrotic, and antitumor effects.^11,12 It has been found that plumbagin has certain anti-inflammatory effects in organisms, and can effectively inhibit the production and secretion of inflammatory factors Interleukin-1β(IL-1β), Tumor necrosis factor-a（TNF-α）and Interleukin-6 (IL-6) in macrophages due to Lipopolysaccharide (LPS) stimulation production and secretion, and attenuate the inflammatory response. ¹³ In an animal model of LPS-induced ARDS in mice, it was demonstrated that the application of plumbagin had a protective effect on mice with ARDS, and that it might play an anti-inflammatory and antioxidant role by inhibiting the activation of the Wnt/β-catenin pathway, thus alleviating LPS-induced ARDS. ¹⁴

Syringin is an active substance isolated from the Acanthopanax plant, which has a good anti-inflammatory effect. ¹⁵ It has been shown that Syringin have a protective effect against brain injury by mediating the Forkhead box O3a (FOXO3a) nuclear factor kappa-B (NF-kB) pathway to reduce the inflammatory response during cerebral ischemia. ¹⁶ In the LPS-induced mice ARDS model, Syringin significantly inhibited the LPS-induced elevation of lung dry-to-wet ratio, myeloperoxidase activity, malondialdehyde content, and levels of TNF-α, IL-1β, and IL-6, and, through the activation of nuclear factor erythroid-2-related factor 2 (Nrf2) inhibits the NF-κB signaling pathway to ameliorate LPS-induced ARDS. ¹⁷ Meanwhile, Syringin attenuated inflammatory infiltrates, improved hypoxemia, and decreased alveolar lavage fluid IL-1β, interleukin-18 (IL-18) and TNF-α levels in ARDS rats, possibly through the modulation of miR-124-3p/mitogen-activated protein kinase 14 (MAPK 14) signaling pathway axis to alleviate ARDS in rats. ¹⁸

The Chinese medicine Scutellaria baicalensis is the dried root of Scutellaria baicalensis, a medicinal plant of the family Labiatae, which has the functions of regulating immunomodulation, antioxidant, anti-inflammatory and sedative. Meanwhile, baicalin, one of the basic components of Scutellaria baicalensis to exert its medicinal effects, and it has been confirmed in the relevant literature that baicalin may be exerting an inhibitory effect on the NF-κB signaling pathway, thus exerting anti-inflammatory and antioxidant efficacy to improve the damage of the organism to a certain extent.^19,20 In the LPS-induced mice ARDS model, baicalin effectively attenuated the levels of inflammatory factors in the lung tissue of mice, while Western blot was applied to detect the levels of pNF-κB p65, NF-κB p65, Toll-like Receptor4 (TLR4), Myeloid differentiation primary response88(MyD88),and other inflammatory factors in lung tissues. This finding suggest that baicalin likely exerts therapeutic effects on ARDS through inhibition of TLR4/MyD88/NF-κB signaling pathway activation, thereby mitigating pulmonary inflammatory responses. ²¹ This is consistent with the conclusion of Zhou et al's study, ²² which demonstrated that Tetrastigma hemsleyanum polysaccharide alleviates lung injury by modulating the TLR4/NF-κB-mediated inflammatory cascade.

Macrophage-Mediated ARDS

Role of Macrophages in ARDS

Macrophages are critical in ARDS pathogenesis. During the exudative phase, resident macrophages rapidly differentiate into M1-type macrophages upon stimulation. These activated M1 macrophages synthesize and secrete large quantities of chemokines, inflammatory cytokines (eg, IL-1β, IL-6, TNF-α), and proteolytic enzymes, exacerbating inflammation and promoting lung tissue damage. Additionally, alveolar macrophages recruit neutrophils through chemokine release, leading to neutrophil accumulation and infiltration into lung tissue. The released proteases degrade extracellular matrix components, further damaging lung structure and triggering a cascade of inflammatory responses. ²³ In the later stages of ARDS, macrophages transition to the M2 phenotype, which suppresses pro-inflammatory cytokine production and facilitates tissue repair. M2 macrophages also modulate fibrotic responses, potentially influencing the development of pulmonary fibrosis as a late complication. Thus, macrophages are integral to ARDS progression, with M1 macrophages dominating the acute inflammatory phase and M2 macrophages promoting resolution. Maintaining M1/M2 balance is crucial for therapeutic intervention. ²³

CHMs Regulation of Macrophage Function

Rhubarb (Rheum palmatum; Polygonaceae), consisting of the dried root and rhizome of the Rheum genus, is bitter and cold in nature, with TCM meridian tropism to the spleen, liver, stomach, large intestine, and pericardium. It exhibits therapeutic actions including purgation, heat clearance, blood-cooling detoxification, stasis elimination, and meridian dredging. The primary bioactive constituents are anthraquinones (eg, emodin), which demonstrate anti-inflammatory, antioxidant, antimicrobial, antitumor, and immunomodulatory effects.^24,25 Experimental evidence indicates that emodin ameliorates LPS-induced ARDS in rats via the vasoactive intestinal peptide (VIP)/cyclic adenosine monophosphate (cAMP)/protein kinase A (PKA) pathway, enhancing VIP, cAMP, and phosphorylated PKA (p-PKA) expression in lung tissues while suppressing NF-κB and MAPK phosphorylation. This dual modulation inhibits M1-type macrophage polarization, promotes M2-type polarization, and alleviates pulmonary edema. ²⁶

Paeoniflorin, a monoterpene glycoside from Paeonia lactiflora. Mice models suggest that Paeoniflorin may mitigate toxin-induced lung injury by inhibiting alveolar macrophage activation, restoring the M1/M2 macrophage balance, reducing neutrophil infiltration, decreasing myeloperoxidase activity, and suppressing the release of inflammatory factors, thereby exerting therapeutic effects against such injury. ⁵

Alveolar Epithelial and Pulmonary Capillary Endothelial Injury Mediated ARDS

The alveolar epithelium is composed of type I alveolar cells and type II alveolar cells. The extent of alveolar epithelial damage is a key determinant of survival in ARDS patients. Damage to the alveolar epithelial barrier leads to impaired fluid transport in the alveolar epithelium.^27,28 Injury to type II alveolar epithelial cells may impair surfactant production, and due to necrosis of pulmonary epithelium and leakage of cellular contents, damage-associated molecular patterns are released into the alveoli, amplifying pro-inflammatory signals. ²⁹ Activation of and damage to the alveolar epithelium also results in shedding of anticoagulant molecules and release of tissue factor from the alveolar epithelium into the alveolar space. Pulmonary endothelial injury is a core feature of ARDS, characterized by gap formation between endothelial cells, upregulation of adhesion molecules such as P-selectin and E-selectin, and elevated levels of endothelial injury mediators like angiopoietin-2. ³⁰ Endothelial injury leads to reduced expression of anticoagulant molecules (eg, thrombomodulin and endothelial cell protein C receptor) on the endothelial surface and increased procoagulant molecule expression, promoting microvascular thrombosis. ³¹ Alveolar epithelial and endothelial injury, through barrier disruption, amplified inflammation, and coagulation abnormalities, form the core pathological network of ARDS. These changes culminate in alveolar edema, dysregulation of ventilation-perfusion ratios, increased shunting, lung atelectasis, reduced lung compliance, and potentially pulmonary hypertension with acute right ventricular dysfunction.

CHMs Regulates Alveolar Epithelial and Vascular Endothelial Cell Function to Improve ARDS

Biochanin A (BCA), a phytoestrogen extracted from chickpea, belongs to the flavonoids group and possesses a variety of biological activities such as anti-inflammatory, antitumor, antiviral, and neuroprotective activities. ³² BCA is also a natural antioxidant, which can alleviate LPS-induced ARDS in mice by inhibiting the TLR4/NF-κB signaling pathway and thereby suppressing the inflammatory response. ³³ In LPS-induced injury in human alveolar epithelial cells, intervention with BCA resulted in elevated superoxide dismutase (SOD) activity in alveolar epithelial cells, whereas apoptosis rate, reactive oxygen species (ROS) and malondialdehyde (MDA) levels, TNF-α, IL-6, Bcl-2-associated X protein (Bax), and cysteine-aspartic protease-3 (Caspase-3) were reduced, suggesting that BCA enhanced the proliferation and inhibited the apoptosis of LPS-induced alveolar epithelial cells, and that this may be related to the activation of the Nrf2/heme oxygenase 1 (HO-1) signaling pathway. ³⁴

The main ingredients of Fu Zheng Detoxification Formula consist of 8 Chinese medicines in proportion, namely, cooked dried ginger, epimedium, saponaria, roasted licorice, honeysuckle, Chenpi, Wu Jia Long, and patchouli, which is an empirical formula used by Prof. Zhong De Zhang, a renowned scholar in Traditional Chinese Medicine, in the clinical treatment of COVID-19 patients with ARDS. ³⁵ Some studies have shown that Fu Zheng Xie Du Fang is effective in the treatment of ARDS in COVID-19 patients, alleviating disease progression, reducing mortality rates, and significantly shortening fever duration. ³⁵ It has also been demonstrated that in LPS-induced co-culture systems of mice alveolar macrophages and type II alveolar epithelial cells, Fuzheng Detoxification Formula down-regulates the activation of the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt) signaling pathway, suppresses oxidative stress molecules and inflammatory mediators, inhibits M1-type macrophage proliferation, and improves the barrier function of type II alveolar epithelial cells, thereby exerting a protective effect against ARDS.^36,37

Oxidative Stress-Mediated ARDS

Role of Oxidative Stress in ARDS

Studies have shown that oxidative stress plays a key role in damaging DNA, inducing lipid peroxidation (LPO), and inducing pulmonary edema, as well as promoting LPO production and macrophage activation, which can cause upregulation of pro-inflammatory cytokines, leading to the development of ARDS.^38,39 Immune cells in the lung microenvironment generate excess ROS via NADPH oxidase (NOX) and the mitochondrial electron transport chain. ROS directly induce LPO, protein inactivation, and DNA damage in alveolar epithelial and endothelial cells, leading to apoptosis and barrier integrity destruction. Simultaneously, ROS amplify the inflammatory cascade by activating signaling pathways such as NF-κB and nucleotide-binding oligomerization domain-like receptor 3 (NLRP3) inflammasome, promoting the release of pro-inflammatory factors such as IL-1β and TNF-α, and forming an oxidative-inflammatory vicious cycle. Therefore, oxidative-antioxidant balance is crucial for vascular homeostasis, and antioxidants are gradually becoming one of the most important therapeutic approaches for ARDS. ⁴⁰

CHMs Modulation of Oxidative Stress Improves ARDS

Honokiol (HKL) is a natural small molecule product extracted from the bark of Magnolia officinalis. Some studies have demonstrated that HKL has antioxidant, anti-inflammatory, antitumor, and antiangiogenic effects. ⁴¹ In one study, HKL was found to have protective effects on epithelial and endothelial cells in mice with LPS-induced ARDS.^42,43 In another study, HKL was found to activate the Nrf2 signaling pathway, up-regulate the expression of SOD, HO-1, and Nrf2, down-regulate the expression of MDA and LPO, and reduce oxidative stress, as well as inhibit the NLRP3 inflammasome, in order to attenuate LPS-induced ARDS in mice. ⁴² In addition, it has also been found that in LPS-treated endothelial cell membranes were disrupted and lung microvascular endothelial cells in mice, only intracellular structures were retained, which demonstrated that LPS disrupts intercellular tight junction structures, while HKL ameliorates LPS-induced ARDS by stabilizing cellular endothelial cells. ⁴⁴

Salvia divinorum is the dried root and rhizome of Salvia divinorum, a dicotyledonous herb of the Lamiaceae family. The main active ingredient of Salvia miltiorrhiza is Salvianolic acid A (SalA), a water-soluble phenolic compound with various effects such as scavenging free radicals, antioxidant, anti-inflammatory, etc, which has a protective effect on the heart, liver, brain, and kidneys, etc ⁴⁵ An experiment showed that SalA could significantly reduce the release of systemic and intracellular inflammatory factors TNF-α and IL-6, alter LPS-stimulated cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) expression, and significantly improve LPS-induced ARDS. ⁴⁶ In a study by Shilin He et al, ⁴⁷ the protective effect of SalA on LPS-induced ARDS was confirmed in relation to the sirtuin-3 (SIRT3) signaling pathway; the selective SIRT3 inhibitor, 3-TYP, significantly reduced these protective effects of SalA on ARDS, suggesting that SalA may exert its protective effect on ARDS through activation of the SIRT3 signaling pathway.

Cellular Autophagy-Mediated ARDS

Role of Cellular Autophagy in ARDS

Cellular autophagy is a process of cellular degradation and recycling that maintains cellular homeostasis and plays an important role in immunity, inflammation, and cell survival. Cellular autophagy plays a dual role in the occurrence and development of ARDS. On the one hand, autophagy reduces ROS accumulation and inflammasome activation by degrading damaged mitochondria and misfolded proteins, thereby inhibiting the release of pro-inflammatory factors and attenuating lung injury; on the other hand, autophagy can lead to apoptosis and exacerbate lung injury. ⁴⁸ Some studies have shown that in the LPS-induced ARDS model, the expression of PI3K, Akt, and mammalian target of rapamycin (mTOR) increased in lung tissues, which decreased autophagy and aggravated the inflammatory response of lung tissues. Blocking the mTOR pathway significantly reduced lung injury, suggesting that increasing autophagy is beneficial to alleviate lung injury. ⁴⁹ Other studies have shown that LPS can induce apoptosis in lung macrophages through autophagy, and blocking autophagy can reduce the level of inflammatory factors, while increasing autophagy can aggravate lung injury. ⁵⁰ In a rat model of lung injury, He et al demonstrated that miR-223-3p-mediated regulation of autophagy not only enhanced autophagic activity but also suppressed apoptosis and inflammatory responses, thereby effectively alleviating lung injury. ⁵¹ Therefore, targeted regulation of autophagy in cells may be an effective strategy for treating ARDS and is of great significance for controlling the progression of ARDS.

CHMs Regulation of Autophagy in ARDS

The roots and stems of Glycyrrhiza glabra act as natural sweeteners and herbs. Glycyrrhizic acid (GA), one of the components extracted from the roots of Glycyrrhiza glabra, consists of 18β-glycyrrhizic acid and two molecules of glucuronide, which is known to have anti-inflammatory, anti-apoptotic, and antiviral effects. ⁵² In the LPS-induced lung injury model in mice, GA was applied to intervene and inhibit the expression of inflammatory factors TNF-α, IL-1β, and high mobility group box 1 protein (HMGB1) in ARDS by inducing autophagy, which may induce cellular autophagy through the PI3K/AKT/mTOR pathway, thereby inhibiting the expression of inflammatory factors in LPS-induced ARDS, thus exerting a lung-protective effect. ⁵³

Liang-Ge-San is a classic Chinese medicine prescription, composed of several Chinese medicines, including forsythia, scutellaria, gardenia, rhubarb, mangosteen, peppermint, bamboo leaves, licorice, and honey. It can clear and dissipate the pent-up heat of the middle and upper Jiao, and it is mainly used in the clinical treatments of pharyngitis, tonsillitis, ARDS, acute pancreatitis, gastroenteritis, and other diseases. In the LPS-induced acute inflammation model of zebrafish, Liang-Ge-San reduced the levels of TNF-α and IL-6, inhibited the acute inflammatory response, and improved the survival rate of zebrafish. ⁵⁴ In ARDS patients and vivo study, the application of hemopexin combined with Liang-Ge-San reduced the percentage of neutrophils and white blood cell counts and improved ARDS.^54,55 The significant therapeutic effect of Liang-Ge-San on ARDS rats may be related to the inhibition of extracellular signal-regulated kinase 1/2 (ERK1/2), p-PI3K, p-AKT, and p-ERK1/2, the increase of autophagy, the reduction of pro-inflammatory factor release, and the inhibition of inflammatory response. ⁵⁶

Ferroptosis-Mediated ARDS

Role of Cellular Ferroptosis in ARDS

Ferroptosis is a form of cell death induced by oxidative stress. Under physiological conditions, low levels of ROS are involved in cell signaling and maintaining normal cellular metabolic functions. However, an imbalance between ROS generation and antioxidant scavenging causes oxidative stress, damaging pulmonary capillary endothelial cells and alveolar epithelial cells. Lipid peroxidation of the lipid bilayer occurs, and iron overload promotes the conversion of hydrogen peroxide into free radicals via the Fenton reaction, further aggravating cellular damage, leading to irreversible cellular changes, cell death, and ARDS progression.^57,58 Studies have shown that iron overload, ROS accumulation, increased MDA, and decreased expression of solute carrier family 7 member 11 (SLC7A11) are present in bronchial epithelial cells of LPS-induced ARDS mice. Ferroptosis inhibitors effectively alleviated LPS-induced lung injury, suggesting that ferroptosis contributes to sepsis-associated lung injury. ⁵⁹

CHMs Modulation of Ferroptosis in ARDS

Phillyrin(KD-1), which is mainly found in the roots, stems, leaves and fruits of plants, is an effective lignan extracted from the traditional Chinese medicine forsythia. KD-1 has been shown to possess anti-inflammatory, antiviral, antibacterial, and antitumor efficacy in in vitro and in vivo models. Studies have shown that KD-1 can attenuate ARDS by inhibiting NF-κB and MAPK activation in ARDS mice. ⁶⁰ It has also been shown that Ferroptosis was present in both in vivo and in vitro models of LPS-induced ARDS, while iron inhibitors attenuated inflammation in the corresponding models, suggesting that inhibition of Ferroptosis may contribute to the amelioration of ARDS. Similar to the effects of iron inhibitors, KD-1 can modulate the Janus kinase 2（JAK2）/Signal transducer and activator of transcription 1（STAT1）signaling pathway and alter changes in indicators of Ferroptosis, thereby attenuating ARDS, and offering new possibilities for future ARDS treatment by providing new ideas. ⁶¹

Qingqi Liangying Fang is composed of Gypsum, Zhi Mu, Draba hebecarpa, Red Peony, Xuan Shen, Sheng Gan Cao,Radix et Rhizoma Glycyrrhizae, Rhizoma Dioscoreae, Forsythia, Dandelion, Rhizoma Polygonati Odorati, and Bamboo Leaf, which has antipyretic, anti-inflammatory, antiviral, and antioxidant pharmacological effects. Qingqi Liangying Fang reduces pro-inflammatory factor levels, decreases MDA content, increases SOD activity to alleviate oxidative stress injury, and effectively inhibits ferroptosis by upregulating the Nrf2/SLC7A11/GPX4 signaling pathway in LPS-induced ARDS mice, confirming its therapeutic role in sepsis-induced ARDS. ⁶²

Cellular Pyroptosis-Mediated ARDS

Role of Cellular Pyroptosis in ARDS

Cellular pyroptosis is a form of inflammatory cell death characterized by cell membrane pore formation, DNA cleavage, nuclear condensation, and subsequent cell lysis, which triggers an immune-inflammatory response. In sepsis, moderate pyroptosis aids pathogen control, while excessive pyroptosis may lead to immune dysregulation and organ dysfunction. ⁶³ Pyroptosis is mediated by inflammasomes (eg, NLRP3) that recognize pathogen-associated molecular patterns (PAMPs) or damage-associated molecular patterns (DAMPs), activating cysteinyl aspartate-specific proteinase-1 (Caspase-1). This process promotes the secretion of mature IL-1β and IL-18, ultimately exacerbating lung injury. ⁶⁴ Recent studies indicate that Caspase-1 inhibitors attenuate LPS-induced ARDS in mice by suppressing macrophage pyroptosis, highlighting the involvement of NLRP3 inflammasome and Caspase-1 activation in ARDS pathogenesis. ⁶⁵ Additionally, in vivo models,LPS induces mice pulmonary vascular endothelial cell pyroptosis through TLR4-mediated activation of Caspase-1 and NLRP3 inflammasome. ⁶⁶ Thus, pyroptosis of pulmonary endothelial cells and macrophages plays a pivotal role in ARDS progression.

Modulation of Cellular Pyroptosis by CHMs in ARDS

Oridonin (Ori), a compound derived from Gaultheria procumbens (wintergreen), exhibits anti-inflammatory, antitumor, and immunomodulatory properties. ⁶⁷ Studies indicate that the methanol extract of Rabdosia rubescens (dongling grass) specifically inhibits NLRP3 inflammasome activation and ameliorates ARDS in mice. ⁶⁸ In the study by Dang Wenpei et al, ⁶⁹ intervention with Ori reduced inflammatory response levels, pulmonary capillary permeability, and alveolar macrophage pyroptosis in LPS-induced ARDS mice, attenuating lung injury. This suggests that its therapeutic effect is mediated through inhibition of alveolar macrophage pyroptosis.

The main bioactive components of tetrastigma hemsleyanum Diels et.Gilg are flavonoids, which exert antioxidant effects and modulate apoptotic and necrotic pathways. Their mechanisms include inhibiting viral replication, blocking viral adsorption, suppressing inflammatory factor secretion, enhancing immunity, regulating inflammatory protein expression, and inhibiting inflammatory pathway activation (eg, MAPK and NF-κB). ⁷⁰ A mice in vivo model, tetrastigma hemsleyanum Diels et.Gilg Flavone significantly attenuated oxidative stress by upregulating SOD and glutathione peroxidase activity, downregulating MDA and lactate dehydrogenase (LDH) levels, and suppressing TLR4, COX-2, and NF-κB p50 protein expression. These findings suggest that tetrastigma hemsleyanum Diels et.Gilg Flavone ameliorate ARDS by mitigating oxidative stress and inflammation via the TLR4/COX-2/NF-κB signaling pathway. ⁷¹ Additionally, tetrastigma hemsleyanum Diels et.Gilg Flavone from Triticum aestivum inhibit serum inflammatory factor secretion and NLRP3 inflammasome-associated protein expression in lung tissues of ARDS mice, indicating their role in alleviating ARDS through NLRP3 inflammasome-mediated pyroptosis inhibition. ⁷²

Conclusion

ARDS, a highly lethal complication in critically ill patients, involves multiple pathologic mechanisms, including uncontrolled inflammation, oxidative stress, cell death modalities (eg, pyroptosis, ferroptosis), and barrier function disruption. Despite advancements in lung-protective ventilation and anti-inflammatory therapies, there remains a lack of specific pharmacological agents targeting the core pathological pathways. Herbal medicines and their bioactive components demonstrate unique therapeutic potential through multi-target and multi-pathway interventions. However, current research is predominantly limited to animal models or small clinical cohorts, and mechanistic analyses are constrained by the complexity of herbal constituents. Additionally, large-scale randomized controlled trials are needed to validate efficacy and safety. Future studies should integrate metabolomics, single-cell sequencing, and network pharmacology to systematically elucidate the targets and metabolic pathways of herbal active ingredients. Furthermore, developing targeted drug delivery systems to enhance lung tissue specificity is critical. In conclusion, while Chinese herbal medicines offer innovative therapeutic strategies for ARDS, their clinical translation requires interdisciplinary collaboration to overcome challenges in mechanistic evaluation, standardized preparation, and bridging the gap between experimental evidence and clinical application.