Inflammation In Acute Lung Injury Research Articles

Investigation of the Molecular Mechanism Underlying the Therapeutic Effect of Perilla frutescens L. Essential Oil on Acute Lung Injury Using Gas Chromatography Mass Spectrometry and Network Pharmacology.

The present study aimed to investigate the molecular mechanism through which Perilla essential oil treats acute lung injury (ALI) through network pharmacology, molecular docking, and in vitro assays. Relevant ALI targets of the active ingredients of Perilla essential oil were predicted using the SwissTargetPrediction database and meta TarFisher database. These ALI targets were then screened using GeneCards and DisGeNET, and differentially expressed ALI target genes were identified using the Gene Expression Omnibus (GEO) database. Next, key targets were enriched using Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG). Protein-protein interaction network analysis was performed to obtain targets with the highest degree values for molecular docking with Perilla essential oil active ingredients. For in vitro experiments, lipopolysaccharide (LPS) was used to induce an ALI inflammation model using RAW264.7 cells. The model cells were then treated with Perilla essential oil to detect the protein expression levels of vascular endothelial factor (NO), tumor necrosis factor (TNF-α), and p65 nuclear transcription factor in them. Sixty-eight key targets of Perilla oil were identified for the treatment of ALI. These targets were found to be involved in biological processes related to peptides, response to lipopolysaccharides, the positive regulation of cytokine production, etc., using GO. The signaling pathways found to be associated with the targets included the AGE-RAGE signaling pathway in diabetic complications, the NF-kappa B signaling pathway, and small cell lung cancer and other inflammatory signaling pathways. The five key targets that showed good binding activity with Perilla oil active ingredients included TNF, RELA, PARP1, PTGS2, and IRAK4. In vitro assays showed that Perilla essential oil could significantly reduce NO and TNF-α levels and inhibit the phosphorylation of nuclear transcription factor P65, thus inhibiting the activation of NF-κB signaling pathway. Conclusion Perilla essential oil can play a role in the treatment of ALI by inhibiting the activation of the NF-κB signaling pathway and preventing an excessive inflammatory response. This study thus provides a reference for the in-depth study of the mechanisms through which Perilla essential oil treats ALI.

Heterogeneity of immune cells and their communications unveiled by transcriptome profiling in acute inflammatory lung injury.

Acute Respiratory Distress Syndrome (ARDS) or its earlier stage Acute lung injury (ALI), is a worldwide health concern that jeopardizes human well-being. Currently, the treatment strategies to mitigate the incidence and mortality of ARDS are severely restricted. This limitation can be attributed, at least in part, to the substantial variations in immunity observed in individuals with this syndrome. Bulk and single cell RNA sequencing from ALI mice and single cell RNA sequencing from ARDS patients were analyzed. We utilized the Seurat program package in R and cellmarker 2.0 to cluster and annotate the data. The differential, enrichment, protein interaction, and cell-cell communication analysis were conducted. The mice with ALI caused by pulmonary and extrapulmonary factors demonstrated differential expression including Clec4e, Retnlg, S100a9, Coro1a, and Lars2. We have determined that inflammatory factors have a greater significance in extrapulmonary ALI, while multiple pathways collaborate in the development of pulmonary ALI. Clustering analysis revealed significant heterogeneity in the relative abundance of immune cells in different ALI models. The autocrine action of neutrophils plays a crucial role in pulmonary ALI. Additionally, there was a significant increase in signaling intensity between B cells and M1 macrophages, NKT cells and M1 macrophages in extrapulmonary ALI. The CXCL, CSF3 and MIF, TGFβ signaling pathways play a vital role in pulmonary and extrapulmonary ALI, respectively. Moreover, the analysis of human single-cell revealed DCs signaling to monocytes and neutrophils in COVID-19-associated ARDS is stronger compared to sepsis-related ARDS. In sepsis-related ARDS, CD8+ T and Th cells exhibit more prominent signaling to B-cell nucleated DCs. Meanwhile, both MIF and CXCL signaling pathways are specific to sepsis-related ARDS. This study has identified specific gene signatures and signaling pathways in animal models and human samples that facilitate the interaction between immune cells, which could be targeted therapeutically in ARDS patients of various etiologies.

STING-deficiency in lung resident mesenchymal stromal cells contributes to the alleviation of LPS-induced lung injury

Acute respiratory distress syndrome (ARDS) is characterized by acute diffuse inflammatory lung injury with a high mortality rate. Mesenchymal stromal cells (MSC) are pluripotent adult cells that can be extracted from a variety of tissues, including the lung. Lung-resident MSC (LR-MSC) located around vascular vessels and act as important regulators of lung homeostasis, regulating the balance between lung injury and repair processes. LR-MSC support the integrity of lung tissue by modulating immune responses and releasing trophic factors. Studies have reported that the STING pathway is involved in the progression of lung injury inflammation, but the specific mechanism is unclear. In this study, we found that STING deficiency could ameliorate lipopolysaccharides (LPS)-induced acute lung injury, STING knockout (STING KO) LR-MSC had an enhanced treatment effect on acute lung injury. STING depletion protected LR-MSC from LPS-induced apoptosis. RNA-sequencing and Western blot results showed that STING KO LR-MSC expressed higher levels of MSC immunoregulatory molecules, such as Igfbp4, Icam1, Hgf and Cox2, than WT LR-MSC. This study highlights that LR-MSC have a therapeutic role in acute lung injury, and we demonstrate that STING deficiency can enhance the immunomodulatory function of LR-MSC in controlling lung inflammation. Thus, STING can be used as an intervention target to enhance the therapeutic effect of MSC.

Hyaluronic acid modified nanocarriers for aerosolized delivery of verteporfin in the treatment of acute lung injury

Verteporfin (VER), a photosensitizer used in macular degeneration therapy, has shown promise in controlling macrophage polarization and alleviating inflammation in acute lung injury (ALI)/acute respiratory distress syndrome (ARDS). However, its hydrophobicity, limited bioavailability, and side effects hinder its therapeutic potential. In this study, we aimed to enhance the therapeutic potential of VER through pulmonary nebulized drug delivery for ALI/ARDS treatment. We combined hydrophilic hyaluronic acid (HA) with an oil-in-water system containing a poly(lactic acid-co-glycolic acid) (PLGA) copolymer of VER to synthesize HA@PLGA-VER (PHV) nanoparticles with favorable surface characteristics to improve the bioavailability and targeting ability of VER. PHV possesses suitable electrical properties, a narrow size distribution (approximately 200 nm), and favorable stability. In vitro and in vivo studies demonstrated the excellent biocompatibility, safety, and anti-inflammatory responses of the PHV by suppressing M1 macrophage polarization while inducing M2 polarization. The in vivo experiments indicated that the treatment with aerosolized nano-VER (PHV) allowed more drugs to accumulate and penetrate into the lungs, improved the pulmonary function and attenuated lung injury, and mortality of ALI mice, achieving improved therapeutic outcomes. These findings highlight the potential of PHV as a promising delivery system via nebulization for enhancing the therapeutic effects of VER in ALI/ARDS.

Manufacturing, quality control, and GLP-grade preclinical study of nebulized allogenic adipose mesenchymal stromal cells-derived extracellular vesicles

BackgroundHuman adipose stromal cells-derived extracellular vesicles (haMSC-EVs) have been shown to alleviate inflammation in acute lung injury (ALI) animal models. However, there are few systemic studies on clinical-grade haMSC-EVs. Our study aimed to investigate the manufacturing, quality control (QC) and preclinical safety of clinical-grade haMSC-EVs.MethodshaMSC-EVs were isolated from the conditioned medium of human adipose MSCs incubated in 2D containers. Purification was performed by PEG precipitation and differential centrifugation. Characterizations were conducted by nanoparticle tracking analysis, transmission electron microscopy (TEM), Western blotting, nanoflow cytometry analysis, and the TNF-α inhibition ratio of macrophage [after stimulated by lipopolysaccharide (LPS)]. RNA-seq and proteomic analysis with liquid chromatography tandem mass spectrometry (LC–MS/MS) were used to inspect the lot-to-lot consistency of the EV products. Repeated toxicity was evaluated in rats after administration using trace liquid endotracheal nebulizers for 28 days, and respiratory toxicity was evaluated 24 h after the first administration. In vivo therapeutic effects were assessed in an LPS-induced ALI/ acute respiratory distress syndrome (ARDS) rat model.ResultsThe quality criteria have been standardized. In a stability study, haMSC-EVs were found to remain stable after 6 months of storage at − 80°C, 3 months at − 20 °C, and 6 h at room temperature. The microRNA profile and proteome of haMSC-EVs demonstrated suitable lot-to-lot consistency, further suggesting the stability of the production processes. Intratracheally administered 1.5 × 108 particles/rat/day for four weeks elicited no significant toxicity in rats. In LPS-induced ALI/ARDS model rats, intratracheally administered haMSC-EVs alleviated lung injury, possibly by reducing the serum level of inflammatory factors.ConclusionhaMSC-EVs, as an off-shelf drug, have suitable stability and lot-to-lot consistency. Intratracheally administered haMSC-EVs demonstrated excellent safety at the tested dosages in systematic preclinical toxicity studies. Intratracheally administered haMSC-EVs improved the lung function and exerted anti-inflammatory effects on LPS-induced ALI/ARDS model rats.

Engineered extracellular vesicles carrying let-7a-5p for alleviating inflammation in acute lung injury

BackgroundAcute lung injury (ALI) is a life-threatening respiratory condition characterized by severe inflammation and lung tissue damage, frequently causing rapid respiratory failure and long-term complications. The microRNA let-7a-5p is involved in the progression of lung injury, inflammation, and fibrosis by regulating immune cell activation and cytokine production. This study aims to use an innovative cellular electroporation platform to generate extracellular vesicles (EVs) carring let-7a-5p (EV-let-7a-5p) derived from transfected Wharton’s jelly-mesenchymal stem cells (WJ-MSCs) as a potential gene therapy for ALI.MethodsA cellular nanoporation (CNP) method was used to induce the production and release of EV-let-7a-5p from WJ-MSCs transfected with the relevant plasmid DNA. EV-let-7a-5p in the conditioned medium were isolated using a tangential flow filtration (TFF) system. EV characterization followed the minimal consensus guidelines outlined by the International Society for Extracellular Vesicles. We conducted a thorough set of therapeutic assessments, including the antifibrotic effects using a transforming growth factor beta (TGF-β)-induced cell model, the modulation effects on macrophage polarization, and the influence of EV-let-7a-5p in a rat model of hyperoxia-induced ALI.ResultsThe CNP platform significantly increased EV secretion from transfected WJ-MSCs, and the encapsulated let-7a-5p in engineered EVs was markedly higher than that in untreated WJ-MSCs. These EV-let-7a-5p did not influence cell proliferation and effectively mitigated the TGF-β-induced fibrotic phenotype by downregulating SMAD2/3 phosphorylation in LL29 cells. Furthermore, EV-let-7a-5p regulated M2-like macrophage activation in an inflammatory microenvironment and significantly induced interleukin (IL)-10 secretion, demonstrating their modulatory effect on inflammation. Administering EVs from untreated WJ-MSCs slightly improved lung function and increased let-7a-5p expression in plasma in the hyperoxia-induced ALI rat model. In comparison, EV-let-7a-5p significantly reduced macrophage infiltration and collagen deposition while increasing IL-10 expression, causing a substantial improvement in lung function.ConclusionThis study reveals that the use of the CNP platform to stimulate and transfect WJ-MSCs could generate an abundance of let-7a-5p-enriched EVs, which underscores the therapeutic potential in countering inflammatory responses, fibrotic activation, and hyperoxia-induced lung injury. These results provide potential avenues for developing innovative therapeutic approaches for more effective interventions in ALI.

Neutrophil Extracellular Traps Upregulate p21 and Suppress Cell Cycle Progression to Impair Endothelial Regeneration after Inflammatory Lung Injury.

Background: Sepsis is a major cause of ICU admissions, with high mortality and morbidity. The lungs are particularly vulnerable to infection and injury, and restoration of vascular endothelial homeostasis after injury is a crucial determinant of outcome. Neutrophil extracellular trap (NET) release strongly correlates with the severity of lung tissue damage. However, little is known about whether NETs affect endothelial cell (EC) regeneration and repair. Methods: Eight- to ten-week-old male C57BL/6 mice were injected intraperitoneally with a sublethal dose of LPS to induce acute lung inflammatory injury or with PBS as a control. Blood samples and lung tissues were collected to detect NET formation and lung endothelial cell proliferation. Human umbilical vein endothelial cells (HUVECs) were used to determine the role of NETs in cell cycle progression in vitro. Results: Increased NET formation and impaired endothelial cell proliferation were observed in mice with inflammatory lung injury following septic endotoxemia. Degradation of NETs with DNase I attenuated lung inflammation and facilitated endothelial regeneration. Mechanistically, NETs induced p21 upregulation and cell cycle stasis to impair endothelial repair. Conclusions: Our findings suggest that NET formation impairs endothelial regeneration and vascular repair through the induction of p21 and cell cycle arrest during inflammatory lung injury.

Gpnmb silencing protects against hyperoxia-induced acute lung injury by inhibition of mitochondrial-mediated apoptosis.

Background: Hyperoxia-induced acute lung injury (HALI) is a complication to ventilation in patients with respiratory failure, which can lead to acute inflammatory lung injury and chronic lung disease. The aim of this study was to integrate bioinformatics analysis to identify key genes associated with HALI and validate their role in H2O2-induced cell injury model.Methods: Integrated bioinformatics analysis was performed to screen vital genes involved in hyperoxia-induced lung injury (HLI). CCK-8 and flow cytometry assays were performed to assess cell viability and apoptosis. Western blotting was performed to assess protein expression.Results: In this study, glycoprotein non-metastatic melanoma protein B (Gpnmb) was identified as a key gene in HLI by integrated bioinformatics analysis of 4 Gene Expression Omnibus (GEO) datasets (GSE97804, GSE51039, GSE76301 and GSE87350). Knockdown of Gpnmb increased cell viability and decreased apoptosis in H2O2-treated MLE-12 cells, suggesting that Gpnmb was a proapoptotic gene during HALI. Western blotting results showed that knockdown of Gpnmb reduced the expression of Bcl-2 associated X (BAX) and cleaved-caspase 3, and increased the expression of Bcl-2 in H2O2 treated MLE-12 cells. Furthermore, Gpnmb knockdown could significantly reduce reactive oxygen species (ROS) generation and improve the mitochondrial membrane potential.Conclusion: The present study showed that knockdown of Gpnmb may protect against HLI by repressing mitochondrial-mediated apoptosis.

The blood lactate/serum albumin ratio might represent a good prognostic indicator of 28-day mortality in patients with acute respiratory distress syndrome: a retrospective observational study

Abstract Background Acute respiratory distress syndrome (ARDS) is an acute inflammatory lung injury with a high mortality rate. However, previous ARDS prognostic scoring systems or predictors have been limited by complex formulas that are relatively expensive and inconvenient to obtain. Thus, this study aimed to explore the clinical significance of the blood lactate/serum albumin ratio (LAR) in assessing the prognosis of ARDS patients and compare it with other indicators related to 28-day mortality in ARDS patients. Methods We conducted a single-center retrospective study involving patients who fulfilled the Berlin definition of ARDS between 2016 and 2021. Clinical data were collected from medical records within 24 hours after ARDS diagnosis. The LAR, neutrophil-to-lymphocyte ratio, and monocyte-to-lymphocyte ratio (MLR) were calculated. The primary clinical outcome was 28-day mortality. The risk factors for 28-day mortality were determined using logistic regression analysis. The receiver operating characteristic curve was used to evaluate the area under the curve (AUC). Results A total of 276 ARDS patients met the inclusion criteria and were divided into surviving and nonsurviving groups according to 28-day mortality. There were significant differences in the Acute Physiologic Assessment and Chronic Health Evaluation II scores, Sequential Organ Failure Assessment scores, MLRs, and LARs between the surviving and nonsurviving groups. The AUC for the LAR was 0.790 (P < 0.001), whereas the AUCs for the Acute Physiologic Assessment and Chronic Health Evaluation II score, Sequential Organ Failure Assessment score, neutrophil-to-lymphocyte ratio, and MLR were 0.584, 0.599, 0.524, and 0.587, respectively. After grouping according to an LAR optimal cutoff value of 0.07, 28-day mortality was significantly higher in the high-LAR group than in the low-LAR group (47.18 vs 12.69, P < 0.001). Conclusions The LAR is an independent risk factor for 28-day mortality in ARDS patients and can be used to assess the severity of ARDS to a certain extent, making it superior to other commonly used indicators.

Adhesion molecule-targeted magnetic particle imaging nanoprobe for visualization of inflammation in acute lung injury.

Uncontrolled intra-alveolar inflammation is a central pathogenic feature, and its severity translates into a valid prognostic indicator of acute lung injury (ALI). Unfortunately, current clinical imaging approaches are unsuitable for visualizing and quantifying intra-alveolar inflammation. This study aimed to construct a small-sized vascular cell adhesion molecule-1 (VCAM-1)-targeted magnetic particle imaging (MPI) nanoprobe (ESPVPN) to visualize and accurately quantify intra-alveolar inflammation at the molecular level. ESPVPN was engineered by conjugating a peptide (VHPKQHRGGSK(Cy7)GC) onto a polydopamine-functionalized superparamagnetic iron oxide core. The MPI performance, targeting, and biosafety of the ESPVPN were characterized. VCAM-1 expression in HUVECs and mouse models was evaluated by western blot. The degree of inflammation and distribution of VCAM-1 in the lungs were assessed using histopathology. The expression of pro-inflammatory markers and VCAM-1 in lung tissue lysates was measured using ELISA. After intravenous administration of ESPVPN, MPI and CT imaging were used to analyze the distribution of ESPVPN in the lungs of the LPS-induced ALI models. The small-sized (~10 nm) ESPVPN exhibited superior MPI performance compared to commercial MagImaging® and Vivotrax, and ESPVPN had effective targeting and biosafety. VCAM-1 was highly expressed in LPS-induced ALI mice. VCAM-1 expression was positively correlated with the LPS-induced dose (R = 0.9381). The in vivo MPI signal showed positive correlations with both VCAM-1 expression (R = 0.9186) and representative pro-inflammatory markers (MPO, TNF-α, IL-6, IL-8, and IL-1β, R > 0.7). ESPVPN effectively targeted inflammatory lungs and combined the advantages of MPI quantitative imaging to visualize and evaluate the degree of ALI inflammation.

Lactate produced by alveolar type II cells suppresses inflammatory alveolar macrophages in acute lung injury.

Alveolar inflammation is a hallmark of acute lung injury (ALI), and its clinical correlate is acute respiratory distress syndrome-and it is as a result of interactions between alveolar type II cells (ATII) and alveolar macrophages (AM). In the setting of acute injury, the microenvironment of the intra-alveolar space is determined in part by metabolites and cytokines and is known to shape the AM phenotype. In response to ALI, increased glycolysis is observed in AT II cells, mediated by the transcription factor hypoxia-inducible factor (HIF) 1α, which has been shown to decrease inflammation. We hypothesized that in acute lung injury, lactate, the end product of glycolysis, produced by ATII cells shifts AMs toward an anti-inflammatory phenotype, thus mitigating ALI. We found that local intratracheal delivery of lactate improved ALI in two different mouse models. Lactate shifted cytokine expression of murine AMs toward increased IL-10, while decreasing IL-1 and IL-6 expression. Mice with ATII-specific deletion of Hif1a and mice treated with an inhibitor of lactate dehydrogenase displayed exacerbated ALI and increased inflammation with decreased levels of lactate in the bronchoalveolar lavage fluid; however, all those parameters improved with intratracheal lactate. When exposed to LPS (to recapitulate an inflammatory stimulus as it occurs in ALI), human primary AMs co-cultured with alveolar epithelial cells had reduced inflammatory responses. Taken together, these studies reveal an innate protective pathway, in which lactate produced by ATII cells shifts AMs toward an anti-inflammatory phenotype and dampens excessive inflammation in ALI.

Acute respiratory distress syndrome heterogeneity and the septic ARDS subgroup.

Acute respiratory distress syndrome (ARDS) is an acute diffuse inflammatory lung injury characterized by the damage of alveolar epithelial cells and pulmonary capillary endothelial cells. It is mainly manifested by non-cardiogenic pulmonary edema, resulting from intrapulmonary and extrapulmonary risk factors. ARDS is often accompanied by immune system disturbance, both locally in the lungs and systemically. As a common heterogeneous disease in critical care medicine, researchers are often faced with the failure of clinical trials. Latent class analysis had been used to compensate for poor outcomes and found that targeted treatment after subgrouping contribute to ARDS therapy. The subphenotype of ARDS caused by sepsis has garnered attention due to its refractory nature and detrimental consequences. Sepsis stands as the most predominant extrapulmonary cause of ARDS, accounting for approximately 32% of ARDS cases. Studies indicate that sepsis-induced ARDS tends to be more severe than ARDS caused by other factors, leading to poorer prognosis and higher mortality rate. This comprehensive review delves into the immunological mechanisms of sepsis-ARDS, the heterogeneity of ARDS and existing research on targeted treatments, aiming to providing mechanism understanding and exploring ideas for accurate treatment of ARDS or sepsis-ARDS.

Acute Respiratory Distress Syndrome: A Review on Animal Models

Acute Respiratory Distress Syndrome (ARDS) is an acute inflammatory lung injury. ARDS occurs when there is disruption in the alveolar-capillary barrier followed by the deposition of protein rich fluid inside the alveoli of the lungs. This protein-rich fluid stops the lungs from filling with enough air, resulting in less oxygen reaching the bloodstream. This depletes the organs of the oxygen that they need for proper functioning. The various clinical disorders that are associated with the development of ARDS include sepsis, pneumonia, aspiration of gastric contents, and major trauma. Human ARDS is not caused by any single event and hence there is no such existing animal model that would completely mimic Human ARDS. This review provides the various methods for insulting ARDS in animal model, along with advantage and disadvantage of each method.

Comparison on anti-inflammatory activity of Gynostemma pentaphyllum processed with different methods

The aim of this study is to investigate the effects of Gynostemma pentaphyllum dried with two different methods(air drying and heating) on inflammation in acute lung injury(ALI) mice in vivo and in vitro. Lipopolysaccharide(LPS) was sprayed into the airway of wild type C57BL/6J male mice to establish the model, and the drug was injected into the tail vein 24 h after modeling. Lung function, lung tissue wet/dry weight(W/D) ratio, the total protein concentration, interleukin 6(IL-6), IL-1β, and tumor necrosis factor-α(TNF-α) in the bronchoalveolar lavage fluid(BALF), and pathological changes of the lung tissue were used to evaluate the effects of different gypenosides on ALI mice. The results showed that total gypenosides(YGGPs) and the gypenosides substituted with one or two glycosyl(GPs_(1-2)) in the air-dried sample improved the lung function, significantly lowered the levels of IL-1β and TNF-α in BALF, and alleviated the lung inflammation of ALI mice. Moreover, GPs_(1-2) had a more significant effect on inhibiting NO release in RAW264.7 cells. This study showed that different drying methods affected the anti-inflammatory activity of G. pentaphyllum, and the rare saponins in the air-dried sample without heating had better anti-inflammatory activity.

A Standardized Botanical Composition Mitigated Acute Inflammatory Lung Injury and Reduced Mortality through Extracellular HMGB1 Reduction.

HMGB1 is a key late inflammatory mediator upregulated during air-pollution-induced oxidative stress. Extracellular HMGB1 accumulation in the airways and lungs plays a significant role in the pathogenesis of inflammatory lung injury. Decreasing extracellular HMBG1 levels may restore innate immune cell functions to protect the lungs from harmful injuries. Current therapies for air-pollution-induced respiratory problems are inadequate. Dietary antioxidants from natural sources could serve as a frontline defense against air-pollution-induced oxidative stress and lung damage. Here, a standardized botanical antioxidant composition from Scutellaria baicalensis and Acacia catechu was evaluated for its efficacy in attenuating acute inflammatory lung injury and sepsis. Murine models of disorders, including hyperoxia-exposed, bacterial-challenged acute lung injury, LPS-induced sepsis, and LPS-induced acute inflammatory lung injury models were utilized. The effect of the botanical composition on phagocytic activity and HMGB1 release was assessed using hyperoxia-stressed cultured macrophages. Analyses, such as hematoxylin-eosin (HE) staining for lung tissue damage evaluation, ELISA for inflammatory cytokines and chemokines, Western blot analysis for proteins, including extracellular HMGB1, and bacterial counts in the lungs and airways, were performed. Statistically significant decreases in mortality (50%), proinflammatory cytokines (TNF-α, IL-1β, IL-6) and chemokines (CINC-3) in serum and bronchoalveolar lavage fluid (BALF), and increased bacterial clearance from airways and lungs; reduced airway total protein, and decreased extracellular HMGB1 were observed in in vivo studies. A statistically significant 75.9% reduction in the level of extracellular HMGB1 and an increase in phagocytosis were observed in cultured macrophages. The compilations of data in this report strongly suggest that the botanical composition could be indicated for oxidative-stress-induced lung damage protection, possibly through attenuation of increased extracellular HMGB1 accumulation.

LAIR-1 limits macrophage activation in acute inflammatory lung injury

Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are serious health problems that manifest as acute respiratory failure in response to different conditions, including viral respiratory infections. Recently, the inhibitory properties of leukocyte-associated immunoglobulin-like receptor-1 (LAIR-1) were demonstrated in allergic and viral airway inflammation. In this study, we investigate the implication of LAIR-1 in ALI/ARDS and explore the underlying mechanisms. Polyinosinic:polycytidylic acid, a synthetic analog of double-stranded RNA, was used to mimic acute inflammation in viral infections. We demonstrate that LAIR-1 is predominantly expressed on macrophages and regulates their recruitment to the lungs as well as their activation in response to polyinosinic:polycytidylic acid. Interestingly, LAIR-1 deficiency increases neutrophil recruitment as well as lung resistance and permeability. In particular, we highlight the capacity of LAIR-1 to regulate the secretion of CXCL10, considered a key marker of macrophage overactivation in acute lung inflammation. We also reveal in COVID-19-induced lung inflammation that LAIR1 is upregulated on lung macrophages in correlation with relevant immune regulatory genes. Altogether, our findings demonstrate the implication of LAIR-1 in the pathogenesis of ALI/ARDS by means of the regulation of macrophages, thereby providing the basis of a novel therapeutic target.

Advances of mesenchymal stem cells and their derived extracellular vesicles as a promising therapy for acute respiratory distress syndrome: from bench to clinic.

Acute respiratory distress syndrome (ARDS) is an acute inflammatory lung injury characterized by diffuse alveolar damage. The period prevalence of ARDS was 10.4% of ICU admissions in 50 countries. Although great progress has been made in supportive care, the hospital mortality rate of severe ARDS is still up to 46.1%. Moreover, up to now, there is no effective pharmacotherapy for ARDS and most clinical trials focusing on consistently effective drugs have met disappointing results. Mesenchymal stem cells (MSCs) and their derived extracellular vesicles (EVs) have spawned intense interest of a wide range of researchers and clinicians due to their robust anti-inflammatory, anti-apoptotic and tissue regeneration properties. A growing body of evidence from preclinical studies confirmed the promising therapeutic potential of MSCs and their EVs in the treatment of ARDS. Based on the inspiring experimental results, clinical trials have been designed to evaluate safety and efficacy of MSCs and their EVs in ARDS patients. Moreover, trials exploring their optimal time window and regimen of drug administration are ongoing. Therefore, this review aims to present an overview of the characteristics of mesenchymal stem cells and their derived EVs, therapeutic mechanisms for ARDS and research progress that has been made over the past 5 years.

Human umbilical cord mesenchymal stromal cell small extracellular vesicle transfer of microRNA-223-3p to lung epithelial cells attenuates inflammation in acute lung injury in mice.

Acute lung injury (ALI), manifested as strong pulmonary inflammation and alveolar epithelial damage, is a life-threatening disease with high morbidity and mortality. Small extracellular vesicles (sEVs), secreted by multiple types of cells, are critical cellular communication mediators and can inhibit inflammation by transferring bioactive molecules, such as microRNAs (miRNAs). Thus, we hypothesized that sEVs derived from mesenchymal stromal cells (MSC sEVs) could transfer miRNAs to attenuate inflammation of lung epithelial cells during ALI. C57BL/6 male mice were intratracheally administered LPS (10mg/kg). Six hours later, the mice were randomly administered with MSC sEVs (40µg per mouse in 150µl of saline), which were collected by ultracentrifugation. Control group received saline administration. After 48h, the mice were sacrificed to evaluate pulmonary microvascular permeability and inflammatory responses. In vitro, A549 cells and primary human small airway epithelial cells (SAECs) were stimulated with LPS with or without MSC sEVs treatment. In vitro, MSC sEVs could also inhibit the inflammation induced by LPS in A549 cells and SAECs (reducing TNF-α, IL-1β, IL-6 and MCP-1). Moreover, MSC sEV treatment improved the survival rate, alleviated pulmonary microvascular permeability, and inhibited proinflammatory responses (reducing TNF-α, IL-1β, IL-6 and JE-1) in ALI mice. Notably, miR-223-3p was found to be served as a critical mediator in MSC sEV-induced regulatory effects through inhibition of poly (adenosine diphosphate-ribose) polymerase-1 (PARP-1) in lung epithelial cells. Overall, these findings suggest that MSC sEVs may offer a novel promising strategy for ALI.

Inhibiting oxidative stress and inflammation in acute lung injury using hydrogen: A preclinical systematic review and meta-analysis

Acute lung injury (ALI) results from excessive inflammation and disruption of the alveolar-capillary barrier, leading to acute respiratory distress syndrome. Hydrogen, known as a reducing substance, has been commonly used in preclinical trials of ALI. The present paper aims to summarize the effects of hydrogen on animal models of ALI and the possible antioxidant and anti-inflammation mechanisms of hydrogen. We conducted a thorough search of the relevant literature on PubMed, EMBASE, Web of Science, and CNKI. Data retrieved from 20 studies were analyzed to assess the beneficial effects of hydrogen therapy on ALI animal models. To evaluate the effects of hydrogen, commonly assessed outcome indicators include wet-to-dry ratio (W/D), arterial oxygen partial pressure (PaO2), malondialdehyde (MDA), superoxide dismutase (SOD), and tumor necrosis factor-alpha (TNF-α). The results demonstrate that hydrogen reduces pulmonary edema (W/D: 95% CI = −0.98 – −0.85, P < 0.001), mitigates hypoxia (PaO2: 95% CI = 6.08 – 22.30, P < 0.001), represses lipid peroxidation (MDA: 95% CI = −2.12 – −1.06, P < 0.001), scavenges free radicals (SOD: 95% CI = 10.12 – 30.07, P < 0.001), and inhibits inflammatory response (TNF-α: 95% CI = −5.52 – −1.72, P < 0.001). The subgroup analysis showed significant differences between interventions (MDA: P < 0.05; TNF-α: P < 0.05; SOD: P < 0.001). The meta-regression suggests that species may cause heterogeneity (P < 0.05). These results suggest the potential of using hydrogen in clinical trials. Different interventions with hydrogen can affect metabolic transport and distribution in vivo. Further studies should be conducted to validate and confirm these findings.

LncRNA NEAT1: A novel regulator associated with the inflammatory response in acute respiratory distress syndrome

BackgroundAcute respiratory distress syndrome (ARDS) is a life-threatening condition with an unfavorable prognosis. As the pathogenesis of ARDS remains unclear, we aimed to identify the core genes associated with ARDS and the mechanisms by which competing endogenous RNAs (ceRNAs) regulate the disease’s progression. MethodsThree mRNA microarray datasets (GSE17355, GSE48787, and GSE130936), derived from the Gene Expression Omnibus (GEO) database, were selected. Common differentially expressed genes (DEGs) related to acute lung injury (ALI) were identified and subjected to enrichment analysis. Then, hub genes were figured out through the protein–protein interaction (PPI) network and functional analysis, and targeted miRNAs and lncRNAs were predicted. Finally, the ceRNA networks associated with ALI were constructed and validated experimentally. ResultsA total of 155 upregulated and 93 downregulated DEGs were identified in the three datasets. The TNF signaling pathway and IL-17 signaling pathway were the most enriched pathways. Then, eleven DEGs enriched in the IL-17 signaling pathway were selected as the hub genes. Three miRNAs (mmu-mir-155-5p, mmu-mir-21a-5p, and mmu-mir-122-5p), which were located in the lung tissue and predicted to bind the hub genes at the same time, and two lncRNAs (Neat1 and Tug1), which have binding sites for the aforementioned miRNAs, were filtered. With qPCR verification, we identified a ceRNA network composed of NEAT1, miR-21-5p, MMP9, and CXCL5. NEAT1 knockdown promoted the migration and reduced the expression of pro-inflammatory factor and reactive oxygen species (ROS) in lung epithelial cells. We eventually confirmed that NEAT1/miR-21-5p/CXCL5/MMP9 played a pivotal role in regulating the inflammatory response in ALI. ConclusionThe IL-17 signaling pathway is of great importance in the pathogenesis of ARDS. NEAT1/miR-21-5p is involved in the inflammation of ALI by regulating CXCL5 and MMP9.