lignans and Acute-Lung-Injury

Acute lung injury (ALI) is a challenging clinical syndrome that manifests as an acute inflammatory response. Schisandrin B (Sch B), a bioactive lignan from Schisandra genus plants, has been shown to suppress inflammatory responses and oxidative stress. However, the underlying molecular mechanisms have remained elusive.. This study performed an in-depth investigation of the anti-inflammatory mechanism of Sch B in macrophages and in an animal model of ALI.. qPCR array was used to probe the differential effects and potential target of Sch B. ALI was induced by intratracheal administration of LPS in experimental mice with or without Sch B treatment.. Our studies show that Sch B differentially modulates inflammatory factor induction by LPS in macrophages by directly binding myeloid differentiation response factor-88 (MyD88), an essential adaptor protein in the toll-like receptor-4 (TLR4) pathway. Sch B spares non-MyD88-pathways downstream of TLR4. Such inhibition suppressed key signaling mediators such as TAK1, MAPKs, and NF-κB, and pro-inflammatory factor induction. Pull down assay using biotinylated-Sch B validate the direct interaction between Sch B and MyD88 in macrophages. Treatment of mice with Sch B prior to LPS challenge reduced inflammatory cell infiltration in lungs, induction of MyD88-pathway signaling proteins, and prevented inflammatory cytokine induction.. In summary, our studies have identified MyD88 as a direct target of Sch B for its anti-inflammatory activity, and suggest that Sch B may have therapeutic value for acute lung injury and other MyD88-dependent inflammatory diseases.

Topics: Acute Lung Injury; Animals; Anti-Inflammatory Agents; Lignans; Lipopolysaccharides; Mice; Myeloid Differentiation Factor 88; NF-kappa B; Toll-Like Receptor 4

Sepsis is a systemic inflammatory response, and vascular leakage associated with acute lung injury (ALI) is an important pathophysiological process during sepsis. Schisandrin A (SchA) is a bioactive lignan which has been reported to have the anti-inflammatory effects in many studies, while whether SchA can ameliorate ALI-related vascular leakage caused by sepsis is unknown.. To evaluate the role and the underlying mechanism of SchA in increase of pulmonary vascular permeability induced by sepsis.. The effect of SchA on pulmonary vascular permeability was examined in rat acute lung injury model. The effect of SchA on skin vascular permeability of mice was investigated through Miles assay. MTT assay was performed to detect the cell activity, and transwell assay was used to detect the effect of SchA on cell permeability. The effects of SchA on junction proteins and RhoA/ROCK1/MLC signaling pathway were manifested by immunofluorescence staining and western blot.. The administration of SchA alleviated rat pulmonary endothelial dysfunction, relieved increased permeability in the mouse skin and HUVECs induced by lipopolysaccharide (LPS). Meanwhile, SchA inhibited the formation of stress fibers, reversed the decrease of expression of ZO-1 and VE-cadherin. Subsequent experiments confirmed that SchA inhibited RhoA/ROCK1/MLC canonical pathway in rat lungs and HUVECs induced by LPS. Moreover, overexpression of RhoA reversed the inhibitory effect of SchA in HUVECs, which suggested that SchA protected the pulmonary endothelial barrier by inhibiting RhoA/ROCK1/MLC pathway.. In summary, our results indicate that SchA ameliorates the increase of pulmonary endothelial permeability induced by sepsis through inhibition of RhoA/ROCK1/MLC pathway, providing a potentially effective therapeutic strategy for sepsis.

Topics: Acute Lung Injury; Animals; Capillary Permeability; Lignans; Lipopolysaccharides; Lung; Mice; Permeability; Rats; rho-Associated Kinases; Sepsis

Acute lung injury (ALI) is a common lung disease characterized by severe acute inflammatory lung injury in patients with sepsis. Syringaresinol (SYR) has been reported to have anti-apoptotic and anti-inflammatory effects, but whether it could prevent pyroptosis to improve sepsis-induced ALI remains unclear. The purpose of this work was to examine the impact of SYR on sepsis-induced ALI and investigate the underlying mechanisms. The ALI model was induced by caecal ligation and puncture (CLP) in C57BL/6 mice, structural damage in the lung tissues was determined using haematoxylin and eosin (HE) staining, and the levels of related inflammatory cytokines and macrophage polarization were examined by enzyme-linked immunosorbent assays (ELISAs) and flow cytometry, respectively. The activation of the NLRP3 inflammasome and the protein levels of TLR4, NF-κB and MAPKs was measured by western blotting. The results demonstrated that SYR pretreatment significantly reduced lung tissue histological damage, inhibited the production of proinflammatory cytokines and albumin in bronchoalveolar lavage fluid (BALF), and decreased myeloperoxidase (MPO) levels, thereby alleviating lung tissue injury. Meanwhile, septic mice treated with SYR displayed a higher survival rate and lower percentage of M1 macrophages in the BALF and spleen than septic mice. In addition, lung tissues from the CLP + SYR group exhibited downregulated protein expression of NLRP3, ASC, GSDMD caspase-1 p20 and TLR4, along with decreased phosphorylated levels of NF-κB, ERK, JNK and P38, indicating that SYR administration effectively prevented CLP-induced pyroptosis in the lung. SYR also suppressed LPS-induced pyroptosis in RAW 264.7 cells by inhibiting the activation of the NLRP3 inflammasome, which was abolished by an oestrogen receptor-β (ERβ) antagonist (PHTPP). In conclusion, SYR exerted protective effects on CLP-induced ALI via the oestrogen receptor-β signalling pathway.

Topics: Acute Lung Injury; Animals; Furans; Lignans; Mice; Mice, Inbred C57BL; Pyroptosis; Receptors, Estrogen; Sepsis

Acute lung injury (ALI) is characterized by an excessive inflammatory response, closely related to sepsis occurrence and development. It has been reported that Schisandrin (Sch) exhibits anti-inflammatory activity. However, whether the beneficial effects of Sch exists during ALI remains to be studied. In this study, the impact of Sch was evaluated by studying lung tissue damage, measuring the concentrations of pro-inflammatory factors, and the expression of apoptotic proteins in the LPS-induced ALI mice model. Protein expression of inflammation-related signaling pathway within the lung tissue and A549 cells were also measured. In addition, the effect of Sch on A549 cell apoptosis and inflammatory markers was also detected. Animal experiments demonstrated that pre-feeding Sch alleviated the production of inflammation mediators, abnormal pathological injuries, and blocked the progression of apoptotic events in the lung tissue. The in vitro experiments showed that Sch pretreatment reduced LPS upregulated interleukin-1β (IL-1β), IL-18, and IL-6 levels, and improved LPS-induced abnormal apoptosis. Sch and the pathway inhibitor AG490 also inhibited the expression levels of p-JAK2 and p-STAT3 in A549 cells. Moreover, pretreatment with Sch significantly inhibited the activation of NLRP3 inflammasomes, reduced inducible nitric oxide synthase, and cyclooxygenase 2 proteins expression during ALI in vitro and in vivo. Overall, Sch effectively alleviated ALI and provided a new mechanism to support the protective effect of Sch for sepsis-induced ALI. PRACTICAL IMPLICATIONS: ALI is characterized by inflammatory injury of the lungs, which is an important cause of high morbidity and mortality in severe patients. Sch is considered as a botanical active ingredient with various pharmacological activities, such as neuroprotective and vascular protective effects. However, the effect of Sch on ALI and its mechanism remains largely unknown. Research data indicate that Sch exerts an anti-inflammatory effect by reducing the production of inflammatory factors and abnormal apoptosis of cells, further alleviating lung damage. The protective effect of Sch was associated with inhibition of the activation of NLRP3 and the JAK2/STAT3 inflammatory pathways. The study, therefore, confirmed that Sch has a potential as an effective drug to prevent ALI diseases.

Topics: Acute Lung Injury; Animals; Anti-Inflammatory Agents; Cyclooctanes; Lignans; Lipopolysaccharides; Mice; NLR Family, Pyrin Domain-Containing 3 Protein; Polycyclic Compounds; Sepsis

Acute lung injury (ALI) is often responsible for the high morbidity of critically ill patients. The present study aimed to investigate whether phillygenin (PHI) can inhibit inflammation and apoptosis of pulmonary epithelial cells by activating peroxisome proliferator‑activated receptor γ (PPARγ) signaling. The

Topics: Acute Lung Injury; Anti-Inflammatory Agents; Apoptosis; Cell Line; Child; Child, Preschool; Epithelial Cells; Female; Humans; Inflammation; Lignans; Male; Matrix Metalloproteinase 8; PPAR gamma

Epidemic modeling has been a key tool for understanding the impact of global viral outbreaks for over two decades. Recent developments of the COVID-19 pandemic have accelerated research using compartmental models, like SI, SIR, SEIR, with their appropriate modifications. However, there is a large body of recent research consolidated on homogeneous population mixing models, which are known to offer reduced tractability, and render conclusions hard to quantify. As such, based on our recent work, introducing the heterogeneous geo-spatial mobility population model (GPM), we adapt a modified SIR-V (susceptible-infected-recovered-vaccinated) epidemic model which embodies the idea of patient relapse from R back to S, vaccination of R and S patients (reducing their infectiousness), thus altering the infectiousness of V patients (from

Topics: Acute Lung Injury; Adherens Junctions; Animals; Anti-Bacterial Agents; Anti-Inflammatory Agents; Antigens, CD; Antineoplastic Agents, Phytogenic; Antioxidants; Apoptosis; beta Catenin; Brain Ischemia; Cadherins; Carcinogenesis; Catalysis; Cell Line; Cells, Cultured; Curcuma; Curcumin; Dioxoles; Disease Models, Animal; Endothelial Cells; Epithelial Cells; Heme Oxygenase (Decyclizing); Humans; Inflammasomes; Intestinal Diseases; Intestinal Mucosa; Ischemic Stroke; Kidney Neoplasms; Lignans; Lung; Macrophages; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Microglia; NAD(P)H Dehydrogenase (Quinone); Nanostructures; NF-E2-Related Factor 2; NF-kappa B; NLR Family, Pyrin Domain-Containing 3 Protein; Oxidative Stress; Phosphatidylinositol 3-Kinases; Phytotherapy; Plant Extracts; Pneumonia; PPAR gamma; Proto-Oncogene Proteins c-akt; Pyroptosis; Rats; Rats, Sprague-Dawley; Rats, Wistar; Reperfusion Injury; Respiratory Distress Syndrome; Sepsis; Sesamum; Signal Transduction; Silybin; Silybum marianum; Silymarin; Sirtuin 3; Titanium; Transfection; Treatment Outcome; White Matter

Previously, we have investigated the therapeutic mechanism of Qingzao Jiufei Decoction (QZJFD), a Chinese classic prescription, on acute lung injury (ALI), however, which remained to be further clarified together with the underlying efficacy related compounds for quality markers (Q-markers).. To explore Q-markers of QZJFD on ALI by integrating a stepwise multi-system with 'network pharmacology-metabolomics- pharmacokinetic (PK)/ pharmacodynamic (PD) modeling'.. First, based on in vitro and in vivo component analysis, a network pharmacology strategy was developed to identify active components and potential action mechanism of QZJFD on ALI. Next, studies of poly-pharmacology and non-targeted metabolomics were used to elaborate efficacy and verify network pharmacology results. Then, a comparative PK study on active components in network pharmacology was developed to profile their dynamic laws in vivo under ALI, suggesting Q-marker candidates. Next, quantified analytes with marked PK variations after modeling were fitted with characteristic endogenous metabolites along drug concentration-efficacy-time curve in a PK-PD modeling to verify and select primary effective compounds. Finally, Q-markers were further chosen based on representativeness among analytes through validity analysis of PK quantitation of primary effective compounds.. In virtue of 121 and 33 compounds identified in vitro and in vivo, respectively, 33 absorbed prototype compounds were selected to construct a ternary network of '20 components-47 targets-113 pathways' related to anti-ALI of QZJFD. Predicted mechanism (leukocytes infiltration, cytokines, endogenous metabolism) were successively verified by poly-pharmacology and metabolomics. Next, 18 measurable components were retained from 20 analytes by PK comparison under ALI. Then, 15 primary effective compounds from 18 PK markers were further selected by PK-PD analysis. Finally, 9 representative Q-markers from 15 primary effective compounds attributed to principal (chlorogenic acid), ministerial (methylophiopogonanone A, methylophiopogonanone B), adjuvant (sesamin, ursolic acid, amygdalin), conductant drugs (liquiritin apioside, liquiritigenin and isoliquiritin) in QZJFD, were recognized by substitutability and relevance of plasmatic concentration at various time points.. 9 Q-markers for QZJFD on ALI were identified by a stepwise integration strategy, moreover, which was a powerful tool for screening Q-makers involved with the therapeutic action of traditional Chinese medicine (TCM) prescription and promoting the process of TCM modernization and scientification.

Topics: Acute Lung Injury; Administration, Oral; Amygdalin; Animals; Biological Availability; Biomarkers, Pharmacological; Chalcone; Chlorogenic Acid; Dioxoles; Drugs, Chinese Herbal; Flavanones; Glucosides; Lignans; Male; Metabolomics; Rats, Wistar; Triterpenes; Ursolic Acid

To explore the effects of honokiol (HKL) on pulmonary microvascular endothelial cells in lipopolysaccharide (LPS)-induced acute respiratory distress syndrome (ARDS) and the underlying mechanisms.
 Methods: In animal experiment, a total of 40 C57BL/6J mice were randomly divided into a control group (Con group), a LPS intervention group (LPS group), a LPS+honokiol (HKL) intervention group (HKL group) and a LPS+HKL+nicotinamide (NAM) intervention group (NAM group) (n=10 in each group). In the cell experiment, the experiment cells were divided into a control group (Con group), a LPS intervention group (LPS group), a LPS+HKL intervention group (HKL group), a LPS+HKL+NAM intervention group (NAM group), and a LPS+HKL+compound C (CMC) intervention group (CMC group). The pathological changes of the lung tissues were evaluated by hematoxylin and eosin (HE) staining; the protein concentration, total cells and neutrophils in the bronchoalveolar lavage fluid (BALF) and myeloperoxidase (MPO) activity in the lung tissues were detected; the changes of pulmonary microvascular permeability were determined by Evans blue assay; the effect of HKL on the vitality of human pulmonary microvascular endothelial cells were examined by cell counting kit-8 (CCK-8); the inhibitors including NAM and CMC were applied to explore the molecular mechanism of the protective effects of HKL. The expression levels of Sirt3, caspase-3, cleaved caspase-3, Bcl-2, Bax, p-adenosine monophosphate activated protein kinase (p-AMPK) and AMPK in lung tissues or cells were detected by Western blot.
 Results: In animal models, compared with the Con group, the mice in the LPS group displayed typical ARDS pathological changes, and the ratio of lung wet/dry weight (W/D) and MPO activity in the lung tissues, protein concentration, total cells and neutrophils in BALF, Evans blue leaking index (ELI), expression levels of cleaved caspase-3 were significantly increased (all P<0.05), while the expression levels of Sirt3 was obviously decreased (P<0.05). Compared with the LPS group, the above changes in the LPS group were significantly improved in the HKL group (all P<0.05); Compared with the HKL group, the curative effect of HKL intervention could be partly inhibited in the NAM group (P<0.05). In cell experiments, compared with the LPS group, the HPMECs viability in the HKL group was markedly improved (P<0.05), while the expression levels of Bcl-2 and Sirt3 were significantly upregulated (P<0.05), and the expressio. 目的：探讨和厚朴酚(honokiol，HKL)对脂多糖(lipopolysaccharide，LPS)所致的急性呼吸窘迫综合征(acute respiratory distress syndrome，ARDS)肺微血管内皮细胞的作用及潜在机制。方法：动物实验中，40只C57BL/6J小鼠随机分为对照组(Con组)、LPS干预组(LPS组)、LPS+HKL干预组(HKL组)、LPS+HKL+尼克酰胺(nicotinamide，NAM)干预组(NAM组)，每组10只。细胞实验中，实验分为对照组(Con组)、LPS干预组(LPS组)、LPS+HKL干预组(HKL组)、LPS+HKL+NAM干预组(NAM组)和LPS+HKL+混合抑制剂(compound C，CMC)干预组(CMC组)。采用HE染色观察肺组织病理改变；检测支气管肺泡灌洗液(bronchoalveolar lavage fluid，BALF)中蛋白浓度、细胞总数、中性粒细胞数及肺组织髓过氧化物酶(myeloperoxidase，MPO)活性；伊文思蓝实验检测肺微血管渗透性的改变；采用细胞计数试剂盒(cell counting kit-8，CCK-8)检测HKL对人肺微血管内皮细胞(human pulmonary microvascular endothelial cells，HPMECs) 活力的影响；采用抑制剂NAM和CMC干预探讨HKL保护性作用的分子机制；采用Western印迹检测组织或细胞Sirt3，caspase-3，cleaved caspase-3，Bcl-2，Bax，p-腺苷酸活化蛋白激酶(p-adenosine monophosphate activated protein kinase，p-AMPK)和AMPK蛋白表达。结果：动物实验中，与Con组比较，LPS组小鼠肺组织呈典型的ARDS病理改变，肺组织湿干重比(W/D)值及MPO活性、BALF蛋白浓度、细胞总数和中性粒细胞数、伊文思蓝渗漏指数(evans blue leaking index，ELI)和肺组织cleaved caspase-3表达均显著升高(均P<0.05)，而Sirt3表达明显下调(P<0.05)；与LPS组比较，HKL组的上述改变显著改善(均P<0.05)；与HKL组比较，NAM组中HKL干预的疗效可部分抑制(均P<0.05)。细胞实验中，与LPS组比较，HKL组HPMECs的存活率升高(P<0.05)，Bcl-2和Sirt3蛋白表达显著上调(均P<0.05)， Bax和cleaved caspase-3蛋白表达下调(均P<0.05)，AMPK通路活化加强(P<0.05)；与HKL组比较，CMC组HKL干预的疗效被部分抑制(均P<0.05)。结论：HKL能够显著减轻LPS所致的ARDS，抑制肺微血管内皮凋亡，其作用可能是通过线粒体依赖的Sirt3/AMPK途径实现的。.

Topics: Acute Lung Injury; AMP-Activated Protein Kinases; Animals; Biphenyl Compounds; Humans; Lignans; Lipopolysaccharides; Lung; Mice; Mice, Inbred C57BL; Mitochondria; Signal Transduction; Sirtuin 3

Recent studies suggested that TLR4 signaling pathways played an important role in the development of LPS-induced acute lung injury (ALI). Sesamin, a sesame lignan exacted from sesame seeds, has been shown to exhibit significant anti-inflammatory activity. The purpose of this study was to investigate the anti-inflammatory effects of sesamin on LPS-induced ALI in mice. Mice ALI model was induced by intratracheal instillation of LPS. Sesamin was given 1 h after LPS challenge. Our results showed that sesamin inhibited LPS-induced lung pathological change, edema, and myeloperoxidase (MPO) activity. Sesamin suppressed LPS-induced inflammatory cytokines TNF-α, IL-6, and IL-1β production. Furthermore, sesamin inhibited LPS-induced TLR4 expression and NF-κB activation. In conclusion, the results of this study indicated that sesamin protected against LPS-induced ALI by inhibition of TLR4 signaling pathways.

Topics: Acute Lung Injury; Animals; Anti-Inflammatory Agents; Dioxoles; Edema; Enzyme Activation; Interleukin-1beta; Interleukin-6; Lignans; Lipopolysaccharides; Lung; Male; Mice; Mice, Inbred BALB C; NF-kappa B; Peroxidase; Signal Transduction; Toll-Like Receptor 4; Tumor Necrosis Factor-alpha

The aim of the present study was to assess the effects and mechanisms of Schisandrin B (SchB) on lipopolysaccharide (LPS)-induced acute lung injury (ALI). ALI was induced in mice by intratracheal instillation of LPS (1 mg/kg), and SchB (25, 50, and 75 mg/kg) was injected 1 h before LPS challenge by gavage. After 12 h, bronchoalveolar lavage fluid (BALF) samples and lung tissues were collected. Histological studies demonstrated that SchB attenuated LPS-induced interstitial edema, hemorrhage, and infiltration of neutrophils in the lung tissue. SchB pretreatment at doses of 25, 50, and 75 mg/kg was shown to reduce LPS-induced lung wet-to-dry weight ratio and lung myeloperoxidase activity. In addition, pretreatment with SchB lowered the number of inflammatory cells and pro-inflammatory cytokines including tumor necrosis factor-α, interleukin-1β, and interleukin-6 in BALF. The mRNA and protein expression levels of nuclear factor kappa B (NF-κB) signaling-related molecules activated by P2X7 were investigated to determine the molecular mechanism of SchB. The findings presented here suggest that the protective mechanism of SchB may be attributed partly to the decreased production of pro-inflammatory cytokines through the inhibition of P2X7/NF-κB activation.

Topics: Acute Lung Injury; Animals; Anti-Inflammatory Agents; Bronchoalveolar Lavage Fluid; Cyclooctanes; Cytokines; Disease Models, Animal; Dose-Response Relationship, Drug; Lignans; Lipopolysaccharides; Lung; Male; Mice, Inbred BALB C; NF-kappa B; Polycyclic Compounds; Receptors, Purinergic P2X7; Signal Transduction

Magnolol has shown inhibitory effects on NO production and TNF-alpha production in lipopolysaccharide (LPS)-activated macrophages and LPS-induced acute lung injury; however, the poor solubility of magnolol has hindered its clinical success. In this study, magnolol-loaded microparticles were prepared via single emulsion method from a polyketal polymer, termed PK3. The particle sizes of magnolol-loaded PK3 microparticle is 3.73 ± 0.41 μm, and was suitable for phagocytosis by macrophages and pulmonary drug delivery. PK3 microparticles exhibited excellent biocompatibility both in vitro and in vivo. More importantly, intratracheal delivery of these magnolol-loaded microparticles significantly reduced the lung inflammatory responses at low dosage of magnolol (0.5 mg/kg), and have great clinical potential in treating acute lung injury.

Topics: Acute Lung Injury; Animals; Biphenyl Compounds; Drug Delivery Systems; Lignans; Lipopolysaccharides; Male; Mice; Rats; Rats, Sprague-Dawley; RAW 264.7 Cells

Arctigenin (ATG) has been reported to possess anti-inflammatory properties. However, the effects of ATG on lipopolysaccharide (LPS)-induced acute lung injury (ALI) remains not well understood. In the present study, our investigation was designed to reveal the effect of ATG on LPS-induced ALI in rats. We found that ATG pretreatment attenuated the LPS-induced ALI, as evidenced by the reduced histological scores, myeloperoxidase activity, and wet-to-dry weight ratio in the lung tissues. This was accompanied by the decreased levels of tumor necrosis factor alpha (TNF-α), interleukin-1β (IL-1β), and interleukin-1 (IL-6) in the bronchoalveolar lavage fluid. Furthermore, ATG downregulated the expression of nuclear factor kappa B (NF-κB) p65, promoted the phosphorylation of inhibitor of nuclear factor-κB-α (IκBα) and activated the adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPKα) in the lung tissues. Our results suggested that ATG attenuates the LPS-induced ALI via activation of AMPK and suppression of NF-κB signaling pathway.

Topics: Acute Lung Injury; AMP-Activated Protein Kinases; Animals; Anti-Inflammatory Agents; Bronchoalveolar Lavage Fluid; Down-Regulation; Enzyme Activation; Furans; I-kappa B Proteins; Interleukin-1beta; Interleukin-6; Lignans; Lipopolysaccharides; Lung; Male; Neutrophil Infiltration; NF-KappaB Inhibitor alpha; Peroxidase; Phosphorylation; Random Allocation; Rats; Rats, Sprague-Dawley; Transcription Factor RelA; Tumor Necrosis Factor-alpha

Arctigenin, a bioactive component of Arctium lappa (Nubang), has anti-inflammatory activity. Here, we investigated the effects of arctigenin on lipopolysaccharide (LPS)-induced acute lung injury. Mice were divided into four groups: control, LPS, LPS + DMSO, and LPS + Arctigenin. Mice in the LPS + Arctigenin group were injected intraperitoneally with 50 mg/kg of arctigenin 1 h before an intratracheal administration of LPS (5 mg/kg). Lung tissues and bronchoalveolar lavage fluids (BALFs) were collected. Histological changes of the lung were analyzed by hematoxylin and eosin staining. Arctigenin decreased LPS-induced acute lung inflammation, infiltration of inflammatory cells into BALF, and production of pro-inflammatory cytokines. Moreover, arctigenin pretreatment reduced the malondialdehyde level and increased superoxide dismutase and catalase activities and glutathione peroxidase/glutathione disulfide ratio in the lung. Mechanically, arctigenin significantly reduced the production of nitric oxygen and inducible nitric oxygen synthase (iNOS) expression, enhanced the expression of heme oxygenase-1, and decreased the phosphorylation of mitogen-activated protein kinases (MAPKs). Arctigenin has anti-inflammatory and antioxidative effects on LPS-induced acute lung injury, which are associated with modulation of MAPK, HO-1, and iNOS signaling.

Topics: Acute Lung Injury; Animals; Disease Models, Animal; Furans; Heme Oxygenase-1; Lignans; Lipopolysaccharides; Male; MAP Kinase Signaling System; Membrane Proteins; Mice; Mice, Inbred C57BL; Nitric Oxide Synthase Type II; Oxidative Stress; Protective Agents

Acute lung injury (ALI) has a high morbidity and mortality rate due to the serious inflammation and edema occurred in lung. Magnolol extracted from Magnolia officinalis, has been reported to exhibit anti-inflammatory, and antioxidant activities. Peroxisome proliferator-activated receptors (PPARs) are known to exert a cytoprotective effect against cellular inflammatory stress and oxidative injury. The aim of this study was to explore the involvement of PPAR-γ in the beneficial effect of magnolol in lipopolysaccharide (LPS)-induced ALI. We found that treatment with magnolol greatly improved the pathological features of ALI evidenced by reduction of lung edema, polymorphonuclear neutrophil infiltration, ROS production, the levels of pro-inflammatory cytokines in bronchoalveolar lavage fluid (BALF), the expression of iNOS and COX-2, and NF-κB activation in lungs exposed to LPS. Importantly, magnolol is capable of increasing the PPAR-γ expression and activity in lungs of ALI. However, blocking PPAR-γ activity with GW9662 markedly abolished the protective and anti-inflammatory effects of magnolol. Taken together, the present study provides a novel mechanism accounting for the protective effect of magnolol in LPS-induced ALI is at least partly attributed to induction of PPAR-γ in lungs, and in turn suppressing NF-κB-related inflammatory responses.

Topics: Acute Lung Injury; Anilides; Animals; Anti-Inflammatory Agents, Non-Steroidal; Biphenyl Compounds; Bronchoalveolar Lavage Fluid; Cytokines; Lignans; Lipopolysaccharides; Male; Neutrophil Infiltration; NF-kappa B; Oxidative Stress; Peroxidase; PPAR gamma; Pulmonary Edema; Rats; Rats, Sprague-Dawley; Reactive Oxygen Species

In this study, we aimed to investigate our hypothesis starting that Schisantherin A (SchA), which exerts significant anti-inflammatory effects in vitro, could reduce the pulmonary inflammatory response in an acute lung injury (ALI) model. ALI was induced in mice by exposure to lipopolysaccharide (LPS, 20 mg/kg), and the inflammatory mediator production, neutrophil infiltration, and histopathological changes were evaluated. SchA at a dose of 100 mg/kg significantly improved survival rate of mice injected with LPS. The levels of TNF-α and IL-6 in bronchoalveolar lavage fluid (BALF) and the histopathological changes due to the injury were significantly inhibited when SchA was administered before or after LPS insult, and the infiltration of neutrophils and macrophages in lung tissues induced by LPS were suppressed by SchA. Additionally, pretreatment with SchA notably blocked the activation of nuclear factor-kappaB (NF-κB) and mitogen-activated protein kinases (MAPKs). Taken together, SchA showed obvious anti-inflammatory effects in an LPS-induced ALI model via blockage of the NF-κB and MAPK pathways. Thus, SchA may be an innovative therapy for inflammatory diseases.

Topics: Acute Lung Injury; Animals; Anti-Inflammatory Agents; Bronchoalveolar Lavage Fluid; Cell Movement; Cyclooctanes; Dioxoles; Disease Models, Animal; Dose-Response Relationship, Drug; Lignans; Lipopolysaccharides; Male; Malondialdehyde; Mice; Mice, Inbred BALB C; Neutrophil Infiltration; Neutrophils; Peroxidase; Pulmonary Edema; Signal Transduction; Superoxide Dismutase; Survival Analysis

Previous studies have shown that sauchinone modulates the expression of inflammatory mediators through mitogen-activated protein kinase (MAPK) pathways in various cell types. However, little information exists about the effect of sauchinone on neutrophils, which play a crucial role in inflammatory process such as acute lung injury (ALI). We found that sauchinone decreased the phosphorylation of p38 MAPK in lipopolysaccharide (LPS)-stimulated murine bone marrow neutrophils, but not ERK1/2 and JNK. Exposure of LPS-stimulated neutrophils to sauchinone or SB203580, a p38 inhibitor, diminished production of tumor necrosis factor (TNF)-α and macrophage inflammatory protein (MIP)-2 compared to neutrophils cultured with LPS. Treatment with sauchinone decreased the level of phosphorylated ribosomal protein S6 (rpS6) in LPS-stimulated neutrophils. Systemic administration of sauchinone to mice led to reduced levels of phosphorylation of p38 and rpS6 in mice lungs given LPS, decreased TNF-α and MIP-2 production in bronchoalveolar lavage fluid, and also diminished the severity of LPS-induced lung injury, as determined by reduced neutrophil accumulation in the lungs, wet/dry weight ratio, and histological analysis. These results suggest that sauchinone diminishes LPS-induced neutrophil activation and ALI.

Topics: Acute Lung Injury; Animals; Benzopyrans; Cell Movement; Cells, Cultured; Chemokine CXCL2; Cytokines; Dioxoles; Inflammation Mediators; Lignans; Lipopolysaccharides; Macrophages; Male; MAP Kinase Signaling System; Mice; Mice, Inbred BALB C; Neutrophils; p38 Mitogen-Activated Protein Kinases; Phosphorylation; Ribosomal Protein S6; Saururaceae; Tumor Necrosis Factor-alpha

Severe acute pancreatitis remains a life-threatening disease with a high mortality rate among a defined proportion of those affected. Apoptosis has been hypothesized to be a beneficial form of cell death in acute pancreatitis. Honokiol, a low-molecular-weight natural product, possesses the ability of anti-inflammation and apoptosis induction. Here, we investigate whether honokiol can ameliorate severe acute pancreatitis and the associated acute lung injury in a mouse model. Mice received six injections of cerulein at 1-h intervals, then given one intraperitoneal injection of bacterial lipopolysaccharide for the induction of severe acute pancreatitis. Moreover, mice were intraperitoneally given vehicle or honokiol 10 min after the first cerulein injection. Honokiol protected against the severity of acute pancreatitis in terms of increased serum amylase and lipase levels, pancreas pathological injury, and associated acute lung injury. Honokiol significantly reduced the increases in serum tumor necrosis factor-α, interleukin 1, and nitric oxide levels 3 h and serum high-mobility group box 1 24 h after acute pancreatitis induction. Honokiol also significantly decreased myeloperoxidase activities in the pancreas and the lungs. Endoplasmic reticulum stress-related molecules eIF2α (phosphorylated) and CHOP protein expressions, apoptosis, and caspase-3 activity were increased in the pancreas of mice with severe acute pancreatitis, which was unexpectedly enhanced by honokiol treatment. These results suggest that honokiol protects against acute pancreatitis and limits the spread of inflammatory damage to the lung in a severe acute pancreatitis mouse model. The acceleration of pancreatic cell apoptosis by honokiol may play a pivotal role.

Topics: Acinar Cells; Acute Disease; Acute Lung Injury; Amylases; Animals; Apoptosis; Biphenyl Compounds; Caspase 3; Disease Models, Animal; Endoplasmic Reticulum; Enzyme Inhibitors; HMGB1 Protein; Interleukin-1beta; Lignans; Lipase; Lung; Male; Mice; Mice, Inbred BALB C; Pancreas; Pancreatitis; Time Factors; Transcription Factor CHOP; Tumor Necrosis Factor-alpha

Magnolol, a hydroxylated biphenyl compound isolated from Magnolia officinalis has been reported to have anti-inflammatory properties. The purpose of this study was to evaluate the effect of magnolol on acute lung injury induced by lipopolysaccharide in mice. Male BALB/c mice were pretreated with dexamethasone or magnolol 1 h before intranasal instillation of lipopolysaccharide (LPS). 7 h after LPS administration, the myeloperoxidase in lung tissues, lung wet/dry weight ratio and inflammatory cells in the bronchoalveolar lavage fluid were determined. The levels of tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6) and interleukin-1β (IL-1β) in the bronchoalveolar lavage fluid were measured by enzyme-linked immunosorbent assay (ELISA). The extent of phosphorylation of nuclear factor of inhibitory kappa B alpha (IκB-α), nuclear factor kappa-B (NF-κB) p65 and the expression of Toll-like receptor-4 (TLR4) were detected by western blot. The results showed that magnolol markedly attenuated the histological alterations in the lung; reduced the number of total cells, neutrophils, and macrophages in the bronchoalveolar lavage fluid; decreased the wet/dry weight ratio of lungs in the bronchoalveolar lavage fluid; down-regulated the level of pro-inflammatory mediators, including TNF-α, IL-1β and IL-6; inhibited the phosphorylation of IκB-α, NF-κB p65 and the expression of TLR4, caused by LPS. Taken together, our results suggest that anti-inflammatory effects of magnolol against the LPS-induced acute lung injury may be due to its ability of inhibition TLR4 mediated NF-κB signaling pathways. Magnolol may be a promising potential therapeutic reagent for acute lung injury treatment.

Topics: Acute Lung Injury; Animals; Anti-Inflammatory Agents, Non-Steroidal; Biphenyl Compounds; Lignans; Lipopolysaccharides; Male; Mice; Mice, Inbred BALB C; NF-kappa B; Random Allocation; Signal Transduction; Toll-Like Receptor 4; Treatment Outcome

Magnolol, a tradition Chinese herb, displays an array of activities including antifungal, antibacterial, and antioxidant effects. To investigate the protective effect of magnolol on lipopolysaccharide (LPS)-induced acute lung injury (ALI) in mice. ALI was induced in mice by intratracheal instillation of LPS (1 mg/kg). The mice received intratracheal instillation of magnolol (5 μg/kg) 30 min before LPS administration. Pulmonary histological changes were evaluated by hematoxylin-eosin stain and lung wet/dry weight ratios were observed. Concentrations of tumor necrosis factor (TNF)-α and interleukin (IL)-1β, and myeloperoxidase (MPO) activity were measured by enzyme-linked immunosorbent assay. Expression of cyclooxygenase (COX)-2 in lung tissues was determined by Western blot analysis. Magnolol pretreatment significantly attenuated the severity of lung injury and inhibited the production of TNF-α and IL-1β in mice with ALI. After LPS administration, the lung wet/dry weight ratios, as an index of lung edema, and MPO activity were also markedly reduced by magnolol pretreatment. The expression of COX-2 was significantly suppressed by magnolol pretreatment. Magnolol potently protected against LPS-induced ALI and the protective effects of magnolol may attribute partly to the suppression of COX-2 expression.

Topics: Acute Lung Injury; Animals; Anti-Inflammatory Agents, Non-Steroidal; Biphenyl Compounds; Bronchoalveolar Lavage Fluid; Cyclooxygenase 2; Disease Models, Animal; Edema; Interleukin-1beta; Lignans; Lipopolysaccharides; Lung; Male; Mice; Mice, Inbred BALB C; Peroxidase; Respiratory Distress Syndrome; Tumor Necrosis Factor-alpha

Sepsis has a high mortality rate despite the recent advances in intensive care medicine and antibiotics. Honokiol, a low molecular weight natural product, is known to possess anti-inflammatory activity. Here, we investigate whether honokiol can ameliorate acute lung injury and lethal response in murine models of sepsis.. Mice were intraperitoneally given vehicle or honokiol 30 min after the induction of sepsis by cecal ligation and puncture (CLP) and endotoxemia by administration of E. coli lipopolysaccharide (LPS).. The productions of serum tumor necrosis factor-α (TNF-α), nitric oxide (NO), and high mobility group box 1 (HMGB 1) were increased in mice during sepsis, which could be reversed by honokiol. Honokiol could also effectively reduce the increased blood lipid peroxidation and nitrotyrosine in septic mice. Honokiol significantly reversed the inductions of inducible NO synthase and nuclear factor-κB (NF-κB) activation in the lungs of mice during sepsis. Honokiol also effectively rescued the lung edema, lung pathological changes, and lethality in septic mice.. These findings suggest that honokiol is capable of suppressing the lethal response and acute lung injury associated with sepsis, and support the potential use of honokiol as a therapeutic agent for the conditions associated with septic shock.

Topics: Acute Lung Injury; Animals; Anti-Infective Agents; Biphenyl Compounds; Endotoxemia; Inflammation; Lignans; Lipopolysaccharides; Male; Mice; Mice, Inbred ICR; Oxidative Stress; Sepsis