Lipopolysaccharide-induced Acute Lung Injury Research Articles

CIRC_0033530 KNOCKDOWN ALLEVIATES LIPOPOLYSACCHARIDE-INDUCED ACUTE LUNG INJURY MODEL OF HUMAN LUNG FIBROBLASTS BY MIR-1184/TLR4 AXIS.

Background: Circular RNAs have been reported to be involved in regulating the progression of sepsis and sepsis-associated damage. Herein, this work investigated whether circ_0033530 had roles in the process of septic acute lung injury (sepsis-ALI) and its associated mechanism. Methods: Lipopolysaccharide (LPS)-stimulated human lung fibroblasts MRC-5 were used to mimic the cell model of sepsis-ALI in vitro . Levels of genes and proteins were detected by quantitative real-time polymerase chain reaction and Western blotting. Functional experiments were conducted using 5-ethynyl-2'-deoxyuridine assay, Cell Counting Kit-8 assay, flow cytometry, and enzyme-linked immunosorbent assay. The interaction between miR-1184 and circ_0033530 or toll-like receptor 4 (TLR4) was confirmed by dual-luciferase reporter and RNA immunoprecipitation assays. Results: Circ_0033530 expression was lower in sepsis patients and LPS-induced fibroblasts than those in healthy control and untreated cells. Functionally, knockdown of circ_0033530 protected fibroblasts against LPS-induced proliferation arrest, apoptosis, and inflammatory response. Mechanistically, circ_0033530 acted as a sponge for miR-1184, and TLR4 RNA was targeted by miR-1184, indicating the circ_0033530/miR-1184/TLR4 axis. Further rescue experiments showed that circ_0033530 silencing-mediated growth inhibition and inflammation on fibroblasts were attenuated by miR-1184 downregulation or TLR4 upregulation. Conclusion: Circ_0033530 knockdown alleviated LPS-induced proliferation arrest, apoptosis, and inflammation in lung fibroblasts by miR-1184/TLR4 axis, and provided molecular theoretical basis for circ_0033530 on the pathogenesis of sepsis-ALI.

The SMAC mimetic birinapant alleviates lipopolysaccharide-induced acute lung injury by inhibiting MAPK signaling

The second mitochondria-derived activator of caspases (SMAC) mimetic birinapant attenuated liver injury by inhibited the degradation of tumor necrosis factor receptor-associated factor 3 (TRAF3) and activation of mitogen-activated protein kinase (MAPK) signaling pathway in liver macrophage, but its role in LPS induced acute lung injury (ALI) is not understood. The present study was to investigate the effects of birinapant on ALI and its possible mechanism. A dose of birinapant (30 mg/kg) or a vehicle was administered intravenously 24 hours before LPS (100 μg) stimulation in mice. The levels of TNF-α, IL-6 and IL-1β in bronchoalveolar lavage fluid (BALF) were measured by ELISA. The infiltrated macrophages and expression of monocyte chemoattractant protein-1 (MCP-1) was determined by immunohistochemistry staining in the lung tissues. The JNK and p38 MAPK activation, protein expression and K48-linked polyubiquitination of TRAF3 were determined in alveolar macrophage cell line (MH-S cells) after 1μg/ml LPS stimulation. The results showed that the birinapant down-regulated the levels of TNF-α, IL-6 and IL-1β in the BALF. In addition, birinapant markedly inhibited macrophages infiltration and MCP-1 protein expression in lung tissues. At last, birinapant suppressed the MAPKsignaling pathway and K48-linked ubiquitinated degradation of TRAF3 in MH-S cells after LPS administration. In conclusion, the results proved that birinapant protected against LPS-induced ALI through inhibiting MAPK activation and K48-linked ubiquitination of TRAF3 in alveolar macrophages.

Diterpene Coronarin Attenuates Lipopolysaccharide-Induced Acute Lung Injury in Both In Vivo and In Vitro Models.

Acute lung injury (ALI) is a clinical condition occurs due to severe systemic inflammatory response for clinical stimulus like pneumonia, sepsis, trauma, aspiration, inhalation of toxic gases, and pancreatitis. Disruption of alveolar barriers, activation of macrophages, infiltration of neutrophils, and proinflammatory cytokines are the vital events occurs during ALI. The drugs which inhibit these inflammatory response can protect lungs from inflammatory insults. In this study, we examined the potency of phytochemical coronarin, a diterpene which have been proven to possess anti-inflammatory, antioxidant, antiangiogenic, and antitumor activities. Healthy BALB/c mice were induced to acute lung injury with intra-tracheal administration of LPS and then treated with 5 and 10 mg/kg concentration of coronarin. The wet/dry lung weight of mice were estimated to assess the induction of pulmonary edema. BALF fluid was analyzed for protein concentrations and immune cells count. Myeloperoxidase activity and levels of chemokines MCP-2 and MIP-2, iNOS, COX-2, and PGE-2 were quantified to assess the immunomodulatory effect of coronarin against LPS-induced ALI. The levels of proinflammatory cytokines was measured to examine the anti-inflammatory property of coronarin, and it was confirmed with histopathological analysis of the lung tissue. Murine RAW 264.7 cells were utilized for the in vitro analysis. Cell cytoxicity and cytoprotective property of coronarin was assessed with MTT assay in LPS-treated Murine RAW 264.7. The anti-inflammatory property of coronarin was further confirmed in in vitro condition by estimating the levels of pro-inflammatory cytokines in coronarin-treated and untreated LPS-induced cells. Overall, our in vivo and in vitro results confirm coronarin significantly inhibited the infiltration of neutrophils prevented immunodulatory activity and synthesis of proinflammatory cytokines and alleviated the acute lung injury induced by LPS. Coronarin is a potent anti-inflammatory drug which can be subjected to further research to be prescribed as drug for ALI.

Expression of Angiopoietin-2 in Lung Tissue of Juvenile SD Rats with Lipopolysaccharide-Induced Acute Lung Injury and the Role of Ulinastatin.

This study aimed to observe the expression of angiopoietin-2 (Ang-2) in the lung tissue of juvenile SD rats with lipopolysaccharide (LPS)-induced acute lung injury (ALI) and to clarify the role of ulinastatin (UTI). Ninety 18-21-day-old juvenile SD male rats were randomly divided into five groups (n = 18). ALI rat model was established by intraperitoneal injection of LPS (LPS 10mg/kg), while the control group was given the same dose of normal saline. The UTI intervention group was given the injection of UTI (5000 U/mL) immediately after the injection of LPS, which was divided into UTI low-dose group (LPS + 5ml/kg UTI), UTI medium-dose group (LPS + 10ml/kg UTI), and UTI high-dose group (LPS + 20ml/kg UTI).The respiratory status of each group of rats was observed, and six rats were randomly selected to be killed in each group at 6, 12, and 24h, and the lung tissues were dissected and retained. The pathological changes of the lung tissues were observed by hematoxylin-eosin (HE) staining, the expression levels and locations of Ang-2 and vascular endothelial growth factor (VEGF) in lung tissue were observed by immunohistochemical staining, and the expressions of genes and proteins of Ang-2 and VEGF were detected by quantitative reverse transcription polymerase chain reaction (RT-PCR) and Western blot analysis. Three hours after intraperitoneal injection, rats in the model group developed shortness of breath and the developed respiratory distress progressed over time. The lung pathological changes in the model group were obvious compared with those in the control group, and gradually worsened with time, and the pathological changes of lung in the rats in the UTI intervention group were reduced compared with those in the model group. At different time points, the expressions of Ang-2 and VEGF in the lung tissue of rats in the model group were higher than those in the control group, and were lower in the UTI intervention group than those in the model group. The expressions of Ang-2 and VEGF protein were lower in the low-dose group of UTI group than those in the high-dose group of UTI group at different time points (P < 0.05), and the expressions of Ang-2 and VEGF protein in the low-dose group of UTI were significantly lower than those in the medium-dose group at 12h and 24h (P < 0.05). The expression of Ang-2 was increased in the lung tissue of juvenile SD rats with LPS-induced ALI, and was associated with the degree of lung injury. UTI might attenuate LPS-induced ALI by inhibiting the expression of Ang-2 in lung tissue, and the low dose was more obvious than the medium and high dose.

R( R)Lipopolysaccharide-induced acute lung injury in experimental male albino rats.

R( R)Lipopolysaccharide-induced acute lung injury in experimental male albino rats.

Hypoxic bone marrow mesenchymal stem cell-derived exosomal lncRNA XIST attenuates lipopolysaccharide-induced acute lung injury via the miR-455-3p/Claudin-4 axis

Mesenchymal stem cell-derived exosomes and long non-coding RNAs (lncRNAs) have been identified to play a role in acute lung injury (ALI). In this study, we investigated whether exosomal lncRNAs could regulate ALI and the underlying mechanisms. Bone marrow mesenchymal stem cells (BM-MSCs) were pretreated with hypoxia or normoxia, and exosomes were subsequently extracted from normoxic BM-MSCs (Nor-exos) and hypoxic BM-MSCs (Hypo-exos). A rat model of ALI was established via an airway perfusion of lipopolysaccharide (LPS). Exosomes were administered via the tail vein to evaluate the in vivo effect of exosomes in ALI. LPS-exposed RLE-6TN cells were incubated with exosomes to explore their in vitro effect in ALI. A luciferase reporter assay was used to evaluate the interaction between lncRNA XIST and miR-455-3p, as well as miR-455-3p and Claudin-4. We found that the exosomes attenuated LPS-induced ALI and Hypo-Exos exerted a greater therapeutic effect compared with Nor-exos both in vitro and in vivo. Moreover, an abundance of lncRNA XIST was observed in Hypo-exos compared with Nor-exos. Mechanistically, LncRNA XIST functioned as a miR-455-3p sponge and targeted Claudin-4 in ALI. Our results provide novel insight into the role of exosomal lncRNA XIST for the treatment of ALI. Thus, hypoxic pretreatment may represent an effective method for improving the therapeutic effects of exosomes.

Fibroblast Growth Factor 21 Relieves Lipopolysaccharide-Induced Acute Lung Injury by Suppressing JAK2/STAT3 Signaling Pathway

Acute lung injury (ALI)/acute respiratory distress syndrome (ARDS) is a life‐threatening disease without an effective drug at present. Fibroblast growth factor 21 (FGF21) was reported to be protective against inflammation in metabolic disease in recent studies. However, the role of FGF21 in ALI has been rarely investigated. In this study, it was found that the expression of FGF21 was markedly increased in lung tissue under lipopolysaccharide (LPS) stimulation in vivo, whereas it was decreased in lung epithelial cells under LPS stimulation in vitro. Therefore, our research aimed to elucidate the potential role of FGF21 in LPS-induced ALI and to detect possible underlying mechanisms. The results revealed that the deficiency of FGF21 aggravated pathological damage, inflammatory infiltration, and pulmonary function in LPS-induced ALI, while exogenous administration of FGF21 improved these manifestations. Moreover, through RNA sequencing and enrichment analysis, it was unveiled that FGF21 might play a protective role in LPS-induced ALI via JAK2/STAT3 signaling pathway. The therapeutic effect of FGF21 was weakened after additional usage of JAK2 activator in vivo. Further investigation revealed that FGF21 significantly inhibited STAT3 phosphorylation and impaired the nuclear translocation of STAT3 in vitro. In addition, the aggravation of inflammation caused by silencing FGF21 can be alleviated by JAK2 inhibitor in vitro. Collectively, these findings unveil a potent protective effect of FGF21 against LPS-induced ALI by inhibiting the JAK2/STAT3 pathway, implying that FGF21 might be a novel and effective therapy for ALI.

Lactobacillus reuteri Ameliorates Lipopolysaccharide-Induced Acute Lung Injury by Modulating the Gut Microbiota in Mice.

Acute lung injury (ALI) causes lung inflammation and edema as well as resulting in gut microbiota disorder. Probiotics, however, can improve the gut microbiota composition and modulate its immune response, playing an important role in ALI pathogenesis. Therefore, our study aims to investigate the effect of Lactobacillus reuteri on Lipopolysaccharide (LPS)-induced ALI in mice and to probe the mechanism of its synergistic modulatory effect on the lungs and intestines. We assessed the therapeutic effects of L. reuteri in the ALI mouse model by histopathology, alveolar lavage fluid and serum inflammatory factor analysis and explored microbiome and transcriptome alterations. L. reuteri intervention effectively attenuated lung tissue injury and significantly reduced the LPS-induced inflammatory response and macrophage and neutrophil infiltration. Additionally, L. reuteri improved the intestinal barrier function and remodeled the disordered microbiota. In conclusion, our study showed that L. reuteri attenuated the inflammatory response, ameliorated the pulmonary edema, repaired the intestinal barrier, and remodeled the gut microbiota in ALI mice. This study provides new perspectives on the clinical treatment of ALI.

Genetically Engineered Cellular Nanovesicle as Targeted DNase I Delivery System for the Clearance of Neutrophil Extracellular Traps in Acute Lung Injury.

Acute lung injury (ALI)/acute respiratory distress syndrome (ARDS) are prevalent critical illnesses with a high mortality rate among patients in intensive care units. Neutrophil extracellular traps (NETs) are implicated in the pathogenesis of ALI/ARDS and represent a promising therapeutic target. However, the clinical application of deoxyribonuclease I (DNase I), the only drug currently available to clear NETs, is limited due to the lack of precise and efficient delivery strategies. Therefore, targeted delivery of DNase I to the inflamed lung remains a critical issue to be addressed. Herein, a novel biomimetic DNase I delivery system is developed (DCNV) that employs genetically and bioorthogonally engineered cellular nanovesicles for pulmonary NETs clearance. The CXC motif chemokine receptor 2 overexpressed cellular nanovesicles can mimic the inflammatory chemotaxis of neutrophils in ALI/ARDS, leading to enhanced lung accumulation. Furthermore, DNase I immobilized through bioorthogonal chemistry exhibits remarkable enzymatic activity in NETs degradation, thus restraining inflammation and safeguarding lung tissue in the lipopolysaccharide-induced ALI murine model. Collectively, the findings present a groundbreaking proof-of-concept in the utilization of biomimetic cellular nanovesicles to deliver DNase I for treating ALI/ARDS. This innovative strategy may usher in a new era in the development of pharmacological interventions for various inflammation-related diseases.

EGR-1 Contributes to Pulmonary Edema by Regulating the Epithelial Sodium Channel in Lipopolysaccharide-Induced Acute Lung Injury

ABSTRACT Acute lung injury (ALI) is a common lung disease with increasing morbidity and mortality rates due to the lack of specific drugs. Impaired alveolar fluid clearance (AFC) is a primary pathological feature of ALI. Epithelial sodium channel (ENaC) is a primary determinant in regulating the transport of Na+ and the clearance of alveolar edema fluid. Therefore, ENaC is an important target for the development of drugs for ALI therapy. However, the role of ENaC in the progression of ALI remains unclear. Inhibition of early growth response factor (EGR-1) expression has been reported to induce a protective effect on ALI; therefore, we evaluated whether EGR-1 participates in the progression of ALI by regulating ENaC-α in alveolar epithelium. We investigated the potential mechanism of EGR-1-mediated regulation of ENaC in ALI. We investigated whether EGR-1 aggravates the pulmonary edema response in ALI by regulating ENaC. ALI mouse models were established by intrabronchial injection of lipopolysaccharides (LPS). Lentiviruses with EGR-1 knockdown were transfected into LPS-stimulated A549 cells. We found that EGR-1 expression was upregulated in the lung tissues of ALI mice and in LPS-induced A549 cells, and was negatively correlated with ENaC-α expression. Knockdown of EGR-1 increased ENaC-α expression and relieved cellular edema in ALI. Moreover, EGR-1 regulated ENaC-α expression at the transcriptional level, and correspondingly promoted pulmonary edema and aggravated ALI symptoms. In conclusion, our study demonstrated that EGR-1 could promote pulmonary edema by downregulating ENaC-α at the transcriptional level in ALI. Our study provides a new potential therapeutic strategy for treatment of ALI.

A natural sesquiterpene lactone isolinderalactone attenuates lipopolysaccharide-induced inflammatory response and acute lung injury through inhibition of NF-κB pathway and activation Nrf2 pathway in macrophages

Isolinderalactone is the main sesquiterpene lactone isolated from Lindera aggregata, a traditional Chinese medicine widely used to treat pain and inflammation. Although isolinderalactone has been demonstrated to possess anti-cancer effect, its anti-inflammatory activity and underlying mechanism has not been well characterized. Herein, isolinderalactone was able to significantly inhibit the production of NO and PGE2 by reducing the expressions of iNOS and COX2 in LPS-stimulated RAW264.7 macrophages and BMDMs, and decreased the mRNA levels of IL-1β, IL-6, and TNF-α in LPS-induced RAW264.7 cells. In vivo, isolinderalactone effectively alleviated LPS-induced acute lung injury (ALI), which manifested as reduction in pulmonary inflammatory infiltration, myeloperoxidase activity, and production of PGE2, IL-1β, IL-6, TNF-α, and malondialdehyde. Furthermore, isolinderalactone inhibited phosphorylation of IKKα/β, phosphorylation and degradation of IκBα, and nuclear translocation of NF-κB p65, thereby blocking NF-κB pro-inflammatory pathway. Meanwhile, isolinderalactone reduced the intracellular ROS through promoting the activation of Nrf2-HMOX1 antioxidant axis. By using drug affinity responsive target stability assay and molecular docking, isolinderalactone was found to covalently interact with IKKα/β and Keap1, which may contribute to its anti-inflammatory action. Additionally, a thiol donor β-mercaptoethanol significantly abolished isolinderalactone-mediated anti-inflammatory action in vitro, indicating the crucial role of the unsaturated lactone of isolinderalactone on its anti-inflammatory effects. Taken together, isolinderalactone protected against LPS-induced ALI in mice, which may be associated with its inhibition of NF-κB pathway and activation of Nrf2 signaling in macrophages.

Qingjin Huatan decoction attenuates lipopolysaccharide-induced acute lung injury in mice by controlling platelet-associated formation of neutrophil extracellular traps

Abstract Background Acute lung injury (ALI) is a severe and life-threatening lung inflammation with high morbidity and mortality, underscoring the importance to develop effective drugs. Qingjin Huatan decoction (QJHTD), as a classic ancient prescription, has been widely used for treating respiratory diseases. However, the role and mechanism of QJHTD against ALI remain unclear. Objective This study aimed to explore the therapeutic effect of QJHTD on lipopolysaccharide (LPS)-induced ALI in mice and uncover its mechanism. Methods The therapeutic effect of QJHTD on LPS-induced ALI in mice was evaluated by the histopathological changes in the lung tissue, the lung wet/dry weight ratio, and the levels of inflammatory cytokines and thrombin-antithrombin complexes. Transcriptomics was used to predict the mechanism of QJHTD in treating ALI. The expression levels of citrullinated histone 3 in the lung tissue, the content of cell-free DNA in the bronchoalveolar lavage fluid (BALF), and the platelet-associated formation of neutrophil extracellular traps (NETs) in vitro were determined. Results Qingjin Huatan decoction exerted protective effect against LPS-induced ALI by suppressing interstitial edema, maintaining the alveolar-capillary barrier, inhibiting the infiltration of neutrophils and platelets in the lung tissue, and lowering the levels of tumor necrosis factor α, interleukin 1β, interleukin 6, and thrombin-antithrombin complexes in BALF. Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis indicated that the formation of NETs was the main regulatory pathway for QJHTD against ALI. Qingjin Huatan decoction could treat ALI by inhibiting the release of NETs via reducing the content of citrullinated histone 3 in lung tissue and cell-free DNA in BALF in vivo, and suppressing the NETs formation induced by LPS-stimulated platelets under flow and static conditions in vitro. The formation of NETs was considered to bridge the interactions between neutrophils and platelets. Conclusions This research demonstrated the effects of QJHTD in treating ALI and provided new insights for clarifying the complex regulation of neutrophils, platelets, and NETs in ALI.

Sivelestat sodium alleviated lipopolysaccharide-induced acute lung injury by improving endoplasmic reticulum stress

Acute lung injury (ALI) is a common inflammatory respiratory disorder characterized by a high incidence and mortality rate. This study aimed to investigate the potential therapeutic effects of the neutrophil elastase inhibitor Sivelestat sodium (SIV) in improving endoplasmic reticulum stress (ERS) while treating lipopolysaccharide (LPS)-induced ALI. An ALI model was established using LPS induction. The effects of SIV on ALI were observed both in vivo and in vitro, along with its impact on ERS. Lung tissue damage was assessed using Hematoxylin-eosin (H&E) staining. Lung edema was measured by the lung wet/dry weight ratio. The expression levels of protein kinase R-like ER kinase (PERK), Phospho-protein kinase R-like ER kinase (p-PERK), activating transcription factor 4 (ATF4), eukaryotic translation initiation factor 2α (EIF2a), phosphorylated α subunit of eukaryotic initiation factor 2α (P-EIF2a), and C/EBP homologous protein (CHOP) were analyzed by Western blotting in vivo and in vitro. The levels of tumor necrosis factor-alpha (TNF-α), interleukin-1β (IL-1β), and interleukin-6 (IL-6) in Lung tissue samples supernatants were measured by ELISA. Oxidative stress markers were measured by ELISA. Apoptosis was measured using the TUNEL assay. Apoptosis-associated proteins B-cell lymphoma-2 (Bcl-2)、Bcl2-associated × (Bax)、caspase-3 were evaluated through Western blotting in vivo and in vitro. The expression levels of ERS-related proteins, including p-PERK, ATF4, P-EIF2a, and CHOP, were significantly increased in the LPS-induced ALI model. However, SIV markedly reduced the expression levels of these proteins, suppressing the LPS-induced ERS response. Further investigations revealed that SIV exerted a protective effect on ALI by alleviating lung tissue damage and apoptosis, improving lung function, and reducing inflammation and oxidative stress levels. However, when SIV was co-administered with Tunicamycin (TUN), TUN blocked the beneficial effects of SIV on ERS and reversed the protective effects of SIV on ALI. In conclusion, SIV alleviated lung tissue damage and apoptosis, improving lung function, and reducing inflammation and oxidative stress in LPS-induced ALI by improving ERS.

The potential mechanism of Choulingdan mixture in improving acute lung injury based on HPLC-Q-TOF-MS, network pharmacology and in vivo experiments.

Choulingdan mixture (CLDM) is an empirical clinical prescription for the adjuvant treatment of acute lung injury (ALI). CLDM has been used for almost 30 years in the clinic. However, its mechanism for improving ALI still needs to be investigated. In this study, high-performance liquid chromatography-quadrupole/time-of-flight mass spectrometry (HPLC-Q-TOF-MS/MS) was applied to characterize the overall chemical composition of CLDM. A total of 93 ingredients were characterized, including 25 flavonoids, 20 organic acids, 11 saponins, nine terpenoids, seven tannins and 21 other compounds. Then network pharmacology was applied to predict the potential bioactive components, target genes and signaling pathways of CLDM in improving ALI. Additionally, molecular docking was performed to demonstrate the interaction between the active ingredients and the disease targets. Finally, animal experiments further confirmed that CLDM significantly inhibits pulmonary inflammation, pulmonary edema and oxidative stress in lipopolysaccharide-induced ALI mice by inhibiting the PI3K-AKT signaling pathway. This study enhanced the amount and accuracy of compounds of CLDM and provided new insights into CLDM preventing and treating ALI.

Ligustilide, a novel SIRT1 agonist, alleviates lipopolysaccharide-induced acute lung injury through deacetylation of NICD.

Development and progression of sepsis-induced acute lung injury (ALI) involve apoptosis and oxidative stress in lung epithelial cells. Ligustilide (LIG) is one of the main bioactive constituents derived from the Angelica sinensis. As a novel SIRT1 agonist, LIG owns powerful anti-inflammatory and antioxidative properties, exerting remarkable therapeutic effects on cancers, neurological disorders, and diabetes mellitus. However, whether LIG could protect against lipopolysaccharide (LPS)-induced ALI by activating SIRT1 remains unclear. Mice underwent intratracheal LPS injection to mimic sepsis-induced ALI while MLE-12 cells were treated with LPS for 6h to establish an in vitro ALI model. At the same time, mice or MLE-12 cells were treated with different doses of LIG to access its pharmacological effect. The results demonstrated that LIG pretreatment could improve LPS-induced pulmonary dysfunction and pathological injury, apart from increasing 7-day survival rate. In addition, LIG pretreatment also decreased inflammation, oxidative stress and apoptosis during LPS-induced ALI. Mechanically, LPS stimulation decreased the expression and activity of SIRT1 but increased the expression of Notch1 and NICD. And LIG could also enhance the interaction between SIRT1 and NICD, thus deacetylating NICD. In vitro experiments also unveiled that EX-527, a selective SIRT1 inhibitor, could abolish LIG-elicited protection in LPS-treated MLE-12 cells. And in SIRT1 knockout mice with ALI, LIG pretreatment also lost its effects on inflammation, apoptosis, and oxidative stress during ALI.

Penehyclidine hydrochloride protects against lipopolysaccharide-induced acute lung injury by promoting the PI3K/Akt pathway.

Acute lung injury (ALI) attracted attention among physicians because of its high mortality. We aimed to determine whether the phosphatidylinositol-3 kinase (PI3K)/protein kinase B (Akt) pathway is involved in the protective effects of penehyclidine hydrochloride (PHC) against lipopolysaccharide (LPS)-induced ALI. H&E staining was used to observed pathological changes in the lung tissues. ELISA was used to evaluate the concentration of inflammatory mediators in the bronchoalveolar lavage fluid (BALF). White-light microscopy was performed to observe the TUNEL-positive nuclei. The viability of NR8383 alveolar macrophages was determined by using CCK-8. The levels of MPO, MDA, SOD, and GSH-Px were analyzed using ELISA kits. Western blotting was used to evaluate the ERS-associated protein levels and the phosphorylation of PI3K and Akt. PHC administration defended against LPS-induced histopathological deterioration and increased pulmonary edema and lung injury scores, while all of these beneficial effects were inhibited by LY. In addition, PHC administration mitigated oxidative stress as indicated by decreases in lung myeloperoxidase (MPO) and malondialdehyde (MDA) concentrations, and increases in glutathione peroxidase (GSH-Px) and superoxide dismutase (SOD) concentrations. It also alleviated LPS-induced inflammation. PHC administration attenuated apoptosis-associated protein levels, improved cell viability, and decreased the number of TdT-mediated dUTP Nick-End Labeling (TUNEL)-positive cells. Furthermore, PHC inhibited ERS-associated protein levels. Meanwhile, the protection of PHC against inflammation, oxidative stress, apoptosis, and ERS was inhibited by LY. Moreover, PHC administration increased PI3K and Akt phosphorylation, indicating that the upregulation of the PI3K/Akt pathway, while this pathway was inhibited by LY. PHC significantly activates the PI3K/Akt pathway to ameliorate the extent of damage to pulmonary tissue, inflammation, oxidative stress, apoptosis, and ERS in LPS-induced ALI.

Insight into the lncRNA-mRNA Co-Expression Profile and ceRNA Network in Lipopolysaccharide-Induced Acute Lung Injury.

Long non-coding RNAs (lncRNAs) participate in acute lung injury (ALI). However, their latent biological function and molecular mechanism have not been fully understood. In the present study, the global expression profiles of lncRNAs and mRNAs between the control and lipopolysaccharide (LPS)-stimulated groups of human normal lung epithelial cells (BEAS-2B) were determined using high-throughput sequencing. Overall, a total of 433 lncRNAs and 183 mRNAs were differentially expressed. A lncRNA-mRNA co-expression network was established, and then the top 10 lncRNAs were screened using topological methods. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analysis results showed that the key lncRNAs targeting mRNAs were mostly enriched in the inflammatory-related biological processes. Gene set variation analysis and Pearson's correlation coefficients confirmed the close correlation for the top 10 lncRNAs with inflammatory responses. A protein-protein interaction network analysis was conducted based on the key lncRNAs targeting mRNAs, where IL-1β, IL-6, and CXCL8 were regarded as the hub genes. A competing endogenous RNA (ceRNA) modulatory network was created with five lncRNAs, thirteen microRNAs, and twelve mRNAs. Finally, real-time quantitative reverse transcription-polymerase chain reaction was employed to verify the expression levels of several key lncRNAs in BEAS-2B cells and human serum samples.

Goniothalamin prevents lipopolysaccharide-induced acute lung injury and inflammation via TLR-4/NF-κB signaling pathway.

Goniothalamin (GTN) is a natural compound isolated from Goniothalamus species. It is a potent anti-inflammatory agent. However, there is a paucity of scientific data about its toxicity. This study investigated GTN's anti-inflammatory mechanism and lipopolysaccharide (LPS)-induced lung injury in mice. Mice were distributed into four groups and injected with GTN intraperitoneally (Dosage-50 and 100 mg/kg). We analyzed the wet/dry weight ratio, infiltrated inflammatory cell count, myeloperoxidase (MPO) activity, and histopathological changes in the lung tissues of the mice. Results revealed GTN alleviated LPS-induced inflammation in mice. Western Blot and enzyme-linked immunosorbent assay techniques were used to investigate the effect of GTN on pro-inflammatory cytokines and proteins involved in the MAPK and nuclear factor-B (NF-κB) signaling pathways. Cytokines (macrophage migration inhibitory factor, interleukin [IL]-13, IL-6, TNF-α, and IL-1β) were inhibited by GTN. However, IL-10 was upregulated. Western blot analysis indicated that GTN suppressed the phosphorylation of jun N-terminal kinase, nuclear factor NF-kappa-B p65, I-kappa-B, extracellular signal-regulated kinases, NF-κB, and p38. GTN also suppressed the expression of TLR-4 protein, thereby, inhibiting MAPK and NF-κB signaling pathways. Thus, GTN can effectively prevent and cure acute lung injury.

Focus on the anti-inflammatory effect of glucocorticosteroids in experimental acute lung injury

AIM: Assessment of the effect of various doses of dexamethasone as an inflammation modulator in experimental lipopolysaccharide-induced acute lung injury in rats.&#x0D; MATERIALS AND METHODS: Acute lung injury in rats was modeled by intratracheal administration of cell wall lipopolysaccharide from the Salmonella enterica. White male rats were divided into groups: a group of intact animals (n = 10); the control group (n = 40), in which the animals were simulated acute lung injury without further treatment and removed from the experiment on day 3; three experimental groups (n = 40), in which, 3 hours after modeling acute lung injury, and then daily once a day for 3 days, dexamethasone solution was administered intraperitoneally in the following doses: in group 1 0.52 mg/kg (equivalent to 6.0 mg/day for a person), in group 2 1.71 mg/kg (20.0 mg/day for a person), in group 3 8.0 mg/kg (94.0 mg/day, pulse therapy for humans). On the 3rd day, blood samples were taken from the caudal vena cava in surviving animals for clinical analysis and evaluation of the function of mitochondria of peripheral blood leukocytes. To determine the severity of local inflammatory reactions and pulmonary edema, bronchoalveolar lavage was performed with the study of an endopulmonary cytogram and an assessment of pathomorphological changes in the lung tissue.&#x0D; RESULTS: indicate that dexamethasone reduces the amount of lung tissue damage and animal mortality, dose-dependently reduces the functions of mitochondria and the number of lymphocytes and monocytes in peripheral blood, as well as neutrophils, lymphocytes and macrophages in bronchoalveolar lavage samples.&#x0D; CONCLUSION: The use of dexamethasone at a dose of 0.52 mg/kg (equivalent to 6.0 mg/day for humans) is accompanied by better survival, minimal effect on the viability and functional activity of inflammatory cells. Pulse therapy leads to a significant decrease in the number of immunocompetent cells in bronchoalveolar lavage, mitochondrial dysfunction in the form of a decrease in the ability of these cells to use the reserve power of mitochondrial respiration in response to the action of a stress factor. Excessive inhibition of immunocompetent cells can contribute to the activation of latent and opportunistic infections, which must be taken into account when choosing a dosing regimen for glucocorticosteroids.

Human placenta-derived mesenchymal stem cell administration protects against acute lung injury in a mouse model.

This study aims to investigate the effect of placenta-derived mesenchymal stem cells (PMSCs) administration on tissue repair following acute lung injury (ALI). PMSCs were transplanted intravenously to a mouse model of lipopolysaccharide-induced ALI. The therapeutic effects were determined by evaluating several indicators, including pathology; the wet/dry ratio of the lungs; blood gas analysis; the total protein content, cell numbers, and the activity of myeloperoxidase (MPO) in bronchial alveolar lavage fluid (BALF); and the levels of anti-inflammatory and proinflammatory cytokines in serum and BALF. To investigate the underlying mechanism, PMSC-derived exosomes were used for ALI treatment. Administration of PMSCs improved the degree of lung injury, reduced inflammation, increased the expression levels of anti-inflammatory cytokines, and protected lung function. As expected, the effects of PMSC-derived exosomes in the ALI model were similar to those of PMSCs, both in terms of improved lung function and reduced inflammation. These findings suggest that PMSCs have ameliorating effects on ALI that are potentially mediated via their secreted exosomes.