Foxq1 Promotes Alveolar Epithelial Cell Death through Tle1-mediated Inhibition of the NFκB Signaling Pathway.

Acute lung injury is a common respiratory disease characterized by diffuse alveolar injury and interstitial edema, as well as a hyperinflammatory response, lung cell damage and oxidative stress. Foxq1, a member of the FOX family of transcription factors, is expressed in various tissues, such as the lungs, liver, and kidneys, and contributes to various biological processes, such as stress, metabolism, cell cycle arrest, and aging-related apoptosis. However, the role of Foxq1 in acute lung injury is unknown. We constructed ex vivo and in vivo acute lung injury models by lipopolysaccharide tracheal perfusion of ICR mice and conditioned medium stimulation of injured MLE-12 cells. Foxq1 expression was increased, and its localization was altered in our acute lung injury model. In normal or injured MLE-12 cells, knockdown of Foxq1 promoted cell survival, and overexpression had the opposite effect. This regulatory effect was likely mediated by Tle1 and the NFκB/Bcl2/Bax signaling pathway. These data suggest a potential link between Foxq1 and acute lung injury, indicating that Foxq1 can be used as a biomarker for the diagnosis of acute lung injury. Targeted inhibition of Foxq1 expression could promote alveolar epithelial cell survival and may provide a strategy for mitigating acute lung injury.

IL-10 Counteracts IFN-γ to Alleviate Acute Lung Injury in a Viral-Bacterial Superinfection Model.

Immune activation is essential for lung control of viral and bacterial infection, but an overwhelming inflammatory response often leads to the onset of acute respiratory distress syndrome (ARDS). Interleukin-10 (IL-10) plays a crucial role in regulating the balance between antimicrobial immunity and immunopathology. In the current study, we have investigated the role of IL-10 in acute lung injury (ALI) induced by influenza A virus (IAV) and methicillin-resistant Staphylococcus aureus (MRSA) coinfection. This unique coinfection model resembles acute pneumonia patients undergoing appropriate antibiotic therapies. Using global IL-10 and IL-10 receptor (IL-10R) gene-deficient mice, as well as in vivo neutralizing antibodies, here we show that IL-10 deficiency promotes IFN-γ-dominant cytokine responses and triggers acute animal death. Interestingly, this extreme susceptibility is fully preventable by IFN-γ neutralization during coinfection. Further studies using mice with Il10ra deletion in selective myeloid subsets reveal that IL-10 primarily acts on mononuclear phagocytes to prevent IFN-γ/TNF-α hyper-production and acute mortality. Importantly, this anti-inflammatory IL-10 signaling is independent of its inhibitory effect on antiviral and antibacterial defense. Collectively, our results demonstrate a key mechanism of IL-10 in preventing hypercytokinemia and ARDS pathogenesis by counteracting the IFN-γ response.

P75NTR+CD64+ neutrophils promote sepsis-induced acute lung injury.

Patients suffering from sepsis-induced acute lung injury (ALI) exhibit a high mortality rate, and their prognosis is closely associated with infiltration of neutrophils into the lungs. In this study, we found a significant elevation of CD64+ neutrophils, which highly expressed p75 neurotrophin receptor (p75NTR) in peripheral blood of mice and patients with sepsis-induced ALI. p75NTR+CD64+ neutrophils were also abundantly expressed in the lung of ALI mice induced by lipopolysaccharide. Conditional knock-out of the myeloid lineage's p75NTR gene improved the survival rates, attenuated lung tissue inflammation, reduced neutrophil infiltration and enhanced the phagocytic functions of CD64+ neutrophils. In vitro, p75NTR+CD64+ neutrophils exhibited an upregulation and compromised phagocytic activity in blood samples of ALI patients. Blocking p75NTR activity by soluble p75NTR extracellular domain peptide (p75ECD-Fc) boosted CD64+ neutrophil phagocytic activity and reduced inflammatory cytokine production via activation of the NF-κB pathway. The findings strongly indicate that p75NTR+CD64+ neutrophils are a novel pathogenic neutrophil subpopulation promoting sepsis-induced ALI.

Exosomes derived from induced cardiopulmonary progenitor cells alleviate acute lung injury in mice.

Cardiopulmonary progenitor cells (CPPs) constitute a minor subpopulation of cells that are commonly associated with heart and lung morphogenesis during embryonic development but completely subside after birth. This fact offers the possibility for the treatment of pulmonary heart disease (PHD), in which the lung and heart are both damaged. A reliable source of CPPs is urgently needed. In this study, we reprogrammed human cardiac fibroblasts (HCFs) into CPP-like cells (or induced CPPs, iCPPs) and evaluated the therapeutic potential of iCPP-derived exosomes for acute lung injury (ALI). iCPPs were created in passage 3 primary HCFs by overexpressing GLI1, WNT2, ISL1 and TBX5 (GWIT). Exosomes were isolated from the culture medium of passage 6-8 GWIT-iCPPs. A mouse ALI model was established by intratracheal instillation of LPS. Four hours after LPS instillation, ALI mice were treated with GWIT-iCPP-derived exosomes (5 × 109, 5 × 1010 particles/mL) via intratracheal instillation. We showed that GWIT-iCPPs could differentiate into cell lineages, such as cardiomyocyte-like cells, endothelial cells, smooth muscle cells and alveolar epithelial cells, in vitro. Transcription analysis revealed that GWIT-iCPPs have potential for heart and lung development. Intratracheal instillation of iCPP-derived exosomes dose-dependently alleviated LPS-induced ALI in mice by attenuating lung inflammation, promoting endothelial function and restoring capillary endothelial cells and the epithelial cells barrier. This study provides a potential new method for the prevention and treatment of cardiopulmonary injury, especially lung injury, and provides a new cell model for drug screening.

Bovine lactoferrin inhibits inflammatory response and apoptosis in lipopolysaccharide-induced acute lung injury by targeting the PPAR-γ pathway.

BACKGROUND: Lactoferrin (LF) is an iron-binding multifunctional cationic glycoprotein. Previous studies have demonstrated that LF may be a potential drug for treating acute lung injury (ALI) and acute respiratory distress syndrome (ARDS). In this study, we explored the anti-inflammatory effect and mechanism of bovine lactoferrin (bLF) in ALI using the RNA sequencing (RNA-seq) technology and transcriptome analysis. METHODS AND RESULTS: Based on the differentially expressed genes (DEGs) obtained from RNA-seq of the Lung from mouse model, the bioinformatics workflow was implemented using the BGISEQ-500 platform. The protein-protein interaction (PPI) network was obtained using STRING, and the hub gene was screened using Cytoscape. To verify the results of transcriptome analysis, the effects of bLF on Lipopolysaccharide (LPS)-induced BEAS-2B cells and its anti-reactive oxygen species (ROS), anti-inflammatory, and antiapoptotic effects were studied via Cell Counting Kit-8 (CCK-8) test, active oxygen detection test, ELISA, and western blot assay. Transcriptome analysis revealed that two hub gene modules of DEGs were screened via PPI analysis using the STRING and MCODE plug-ins of Cytoscape. Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis revealed that these core modules are enriched in the PPAR (peroxisome proliferator-activated receptor) and AMPK (AMP-activated protein kinase) signaling pathways. Through cell experiments, our study shows that bLF can inhibit ROS, inflammatory reaction, and LPS-induced BEAS-2B cell apoptosis, which are significantly antagonized by the PPAR-γ inhibitor GW9662. CONCLUSION: This study has suggested that the PPAR-γ pathway is the critical target of bLF in anti-inflammatory reactions and apoptosis of ALI, which provides a direction for further research.

Integrating UPLC-Q-Orbitrap MS with serum pharmacochemistry network and experimental verification to explore the pharmacological mechanisms of Cynanchi stauntonii rhizoma et radix against sepsis-induced acute lung injury.

Introduction: Patients with sepsis are at an incremental risk of acute lung injury (ALI). Baiqian, also known as Cynanchi stauntonii rhizoma et radix (Csrer), has anti-inflammatory properties and is traditionally used to treat cough and phlegm. This study aimed to demonstrate the multicomponent, multitarget, and multi-pathway regulatory molecular mechanisms of Csrer in treating lipopolysaccharide (LPS)-induced ALI. Methods: The bioactive components of Csrer were identified by ultrahigh-performance liquid chromatography Q-Orbitrap mass spectrometry (UPLC-Q-Orbitrap MS). Active targets predicted from PharmMapper. DrugBank, OMIM, TTD, and GeneCards were used to identify potential targets related to ALI. Intersection genes were identified for Csrer against ALI. The PPI network was analysed to identify prime targets. GO and KEGG analyses were performed. A drug-compound-target-pathway-disease network was constructed. Molecular docking and simulations evaluated the binding free energy between key proteins and active compounds. The protective effect and mechanism of Csrer in ALI were verified using an ALI model in mice. Western blot, Immunohistochemistry and TUNEL staining evaluated the mechanisms of the pulmonary protective effects of Csrer. Results: Forty-six bioactive components, one hundred and ninety-two potential cross-targets against ALI and ten core genes were identified. According to GO and KEGG analyses, the PI3K-Akt, apoptosis and p53 pathways are predominantly involved in the "Csrer-ALI" network. According to molecular docking and dynamics simulations, ten key genes were firmly bound by the principal active components of Csrer. The "Csrer-ALI" network was revealed to be mediated by the p53-mediated apoptosis and inflammatory pathways in animal experiments. Conclusion: Csrer is a reliable source for ALI treatment based on its practical components, potential targets and pathways.

Exocarpium Citri Grandis ameliorates LPS-induced acute lung injury by suppressing inflammation, NLRP3 inflammasome, and ferroptosis.

ETHNOPHARMACOLOGICAL RELEVANCE: Exocarpium Citri Grandis (ECG), the epicarp of C. grandis 'Tomentosa' which is also known as Hua-Ju-Hong in China, has been widely used for thousands of years to treat inflammatory lung disorders such as asthma, and cough as well as dispelling phlegm. However, its underlying pharmacological mechanisms in acute lung injury (ALI) remain unclear. AIM OF THE STUDY: To explore the therapeutic effect of ECG on ALI and reveal the potential mechanisms based on experimental techniques in vivo and in vitro. MATERIALS AND METHODS: Lipopolysaccharides (LPS) induced ALI in mice and induced RAW 264.7 cell inflammatory model were established to investigate the pharmacodynamics of ECG. ELISA kits, commercial kits, Western Blot, qPCR, Hematoxylin and Eosin (H&E) staining, immunohistochemistry, and immunofluorescence technologies were used to evaluate the pharmacological mechanisms of ECG in ameliorating ALI. RESULTS: ECG significantly attenuated pulmonary edema in LPS-stimulated mice and decreased the levels of IL1ß, IL6, and TNF-α in serum and BALF, reduced MDA and iron concentration as well as increased SOD and GSH levels in lung tissues, and also decreased the ROS level in BALF and Lung tissue. Further pharmacological mechanism studies showed that ECG significantly inhibited mRNA expression of inflammatory signaling factors and chemokines, and down-regulated the expression of TLR4, MyD88, NF-κB p65, NF-κB p-p65 (S536), COX2, iNOS, Txnip, NLRP3, ASC, Caspase-1, JAK1, p-JAK1 (Y1022), JAK2, STAT1, p-STAT1 (S727), STAT3, p-STAT3 (Y705), STAT4, p-STAT4 (Y693), and Keap1, and also up-regulated the expression of Trx-1, Nrf2, HO-1, NQO1, GPX4, PCBP1, and SLC40A1. In the LPS-induced RAW264.7 cell inflammatory model, ECG showed similar results to animal experiments. CONCLUSIONS: Our results showed that ECG alleviated ALI by inhibiting TLR4/MyD88/NF-κB p65 and JAK/STAT signaling pathway-mediated inflammatory response, Txnip/NLRP3 signaling pathway-mediated inflammasome activation, and regulating Nrf2/GPX4 axis-mediated ferroptosis. Our findings provide an experimental basis for the application of ECG.

Immunometabolic reprogramming of macrophages with inhalable CRISPR/Cas9 nanotherapeutics for acute lung injury intervention.

Acute lung injury (ALI) represents a critical respiratory condition typified by rapid-onset lung inflammation, contributing to elevated morbidity and mortality rates. Central to ALI pathogenesis lies macrophage dysfunction, characterized by an overabundance of pro-inflammatory cytokines and a shift in metabolic activity towards glycolysis. This study emphasizes the crucial function of glucose metabolism in immune cell function under inflammatory conditions and identifies hexokinase 2 (HK2) as a key regulator of macrophage metabolism and inflammation. Given the limitations of HK2 inhibitors, we propose the CRISPR/Cas9 system for precise HK2 downregulation. We developed an aerosolized core-shell liposomal nanoplatform (CSNs) complexed with CaP for efficient drug loading, targeting lung macrophages. Various CSNs were synthesized to encapsulate an mRNA based CRISPR/Cas9 system (mCas9/gHK2), and their gene editing efficiency and HK2 knockout were examined at both gene and protein levels in vitro and in vivo. The CSN-mCas9/gHK2 treatment demonstrated a significant reduction in glycolysis and inflammation in macrophages. In an LPS-induced ALI mouse model, inhaled CSN-mCas9/gHK2 mitigated the proinflammatory tumor microenvironment and reprogrammed glucose metabolism in the lung, suggesting a promising strategy for ALI prevention and treatment. This study highlights the potential of combining CRISPR/Cas9 gene editing with inhalation delivery systems for effective, localized pulmonary disease treatment, underscoring the importance of targeted gene modulation and metabolic reprogramming in managing ALI. STATEMENT OF SIGNIFICANCE: This study investigates an inhalable CRISPR/Cas9 gene editing system targeting pulmonary macrophages, with the aim of modulating glucose metabolism to alleviate Acute Lung Injury (ALI). The research highlights the role of immune cell metabolism in inflammation, as evidenced by changes in macrophage glucose metabolism and a notable reduction in pulmonary edema and inflammation. Additionally, observed alterations in macrophage polarization and cytokine levels in bronchoalveolar lavage fluid suggest potential therapeutic implications. These findings not only offer insights into possible ALI treatments but also contribute to the understanding of immune cell metabolism in inflammatory diseases, which could be relevant for various inflammatory and metabolic disorders.

The Scutellaria-Coptis herb couple and its active small-molecule ingredient wogonoside alleviate cytokine storm by regulating the CD39/NLRP3/GSDMD signaling pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: A drug pair is a fundamental aspect of traditional Chinese medicine prescriptions. Scutellaria baicalensis Georgi and Coptis chinensis Franch, commonly used as an herb couple (SBCC), are representative heat-clearing and dampness-drying drugs. They possess functions such as clearing heat, drying dampness, purging fire, and detoxifying. These herbs are used in both traditional and modern medicine for treating inflammation. AIM OF THE STUDY: This study investigated the effects of SBCC on cytokine storm syndrome (CSS) and explored its potential regulatory mechanism. MATERIALS AND METHODS: We assessed the impact of SBCC in a sepsis-induced acute lung injury mouse model by administering an intraperitoneal injection of LPS (15 mg/kg). The cytokine levels in the serum and lungs, the wet-to-dry ratio of the lungs, and lung histopathological changes were evaluated. The macrophages in the lung tissue were examined through transmission electron microscopy. Western blot was used to measure the levels of the CD39/NLRP3/GSDMD pathway-related proteins. Immunofluorescence imaging was used to assess the activation of pro-caspase-1 and ASC and their interaction. AMP-Glo™ assay was used to screen for active ingredients in SBCC targeting CD39. One of the ingredients was selected, and its effect on cell viability was assessed. We induced inflammation in macrophages using LPS + ATP and detected the levels of proinflammatory factors. The images of cell membrane large pores were captured using scanning electron microscopy, the interaction between NLRP3 and ASC was detected using immunofluorescence imaging, and the levels of CD39/NLRP3/GSDMD pathway-related proteins were assessed using Western blot. RESULTS: SBCC administration effectively mitigated LPS-induced cytokine storm, pulmonary edema and lung injury. Furthermore, it repressed the programmed death of lung tissue macrophages by inhibiting the NLRP3/GSDMD pyroptosis pathway and regulating the CD39 purinergic pathway. Based on the results of the AMP-Glo™ assay, we selected wogonoside for further valuation. Wogonoside alleviated LPS + ATP-induced inflammatory damage by regulating the inhibiting the NLRP3/GSDMD pyroptosis pathway and regulating the CD39 purinergic pathway. However, its effect on NLRP3 is not mediated though CD39. CONCLUSION: SBCC and its active small-molecule ingredient, wogonoside, improved CSS by regulating the NLRP3/GSDMD pyroptosis pathway and its upstream CD39 purinergic pathway. It is essential to note that the regulatory effect of wogonoside on NLRP3 is not mediated by CD39.

Network pharmacology-based research into the mechanism of ferulic acid on acute lung injury through enhancing transepithelial sodium transport.

ETHNOPHARMACOLOGICAL RELEVANCE: Ferulic acid (FA) has shown potential therapeutic applications in treating lung diseases. However, the underlying mechanisms by which FA ameliorates acute lung injury (ALI) have not been distinctly elucidated. AIM OF THE STUDY: The project aims to observe the therapeutic effects of FA on lipopolysaccharide-induced ALI and to elucidate its specific mechanisms in regulating epithelial sodium channel (ENaC), which majors in alveolar fluid clearance during ALI. MATERIALS AND METHODS: In this study, the possible pathways of FA were determined through network pharmacology analyses. The mechanisms of FA in ALI were verified by in vivo mouse model and in vitro studies, including primary alveolar epithelial type 2 cells and three-dimensional alveolar organoid models. RESULTS: FA ameliorated ALI by improving lung pathological changes, reducing pulmonary edema, and upregulating the α/γ-ENaC expression in C57BL/J male mice. Simultaneously, FA was observed to augment ENaC levels in both three-dimensional alveolar organoid and alveolar epithelial type 2 cells models. Network pharmacology techniques and experimental data from inhibition or knockdown of IkappaB kinase ß (IKKß) proved that FA reduced the phosphorylation of IKKß/nuclear factor-kappaB (NF-κB) and eliminated the lipopolysaccharide-inhibited expression of ENaC, which could be regulated by nuclear protein NF-κB p65 directly. CONCLUSIONS: FA could enhance the expression of ENaC at least in part by inhibiting the IKKß/NF-κB signaling pathway, which may potentially pave the way for promising treatment of ALI.

Post-pandemic acute respiratory distress syndrome: A New Global Definition with extension to lower-resource regions.

Acute respiratory distress syndrome (ARDS), first described in 1967, is characterized by acute respiratory failure causing profound hypoxemia, decreased pulmonary compliance, and bilateral CXR infiltrates. After several descriptions, the Berlin definition was adopted in 2012, which established three categories of severity according to hypoxemia (mild, moderate and severe), specified temporal aspects for diagnosis, and incorporated the use of non-invasive ventilation. The COVID-19 pandemic led to changes in ARDS management, focusing on continuous monitoring of oxygenation and on utilization of high-flow oxygen therapy and lung ultrasound. In 2021, a New Global Definition based on the Berlin definition of ARDS was proposed, which included a category for non-intubated patients, considered the use of SpO2, and established no particular requirement for oxygenation support in regions with limited resources. Although debates persist, the continuous evolution seeks to adapt to clinical and epidemiological needs, and to the search of personalized treatments.

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.

Ginsenoside Rg1 Alleviates Sepsis-Induced Acute Lung Injury by Reducing FBXO3 Stability in an m6A-Dependent Manner to Activate PGC-1α/Nrf2 Signaling Pathway.

BACKGROUND: Sepsis-induced acute lung injury (ALI) is one of the serious life-threatening complications of sepsis and is pathologically associated with mitochondrial dysfunction. Ginsenoside Rg1 has good therapeutic effects on ALI. Herein, the pharmacological effects of Rg1 in sepsis-induced ALI were investigated. METHODS: Sepsis-induced ALI models were established by CLP operation and LPS treatment. HE staining was adopted to analyze lung pathological changes. The expression and secretion of cytokines were measured by RT-qPCR and ELISA. Cell viability and apoptosis were assessed by MTT assay, flow cytometry and TUNEL staining. ROS level and mitochondrial membrane potential (MMP) were analyzed using DHE probe and JC-1 staining, respectively. FBXO3 m6A level was assessed using MeRIP assay. The interactions between FBXO3, YTHDF1, and PGC-1α were analyzed by Co-IP or RIP. RESULTS: Rg1 administration ameliorated LPS-induced epithelial cell inflammation, apoptosis, and mitochondrial dysfunction in a dose-dependent manner. Mechanically, Rg1 reduced PGC-1α ubiquitination modification level by inhibiting FBXO3 expression m6A-YTHDF1 dependently. As expected, Rg1's mitigative effect on LPS-induced inflammation, apoptosis and mitochondrial dysfunction in lung epithelial cells was abolished by FBXO3 overexpression. Moreover, FBXO3 upregulation eliminated the restoring effect of Rg1 on CLP-induced lung injury in rats. CONCLUSION: Rg1 activated PGC-1α/Nrf2 signaling pathway by reducing FBXO3 stability in an m6A-YTHDF1-dependent manner to improve mitochondrial function in lung epithelial cells during sepsis-induced ALI progression.

S100A9 exacerbates sepsis-induced acute lung injury via the IL17-NFκB-caspase-3 signaling pathway.

BACKGROUND: Sepsis-induced acute lung injury (ALI) is associated with considerable morbidity and mortality in critically ill patients. S100A9, a key endothelial injury factor, is markedly upregulated in sepsis-induced ALI; however, its specific mechanism of action has not been fully elucidated. METHODS: The Gene Expression Omnibus database transcriptome data for sepsis-induced ALI were used to screen for key differentially expressed genes (DEGs). Using bioinformatics analysis methods such as Gene Ontology, Kyoto Encyclopedia of Genes and Genomes, and protein-protein interaction network analyses, the pathogenesis of sepsis-induced ALI was revealed. Intratracheal infusion of lipopolysaccharide (LPS, 10 mg/kg) induced ALI in wild-type (WT) and S100A9 knockout mice. Multiomics analyses (transcriptomics and proteomics) were performed to investigate the potential mechanisms by which S100A9 exacerbates acute lung damage. Hematoxylin-eosin, Giemsa, and TUNEL staining were used to evaluate lung injury and cell apoptosis. LPS (10 µg/mL)-induced murine lung epithelial MLE-12 cells were utilized to mimic ALI and were modulated by S100A9 lentiviral transfection. The impact of S100A9 on cell apoptosis and inflammatory responses were identified using flow cytometry and PCR. The expression of interleukin (IL)-17-nuclear factor kappa B (NFκB)-caspase-3 signaling components was identified using western blotting. RESULTS: Six common DEGs (S100A9, S100A8, IFITM6, SAA3, CD177, and MMP9) were identified in the six datasets related to ALI in sepsis. Compared to WT sepsis mice, S100A9 knockout significantly alleviated LPS-induced ALI in mice, with reduced lung structural damage and inflammatory exudation, decreased exfoliated cell and protein content in the lung lavage fluid, and reduced apoptosis and necrosis of pulmonary epithelial cells. Transcriptomic analysis revealed that knocking out S100A9 significantly affected 123 DEGs, which were enriched in immune responses, defense responses against bacteria or lipopolysaccharides, cytokine-cytokine receptor interactions, and the IL-17 signaling pathway. Proteomic analysis revealed that S100A9 knockout alleviated muscle contraction dysfunction and structural remodeling in sepsis-induced ALI. Multiomics analysis revealed that S100A9 may be closely related to interferon-induced proteins with tetratricopeptide repeats and oligoadenylate synthase-like proteins. LPS decreased MLE12 cell activity, accompanied by high expression of S100A9. The expression of IL-17RA, pNFκB, and cleaved-caspase-3 were increased by S100A9 overexpression and reduced by S100A9 knockdown in LPS-stimulated MLE12 cells. S100A9 knockdown decreases transcription of apoptosis-related markers Bax, Bcl and caspase-3, alleviating LPS-induced apoptosis. CONCLUSIONS: S100A9 as a key biomarker of sepsis-induced acute lung injury, and exacerbates lung damage and epithelial cell apoptosis induced by LPS via the IL-17-NFκB-caspase-3 signaling pathway.

Targeting BRD4 with PROTAC degrader ameliorates LPS-induced acute lung injury by inhibiting M1 alveolar macrophage polarization.

OBJECTIVES: Acute lung injury (ALI) is a highly inflammatory condition with the involvement of M1 alveolar macrophages (AMs) polarization, eventually leading to the development of non-cardiogenic edema in alveolar and interstitial regions, accompanied by persistent hypoxemia. Given the significant mortality rate associated with ALI, it is imperative to investigate the underlying mechanisms of this condition so as to identify potential therapeutic targets. The therapeutic effects of the inhibition of bromodomain containing protein 4 (BRD4), an epigenetic reader, has been proven with high efficacy in ameliorating various inflammatory diseases through mediating immune cell activation. However, little is known about the therapeutic potential of BRD4 degradation in acute lung injury. METHODS: This study aimed to assess the protective efficacy of ARV-825, a novel BRD4-targeted proteolysis targeting chimera (PROTAC), against ALI through histopathological examination in lung tissues and biochemical analysis in bronchoalveolar lavage fluid (BALF). Additionally, the underlying mechanism by which BRD4 regulated M1 AMs was elucidated by using CUT & Tag assay. RESULTS: In this study, we found the upregulation of BRD4 in a lipopolysaccharide (LPS)-induced ALI model. Furthermore, we observed that intraperitoneal administration of ARV-825, significantly alleviated LPS-induced pulmonary pathological changes and inflammatory responses. These effects were accompanied by the suppression of M1 AMs. In addition, our findings revealed that the administration of ARV-825 effectively suppressed M1 AMs by inhibiting the expression of IRF7, a crucial transcriptional factor involved in M1 macrophages. CONCLUSION: Our study suggested that targeting BRD4 using ARV-825 is a potential therapeutic approach for ALI.

Effect of TRPV4 Antagonist GSK2798745 on Chlorine Gas-Induced Acute Lung Injury in a Swine Model.

As a regulator of alveolo-capillary barrier integrity, Transient Receptor Potential Vanilloid 4 (TRPV4) antagonism represents a promising strategy for reducing pulmonary edema secondary to chemical inhalation. In an experimental model of acute lung injury induced by exposure of anesthetized swine to chlorine gas by mechanical ventilation, the dose-dependent effects of TRPV4 inhibitor GSK2798745 were evaluated. Pulmonary function and oxygenation were measured hourly; airway responsiveness, wet-to-dry lung weight ratios, airway inflammation, and histopathology were assessed 24 h post-exposure. Exposure to 240 parts per million (ppm) chlorine gas for ≥50 min resulted in acute lung injury characterized by sustained changes in the ratio of partial pressure of oxygen in arterial blood to the fraction of inspiratory oxygen concentration (PaO2/FiO2), oxygenation index, peak inspiratory pressure, dynamic lung compliance, and respiratory system resistance over 24 h. Chlorine exposure also heightened airway response to methacholine and increased wet-to-dry lung weight ratios at 24 h. Following 55-min chlorine gas exposure, GSK2798745 marginally improved PaO2/FiO2, but did not impact lung function, airway responsiveness, wet-to-dry lung weight ratios, airway inflammation, or histopathology. In summary, in this swine model of chlorine gas-induced acute lung injury, GSK2798745 did not demonstrate a clinically relevant improvement of key disease endpoints.

Novel application of nanomedicine for the treatment of acute lung injury: a literature review.

Nanoparticles have attracted extensive attention due to their high degree of cell targeting, biocompatibility, controllable biological activity, and outstanding pharmacokinetics. Changing the size, morphology, and surface chemical groups of nanoparticles can increase the biological distribution of agents to achieve precise tissue targeting and optimize therapeutic effects. Examples of their use include nanoparticles designed for increasing antigen-specific immune responses, developing vaccines, and treating inflammatory diseases. Nanoparticles show the potential to become a new generation of therapeutic agents for regulating inflammation. Recently, many nanomaterials with targeted properties have been developed to treat acute lung injury/acute respiratory distress syndrome (ALI/ARDS). In this review, we provide a brief explanation of the pathological mechanism underlying ALI/ARDS and a systematic overview of the latest technology and research progress in nanomedicine treatments of ALI, including improved nanocarriers, nanozymes, and nanovaccines for the targeted treatment of lung injury. Ultimately, these nanomedicines will be used for the clinical treatment of ALI/ARDS.

The Top 100 Cited Articles Focusing on Acute Lung Injury and ARDS: Bibliometric and Visualization Analyses.

BACKGROUND: In recent years, acute lung injury (ALI) and ARDS have emerged as critical health concerns, drawing considerable attention from clinicians. The volume of published articles on ALI/ARDS is on the rise, indicating the expanding research interest in this field. However, the precise quantity and quality of studies on ALI/ARDS remain unclear. Consequently, we employed bibliometric and visual techniques to comprehensively analyze the patterns and focal points of these articles. METHODS: To investigate the characteristics of highly referenced papers on ALI/ARDS and offer insights into the progress and advancements in research on ALI/ARDS, we conducted a comprehensive search in the core Web of Science database for cited articles using the terms "ALI," "acute lung injury," "ARDS," or "acute respiratory distress syndrome." A total of 60,282 citations were retrieved by narrowing the scope to reviews, articles, and publications in English. From the obtained citations, we selected materials for analysis from the top 100 articles with the highest number of citations. Subsequently, the articles were visualized and analyzed using VOSviewer, CiteSpace, and bibliometric techniques. This analysis focused on identifying trends related to authors, journals, countries, institutions, collaborative networks, key words, and other relevant factors in the field of ALI/ARDS research. RESULTS: Among the top 100 cited articles, the highest and lowest number of citations were 6,957 and 451, respectively. A total of 100 articles were published between 1991-2020, with a peak in publications observed in 2004, 2005, and 2012 (no. = 7). Among 29 journals, The New England Journal of Medicine (no. = 21) had the highest number of publications, followed by the American Journal of Respiratory and Critical Care Medicine (no. = 14). Among the 29 countries represented in the top 100 cited articles, the United States (no. = 51) emerged as the leading country in the number of publications, followed by Canada (no. = 19) (there was some overlap in paper output between countries due to co-publication). The 3 predominant keywords identified in studies within the ALI/ARDS domain were ALI, mechanical ventilation, and PEEP. CONCLUSIONS: This study provides a historical perspective on the scientific advancements in ALI/ARDS research, highlighting the need for further investigation and development in specific areas within the field. Bibliometric analyses reveal that the United States is the predominant force in the field of ALI/ARDS, contributing significantly to its development. Through an examination of highly cited papers on ALI/ARDS, we have identified global research trends, assessed the quality of studies, and identified hot topics in the field of ALI/ARDS.

Icariside II alleviates lipopolysaccharide-induced acute lung injury by inhibiting lung epithelial inflammatory and immune responses mediated by neutrophil extracellular traps.

AIMS: Acute lung injury (ALI) is a life-threatening lung disease characterized by inflammatory cell infiltration and lung epithelial injury. Icariside II (ICS II), one of the main active ingredients of Herba Epimedii, exhibits anti-inflammatory and immunomodulatory effects. However, the effect and mechanism of ICS II in ALI remain unclear. The purpose of the current study was to investigate the pharmacological effect and underlying mechanism of ICS II in ALI. MAIN METHODS: Models of neutrophil-like cells, human peripheral blood neutrophils, and lipopolysaccharide (LPS)-induced ALI mouse model were utilized. RT-qPCR and Western blotting determined the gene and protein expression levels. Protein distribution and quantification were analyzed by immunofluorescence. KEY FINDINGS: ICS II significantly reduced lung histopathological damage, edema, and inflammatory cell infiltration, and it reduced pro-inflammatory cytokines in ALI. There is an excessive activation of neutrophils leading to a significant production of NETs in ALI mice, a process mitigated by the administration of ICS II. In vivo and in vitro studies found that ICS II could decrease NET formation by targeting neutrophil C-X-C chemokine receptor type 4 (CXCR4). Further data showed that ICS II reduces the overproduction of dsDNA, a NETs-related component, thereby suppressing cGAS/STING/NF-κB signalling pathway activation and inflammatory mediators release in lung epithelial cells. SIGNIFICANCE: This study suggested that ICS II may alleviate LPS-induced ALI by modulating the inflammatory response, indicating its potential as a therapeutic agent for ALI treatment.

Exosomal Tenascin-C primes macrophage pyroptosis amplifying aberrant inflammation during sepsis-induced acute lung injury.

Sepsis-induced acute lung injury (ALI) is a serious complication of sepsis and the predominant cause of death. Exosomes released by lung tissue cells critically influence the progression of ALI during sepsis by modulating the inflammatory microenvironment. However, the molecular mechanisms by which exosome-mediated intercellular signaling exacerbates ALI in septic infection remain undefined. Our study found increased levels of exosomal Tenascin-C (TNC) in the plasma of both patients and mice with ALI, showing a strong association with disease progression. By integrating exosomal proteomics with transcriptome sequencing and experimental validation, we elucidated that LPS induce unresolved endoplasmic reticulum stress (ERs) in alveolar epithelial cells (AECs), ultimately leading to the release of exosomal TNC through the activation of PERK-eIF2α and the transcription factor CHOP. In the sepsis mouse model with TNC knockout, we noted a marked reduction in macrophage pyroptosis. Our detailed investigations found that exosomal TNC binds to TLR4 on macrophages, resulting in an augmented production of ROS, subsequent mitochondrial damage, activation of the NF-κB signaling pathway, and induction of DNA damage response. These interconnected events culminate in macrophage pyroptosis, thereby amplifying the release of inflammatory cytokines. Our findings demonstrate that exosomal Tenascin-C, released from AECs under unresolved ER stress, exacerbates acute lung injury by intensifying sepsis-associated inflammatory responses. This research provides new insights into the complex cellular interactions underlying sepsis-induced ALI.