Role of Nuclear Factor-κB in Acute Respiratory Distress Syndrome Mechanism
Inflammatory Response
Inflammation is a critical pathophysiological change in ARDS.[8] Its mechanism involves polymorphonuclear leukocyte aggregation, adhesion, protease
release, oxygen radicals damaging the alveolar membrane, and production of procoagulants
leading to microthrombosis. Inflammatory mediators cause pulmonary vasoconstriction,
bronchospasm, and increased permeability.
Severe pneumonia releases inflammatory mediators, and NF-κB regulates the expression
of various inflammatory mediator genes while being activated by inflammatory mediators.
Cytokines such as TNF-α and IL-1β, activate NF-κB through classical pathways. Activated
NF-κB amplifies inflammation by increasing the transcription of genes encoding IL-6,
IL-8, TNF-α, and IL-1β in host Ams, ultimately leading to ALI.[9] Inflammatory factors in ALI disrupt intercellular tight junctions and adhesion connections,
increase cellular permeability, cause pulmonary edema, and trigger ARDS.[10] Numerous studies confirm that intervening in the NF-κB signaling pathway to inhibit
the expression of inflammatory factors can alleviate the inflammatory response. Therefore,
NF-κB is a versatile nuclear transcription factor that exacerbates the inflammatory
response in ARDS when dysregulated. Conversely, modulating NF-κB and its related signaling
pathways to inhibit its transcription and expression can mitigate the severity of
the inflammatory storm and improve ARDS severity.[7]
Endothelial Barrier Dysfunction
Endothelial barrier dysfunction is another important pathophysiological change in
ARDS.[8] Damaged vascular endothelium caused by factors such as immune response dysregulation
and disruption of intercellular connections can activate platelets. This activation
is accompanied by increased procoagulant substances, and activation of kinins, complement,
and fibrinolytic systems, further promoting disseminated intravascular coagulation.
This process increases the permeability of the alveolar–capillary membrane, leading
to inflammatory edema and exacerbating ARDS.
NF-κB is an important signaling pathway that reduces endothelial cell permeability
and barrier damage. Patients with uncontrolled or allergic reactions often develop
septicopyemia and systemic inflammatory response syndrome (SIRS) after trimeresurus
snakebite, with ARDS representing the pulmonary manifestation of SIRS. Treatment with
Sheshang capsules, a representative agent for fire-purging and detoxification therapy,
significantly reduces the expression of vascular endothelial cell IKK, NF-κB-inducing
kinase, and NF-κB p65 (Rel-A) proteins.[11]
Oxidative Stress
Oxidative stress results from an imbalance between oxidation and antioxidation. In
response to inflammatory stimuli, various lung cells produce ROS. ROS-induced oxidative
stress plays a crucial role in lung injury and the progression of ARDS.
TNF-α induces ROS production and promotes neutrophil “oxidative burst,” while ROS
can also increase the level of TNF-α. TNF-α activates NF-κB-mediated transcription
and expression of inflammatory mediators, forming a cyclic loop. ROS produced by neutrophils
disrupt the endothelial barrier, allowing large numbers of inflammatory cells to migrate
through the endothelial barrier, thereby exacerbating inflammation.[12]
Therefore, under conditions of oxidative stress, NF-κB can exert a protective effect
through antioxidation. Studies have shown that NF-κB has many antioxidant targets,
such as superoxide dismutase (SOD).[12] Oxidative stress and inflammatory responses interact in ARDS, leading to intensified
cellular damage and inflammation.
Impaired Alveolar Fluid Clearance
Impaired alveolar fluid clearance (AFC) is a significant cause of pulmonary edema
in ARDS patients. Basal AFC is determined by ion and fluid transport across alveolar
epithelium, where the epithelial Na+ channel (EnaC) plays a critical role in sodium ion active transport.
Normally, pulmonary edema is resolved through the reabsorption of edema fluid by the
alveolar–epithelial barrier. However, in most ARDS patients, epithelial barrier function
is compromised due to inflammation, resulting in early impairment of AFC and persistent
alveolar edema. Failure to clear alveolar edema significantly increases mortality
in ARDS.[7] Zhai et al demonstrated that natural ferulic acid (FA) regulates ENaC via the IKKβ/NF-κB
pathway. FA reduces phosphorylation of IKKβ/NF-κB, and eliminates the lipopolysaccharide
(LPS)-inhibited ENaC expression, which is closely associated with NF-κB p65 regulation.[13] Therefore, NF-κB plays a crucial role in improving AFC.
Coagulation Dysfunction
ALI induces microthrombosis, degradation of fibrinogen products, and release of vasoactive
substances, which further aggravate damage to the alveolar–capillary membrane. This
results in increased permeability, manifested as gas diffusion impairment, intrapulmonary
shunting, and dead space-like ventilation, ultimately leading to ventilation/perfusion
mismatch and hypoxemia, and in severe cases, respiratory failure.[14]
Inflammatory factors released by NF-κB activation can cause local tissue factor (TF)
exposure and upregulate plasminogen activator inhibitor-1 (PAI-1) and activated protein
C (APC) expression. Therefore, NF-κB expression can regulate pulmonary tissue coagulation/fibrinolysis
function.[15] For example, Richard et al found in a TNF-α-mediated mouse lung injury model that
inhibiting NF-κB activation regulates APC expression, thus achieving antithrombotic
and anticoagulant effects to mitigate lung injury.[16]
TCM Treatments for Acute Lung Injury/Acute Respiratory Distress Syndrome via Nuclear
Factor-κB Signaling Pathway Intervention
Chinese Herbal Monomers
Alkaloid Compounds
Palmatine is a type of botanical medicine composed of palmatine chloride, which possesses
antibacterial, anti-inflammatory, heat-clearing, and detoxifying effects and is mainly
used for various inflammatory and infectious diseases.[17] Pretreatment of palmatine significantly inhibits IL-1β expression and secretion
in bronchoalveolar lavage fluid (BALF) of LPS-induced ALI mice, and markedly reduces
inducible nitric oxide synthase (iNOS) protein level. Further mechanistic studies
revealed that palmatine and coptisine interact with AKT via hydrogen bonding, which
can significantly inhibit AKT/NF-κB signaling pathway activation and effectively alleviate
ALI.[18]
[19] By inhibiting NF-κB and NLRP3 protein (NOD-, LRR-, and pyrin domain-containing protein
3, NLRP3) transcription and protein expression levels, ligustrazine reduces the contents
of inflammatory factors such as IL-2, IL-6, and TNF-α, improves lung injury in severely
burned rats with ALI and increases their survival rate.[20] Peimine and peiminine derived from Zhebeimu (Bulbus Fritillariae Thunbergii). It
was found that the combined use of the two and forsythin A was superior to that of
forsythin A alone, and could significantly inhibit the upregulation of Toll-like receptor
(TLR) 4 (TLR4)/MAPK/NF-κB signaling pathway-related proteins and activation of IL-17,
and also improved the thickening of the bronchoalveolar wall.[21] Protostemonine (PSN) has an anti-inflammatory effect, which can reduce neutrophil
infiltration and tissue permeability in ALI mice induced by methicillin-resistant
Staphylococcus aureus. Simultaneously, PSN plays an anti-inflammatory role by reducing the production of
nitric oxide (NO) in medullary macrophages induced by inflammation.[22]
Terpenoids
Macrophages mainly derive from monocytes, and their phagocytic function can eliminate
abnormal cells and regulate the body's immunity. Apoptosis of macrophages induced
by ALI can upregulate the level of inflammatory responses and further exacerbate immune
dysregulation, and potentially progress to ARDS. ALI/ARDS can polarize AMs toward
the M1 phenotype, and promote secretion of proinflammatory cytokines and chemokines
such as IL-6, IL-12, and TNF-α. Therefore, treatment with hederagenin reduces the
number of M1 macrophages in the lung tissues of septic rats, which can inhibit the
release of inflammatory factors, thereby improving the rats' survival rate and alleviating
pulmonary inflammatory responses and pathological damage.[23] 23-O-acetylshengmanol-3-O-α-L-arabinoside (DA) is a triterpenoid compound found
in the roots and stems of Shengma (Cimicifugae Rhizoma), which improves lung immune
system disorders in ALI mice by regulating abnormal apoptosis of lung cells. Additionally,
research by Chen found that DA also reduces lung inflammation damage, lung function
impairment, and pulmonary edema by downregulating IκBα/NF-κB expression.[24] Loganin is a major active ingredient in Shanzhuyu (Corni Fructus), which can regulate
macrophage polarization via the NF-κB pathway and inhibit NLRP3 inflammasome activation
to alleviate ALI caused by sepsis.[25] Research has found that Euphorbia factor L2 can significantly inhibit the levels
of inflammatory factors such as IL-1β, IL-6, TNF-α, and IL-8, and this effect is mediated
by inhibiting the activation of NF-κB signaling.[26] Triptolide can significantly reduce the levels of white blood cells, pulmonary edema,
and myeloperoxidase (MPO) activity in ALI mice.[27] Tumor necrosis factor receptor- associated factor 6 (TRAF6) is a ubiquitin ligase
that, when ubiquitinated, recruits Transforming growth factor β-activated kinase 1
(TAK1) through adaptor protein TAB, thereby activating NF-κB and MAPK to induce the
release of inflammatory cytokines and chemokines. Effective parts of Andrographis
diterpene lactone inhibit the interaction between TRAF6 and TAK1 to achieve deubiquitination
and dephosphorylation purposes.[28] Limonene, abundant in kumquat peel essential oil, has antioxidative and antifibrotic
functions. Different doses of limonene can reduce phosphorylation levels of p38, p65,
and IκBα, thereby blocking the p38 MAPK/NF-κB signaling pathway and exerting anti-inflammatory
effects.[29]
TLRs are transmembrane proteins that mediate recognition and responses to external
pathogens. There are two signal transduction pathways of activated TLRs: myeloid differentiation
primary response protein 88 (MyD88)-dependent signal transduction pathway and MyD88-independent
signal transduction pathway. TLR4 can mediate both signaling pathways, and targeting
TLR4 is a therapeutic approach for treating ALI.[30]
Bilobalide (BB) can regulate T Helper 1 Cell/ T Helper 2 Cell balance and improve
lung tissue damage in septic ALI rats by inhibiting TLR4/NF-κB signaling pathway activation.[31] High doses of Chinese herbal monomers can achieve effects similar to glucocorticoids,
and BB and splatycodin D can also achieve effects similar to glucocorticoids.[32] Researchers have found that ingredients in Chaihu (Bupleuri Radix), such as saikosaponins
A, b1, b2, and D (SSA, SSb1, SSb2, SSD). The contents of SSb1 and SSb2 increased significantly
after vinegar treatment, which can reduce lung edema in ALI mice. Both have anti-inflammatory
effects through TLR4/NF-κB, with SSb2 showing superior lung protective effect at the
same dose compared with other drugs.[33]
Flavonoid Compounds
Baicalin is the flavonoid compound found in the highest concentration in Huangqin
(Scutellariae Radix), primarily existing in the form of a magnesium salt. The Mg2+ in baicalin magnesium salt (BA-Mg) promotes the generation of intracellular cyclic
adenosine monophosphate to control the activity of sodium channels on alveolar epithelial
cells, thereby alleviating pulmonary edema. Additionally, the antagonism of Mg2+ to Ca2+ can block its inflow into effector cells and aggravate lung injury. Studies indicate
a close correlation between oxidative stress and the occurrence and development of
ALI. Lipid peroxidation damages endothelial cells and alveolar epithelial cells. ROS
stimulate increased activity of iNOS in blood, leading to excessive NO production,
pulmonary vasodilation, and ultimately pulmonary edema. Excessive ROS also damages
cellular DNA, causing DNA mutations and breakage, mitochondrial dysfunction, destroyed
mitochondrial structure leading to insufficient cell energy supply, apoptosis, and
necrosis. BA-Mg demonstrates superior antioxidant efficacy compared with equimolar
doses of the baicalin group and magnesium sulfate group.[34]
[35]
Silymarin, extracted from the Compositae plant, Silybum marianum, possesses antioxidant, toxin-removing, and protein synthesis-promoting properties.
It protects lung function in ALI rats by inhibiting oxidative stress and inflammatory
reactions through modulation of the TLR4/NF-κB pathway.[36] Trifolium flavone improves lung function in elderly ALI mice through the MAPK/NF-κB
pathway.[37] Ampelopsin, a major flavonoid in vine tea, enhances lung function by increasing
lung volume, ventilation, and elasticity.[38] Nobiletin is extracted from Chenpi (Citri Reticulatae Pericarpium), which, at a
dose of 50 mg/kg, downregulates MAPK/NF-κB expression in ALI mice, significantly inhibits
NF-κB p65, p38 MAPK, extracellular regulated protein kinases (ERKs), and c-Jun N-terminal
kinase phosphorylation.[39] Dihydroquercetin can reduce LPS-induced inflammation and cell apoptosis via the
miR-132-3p/Forkhead Box O3 (FOXO3)/NF-κB pathway.[40]
Halofuginone can significantly inhibit the secretion of inflammatory factors (IL-1β,
IL-6, IL-18) and reduce the peripheral blood CD14+ cell count in ALI rats to regulate immune imbalance.[41] Zhong et al[42] found that isorhamnetin from sea buckthorn berry extract combined with Ressatovi
significantly improved arterial oxygen partial pressure (PaO2), decreased arterial partial pressure of carbon dioxide (PaCO2), and markedly reduced lung injury in ALI rats induced by high-concentration oxygen
therapy.
Glycoside Compounds
Cordycepin is an active component isolated from Dongchong Xiacao (Cordyceps). Li et
al[43] demonstrated that intervening in ALI rats can improve rat capillary dilation, reduce
red blood cell leakage, and decrease pulmonary tissue fluid secretion. It can also
increase PaO2 level, decrease PaCO2 level, and exhibit dose dependency. Experimental results indicate that Allium macrostemon saponin can inhibit IκBα degradation, suppress inflammation, and reduce the expression
of vascular cell adhesion molecule-1, thereby decreasing monocyte adhesion to endothelial
cells to prevent and treat ALI.[44]
Research has confirmed that one of the clinical markers of ALI/ARDS is the deposition
of fibrin in the alveoli. This is because the inflammatory storm caused by ALI damages
pulmonary capillary endothelial cells, and activates the body's coagulation and fibrinolytic
system, thus leading to early hypercoagulability, microcirculatory disorders, tissue
ischemia, and hypoxia. Therefore, adjusting coagulation function has become one of
the important clinical treatments for reducing fibrin deposition in the alveolar cavity.[45]
Panax notoginseng saponins are the most effective components in Sanqi (Notoginseng Radix et Rhizoma).
Besides significantly reducing NF-κB expression in ALI mice, they can improve coagulation
function and resist non-microvascular thrombosis, thus contributing to their mechanism
of treating ALI.[46]
Xu[47] found that high doses of ginsenosides Ro and Rb3 can block the binding of LPS to
RAW 264.7 macrophages at the TLR4 cell membrane receptor level, improve pulmonary
interstitial congestion and hemorrhage, reduce inflammatory cell infiltration, without
affecting liver function. In the inflammatory response of ALI, the Rho A/ROCK pathway
mainly regulates the activation of filamentous actin and globular actin and the stability
of adhesive junctions, playing an important role in protecting the reconstruction
and permeability of the alveolar epithelium–pulmonary microvascular endothelial cytoskeleton.
Astragaloside, by inhibiting the expression of the Rho A/ROCK/NF-κB signaling pathway,
protects cellular structural function, decreases the contents of inflammatory factors
induced by PM2.5 in ALI rats, and reduces edema fluid and protein leakage.[48] By inhibiting TLR4-NF-κB activation, salidroside delays the pathological process
of lung injury in ALI rats poisoned by paraquat, thus reducing the severity of lung
injury.[49] This study used high-dose polyphyllin VII to intervene in severe acute pancreatitis-induced
ALI and reduce proinflammatory cytokine secretion while addressing pancreatic and
pulmonary tissue damage.[50]
Phenylpropanoids
Cnidiadin can effectively alleviate ALI caused by hemorrhagic shock, which is associated
with inhibition of the NF-κB signaling pathway-mediated inflammatory response.[51]
The PI3K/AKT signaling pathway is one of the important pathways involved in ALI/ARDS.
Activation of the PI3K/AKT pathway leads to activation of downstream NF-κB signaling
and increased production of inflammatory cytokines. Arctiin, a major component of
Niubangzi (Arctii Fructus), belongs to lignan compounds. A high dose of arctiin can
inhibit IκBα and NF-κB phosphorylation levels through PI3K/AKT, and reduce lung inflammation.[52] However, research has shown that activation of PI3K/AKT can inhibit downstream NF-κB
and NLRP3 inflammasome to alleviate lung inflammation in LPS-induced ALI models. Whether
this pathway plays a positive or negative role in regulating inflammation in ARDS
needs further clarification.[7]
Aesculetin is found in various natural plants (such as Datura stramonium and Rehmannia) and possesses anti-inflammatory properties. Pretreatment with aesculetin inhibits
the expression of AKT/ERK/NF-κB, Retinoic acid receptor-related orphan receptor gamma-t
(RORγt)/IL-17 pathways, which significantly reduce histopathological changes and inflammatory
cell infiltration (such as TNF-α, IL-1β, IL-6) in lung tissue.[53]
Organic Compounds
Eupalinolide B (EB) exhibits anti-inflammatory and antiviral effects and can be used
in the treatment of ALI. EB binds to the Cys174 site of TAK1, inhibits the activation
of the target protein TAK1 and the activation of TAK1-mediated NF-κB/MAPKs pathway,
thereby alleviating ALI.[54] Codonopsis polysaccharides not only reduce the levels of neutrophils and lymphocytes
in the BALF of ALI mice, alleviate the infiltration of inflammatory cells into lung
tissue and the proliferation of alveolar epithelial cells to varying degrees, but
also improve lung function in ALI mice.[55] Chicoric acid has the effects of clearing heat and resolving toxicity, promoting
diuresis, and reducing swelling. It can alleviate lung damage and pulmonary edema
in ALI mice induced by sepsis by acting on key proteins MyD88 and P65 levels in the
TLR9, Interferon regulatory factor 7 (IRF7), and NF-κB signaling pathways while reducing
damage to normal lung epithelial cells and oxidative stress in LPS-induced patients.[56] Trans-cinnamaldehyde is a major component of cinnamon essential oil, which significantly
improves lung function in ALI mice and can induce a shift of lung tissue M1 macrophages
to the M2 phenotype, thereby reducing lung cell apoptosis.[57] Chinese yam glycoprotein is one of the components of Chinese yam polysaccharides.
It has anti-inflammatory and immune-regulating functions, which are possibly associated
with the regulation of TLR4/NF-κB/NLRP3 expression.[58]
Other Compounds
Ginger exhibits various medicinal forms with diverse functions. 6-shogaol, the main
active ingredient in dried ginger, belongs to the phenolic compound category and shows
therapeutic effects on cardiovascular, gastrointestinal, hepatic, and biliary diseases.
Research has found that 6-shogaol inhibits NF-κB-related expression to reduce alveolar
capillary permeability in the lung and alleviate neutrophil infiltration and pulmonary
edema, thus exerting anti-inflammatory and antioxidant effects in a dose-dependent
manner.[59] Gingerol is the primary active substance in ginger. Li et al[60] observed that gingerol not only downregulates TF and PAI-1 protein expression levels
in the lung tissue but also improves the hypercoagulable state.
Tanshinone IIA sodium sulfonate, derived from Danshen (Salviae Miltiorrhizae Radix
et Rhizoma), belongs to the fat-soluble non-quinone pigment compounds. It exhibits
a dose-dependent repair effect on firearm-induced ALI guinea pig lung injuries.[61] The combined use of resveratrol and curcumin significantly inhibits inflammation
and apoptosis in septic ALI, with better results than using either alone.[62] High doses of pine cone of Pinus yunnanensis and extract of wartwort can reduce LPS-induced ALI in rats; the former inhibits the
TLR4/NF-κB signaling pathway to lower levels of inflammatory and oxidative factors,
while the latter achieves anti-inflammatory effects through the MAPK/NF-κB pathway.[63]
[64]
MBAP-5 is a novel flavonol polysaccharide extracted from Tamarix chinensis. Its oral administration can inhibit TLR4/NF-κB to reduce pulmonary edema, viral
replication, and inflammatory responses in influenza A virus-induced ALI.[65] Research indicates that the ethanolic extract of atractylodis rhizoma (EEAR) is
rich in four main components: atractylol, atractylenolide I, atractylenolide II, and
atractylenolide III. After treatment with EEAR, it improved lung barrier function
and inhibited oxidative stress by regulating nuclear factor-erythroid 2-related factor-2
and its downstream targets heme oxygenase-1 (HO-1) and NADPH quinone acceptor oxidoreductase
1 (NQO-1).[66] See [Table 1].
Table 1
Research models and action mechanisms of Chinese herbal monomers in treating acute
lung injury/acute respiratory distress syndrome through nuclear factor-κB-related
signaling pathways
|
Medicines
|
Models
|
Action mechanisms
|
References
|
|
Palmatine
|
ALI mice
|
AKT/NF-κB↓, reducing inflammatory responses
|
[18]
|
|
Coptisine
|
ALI mice
|
PI3K/AKT/NF-κB↓, reducing inflammatory responses
|
[19]
|
|
Ligustrazine
|
ALI rats
|
NF-κB/NLRP3↓, reducing inflammatory responses
|
[20]
|
|
Peimine, Peiminine
|
ALI mice
|
TLR4/MAPK/NF-κB↓, reducing inflammatory responses
|
[21]
|
|
Stemonine
|
ALI mice
|
MAPK/NF-κB↓, reducing inflammatory responses
|
[22]
|
|
Hederagenin
|
ALI rats
|
NF-κB/NLRP3↓, M1 macrophages↓, reducing inflammatory responses, resisting oxidization
stress
|
[23]
|
|
3-O-acetylshengmanol-3-O-α-L-arabinoside
|
ALI mice, RAW 264.7 macrophages
|
IκBα/NF-κB↓, NLRP3↓, reducing inflammation
|
[24]
|
|
Loganin
|
ALI mice
|
NF-κB/NLRP3↓, reducing inflammatory responses
|
[25]
|
|
Euphorbia factor L2
|
RAW 264.7 macrophages, ALI mice
|
NF-κB↓, reducing inflammatory responses
|
[26]
|
|
Triptolide
|
ALI mice
|
TLR4/NF-κB↓, reducing inflammatory responses
|
[27]
|
|
Andrographolide
|
ALI mice, RAW 264.7 macrophages
|
TAK1/NF-κB↓, inhibiting inflammatory responses
|
[28]
|
|
Limonene
|
ALI mice
|
MAPK/NF-κB↓, reducing inflammatory responses
|
[29]
|
|
Bilobalide
|
ALI rats
|
TLR4/NF-κB↓, reducing inflammatory responses
|
[31]
|
|
Platycodin D
|
ALI rats
|
NF-κB↓, resisting oxidization stress
|
[32]
|
|
Saikosaponins A, b1, b2, and D
|
ALI mice
|
TLR4/NF-κB↓, reducing inflammatory responses
|
[33]
|
|
Baicalin magnesium salt
|
ALI mice
|
TLR4/MyD88/NF-κB↓, reducing inflammation, resisting oxidization stress
|
[34]
|
|
Silymarin
|
ALI rats
|
TLR4/NF-κB↓, resisting oxidization stress, reducing inflammatory responses
|
[36]
|
|
Trifolium flavone
|
ALI mice
|
MAPK/NF-κB↓, reducing inflammatory responses
|
[37]
|
|
Dihydromyricetin
|
ALI mice
|
TLR4/MyD88/NF-κB↓, reducing inflammatory responses
|
[38]
|
|
Nobiletin
|
ALI mice
|
MAPK/NF-κB↓, reducing inflammatory responses
|
[39]
|
|
Dihydroquercetin
|
TC-1 cell
|
miR-132-3p/FOXO3/NF-κB↓, reducing inflammatory responses
|
[40]
|
|
Halofuginone
|
ALI rats
|
CD14/NF-κB↓, reducing inflammatory responses
|
[41]
|
|
Isorhamnetin
|
ALI rats
|
TLR4/NF-κB↓, reducing inflammatory responses
|
[42]
|
|
Cordycepin
|
ALI rats
|
TLR4/NF-κB↓, reducing inflammatory responses
|
[43]
|
|
Allium macrostemon saponin
|
ALI mice, human umbilical vein endothelial cell (HUVEC) cell
|
NF-κB/VCAM-1↓, inhibiting inflammatory factors
|
[44]
|
|
Panax notoginseng saponin
|
ALI mice
|
NF-κB↓, resisting coagulation, inhibiting inflammatory responses
|
[46]
|
|
Gginsenoside Ro, Rb3
|
ALI mice, RAW 264.7 macrophages
|
TLR4/NF-κB/MAPK↓, reducing inflammatory responses
|
[47]
|
|
Astragaloside
|
ALI rats
|
Rho A/ROCK/NF-κB↓, reducing inflammatory responses
|
[48]
|
|
Salidroside
|
ALI rats
|
TLR4/NF-κB↓, reducing inflammatory responses
|
[49]
|
|
Polyphyllin VII
|
severe acute pancreatitis-associated acute lung injury (SAP-ALI) rats
|
NF-κB↓, reducing inflammatory responses
|
[50]
|
|
Forsythin A
|
ALI mice
|
TLR4/MAPK/NF-κB↓, reducing inflammatory responses
|
[21]
|
|
Cnidiadin
|
ALI rats
|
NF-κB↓, reducing inflammatory responses
|
[51]
|
|
Arctiin
|
RAW 264.7 macrophages
|
PI3K/AKT/NF-κB↓, reducing inflammatory responses
|
[52]
|
|
Aesculetin
|
ALI mice
|
AKT/ERK/NF-κB↓, RORγt/IL-17↓, reducing inflammatory responses
|
[53]
|
|
Eupalinolide B
|
ALI mice, RAW 264.7 cell
|
NF-κB↓, reducing inflammatory responses
|
[54]
|
|
Codonopsis polysaccharide
|
ALI mice
|
MAPK/NF-κB↓, reducing inflammatory responses
|
[55]
|
|
Chicoric acid
|
ALI mice, BEAS-2B cell
|
TLR9/NF-κB↓, reducing inflammatory responses
|
[56]
|
|
Trans-cinnamaldehyde
|
ALI mice
|
TLR4/MyD88/NF-κB↓, reducing inflammatory responses
|
[57]
|
|
Chinese yam glycoprotein
|
ALI mice
|
TLR4/NF-κB/NLRP3↓, reducing inflammatory responses
|
[58]
|
|
6-shogaol
|
ALI mice
|
NF-κB↓, resisting oxidization stress, reducing inflammatory responses
|
[59]
|
|
Gingerol
|
ALI rats
|
NF-κB↓, resisting coagulation, reducing inflammatory responses
|
[60]
|
|
Tanshinone IIA sodium sulfonate
|
ALI guinea pigs
|
NF-κB↓, reducing inflammatory responses
|
[61]
|
|
Resveratrol, curcumin
|
ALI mice
|
NF-κB↓, inhibiting inflammatory responses
|
[62]
|
|
Extract of pine cone of Pinus yunnanensis
|
ALI rats
|
TLR4/NF-κB↓, resisting oxidization stress, reducing inflammatory responses
|
[63]
|
|
Alcohol extract of wartwort
|
ALI mice
|
MAPK/NF-κB↓, reducing inflammatory responses
|
[64]
|
|
MBAP-5
|
ALI mice
|
TLR4/NF-κB↓, reducing inflammatory responses
|
[65]
|
|
Atractylodes root nodule ethanol extract
|
ALI rats
|
TLR4/NF-κB↓, kelch-like ECH-associated protein 1 (Keap1)/Nrf2↓, resisting oxidization
stress, reducing inflammatory responses
|
[66]
|
Abbreviations: AKT, protein kinase B; ALI, acute lung injury; ARDS, acute respiratory
distress syndrome; ERK, extracellular regulated protein kinase; IL-17, interleukin-17;
IκB, inhibitor of NF-κB; MAPK, mitogen-activated protein kinase; MyD88, myeloid differentiation
primary response protein 88; NF-κB, nuclear factor-κB, NLRP3; NOD-, LRR-, and pyrin
domain-containing protein 3; Nrf2, nuclear factor-erythroid 2-related factor-2; PI3K,
phosphoinositide 3-kinase; TLR, Toll-like receptor; VCAM-1, vascular cell adhesion
molecule-1.
TCM Couplet Medicines
Jingjie (Schizonepetae Herba) and Fangfeng (Saposhnikovia Radix) are both pungent-warm
herbs that dispel exterior pathogenic factors. Their combination exhibits antipyretic,
antalgic, anti-inflammatory, antiviral, antiallergic, and hemostatic effects. RAO
extracted the effective anti-inflammatory parts of Jingjie and Fangfeng (Jing-Fang
n-butanol extraction, JFNE) for the study of their effects on AIL. In vivo experiments
confirmed that JFNE suppresses the release of inflammatory factors IL-6, IL-1β, IFN-γ,
and TNF-α, thus significantly inhibiting the transcription levels of target genes
related to the NF-κB signaling pathways. Moreover, JFNE can downregulate the level
of iNOS, control the excessive secretion of proinflammatory cytokines, and simultaneously
resist tissue oxidative damage. In vitro experiments, the inhibitory effect of JFNE
on the expression level of target protein related to NF-κB signaling pathway in RAW
264.7 cells and A549 cells was consistent with in vivo experiments. Cimifugin, hesperetin,
luteolin, and 5-O-methylvisamminol glycoside are its main effective active substances
with anti-inflammatory and antioxidant effects, and luteolin is particularly superior.[67]
The simultaneous treatment of the lung and intestine is highly effective in the treatment
of ALI, represented by Mahuang Decoction and Dachengqi Decoction. Mahuang (Ephedrae
Herba) and Dahuang (Rhei Radix et Rhizoma) are the main couplet medicines used in
this method, which can significantly inhibit inflammation cell infitration in ALI
rats, reduce activation of AMs and polarization of M1 macrophages, and improve pathological
conditions such as interstitial edema and pulmonary tissue structure disorder.[68]
The Huangqi–Danshen couplet medicines have anti-inflammatory, anti-infection, and
immune-regulating effects, and show remarkable therapeutic effects on sepsis, pulmonary
fibrosis, liver damage, and diabetic nephropathy.[69] They can inhibit the TLR4/NF-κB signaling pathway to prevent lung injury in ALI
rats and improve the extent of lung tissue damage, and pretreatment is particularly
beneficial in reducing inflammatory damage.[70] See [Table 2].
Table 2
Research models and action mechanisms of Chinese couplet medicines treating acute
lung injury/acute respiratory distress syndrome through nuclear factor-κB-related
signaling pathways
|
Medicines
|
Models
|
Action mechanisms
|
References
|
|
Jingjie–Fangfeng
|
ALI mice, RAW 264.7 macrophages, A549 cell
|
NF-κB↓, reducing inflammation, resisting oxidization
|
[67]
|
|
Mahuang–Dahuang
|
ALI rats
|
NF-κB↓, M1 macrophages↓, reducing inflammatory responses
|
[68]
|
|
Huangqi–Danshen
|
ALI rats
|
TLR4/NF-κB↓, reducing inflammatory responses
|
[70]
|
Abbreviations: ALI, acute lung injury; ARDS, acute respiratory distress syndrome;
Nf-κB, nuclear factor-κB; TLR, Toll-like receptor.
TCM Injections
Re Du Ning Injection is a TCM injection mainly composed of Qinghao (Artemisiae Annuae
Herba), Jinyinhua (Lonicerae Japonicae Flos), and Zhizi (Gardeniae Fructus). It has
the effects of clearing heat and resolving toxins, reducing swelling and stopping
bleeding, protecting the liver and benefiting the gallbladder, relieving summer heat,
and eliminating steaming heat. It is widely used in the treatment of pneumonia and
upper respiratory tract infections.[71] Research shows that Re Du Ning Injection can reduce the level of inflammatory factors,
alleviate the “inflammatory storm” of ALI/ARDS, which is associated with its ability
to inhibit the activation of the TLR4/MyD88/NF-κB pathway and block the recruitment
of neutrophils.[72] Chuan Ke Zhi Injection acts by inhibiting the TLR4/NF-κB/NLRP3 pathway to exert
its anti-lung injury effect.[73]
Cylindromatosis (CYLD) is a negative regulator of NF-κB. Studies have found that CYLD
plays a negative regulatory role in the process of ALI. Compound Danshen Injection
can activate lung tissue CYLD and inhibit NF-κB signaling pathway activation to alleviate
inflammation-induced ALI in rats.[74]
Tan Re Qing Injection is composed of Huangqin (Scutellariae Radix), bear gall powder,
goat horn, Jinyinhua (Lonicerae Japonicae Flos), and Lianqiao (Forsythiae Fructus).
It has the effects of clearing heat and removing toxins, dispersing the lung, and
relieving the exterior, which can inhibit lung tissue NF-κB activation in septic ALI/ARDS
rats and block the inflammatory cascade reaction.[75] Dazhu Hongjingtian Injection can also be used for septic ALI.[76] Jin Na Duo Injection is composed of the Yinxingye (Ginkgo Folium) extracts (ginaton),
which has the effects of scavenging free radicals, resisting oxidant reactions, protecting
vascular endothelium, and improving microcirculation. After treatment with ginaton,
NF-κB expression decreases and TNF-α content reduces.[77] Within a certain range, moderate doses of Xuebijing Injection have the best protective
effect on the lung tissue of firearm injury-induced ALI rabbits, but the protective
effect of Xuebijing Injection weakens with doses exceeding the moderate level.[78] See [Table 3].
Table 3
Research models and action mechanisms of TCM injections treating acute lung injury/acute
respiratory distress syndrome through nuclear factor-κB-related signaling pathways
|
Medicines
|
Models
|
Action mechanisms
|
References
|
|
Re Du Ning Injection
|
ALI mice
|
TLR4/MyD88/NF-κB↓, reducing inflammatory responses
|
[72]
|
|
Chuan Ke Zhi Injection
|
ALI mice
|
TLR4/NF-κB/NLRP3↓, reducing inflammatory responses
|
[73]
|
|
Compound Danshen Injection
|
ALI rats
|
CYLD/NF-κB↓, reducing inflammatory responses
|
[74]
|
|
Tan Re Qing Injection
|
ALI rats
|
NF-κB↓, reducing inflammatory responses
|
[75]
|
|
Dazhu Hongjingtian Injection
|
ALI mice
|
NF-κB↓, reducing inflammatory responses
|
[76]
|
|
Jin Na Duo Injection
|
ALI rats
|
NF-κB↓, reducing inflammatory responses
|
[77]
|
|
Xuebiqing Injection
|
ALI rabbits
|
NF-κB↓, reducing inflammatory responses
|
[78]
|
Abbreviations: ALI, acute lung injury; CYLD, Cylindromatosis; MyD88, myeloid differentiation
primary response protein 88; NF-κB, nuclear factor-κB; NLRP3, NOD-, LRR-, and pyrin
domain-containing protein 3; TLR, Toll-like receptor.
Chinese Herbal Compound Formulas and Their Preparations
Chinese herbal compound formulas and their preparations are an important therapeutic
approach for downregulating NF-κB expression in ALI. Yantiao Formula, Qingfu Tongchang
Granules, and dexamethasone have similar effects and can avoid the adverse effects
of systemic glucocorticoid application.[79]
[80] Linggui Zhugan Decoction is a representative formula for warming yang and transforming
water retention. Research has confirmed that after treatment with Linggui Zhugan Decoction,
inflammatory cell and red blood cell exudation in lung tissues is significantly reduced,
especially in the low-dose group.[81] Meanwhile, Jinyin Qingre Oral Liquid shows the most significant improvement in lung
alveolar capillary permeability and lung tissue lesions in the high-dose group.[82] Extrapulmonary ARDS in patients primarily exhibits diffuse inflammatory exudation
in the lung early on, followed by respiratory failure. According to TCM, the main
pathogenesis involves a deficiency of primordial yang and diffuse invasion of yin
pathogens. The Fusu Mixture (Resuscitation Compound) is composed of the Qianyang Bunus
for treating edema and the Sini Decoction for treating collapse syndrome which jointly
warms the kidney and suppresses yang, and warms yang and dredges the meridians. The
Fusu Mixture has a protective effect on human microvascular endothelial cells,[83] involving long noncoding RNA in regulating NF-κB to alleviate the inflammatory response
and oxidative stress associated with sepsis-related ARDS.[84]
The TLR4-mediated NF-κB pathway is also a common therapeutic target for the treatment
of ALI. Yiqi Kangfei Formula, derived from modified Xiangsha Liujunzi Decoction, Yupingfeng
Powder, and Xiaoxianxiong Decoction, can inhibit the activation of the TLR4/MyD88/NF-κB
signaling pathway to reduce the synthesis and release of inflammatory factors, thereby
improving the capillary membrane permeability and pulmonary edema in ALI hamster.[85] The active ingredients in Shengjiang Powder (Ascending and Descending Powder) for
the treatment of ALI are mainly phytosterols such as campesterol and cholesterol because
the powder contains more phytosterols. Therefore, the efficacy of powder is superior
to decoction.[86] Qingfei Litan Formula originates from Traditional Chinese Medicine Diagnosis and Treatment Plan for Wind-Warm Disease with
Lung Heat issued by the National Administration of Traditional Chinese Medicine, with effects
of relieving the fleshy exterior and clearing heat, eliminating restlessness and quenching
thirst, so it can be used for lung heat syndrome. Experimental results confirm that
Qingfei Litan Formula also acts on ALI rats.[87]
NLRP3 is the most common inflammasome in ALI mechanism research, whose activation
induces the maturation of effector protein caspase-1 promotes the production of IL-1β
and IL-18, and further accelerates cell apoptosis and ALI progression.[88] Therefore, inhibiting the TLR4/NF-κB/NLRP3 signaling pathway activation is an effective
approach to improving ALI. Through this pathway, Yiqi Huayu Jiedu Formula can reduce
downstream inflammatory factor content and cell apoptosis to alleviate lung alveolar
and interstitial congestion and edema.[89] Additionally, Shiwei Qingwen Decoction (SWQD) also acts through this pathway. High-performance
liquid chromatography and liquid chromatography mass spectrometry techniques have
identified effective chemical components in SWQD derived mainly from Jinyinhua (Lonicerae
Japonicae Flos), Fangfeng (Saposhnikovia Radix), and Huangqin (Scutellariae Radix).
Among them, cimifugin in Fangfeng is the main chemical component of SWQD's medicinal
serum. SWQD can upregulate the expression of Aquaporin (AQP) 1 (AQP1) and AQP5 to
promote lung alveolar fluid transport and thus reduce pulmonary edema, and alleviate
lung tissue pathological damage by inhibiting MPO and neutrophil elastase expression.
In vitro experiments show that SWQD can suppress the level of NO secreted by human
monocytic-leukemia cells (THP-1) macrophages by inhibiting the expression of iNOS.[90] Maxing Shigan Decoction can reduce inflammatory cytokine levels in ALI mice, increase
SOD activity and glutathione content, reduce malondialdehyde level, enhance antioxidant
capacity, and improve lung function and lung CT scan results.[91]
Qingyi Decoction promotes the recovery of ALI associated with severe acute pancreatitis
while enhancing intestinal barrier function treatment. Its mechanism is related to
targeted regulation along the gut–lung axis via the MAPK/NF-κB/NLRP3 pathway.[92] The primary compound in Mahuang Shengma Decoction mainly derives Mahuang (Ephedrae
Herba), which has been found to inhibit the expression of key gene receptor for advanced
glycation end products (RAGE) and downstream NF-κB p65 in the RAGE/NF-κB signaling
pathway.[93] Qingwen Baidu Beverage has the effects of clearing heat and purging fire, and simultaneously
clearing qi and blood, which is a classical prescription for the treatment of warm
diseases and can significantly reduce the mortality rate of ALI rats.[94] Jinzhen Oral Liquid originates from the empirical formula Lingyang Qingfei Powder,
with effects of clearing heat and removing toxins, resolving phlegm and stopping cough.
It is clinically used for infantile acute bronchitis and pediatric pneumonia. And
by inhibiting protein phosphorylation of the PI3K/AKT/NF-κB pathway, it can improve
lung tissue interstitial edema and inflammatory reactions in LPS-induced ALI.[95] Qidong Huoxue Drink consists of Huzhang (Polygoni Cuspidati Rhizoma et Radix), Danggui
(Angelicae Sinensis Radix), Huangqi (Astragali Radix) and Maidong (Ophiopogonis Radix).
The whole formula exerts the effects of clearing heat and nourishing yin, tonifying
qi and lifting yang, nourishing blood and dispelling blood stasis, and expelling pathogens
while reinforcing healthy qi. Medium and high doses of Qidong Huoxue Drink can significantly
reduce Cav-1 expression. Through pathways such as endothelial NO synthase and HO-1,
it can regulate NF-κB activation, reduce the synthesis and secretion of proinflammatory
cytokines, increase anti-inflammatory cytokine levels, and correct inflammatory imbalance.[96] See [Table 4].
Table 4
Research models and action mechanisms of Chinese herbal compounds and their preparations
for treating acute lung injury/acute respiratory distress syndrome through nuclear
factor-κB signaling pathways
|
Medicines
|
Models
|
Action mechanisms
|
References
|
|
Inflammation Regulation Formula
|
ALI rats
|
NF-κB↓, reducing inflammatory responses
|
[79]
|
|
Qingfu Tongchang Granules
|
ALI rats
|
NF-κB↓, reducing inflammatory responses
|
[80]
|
|
Linggui Zhugan Decoction
|
ALI mice
|
NF-κB↓, reducing inflammatory responses
|
[81]
|
|
Jinyin Qingre Oral Liquid
|
ALI mice
|
NF-κB↓, reducing inflammatory responses
|
[82]
|
|
Fusu Mixture
|
ALI rats, human pulmonary microvascular endothelial cell (HPMEC) cell
|
NF-κB↓, reducing inflammatory responses
|
[84]
|
|
Yiqi Kangfei Formula
|
ALI hamsters
|
TLR4/MyD88/NF-κB↓, reducing inflammatory responses
|
[85]
|
|
Ascending and Descending Powder
|
ALI mice
|
TLR4/NF-κB/MAPK↓, reducing inflammation
|
[86]
|
|
Qingfei Litan Formula
|
ALI rats
|
TLR4/NF-κB↓, reducing inflammatory responses
|
[87]
|
|
Yiqi Huayu Jiedu Formula
|
ALI rats
|
TLR4/NF-κB/NLRP3↓, reducing inflammatory responses
|
[89]
|
|
Shiwei Qingwen Decoction
|
ALI rats, THP-1 cell
|
TLR4/NF-κB/NLRP3↓, THP-1 cell↓, reducing inflammatory responses
|
[90]
|
|
Maxing Shigan Decoction
|
ALI mice
|
MAPK/NF-κB↓, reducing inflammation, resisting oxidization
|
[91]
|
|
Qingyi Decoction
|
ALI mice
|
MAPK/NF-κB/NLRP3↓, reducing inflammatory responses
|
[92]
|
|
Mahuang Shengma Decoction
|
ALI mice
|
RAGE/NF-κB↓, reducing inflammatory responses
|
[93]
|
|
Qingwen Baidu Beverage
|
ALI rats
|
IKKα/NF-κB↓, reducing inflammatory responses
|
[94]
|
|
Jinzhen Oral Liquid
|
ALI mice
|
PI3K/AKT/NF-κB↓, reducing inflammatory responses
|
[95]
|
|
Qidong Huoxue Drink
|
ALI rats
|
Cav-1/NF-κB↓, reducing inflammation
|
[96]
|
Abbreviations: ALI, acute lung injury; AKT, protein kinase B; ARDS, acute respiratory
distress syndrome; IKKα, inhibitor of κB kinase α; MAPK, mitogen-activated protein
kinase; MyD88, myeloid differentiation primary response protein 88; NF-κB, nuclear
factor-κB; NLRP3, NOD-, LRR-, and pyrin domain-containing protein 3; PI3K, phosphoinositide
3-kinase; TLR, Toll-like receptor.
