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| REVIEW ARTICLE |
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| Year : 2022 | Volume
: 8
| Issue : 2 | Page : 169-180 |
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Progression of the Wei-Qi-Ying-Xue syndrome, microcirculatory disturbances, in infectious diseases and treatment with traditional Chinese medicine
Jing-Yan Han1, Quan Li2, Chun-Shui Pan2, Kai Sun2, Jing-Yu Fan2
1 Department of Integration of Chinese and Western Medicine, School of Basic Medical Sciences, Peking University; Academy of Integration of Chinese and Western Medicine, Peking University Health Science Center; Tasly Microcirculation Research Center, Peking University Health Science Center; Department of Integration of Chinese and Western Medicine, Peking University, Key Laboratory of Stasis and Phlegm, State Administration of Traditional Chinese Medicine of the People's Republic of China; Department of Integration of Chinese and Western Medicine, Peking University, Beijing Laboratory of Integrative Microangiopathy; Department of Integration of Chinese and Western Medicine, Peking University, State Key Laboratory of Core Technology in Innovative Chinese Medicine, Beijing, People's Republic of China
2 Tasly Microcirculation Research Center, Peking University Health Science Center; Department of Integration of Chinese and Western Medicine, Peking University, Key Laboratory of Stasis and Phlegm, State Administration of Traditional Chinese Medicine of the People's Republic of China; Department of Integration of Chinese and Western Medicine, Peking University, Beijing Laboratory of Integrative Microangiopathy; Department of Integration of Chinese and Western Medicine, Peking University, State Key Laboratory of Core Technology in Innovative Chinese Medicine, Beijing, People's Republic of China
| Date of Submission | 28-Apr-2022 |
| Date of Acceptance | 20-May-2022 |
| Date of Web Publication | 30-Jun-2022 |
Correspondence Address:
Jing-Yan Han
Department of Integration of Chinese and Western Medicine, School of Basic Medical Sciences, Peking University, 38 Xueyuan Road, Beijing 100191
People's Republic of China
 Source of Support: None, Conflict of Interest: None  | 2 |
DOI: 10.4103/wjtcm.wjtcm_28_22
Lipopolysaccharide (LPS)-induced endotoxemia is a critical condition that initiates microcirculatory disturbance and may progress to multiple organ failure that threatens the lives of millions of people around the world each year. The pathology of endotoxemia involves multiple insults mediated by a range of signaling pathways. Multitarget management is required to relieve endotoxemia. Traditional Chinese medicine (TCM) is a type of therapeutic that commonly contains numerous components and, thus, exhibits multitarget potential. More importantly, some TCM formulas have been proposed and used for effective treatment of endotoxemia-like diseases. In the past 20 years, an increasing number of studies have explored the effects and mechanisms of these formulas and their major bioactive components on microcirculatory disturbance and organ injury caused by LPS. The results obtained thus far provide support for the clinical use of TCM and shed light on the underlying mechanisms.
Keywords: Chinese medicine, hyperpermeability, leukocyte-endothelium interactions, lipopolysaccharide, microvascular hemorrhage
How to cite this article:
Han JY, Li Q, Pan CS, Sun K, Fan JY. Progression of the Wei-Qi-Ying-Xue syndrome, microcirculatory disturbances, in infectious diseases and treatment with traditional Chinese medicine. World J Tradit Chin Med 2022;8:169-80 |
How to cite this URL:
Han JY, Li Q, Pan CS, Sun K, Fan JY. Progression of the Wei-Qi-Ying-Xue syndrome, microcirculatory disturbances, in infectious diseases and treatment with traditional Chinese medicine. World J Tradit Chin Med [serial online] 2022 [cited 2023 Dec 8];8:169-80. Available from: https://www.wjtcm.net/text.asp?2022/8/2/169/349266 |
| Introduction | |  |
Infectious diseases are caused by pathogenic microorganisms, such as bacteria and viruses. Despite the development of modern medicine, the struggle between humans and pathogens is ongoing. In recent years, acute infectious diseases, particularly respiratory infectious diseases, have been detrimental to human health. Pandemics due to infectious diseases such as severe acute respiratory syndrome (SARS), H1N1 influenza, and H7N9 avian influenza have caused panic worldwide and have stagnated economic development, thus seriously affecting the stability and development of society. The outbreak of coronavirus disease 2019 (COVID-19) became a pandemic with more than 211 million cases and 4.4 million deaths (as of August 24, 2021).[1] The uncontained outbreak remains challenging to manage, with new strains/mutants of the virus emerging constantly.
Accumulating clinical data suggest that the main causes of death due to COVID-19 include respiratory failure and sepsis. Importantly, sepsis has been observed in nearly all deceased patients.[2] However, how SARS-CoV-2 infection results in viral sepsis in humans remains elusive. A recent study revealed that SARS-CoV-2 infection provoked an antibacterial-like response at the very early stage of infection via toll-like receptor (TLR) 4.[2]
Overview of microcirculatory disturbance induced by lipopolysaccharide
Lipopolysaccharide (LPS), a component of the outer membrane of Gram-negative bacteria, is widely used to assess the role and mechanism of infection. LPS binds to LPS-binding protein,[3] which in turn transfers LPS to CD14.[4] CD14 concentrates LPS and binds to the TLR4-myeloid differentiation protein-2 complex,[5] thus activating a variety of intracellular pathways, including Src protein tyrosine kinase (Src).[6] Src mediates the degradation of the inhibitor of nuclear factor-kappa B (Iκ-B), inducing the release of NF-κB and nuclear translocation of subunits, which triggers the synthesis and release of a range of inflammatory factors, such as tumor necrosis factor-alpha (TNF-α), interleukin (IL)-6, and IL-1β;[7],[8] it also upregulates the expression of E-selectin on vascular endothelial cells and L-selectin on leukocytes, causing leukocytes to adhere to vascular endothelial cells.[9],[10] Overexpression of vascular cell adhesion molecule-1 (VCAM-1) and intercellular cell adhesion molecule-1 (ICAM-1) on endothelial cells and of adhesion molecules CD11a/CD18 and CD11b/CD18 on leukocytes promotes adhesion of neutrophils to vascular endothelial cells.[11],[12] Activated leukocytes and vascular endothelial cells release inflammatory factors,[13] peroxides,[14] and other factors that damage microvascular endothelial cells and vascular basement membranes, thereby causing leukocyte extravasation.[13]
LPS bound to TLR4 receptors also triggers vascular endothelial cytoskeleton depolymerization and rearrangement through the activation of RhoA/ROCK-1 and myosin light chain kinase,[15] leading to the opening of junctions between vascular endothelial cells and leakage of plasma albumin and water, which causes edema around the blood vessels.
The basement membrane significantly contributes to the vascular barrier, which is impaired by LPS. LPS can induce the degradation of focal adhesions between vascular endothelial cells and the vascular basement membrane via the activation of TLR-4/Src/phosphatidylinositol-3 kinase (PI3K) and focal adhesion kinase (FAK). LPS stimulation also leads to the activation of cathepsin B through TLR-4/Src/PI3K, resulting in the degradation of collagen IV and laminin, which are the main components of the vascular basement membrane. In addition, LPS-induced activation of matrix metalloproteinases (MMP) can degrade the extracellular matrix. Therefore, microvessel bleeding may occur as a consequence of basement membrane damage.[6],[16]
Injury of microvascular endothelial cells and exposure of the basement membrane evoke platelet adhesion and aggregation, followed by fibrinogen activation to form fibrin, which encloses blood cells by forming a fibrin thrombus. The activated fibrinolytic system dissolves the thrombus and damages the vascular endothelium and basement membrane, triggering disseminated intravascular coagulation (DIC).[17]
The interaction between leukocytes and vascular endothelial cells, microvascular hyperpermeability, and microvascular hemorrhage are three key pathological links in the microcirculatory disturbances induced by LPS [Figure 1]. Microcirculatory disturbance results in a decreased supply of oxygen and nutrition to the surrounding tissue, which along with the surge of pro-inflammatory cytokines, chemokines, and reactive oxygen species (ROS) damages the parenchymal tissue cells. However, at present, the options to contain these insults and organ injuries are limited. | Figure 1: The interaction of leukocytes and vascular endothelial cells, microvascular hyperpermeability, and microvascular hemorrhage are three key pathological events in the microcirculatory disturbance induced by LPS. FAK: Focal adhesion kinase, GSK-3β: Glycogen synthase kinase-3β, ICAM-1: Intercellular adhesion molecule-1, LBP: Lipopolysaccharide-binding protein, LPS: Lipopolysaccharide, MD2: Myeloid differentiation protein-2, MMP: Matrix metalloproteinases, NF-κB: Nuclear factor-kappa B, PI3K: Phosphatidylinositol-3 kinase, Src: Src protein tyrosin kinase, TLR-4: Toll like receptor-4, VCAM-1: Vascular cell adhesion molecule-1
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Traditional Chinese medicine has a long history and unique theory on the prevention and treatment of infectious diseases
Traditional Chinese medicine (TCM) has been used for over thousands of years for fighting against various infectious diseases. Several prescriptions have been presented in “Treatise on Febrile Diseases (Shang-Han-Lun)” and “Synopsis of the Golden Chamber (Jin-Gui-Yao-Lue)” during the Eastern Han dynasty era to combat infection-related symptoms. During the period of late Ming and early Qing dynasties, the theory of epidemic febrile disease emerged for treating plague epidemics, in which the process of exogenous febrile diseases was divided into four stages, i.e., “Wei,” “Qi,” “Ying,” and “Xue,” which as per the exhibited symptoms, roughly correspond to initiation of infection; activation of inflammatory response; vascular barrier breakdown and albumin extravasation; and microvascular hemorrhage, coagulation, multiple organ failure, and DIC, respectively. This differentiation provides a guideline for the treatment of exogenous febrile diseases, based on which a number of formulas have been proposed to efficiently cope with the symptoms at each stage of the disease[13],[16],[18],[19],[20],[21],[22],[23],[24],[25],[26] [Table 1]. | Table 1: The name, composition and origin of traditional compound Chinese medicine tested for lipopolysaccharide-induced microcirculatory disturbance and organ injury
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Over the past two decades, numerous experimental studies have been published to verify the effects of TCMs, which have shed light on the mechanisms by which various TCMs improve microcirculatory disturbance and organ injury induced by LPS. This article provides an overview of the results obtained in this field.
| The Ameliorating Effects of Traditional Chinese Medicine on Microcirculatory Disturbance at Different Stages of Infection | | |
“Wei-fen” stage
“Wei-fen” is the initial stage of exogenous febrile diseases. Pathogenic factors invade the human body from the exterior via the mouth, nose, or body surface, resulting in dysfunctional lung defense. Clinically, it is characterized by fever, slight aversion to cold, red tongue tip, thin and white fur-coated tongue, and floating pulse. Yin-Qiao-San or Sang-Ju-Yin is a classic Chinese medicine used to cope with symptoms at this stage.[21],[23] At this stage, no obvious microcirculatory disturbance occurs.
“Qi-fen” stage
“Qi-Fen” is the stage when pathogenic factors enter the circulation. Clinically, it is characterized by high fever, sweating, thirst, upset, red urine, yellow coating of the tongue, and full and rapid pulse. The interaction between leukocytes and vascular endothelial cells is the main pathological event at this stage.
The interaction between leukocytes and vascular endothelial cells, including neutrophil rolling, adhesion, and migration along the vessel wall, is mediated by the activation of NF-κB signaling and the expression of the adhesion molecules ICAM-1 and VCAM-1 on vascular endothelial cells and of CD11b/CD18 on neutrophils; the interaction triggers the adhesion of neutrophils to vascular endothelial cells.[27],[28] This interaction induces a cascade of insults, including the release of inflammatory factors such as IL-1β, TNF-α, IL-6, and IL-8, which causes fever and aggravates the expression of adhesion molecules on neutrophils and endothelial cells.[29] Nicotinamide adenine dinucleotide phosphate (NADPH)-oxidase activation of neutrophils upon adhesion results in the release of ROS, which cause endothelial cell necrosis and apoptosis.[30] Adherent neutrophils also release elastase, MMP, leukotriene, and platelet-activating factor, which damage the basement membrane. These insults collectively result in the leakage of plasma albumin, edema, and bleeding around the microvasculature, as well as leukocyte emigration.[31] Thus, inhibiting the interaction between neutrophils and endothelial cells is thought to be a promising strategy to block the progression of infection in the early phase. However, no such management strategies are available at clinics, especially treatments that can dissociate adherent leukocytes from the endothelium.
To this end, studies in our laboratory using animal models have shown promise for some TCM formulas with heat-clearing and detoxifying potential. In a rat model of LPS-induced acute lung injury, we examined the effect of Ma-Xing-Shi-Gan-Tang (MXSGT), a TCM compound commonly used to relieve fever, particularly in case of upper respiratory tract infection, bronchitis, and pneumonia. We found that the administration of MXSGT 6 h after LPS challenge restored body temperature, heart rate, partial pressure of oxygen, oxygen saturation, and partial pressure of carbon dioxide, reduced lung tissue damage, and decreased the levels of TNF-α and IL-6 in peripheral blood, alveolar lavage fluid, and lung tissue, thus demonstrating the potential of MXSGT to relieve the inflammatory response and lung injury. It is worth noting that treatment with MXSGT resulted in the dissociation of leukocytes adhered to pulmonary microvessels following LPS stimulation. This result is particularly interesting because it indicates that MXSGT may act during the initial interaction between the inflammatory response and leukocyte adhesion in microvessels, thus preventing disease progression.[13] Using the same animal model, the potential of andrographolide pills, which are composed of ingredients extracted from Andrographis paniculata, to protect against the adhesion of leukocytes to microvessels, was tested; the results revealed that pretreatment with andrographolide pills prevented the expression of adhesion molecule ICAM-1 and leukocyte adhesion to pulmonary microvessels, along with reduced oxidative stress and lung tissue injury.[32] Increasing evidence indicates that inhibition of the interaction between neutrophils and vascular endothelial cells is a common feature of heat-clearing and detoxifying compounds of Chinese medicine (CCM), such as andrographolide pills,[32] Danshen,[14] and major bioactive components (MBCs), such as emodin,[33] paeonol,[34] 3,4-dihydroxyphenyl lactic acid (DLA),[35] salvianolic acid B,[35] Panax notoginseng saponins,[36],[37] ginsenoside Rb1, ginsenoside Rg1, and notoginsenoside R1.[38] This inhibition accounts for the potential of this type of TCM in treating endotoxemia-like conditions at an early stage.
“Ying-fen” stage
“Ying-fen” is the stage in which pathogenic factors penetrate into the heart and blood vessels, burn “Ying Yin,” and lead to the depletion of body fluid in the blood and disturbance of mind and spirit. The main clinical manifestations are body heat at night, lack of thirst, restlessness, delirium, rash, looming, red tongue, fainting, and rapid pulse. Microvascular hyperpermeability is the main pathological feature for transition from the “Qi-fen” to the “Ying-fen” stage.
Microvascular permeability is regulated by the paracellular and transcellular pathways. The paracellular pathway remains closed under physiological conditions due to the presence of adherens junctions and tight junctions (TJs) between vascular endothelial cells. The transcellular pathway is mediated by caveolae, which is a type of lipid raft-like invagination of the plasma membrane of endothelial cells; it is enriched in albumin receptor glycoprotein 60 and is critical for cellular albumin uptake and transport across endothelial cells. Nevertheless, this process is controlled in normal situations; thus, the permeability of endothelial cells remains low.[39] LPS degrades intercellular junction proteins, thus disrupting the barrier between cells and enhances the expression and activity of caveolin-1;[40] caveolin-1 is the principal protein expressed in caveolae, which leads to the formation of vesicles and increases transcellular transport. As a result, both paracellular and transcellular pathways increase upon LPS stimulation, leading to microvascular hyperpermeability and albumin extravasation.
Microvascular hyperpermeability manifests as acute respiratory distress syndrome in the lungs and causes edema around the microvessels in the brain, leading to intracranial hypertension, hazy consciousness, and dizziness, which results in gastrointestinal edema and ascites in the peritoneum.
Based on the theory of epidemic febrile disease of TCM, we studied the effects of Qing-Ying-Tang (QYT), a TCM compound designed to relieve the epidemic febrile disease at the “Ying” stage, on LPS-induced cerebral microcirculation disturbance. The results showed that QYT inhibited plasma albumin leakage through cerebral microvessels and edema around cerebral microvessels; protected against the rupture of cerebral vascular endothelial cell junctions; ameliorated the downregulation of claudin-5, occludin, JAM-1, ZO-1, and collagen IV, as well as the phosphorylation of VE-cadherin in the mouse brain; and inhibited caveolin-1 phosphorylation. These results suggest the ability of QYT to attenuate blood–brain barrier (BBB) impairment after LPS stimulation by interfering with both paracellular and transcellular pathways.[16]
Microvascular hyperpermeability-induced leakage of plasma albumin and water, which results in a reduction in blood volume and shock, is a symptom of depletion of Qi and body fluid as per TCM. Sheng-Mai-San (SMS) is a representative prescription for treating this syndrome, which consists of Radix ginseng, Raidix ophiopogonis, and Schisandra chinensis. Yiqifumai (YQFM) is a lyophilized powder for injection of SMS, approved by the Chinese State Food and Drug Administration (Z20060463) for the treatment of microcirculatory disturbance-related diseases in China.[15] A previous study demonstrated that YQFM can inhibit LPS-induced production of ROS in mesenteric venules, degranulation of perivascular mast cells, and leakage of plasma albumin from mesenteric venules.[45] A similar effect of YQFM was observed on LPS-induced leakage of plasma albumin and peripheral edema of cerebral microvessels, along with a decrease in the expression of junction proteins in cerebral microvascular endothelial cells and downregulation of caveolae.[15] Ginsenoside Rb1 (Rb1), the main active ingredient of ginseng in YQFM, and the combination of Rb1 and schisandrin (Sch), the main component of Schisandra chinensis, were found to improve the activity of mitochondrial respiratory chain complex V in the brain tissue and energy metabolism; they played a role in invigorating qi, when relieving the impaired expression of VE-cadherin, increasing the number of caveolae, and playing a role in astringency.[15] Sch restored the barrier function of the endothelium and epithelium by inhibiting alveolar epithelial apoptosis, activating cell proliferation, and promoting repair and regeneration of the pulmonary microvascular endothelium and alveolar epithelium after LPS injury.[42]
Postadministration of MXSGT also reduced LPS-induced pulmonary microvascular hyperpermeability. The effect of MXSGT is associated with the upregulation of claudin-5, junctional adhesion molecule (JAM)-1, and occludin in microvascular endothelial cells and inhibition of caveolin-1 phosphorylation.[13]
“Xue-fen” stage
The stage “Xue-fen” is characterized by heat toxin penetration into blood, exuberant heat stirring the blood, Yin depletion, and convulsion. The main clinical manifestations are body heat at night, irritability, manic psychosis and delirium, eruption of purple-black macula, epistaxis, spitting blood, blood in the stool, blood in the urine, dark red tongue, fainting, and rapid pulse. Microvascular barrier injury, especially the breakdown of the endothelial basement membrane, is the main pathological feature of this stage. Autopsy analyses of lung tissues from COVID-19 patients indicated severe endothelial injury and disrupted endothelial cell membranes.[43]
The endothelial basement membrane consists of a number of proteins, including collagen IV, laminin, and fibronectin,[44] which bind to endothelial cells via focal adhesions.[45] In addition to the degradation of junction proteins, LPS activates FAK, cathepsin B, and MMP-2,[46],[47],[48],[49] leading to the disintegration of the basement membrane. Microvascular hemorrhage in endotoxemia is the consequence of disruption of endothelial cell junctions and breakdown of the basement membrane of the endothelium; this phenomenon along with the microthrombus that follows may ultimately progress to DIC and/or multiple organ dysfunction syndrome (MODS), if not treated.
LPS-induced microvascular hemorrhage exhibits the symptoms of heat toxin and blood stasis explained in TCM; thus, some TCMs with the potential to clear heat and prevent hemostasis are expected to ameliorate this condition. In this respect, we explored the effect of catalpol, which is the active ingredient of Rehmannia glutinosa and an herbal medicine known to have the potential to clear heat and prevent hemostasis. The results showed that intravenous administration of catalpol could inhibit mesenteric venule bleeding in rats 120 min after LPS infusion and protect against venular wall rupture and red blood cell extravasation in the rat ileum and lungs. A study of the underlying mechanisms revealed that catalpol restored the decreased expression and abnormal arrangement of claudin-5, JAM-1, and VE-cadherin in the pulmonary microvessels; elevated the content of type IV collagen and laminin; and inhibited the activation of cathepsin B and FAK.[6]
DIC is characterized by the overactivation of the coagulation system, widespread formation of intravascular thrombi, and a severe inflammatory reaction due to the exhaustion of coagulation factors and platelets.[50] DIC can have serious outcomes, including hemorrhage, anemia, shock, MODS, and even death, because microthrombi and necrotic tissues can obstruct arterioles and veins in multiple organs. Studies have shown that some TCMs act to ameliorate LPS-induced DIC via the modulation of the coagulation process. Xiang-Qi-Tang and its active components α-cyperone, astragaloside IV, and andrographolide downregulated LPS-induced production of plasminogen activator inhibitor-1 and tissue factor, when inhibiting the phosphorylation of ERK, JNK, p38MAPK, and NF-κB p65 in LPS-stimulated rat cardiac microvascular endothelial cells.[51] Several MBCs extracted from TCM, such as tanshinone IIA,[52] quercetin,[53] and salvianolic acid B,[54] have been found to have anticoagulant and anti-inflammatory effects against LPS-induced DIC as per the classical indices of the condition, such as activated partial thromboplastin time, prothrombin time, platelet count, protein C concentrations, fibrin degradation products, and TNF-α level.
| The Ameliorating Effects of Traditional Chinese Medicines on Microcirculatory Disturbance in Lipopolysaccharide-Induced Organ Injury | | |
Microcirculatory disturbances contribute to systemic organ injuries, such as those of the lung, brain, and intestine. TCMs have been reported to protect against LPS-induced organ injury by ameliorating microcirculatory disturbances.
Lung
Acute lung injury is the primary and most common manifestation of viral infection and sepsis; it is the consequence of pulmonary microvascular hyperpermeability and edema due to the overproduction of cytokines, chemokines, and adhesion molecules, followed by increased pulmonary neutrophil sequestration, which impairs lung structure and function.[55] CCM has been extensively used for the treatment of lung diseases in China and other Asian countries. In recent years, researchers have explored the effect of CCM on LPS-induced lung injury in animal models and their underlying mechanisms. For example, MXSGT, a traditional Chinese medicinal formula consisting of four herbs, has been shown to reduce LPS-induced leukocyte adhesion to pulmonary venules and to attenuate the release of pro-inflammatory cytokines, MPO activity, and malonaldehyde production. Meanwhile, pulmonary edema and lung dysfunction were reversed by MXSGT post treatment. Further studies revealed an increase in the expression of TJ proteins and a decrease in caveolin-1 phosphorylation, demonstrating that both paracellular and transcellular pathways are implicated in the role of MXSGT in ameliorating pulmonary microvascular hyperpermeability. In addition, MXSGT decreased TLR-4 expression and abrogated the activation of Src kinase and NF-κB, suggesting the involvement of the TLR4, Src, and NF-κB signaling pathways in MXSGT activity[13] [Figure 2]. Kim et al. also demonstrated that MXSGT relieved acute lung injury by decreasing neutrophil infiltration and MPO activity, which was associated with the activation of anti-inflammatory nuclear factor erythroid-2-related factor 2 (Nrf2) and suppression of pro-inflammatory NF-κB.[56] Similarly, Huang-Lian-Jie-Du-Tang[57] and Sheng-Fei-Yu-Chuan-Tang[58] have been reported to decrease the number of leukocytes that adhere to the endothelium of rat pulmonary venules and inhibit the production of pro-inflammatory cytokines, including TNF-α, L-1β, and IL-6, in a dose-dependent manner. Sheng-Fei-Yu-Chuan-Tang treatment decreased iNOS activity, NO generation, and ROS production in a dose-dependent manner after LPS challenge, which was attributed to the inhibition of NF-κB phosphorylation and nuclear translocation.[58] | Figure 2: Ma-Xing-Shi-Gan-Tang ameliorates LPS-induced lung microvascular hyperpermeability and inflammatory reaction. LBP: Lipopolysaccharide-binding protein, LPS: Lipopolysaccharide, MXSGT: Ma-Xing-Shi-Gan-Tang, MD2: Myeloid differentiation protein-2, NF-κB: Nuclear factor-kappa B, Src: Src protein tyrosin kinase, TLR-4: Toll like receptor-4. ↑ induce: 〦inhibition
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Some single Chinese herbs and the MBCs of CCM have also been studied for their roles in LPS-induced lung injury. In this regard, andrographolide from Andrographis paniculata has been demonstrated to attenuate LPS-induced pulmonary microcirculatory disturbance in rats, by decreasing leukocyte adhesion to pulmonary venules, oxidative stress, and inflammatory cytokine levels, and alleviating pulmonary microvascular hyperpermeability and lung edema; this leads to the improvement of arterial hypoxemia and decrease in mortality. Furthermore, andrographolide was found to attenuate LPS provoked decrease in the expression of the TJs proteins JAM-1 and claudin-5, increase the expression and activation of Src and caveolin-1, and inhibit TLR-4 expression in lung tissue concurrently.[32],[59] A recent study further showed that Sch, the major MBC of Wu-Wei-Zi, attenuated LPS-induced pulmonary inflammation, reduced leukocyte adhesion to pulmonary venules and cytokine and chemokine expression in serum and lung homogenates, and upregulated the expression of adhesion molecules, likely by inhibiting the TLR-4/NF-κB/MAPK signaling pathway. Moreover, Sch attenuated microvascular hyperpermeability and lung edema when accelerating pulmonary endothelial and epithelial regeneration and barrier function recovery, partly due to the activation of Akt/FoxO1 signaling pathways.[42] Similarly, salvianolic acid B, an MBC from Salvia miltiorrhiza, has been shown to attenuate LPS-induced pulmonary microcirculatory disturbances, including an increase in leukocyte adhesion and albumin leakage. In addition, salvianolic acid B decreased the wet/dry weight ratio of pulmonary tissue, TNF-α and IL-8 levels in plasma and bronchoalveolar lavage fluid, and the expression of E-selectin, ICAM-1, MPO, MMP-2, and MMP-9 in pulmonary tissue; it also increased the expression of aquaporin-1 and aquaporin-5 in pulmonary tissue.[60] Other single Chinese herbs and MBCs have been studied in this regard, including flos Lonicerae japonicae,[61] total alkaloids from Aconitum tanguticum,[62] polysaccharides from Bupleurum chinense,[63] matrine from Sophora flavescens,[64] patchouli alcohol from Pogostemon cablin,[65] esculentoside A from Phytolacca esculenta,[66] and phillyrin from Forsythia suspense.[67] Most of them showed protective effects against LPS-induced pulmonary inflammatory cell infiltration and lung edema; they inhibited pro-inflammatory cytokine, chemokine, and adhesion molecule expression and excessive ROS production via suppressing I-κBα degradation, NF-κB nuclear translocation, and p38MAPK and ERK phosphorylation.
Brain
LPS-induced inflammatory processes and cerebral microcirculatory disturbances, including overproduction of cytokines and adhesion molecules, leukocyte adhesion to the vascular endothelium, and outburst of ROS, promote BBB disruption and cerebral tissue edema, which ultimately evoke ischemic brain injury and neuronal damage.[68] Increasing evidence has shown that CCMs and MBCs with anti-inflammatory activity may play a role in ameliorating LPS-induced cerebral microcirculatory disturbances. For instance, DLA from Salvia miltiorrhiza has been demonstrated to abrogate LPS-induced cerebral microcirculatory disturbance in mice, increase red blood cell velocity, prevent leukocytes from rolling and adhering to the venular wall, and prevent albumin leakage from cerebral microvessels. Further in vitro experiments showed that DLA inhibited the expression of CD11b/CD18 in neutrophils and the production of TNF-α from mononuclear cells.[69] Astragaloside IV from Astragalus membranaceus was found to prevent BBB leakage in LPS-induced mice, accompanied by increased ZO-1 and occludin expression but reduced VCAM-1 expression in brain microvessels. Astragaloside IV attenuated the LPS-induced increase in the permeability of brain endothelial cells, as evidenced by increased transendothelial electrical resistance and reduced sodium fluorescein extravasation. Further studies revealed that AS-IV could decrease ROS levels and activate the Nrf2 antioxidant pathway.[70] Interestingly, a recent study demonstrated that both pre-and posttreatment with YQFM attenuated cerebral microvascular hyperpermeability induced by LPS, manifesting as reduced albumin leakage from cerebral microvessels and edema around microvessels. Moreover, YQFM has been shown to restrain the decrease in junction protein expression, which was achieved by attenuating the energy metabolism disorder via the inhibition of Rho/ROCK pathway activation. Meanwhile, the attenuation effect of YQFM on TLR-4-Src activation and the expression and phosphorylation of caveolin-1 suggested that the improvement of the transcellular pathway plays a role in this effect. Moreover, this study showed that Rb1 and Sch, two of the bioactive components from YQFM, worked differently, with Rb1 being more effective in enhancing energy metabolism, while Sch attenuated TLR-4 expression and Src activation; this demonstrates the advantage of TCMs in coping with complex diseases due to the presence of multiple components and targets[15] [Figure 3]. In addition to YQFM administration, posttreatment with QYT, another classical Chinese prescription, attenuated LPS-induced cerebral microcirculation disturbances in mice, as shown by the decreased leukocyte adhesion, albumin leakage, and cytokine levels in brain tissue, which was related to the suppression of the TLR-4-NF-κB signaling pathway. Moreover, QYT protected from LPS-induced BBB breakdown by alleviating cerebral microvascular endothelial junction and basement membrane disruption as well as down-regulation of caveolin-1 expression[16] [Figure 4]. | Figure 3: Yiqifumai injection and its main ingredients attenuate LPS-induced cerebrovascular hyperpermeability through a multi-pathway mode. LBP: Lipopolysaccharide-binding protein, LPS: Lipopolysaccharide, MD2: Myeloid differentiation protein-2, Rb1: Ginsenoside Rb1, Sch: Schisandrin, Src: Src protein tyrosin kinase, TLR-4: Toll like receptor-4, YQFM: Yiqifumai injection. ↑ induce: 〦inhibition
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 | Figure 4: Qing-Ying-Tang relieves LPS-induced cerebral microcirculation disturbance. ICAM-1: Intercellular adhesion molecule-1, LBP: Lipopolysaccharide-binding protein, LPS: Lipopolysaccharide, MD2: Myeloid differentiation protein-2, MMP: Matrix metalloproteinases, NF-κB: Nuclear factor-kappa B, Src: Src protein tyrosin kinase, TLR-4: Toll like receptor-4, VCAM-1: Vascular cell adhesion molecule-1. ↑ induce: 〦inhibition
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Intestine
Mesenteric venules are commonly used to study microcirculatory disturbances induced by LPS. Using mesenteric venules as an experimental model, YQFM was demonstrated to decrease the number of leukocytes adherent to the venular endothelium; increased ROS production in the venular walls, albumin leakage from microvessels, and mast cell degranulation.[45] Similarly, treatment with compound Dan-Shen[14] and Panax notogiseng saponins[36],[37] inhibited LPS-induced leukocyte adhesion and cytokine production in plasma, suppressing leukocyte adhesion molecules CD11b/CD18 and the expression of ICAM-1 in HUVECs. MBCs, including ginsenoside Rb1, ginsenoside Rg1, and notoginsenoside R1 from Panax notoginseng;[38] salvianolic acid B and DLA from Salvia miltiorrhiza;[35] and emodin from Rheum officinale,[33] have been reported to inhibit leukocyte adhesion, adhesion molecule expression, ROS production, albumin leakage, and mast cell degranulation in the mesentery to different extents. Posttreatment with catalpol from Rehmannia was recently shown to inhibit hemorrhage from mesenteric microvessels after the onset of endotoxemia. In further in vivo and in vitro experiments, researchers demonstrated that catalpol could ameliorate the alteration in the distribution of claudin-5 and JAM-1; it also reduced the degradation of collagen IV and laminin and attenuated the increase in TLR-4 levels, phosphorylation of Src tyrosine kinase, and activation of PI3K, FAK, and cathepsin B.[6] Consistent with the results obtained using mesentery, CCMs and MBCs have been shown to have beneficial effects on LPS-induced intestinal injury. For example, ginsenoside Rb1 from Radix ginseng ameliorated intestinal edema after the onset of endotoxemia and decreased the number of caveolae in the endothelial cells of microvessels. Caveolin-1 expression and phosphorylation, VE-cadherin phosphorylation, and ZO-1 degradation were also inhibited by ginsenoside Rb1, suggesting that the therapeutic effects of ginsenoside Rb1 on LPS-induced tissue edema were attributed to the regulation of both transcellular and paracellular pathways.[71] In a recent study, Da-Cheng-Qi-Tang attenuated intestinal histological abnormalities and erythrocyte and inflammatory cell extravasation in the interstitium of the intestine. Moreover, the capillary permeability of the intestinal tissue and serum levels of TNF-α, IL-1β, IL-2, and IL-6 were also abrogated by Da-Cheng-Qi-Tang pretreatment.[72]
| Mechanisms Responsible for the Protective Role of Traditional Chinese Medicine in Lipopolysaccharide-Induced Injury | | |
LPS-induced injury is a complex pathological condition mediated by a variety of signaling pathways. Growing evidence indicates that TCMs exert a protective effect against LPS-induced injury involving multiple targets. The following are the targets reported to be implicated in the effects of TCMs on LPS-induced injury.
Toll-like receptor 4/nuclear factor-kappa B signal pathway
LPS binding to TLR-4 on macrophages activates a cascade of signaling pathways, among which the MyD88-dependent pathway is known to induce the expression of pro-inflammatory cytokines, including IL-1β, IL-6, and TNF-α. In this pathway, the phosphorylation of IκB leads to its degradation and the subsequent translocation of the transcription factor NF-κB (p65 and p50) to the nucleus, which results in the expression of the molecules involved. LPS induces pro-inflammatory cytokines and chemokines, which in turn activate neutrophils and endothelial cells, leading to the expression of adhesion molecules, neutrophil adhesion and infiltration, and as a result inflammation. In addition, LPS exposure has been reported to upregulate the expression of TLR-4, which is expected to further enhance the effect of LPS. Activation of the TLR4-NF-κB signaling pathway is thus the initiator of endotoxemia, and interference with this pathway is anticipated to be an option to cope with endotoxemia. A number of TCMs and MBCs have been reported to relieve endotoxemia by targeting the TLR4-NF-κB signaling pathway. Some of the TCMs and MBCs, such as catalpol[6] and andrographolide,[32] have shown the potential to downregulate the expression of TLR4 after LPS challenge; TCMs, such as QYT,[16] ginsenoside Rb1 (one of the major active ingredients of Panax ginseng), baicalin, baicalein, and wogonin,[71],[73] have been shown to inhibit NF-κB activation and nuclear translocation; and TCMs such as YQFM, Sch,[15] and MXSGT[13] downregulate TLR4 and inactivate NF-κB after LPS. Regarding the mechanism, catalpol was reported to directly bind to TLR-4.[6] However, the detailed mechanism through which TCMs or MBCs intervene in the TLR4-NF-κB signaling pathway remains elusive. An in-depth study of different pure chemical compounds isolated from TCMs that share identical potential, such as andrographolide, Sch, and catalpol, may offer insight for understanding the underlying mechanisms.
RhoA/ROCK pathway
LPS treatment activates the RhoA/ROCK pathway, which is known to mediate a spectrum of events, including actin-cytoskeletal assembly, cell contraction, stress fiber formation, caveolin-1 phosphorylation and activation, and modulation of cell-matrix adhesions,[74],[75] that contribute to vascular hyperpermeability in endotoxemia. Thus, inhibiting the activation of the RhoA/ROCK pathway is considered a promising option to inhibit the progression of endotoxemia. In this respect, pretreatment and posttreatment of cerebral vascular hyperpermeability animal model with YQFM attenuated LPS-induced RhoA/ROCK pathway activation, depressing the phosphorylation of RhoA and lowering the expression of ROCK1. Further studies demonstrated that the synergetic effects of Sch and Rb1, two major active ingredients of YQFM, are responsible for its activity.[15]
PI3K/AKT and PI3K/Src pathway
LPS is known to activate PI3K, provoking activation of a range of signaling pathways, among which PI3K/AKT signaling is reported to mediate the expression of inflammatory cytokines, adhesion molecules, and MMPs, energy metabolism, apoptosis, and oxidative stress, contributing to microcirculatory disturbance and tissue injury; PI3K/Src signaling engages in the phosphorylation of caveolin-1 and activation of cathepsin B,[76] thus enhancing transcellular transport and vascular endothelium permeability. Studies have shown that some TCMs and MBCs exert protective effects against LPS-induced microcirculatory disturbance and tissue injury by acting on PI3K-related signaling pathways. For example, posttreatment with catalpol was reported to ameliorate the degradation of collagen IV and laminin and the increase in PI3K level, suggesting the involvement of this signaling pathway.[6] Ginsenoside Rg3 has been shown to be effective via PI3K/AKT signaling. A number of TCMs and MBCs, including QYT, MXSGT, and YQFM and their main ingredients Rb1+ Sch, AP, catalpol, Rb1, and salvianolic acid B have been reported to attenuate LPS-induced vascular hyperpermeability and lower Src activity.[6],[13],[15],[16],[32],[71],[77],[78]
Oxidative stress
Oxidative stress plays a vital role in endotoxemia. The overproduction of ROS in response to LPS stimulation directly damages biomacromolecules and cell structures and activates NF-κB, which aggravates the production of pro-inflammatory cytokines. The ROS produced during LPS-induced oxidative stress are derived from a range of sources, including activated iNOS, dysfunctional mitochondria, NAD (P) H oxidase, and GSH peroxidase (GSH-Px). Moreover, the downregulation of superoxide dismutase (SOD) may contribute to oxidative stress.
Only a limited number of TCMs and MBCs have been reported to attenuate LPS-induced oxidative stress, including MXSGT,[13] Danshen injection,[14] emodin,[33] salvianolic acid B,[60] Rg1 and R1,[38] and andrographolide pills.[32] The exact targets of most of them have not been identified. However, andrographolide pills are an exception, as they have been demonstrated to inhibit NADPH oxidase.
Mitochondrial respiratory chain
Mitochondria are the central mediators of LPS-induced organ injury. LPS-caused microcirculatory disturbances restrict the supply of oxygen and nutrition to organ tissues, which impairs the function of the mitochondrial respiratory chain. Free radicals, particularly NO, produced by LPS stimulation are known to damage mitochondria. In addition, dysfunctional mitochondria lead to ATP depletion, oxidative stress, and apoptosis, which lead to end-organ tissue injury. Thus, preventing mitochondrial dysfunction can be considered a strategy to prevent endotoxemia.
Consistent with this notion, our lab revealed that LPS challenge reduced the levels of ATP and the activity of mitochondrial complexes (complexes I, II, IV, and V) in brain tissue, indicating the occurrence of mitochondrial dysfunction. The activity of complexes I and V was relieved by both pre-and posttreatment with YQFM, while that of complexes II and IV was attenuated only by pretreatment with YQFM. However, the mechanism underlying this difference is unclear. The two major active ingredients of YQFM, Rb1 and Sch, were also examined for their effects on the mitochondrial respiratory chain. The results showed that Rb1 exhibited an effect similar to that of YQFM, while Sch did not exhibit any such effect, indicating that Rb1 mediates the effect of YQFM on complexes I and V. Furthermore, neither Rb1 nor Sch showed any effect on complexes II and IV, suggesting that some other ingredient (s) present in YQFM are responsible for its effect on these two complexes.[18] These results suggest the superiority of TCMs as multicomponent medicines.
| Summary | | |
An increasing number of TCMs and MBCs have been explored with regard to their effect on endotoxemia and underlying mechanisms using LPS-induced endotoxemia animal models. The results so far are encouraging, showing the effectiveness of a spectrum of TCMs for endotoxemia, which have been traditionally used for the treatment of endotoxemia-like illnesses in China. The investigations of MBC are of particular importance, as they provide clues regarding the underlying mechanisms; therefore, TCMs play a role in attenuating endotoxemia.
Some therapeutic potential is observed for several TCMs with different composition. For example, the potential to attenuate microvascular hyperpermeability has been reported for QYT, used in relieving “Ying-fen,” and YQFM, used for collapse syndrome of shock, although both have a unique composition. This fact implies that LPS-induced microvascular hyperpermeability is an intricate process that involves numerous events; thus, treatment with different TCM formulas may lead to similar outcomes, although they different pathways.
A comparative study on the effects of components of TCMs and their MBCs provided a way for understanding how the various MBCs work synergistically to produce beneficial effects.
Financial support and sponsorship
This work was supported by the National Natural Science Foundation of China (No. 81873217).
Conflicts of interest
Prof. Jing-Yan Han is the editor in cheif of World Journal of Traditional Chinese Medicine. The article was subject to the journal's standard procedures, with peer review handled independently of this editorial board member and their research groups. There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3], [Figure 4]
[Table 1]
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