RESUMEN
ETHNOPHARMACOLOGICAL RELEVANCE: Acute lung injury (ALI) can lead to respiratory failure and even death. KAT2A is a key target to suppress the development of inflammation. A herb, perilla frutescens, is an effective treatment for pulmonary inflammatory diseases with anti-inflammatory effects; however, its mechanism of action remains unclear. AIM OF THE STUDY: The purpose of this study was to investigate the therapeutic effect and underlying mechanism of perilla frutescens leaf extracts (PLE), in the treatment of ALI by focusing on its ability to treat inflammation. MATERIALS AND METHODS: In vivo and in vitro models of ALI induced by LPS. Respiratory function, histopathological changes of lung, and BEAS-2B cells damage were assessed upon PLE. This effect is also tested under conditions of KAT2A over expression and KAT2A silencing. RESULTS: PLE significantly attenuated LPS-induced histopathological changes in the lungs, improved respiratory function, and increased survival rate from LPS stimuation background in mice. PLE remarkably suppressed the phosphorylation of STAT3, AKT, ERK (1/2) and the release of cytokines (IL-6, TNF-α, and IL-1ß) induced by LPS via inhibiting the expression of KAT2A. CONCLUSIONS: PLE has a dose-dependent anti-inflammatory effect by inhibiting KAT2A expression to suppress LPS-induced ALI n mice. Our study expands the clinical indications of the traditional medicine PLE and provide a theoretical basis for clinical use of acute lung injury.
Asunto(s)
Lesión Pulmonar Aguda , Lipopolisacáridos , Perilla frutescens , Extractos Vegetales , Hojas de la Planta , Animales , Lesión Pulmonar Aguda/tratamiento farmacológico , Lesión Pulmonar Aguda/patología , Lesión Pulmonar Aguda/inducido químicamente , Perilla frutescens/química , Extractos Vegetales/farmacología , Extractos Vegetales/uso terapéutico , Hojas de la Planta/química , Masculino , Ratones , Humanos , Antiinflamatorios/farmacología , Antiinflamatorios/aislamiento & purificación , Antiinflamatorios/uso terapéutico , Citocinas/metabolismo , Línea Celular , Ratones Endogámicos C57BL , Pulmón/efectos de los fármacos , Pulmón/patología , Pulmón/metabolismo , Modelos Animales de EnfermedadRESUMEN
ETHNOPHARMACOLOGICAL RELEVANCE: Acute lung injury (ALI) is a serious health-threatening syndrome of intense inflammatory response in the lungs, with progression leading to acute respiratory distress syndrome (ARDS). Dachengqi decoction dispensing granule (DDG) has a pulmonary protective role, but its potential modulatory mechanism to alleviate ALI needs further excavation. AIM OF THE STUDY: This study aims to investigate the effect and potential mechanism of DDG on lipopolysaccharide (LPS)-induced ALI models in vivo and in vitro. MATERIALS AND METHODS: LPS-treated Balb/c mice and BEAS-2B cells were used to construct in vivo and in vitro ALI models, respectively. Hematoxylin-eosin (HE), Wet weight/Dry weight (W/D) calculation of lung tissue, and total protein and Lactic dehydrogenase (LDH) assays in BALF were performed to assess the extent of lung tissue injury and pulmonary edema. Enzyme-linked immunosorbent assay (ELISA) was used to detect the levels of tumor necrosis factor-alpha (TNF-α), interleukin-1ß (IL-1ß), and interleukin-18 (IL-18) in BALF, serum, and cell supernatant. The qRT-PCR was used to detect inflammatory factors, Z-DNA binding protein 1 (ZBP1), and receptor-interacting protein kinase 1 (RIPK1) expression in lung tissues and BEAS-2B cells. Double immunofluorescence staining and co-immunoprecipitation were used to detect the relative expression and co-localization of ZBP1 and RIPK1. The effects of LPS and DDG on BEAS-2B cell activity were detected by Cell Counting Kit-8 (CCK-8). Western blot (WB) was performed to analyze the expression of PANoptosis-related proteins in lung tissues and BEAS-2B cells. RESULTS: In vivo, DDG pretreatment could dose-dependently improve the pathological changes of lung tissue in ALI mice, and reduce the W/D ratio of lung, total protein concentration, and LDH content in BALF. In vitro, DDG reversed the inhibitory effect of LPS on BEAS-2B cell viability. Meanwhile, DDG significantly reduced the levels of inflammatory factors in vitro and in vivo. In addition, DDG could inhibit the expression levels of PANoptosis-related proteins, especially the upstream key regulatory molecules ZBP1 and RIPK1. CONCLUSION: DDG could inhibit excessive inflammation and PANoptosis to alleviate LPS-induced ALI, thus possessing good anti-inflammatory and lung-protective effects. This study establishes a theoretical basis for the further development of DDG and provides a new prospect for ALI treatment by targeting PANoptosis.
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Lesión Pulmonar Aguda , Lipopolisacáridos , Ratones Endogámicos BALB C , Animales , Lesión Pulmonar Aguda/tratamiento farmacológico , Lesión Pulmonar Aguda/inducido químicamente , Lesión Pulmonar Aguda/metabolismo , Lesión Pulmonar Aguda/patología , Lipopolisacáridos/toxicidad , Humanos , Masculino , Ratones , Línea Celular , Pulmón/efectos de los fármacos , Pulmón/patología , Pulmón/metabolismo , Líquido del Lavado Bronquioalveolar/química , Extractos Vegetales/farmacología , Citocinas/metabolismo , Antiinflamatorios/farmacología , Modelos Animales de Enfermedad , Medicamentos Herbarios Chinos/farmacología , Medicamentos Herbarios Chinos/uso terapéuticoRESUMEN
ETHNOPHARMACOLOGICAL RELEVANCE: Shuangdan Jiedu Decoction (SJD) is a formula composed of six Chinese herbs with heat-removing and detoxifying, antibacterial, and anti-inflammatory effects, which is clinically used in the therapy of various inflammatory diseases of the lungs including COVID-19, but the therapeutic material basis of its action as well as its molecular mechanism are still unclear. AIM OF THE STUDY: The study attempted to determine the therapeutic effect of SJD on LPS-induced acute lung injury (ALI), as well as to investigate its mechanism of action and assess its therapeutic potential for the cure of inflammation-related diseases in the clinical setting. MATERIALS AND METHODS: We established an ALI model by tracheal drip LPS, and after the administration of SJD, we collected the bronchoalveolar lavage fluid (BALF) and lung tissues of mice and examined the expression of inflammatory factors in them. In addition, we evaluated the effects of SJD on the cyclic guanosine monophosphate-adenosine monophosphate synthase -stimulator of interferon genes (cGAS-STING) and inflammasome by immunoblotting and real-time quantitative polymerase chain reaction (RT-qPCR). RESULTS: We demonstrated that SJD was effective in alleviating LPS-induced ALI by suppressing the levels of pro-inflammatory cytokines in the BALF, improving the level of lung histopathology and the number of neutrophils, as well as decreasing the inflammatory factor-associated gene expression. Importantly, we found that SJD could inhibit multiple stimulus-driven activation of cGAS-STING and inflammasome. Further studies showed that the Chinese herbal medicines in SJD had no influence on the cGAS-STING pathway and inflammasome alone at the formulated dose. By increasing the concentration of these herbs, we observed inhibitory effects on the cGAS-STING pathway and inflammasome, and the effect exerted was maximal when the six herbs were combined, indicating that the synergistic effects among these herbs plays a crucial role in the anti-inflammatory effects of SJD. CONCLUSIONS: Our research demonstrated that SJD has a favorable protective effect against ALI, and its mechanism of effect may be associated with the synergistic effect exerted between six Chinese medicines to inhibit the cGAS-STING and inflammasome abnormal activation. These results are favorable for the wide application of SJD in the clinic as well as for the development of drugs for ALI from herbal formulas.
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Lesión Pulmonar Aguda , Medicamentos Herbarios Chinos , Inflamasomas , Lipopolisacáridos , Proteínas de la Membrana , Nucleotidiltransferasas , Transducción de Señal , Animales , Lesión Pulmonar Aguda/tratamiento farmacológico , Lesión Pulmonar Aguda/inducido químicamente , Lesión Pulmonar Aguda/metabolismo , Lipopolisacáridos/toxicidad , Medicamentos Herbarios Chinos/farmacología , Medicamentos Herbarios Chinos/uso terapéutico , Nucleotidiltransferasas/metabolismo , Inflamasomas/metabolismo , Inflamasomas/efectos de los fármacos , Proteínas de la Membrana/metabolismo , Proteínas de la Membrana/genética , Ratones , Masculino , Transducción de Señal/efectos de los fármacos , Ratones Endogámicos C57BL , Antiinflamatorios/farmacología , Antiinflamatorios/uso terapéutico , Modelos Animales de Enfermedad , Pulmón/efectos de los fármacos , Pulmón/patología , Pulmón/metabolismo , Líquido del Lavado Bronquioalveolar/citologíaRESUMEN
Sepsis is a systemic inflammatory reaction syndrome caused by infections. Acute lung injury (ALI) occurs first and most frequently in patients with sepsis. Gentiopicroside (GPS), which originates mostly from Gentiana, is classified as a secoiridoid glycosides. Terpenoid glycosides have various biological effects, including liver protection, blood glucose and cholesterol level management, and anti-inflammatory and antitumor effects. However, presently, the biochemical foundation and mechanism of the anti-inflammatory effects of GPS in sepsis-induced ALI have not been explained. In the present study, we established a rat model of sepsis ALI induced by cecal ligation and puncture. This enables us to observe the effects of GPS therapy, which significantly reduced the inflammatory response (TNF-α, IL-1ß, and IL-6), nitrogen stress, oxidative stress, and severity of ALI at both the whole animal and molecular levels. In addition, GPS ameliorates LPS-induced ALI via regulation of inflammatory response and cell proptosis in BEAS-2B. This study provides a theoretical basis for treating sepsis-induced ALI with GPS.
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Lesión Pulmonar Aguda , Glucósidos Iridoides , Sepsis , Animales , Sepsis/complicaciones , Sepsis/tratamiento farmacológico , Glucósidos Iridoides/farmacología , Glucósidos Iridoides/uso terapéutico , Lesión Pulmonar Aguda/etiología , Lesión Pulmonar Aguda/tratamiento farmacológico , Ratas , Masculino , Ratas Sprague-Dawley , Modelos Animales de Enfermedad , Estrés Oxidativo/efectos de los fármacos , Inflamación/tratamiento farmacológicoRESUMEN
INTRODUCTION: Acute lung injury (ALI) as one kind of acute pulmonary inflammatory disorder, manifests primarily as damage to alveolar epithelial cells and microvascular endothelial cells. Activation of the complement system is a common pathological mechanism in ALI induced by diverse factors, with the complement alternative pathway assuming a pivotal role. Baicalin, a flavonoid derived from the root of Scutellaria baicalensis Georgi, exhibits noteworthy biological activities. The present study attempted the interventional effects and underlying mechanisms of baicalin in microangiopathy in ALI induced by complement alternative pathway activation. METHODS: Activation of the complement alternative pathway by cobra venom factor (CVF). HMEC cells were pretreated with baicalin and then exposed to complement activation products. The expression of inflammatory mediators was detected by ELISA, and the intranuclear transcriptional activity of NF-κB was assessed by a dual fluorescent kinase reporter gene assay kit. Before establishing the ALI mouse model, baicalin or PDTC was gavaged for 7 d. CVF was injected into the tail vein to establish the ALI model. The levels of inflammatory mediators in BALF and serum were determined by ELISA. HE staining and immunohistochemistry evaluated pathological changes, complement activation product deposition, and NF-κB p65 phosphorylation in lung tissue. RESULTS: Baicalin reduced complement alternative activation product-induced expression of HMEC cells adhesion molecules (ICAM-1, VCAM-1, E-selectin) and cytokines (IL-6, TNF-α) as well as upregulation of NF-κB intranuclear transcriptional activity. Baicalin intervention reduced the number of inflammatory cells and protein content in the BALF and decreased the levels of IL-6, TNF-α, and ICAM-1 in serum and IL-6, TNF-α, ICAM-1, and P-selectin in BLAF. In addition, baicalin attenuated inflammatory cell infiltration in the lung of ALI mice and reduced the deposition of complement activation products (C5a, C5b-9) and phosphorylation of NF-κB p65 in lung tissue. CONCLUSION: Baicalin relieves complement alternative pathway activation-induced lung inflammation by inhibition of NF-κB pathway, delaying the progression of ALI.
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Lesión Pulmonar Aguda , Flavonoides , FN-kappa B , Animales , Flavonoides/farmacología , Ratones , FN-kappa B/metabolismo , Lesión Pulmonar Aguda/tratamiento farmacológico , Humanos , Modelos Animales de Enfermedad , Masculino , Vía Alternativa del Complemento/efectos de los fármacos , Neumonía/tratamiento farmacológico , Ratones Endogámicos C57BL , Pulmón/efectos de los fármacos , Venenos Elapídicos/farmacologíaRESUMEN
Acute lung injury (ALI) is a severe clinical respiratory condition characterized by high rates of mortality and morbidity, for which effective treatments are currently lacking. In this study, lipopolysaccharide (LPS) was used to induce ALI mice, demonstrating the efficacy of tetramethylpyrazine (TMP) in ameliorating ALI. Subsequent we perfored high-throughput sequencing analysis and used Targetscan 8.0 and miRWalk 3.0 databases to predict the interaction between microRNAs and destrin (DSTN), ultimately identifying miR-369-3p as the focus of the investigation. The adenovirus carrying miR-369-3p was administered one week prior to LPS-induced in order to assess its potential efficacy in ameliorating ALI in mice. The findings indicated that the overexpression of miR-369-3p resulted in enhanced lung function, reduced pulmonary edema, inflammation, and permeability in LPS-induced ALI mice, while the suppression of miR-369-3p exacerbated the damage in these mice. Furthermore, the beneficial effects of TMP on LPS-induced ALI were negated by the downregulation of miR-369-3p. The results of our study demonstrate that TMP mitigates LPS-induced ALI through upregulation of miR-369-3p. Consequently, the findings of this study advocate for the clinical utilization of TMP in ALI treatment, with miR-369-3p emerging as a promising target for future ALI interventions.
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Lesión Pulmonar Aguda , Lipopolisacáridos , MicroARNs , Pirazinas , Animales , Lesión Pulmonar Aguda/inducido químicamente , Lesión Pulmonar Aguda/tratamiento farmacológico , Lesión Pulmonar Aguda/metabolismo , Lesión Pulmonar Aguda/genética , Pirazinas/farmacología , MicroARNs/genética , MicroARNs/metabolismo , Ratones , Masculino , Modelos Animales de Enfermedad , Ratones Endogámicos C57BLRESUMEN
Xanthoxylin, a bioactive phenolic compound extracted from the traditional herbal medicine Penthorum Chinense Pursh, is renowned for its anti-inflammatory effects. While previous studies have highlighted the anti-inflammatory and antioxidant properties of Xanthoxylin, its precise mechanisms, particularly concerning immune response and organ protection, remain underexplored. This study aimed to elucidate the effects of Xanthoxylin on inflammation and associated signaling pathways in a mouse model of lipopolysaccharide (LPS)-induced acute lung injury (ALI). ALI was induced via intratracheal administration of LPS, followed by intraperitoneal injections of Xanthoxylin at doses of 1, 2.5, 5, and 10 mg/kg, administered 30 min post-LPS exposure. Lung tissues were harvested for analysis 6 h after LPS challenge. Xanthoxylin treatment significantly mitigated lung tissue damage, pathological alterations, immune cell infiltration, and the production of pro-inflammatory cytokines, including tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6). Additionally, Xanthoxylin modulated the expression of key proteins in the protein kinase B (Akt)/hypoxia-inducible factor 1-alpha (HIF-1α)/nuclear factor-kappa B (NF-κB) signaling pathway, as well as nuclear factor erythroid 2-related factor 2 (Nrf2) and oxidative markers such as superoxide dismutase (SOD) and malondialdehyde (MDA) in the context of LPS-induced injury. This study demonstrates that Xanthoxylin exerts protective and anti-inflammatory effects by down-regulating and inhibiting the Akt/HIF-1α/NF-κB pathways, suggesting its potential as a therapeutic target for the prevention and treatment of ALI or acute respiratory distress syndrome (ARDS).
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Lesión Pulmonar Aguda , Subunidad alfa del Factor 1 Inducible por Hipoxia , Lipopolisacáridos , Factor 2 Relacionado con NF-E2 , FN-kappa B , Proteínas Proto-Oncogénicas c-akt , Transducción de Señal , Animales , Lipopolisacáridos/efectos adversos , Lipopolisacáridos/toxicidad , Factor 2 Relacionado con NF-E2/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , FN-kappa B/metabolismo , Ratones , Lesión Pulmonar Aguda/inducido químicamente , Lesión Pulmonar Aguda/tratamiento farmacológico , Lesión Pulmonar Aguda/metabolismo , Lesión Pulmonar Aguda/patología , Transducción de Señal/efectos de los fármacos , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Masculino , Antiinflamatorios/farmacología , Antiinflamatorios/uso terapéutico , Estrés Oxidativo/efectos de los fármacosRESUMEN
BACKGROUND: Acute lung injury (ALI) is a devastating condition caused by sepsis, pneumonia, trauma, and more recently, COVID-19. SH003, an herbal formula consisted of Astragalus membranaceus, Angelica gigas and Trichosanthes kirilowii, is known for its effects on cancer and immunoregulation. HYPOTHESIS/PURPOSE: Previous studies show SH003 exerts a promising anti-inflammatory effect. This study investigates the effect of modified SH003 on ALI using in silico, in vivo, and in vitro models. STUDY DESIGN AND METHODS: We performed in silico-based analysis of SH003 on ALI-related pathways. C57BL/6 mice were intraperitoneally subjected to lipopolysaccharide (LPS) to induce septic ALI, followed by oral administration of SH003 for 2 weeks. Dexamethasone was used as the positive control. Human peripheral blood-derived polymorphonuclear neutrophils (PMN) were used to investigate the effect and mechanisms of SH003 on neutrophil extracellular trap (NET) formation. RESULTS: Network pharmacology analysis suggested SH003 regulates lung inflammation by modulating NET formation. SH003 significantly reduced mortality in sepsis in vivo by inhibiting local and systemic inflammation, likely via nuclear factor kappa B and mitogen-activated protein kinase pathways-mediated inflammasome suppression. SH003 also decreased NET-related markers in lung tissues and inhibited LPS- and phorbol myristate acetate-induced NET formation in PMN. Cytometry time-of-flight analysis confirmed regulation of NETosis-related pathways by SH003. CONCLUSION: SH003 effectively inhibits excessive immune responses in the lung by suppressing inflammasome activation and NET formation. These findings suggest SH003 as a potential therapeutic agent for septic ALI.
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Lesión Pulmonar Aguda , Angelica , Astragalus propinquus , Trampas Extracelulares , Inflamasomas , Lipopolisacáridos , Ratones Endogámicos C57BL , Neutrófilos , Animales , Lesión Pulmonar Aguda/tratamiento farmacológico , Lesión Pulmonar Aguda/inducido químicamente , Trampas Extracelulares/efectos de los fármacos , Ratones , Neutrófilos/efectos de los fármacos , Humanos , Inflamasomas/metabolismo , Inflamasomas/efectos de los fármacos , Astragalus propinquus/química , Masculino , Angelica/química , Medicamentos Herbarios Chinos/farmacología , Antiinflamatorios/farmacología , Modelos Animales de EnfermedadRESUMEN
BACKGROUND: Pulmonary fibrosis (PF) is a progressive lung disease caused by previous acute lung injury (ALI), but there is currently no satisfactory therapy available. Aerosol inhalation of medicine is an effective way for treating PF. Total ginsenosides (TG) shows potential for the treatment of ALI and PF, but the effects of inhaled TG remain unclear. PURPOSE: To determine the therapeutic effects of TG in ALI and PF, to assess the superiority of the inhaled form of TG over the routine form, and to clarify the mechanism of action of inhaled TG. METHODS: Ultrahigh-performance liquid chromatography coupled with Q-Exactive Orbitrap mass spectrometry (UPLC-QE-MS) was applied to determine the chemoprofile of TG. A mouse model of ALI and PF was established to evaluate the effects of inhaled TG by using bronchoalveolar lavage fluid (BALF) analysis, histopathological observation, hydroxyproline assay, and immunohistochemical analysis. Primary mouse lung fibroblasts (MLF) and human lung fibroblast cell line (HFL1) were applied to determine the in vitro effects and mechanism of TG by using cell viability assay, quantitative real time PCR (qPCR) assay, and western blot (WB) analysis. RESULTS: The UPLC-QE-MS results revealed the main types of ginsenosides in TG, including Re (14.15 ± 0.42%), Rd (8.42 ± 0.49%), Rg1 (6.22 ± 0.42%), Rb3 (3.28 ± 0.01%), Rb2 (3.09 ± 0.00%), Rc (2.33 ± 0.01%), Rg2 (2.09 ± 0.04%), Rb1 (1.43 ± 0.24%), and Rf (0.13 ± 0.06%). Inhaled TG, at dosages of 10, 20, and 30 mg/kg significantly alleviated both ALI and PF in mice. Analyses of BALF and HE staining revealed that TG modulated the levels of IFN-γ, IL-1ß, and TGF-ß1, reduced inflammatory cell infiltration, and restored the alveolar architecture of the lung tissues. Furthermore, HE and Masson's trichrome staining demonstrated that TG markedly decreased fibroblastic foci and collagen fiber deposition, evidenced by the reduction of blue-stained collagen fibers. Hydroxyproline assay and immunohistochemical analyses indicated that TG significantly decreased hydroxyproline level and down-regulated the expression of Col1a1, Col3a1, and α-sma. The inhaled administration of TG demonstrated enhanced efficacy over the oral route when comparable doses were used. Additionally, inhaled TG showed superior safety and therapeutic profiles compared to pirfenidone, as evidenced by a CCK8 assay, which confirmed that TG concentrations ranging from 20 to 120 µg/ml were non-cytotoxic. qPCR and WB analyses revealed that TG, at concentrations of 25, 50, and 100 µg/ml, significantly suppressed the phosphorylation of smad2 induced by TGF-ß1 and down-regulated the expression of fibrotic genes and proteins, including α-sma, Col1a1, Col3a1, and FN1, suggesting an anti-fibrotic mechanism mediated by the smad2 signaling pathway. In vitro, TG's safety and efficacy were also found to be superior to those of pirfenidone. CONCLUSIONS: This study demonstrates, for the first time, the therapeutic efficacy of inhaled TG in treating ALI and PF. Inhaled TG effectively inhibits inflammation and reduces collagen deposition, with a particular emphasis on its role in modulating the Smad2 signaling pathway, which is implicated in the anti-fibrotic mechanism of TG. The study also highlights the superiority of inhaled TG over the oral route and its favorable safety profile in comparison to pirfenidone, positioning it as an ideal alternative for ALI and PF therapy.
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Lesión Pulmonar Aguda , Ginsenósidos , Fibrosis Pulmonar , Transducción de Señal , Proteína Smad2 , Ginsenósidos/farmacología , Ginsenósidos/administración & dosificación , Animales , Lesión Pulmonar Aguda/tratamiento farmacológico , Fibrosis Pulmonar/tratamiento farmacológico , Transducción de Señal/efectos de los fármacos , Masculino , Ratones , Proteína Smad2/metabolismo , Humanos , Administración por Inhalación , Líquido del Lavado Bronquioalveolar/química , Ratones Endogámicos C57BL , Pulmón/efectos de los fármacos , Pulmón/patología , Modelos Animales de Enfermedad , Fibroblastos/efectos de los fármacos , Aerosoles , Línea Celular , Factor de Crecimiento Transformador beta1/metabolismoRESUMEN
Acute lung injury (ALI) and its severe form, acute respiratory distress syndrome (ARDS), induce high morbidity and mortality rates, which challenge the present approaches for the treatment of ALI/ARDS. The clinically used photosensitizer verteporfin (VER) exhibits great potential in the treatment of acute lung injury and acute respiratory distress syndrome (ALI/ARDS) by regulating macrophage polarization and reducing inflammation. Nevertheless, its hydrophobic characteristics, nonspecificity, and constrained bioavailability hinder its therapeutic efficacy. In this work, we developed a type of VER-cored artificial exosome (EVM), which was produced by using mesoporous silica nanoparticles (MSNs) to load VER, followed by the exocytosis of internalized VER-MSNs from mouse bone marrow-derived mesenchymal stem cells (mBMSCs) without further modification. Both in vitro and in vivo assessments confirmed the powerful anti-inflammation induced by EVM. EVM also showed significant higher accumulation to inflammatory lungs compared with healthy ones, which was beneficial to the treatment of ALI/ARDS. EVM improved pulmonary function, attenuated lung injury, and reduced mortality in ALI mice with high levels of biocompatibility, exhibiting a 5-fold higher survival rate than the control. This type of artificial exosome emitted near-infrared light in the presence of laser activation, which endowed EVM with trackable ability both in vitro and in vivo. Our work developed a type of clinically used photosensitizer-loaded artificial exosome with membrane integrity and traceability. To the best of our knowledge, this kind of intracellularly synthesized artificial exosome was developed and showed great potential in ALI/ARDS therapy.
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Lesión Pulmonar Aguda , Exosomas , Dióxido de Silicio , Animales , Lesión Pulmonar Aguda/tratamiento farmacológico , Lesión Pulmonar Aguda/patología , Lesión Pulmonar Aguda/metabolismo , Lesión Pulmonar Aguda/terapia , Ratones , Exosomas/metabolismo , Exosomas/química , Dióxido de Silicio/química , Verteporfina/farmacología , Verteporfina/química , Verteporfina/uso terapéutico , Nanopartículas/química , Células Madre Mesenquimatosas/efectos de los fármacos , Células Madre Mesenquimatosas/metabolismo , Ratones Endogámicos C57BL , Masculino , Fármacos Fotosensibilizantes/farmacología , Fármacos Fotosensibilizantes/química , PorosidadRESUMEN
The effective treatment of acute lung injury (ALI) remains a significant challenge. Patients with ALI demonstrate an abundance of proinflammatory mediators in both bronchoalveolar lavage fluid (BALF) and circulating plasma. Bardoxolone methyl (BM) is a semi-synthetic triterpenoid derived from oleanolic acid, a natural product known for its ability to inhibit proinflammatory signaling. GSDMD is a signaling protein involved in pyroptosis, a form of programmed cell death. It has been reported that its upstream proteins play a role in the pathogenesis of ALI. However, there is currently no research examining whether the effect of BM on the occurrence and development of ALI is associated with changes in GSDMD protein. In this study, we prepared nanostructured lipid carriers loaded with BM and conjugated with anti-PECAM-1 antibody (PECAM@BM NLCs). PECAM@BM NLCs were designed to specifically bind to pulmonary vascular endothelial cells that highly express the PECAM-1 receptors. We also aimed to investigate the protective effects of PECAM@BM NLCs on ALI and elucidate the underlying molecular mechanisms. The results demonstrated that PECAM@BM NLCs accumulated in the lung tissues and significantly alleviated the inflammatory injury of ALI. This was evidenced by the changes in the lung wet/dry ratio, the total protein concentration, proinflammatory cytokines in BALF, and the histopathological progress. Additionally, we elucidated that PECAM@BM NLCs had the ability to inhibit the assembly of NLRP3 inflammasome and pro-caspase-1 complex, thereby suppressing the induction of pyroptosis. This mechanism resulted in the inhibition of N-terminal GSDMD expression and effectively prevented the progression of ALI.
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Lesión Pulmonar Aguda , Pulmón , Nanoestructuras , Ácido Oleanólico , Molécula-1 de Adhesión Celular Endotelial de Plaqueta , Ácido Oleanólico/farmacología , Ácido Oleanólico/análogos & derivados , Ácido Oleanólico/administración & dosificación , Ácido Oleanólico/química , Animales , Lesión Pulmonar Aguda/tratamiento farmacológico , Lesión Pulmonar Aguda/patología , Nanoestructuras/química , Molécula-1 de Adhesión Celular Endotelial de Plaqueta/metabolismo , Pulmón/efectos de los fármacos , Pulmón/metabolismo , Pulmón/patología , Portadores de Fármacos/química , Masculino , Ratones , Neumonía/tratamiento farmacológico , Neumonía/patología , Neumonía/metabolismo , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Ratones Endogámicos C57BL , Lípidos/química , Anticuerpos/farmacología , Líquido del Lavado Bronquioalveolar/química , Humanos , Sistemas de Liberación de Medicamentos/métodos , Inflamasomas/metabolismo , Inflamasomas/efectos de los fármacosRESUMEN
Infection-related lipopolysaccharide (LPS) release causes cytokine storm and acute lung injury. Emerging data show that the interleukin 6 (IL-6) inhibitor tocilizumab can improve lung damage in patients with sepsis. This study aimed to investigate the therapeutic effect of tocilizumab on acute lung injury in cirrhotic rats. Biliary cirrhosis was induced in Sprague-Dawley rats with common bile duct ligation (BDL). Sham-operated rats served as surgical controls. Tocilizumab was administered on post-operative day 21, and LPS was injected intraperitoneally on day 29. Three hours after LPS injection, hemodynamic parameters, biochemistry data, and arterial blood gas analysis were evaluated, along with measurements of IL-6 and tumor necrosis factor-α (TNF-α). Liver and lung histology was examined, and protein levels were analyzed. LPS administration reduced portal pressure, portal venous flow and cardiac index in the BDL rats. In addition, LPS administration induced acute lung injury, hypoxia and elevated TNF-α and IL-6 levels. Pre-treatment with tocilizumab did not affect hemodynamic and biochemistry data, but it ameliorated lung injury and decreased TNF-α, IL-6, and CD68-positive macrophage infiltration. Moreover, tocilizumab administration improved hypoxia and gas exchange in the BDL rats, and downregulated hepatic and pulmonary inflammatory protein expression. In conclusion, LPS administration induced acute lung injury in biliary cirrhotic rats. Pre-treatment with tocilizumab reduces lung damage and hypoxia, possibly by downregulating inflammatory proteins and reducing IL-6, TNF-α and CD68-positive macrophage recruitment in the lung.
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Lesión Pulmonar Aguda , Anticuerpos Monoclonales Humanizados , Interleucina-6 , Lipopolisacáridos , Cirrosis Hepática Biliar , Ratas Sprague-Dawley , Animales , Lesión Pulmonar Aguda/tratamiento farmacológico , Lesión Pulmonar Aguda/patología , Lesión Pulmonar Aguda/etiología , Masculino , Anticuerpos Monoclonales Humanizados/farmacología , Anticuerpos Monoclonales Humanizados/uso terapéutico , Ratas , Interleucina-6/metabolismo , Cirrosis Hepática Biliar/tratamiento farmacológico , Cirrosis Hepática Biliar/complicaciones , Cirrosis Hepática Biliar/patología , Pulmón/patología , Pulmón/efectos de los fármacos , Pulmón/metabolismo , Factor de Necrosis Tumoral alfa/metabolismo , Hígado/efectos de los fármacos , Hígado/patología , Hígado/metabolismo , Hemodinámica/efectos de los fármacosRESUMEN
Acute lung injury (ALI) arises from an excessive inflammatory response, usually progressing to acute respiratory distress syndrome (ARDS) if not promptly addressed. There is currently a limited array of effective treatments available for ALI. In this study, we developed disulfide bond-bridged prodrug self-assembled nanoparticles (referred to as DSSS NPs). These nanoparticles were consisted of Dexamethasone (Dex) and stearic acid (SA), and were designed to target and treat ALI. DSSS NPs demonstrated a substantial drug loading capacity with 37.75 % of Dex, which is much higher than conventional nanomedicines (usually < 10 %). Moreover, they exhibited the potential to specifically target injured lung tissue and inflammatory microenvironment-responsive release drugs. Consequently, DSSS NPs reduced significantly the levels of pro-inflammatory cytokines and tissue damage in mice with ALI induced by lipopolysaccharide (LPS). Overall, DSSS NPs offer a promising strategy for treatment of acute lung injury.
Asunto(s)
Lesión Pulmonar Aguda , Antiinflamatorios , Dexametasona , Disulfuros , Lipopolisacáridos , Nanopartículas , Oxidación-Reducción , Ácidos Esteáricos , Dexametasona/administración & dosificación , Dexametasona/química , Lesión Pulmonar Aguda/tratamiento farmacológico , Animales , Nanopartículas/química , Disulfuros/química , Ratones , Antiinflamatorios/administración & dosificación , Antiinflamatorios/química , Antiinflamatorios/farmacología , Ácidos Esteáricos/química , Masculino , Liberación de Fármacos , Citocinas/metabolismo , Profármacos/química , Profármacos/administración & dosificación , Humanos , Ratones Endogámicos C57BL , Pulmón/efectos de los fármacos , Pulmón/metabolismo , Portadores de Fármacos/químicaRESUMEN
Increasing evidence has demonstrated that coenzyme Q10 (CoQ10) exhibits a range of biological properties. Herein, we explored the protective effect and potential molecular mechanism of CoQ10 on lipopolysaccharide (LPS)-induced acute lung injury (ALI). We found that medium (10 mg/kg) and high (50 mg/kg) doses of CoQ10 ameliorated LPS (50 µg/µL)-induced ALI to varying degrees, as demonstrated by reduced lung coefficient, lower wet/dry weight lung tissue ratio, decreased bronchoalveolar lavage fluid protein concentration, less anatomical and histopathological damage to the lung, and increased expression of proteins related to lung epithelial barrier structure. CoQ10 also alleviated LPS-induced oxidative stress and inflammation mediated by NOD-like receptor protein 3 (NLRP3) by reducing the reactive oxygen species (ROS), malondialdehyde, and mitochondrial ROS concentrations, increasing superoxide dismutase, glutathione, and catalase activity, and decreasing NLRP3 expression at the protein and mRNA levels. Moreover, CoQ10 alleviated structural and functional damage to the mitochondria, inhibited mitochondrial fission, and promoted mitochondrial fusion, mainly by inhibiting phosphorylation of dynamin-related protein 1 (Drp1) at Ser616 and Ser637. Correlation analysis revealed that mitochondrial fission (especially Drp1) was positively correlated with oxidative stress, NLRP3-mediated inflammation, and structural damage to the lung epithelial barrier. Molecular docking analysis showed that CoQ10 binds stably to Drp1, with a binding energy of -5.9 kcal/mol. Furthermore, the use of schaftoside (a Drp1 inhibitor) has further elucidated the mechanism of action of CoQ10. Together, these results suggest that CoQ10 alleviates LPS-induced ALI by regulating mitochondrial dynamics, attenuating oxidative stress, and decreasing NLRP3-medated inflammation, thereby promoting lung epithelial barrier structural remodeling.
Asunto(s)
Lesión Pulmonar Aguda , Lipopolisacáridos , Dinámicas Mitocondriales , Proteína con Dominio Pirina 3 de la Familia NLR , Estrés Oxidativo , Ubiquinona , Ubiquinona/análogos & derivados , Ubiquinona/farmacología , Ubiquinona/uso terapéutico , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Estrés Oxidativo/efectos de los fármacos , Lesión Pulmonar Aguda/tratamiento farmacológico , Lesión Pulmonar Aguda/inducido químicamente , Lesión Pulmonar Aguda/patología , Lesión Pulmonar Aguda/metabolismo , Animales , Dinámicas Mitocondriales/efectos de los fármacos , Masculino , Pulmón/efectos de los fármacos , Pulmón/patología , Pulmón/metabolismo , Pulmón/inmunología , Ratones , Antiinflamatorios/farmacología , Antiinflamatorios/uso terapéutico , Humanos , Inflamación/tratamiento farmacológico , Inflamación/inducido químicamente , Ratones Endogámicos C57BL , Mitocondrias/efectos de los fármacos , Mitocondrias/metabolismo , Especies Reactivas de Oxígeno/metabolismoRESUMEN
Sepsis, characterized by high mortality rates, causes over 50 % of acute lung injury (ALI) cases, primarily due to the heightened susceptibility of the lungs during this condition. Suppression of the excessive inflammatory response is critical for improving the survival of patients with sepsis; nevertheless, no specific anti-sepsis drugs exist. Huperzine A (HupA) exhibits neuroprotective and anti-inflammatory properties; however, its underlying mechanisms and effects on sepsis-induced ALI have yet to be elucidated. In this study, we demonstrated the potential of HupA for treating sepsis and explored its mechanism of action. To investigate the in vivo impacts of HupA, a murine model of sepsis was induced through cecal ligation and puncture (CLP) in both wild-type (WT) and α7 nicotinic acetylcholine receptor (α7nAChR) knockout mice. Our results showed that HupA ameliorates sepsis-induced acute lung injury by activating the α7nAChR. We used the CLP sepsis model in wild-type and α7nAChR -/- mice and found that HupA significantly increased the survival rate through α7nAChR, reduced the pro-inflammatory cytokine levels and oxidative stress, ameliorated histopathological lung injury, altered the circulating immune cell composition, regulated gut microbiota, and promoted short-chain fatty acid production through α7nAChR in vivo. Additionally, HupA inhibited Toll-like receptor NF-κB signaling by upregulating the α7nAChR/protein kinase B/glycogen synthase kinase-3 pathways. Our data elucidate HupA's mechanism of action and support a "new use for an old drug" in treating sepsis. Our findings serve as a basis for further in vivo studies of this drug, followed by application to humans. Therefore, the findings have the potential to benefit patients with sepsis.
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Lesión Pulmonar Aguda , Alcaloides , Ratones Endogámicos C57BL , Ratones Noqueados , Estrés Oxidativo , Sepsis , Sesquiterpenos , Receptor Nicotínico de Acetilcolina alfa 7 , Animales , Receptor Nicotínico de Acetilcolina alfa 7/metabolismo , Receptor Nicotínico de Acetilcolina alfa 7/genética , Lesión Pulmonar Aguda/tratamiento farmacológico , Lesión Pulmonar Aguda/etiología , Lesión Pulmonar Aguda/patología , Sepsis/tratamiento farmacológico , Sepsis/complicaciones , Sepsis/inmunología , Estrés Oxidativo/efectos de los fármacos , Alcaloides/uso terapéutico , Alcaloides/farmacología , Ratones , Masculino , Sesquiterpenos/uso terapéutico , Sesquiterpenos/farmacología , Antiinflamatorios/uso terapéutico , Antiinflamatorios/farmacología , Citocinas/metabolismo , Modelos Animales de Enfermedad , Humanos , Pulmón/patología , Pulmón/efectos de los fármacos , Pulmón/inmunología , Microbioma Gastrointestinal/efectos de los fármacos , Inflamación/tratamiento farmacológicoRESUMEN
BACKGROUND: Human neutrophil elastase (HNE) is an important contributor to lung diseases such as acute lung injury (ALI) or acute respiratory distress syndrome. Therefore, this study aimed to identify natural HNE inhibitors with anti-inflammatory activity through machine learning algorithms, in vitro assays, molecular dynamic simulation, and an in vivo ALI assay. METHODS: Based on the optimized Discovery Studio two-dimensional molecular descriptors, combined with different molecular fingerprints, six machine learning models were established using the Naïve Bayesian (NB) method to identify HNE inhibitors. Subsequently, the optimal model was utilized to screen 6925 drug-like compounds obtained from the Traditional Chinese Medicine Systems Pharmacy Database and Analysis Platform (TCMSP), followed by ADMET analysis. Finally, 10 compounds with reported anti-inflammatory activity were selected to determine their inhibitory activities against HNE in vitro, and the compounds with the best activity were selected for a 100 ns molecular dynamics simulation and its anti-inflammatory effect was evaluated using Poly (I:C)-induced ALI model. RESULTS: The evaluation of the in vitro HNE inhibition efficiency of the 10 selected compounds showed that the flavonoid tricetin had the strongest inhibitory effect on HNE. The molecular dynamics simulation indicated that the binding of tricetin to HNE was relatively stable throughout the simulation. Importantly, in vivo experiments indicated that tricetin treatment substantially improved the Poly (I:C)-induced ALI. CONCLUSION: The proposed NB model was proved valuable for exploring novel HNE inhibitors, and natural tricetin was screened out as a novel HNE inhibitor, which was confirmed by in vitro and in vivo assays for its inhibitory activities.
Asunto(s)
Elastasa de Leucocito , Simulación de Dinámica Molecular , Elastasa de Leucocito/antagonistas & inhibidores , Elastasa de Leucocito/metabolismo , Humanos , Animales , Masculino , Lesión Pulmonar Aguda/tratamiento farmacológico , Antiinflamatorios/farmacología , Antiinflamatorios/química , Evaluación Preclínica de Medicamentos , Productos Biológicos/farmacología , Productos Biológicos/química , Ratones , Aprendizaje AutomáticoRESUMEN
There has been significant global interest in respiratory health driven by the coronavirus disease (COVID-19) and severe environmental pollution. This study explored the potential of schisantherin A (SchA), a compound derived from Schisandra chinensis, to protect against acute pneumoconiosis. We assessed the effects of SchA on phorbol 12-myristate 13-acetate (PMA)-stimulated A549 alveolar epithelial cells and SiO2/TiO2-induced pulmonary injury in mice. In A549 cells, SchA significantly decreased pro-inflammatory mediators such as inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), and interleukin (IL)-8 levels. SchA-mediated reduction in inflammatory mediators was associated with the downregulation of PMA-stimulated nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and mitogen-activated protein kinase (MAPK) signaling activation. In SiO2/TiO2-induced lung-injured mice, SchA administration significantly reduced MUC5AC production in lung tissue. SchA administration significantly downregulated the overexpression of NK-κB and the subsequent production of COX-2, iNOS, and NOD-like receptor pyrin domain-containing protein 3 (NLRP3) inflammasomes. It significantly suppressed expected increases in total cell numbers and pro-inflammatory cytokines, including tumor necrosis factor-alpha (TNF-α) and IL-1ß in the bronchoalveolar lavage fluid (BALF) in SiO2/TiO2-stimulated mice. In contrast, the SiO2/TiO2-mediated decrease in IL-10 levels was significantly improved by SchA treatment. These fundamental results can be used to develop potential treatments involving SchA for acute pneumoconiosis.
Asunto(s)
Lesión Pulmonar Aguda , Ciclooctanos , Nanopartículas , Dióxido de Silicio , Titanio , Animales , Dióxido de Silicio/toxicidad , Titanio/toxicidad , Humanos , Ciclooctanos/farmacología , Ciclooctanos/uso terapéutico , Ratones , Lesión Pulmonar Aguda/inducido químicamente , Lesión Pulmonar Aguda/tratamiento farmacológico , Lesión Pulmonar Aguda/patología , Lesión Pulmonar Aguda/metabolismo , Células A549 , Masculino , Nanopartículas/química , Lignanos/farmacología , Lignanos/uso terapéutico , Mucina 5AC/metabolismo , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , FN-kappa B/metabolismo , Óxido Nítrico Sintasa de Tipo II/metabolismo , Silicosis/patología , Silicosis/tratamiento farmacológico , Silicosis/metabolismo , Ciclooxigenasa 2/metabolismoRESUMEN
Acute lung injury (ALI) is a severe respiratory disorder closely associated with the excessive activation of the NLRP3 inflammasome. Oridonin (Ori), a natural diterpenoid compound, had been confirmed as a specific covalent NLRP3 inflammasome inhibitor, which was completely different from that of MCC950. However, the further clinical application of Ori was limited by its weak inhibitory activity against NLRP3 inflammasome (IC50 = 1240.67 nM). Fortunately, through systematic structure-optimization of Ori, D6 demonstrated the enhancement of IL-1ß inhibitory activity (IC50 = 41.79 nM), which was better than the parent compound Ori. Then, by using SPR, molecular docking and MD simulation, D6 was verified to directly interact with NLRP3 via covalent and non-covalent interaction. The further anti-inflammatory mechanism studies were revealed that D6 could inhibit the activation of NLRP3 inflammasome without affecting the initiation phase of NLRP3 inflammasome activation, and D6 was a broad-spectrum and selective NLRP3 inflammasome inhibitor. Finally, D6 demonstrated a favorable therapeutic effect on LPS-induced ALI in mice model, and the potent pharmacodynamic effect of D6 was correlated with the specific inhibition of NLRP3 inflammasome activation in vivo. Thus, D6 is proved as a potent NLRP3 inhibitor, and has the potential to develop as a novel anti-ALI agent.
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Lesión Pulmonar Aguda , Diterpenos de Tipo Kaurano , Diseño de Fármacos , Inflamasomas , Proteína con Dominio Pirina 3 de la Familia NLR , Lesión Pulmonar Aguda/tratamiento farmacológico , Lesión Pulmonar Aguda/metabolismo , Diterpenos de Tipo Kaurano/farmacología , Diterpenos de Tipo Kaurano/síntesis química , Diterpenos de Tipo Kaurano/química , Proteína con Dominio Pirina 3 de la Familia NLR/antagonistas & inhibidores , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Animales , Inflamasomas/antagonistas & inhibidores , Inflamasomas/metabolismo , Ratones , Relación Estructura-Actividad , Estructura Molecular , Humanos , Relación Dosis-Respuesta a Droga , Lipopolisacáridos/farmacología , Lipopolisacáridos/antagonistas & inhibidores , Masculino , Ratones Endogámicos C57BL , Simulación del Acoplamiento MolecularRESUMEN
The aim of this study was to investigated the effects of forsythiaside A (FA) on acute lung injury (ALI). The lung tissue pathological was detected by hematoxylin-eosin staining (HE) staining. Wet weight/dry weight (w/d) of the lung in mice was measured. Cytokine such as interleukin 1ß (IL-1ß), IL-6 and tumor necrosis factor-α (TNF-α) were also detected. Compared with the vector group, the protein expression levels of TRAF6 and TAK1 the RNF99 group were significantly reduced. Ubiquitinated TRAF6 protein was increased after knockdown of RNF99. Finally, it was found that FA significantly ameliorated ALI via regulation of RNF99/TRAF6/NF-κB signal pathway. In conclusion, RNF99 was an important biomarker in ALI and FA alleviated ALI via RNF99/ TRAF6/NF-κB signal pathway.
Asunto(s)
Lesión Pulmonar Aguda , Transducción de Señal , Animales , Humanos , Masculino , Ratones , Lesión Pulmonar Aguda/tratamiento farmacológico , Lesión Pulmonar Aguda/patología , Lesión Pulmonar Aguda/metabolismo , Antiinflamatorios/uso terapéutico , Antiinflamatorios/farmacología , Citocinas/metabolismo , Glicósidos/farmacología , Glicósidos/uso terapéutico , Pulmón/patología , Pulmón/efectos de los fármacos , Pulmón/metabolismo , Ratones Endogámicos C57BL , FN-kappa B/metabolismo , Transducción de Señal/efectos de los fármacos , Factor 6 Asociado a Receptor de TNF/metabolismo , Ubiquitina-Proteína Ligasas/metabolismo , Ubiquitina-Proteína Ligasas/genéticaRESUMEN
OBJECTIVES: To investigate the effect of dexamethasone (DXM) on acute lung and kidney injury with sepsis and its possible mechanism. METHODS: Control (NC), lipopolysaccharide (LPS) and lipopolysaccharide + dexamethasone (LPS+DXM) treated groups were established by random assignment of 72 Wistar rats. The NC rats were injected with physiological saline, while the LPS group was injected with LPS (5 mg/kg) and LPS+DXM group was injected with LPS(5 mg/kg) first and followed by DXM (1 mg/kg). Serum tumor necrosis factor-α (TNF-α) and serum macrophage inflammatory protein 1α (MIP-1α) were measured by ELISA. Lung wet/dry weight ratio, serum creatinine(SCR) and blood urea nitrogen(BUN) were determined at various time points. Hematoxylin Eosin staining (HE) for pathological changes in the lung and kidney. Radioimmunoassay was used to detect the levels of angiotensin II (Ang II) in plasma, lung and kidney tissues. Immunohistochemistry and western blot (WB) were used to detect angiotensin II receptor type 1 (AT1R) protein and angiotensin II receptor type 2 (AT2R) protein in lung and kidney tissues. The level of nitric oxide (NO) in serum, lung and kidney were detected using nitrate reductase method. RESULTS: Compared with control group, serum TNF-α, MIP-1α, SCR, BUN, lung W/D, Ang II level in plasma, lung and kidney, lung and kidney AT2R protein, NO level in serum, lung and kidney were significantly elevated(P<0.05) and pathological damage of lung and kidney tissues were showed in LPS group rats (P<0.05), whereas DXM down-regulated the above indexes and alleviate pathological damage of lung and kidney tissues. However, the expression of the lung and kidney AT1R protein was opposite to the above results. CONCLUSIONS: Sepsis can cause acute lung and kidney injury and changes RAAS components in circulating, lung and renal. DXM can improve acute lung and kidney injury in septic rats, and the mechanism may be related to the down-regulation of inflammatory factors, AngII, AT2R, NO and up-regulation of AT1R expression by DXM.