YiQiFuMai Lyophilized Injection Attenuates Sepsis-Induced Acute Lung Injury via TLR4/Src/VE-cadherin/p120-catenin Signaling Pathway

2020 ◽  
Author(s):  
Xue-wei Pan ◽  
Li-xuan Xue ◽  
Qian-liu Zhou ◽  
Jia-zhi Zhang ◽  
Yu-jie Dai ◽  
...  
Keyword(s):  
Acute Lung Injury ◽  
Lung Injury ◽  
Signaling Pathway ◽  
Therapeutic Potential ◽  
Cecal Ligation ◽  
Inflammatory Cells ◽  
Underlying Mechanism ◽  
Lavage Fluid ◽  
Lung Edema ◽  
P120 Catenin

Abstract Background: Sepsis is a severe disorder leading to a clinically critical syndrome of multiple organ dysfunction syndrome. Most patients with sepsis will be associated with acute lung injury (ALI), which is an independent risk factors of organ failure and death in patients with sepsis at the same time. YiQiFuMai Lyophilized Injection (YQFM) is a modern traditional Chinese prescription preparation, which could ameliorate ALI induced by lipopolysaccharide (LPS) or fine particulate matter. The current study aimed to investigate the effect of YQFM on sepsis-induced ALI and the underlying mechanism.Methods: Male C57BL/6J mice were treated with cecal ligation and puncture (CLP) after tail intravenous injected with YQFM (1, 2 and 4 g/kg). The measurements of lung edema, evans blue leakage, myeloperoxidase content, inflammatory cells in bronchoalveolar lavage fluid, histopathological assay and expression of associated proteins were performed at 18 h after CLP.Results: The results illustrated that YQFM inhibited pulmonary edema and inflammatory response, thus ameliorated ALI in sepsis mice. Furthermore, the expression of TLR4 and phosphorylated Src was down-regulated, and the expression of p120-catenin and VE-cadherin was restored by YQFM administration.Conclusion: Our study suggested the therapeutic potential of YQFM on treating sepsis-induced ALI via regulating TLR4/Src/VE-cadherin/p120-catenin signaling pathway.

scholarly journals Anti-Inflammatory Effects of Monoammonium Glycyrrhizinate on Lipopolysaccharide-Induced Acute Lung Injury in Mice through Regulating Nuclear Factor-Kappa B Signaling Pathway

2015 ◽  
Vol 2015 ◽  
pp. 1-8 ◽  
Author(s):  
Xiaoying Huang ◽  
Jiangfeng Tang ◽  
Hui Cai ◽  
Yi Pan ◽  
Yicheng He ◽  
...  
Keyword(s):  
Acute Lung Injury ◽  
Lung Injury ◽  
Signaling Pathway ◽  
Interleukin 1 ◽  
Intratracheal Instillation ◽  
Weight Ratio ◽  
Dry Weight ◽  
Inflammatory Cells ◽  
Lavage Fluid ◽  
Therapeutic Mechanism

The present study aimed to investigate the therapeutic effect of monoammonium glycyrrhizinate (MAG) on lipopolysaccharide- (LPS-) induced acute lung injury (ALI) in mice and possible mechanism. Acute lung injury was induced in BALB/c mice by intratracheal instillation of LPS, and MAG was injected intraperitoneally 1 h prior to LPS administration. After ALI, the histopathology of lungs, lung wet/dry weight ratio, protein concentration, and inflammatory cells in the bronchoalveolar lavage fluid (BALF) were determined. The levels of tumor necrosis factor-α(TNF-α) and interleukin-1β(IL-1β) in the BALF were measured by ELISA. The activation of NF-κB p65 and IκB-αof lung homogenate was detected by Western blot. Pretreatment with MAG attenuated lung histopathological damage induced by LPS and decreased lung wet/dry weight ratio and the concentrations of protein in BALF. At the same time, MAG reduced the number of inflammatory cells in lung and inhibited the production of TNF-αand IL-1βin BALF. Furthermore, we demonstrated that MAG suppressed activation of NF-κB signaling pathway induced by LPS in lung. The results suggested that the therapeutic mechanism of MAG on ALI may be attributed to the inhibition of NF-κB signaling pathway. Monoammonium glycyrrhizinate may be a potential therapeutic reagent for ALI.

scholarly journals Intravenous Dexamethasone Attenuated Inflammation and Influenced Apoptosis of Lung Cells in an Experimental Model of Acute Lung Injury

2016 ◽  
pp. S663-S672 ◽  
Author(s):  
P. KOSUTOVA ◽  
P. MIKOLKA ◽  
S. BALENTOVA ◽  
M. ADAMKOV ◽  
M. KOLOMAZNIK ◽  
...  
Keyword(s):  
Acute Lung Injury ◽  
Lung Injury ◽  
Caspase 3 ◽  
Diffuse Alveolar Damage ◽  
Weight Ratio ◽  
Dry Weight ◽  
Inflammatory Cells ◽  
Lavage Fluid ◽  
Lung Edema ◽  
Edema Formation

Acute lung injury (ALI) is characterized by diffuse alveolar damage, inflammation, and transmigration and activation of inflammatory cells. This study evaluated if intravenous dexamethasone can influence lung inflammation and apoptosis in lavage-induced ALI. ALI was induced in rabbits by repetitive saline lung lavage (30 ml/kg, 9±3-times). Animals were divided into 3 groups: ALI without therapy (ALI), ALI treated with dexamethasone i.v. (0.5 mg/kg, Dexamed; ALI+DEX), and healthy non-ventilated controls (Control). After following 5 h of ventilation, ALI animals were overdosed by anesthetics. Total and differential counts of cells in bronchoalveolar lavage fluid (BAL) were estimated. Lung edema was expressed as wet/dry weight ratio. Concentrations of IL-1ß, IL-8, esRAGE, S1PR3 in the lung were analyzed by ELISA methods. In right lung, apoptotic cells were evaluated by TUNEL assay and caspase-3 immunohistochemically. Dexamethasone showed a trend to improve lung functions and histopathological changes, reduced leak of neutrophils (P<0.001) into the lung, decreased concentrations of pro-inflammatory IL-1β (P<0.05) and marker of lung injury esRAGE (P<0.05), lung edema formation (P<0.05), and lung apoptotic index (P<0.01), but increased immunoreactivity of caspase-3 in the lung (P<0.001). Considering the action of dexamethasone on respiratory parameters and lung injury, the results indicate potential of this therapy in ALI.

Inactivation of Nf-κb Pathway by Taxifolin Attenuates Sepsis-Induced Acute Lung Injury

2019 ◽  
Vol 18 (2) ◽  
pp. 176-182
Author(s):  
Chen Weiyan ◽  
Deng Wujian ◽  
Chen Songwei
Keyword(s):  
Acute Lung Injury ◽  
B Cells ◽  
Lung Injury ◽  
Signaling Pathway ◽  
Light Chain ◽  
Cecal Ligation ◽  
Nuclear Factor ◽  
Kappa Light Chain ◽  
Cecal Ligation And Puncture ◽  
Light Chain Enhancer

Acute lung injury is a clinical syndrome consisting of a wide range of acute hypoxemic respiratory failure disorders. Sepsis is a serious complication caused by an excessive immune response to pathogen-induced infections, which has become a major predisposing factor for acute lung injury. Taxifolin is a natural flavonoid that shows diverse therapeutic benefits in inflammation- and oxidative stress-related diseases. In this study, we investigated the role of taxifolin in a mouse model of cecal ligation and puncture-induced sepsis. Cecal ligation and puncture-operated mice presented damaged alveolar structures, thickened alveolar walls, edematous septa, and hemorrhage compared to sham-treated controls. Cecal ligation and puncture mice also showed increased wet-to-dry (W/D) lung weight ratio and elevated total protein concentration and lactate dehydrogenase level in bronchoalveolar lavage fluid. Taxifolin treatment protected animals against sepsis-induced pulmonary damage and edema. Septic mice presented compromised antioxidant capacity, whereas the administration of taxifolin prior to cecal ligation and puncture surgery decreased malondialdehyde concentration and enhanced the levels of reduced glutathione and superoxide dismutase in mice with sepsis-induced acute lung injury. Moreover, cecal ligation and puncture-operated mice showed markedly higher levels of proinflammatory cytokines relative to sham-operated group, while taxifolin treatment effectively mitigated sepsis-induced inflammation in mouse lungs. Further investigation revealed that taxifolin suppressed the activation of the nuclear factor kappa-light-chain-enhancer of activated B cells signaling pathway in cecal ligation and puncture-challenged mice by regulating the phosphorylation of p65 and IκBα. In conclusion, our study showed that taxifolin alleviated sepsis-induced acute lung injury via the inhibition of nuclear factor kappa-light-chain-enhancer of activated B cells signaling pathway, suggesting the therapeutic potential of taxifolin in the treatment sepsis-induced acute lung injury.

scholarly journals GLP-1 Analogue Liraglutide Enhances SP-A Expression in LPS-Induced Acute Lung Injury through the TTF-1 Signaling Pathway

2018 ◽  
Vol 2018 ◽  
pp. 1-14 ◽  
Author(s):  
Tao Zhu ◽  
Changyi Li ◽  
Xue Zhang ◽  
Chunyan Ye ◽  
Shuo Tang ◽  
...  
Keyword(s):  
Acute Lung Injury ◽  
Lung Injury ◽  
Signaling Pathway ◽  
Pulmonary Inflammation ◽  
Protein A ◽  
Insulin Level ◽  
Underlying Mechanism ◽  
Ultrastructural Changes

The reduction of pulmonary surfactant (PS) is essential for decreased pulmonary compliance and edema in acute lung injury (ALI). Thyroid transcription factor-1 (TTF-1) plays a major role in the regulation of surfactant protein-A (SP-A), the most abundant protein component of PS. Simultaneously, the glucagon-like peptide-1 (GLP-1) analogue can enhance SP-A expression in the lung. However, the underlying mechanism is still unknown. The purpose of this study was to explore whether liraglutide, a GLP-1 analogue, upregulates SP-A expression through the TTF-1 signaling pathway in ALI. In vivo, a murine model of ALI was induced by lipopolysaccharide (LPS). Pulmonary inflammation, edema, insulin level, ultrastructural changes in type II alveolar epithelial (ATII) cells, and SP-A and TTF-1 expression were analyzed. In vitro, rat ATII cells were obtained. SP-A and TTF-1 expression in cells was measured. ShRNA-TTF-1 transfection was performed to knock down TTF-1 expression. Our data showed that LPS-induced lung injury and increase in insulin level, and LPS-induced reduction of SP-A and TTF-1 expression in both the lung and cells, were significantly compromised by liraglutide. Furthermore, we also found that these effects of liraglutide were markedly blunted by shRNA-TTF-1. Taken together, our findings suggest that liraglutide enhances SP-A expression in ATII cells and attenuates pulmonary inflammation in LPS-induced ALI, most likely through the TTF-1 signaling pathway.

scholarly journals Aqueous extract of Aconitum carmichaelii Debeaux attenuates sepsis-induced acute lung injury via regulation of TLR4/NF-ΚB pathway

2020 ◽  
Vol 19 (3) ◽  
pp. 533-539
Author(s):  
Qinghai You ◽  
Jinmei Wang ◽  
Lijuan Jiang ◽  
Yuanmin Chang ◽  
Wenmei Li
Keyword(s):  
Acute Lung Injury ◽  
Lung Injury ◽  
Protein Content ◽  
Aqueous Extract ◽  
Lung Tissue ◽  
Cecal Ligation ◽  
Underlying Mechanism ◽  
Enzyme Linked Immunosorbent Assay ◽  
Total Protein Content ◽  
Aconitum Carmichaelii

Purpose: To investigate the therapeutic effect of aqueous extract of Aconitum carmichaelii Debeaux (AEACD) on sepsis-induced acute lung injury (ALI), as well as explore the underlying mechanism of action. Methods: C57BL/6 mice were treated with AEACD by gavage (4.0 g/kg/day) for 5 days before cecal ligation and puncture (CLP) challenge. After 24 h, the pathological morphology of lung tissue and the biochemical parameters in bronchoalveolar lavage fluid (BALF) were determined by H&E staining and enzyme-linked immunosorbent assay (ELISA). Furthermore, the total protein content and lactate dehydrogenase (LDH) level of BALF, as well as the oxidative biomarkers (malondialdehyde (MDA), glutathione (GSH), superoxide dismutase (SOD)) were evaluated in the lung homogenates by ELISA assay. The levels of pro-inflammatory cytokines, TNFα, IL-1β, and IL-6, in lung tissue were measured by qRT-PCR or ELISA. Finally, key proteins in Toll-like receptor 4 (TLR4)/nuclear factor-κB (NF-κB) pathway in lung tissue were evaluated by western blot. Results: CLP challenge induced abnormal changes in the histological structures of lung tissue, lung wet-to-dry weight (W/D) ratio, protein content and LDH levels of BALF, which were remarkably reversed by AEACD. In addition, AEACD decreased MDA levels, and increased GSH levels and SOD activity in the lung tissue of CLP–treated mice (p < 0.05). Furthermore, AEACD attenuated the CLP challengeinduced upregulation of TNFα, IL-1β, and IL-6. Finally, AEACD inactivated TLR4/NF-κB pathway by upregulating IκBα and downregulating TLR4 and phosphorylated-p65 levels. Conclusion: AEACD administration protects mice against sepsis-induced ALI through the regulation of oxidative stress and inflammatory responses in lung tissues. The underlying mechanism occurs by inhibiting TLR4/NF-κB signaling pathway. Keywords: Aconitum carmichaelii Debeaux, Acute lung injury, Sepsis, TLR4, NF-κB

scholarly journals Angelica Polysaccharide Ameliorates Sepsis-Induced Acute Lung Injury through Inhibiting NLRP3 and NF-κB Signaling Pathways in Mice

2021 ◽  
Vol 2021 ◽  
pp. 1-9
Author(s):  
Yan Zhu ◽  
Taocheng Meng ◽  
Aichen Sun ◽  
Jintao Li ◽  
Jinlai Li
Keyword(s):  
Acute Lung Injury ◽  
Lung Injury ◽  
Signaling Pathways ◽  
Cecal Ligation ◽  
Weight Ratio ◽  
Receptor Protein ◽  
Lung Edema ◽  
Caspase 1 ◽  
Tnf Α

Objective. This study aimed to explore the role of angelica polysaccharide (AP) in sepsis-induced acute lung injury (ALI) and its underlying molecular mechanism. Methods. A sepsis model of cecal ligation and puncture (CLP) in male BALB/C mice was used. Then, 24 h after CLP, histopathological changes in lung tissue, lung wet/dry weight ratio, and inflammatory cell infiltration were analyzed. Next, levels of inflammatory cytokines (tumor necrosis factor-α (TNF-α), interleukin (IL)-1β, IL-6, and IL-18), as well as the activity of myeloperoxidase (MPO), malondialdehyde (MDA), superoxide dismutase (SOD), and glutathione (GSH), were measured to assess the role of AP. The protein expression of NF-κB p65, p-NF-κB p65, IκBα, p-IκBα, nucleotide-binding domain- (NOD-) like receptor protein 3 (NLRP3), ASC, and caspase-1 was detected by western blot. In addition, the expression of p-NF-κB p65 and NLRP3 was detected by immunohistochemistry. Results. AP treatment ameliorated CLP-induced lung injury and lung edema, as well as decreased the number of total cells, neutrophils, and macrophages in bronchoalveolar lavage fluid (BALF). AP reduced the levels of TNF-α, IL-1β, IL-6, and IL-18 in BALF, as well as in serum. Moreover, AP decreased MPO activity and MDA content, whereas increased SOD and GSH levels. AP inhibited the expression of p-NF-κB p65, p-IκBα, NLRP3, ASC, and caspase-1, while promoted IκBα expression. Conclusion. This study demonstrated that AP exhibits protective effects against sepsis-induced ALI by inhibiting NLRP3 and NF-κB signaling pathways in mice.

Endostatin Inhibits VEGF-Induced Lung Edema by Reducing Vascular Permeability.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 2614-2614
Author(s):  
Gunter Schuch ◽  
Suleyman Erguen ◽  
Shay Soker ◽  
Dieter K. Hossfeld ◽  
Walter Fiedler
Keyword(s):  
Endothelial Cells ◽  
Acute Lung Injury ◽  
Lung Injury ◽  
Vascular Permeability ◽  
Pulmonary Hemorrhage ◽  
Inflammatory Cells ◽  
Endothelial Cell Proliferation ◽  
Lung Edema ◽  
Vegf Receptor

Abstract INTRODUCTION: Acute lung injury is a severe condition developing in patients with acute sepsis characterized by lung edema with extravasation of plasma proteins, infiltration by inflammatory cells and pulmonary hemorrhage. Vascular endothelial growth factor (VEGF), also known as vascular permeability factor, is known to not only promote angiogenesis but also increase vascular permeability and has been linked to pathological conditions like retinopathy and acute lung injury. Patients with sepsis and acute lung injury have increased VEGF levels in their plasma. As shown recently, mice treated with VEGF develop histological changes comparable to acute lung injury in septic patients. Endostatin (ES), a endogenous inhibitor of angiogenesis, has been shown to inhibit tumor growth in various models. The mechanisms by which ES inhibits endothelial cell proliferation and function are not clear, yet. It was proposed that one mechanism is the inhibition of VEGF-induced activation of VEGF receptor 2 (VEGFR-2). This study was performed in order to examine whether ES may antagonize VEGF-induced effects leading to increased permeability and lung injury. METHODS: We established an in vitro permeability model using transwell chambers with human dermal microvascular endothelial cells (HDMEC) seeded in the upper chamber on a porous membrane. VEGF-induced permeability was determined by measuring methylene blue to the lower chamber. In order to test the effect of ES on VEGFR-2 activation porcine aortic endothelial cells expressing human VEGFR-2 were incubated with 50 ng/ml VEGF with or without 5 ug/ml ES for 30 min ice. Cell lysate was precipitated with conacavalin A, separated by SDS-PAGE, blotted and analyzed for KDR phosphorylation using phosphotyrosine specific and KDR antibodies. We generated cells with strong expresssion of either VEGF or mouse ES. The cells were encapsulated in alginate beads and injected s.c. to SCID mice divided in the following groups: A) control, B) VEGF, C) ES, D) VEGF + ES with 5 animals per group. After 5 days lungs were harvested and analyzed by H&E staining of tissue sections. RESULTS: In an in vitro permeability assay VEGF enhanced permeation of dye through a monolayer of endothelial cells. ES significantly inhibited VEGF induced permeability (fig.1). ES alone had no effect compared to controls. On the molecular level VEGF causes phosphorylation of its receptor VEGFR-2 as seen in VEGFR-2 expressing cells (fig.2). This effect was abolished by coincubation with ES showing a direct antagonism of VEGF signalling by ES. In a SCID mouse model animals were treated with VEGF, ES or the combination of both (fig.3). Animals in the VEGF group developed general edema and lung injury resembling acute lung injury with extravasation, accumulation of inflammatory cells and hemorrhage. The animals treated with a combination of VEGF and ES had less generalized edema. The lung sections showed alterations less pronounced than in the VEGF group. ES alone had no effect. CONCLUSIONS: Our results demonstrate that ES inhibits VEGF-induced permeability by blocking VEGFR-2 activation. ES treatment partially restored VEGF-induced lung injury in vivo. The incomplete inhibition may be due to excess VEGF protein levels. Taken together, VEGF blocking with ES may serve as a useful new treatment option for conditions with increased vascular permeability like acute lung injury.

scholarly journals The Activation of Macrophage and Upregulation of CD40 Costimulatory Molecule in Lipopolysaccharide-Induced Acute Lung Injury

2008 ◽  
Vol 2008 ◽  
pp. 1-6 ◽  
Author(s):  
Liang Dong ◽  
Shujuan Wang ◽  
Ming Chen ◽  
Hongjia Li ◽  
Wenxiang Bi
Keyword(s):  
Acute Lung Injury ◽  
Lung Injury ◽  
Costimulatory Molecule ◽  
Inflammatory Cells ◽  
Lavage Fluid ◽  
Vital Role ◽  
Control Group ◽  
Toll Like Receptor 4 ◽  
Activated Macrophage ◽  
Lps Treatment

To study the activation of macrophage and upregulation of costimulatory molecule of CD40 in lipopolysaccharide- (LPS-) induced acute lung injury (ALI) model, and to investigate the pathogenecy of ALI, mice were randomly divided into two groups. ALI model was created by injecting 0.2 mg/kg LPS in phosphate saline (PBS) in trachea. The pathologic changes of mice lungs were observed by HE staining at 24 and 48 hours after LPS treatment, then the alveolar septum damage, abnormal contraction, alveolar space hyperemia, and neutrophils or other inflammatory cells infiltration in the LPS group, but not in the control group, were observed. The expression of CD40 mRNA and CD40 protein molecules were higher in LPS group as compared to the control group by Northern blot and flow cytometry, respectively. Expression of Toll-like receptor-4 (TLR4) in activated macrophage (AM) was higher in LPS group as compared to the control group by RT-PCR. The activation of NF-B binding to NF-B consensus oligos increased in LPS group by EMSA in macrophage. The concentrations of TNF-, MIP-2, and IL-1 cytokines from bronchoalveolar lavage fluid (BALF) were increased significantly in LPS group as compared to the control group by ELISA. The activation of AM and upregulation of costimulatory molecule CD40 induced all kinds of inflammatory cytokines releasing, then led to ALI. Therefore, both of them played vital role in the process of development of ALI.

scholarly journals Inhibition of Lipopolysaccharide E. coli-induced acute lung injury by extracted Antidesma bunius (L.) Spreng fruits as compared to Fluticasone Propionate, a corticosteroid

2021 ◽  
Author(s):  
Maria Nilda Muñoz ◽  
Jennifer Lucero ◽  
Kimberly Stacy Hope Benzon ◽  
Jerica Isabel L. Reyes ◽  
Charina de Silva ◽  
...  
Keyword(s):  
Acute Lung Injury ◽  
Fluticasone Propionate ◽  
Lung Injury ◽  
Murine Model ◽  
Lavage Fluid ◽  
Vehicle Control ◽  
Control Group ◽  
Lung Edema ◽  
Blue Dye ◽  
E Coli

The hallmark of Acute Lung Injury/Acute Respiratory Distress Syndrome (ALI/ARDS) is inflammation-induced alveolar-vascular barrier destruction and neutrophilic infiltration that leads to the formation of cytokines and oxygen radicals. The objective of the study is to investigate the protective and toxicological effects of Antidesma bunius (L.) Spreng [Bignay] in murine model of Lipopolysaccharide E. coli (LPS)-induced ALI and compared with Fluticasone Propionate (FP), a synthetic corticosteroid. We showed that extracted Bignay fruits have high amount of phenols, steroids and flavonoids but insignificant amount of heavy metals and aflatoxins. BALB/c mice of either sex were divided into 4 groups in the ALI mouse model; Group 1: vehicle control; Group 2: LPS alone; Group 3: Bignay + LPS; and Group 4: FP + LPS. Bignay and FP were administered via intraperitoneal injection while LPS was given intra-tracheally. Biomarkers of ALI such as total lung inflammatory cell count, total lung protein content, lung edema and interleukin-6  (IL-6) secretion were measured 24 hrs after vehicle control or LPS treatment. Compared to vehicle controls, LPS caused significant increased in all measured biomarkers of ALI in samples collected from bronchoalveolar lavage fluid and were significantly attenuated by Bignay fruit extract or FP. Pulmonary vascular leakage caused by LPS was also evaluated after injection with Evans blue dye, an indication of lung injury. Extracted Bignay fruits or FP when given to mice 2 hrs after LPS administration substantially decreased the pulmonary vascular leak. Our findings are the first evidence demonstrating the preventive and non-toxic effects of extracted Bignay fruits in a murine model of LPS-induced ALI. The results could be attributed to the presence of active secondary metabolites such as flavonoids, phenols and steroids. It is also evident that extracted Bignay fruits are as effective as FP, well-established steroid, in blocking the biomarkers of ALI caused by LPS.

scholarly journals Milonine Protects Against Acute Lung Injury By Modulating The Akt And NF-κB Signaling Pathway

2021 ◽  
Author(s):  
Larissa Rodrigues Bernardo ◽  
Laércia Karla Diega Paiva Ferreira ◽  
Larissa Adilis Maria Paiva Ferreira ◽  
Cosmo Isaías Duvirgens Vieira ◽  
João Batista de Oliveira ◽  
...  
Keyword(s):  
Acute Lung Injury ◽  
Lung Injury ◽  
Hydrophobic Interactions ◽  
Neutrophil Infiltration ◽  
Lavage Fluid ◽  
Lung Edema ◽  
Toll Like Receptor 4 ◽  
Downstream Signaling ◽  
Tnf Α ◽  
Anti Inflammatory

Abstract Acute lung injury (ALI) is an inflammation that triggers acute respiratory distress syndrome (ARDS) with perialveolar neutrophil infiltration, alveolar-capillary barrier damage, and lung edema. Activation of the toll-like receptor 4 complex and its downstream signaling pathways are responsible for the cytokine storm and cause alveolar damage on ARDS. Due to the complexity of inflammatory events on ALI, a defined pharmacotherapy has not been established. Thus, this study aimed to evaluate the anti-inflammatory potential of milonine, an alkaloid of Cissampelos sympodialis Eichl, in an ALI experimental model. BALB/c mice were lipopolysaccharide (LPS)-challenged and treated with milonine at 2.0 mg/kg. Twenty-four hours later, the bronchoalveolar lavage fluid (BALF), peripheral blood, and lungs were collected for cellular and molecular analysis. The milonine treatment decreased the inflammatory cell migration (principally neutrophils) to the alveolar cavity, the protein exudate, the pulmonary edema, and the level of pro-inflammatory cytokines (IL-1β, IL-6, TNF-α) into the BALF. The systemic level of IL-6 level was also reduced. In the lung tissue, milonine reduced the bronchoalveolar damage. The milonine docking analyzes demonstrated that the molecule formed hydrophobic interactions with the amino-acids Ile124 and Phe126 of the TLR4/MD2 groove. Indeed, the anti-inflammatory effect of milonine was due to the negative regulation of cytoplasmic kinase-Akt and NF-κB by interacting with the TLR4/MD2 complex. Therefore, milonine is an effective inflammatory modulator by blocking the interaction of the LPS-TLR4/MD2 complex and downregulating the intracellular inflammatory pathway axis being a potential molecule for the treatment of ALI.

Sign in / Sign up

Export Citation Format

Share Document