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 Plasma extracellular vesicle delivery of miR-210-3p by targeting ATG7 to promote sepsis-induced acute lung injury by regulating autophagy and activating inflammation

2021 ◽  
Author(s):  
Guang Li ◽  
Bo Wang ◽  
Xiangchao Ding ◽  
Xinghua Zhang ◽  
Jian Tang ◽  
...  
Keyword(s):  
Acute Lung Injury ◽  
Lung Injury ◽  
Recipient Cell ◽  
Cecal Ligation ◽  
Cell Permeability ◽  
Cell Counting ◽  
Inflammatory Factors ◽  
Luciferase Reporter ◽  
Enzyme Linked Immunosorbent Assay ◽  
Vascular Density

AbstractExtracellular vesicles (EVs) can be used for intercellular communication by facilitating the transfer of miRNAs from one cell to a recipient cell. MicroRNA (miR)-210-3p is released into the blood during sepsis, inducing cytokine production and promoting leukocyte migration. Thus, the current study aimed to elucidate the role of plasma EVs in delivering miR-210-3p in sepsis-induced acute lung injury (ALI). Plasma EVs were isolated from septic patients, after which the expression of various inflammatory factors was measured using enzyme-linked immunosorbent assay. Cell viability and apoptosis were measured via cell counting kit-8 and flow cytometry. Transendothelial resistance and fluorescein isothiocyanate fluorescence were used to measure endothelial cell permeability. Matrigel was used to examine the tubulogenesis of endothelial cells. The targeting relationship between miR-210-3p and ATG7 was assessed by dual-luciferase reporter assays. The expression of ATG7 and autophagy-related genes was determined to examine autophagic activation. A sepsis mouse model was established by cecal ligation and puncture (CLP)-induced surgery. The level of miR-210-3p was highly enriched in septic EVs. MiR-210-3p enhanced THP-1 macrophage inflammation, BEAS-2B cell apoptosis, and HLMVEC permeability while inhibiting angiogenesis and cellular activity. MiR-210-3p overexpression reduced ATG7 and LC3II/LC3I expression and increased P62 expression. Improvements in vascular density and autophagosome formation, increased ATG7 expression, and changes in the ratio of LC3II/LC3I were detected, as well as reduced P62 expression, in adenovirus-anti-miR-210-3p treated mice after CLP injury. Taken together, the key findings of the current study demonstrate that plasma EVs carrying miR-210-3p target ATG7 to regulate autophagy and inflammatory activation in a sepsis-induced ALI model.

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 miR-20a attenuates acute lung injury in septic rats via targeting TLR4

2021 ◽  
Keyword(s):  
Acute Lung Injury ◽  
Lung Injury ◽  
Inflammatory Response ◽  
Lung Tissue ◽  
Cecal Ligation ◽  
Normal Group ◽  
Lung Damage ◽  
Luciferase Reporter ◽  
Arterial Bleeding ◽  
Tnf Α

Background: Sepsis is most likely to cause lung damage in patients, and the detection rate and mortality rate are high. Here, we investigated the expression of miR-20a in sepsis-induced acute lung injury (ALI) rats and its effect on inflammatory response, and reveal its possible molecular mechanism. Method: The model of acute lung injury caused by sepsis in rats was established by cecal ligation and puncture. The expression of miR-20a in lung tissue was determined by RT-qPCR. Acute lung injury rats were injected with 5 nmol miR-20a agomir or agomir NC every day for 3 days. Rats were sacrificed by arterial bleeding and lung tissues were removed. Serum interleukin (IL) -1β, IL-6, and tumor necrosis factor alpha (TNF-α) were detected by ELISA. HE staining was used to observe the pathology of lung tissue and calculate the pathological score of lung injury. Western blot to determine the level of TLR4 and nuclear transcription factor κB p65 (NF-κB p65) protein in lung tissue. The luciferase reporter assay was used to verify the binding effect of miR-20a on the 3 non-coding TLR4. Results: We found that compared with that in Normal group, the expression of miR-20a in lung tissues of rats with ALI was decreased (p < 0.05). In miR-20a agomir group, the plasma level of IL-1β, IL-6, and TNF-α was significantly lower than that in agomir NC group and ALI group (p < 0.05), while higher than those in Normal group (p < 0.05). The HE staining results showed that the pathological score of lung injury in rats in miR-20a agomir group was lower than that of agomir NC group and ALI group (p < 0.05). Compared with agomir NC group and ALI group, the expression of TLR4 and NF-κB p65 in miR-20a agomir group was decreased (p < 0.01). The luciferase reporting experiment confirmed that TLR4 was a target gene of miR-20a. Conclusion: To sum up, miR-20a exerts a protective effect on sepsis-induced ALI rats through its anti-inflammatory effect. The targeting of TLR4 by miR-20a may be an effective method to reduce the inflammatory response in sepsis-induced ALI.

scholarly journals Isopropyl 3-(3, 4-Dihydroxyphenyl)-2-Hydroxypropanoate, A Novel Metabolite From Salvia Miltiorrhiza, Protects Against LPS-Induced Acute Lung Injury in Mice by Attenuating the Canonical and Non-Canonical Inflammatory Pathway of Pyroptosis

2021 ◽  
Author(s):  
Mei-Ling Zhang ◽  
Meng Wang ◽  
Jian Chen ◽  
Yan-Jie Liu ◽  
Xiao-Hui Zheng ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Acute Lung Injury ◽  
Survival Rate ◽  
Lung Injury ◽  
Lung Tissue ◽  
Salvia Miltiorrhiza ◽  
Total Protein Content ◽  
High Dose ◽  
Myeloperoxidase Activity ◽  
Lactate Dehydrogenase Activity

Abstract Background: The pathological characteristics of acute lung injury (ALI) or acute respiratory distress syndrome (ARDS) are pulmonary edema resulting from pulmonary permeability increasing. The main cause is uncontrolled inflammatory response leading to the damage of pulmonary vascular endothelial and alveolar epithelial barriers. However, there has not been effective drugs against ALI. In this study, we investigated the function of Isopropyl 3-(3, 4-dihydroxypheny l)-2-hydroxypropanoate (IDHP), a novel metabolite of Danshen dripping pill having anti-inflammatory effect, in lipopolysaccharide (LPS) induced ALI in mice, and its underlying mechanisms.Methods: Pretreatment of IDHP in LPS-induced acute lung injury in mice were observed on survival rate, pulmonary morphologic changes, total protein content in bronchoalveolar lavage fluid (BALF), and inflammatory cytokines in lung tissue and BALF. To further explore its mechanism on ALI, THP-1 macrophages was studied to analyse propotosis related proteins and co-culture with epithelial or endothelial cells to assess protection function of IDHP in vitro.Results: As revealed by survival study, pretreatment with high dose of IDHP reduced the mortality of mice from ALI. IDHP pretreatment significantly improved LPS-induced lung pathological changes, reduced protein leakage and lung myeloperoxidase activity. IDHP also inhibited the release of inflammatory mediators TNFα, IL-1β, IL-6 and IL-18 in BALF and lung tissue. Meanwhile, IDHP decreased the expression of active-caspase1 (in canonical pyroptosis pathway), caspase4/5 (non-canonical pyroptosis pathway), Nrlp3, mature IL-1β, mature IL-18, Asc speck formation, and cleaved Gsdmd, all these are required for pyroptosis, in LPS stimulated THP-1 macrophages. Moreover, IDHP also decreased ROS production in LPS-stimulated THP-1 macrophages, inhibited the expression of tight junction proteins (Occludin, Zo-1) in endothelial cells, and decreased lactate dehydrogenase activity in supernatants of epithelial or endothelial cells, co-cultured with LPS-stimulated THP-1 macrophages. Conclusions: Pretreatment of IDHP improves survival rate and ameliorates LPS-induced ALI in mice possibly via inhibiting canonical and non-canonical pyroptosis pathways.

scholarly journals Effect of penehyclidine hydrochloride on IL-6, TNF-α, HIF- 1α and oxidative stress in lung tissue of young rats with acute lung injury

2020 ◽  
Vol 19 (7) ◽  
pp. 1429-1433
Author(s):  
Jihong Shu ◽  
Zhenjiao Fang ◽  
Xinjun Xiong
Keyword(s):  
Oxidative Stress ◽  
Acute Lung Injury ◽  
Lung Injury ◽  
Lung Tissue ◽  
Enzyme Linked Immunosorbent Assay ◽  
High Dose ◽  
Model Group ◽  
Tnf Α ◽  
Penehyclidine Hydrochloride ◽  
And Oxidative Stress

Purpose: To investigate the effect of penehyclidine hydrochloride (PHC) on interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), hypoxia inducible factor-1α (HIF-1α), and oxidative stress levels in lung tissues of acute lung injury (ALI) neonatal rats.Methods: 40 male Sprague-Dawley (SD) rats were assigned to model, low-dose PHC, high-dose PHC, and control groups (n = 10). Levels of IL-6, TNF-α and HIF-1α were evaluated by enzyme-linked immunosorbent assay (ELISA). Pulmonary lesions were determined histologically using H&E staining.Results: The lung tissue levels of IL-6, TNF-α and HIF-1α were significantly higher in model rats than in control rats, and significantly lower in PHC-treated rats than in model group, with decrease in levels as PHC dose increased (p < 0.05). The lung tissue activity of MPO and level of MDA in model rats were significantly higher than those in control rats, but significantly lower in the lung tissues of the two PHC groups than in the model group; decrease in levels occurred as PHC dose increased (p < 0.05).Conclusion: PHC decreases the lung and serum levels of IL-6, TNF-α and HIF-1α in a rat model of ALI, and mitigates pulmonary oxidative stress and lung tissue damage. Thus, penehyclidine hydrochloride may be useful to mitigate ALI-induced damage in patients. However, further studies and clinical trials are required to ascertain this Keywords: Penehyclidine hydrochloride, Alveolar septum, Acute lung injury, Inflammatory cells, IL-6, TNF-α, HIF-1α, Oxidative stress

scholarly journals Mitochondrial Coenzyme Q Protects Sepsis-Induced Acute Lung Injury by Activating PI3K/Akt/GSK-3β/mTOR Pathway in Rats

2019 ◽  
Vol 2019 ◽  
pp. 1-9 ◽  
Author(s):  
Ruirui Li ◽  
Tao Ren ◽  
Jianqiong Zeng
Keyword(s):  
Acute Lung Injury ◽  
Survival Rate ◽  
Lung Injury ◽  
Lung Tissue ◽  
Coenzyme Q ◽  
Cecal Ligation ◽  
Dry Weight ◽  
Mtor Pathway ◽  
Alveolar Wall ◽  
Pi3k Inhibitor Ly294002

The aim of our study was to assess the effects of mitochondrial coenzyme Q (MitoQ) on sepsis-induced acute lung injury (ALI) and investigate its possible mechanisms. The cecal ligation and puncture (CLP) method was used to establish a septic ALI model. Rats were randomly divided into Con group, CLP group, MitoQ group, and MitoQ + LY294002 group. The survival rate of the rats was recorded, and the survival rate curve was plotted. Moreover, the ratio of wet/dry weight (W/D) in lung tissue was measured. The activity of myeloperoxidase (MPO) was measured by using the MPO colorimetric activity assay kit. The levels of high-mobility group box 1 (HMGB1) and interleukin-6 (IL-6), macrophage inflammatory protein 2 (MIP2), and keratinocyte chemoattractant (KC) were analyzed by ELISA. The histopathological changes were measured by HE staining, and the lung injury was scored. TUNEL assay was applied to detect the apoptotic cells in lung tissue. The protein expressions were detected by western blot. MitoQ increased the survival rate and alleviated pulmonary edema in septic ALI rats. In addition, MitoQ inhibited the MPO activity and decreased the levels of HMGB1 and IL-6. After treatment with MitoQ, alveolar wall edema, inflammatory cell infiltration, and red blood cell exudation were relieved. MitoQ inhibited cell apoptosis in lung tissue of septic ALI rats. Meanwhile, MitoQ treatment remarkedly increased the expression of p-Akt, p-GSK-3β, and p-mTOR but decreased Bax, caspase-3, caspase-9, Beclin-1, and LC-3II/LC-3I. The effects of MitoQ were significantly reversed by the PI3K inhibitor (LY294002). Our study demonstrated that MitoQ could protect sepsis-induced acute lung injury by activating the PI3K/Akt/GSK-3β/mTOR pathway in rats.

scholarly journals Melatonin Attenuates Sepsis-Induced Acute Lung Injury Through Improvement of Epithelial Sodium Channel-Mediated Alveolar Fluid Clearance Via Activation of SIRT1/SGK1/Nedd4-2 Signaling Pathway

2020 ◽  
Vol 11 ◽  
Author(s):  
Jing Li ◽  
Longfei Liu ◽  
Xiaojun Zhou ◽  
Xianzhou Lu ◽  
Xianrong Liu ◽  
...  
Keyword(s):  
Acute Lung Injury ◽  
Lung Injury ◽  
Sodium Channel ◽  
Signaling Pathway ◽  
Cecal Ligation ◽  
Weight Ratio ◽  
Epithelial Sodium Channel ◽  
Enzyme Linked Immunosorbent Assay ◽  
Alveolar Fluid Clearance ◽  
Protein Expressions

Acute lung injury is characterized by alveolar vascular barrier injury, and protein-rich pulmonary oedema. Alveolar fluid clearance is closely related to the prognosis of patients with acute lung injury. Melatonin has been shown to have a protective effect on multiple organ injury induced by sepsis. In this study we investigated the effect of melatonin on alveolar fluid clearance (AFC) and explored its potential mechanisms in sepsis-induced acute lung injury. The cecal ligation and puncture was adopted to establish mouse sepsis model. Morphological changes of lung tissues with the hematoxylin staining were observed. AFC and lung wet/dry weight ratio were measured to assess pulmonary edema. Inflammatory mediators in bronchoalveolar lavage fluid were analyzed via enzyme-linked immunosorbent assay. NAD+/NADH and SIRT1 activity were measured by colorimetric assay kit. The protein expressions of epithelial sodium channel (ENaC), silent information regulator1 (SIRT1), SGK1 and Nedd4-2 were immunoblotted by western blot in vivo and in vitro. The distribution of α-ENaC and SIRT1 was detected by immunofluorescence. We found that melatonin attenuated sepsis induced lung injury, improved survival rate, enhanced alveolar fluid clearance, improved SIRT1 activity, increased protein expressions of SIRT1 and ENaC, and activated SGK1/Nedd4-2 pathway. Furthermore, SIRT1 inhibitor EX527 counteracted the effects of melatonin on alveolar fluid clearance and ENaC. These results revealed that melatonin enhanced ENaC-mediated AFC via the SIRT1/SGK1/Nedd4-2 signaling pathway. Our study demonstrated that melatonin might provide a novel therapeutic strategy for sepsis-induced acute lung injury.

scholarly journals Dexmedetomidine mitigates lipopolysaccharide-induced acute lung injury in septic rats via inhibition of NF-κB associated anti-inflammatory pathway

2021 ◽  
Vol 19 (12) ◽  
pp. 2559-2563
Author(s):  
Hongcheng Zang ◽  
Gang Shao
Keyword(s):  
Acute Lung Injury ◽  
Lung Injury ◽  
Underlying Mechanism ◽  
Enzyme Linked Immunosorbent Assay ◽  
Sprague Dawley ◽  
Pulmonary Tissue ◽  
Treatment Groups ◽  
Protein Levels ◽  
Tnf Α ◽  
Tissue Homogenates

Purpose: To investigate the effect of dexmedetomidine in a rat model of acute lung injury (ALI), and the underlying mechanism. Methods: Acute lung injury (ALI) was induced in adult male Sprague Dawley rats (n = 27) using lipopolysaccharide (LPS). Three rat groups were used (9 rats/group): untreated control, LPS and treatment groups. Pathological lesions in rat pulmonary tissues were assessed and inflammatory scores determined. The levels TNF-α and IL-6 in BALF were determined using their respective enzyme-linked immunosorbent assay (ELISA) kits, while protein levels of p-IκB and NF-κB p65 were assessed by Western blotting. Results: Lung tissue damage was markedly mitigated in treatment mice, relative to LPS mice (p < 0.05). Inflammatory scores and population of neutrophils and macrophages increased significantly in LPS mice, relative to control, but decreased by dexmedetomidine exposure (p < 0.05). Similarly, TNF-α and IL-6 levels in pulmonary tissue homogenates of LPS rats were increased, relative to control rats, but were downregulated by dexmedetomidine exposure (p < 0.05). Moreover, dexmedetomidine downregulated the expressions of p-IκB and NF-κB p65 in pulmonary tissues (p < 0.05). Conclusion: Dexmedetomidine mitigates LPS-induced ALI in rats by blocking the activation of NF-κB and IκB, coupled with inhibition of the secretion of TNF-α and IL-6. Keywords: Acute lung injury, Dexmedetomidine, Inflammatory cytokines, NF-κB pathway, Sepsis

scholarly journals Euphorbia cuneata Represses LPS-Induced Acute Lung Injury in Mice via Its Antioxidative and Anti-Inflammatory Activities

Plants ◽  
2020 ◽  
Vol 9 (11) ◽  
pp. 1620
Author(s):  
Hossam M. Abdallah ◽  
Dina S. El-Agamy ◽  
Sabrin R. M. Ibrahim ◽  
Gamal A. Mohamed ◽  
Wael M. Elsaed ◽  
...  
Keyword(s):  
Acute Lung Injury ◽  
Lung Injury ◽  
Protective Effect ◽  
Lung Tissue ◽  
Histopathological Examination ◽  
Total Protein Content ◽  
Lps Challenge ◽  
Cell Counts ◽  
Anti Inflammatory ◽  
Inflammatory Effect

Euphorbia cuneata (EC; Euphorbiaceae), which widely grows in Saudi Arabia and Yemen, is used traditionally to treat pain and inflammation. This study aimed to evaluate the protective anti-inflammatory effect of a standardized extract of EC against lipopolysaccharide (LPS)-induced acute lung injury (ALI) in mice and the possible underlying mechanism(s) of this pharmacologic activity. ALI was induced in male Balb/c mice using intraperitoneal injection of LPS. A standardized total methanol extract of EC or dexamethasone was administered 5 days prior to LPS challenge. Bronchoalveolar fluid (BALF) and lung samples were collected for analysis. The results demonstrated the protective anti-inflammatory effect of EC against LPS-induced ALI in mice. Standardized EC contained 2R-naringenin-7-O-β-glucoside (1), kaempferol-7-O-β-glucoside (2), cuneatannin (3), quercetin (4), and 2R-naringenin (5) in concentrations of 6.16, 4.80, 51.05, 13.20, and 50.00 mg/g of extract, respectively. EC showed a protective effect against LPS-induced pulmonary damage. EC reduced lung wet/dry weight (W/D) ratio and total protein content in BALF, indicating attenuation of the pulmonary edema. Total and differential cell counts were decreased in EC-treated animals. Histopathological examination confirmed the protective effect of EC, as indicated by an amelioration of LPS-induced lesions in lung tissue. EC also showed a potent anti-oxidative property as it decreased lipid peroxidation and increased the antioxidants in lung tissue. Finally, the anti-inflammatory activity of EC was obvious through its ability to suppress the activation of nuclear factor-κB (NF-κB), and hence its reduction of the levels of downstream inflammatory mediators. In conclusion, these results demonstrate the protective effects of EC against LPS-induced lung injury in mice, which may be due to its antioxidative and anti-inflammatory activities.

scholarly journals Isopropyl 3-(3, 4-dihydroxyphenyl)-2-hydroxypropanoate, A Novel Metabolite From Salvia Miltiorrhiza, Protects Against LPS-induced Acute Lung Injury in Mice by Attenuating the Canonical and Non-canonical Inflammatory Pathways of Pyroptosis

2021 ◽  
Author(s):  
Mei-Ling Zhang ◽  
Meng Wang ◽  
Jian Chen ◽  
Yan-Jie Liu ◽  
Xiao-Hui Zheng ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Acute Lung Injury ◽  
Survival Rate ◽  
Lung Injury ◽  
Lung Tissue ◽  
Salvia Miltiorrhiza ◽  
Total Protein Content ◽  
High Dose ◽  
Myeloperoxidase Activity ◽  
Lactate Dehydrogenase Activity

Abstract BackgroundThe pathological characteristics of acute lung injury (ALI) or acute respiratory distress syndrome (ARDS) are pulmonary edema resulting from pulmonary permeability increasing. The main cause is uncontrolled inflammatory response leading to the damage of pulmonary vascular endothelial and alveolar epithelial barriers. However, there has not been effective drugs against ALI. In this study, we investigated the function of Isopropyl 3-(3, 4-dihydroxypheny l)-2-hydroxypropanoate (IDHP), a novel metabolite of Danshen dripping pill having anti-inflammatory effect, in lipopolysaccharide (LPS) induced ALI in mice, and its underlying mechanisms.MethodsPretreatment of IDHP in LPS-induced acute lung injury in mice were observed on survival rate, pulmonary morphologic changes, total protein content in bronchoalveolar lavage fluid (BALF), and inflammatory cytokines in lung tissue and BALF. To further explore its mechanism on ALI, THP-1 macrophages was studied to analyse pyroptosis related proteins and co-culture with epithelial or endothelial cells to assess protection function of IDHP in vitro.ResultsAs revealed by survival study, pretreatment with high dose of IDHP reduced the mortality of mice from ALI. IDHP pretreatment significantly improved LPS-induced lung pathological changes, reduced protein leakage and lung myeloperoxidase activity. IDHP also inhibited the release of inflammatory mediators TNFα, IL-1β, IL-6 and IL-18 in BALF and lung tissue. Meanwhile, IDHP decreased the expression of active-caspase1 (in canonical pyroptosis pathway), caspase4/5 (non-canonical pyroptosis pathway), Nrlp3, mature IL-1β, mature IL-18, Asc speck formation, and cleaved Gsdmd, all these are required for pyroptosis, in LPS stimulated THP-1 macrophages. Moreover, IDHP also decreased ROS production in LPS-stimulated THP-1 macrophages, inhibited the expression of tight junction proteins (Occludin, Zo-1) in endothelial cells, and decreased lactate dehydrogenase activity in supernatants of epithelial or endothelial cells, co-cultured with LPS-stimulated THP-1 macrophages. ConclusionsPretreatment of IDHP improves survival rate and ameliorates LPS-induced ALI in mice possibly via inhibiting canonical and non-canonical pyroptosis pathways.

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