Regulatory Roles of Traditional Chinese Medicine in Inflammatory in Acute Lung Injury: From Molecular Mechanisms to Clinical Applications

Abstract

Acute lung injury (ALI) is a life-threatening syndrome characterized by dysregulated inflammatory responses, disruption of the alveolar–vascular barrier, and severe respiratory dysfunction. With a complex pathogenesis and high mortality, ALI remains a major clinical challenge. Traditional Chinese medicine (TCM) offers distinctive therapeutic advantages in ALI management through its integrated regulatory mechanism involving “multiple-components, multiple-targets, and multiple-pathways”. TCM monomers, TCM compound prescriptions, and Chinese proprietary medicines have been shown to attenuate pulmonary pathology by suppressing the release of pro-inflammatory mediator, inhibiting inflammatory signaling cascades, modulating immune cell polarization, and alleviating oxidative stress. Retrieve relevant literature from PubMed, Web of Science, and Google Scholar databases based on abstracts, conclusions, and experimental content. Based on the aforementioned literature, this review systematically examines the mechanistic basis by which TCM regulates inflammation in ALI, beginning with the pivotal role of inflammation in disease progression, and aims to provide insights to guide TCM pharmacological research and novel drug development in this field.

Introduction

Acute lung injury (ALI) is a severe clinical syndrome characterized by damage to pulmonary capillary endothelial cells and alveolar epithelial cells, typically arising from severe infection, shock, trauma, and other critical conditions. The resulting disruption of the alveolar–capillary barrier leads to non-cardiogenic pulmonary edema. ¹ Clinically, ALI presents with dyspnea, pulmonary edema, impaired gas exchange, progressive hypoxemia, and decreased lung compliance, and may evolve into the more severe acute respiratory distress syndrome (ARDS). ² The hallmark pathological features of ALI include inflammatory cell infiltration, excessive production of inflammatory mediators, and diffuse pulmonary inflammation, ultimately damaging parenchymal lung cells such as vascular endothelial and alveolar epithelial cells. ³ Clinically, ALI presents with an acute onset and high mortality. Although diverse therapeutic strategies have been explored, effective treatment options remain limited. Current management primarily relies on comprehensive interventions such as nutritional support, mechanical ventilation, and corticosteroid administration to improve survival. However, these approaches may be associated with adverse effects—including exacerbation of lung injury, coagulopathy, and gastric ulceration—and mortality rates remain unacceptably high.^4,5 These challenges highlight the urgent need for more effective and safer therapeutic strategies.

Current consensus holds that a dysregulated cascade of inflammatory responses constitutes the central pathological mechanism of ALI. ⁶ When the body is stimulated, signaling pathways such as the mitogen-activated protein kinase (MAPK) signaling pathway, nuclear factor kappa-B (NF-κB) signaling pathway, NOD-like receptor protein 3 (NLRP3) inflammasome signaling pathway, phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt) signaling pathway, and nuclear factor erythroid 2–related factor 2 (Nrf2) signaling pathway are activated or inhibited to varying degrees. This leads to abnormal activation of inflammatory cells, including mononuclear phagocytes, neutrophils, and T/B lymphocytes, resulting in the release of pro-inflammatory cytokines such as tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and interleukin-1β (IL-1β). These mediators interact through cross-regulation, promoting their accumulation in the alveolar microenvironment and further regulating intracellular signaling pathways, exacerbating cytokine release. This vicious cycle of inflammatory cascades causes severe lung damage and may affect multiple organ systems.^7,8

Traditional Chinese medicine (TCM), an integral component of China's medical heritage, is characterized by favorable safety profiles and low toxicity. Guided by the principles of “holistic regulation” and “syndrome differentiation and treatment,” TCM demonstrates distinct advantages in ALI prevention and therapy through its multi-component, multi-target, and multi-pathway actions. TCM interventions have been shown to modulate inflammatory responses, attenuate oxidative stress, regulate immune function, and ameliorate pulmonary pathological injury,^9–13 thereby conferring significant therapeutic benefits. This paper reviews the roles of signaling pathways such as MAPK, NF-κB, NLRP3, PI3K/Akt, and Nrf2 in the pathological development of ALI. It focuses on the anti-inflammatory effects of TCM monomers, TCM compound prescriptions, and Chinese proprietary medicines in ALI by regulating cytokines such as IL-6, TNF-α, IL-1β, malondialdehyde (MDA), and superoxide dismutase (SOD) through relevant signaling pathways. The aim is to provide a theoretical foundation and reference framework for the prevention and treatment of ALI through TCM the regulation of inflammatory responses.

Regulatory Mechanisms of Inflammatory Responses in ALI

Inflammatory Response and ALI

Inflammatory responses are a critical component of the host defense system, representing a physiological reaction to external insults and pathological injury. However, excessive or uncontrolled inflammation can itself cause significant tissue damage. ¹⁴ In the context of an ALI, hyperactive inflammatory responses—whether localized to the lung or systemic—are recognized as central to disease pathogenesis. ⁶ Excessive inflammation leads to the overproduction of inflammatory mediators, including pro-inflammatory cytokines, reactive oxygen species (ROS), and chemokines. ¹⁵ These mediators interact in a feed-forward manner, driving inflammatory cell recruitment and infiltration into lung tissue, activating downstream signaling pathways, and amplifying cytokine release. This self-perpetuating cycle can culminate in a cytokine storm,^7,16,17 thereby accelerating ALI progression.

Among the various inflammatory cells involved, neutrophils and macrophages play pivotal roles.^18,19 Neutrophils migrate to the site of inflammation when the body experiences inflammation, further exacerbating tissue damage. ²⁰ Activated neutrophils are one of the primary causes of accelerated ALI progression and worsening. ²¹ Myeloperoxidase (MPO), a product of neutrophil activation, promotes the release of a series of inflammatory mediators and pro-inflammatory factors. Similarly, macrophages are central regulators of inflammatory processes in ALI. External stimuli can induce the polarization of alveolar macrophages toward the pro-inflammatory M1 phenotype, which secretes large amounts of inflammatory mediators and aggravates pulmonary injury.^22,23

Oxidative stress is intimately linked with the inflammatory cascade in ALI. When the body is stimulated, it produces excessive ROS, leading to abnormal expression of glutathione (GSH), SOD, catalase (CAT), nitric oxide (NO), etc, causing an imbalance in redox reactions and ultimately resulting in damage to lipids, proteins, and Deoxyribonucleic Acid (DNA). ²⁴ Oxidative stress disrupts the alveolar-vascular barrier, further promoting inflammatory responses and causing sustained damage to the body's cells. This leads to the infiltration of inflammatory factors into the alveolar space, resulting in pulmonary inflammation and edema. ² In addition, oxidative stress in lung tissue can directly damage cellular structures, activate neutrophils, stimulate macrophages to release pro-inflammatory cytokines, and initiate inflammatory signaling cascades. These events promote cytokine storm formation and damage to vascular endothelial and alveolar epithelial cells,^25,26 ultimately worsening the pathological state of ALI. The relevant mechanism is shown in Figure 1.

Figure 1.

Mechanism of action of ALI regulated by major inflammatory response signaling pathways.

ALI Mainly Related Inflammatory Signaling Pathways

MAPK Signaling Pathway

The MAPK signaling pathway plays a pivotal role in the pathogenesis of ALI, regulating inflammatory responses and tissue injury through multiple mechanisms, thereby influencing disease progression. The MAPK family primarily comprises extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK), and p38 MAPK. ²⁷ During ALI development, activation of MAPK signaling promotes the synthesis and secretion of pro-inflammatory mediators, including TNF-α, IL-6, and IL-1β, which further amplify both local and systemic inflammation. ²⁸ Among these subtypes, p38 MAPK and ERK are particularly critical, as they regulate pro-inflammatory gene expression and promote the recruitment and migration of inflammatory cells into lung tissue. ²⁹ In the early stages of ALI, MAPK activation enhances inflammatory cell adhesion and transmigration into injured regions, where they release large quantities of cytokines and chemokines, exacerbating pulmonary inflammation and structural damage. ²⁸ Research on the involvement of MAPK signaling pathways in ALI through regulation of inflammatory responses has made considerable progress. However, due to the intricate mechanisms underlying MAPK signaling in ALI and the cross-talk among its three major pathways—which act on certain common substrates—different stimuli, and even identical ones, can yield varying responses. In-depth investigation into the mechanisms of MAPK signaling pathways during ALI progression will provide additional theoretical foundations for clinical treatment of ALI.

NF-κB Signaling Pathway

The NF-κB signaling pathway is a key regulator inflammatory responses. The NF-κB signaling pathway promotes the occurrence of inflammatory responses by regulating the expression of various pro-inflammatory cytokines. In normal physiological conditions, NF-κB forms a complex with inhibitor of NF-κB (IκB) protein and remains in an inactive state in the cytoplasm. ³⁰ Upon exposure to infection, tissue injury, or inflammatory stimuli, pattern recognition receptors such as Toll-like receptors (TLRs) detect pathogen-associated molecular patterns (PAMPs) or damage-associated molecular patterns (DAMPs), leading to the activation of inhibitor of kappa B kinase (IKK).^2,31 IKK phosphorylates IκB, triggering its degradation and the release of NF-κB, which subsequently translocates into the nucleus to initiate transcription of pro-inflammatory genes, including TNF-α, IL-1β, and IL-6. ³² In ALI, persistent NF-κB activation drives the excessive recruitment of inflammatory cells, particularly neutrophils, which release mediators that not only intensify inflammation but also increase pulmonary microvascular permeability. This vascular leakage allows protein-rich fluid to enter the alveolar space, leading to pulmonary edema, interstitial injury, and impaired gas exchange.^33–35 The NF-κB signaling pathway is closely associated with the onset and progression of ALI, primarily regulating inflammatory responses and oxidative stress while cross-talking with multiple signaling pathways to influence processes such as autophagy and immune responses. Increasing evidence indicates that modulating this signaling pathway can effectively intervene in ALI progression. Consequently, exploring ALI therapeutic agents based on this pathway holds great promise. Although extensive basic research supports that Chinese herbal medicine intervention in the NF-κB signaling pathway significantly improves ALI, sufficient clinical data to validate its safety and efficacy in humans remains lacking. Therefore, conducting clinical studies based on the NF-κB signaling pathway remains a critical area requiring further development.

NLPR3 Inflammasome Signaling Pathway

The NLRP3 inflammasome has emerged as a key intracellular immune complex in the initiation and progression of ALI. Its activation exacerbates pulmonary inflammation by promoting the release of pro-inflammatory cytokines, increasing microvascular permeability, recruiting neutrophils, and inducing oxidative stress. Upon activation, the NLRP3 inflammasome triggers Caspase-1 activation, leading to the maturation and secretion of IL-1β and interleukin-18 (IL-18), which initiate robust local immune responses and recruit additional inflammatory cells into the lungs.^36–38 While physiological ROS levels are essential for cellular homeostasis, excessive ROS in ALI activate the NLRP3 inflammasome, thereby amplifying inflammatory signaling and lung injury.^25,39 Beyond inflammation, NLRP3 activation is associated with increased pulmonary vascular permeability, apoptosis, and structural lung damage.^40,41 NLRP3 inflammasome is closely associated with ALI, and dysregulation of any protein or inflammatory factor in its upstream or downstream pathways may trigger pulmonary inflammatory responses. Further research is needed to elucidate how NLRP3 inflammasome activation contributes to ALI pathogenesis and whether the NLRP3 multiprotein complex is regulated by genetic factors. Future research may focus on upstream regulators of the NLRP3 inflammasome and on developing specific interventions targeting its assembly. As multiple studies on the NLRP3 inflammasome emerge, targeted drug inhibition of the NLRP3 inflammatory pathway may become a significant direction for preventing and treating pulmonary diseases.

PI3K/Akt Signaling Pathway

The PI3K/Akt signaling pathway in regulating inflammation in ALI has been widely studied. This pathway regulates neutrophil apoptosis by modulating cell proliferation, differentiation, programmed cell death, and migration, thereby regulating the inflammatory response in lung tissue and significantly influencing the pathological progression of ALI. ⁴² The PI3K/Akt signaling pathway is activated by ROS, cytokines, etc Persistent activation of Akt enhances the survival capacity of alveolar macrophages, neutrophils, and T lymphocytes, and indirectly leads to the recruitment of these inflammatory cells in the airways and lung parenchyma. ⁴³ The NF-κB signaling pathway is a highly important inflammatory response signaling pathway, and its development is closely related to the PI3K/Akt signaling pathway. On one hand, Akt promotes the degradation of IκB by phosphorylating it, thereby releasing NF-κB and driving the expression of pro-inflammatory cytokines such as TNF-α, IL-1β, and IL-6, which disrupt the stability of the alveolar capillary barrier. On the other hand, Akt can directly phosphorylate the transcription activation domain of NF-κB p65, enhancing its DNA-binding capacity and further amplifying pro-inflammatory signals. ⁴⁴ With advances in medicine and high-tech innovations, research on PI3K/Akt signaling substrates and drug development targeting the PI3K/Akt pathway will continue to mature. However, the precise mechanisms by which the PI3K/Akt signaling pathway regulates cell-related factors remain highly complex. Multiple associated proteins and biomolecules participate in signal modulation, necessitating further in-depth investigation, building upon prior work to provide greater support for clinical diagnosis and drug therapy.

Nrf2 Signaling Pathway

The Nrf2 is an important transcription factor that regulates the inflammatory response in ALI and plays a crucial role in suppressing inflammatory responses. Under physiological conditions, Nrf2 binds to kelch-like ECH-associated protein 1 (Keap1) in the cytoplasm and is ubiquitinated and degraded. ⁴⁵ Under oxidative stress or other pathological stimuli, the cysteine residue of Keap1 is modified, causing Nrf2 to dissociate from the complex and enter the cell nucleus. There, it forms a heterodimer with the small Maf protein and binds to the antioxidant response element (ARE), thereby activating the transcription of a series of antioxidant genes downstream, such as heme oxygenase-1 (HO-1), SOD, and CAT. This process helps eliminate ROS and other harmful substances while initiating cellular protective mechanisms such as antioxidant, anti-inflammatory, and anti-apoptotic responses. ⁴⁶ Among these, HO-1, as a key downstream effector molecule, can catalyze the degradation of heme into biliverdin, Ferrous ion (Fe²⁺), and carbon monoxide (CO). These substances can effectively inhibit lipid peroxidation and ferroptosis, and can suppress the release of pro-inflammatory factors such as TNF-α, IL-6, and IL-1β.^47,48 The Nrf2 signaling pathway scavenges excess ROS and inhibits the inflammatory cascade through the dual mechanism of “antioxidant-anti-inflammatory”, and plays a key protective role in ALI induced by various factors. The Nrf2 signaling pathway exerts a protective effect in various factors-induced acute lung injury (ALI) by scavenging excess reactive oxygen species (ROS) and suppressing cytokine storms. Therefore, the Nrf2 signaling pathway holds promise as a novel therapeutic target for ALI drug development. Certain Chinese herbal medicines have been demonstrated to activate the Nrf2 signaling pathway during ALI pathogenesis; however, these findings remain confined to animal studies. Whether these compounds can be applied clinically requires further investigation and discussion.

TCM Treats ALI by Regulating Inflammatory Responses

Although ALI has no direct equivalent in the terminology of TCM, its clinical manifestations—such as progressive hypoxemia and respiratory distress—can be classified under categories including “asthma syndrome” or “sudden asthma”. ⁴⁹ In TCM clinical practice, common syndrome patterns of ALI include intestinal heat and organ obstruction, phlegm-heat obstructing the lungs, heat-toxin stagnation, blood stasis, and deficiency of vital energy, reflecting the prominent roles of “heat,” “toxicity,” “phlegm,” and “stasis” in its pathogenesis. While the term “inflammation” is not explicitly used in TCM, the concepts of “heat-toxin,” “pathogenic factors,” and “stasis obstruction” ⁵⁰ provide a systematic theoretical framework for understanding and managing inflammatory processes.

From a TCM perspective, the fundamental nature of ALI is “external pathogens invading the lungs,” with “heat-toxin obstructing the lungs” as a central pathogenic mechanism. ⁵¹ Exogenous pathogenic factors, such as the six exogenous pathogens and epidemic pathogens, particularly wind-heat, damp-heat, and toxic pathogens, invade the lungs, leading to impaired lung function, stagnation of qi, and the transformation of qi into fire and heat. This results in “internal accumulation of heat toxins” which can be analogized in modern medicine to immune responses activated by pathogenic infections or inflammatory stimuli. As stated in the Treatise on Warm-Heat Diseases “Warm pathogens invade from above, first affecting the lungs.” In the early stages of ALI, the rapid aggregation and activation of inflammatory cells release large amounts of cytokines such as TNF-α, IL-1β, and IL-6, triggering a cascade of inflammatory responses. The TCM theory of “blood stasis causing disease” also provides insights into explaining microthrombosis formation in capillaries, uneven blood flow perfusion, and pulmonary microcirculatory disorders in ALI. These processes are manifested in TCM as “excessive heat obstructing the lungs”, “heat toxins attacking the interior”, and “blood stasis obstructing the meridians” leading to excessive heat toxins, obstruction of lung meridians, and impaired qi and blood circulation.

One hallmark pathological feature of ALI is markedly increased pulmonary microvascular permeability, resulting in protein-rich alveolar exudates, pulmonary edema, hyaline membrane formation, interstitial fibrosis, and diffuse bilateral pulmonary infiltrates. Modern medical consensus attributes these changes to uncontrolled pulmonary inflammation and subsequent damage to the alveolar–capillary membrane. In TCM theory, the lungs are regarded as “the upper source of water,” responsible for regulating water pathways and fluid transformation. Dysfunction in this role leads to impaired water circulation and fluid retention, consistent with the modern pathophysiological model of pulmonary edema formation.

Based on the aforementioned pathogenesis, TCM treatment often focuses on methods such as heat-clearing and detoxifying, and blood-activating and stasis-removing. The goal is to inhibit the progression of pathogenic factors, reduce lung parenchymal damage, and regulate the body's inflammatory response. TCM does not simply “inhibit” inflammation but emphasizes harmonizing yin and yang and strengthening the body while expelling pathogenic factors. In the later stages of ALI, patients often present with “deficiency of both qi and yin” and “deficiency of both lung and kidney.” At this stage, continuing to solely clear heat may instead harm the body's balance, so treatment principles that tonify qi, nourish yin, and harmonize the viscera must be applied. This “holistic concept” and “syndrome differentiation and treatment” model differs from modern medicine's single-target intervention approach and is better suited to the complexity of ALI, a disease with multiple causes and systemic inflammatory responses.

Research on the Treatment of ALI Using TCM to Regulate Inflammatory Responses

TCM Monomers

TCM monomers, characterized by well-defined pharmacological activities and high chemical stability, play an indispensable role in the prevention and treatment of ALI. In recent years, extensive research has revealed that various classes of TCM monomers—such as flavonoids, terpenoids, alkaloids, quinones, and phenylpropanoids—exhibit pronounced anti-inflammatory properties. These bioactive compounds attenuate inflammation primarily by suppressing the production of pro-inflammatory cytokines, including TNF-α, IL-6, and IL-1β, through diverse molecular mechanisms. In addition, they indirectly mitigate inflammatory responses by reducing MPO activity and MDA levels. Representative TCM monomers and their corresponding mechanisms of action are summarized in Table 1.

Table 1.

TCM Monomers Regulation Mechanism of Inflammatory Responses.

Classifications	TCM Monomers	Experimental Model	Relevant Pharmacological Indicators								Mechanism of Action	References
			TNF-α	IL-1β	IL-6	SOD	MPO	MDA	NO	Others
Flavonoids	Norwogonin	LPS-induced ALI rats LPS-induced RAW264.7 cells	↓	↓	↓		↓			CD86↓	Inhibition of NF-κB/NLRP3 signaling pathway	[52]
	Myricetin	CLP-induced sepsis ALI mice	↓	↓	↓	↑	↓	↓		COX-2↓, iNOS↓, CAT↑, GSH↑	Activation of Nrf/HO-1 signaling pathway	[53]
	Naringenin	LPS-induced ALI mice	↓	↓	↓			↓		MIP2↓, H₂O₂↓	Inhibition of PI3K/AKT signaling pathway	[54]
	Nobiletin	LPS-induced ALI miceLPS-induced A549 cells	↓		↓		↓		↓		Inhibition of NF-κB signaling pathway	[55]
	Icariside II	LPS-induced ALI micePMA-induced HL-60 cells	↓	↓	↓		↓			Cit-H3↓	Inhibition of cGAS/STING/NF-κB signaling pathway	[56]
	Glycitin	LPS-induced ALI miceLPS-induced RAW264.7 cells	↓	↓	↓		↓				Inhibition of NF-κB and MAPK signaling pathway	[57]
	Quercetin	CLP-induced sepsis ALI mice			↓	↑	↓	↓		HMGB1↓, MIP2↓, KC↓	Inhibition of PTEN/β-catenin signaling pathwayActivation of AKT/GSK-3β signaling pathway	[58]
	Isoorientin	LPS-induced ALI mice		↓	↓	↑	↓		↓		Activation of Keap1/Nrf2-HO-1 signaling pathwayInhibition of NLRP3 inflammasome signaling pathway	[59]
Terpenoids	Toosendanin	LPS-induced ALI mice		↓	↓	↑		↓		IL-8↓, ATF6↓, GRP78↓, XBP1↓, ATF4↓, p-eIF2α↓, CHOP↓	Inhibition of mTOR signaling pathwayReduce endoplasmic reticulum stress and apoptosis	[60]
	Andrographolide	CLP-induced sepsis ALI miceLPS-induced MH-S cells	↓	↓	↓					IL-10↑	Inhibition of RAGE/PI3K/AKT/mTOR signaling pathway	[61]
	Celastrol	CLP-induced sepsis ALI miceLPS-induced A549 cells	↓	↓	↓					IL-8↑, HIF-1α↓	Inhibition of NF-κB signaling pathway	[62]
	Eupalinolide B	LPS-induced ALI miceLPS-induced RAW264.7 cells	↓	↓	↓		↓		↓	COX-2↓, iNOS↓, PGE2↓, MPC-1↓	Inhibition of NF-κB and MAPKsignaling pathway	[63]
	Ginkgolide C	PQ-induced ALI ratsPQ-induced RLE-6TN cells	↓	↓	↓	↑		↓		GSH↑, CAT↑, NQO-1↑，LDH↓, CK↓, NADPH↓, ICAM-1↓, VCAM-1↓, iNOS↓	Inhibition of NF-κB signaling pathwayActivation of Nrf2 signaling pathway	[9]
	Hederasaponin C	LPS-induced ALI miceLPS-induced RAW264.7, J774A.1, and THP-1 cells	↓	↓	↓					PIP2↑, DAG↑, IP3↑, PLCγ2↓	Inhibition of PIP2/NF-κB/NLRP3 signaling pathway	[64]
	Thymol	LPS-induced ALI mice	↓		↓	↑	↓	↓			Inhibition of NF-κB signaling pathway	[65]
	Asperuloside	LPS-induced ALI miceLPS-induced RAW264.7 cells	↓	↓	↓		↓				Inhibition of NF-κB and MAPKsignaling pathway	[66]
Alkaloids	Palrnatine	LPS-induced ALI miceLPS-induced RAW264.7 cells		↓						iNOS↓	Inhibition of Akt/NF-κB signaling pathway	[67]
	Matrine	Staphylococcus aureus-induced ALI mice	↓	↓						IL-10↓, RANTES↓, HMGB1↓, HABP2↓	Inhibition of NF-κB and MAPK signaling pathway	[68]
	Sinomenine	Escherichia coli-induced ALI mice	↓	↓	↓	↑	↓	↓			Inhibition of NF-κB signaling pathwayActivation of Nrf2 signaling pathway	[69]
	Lycorine	BLM-induced ALI miceLPSInduced BMDM cells	↓	↓	↓		↓				Inhibition of NLRP3inflammasome signaling pathway	[70]
	Tetrahydropalmatine	Limb IR-induced ALI rats				↑	↓	↓		Beclin-1↓, LC3II/LC3I↓, p62↑	Inhibition of TLR4/NF-κB/NLRP3 signaling pathway	[71]
	Peiminine	LPS-induced ALI miceLPS-induced A549 cells	↓	↓	↓		↓			IL-8↓	Inhibition of PI3K/Akt/NF-κB signaling pathway	[72]
Quinones	Plumbagin	LPS-induced ALI miceLPS-induced RAW264.7 cells	↓	↓	↓	↑	↓			GSH↑, CAT↑	Inhibition of PI3K/Akt/mTOR signaling pathwayActivation of Keap1/Nrf2/HO-1 signaling pathway	[73]
	Aloin	LPS-induced ALI mice	↓	↓		↑	↓	↓		GSH↑, SITR1↑	Inhibition of NF-κB and NLPR3inflammasome signaling pathway	[74]
	Chrysophanol	PQ-induced ALI mice	↓	↓	↓	↑	↓	↓		PPAR-γ↑	Regulation of PPAR-γ/NF-κB signaling pathway	[75]
	Emodin	LPS-induced ALI ratsLPS-induced J774A.1 cells		↓			↓	↓		IL-18↓	Inhibition of NLPR3inflammasome signaling pathway	[76]
	Aurantio-obtusin	LPS-induced ALI miceLPS-induced MH-S cellsIL-1β-induced A549 cells	↓	↓	↓				↓	COX-2↓	Inhibition of NF-κB and MAPK signaling pathway	[77]
	Lapachol	LPS-induced ALI mice		↓	↓						Inhibition of JAK-STAT signaling pathway	[78]
Phenylpropanoids	Bergapten	LPS-induced ALI mice	↓	↓	↓					CCL22↑, CCL24↑, CD206↑, CD163↑, CD86↓, iNOS↓	Inhibition of TLR4/MyD88/NF-κB signaling pathway	[79]
	Oxypeucedanin	LPS-induced ALI miceLPS-induced RAW264.7 cells	↓	↓	↓		↓			COX-2↓, iNOS↓, occludin↑, claudin-3↑	Inhibition of PI3K/AKT/NF-κB and MAPK signaling pathway	[80]
	Phillyrin	CLP-induced sepsis ALI miceLPS-induced MLE-12 cells	↓	↓	↓		↓			IL-18↓	Inhibition of NLRP3/caspase-1/GSDMD signaling pathway	[81]
	Sesamin	LPS-induced ALI mice	↓	↓	↓		↓				Inhibition of TLR4/NF-κB signaling pathway	[82]
	Schisandrin B	LPS-induced ALI miceLPS-induced RAW264.7 cells	↓		↓						Inhibition of TLR4/MyD88/NF-κB and TLR4/MyD88/MAPK signaling pathway	[12]
	Chicoric acid	LPS-induced ALI mice	↓	↓	↓	↑	↓	↓		GSH↑	Inhibition of MAPK and NLPR3 inflammasome signaling pathwayActivation of Nrf2 signaling pathway	[83]
	Silibinin	LPS-induced ALI mice	↓	↓						IL-18↓	Inhibition of NF-κB and NLPR3 inflammasome signaling pathway	[84]
	Wedelolactone	LPS-induced ALI miceLPS-induced RAW264.7 cells	↓		↓	↑		↓		COX-2↓, iNOS↓, HO-1↑, NQO-1↑	Inhibition of NF-κB signaling pathwayActivation of Nrf2 signaling pathway	[85]
Phenols	Curcumin	high-altitude hypoxia-induced ALI rats	↓	↓	↓					IL-10↑, ZO-1↑, occludin↑, claudin-4↑	Inhibition of NF-κB signaling pathway	[86]
	Resveratrol	LPS-induced ALI mice	↓	↓						IL-18↓	Inhibition of NLPR3 inflammasome signaling pathway	[87]
Steroidal saponins	Ruscogenin	Particulate matter-induced ALI mice		↓	↓		↓		↓		Inhibition of TLR4/MyD88/NF-κB signaling pathway	[88]
Esters	Epigallocatechin gallate	LPS-induced ALI miceLPS-induced RAW264.7 cells	↓	↓	↓		↓			PRKCA↑	Inhibition of MAPK signaling pathway	[89]
Polysaccharides	Ganoderma atrum polysaccharides	LPS-induced ALI rats	↓	↓	↓				↓		Inhibits the release of inflammatory mediators, corrects metabolic disorders, and enhances the production of short-chain fatty acids in the intestine.	[90]
Glycosides	Paeoniflorin	IAV-induced ALI mice	↓	↓	↓					MCP-1↓, IFN-γ↓, TGF-β1↓	Inhibition of the NF-κB signaling pathway and MAPK signaling pathway	[91]

Flavonoids

Scutellaria baicalensis is a widely used Chinese herbal medicine with antipyretic properties. Its principal bioactive component, norwogonin, attenuates inflammatory cell infiltration and suppresses the release of TNF-α, IL-6, and IL-1β by inhibiting NF-κB phosphorylation and NLRP3 expression, thereby antagonizing the NF-κB/NLRP3 signaling pathway and mitigating pulmonary inflammation in ALI rats. ⁵² Myricetin, a natural flavonoid extracted from Carthamus tinctorius, alleviates inflammatory responses and oxidative stress in cecal ligation and puncture (CLP)-induced sepsis-associated ALI in mice via activation of the Nrf2/HO-1 signaling pathway. ⁵³ Naringenin improves the survival rate of ALI mice, markedly reduces TNF-α, IL-1β, IL-6, and macrophage inflammatory protein-2 (MIP-2) levels, decreases lung MPO activity and neutrophil counts, and lowers ROS, H₂O₂, and MDA levels through inhibition of the PI3K/Akt signaling pathway. ⁵⁴ Nobiletin, a polymethoxylated flavonoid abundant in Rutaceae plants, exerts anti-inflammatory and antioxidant effects. In Lipopolysaccharide (LPS)-induced ALI mice, it downregulates MPO, TNF-α, IL-6, and NO expression, and inhibits phosphorylation of NF-κB p65 and IκBα. In LPS-stimulated A549 cells, nobiletin suppresses NF-κB activation and cytokine production, confirming its protective effect via NF-κB pathway inhibition. ⁵⁵ Icariside II alleviates LPS-induced ALI by targeting neutrophil CXC chemokine receptor 4 (CXCR4), thereby reducing neutrophil extracellular trap (NET) formation, inhibiting cyclic GMP-AMP synthase (cGAS)/stimulator of interferon genes (STING)/NF-κB pathway activation, and decreasing inflammatory mediator release in lung epithelial cells. ⁵⁶ Glycitin suppresses TLR4-mediated NF-κB and MAPK activation by inhibiting phosphorylation of IKKβ, IκBα, p65, p38, ERK, and JNK, resulting in reduced IL-1β, IL-6, and TNF-α production, and ameliorating LPS-induced ALI. ⁵⁷ Quercetin lowers MPO activity, MDA, IL-6, high mobility group box 1 (HMGB1), and keratinocyte chemoattractant (KC) levels, decreases mutated in multiple advanced cancers 1 (PTEN)/β-catenin phosphorylation, and enhances AKT/GSK-3β phosphorylation, indicating a protective effect against sepsis-induced ALI via inhibition of the PTEN/β-catenin pathway and activation of the AKT/GSK-3β pathway. ⁵⁸ Isoorientin reduces LPS-induced inflammatory cell infiltration and abnormal elevations of MPO, IL-6, and NO. It upregulates Nrf2 and HO-1 expression, downregulates Keap1, and inhibits overexpression of NLRP3, caspase-1, apoptosis-associated speck-like protein containing a CARD (ASC), and IL-1β, suggesting its protective role in LPS-induced ALI through modulation of the Keap1/Nrf2-HO-1 and NLRP3 inflammasome pathways. ⁵⁹

Terpenoids

Toosendanin, a triterpenoid natural compound, exhibits potent anti-inflammatory activity. In ALI mice, it reduces IL-1β and IL-6 levels, downregulates mammalian target of rapamycin (mTOR) and phosphorylated mTOR, and inhibits mTOR signaling, thereby alleviating endoplasmic reticulum stress and apoptosis, ultimately slowing ALI progression. ⁶⁰ Andrographolide significantly decreases phosphorylation (p)-PI3K, p-AKT, and p-mTOR expression, inhibits receptor of advanced glycation endproducts (RAGE)/PI3K/Akt/mTOR pathway activation, induces autophagy in alveolar macrophages, and suppresses NLRP3 inflammasome activation, thereby improving sepsis-induced ALI. ⁶¹ Celastrol reduces IL-1β, IL-6, and TNF-α expression in ALI mice, downregulates p-NF-κB p65 and IκBα protein levels, and blocks NF-κB activation, effectively attenuating LPS-induced inflammation in RAW264.7 cells. ⁶² Eupalinolide B inhibits LPS-induced phosphorylation of IKKα/β, IκBα, and NF-κB p65, prevents IκBα degradation and NF-κB p65 nuclear translocation, and suppresses MAPK phosphorylation. These actions indicate dual regulation of NF-κB and MAPK pathways, resulting in marked anti-inflammatory effects in LPS-induced ALI. ⁶³ Ginkgolide C modulates Nrf2 and NF-κB signaling by restoring GSH, SOD, and CAT activity, reducing TNF-α, IL-1β, and IL-6 levels, and downregulating adhesion molecules intercellular cell adhesion molecule-1 (ICAM-1),vascular cell adhesion molecule-1 (VCAM-1), and nitric oxide synthase (iNOS). It also upregulates HO-1, NAD(P)H:quinone oxidoreductase 1 (NQO-1), and glutamate-cysteine ligase modifier subunit (GCLM) expression, inhibits IKKβ activity, prevents IκBα phosphorylation and degradation, and blocks NF-κB nuclear translocation, thereby exerting synergistic anti-inflammatory and antioxidant effects and improving paraquat (PQ)-induced ALI in rats. ⁹ Hederasaponin C targets the epigenetic regulator phosphatidylinositol 4,5-bisphosphate (PIP2), inhibits NF-κB and NLRP3 inflammasome activation, and modulates the PIP2/NF-κB/NLRP3 signaling pathway, thereby suppressing cytokine storms (IL-6, TNF-α, IL-1β) and alleviating ALI. ⁶⁴ Thymol, a terpenoid with antibacterial and antipruritic effects, reduces IL-6 and TNF-α release, lowers MDA levels, restores SOD activity, decreases pulmonary neutrophil infiltration, and inhibits LPS-induced NF-κB p65 phosphorylation, thereby blocking the inflammatory cascade. ⁶⁵ Asperuloside extract suppresses IκBα, ERK1/2, and JNK phosphorylation, and reduces IL-1β, IL-6, and TNF-α secretion, indicating its therapeutic effect in ALI through concurrent regulation of the MAPK and NF-κB signaling pathways. ⁶⁶

Alkaloids

Palmatine, the major alkaloid component of Daemonorops jenkinsiana (Griff.) Mart., inhibits IL-1β and iNOS protein expression and markedly suppresses phosphorylation of Akt, p65, and IκB in both LPS-induced ALI models and RAW264.7 inflammatory cell models, indicating that it mitigates ALI progression via inhibition of the Akt/NF-κB signaling pathway. ⁶⁷ Matrine, a bioactive alkaloid extracted from Sophora flavescens Aiton, reduces TNF-α, IL-1β, interleukin-10 (IL-10), and regulated upon activation normal T cell expressed and secreted (RANTES) levels in the lungs of Staphylococcus aureus-induced ALI mice. It downregulates high mobility group protein B1 (HMGB1) and hyaluronic acid binding protein 2 (HABP2) expression, and inhibits NF-κB and MAPK activation in macrophages, thereby attenuating inflammation, reducing lung injury, and improving survival rates. ⁶⁸ Sinomenine, derived from Sinomenium acutum, effectively inhibits p65 activation while upregulating Nrf2, HO-1, and NQO-1 expression, suggesting that it modulates the Nrf2/NF-κB pathway to suppress inflammation and oxidative stress, thus slowing ALI progression. ⁶⁹ Lycorine reduces IL-1β, IL-6, and TNF-α secretion, decreases MPO activity, and significantly inhibits caspase-1 activity, indicating that it alleviates bleomycin (BLM)-induced ALI by suppressing NLRP3 inflammasome activation. ⁷⁰ Tetrahydropalmatine decreases MPO and MDA levels, increases SOD activity, promotes PI3K/Akt/mTOR phosphorylation, inhibits Beclin-1 and LC3II/LC3I expression, and elevates p62 levels in limb ischemia–reperfusion (IR)-induced ALI rats. These findings suggest that tetrahydropalmatine activates the PI3K/Akt/mTOR pathway to inhibit excessive autophagy, thereby protecting lung tissue from IR-induced ALI. ⁷¹ Peiminine, a natural alkaloid with potent anti-inflammatory activity, significantly lowers TNF-α, IL-1β, and IL-6 levels in ALI mice, inhibits IL-8 secretion in LPS-induced A549 cells, and suppresses PI3K and Akt phosphorylation as well as NF-κB activation, indicating its protective effect through PI3K/Akt/NF-κB pathway inhibition. ⁷²

Quinones

Plumbagin significantly attenuates LPS-induced pathological lung injury and MPO activity, reduces inflammatory cell infiltration and TNF-α, IL-1β, and IL-6 levels in broncho-alveolar lavage fluid (BALF), and exerts its protective effect by inhibiting the PI3K/Akt/mTOR signaling pathway while activating the Keap1/Nrf2/HO-1 pathway. This activation enhances the activity of antioxidant enzymes, including CAT, SOD, and GSH, thereby alleviating pulmonary inflammation and oxidative stress. ⁷³ Aloe vera, rich in diverse bioactive compounds, contains aloin as its major active component. Aloin upregulates silent information regulator 1 (SIRT1) expression, inhibits the NLRP3/NF-κB signaling pathway, regulates the levels of MDA, TNF-α, SOD, and GSH, as well as modulating enzyme activity, thereby mitigating LPS-induced oxidative stress and inflammatory responses in ALI. ⁷⁴ Chrysophanol and emodin, the principal anthraquinones in rhubarb (Rheum palmatum), exhibit potent anti-inflammatory effects. Chrysophanol suppresses TNF-α, IL-1β, and IL-6 elevation in BALF, reduces MDA levels, restores SOD activity, activates peroxisome proliferators-activated receptor-γ (PPAR-γ), and inhibits NF-κB signaling, thereby reducing inflammatory cell infiltration, cytokine release, and oxidative stress. ⁷⁵ Emodin downregulates the mRNA and protein expression of NLRP3, ASC, caspase-1, and GSDMD in lung tissue, thereby inhibiting NLRP3 inflammasome activation, blocking pyroptosis signaling, decreasing IL-1β and IL-18 release, and reducing oxidative stress, ultimately ameliorating LPS-induced ALI. ⁷⁶ Aurantio-obtusin markedly improves lung pathology in LPS-induced ALI mice, reduces TNF-α, IL-1β, IL-6, and NO levels, and exerts its effect through inhibition of MAPK and NF-κB signaling pathways. ⁷⁷ Lapachol competitively inhibits the JAK1 kinase domain, thereby blocking janus kinase-signal transducer and activator of transcription (JAK-STAT) signaling, reducing IL-6 and IL-1β production, and suppressing the inflammatory cascade in ALI. ⁷⁸

Phenylpropanoids

Bergapten is a psoralen derivative with anti-inflammatory and immunomodulatory activity. However, its poor water solubility and limited bioavailability hinder its clinical application. Liao et al ⁷⁹ developed an inhalable nanomedicine formulation of bergapten and found that it downregulated pro-inflammatory genes such as cluster of differentiation 86 (CD86) and iNOS, as well as TLR4/myeloid differentiation primary response protein 88 (MyD88)/ NF-κB pathway-related gene expression in lung tissue, while upregulating cluster of differentiation 206 (CD206), cluster of differentiation 163 (CD163), markers of M2-type macrophages, in lung tissue of ALI mice, inhibiting the expression of TLR4 and MyD88 proteins, IκBα/p65 phosphorylation, and blocking NF-κB nuclear translocation. This suggests that it inhibits M1 polarization and promotes M2 polarization of macrophages through the TLR4/MyD88/NF-κB pathway, thereby improving the pathological phenotype of ALI. Oxypeucedanin inhibits LPS-induced phosphorylation of PI3K, AKT, and IκB, prevents IκB ubiquitination and degradation, blocks NF-κB p65 nuclear translocation, and concurrently suppresses p38, ERK1/2, and JNK phosphorylation. Through inhibition of PI3K/Akt/NF-κB and MAPK signaling, it reduces inflammatory mediator and ROS production, enhances the alveolar–capillary barrier, and alleviates LPS-induced ALI. ⁸⁰ Phillyrin markedly downregulates pyroptosis-related proteins including NLRP3, caspase-1 p20, gasdermin D (GSDMD) and decreases IL-1β and IL-18 maturation and release, without affecting precursor proteins (pro–caspase-1, pro–IL-1β, pro–IL-18). These findings indicate that Phillyrin alleviates sepsis-induced alveolar epithelial injury and ALI via inhibition of the NLRP3/caspase-1/GSDMD-dependent pyroptosis pathway. ⁸¹ Sesamin, a natural lignan from sesame, exerts significant anti-inflammatory effects by reducing LPS-induced TNF-α, IL-6, and IL-1β release, suppressing TLR4 expression, inhibiting NF-κB activation and IκBα degradation, thereby blocking the TLR4/NF-κB pathway and modulating inflammatory responses. ⁸² Schisandrin B directly binds to MyD88, disrupting its interaction with TLR4, which inhibits MyD88-dependent MAPK and NF-κB signaling, reduces TNF-α and IL-6 levels, and alleviates inflammatory responses and lung injury. ¹² Chicoric acid decreases TNF-α, IL-6, IL-1β, MDA, and ROS levels, increases GSH and SOD activity, inhibits MAPK phosphorylation and NLRP3 inflammasome activation, and activates Nrf2 signaling, exerting both anti-inflammatory and antioxidant effects to attenuate LPS-induced ALI. ⁸³ Silibinin lowers TNF-α, IL-1β, and IL-18 levels via dual regulation of the NF-κB and NLRP3 pathways, effectively mitigating LPS-induced ALI. ⁸⁴ Wedelolactone targets soluble epoxide hydrolase to modulate the glycogen synthase kinase-3β (GSK-3β)/NF-κB/Nrf2 axis, thereby suppressing macrophage-mediated inflammation and oxidative stress, ultimately alleviating LPS-induced ALI. ⁸⁵

Others

Curcumin, a natural phenolic compound derived from turmeric (Curcuma longa) and Curcuma zedoaria, exerts significant anti-inflammatory effects. It reduces TNF-α, IL-1β, and IL-6 levels by inhibiting NF-κB–mediated inflammatory responses, while increasing the anti-inflammatory cytokine IL-10. Curcumin also upregulates tight junction proteins zonula occludens-1 (ZO-1), occludin, and claudin-4, thereby improving lung barrier function, restoring blood gas balance, and attenuating high-altitude hypoxia-induced ALI. ⁸⁶ Resveratrol is a non-flavonoid polyphenolic organic compound, an antitoxin produced by many plants in response to stress, which inhibits the expression of NLRP3, ASC, and caspase-1 p20 proteins induced by LPS, and upregulates autophagy-related proteins such as Beclin-1, autophagy related 5 (Atg5), microtubule-associated proteins 1 A/1B light chain 3B (LC3B-II), and PTEN-induced putative kinase 1 (Pink1)/Parkin pathway proteins, thereby enhancing mitochondrial autophagy. Additionally, resveratrol can inhibit the inflammatory cascade reaction by removing damaged mitochondria, blocking the release of mitochondrial ROS and DNA, and thereby inhibiting the activation of the NLRP3 inflammasome. ⁸⁷ Ruscogenin exhibits strong anti-inflammatory activity, dose-dependently reducing IL-6, IL-1β, MPO, and NO levels in BALF and serum. It downregulates TLR4, MyD88, and phosphorylated NF-κB p65 expression, reduces particulate matter–induced inflammatory cell infiltration and bronchial epithelial thickening, and alleviates ALI via inhibition of the TLR4/MyD88/NF-κB pathway. ⁸⁸ Epigallocatechin gallate (EGCG), a major catechin in green tea, ameliorates LPS-induced ALI by upregulating protein kinase Cα (PRKCA), suppressing p38, ERK, and JNK phosphorylation, blocking MAPK signaling, and reducing TNF-α, IL-6, and IL-1β release. ⁸⁹ Ganoderma atrum polysaccharides mitigate LPS-induced metabolic disorders by inhibiting pro-inflammatory mediator release, restoring histidine, nitrogen, tryptophan, and glycerophospholipid metabolism, and enhancing intestinal short-chain fatty acid production, thereby indirectly reducing pulmonary inflammation and providing synergistic protection against ALI. ⁹⁰ Paeoniflorin is a natural glycoside extracted from Paeonia lactiflora and Paeonia veitchii, which has significant anti-inflammatory effects. Research has found that paeoniflorin can alleviate ALI induced by influenza A virus (IAV) in mice and improve their survival rate. Its mechanism of action may be to inhibit the expression of NF-κB and p38 MAPK in lung tissue, thereby reducing the synthesis of pro-inflammatory cytokines and alleviating pulmonary inflammation. ⁹¹

TCM Compound Prescriptions

Most TCM exert their therapeutic effects through the combination of multiple ingredients in compound prescriptions, which represent the core form of TCM practice. While TCM monomers exhibit specific and well-defined pharmacological effects against ALI, their efficacy may be constrained by single-mechanism regulation. Growing evidence indicates that TCM compound prescriptions can inhibit inflammatory responses and prevent ALI via multiple, complementary pathways, with their diverse components acting synergistically to enhance therapeutic efficacy. The principal therapeutic strategies of TCM compound prescriptions in ALI management encompass three key approaches: heat-clearing and detoxifying, promoting lung function and resolving phlegm, and blood-activating and stasis-removing. In addition, some studies have explored ALI treatment within the framework of modern scientific concepts, such as the “lung–gut axis.” Representative TCM compound prescriptions and their mechanisms of action are summarized in Table 2.

Table 2.

TCM Compound Prescriptions Regulation Mechanism of Inflammatory Responses.

Classifications	TCM Compound Prescriptions	Compositions	Efficacy	Experimental Model	Relevant Pharmacological Indicators								Mechanism of Action	References
					TNF-α	IL-1β	IL-6	SOD	MPO	MDA	NO	Others
Heat-clearing and detoxifying compound prescriptions	Huanglian Jiedu Decoction	Rhizoma coptidis, Radix scutellariae, Cortex phellodendri, Fructus gardenia	Heat-clearing and detoxifying	LPS-induced ALI rats	↓	↓	↓					IL-18↓	Inhibition of the NF-κB signaling pathwayRegulation of sphingolipid metabolism inhibitsInhibition of signaling pathways	[92]
	Ge-Gen-Qin-Lian Decoction	Pueraria Lobatae Radix, Scutellariae Radix, Coptis chinensis Franch, Glycyrrhizae Radix	Exterior-releasing and interior-clearing, Diarrhea with pathogenic heat	LPS-induced ALI mice	↓	↓	↓		↓			Bcl-2↑, Bax↓	Activation of the PI3K/Akt signaling pathway	[93]
	Maxing Shigan Decoction	Ephedrae Herba, Bitter Apricot Seed, Glycyrrhiza uralensis fisch, Gypsum	Heat-clearing and detoxifying, Ventilating the lung to relieve cough	LPS-induced ALI mice	↓	↓	↓	↑		↓		GSH↑	Inhibition of MAPK/NF-κB signaling pathways	[94]
	Xuanfei Baidu formul	Ephedrae Herba, Armeniacae Semen Amarum, Gypsum, Ma - yuen Jobstears Seed, Rhizoma Atractylodis, Cablin Potchouli Herb, Sweet Wormwood Herb, Giant Knotweed Rhizome, Verbenae Herba, Reed Rhizome, Pepperweed Seed, Tomentose Pummelo Peel, Glycyrrhiza uralensis fisch	Difussing lung andresolving dampness, Clearing heat and expelling pathogens	LPS-induced ALI miceLPS-induced RAW264.7 cells	↓	↓	↓				↓	COX-2↓, iNOS↓, IL-10↑	Inhibition of NF-κB signaling pathways	[95]
Promoting lung and resolving phlegm compound prescriptions	Sanzi Yangqing Decoction	Sinapis Semen, Perillae Fructus, Raphani Semen	Warming the lung and resolving phlegm，Reduce qi and aid digestion	LPS-induced ALI miceLPS-induced MH-S cells	↓	↓	↓				↓		Inhibition of the TLR2/NF-κB/NLRP3 signaling pathways	[96]
	Sangxingtang	Morus alba L., Amygdalus Communis Vas, Adenophora stricta, Bulbus Fritillariae Thunbergii, Gardenia jasminoides Ellis	Clear heat, warm dryness, moisten the lungs, and stop coughing	LPS-induced ALI mice	↓		↓	↑	↓				Inhibition of MAPK/NF-κB signaling pathways	[97]
	Linggan Wuwei Jiangxintang	Indian buead, Glycyrrhiza uralensis fisch, Zingiberis Rhizoma, manchurian wildginger, Chinese Magnolcavine Fruit	Warming lung and resolving fluid retention	LPS-induced ALI mice	↓		↓	↑				CAT↑	Inhibition of TLR4/NF-κB signaling pathways	[98]
	Qingfei Litan Decoction	Gypsum, Nervilia plicatae herba, Trichosanthis pericarpium, Scutellariae radix, Fritillariae thunbergii bulbus, Houttuyniae herba, Armeniacae semen amarum, Platycodonis radix, Phragmitis rhizoma, Glycyrrhiza uralensis fisch	Clear heat and promote lung function, dissipating phlegm and blood stasis, Tonify qi and moisten the lungs	LPS-induced ALI miceLPS-induced HM-S and A549 cells	↓	↓	↓	↑		↓		GSH↑, GSH-Px↑	Regulation of TNF and TLR signaling pathways	[99]
Blood-activating and stasis-removing compound prescriptions	Xuefu Zhuyu Decoction	peach kernel, safflower, angelica, Rehmannia glutinosa, Achyranthes bidentata, Ligusticum chuanxiong, Platycodon grandiflorum, red peony, Fructus aurantii, Bupleurum, licorice	Blood-activating and stasis-removing, promotingqi circulation to relieve pain	CPB-induced ALI rats	↓	↓	↓			↓		IL-18↓	Inhibition of NF-κB and NLRP3Inhibition of signaling pathways	[100]
	Yiqi Huayu Jiedu Decoction	Radix Astragali, Panax Notoginseng, Flos Lonicerae, Radix Scutellariae, fried Fructus Aurantii Immaturus, Radix Paeoniae Rubra, Semen Descurainiae, Cortex Mori	Reinforcing qi activating blood, Ｒemoving blood stasis clearing collaterals	LPS-induced ARDS rats	↓		↓						Inhibition of PI3K/Akt and MAPK signaling pathways	[101]
	Qingfei Huoxue Decoction	Lonicera japonica Thunb., Scutellaria baicalensis Georgi, Peucedanum praeruptorum Dunn, Prunus mandshurica (Maxim.) Koehne, Angelica sinensis (Oliv.) Diels, Bupleurum chinense DC., Cyperus rotundus L., Perilla frutescens (L.) Britton, Coix lacryma-jobi var. ma-yuen (Rom. Caill.) Stapf, Forsythia suspensa (Thunb.) Vahl, Taraxacum mongolicum Hand.-Mazz., Platycodon grandiflorus (Jacq.) A. DC., Fritillaria thunbergii Miq., Salvia miltiorrhiza Bunge, Curcuma wenyujin Y.H.Chen & C.Ling, Aesculus chinensis Bunge, Citrus reticulata Blanco, Paeonia lactiflora Pall.	Clearing lungand detoxification, Blood-activating and stasis-removing	LPS-induced ALI mice	↓	↓	↓						Inhibition of TLR4/NF-κB signaling pathways	[102]
Others	Ma Huang Decoction and Da Chengqi Decoction	Ephedrae Herba, Cmnamomi Mmulus, Bitter Apricot Seed, Glycyrrhiza uralensis fisch, rhubarb root and rhizome, Mirabilite, Aurantii Fructus Immaturu, Officinal magnolia bark	Decreasing lung qi, promote bowel movement	LPS-induced ALI rats	↓	↓						IL-18↓	Inhibition of NF-κB/NLRP3 signaling pathways	[103]
	Fuzhengjiedu Formula	Aconitum carmichaelii Debeaux, Zingiber officinale Roscoe, Glycyrrhiza uralensis Fisch. ex DC., Lonicera japonica Thunb., Gleditsia sinensis Lam., Ficus simplicissima Lour., Pogostemon cablin Benth., Citrus reticulata Blanco	Warming Yang and resolving stagnation, strengthening the spleen and reducing dampness	LPS-induced ALI rats	↓	↓						iNOS↓	Regulation of amino acid metabolism	[104]
	Dayuanyin	Areca catechu L., Magnolia officinalis Rehd. et Wils., Amomum tsao-ko Crevost et Lemaire, Anemarrhena asphodeloides Bge., Scutellaria baicalensis Georgi, Paeonia lactiflora Pall., Glycyrrhiza uralensis Fisch.	opening onto the membrane source, Purify and clarify	λ-carrageenan- induced ALI mice	↓	↓	↓						Inhibition of NF-κB and JAK2/STAT3/MMP-9 signaling pathways	[105]

Heat-Clearing and Detoxifying Compound Prescriptions

Huanglian Jiedu Decoction is a representative heat-clearing and detoxifying formula. Studies have shown that it regulates sphingolipid metabolism to inhibit NLRP3 inflammasome activation and reduce caspase-1 activity, thereby decreasing the maturation and release of IL-1β and IL-18. By suppressing the NF-κB signaling pathway, it downregulates the transcription and secretion of pro-inflammatory cytokines such as TNF-α and IL-6, thus protecting lung tissue. ⁹² Ge-Gen-Qin-Lian Decoction, traditionally used for intestinal disorders, has been investigated within the theoretical frameworks of the “lung–gut axis” and the “interior–exterior relationship between the lung and large intestine.” It exerts protective effects against ALI by activating the PI3K/Akt signaling pathway, suppressing inflammatory responses, reducing cell apoptosis, and restoring disordered energy metabolism, thereby alleviating lung injury. ⁹³ Maxing Shigan Decoction reduces phosphorylation of p38 MAPK, JNK, and ERK1/2 in ALI mice, thereby inhibiting MAPK signaling. This results in decreased inflammatory mediator release, along with inhibition of NF-κB nuclear translocation and downstream target gene expression, collectively blocking the amplification of inflammatory signaling. ⁹⁴ Xuanfei Baidu Formula, one of the “three medicines and three prescriptions” recommended during the Coronavirus Disease 2019 (COVID-19) pandemic, addresses ALI, a frequent complication of COVID-19. Its mechanism involves downregulating NF-κB pathway proteins, inhibiting IKK phosphorylation, and preventing NF-κB nuclear translocation, thereby reducing inflammatory cytokine release and alleviating ALI. ⁹⁵

Promoting Lung and Resolving Phlegm Compound Prescriptions

Sanzi Yangqing Decoction exerts multi-target, multi-pathway protective effects against ALI by inhibiting TLR2/MyD88 signaling, reducing IKKα phosphorylation and IκB degradation, blocking NF-κB nuclear translocation, and lowering pro-inflammatory cytokine expression. It also antagonizes NLRP3 inflammasome assembly and caspase-1 activation, thereby preventing IL-1β maturation and pyroptosis, ultimately slowing ALI progression. ⁹⁶ Sangxingtang alleviates LPS-induced neutrophil infiltration and inflammatory cell aggregation in lung tissue by downregulating phosphorylation of key proteins in the MAPK/NF-κB pathway, decreasing TNF-α and IL-6 levels, and effectively mitigating lung injury. ⁹⁷ Linggan Wuwei Jiangxin Decoction, traditionally used to warm the lungs and transform phlegm, significantly reduces TLR4, NF-κB p65, and p-NF-κB p65 expression, lowers serum TNF-α and IL-6 concentrations, and inhibits the activity of inflammation-related genes. By suppressing multiple inflammatory signaling cascades, it improves pulmonary inflammation in ALI. ⁹⁸ Qingfei Litan Decoction markedly suppresses both secretion and mRNA expression of TNF-α, IL-6, and IL-1β in bronchoalveolar lavage fluid and lung tissue of ALI mice. It also decreases MDA and ROS levels while increasing GSH, SOD, and glutathione peroxidase (GSH-Px) activities, thereby alleviating oxidative stress. Its mechanism of action is likely related to the modulation of the TNF and TLR signaling pathways. ⁹⁹

Blood-Activating and Stasis-Removing Compound Prescriptions

Xuefu Zhuyu Decoction, traditionally used to activate blood, remove stasis, and regulate qi to relieve pain, exerts protective effects against ALI by reducing IκBα phosphorylation, inhibiting NF-κB nuclear translocation, and decreasing inflammatory cytokine release. It also downregulates NLRP3, ASC, and caspase-1 expression, thereby blocking inflammasome assembly and suppressing IL-1β and IL-18 maturation and release. Through dual inhibition of NF-κB signaling and NLRP3 inflammasome–dependent pyroptosis, it significantly mitigates cardiopulmonary bypass (CPB)-induced ALI. ¹⁰⁰ Yiqi Huayu Jiedu Decoction, with functions of tonifying qi, promoting blood circulation, resolving stasis, and unblocking meridians, ameliorates ARDS-associated ALI by dual suppression of PI3K/Akt and MAPK signaling pathways. This inhibition reduces TNF-α and IL-6 levels, improves endothelial barrier function, alleviates pulmonary edema, and attenuates lung tissue damage. ¹⁰¹ Qingfei Huoxue Decoction alleviates LPS-induced lung injury, including alveolar dilatation, thickening of alveolar walls, pulmonary edema, and inflammatory cell infiltration. Its mechanism involves inhibition of TLR4 and NF-κB p65 mRNA and protein expression in lung tissue, alongside a reduction in serum IL-6, IL-1β, and TNF-α levels. ¹⁰²

Others

Chinese researchers ¹⁰³ used the “lung-intestine combination therapy” method to treat LPS-induced ALI and found that the combination of Ma Huang Decoction and Da Chengqi Decoction could reduce IκBα phosphorylation, prevent NF-κB p65 from entering the nucleus and activating, decrease the expression of pro-inflammatory factors such as TNF-α and IL-1β, and inhibit the expression of NLRP3 protein and mRNA, thereby blocking the maturation and release of IL-1β and IL-18. The combination of Ma Huang Decoction to promote lung function and Da Chengqi Decoction to clear the intestines regulates the descent of lung qi and the descent of intestinal qi, alleviating the condition of lung heat and intestinal stasis, thereby indirectly inhibiting systemic inflammatory responses. The Fuzhengjiedu Formula ¹⁰⁴ significantly lowers serum IL-1β and TNF-α concentrations, inhibits M1 macrophage polarization in lung tissue, restores beneficial gut microbiota such as Lactobacillus, and reduces pro-inflammatory bacterial genera including Bacteroides and Prevotella. It also corrects LPS-induced metabolic disturbances in key amino acids such as glycine, serine, and glutamic acid, thereby attenuating inflammatory cascades. This formula exerts a multi-targeted anti-inflammatory effect via modulation of immune responses, intestinal microbiota composition, and host metabolic pathways. Dayuanyin can effectively inhibit the inflammatory response in the λ-carrageenan-induced ALI model, block NF-κB nuclear translocation, reduce the production of inflammatory factors such as TNF-α and IL-6, thereby inhibiting the activation of the JAK2/STAT3 pathway, blocking the amplification of inflammatory signals, and reducing matrix metallopeptidase 9 (MMP-9) expression. Through these three mechanisms, it blocks the inflammatory cascade reaction and alleviates lung tissue damage. ¹⁰⁵

Chinese Proprietary Medicines

Chinese proprietary medicines are standardized preparations derived from Chinese herbal medicines under the guidance of TCM theory, characterized by ease of administration and reliable efficacy. Increasing evidence indicates that many of these medicines exert therapeutic effects against ALI by inhibiting inflammatory mediator release and alleviating oxidative stress. Representative examples and their mechanisms of action are summarized in Table 3.

Table 3.

Chinese Proprietary Medicines Prescriptions Regulation Mechanism of Inflammatory Responses.

Classifications	Chinese Proprietary Medicines	Compositions	Efficacy	Experimental Model	Relevant Pharmacological Indicators							Mechanism of Action	References
					TNF-α	IL-1β	IL-6	SOD	MPO	MDA	Others
Oral Liquids	Jin Zhen Oral Liquid	Rhei Radix et Rhizoma, Scutellariae Radix, Fritillariae Ussuriensis Bulbus, Chloriti Lapis, Gypsum Fibrosum, Bovis Calculus Artifactus, Caprae Hircus Cornu, Glycyrrhiza uralensis fisch	Heat-clearing and detoxifying, eliminates phlegm and relieves cough	LPS-induced ALI miceLPS-induced BEAS-2B cells	↓		↓				IL-10↑	Inhibition of TLR4/MyD88/NF-κB signaling pathway	[106]
	Huoxiang Zhengqi Oral Liquid	Atractylodis Rhizoma, Magnoliae Officinalis Cortex, Poria, Pinelliae Rhizoma, Citri Reticulatae Pericarpium, Angelicae Dahuricae Radix, Arecae Pericarpium, Licorice extract, Patchouli oil, volatile oil in Perillae Folium	Relieving superficial dampness, regulating qi and harmonizing the middle	LPS-induced ALI rats	↓	↓	↓				IFN-γ↓	Inhibition of TLR4/NF-κB signaling pathway	[107]
Granules	Yinma Jiedu Granule	Lonicerae Flos, Portulaca oleracea L, Plantago asiatica L, Rheum officinale Baill, Glycyrrhiza uralensis Fisch	Heat-clearing and detoxifyinh, Reduce swelling and disperse lumps, Relieve phlegm and cough	LPS-induced ALI rats	↓	↓		↑		↓	iNOS↓, COX-2↓	Inhibition of JAK2/STAT1 signaling pathway	[108]
	Sanhan Huashi Granule	Officinal magnolia bark, Betelnutpalm Seed, Tsaoko Amomum Fruit, Ephedrae Herba, Bitter Apricot Seed, incised notopterygium rhizome and root, Ginger, Cablin Potchouli Herb, Eupatorii Herba, Rhizoma Atractylodis, Largehead Atractylodes Rh, Indian buead, Crataegus Pinnatifida, Medicated Leaven, Hordei Fructus Germinatus, Dryopteris Crassirhizoma, Paniculate Swallowwort Root, Earthworm, Gypsum, Pepperweed Seed	Disperse cold and transform dampness, Ventilating lungs and expelling pathogens, Purify and clarify, Detoxification and meridian unblocking	Mice infected with SARS-CoV-2LPS-induced ALI mice SARS-CoV-2-induced Vero-E6 cellsLPS-induced RAW264.7 cells	↓	↓	↓				CCL-2↓, CCL-3↓, CXCL-1↓, CXCL-6↓, CXCL-9↓	Inhibits viral invasion and replication, alleviates inflammatory responses	[109]
	Jingfang Granules	Fineleaf Schizonepeta Herb, Divaricate Saposhniovia Root, incised notopterygium rhizome and root, Doubleteeth Pubescent Angelica Root, Radix bupleuri, Peucedani Radix, Sichuan lovase rhizome, Immature Trifoliate-orange Fruit, Indian buead, Platycodon Grandiflorum, Glycyrrhiza uralensis Fisch	Inducing sweating to release the exterior，Disperse wind and remove dampness	BLM-induced ALI mice							α-SMA↓	Inhibition of PI3K/Akt/mTOR signaling pathway	[110]
	Jinhua Qinggan Granules	Lonicera japonica Thunb, Gypsum, honey-fried Ephedra sinica Stapf, stir-baked Prunus sibirica L, Scutellaria baicalensis Georgi, Forsythia suspensa (Thunb.) Vahl, Fritillaria thunbergii Miq, Anemarrhena asphodeloides Bunge, Arctium lappa L, Artemisia annua L, Mentha haplocalyx Briq, and Glycyrrhiza glabra L	Dispelling wind for ventilating the lung，Heat-clearing and detoxifying	LPS-induced ALI mice	↓	↓	↓		↓		MIP-2↓	Inhibition of TLR4/MyD88/NF-κB signaling pathway	[111]
	Biyuan Tongqiao Granules	Magnolia biondii Pamp, Xanthium sibiricum Patr, Ephedra sinica Stapf, Angelica dahurica (Fisch.ex Hoffm.) Benth. et Hook.f, Mentha haplocalyx Briq, Ligusticum sinense Oliv, Scutellaria baicalensis Georgi, Forsythia suspensa (Thunb.) Vahl, Chrysanthemum indicum L, Trichosanthes kirilowii Maxim, Rehmannia glutinosa Libosch, Salvia miltiorrhiza Bge, Poria cocos (Schw.) Wolf,Glycyrrhiza uralensis Fisch	Expelling wind and clearing heat，ventilating lung andopening the orifices	LPS-induced ALI mice	↓	↓	↓	↑	↓	↓	IFN-γ↓, CAT↑, GSH↑	Activation of PI3K/AKT/mTOR signaling pathway	[112]
Injections	XueBiJing injection	Carthamus tinctorius L, Paeonialactiflora Pall, Conioselinum anthriscoides, Danshen Bunge, Angelica sinensis	Removing blood stasis and detoxifying toxins	CLP-induced sepsis ALI ratsLPS-induced BEAS-2B cells	↓		↓			↓	GSSG↓	Regulation of ferroptosis	[113]
	Shenmai injection	Red ginseng, dwarf lilyturf tuber	Tonify qi and consolidate collapse, nourishing yin to generate fluid	SAP-induced ALI rats	↓						IL-10↑, HO-1↑	Increase HO-1	[114]
Mixture	Reyanning mixture	Taraxacum, Polygonum cuspidatum, Scutellariae Barbatae,Patrinia villosa	Heat-clearing and detoxifying	LPS-induced ALI rats	↓		↓	↑		↓	GSH↑, GSSG↑, IL-10↑, Arg-1↑	Inhibition of UDPG/P2Y14/STAT1 signaling pathway	[115]

Jin Zhen Oral Liquid, a heat-clearing and detoxifying formulation that also eliminates phlegm and relieves cough, alleviates LPS-induced ALI by inhibiting the TLR4/MyD88/NF-κB signaling pathway, reducing pro-inflammatory cytokine production, increasing anti-inflammatory cytokine levels, and improving lung pathology. ¹⁰⁶ Huoxiang Zhengqi Oral Liquid, widely used for gastrointestinal and respiratory diseases, mitigates LPS-induced ALI by increasing cecal short-chain fatty acid levels, suppressing IL-6, IL-1β, TNF-α, and interferon-γ (IFN-γ) accumulation, inhibiting TLR4/NF-κB p65 pathway activation, and downregulating TLR4, MyD88, and p–NF-κB p65 expression, thereby exerting a triple anti-inflammatory effect. ¹⁰⁷ Yinma Jiedu Granule, indicated for “lung heat” cough, reduces alveolar type II cell vacuolation, repairs bronchial epithelial microvilli, increases SOD activity, decreases MDA content, inhibits iNOS and cyclooxygenase-2 (COX-2), expression, and modulates the JAK2/STAT1 pathway to alleviate LPS-induced ALI. ¹⁰⁸ Sanhan Huashi Granule, developed by Academician Tong Xiaolin during the COVID-19 pandemic from modifications of five classical formulas (Maxing Shigan Decoction, Tingli Dazao Xiefei Decoction, Dayuanyin, Shenzhu San, and Huopu Xialing Decoction), inhibits severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) aggregation in mouse lungs and reduces inflammatory factor levels in LPS-induced ALI mice and RAW264.7 cells, demonstrating potent antiviral and anti-inflammatory effects. ¹⁰⁹ Jingfang Granules improve alveolar structural integrity, reduce inflammatory infiltration, and inhibit collagen deposition and α-smooth muscle actin (α-SMA) expression to attenuate pulmonary fibrosis. In BLM-induced ALI, their effect is linked to inhibition of the PI3K/Akt/mTOR pathway and regulation of glycolysis, gluconeogenesis, and pyruvate metabolism. ¹¹⁰ Jinhua Qinggan Granules, used for wind-heat invasion of the lungs, promote neutrophil apoptosis and inhibit their pulmonary recruitment via mitochondrial pathways, suppress pro-inflammatory cytokine release, downregulate TLR4, MyD88, and p-p65 expression, and reduce p65 nuclear translocation, thereby inhibiting NF-κB activation and improving ALI symptoms. ¹¹¹ Biyuan Tongqiao Granules significantly reduce IL-1β, IL-6, and TNF-α levels in BALF and serum, while activating the PI3K/Akt/mTOR pathway through upregulation of p-PI3K, p-Akt, and p-mTOR expression, thereby exerting preventive and therapeutic effects against ALI. ¹¹² XueBiJing injection, indicated for infection-induced systemic inflammatory responses, reduces TNF-α and IL-6 levels in serum and lung tissue, lowers MDA content, and modulates ferroptosis in sepsis-induced ALI by downregulating acyl-coenzyme a synthetase long-chain family member 4 (ACSL4) and upregulating glutathione peroxidase 4 (GPX4), ferritin heavy chain 1 (FTH1) expression. ¹¹³ Shenmai injection alleviates acute pancreatitis (AP)-induced ALI by increasing HO-1 and IL-10 levels and decreasing TNF-α levels. ¹¹⁴ Reyanning mixture suppresses neutrophil and macrophage activation, reduces TNF-α and IL-6 levels, and upregulates IL-10 and arginase-1 (Arg-1) expression. Its mechanism involves inhibition of the glycogen synthesis pathway, blockade of the uridine diphosphate glucose (UDPG)/P2Y14/STAT1 axis, and reduction of M1 macrophage polarization, thereby attenuating inflammatory responses and improving ALI. ¹¹⁵

Clinical Application of TCM in the Treatment of ALI

Currently, modern medicine has no specific drugs for the treatment of ALI. Drugs such as dexamethasone, ulinastatin, cefoxitin, and prednisolone have good anti-inflammatory activity and are commonly used in the clinical treatment of ALI. However, these drugs often cause more severe allergic reactions, gastrointestinal reactions, and other side effects, causing secondary harm to patients. In recent years, traditional Chinese medicine formulations containing natural ingredients have been applied to treat ALI due to their advantages of minimal toxicity and side effects, as well as their effective therapeutic outcomes. These formulations help improve lung function, reduce inflammatory damage, and enhance patient survival rates. The mechanisms of action of some traditional Chinese medicine formulations in clinical applications are summarized in Table 4.

Table 4.

Clinical Application of TCM in the Treatment of ALI.

Drugs	Method of Administration	Research Types	Patient Types	Pathological Indicators				References
				TNF-α	IL-6	PaO2/FiO2	Others
Breviscapine injection	Intravenous drip	Randomized controlled trial	Sepsis ALI patients	↓	↓	↑		[116]
Xuanbai Chengqi Decoction	Oral	Randomized controlled trial	ARDS patients	↓	↓	↑	PEEP↑	[117]
Weijing Decoction	Oral	Randomized controlled trial	ARLI patients	↓	↓		IL-1↓, MDA↓, SOD↑, GSH-Px↑, FVC↑, FEV1↑, FEV1/FVC↑	[118]
XueBiJing injection	Intravenous drip	Randomized controlled tria	SCAP patients		↓		CRP↓, PCT↓, IL-17↓, IL-33↓, HMGB1↓, EVLWI↓, PVPI↓, PaO₂↑, SaO2↑	[119]
Tanreqing injection	Intravenous drip	Randomized controlled tria	Sepsis-induced ALI Patients		↓	↑	IL-8↓, MMP-9↓, PA-aDO2↓, PaO2↑	[120]
Shenmai injection and Ulinastatin	Intravenous drip	Randomized controlled tria	PA-related lung damage patients	↓	↓	↑	IL-1β↓	[121]
Reduning injection and cefoxitin	Intravenous drip	Randomized controlled tria	pediatric pneumonia patient	↓	↓		CRP↓	[122]

Breviscapine is an active component extracted from Erigeron breviscapus, exhibiting multiple pharmacological effects including antioxidant, antiplatelet aggregation, and anti-inflammatory properties. In cases of ALI caused by sepsis, the application of Breviscapine injection solution demonstrates particularly significant efficacy. A study ¹¹⁶ used Breviscapine injection in patients with sepsis-induced ALI and found that it effectively improved pulmonary artery pressure, increased pulmonary blood flow, improved the oxygenation index (PaO₂/FiO₂), significantly reduced the levels of inflammatory factors such as IL-6 and TNF-α in patients’ plasma, and alleviated pulmonary inflammatory responses. Xuanbai Chengqi Decoction can improve lung function by Heat-clearing and detoxifying, eliminating dampness and phlegm. Clinical studies have found ¹¹⁷ that administering Xuan Bai Cheng Qi Tang via enema to ARDS patients significantly improves lung compliance, reduces positive end-expiratory pressure (PEEP), shortens mechanical ventilation time, and increases PaO₂/FiO₂. Additionally, patients treated with Xuan Bai Cheng Qi Tang experienced a significant reduction in the duration of parenteral nutrition and a lower incidence of complications. Weijing Decoction, as one of the classic formulas in TCM, possesses the therapeutic effects of blood-activating and stasis-removing, clearing heat and transforming phlegm, and draining pus and eliminating turbidity. Weijing Decoction, a classical TCM formula with effects of activating blood circulation, clearing heat, resolving phlegm, and draining pus, has demonstrated therapeutic benefit in acute radiation-induced lung injury (ARLI). In combination with conventional therapy, it alleviates symptoms such as cough, sputum production, chest pain, fever, and dyspnea, while significantly improving forced vital capacity (FVC), forced expiratory volume in 1 s (FEV1), and FEV1/FVC ratios. It also reduces TNF-α, IL-1, and IL-6 levels and enhances SOD and GSH-Px activity compared with conventional therapy alone. ¹¹⁸ XueBiJing injection, traditionally indicated for warm-heat syndromes with blood stasis and toxin accumulation, has demonstrated significant efficacy in severe community-acquired pneumonia (SCAP). Randomized controlled trials show that it improves pneumonia severity index (PSI) scores, reduces 28-day mortality, shortens mechanical ventilation duration, and decreases ICU length of stay. ¹¹⁹ Tanreqing injection, primarily used for early-stage pneumonia and acute bronchitis, significantly reduces C-reactive protein (CRP), procalcitonin (PCT), IL-6, interleukin-17 (IL-17), interleukin-33, and HMGB1 levels, lowers extra vascular lung water index (EVLWI) and pulmonary vascular permeability index (PVPI), and increases arterial oxygen partial pressure (PaO₂) and arterial oxygen saturation (SaO₂). In sepsis-associated ALI, its efficacy surpasses that of conventional treatment. ¹²⁰ Ulinastatin, widely used to treat acute and recurrent inflammatory conditions, exhibits strong anti-inflammatory effects but may cause allergic reactions. Combination therapy with Ulinastatin and Shenmai injection in acute pancreatitis–associated ALI significantly decreases TNF-α, IL-1β, and IL-6 levels, improves PaO₂/FiO₂, and yields better clinical outcomes than Ulinastatin alone. ¹²¹ Cefoxitin is a commonly used antibiotic for treating pneumonia; however, its efficacy is limited in an environment where bacterial resistance is gradually increasing. A related clinical study ¹²² investigated the combined use of Reduning injection and cefoxitin for the treatment of pediatric pneumonia. The results showed a significant reduction in TNF-α, IL-6, and CRP levels, with clinical efficacy superior to that of cefuroxime sodium alone, and no significant increase in drug-related adverse reactions.

Summary and Prospects

As an important component of China's medical heritage, TCM has demonstrated significant potential in the treatment of ALI by inhibiting inflammation, improving lung function, and promoting tissue repair. This is attributed to its unique “multi-component, multi-target, multi-pathway” regulatory mechanism. Studies have shown that TCM monomers, compound prescriptions, and Chinese proprietary medicines can block NF-κB nuclear translocation by inhibiting IKKβ activity, regulate MAPK-mediated inflammatory cell infiltration and cytokine release, and inhibit NLRP3 inflammasome-driven IL-1β and IL-18 maturation and secretion. They can also effectively inhibit the PI3K/Akt signaling pathway to suppress inflammatory responses while activating Nrf2 to initiate the antioxidant system. To further elucidate the crosstalk mechanisms, some studies have identified the interaction mechanisms between these pathways. Keap1 not only mediates Nrf2 expression but also interacts with IKKβ to regulate NF-κB signaling, thereby linking oxidative and inflammatory responses. ¹²³ PI3K/Akt signaling activation promotes Nrf2 nuclear translocation and antioxidant gene expression, while reducing intracellular ROS and indirectly inhibiting NF-κB and NLRP3 activation. ¹²⁴ In addition to indirectly inhibiting NLRP3 through antioxidant effects, Nrf2 can also directly regulate inflammasome function. Upon nuclear translocation, Nrf2 binds to the ARE within the NLRP3 gene promoter region, inhibiting its transcriptional expression. Furthermore, Nrf2 promotes autophagy-mediated degradation of the NLRP3 inflammasome by upregulating autophagy-related genes, thereby blocking its assembly and activation. This mechanism enables the synergistic effects of antioxidant and anti-inflammatory actions. ¹²⁵ Nrf2 and the MAPK signaling pathway form a bidirectionally regulated anti-inflammatory network. By maintaining cellular redox homeostasis, Nrf2 inhibits the phosphorylation and activation of the MAPK family, thereby reducing the release of downstream NF-κB-mediated inflammatory mediators such as TNF-α and IL-6. ¹²⁶ Conversely, MAPK can phosphorylate Nrf2 via the ERK1/2 pathway, promoting its nuclear translocation and the expression of antioxidant and anti-inflammatory genes such as HO-1 and NQO-1, thereby creating a synergistic effect. ¹²⁷ The PI3K/Akt pathway also exhibits a tightly regulated relationship with the NF-κB pathway, jointly mediating anti-inflammatory effects. Upon activation, PI3K phosphorylates Akt, which inhibits the degradation of IκBα and blocks NF-κB nuclear translocation. This reduces the release of pro-inflammatory factors such as TNF-α and IL-1β, while simultaneously downregulating iNOS and COX-2 expression and NO production, thereby mitigating inflammatory damage and tissue destruction. ¹²⁸ Through these mechanisms, traditional Chinese medicine regulates inflammatory responses, alleviates oxidative stress, protects cellular integrity, and modulates immune function, thereby aiding in the prevention and treatment of ALI. Additionally, combining traditional Chinese medicine with modern medical methods has been shown to improve patient outcomes, reduce complications, and promote lung recovery. Increasing clinical evidence suggests that integrated traditional Chinese and Western medicine treatment strategies can provide better outcomes by simultaneously targeting inflammatory responses and lung injury. Therefore, incorporating traditional Chinese medicine into ALI combined treatment protocols represents an effective direction for clinical translation and targeted therapy.

TCM possesses unique advantages in regulating inflammatory responses and preventing and treating ALI. However, numerous challenges persist in its clinical translation and in-depth mechanism research, limiting its application in ALI management. Clinical translation remains the most prominent issue in TCM research for ALI prevention and treatment, primarily due to insufficient scientific rigor in clinical study design and incomplete evidence chains. Most studies are small-scale, single-center trials, lacking large-scale, multicenter, double-blind randomized controlled trials. This research landscape casts doubt on the reliability and reproducibility of TCM treatments for ALI, making it difficult to gain recognition within mainstream international medicine. Furthermore, research primarily remains confined to animal and cellular models. Due to species differences, altered metabolic pathways, and changes in pharmacokinetics/pharmacodynamics, these models often fail to accurately reflect human cellular physiology, hindering the thorough evaluation of precise efficacy and safety in humans. The complexity of TCM further limits its application in ALI. This complexity manifests both in the diversity of chemical constituents and in the dynamic changes during metabolic processes in vivo. Taking the commonly used ALI treatment Ma Xing Shi Gan Tang as an example, metabolomics studies have identified 9 active components in blood and 12 differential metabolites, involving multiple pathways such as the tricarboxylic acid cycle and tyrosine metabolism. ¹²⁹ TCM formulas typically contain dozens or even hundreds of chemical substances, such as flavonoids, alkaloids, and terpenoids. These components undergo absorption, distribution, metabolism, and excretion within the body, generating numerous bioactive constituents whose identification and functional validation present significant challenges. The traditional theory of formula composition distinguishing “sovereign-minister-assistant-messenger” lacks a thorough modern pharmacological interpretation. While some studies suggest the sovereignty of principal herbs may play dominant roles, synergistic or antagonistic mechanisms between minister and sovereign herbs, as well as the regulatory effects of assistant herbs on efficacy, remain unclear. Limitations in mechanism-of-action research hinder the full scientific elucidation of TCM's role in preventing and treating ALI. Existing studies remain overly focused on classical inflammatory signaling pathways like NF-κB, MAPK, and NLRP3, with insufficient exploration of novel targets and epigenetic regulation. Notably, the ambiguity of the “dose-response” relationship in TCM represents a critical yet often overlooked issue in current research. The regulatory effects of TCM on inflammatory responses may be diametrically opposed at different dosages. This phenomenon has begun to emerge in ALI prevention and treatment research, yet systematic investigations remain scarce. Further exploration of the “dose-response” relationship in TCM holds profound implications for both mechanism studies and clinical translation.

TCM possesses irreplaceable advantages in regulating inflammatory responses and improving ALI. Its multi-component, multi-targets, and multi-pathways regulatory mechanisms offer potential for anti-inflammatory, antioxidant, immunomodulatory, and tissue repair effects. Future efforts should focus on deepening mechanism elucidation, strengthening technological integration, and advancing clinical translation based on existing foundations to establish a more systematic TCM research framework for ALI prevention and treatment. Proactive application of bioinformatics methods, coupled with AI-assisted network pharmacology approaches, enables precise construction of “drug-component-pathway-disease” networks and core target screening. ¹³⁰ Concurrently, integrating genomics, metabolomics, and proteomics data reveals upstream and downstream signaling associations in TCM's regulation of inflammatory responses. Current research increasingly focuses on the lung-gut axis's role in regulating ALI. Traditional Chinese medicine's theory of “lung and large intestine being paired organs” aligns closely with modern discoveries about gut microbiota regulating distant organs. TCM can block the vicious cycle of “gut dysbiosis-systemic inflammation-lung injury” vicious cycle. In-depth investigation of its action targets, core factors, and key genes holds promise as a new breakthrough point for developing effective ALI drugs. Simultaneously, focusing on the precise regulatory mechanisms of inflammatory signaling pathways and thoroughly validating the intervention effects of TCM components on core inflammatory pathways will provide clearer evidence for the anti-inflammatory mechanisms of TCM.