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Ammonia acts as a detrimental atmospheric pollutant, posing a sever threat to respiratory tract health and causing lung injury in humans and animals. Circular RNAs (circRNAs) are a distinctive class of non-coding RNA generated by back-splicing of linear RNA, implicated in various biological processes. However, their role in the immune response of chicken lungs to ammonia exposure remains unclear. In this study, we examined the expression profiles of circRNAs in chicken lungs under ammonia stimulation. In total, 61 differentially expressed (DE) circRNAs were identified between the ammonia exposure and control groups, including 17 up-regulated and 44 down-regulated circRNAs. The source genes of these DE circRNAs were predominantly enriched in Influenza A, SNARE interactions in vesicular transport, and Notch signaling pathway. Notably, nine DE circRNAs (circNBAS, circMTIF2, circXPO1, circSNX24, circRAB11A, circARID3B, circUSP54, circPPARA, and circERG) were selected for validation the reliability and authenticity of RNA-seq data. Results showed the back-splicing circular structure, as well as the reliability and accuracy of RNA-seq data in quantifying circRNA expression, as the RT-qPCR results were in agreement with the RNA-seq data. Moreover, we constructed the circRNA-miRNA-mRNA regulatory networks and identified several regulatory networks in chicken lungs under ammonia stimulation, including circRAB11A-gga-miR-191b-3p-BRD2 and circARID3B-gga-miR-1696-CKS2. Taken together, our study delineates the circRNA expression profile and their potential roles in the immune response of chicken lungs to ammonia exposure. These findings offer insights into molecular mechanisms that may mitigate diseases associated with ammonia induced respiratory tract pollution in humans and animals., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: Idiopathic pulmonary fibrosis (IPF) is a chronic and highly fatal disease characterized by excessive accumulation of extracellular matrix (ECM), foci of myofibroblasts, and a usual pattern of interstitial pneumonia. As suggested by international guidelines, the treatment for this disease involves supportive therapies, as there is currently no effective treatment. Plant-derived nanovesicles have emerged as a new treatment for various diseases and have been tested in cellular and murine models., Methods and Results: This research aimed to test the use of Allium sativum nanovesicles (AS-NV) in a murine model of IPF induced by bleomycin. AS-NV reduced the amount of collagen and restored lung architecture in the mouse model. AS-NV was tested on human lung fibroblasts, which do not affect the viability of healthy cells. AS-NV treatment decreases the mRNA levels of genes related to fibrosis, inflammation, and ECM deposition (Mmp2,Timp-2,Vegf,Pcna,Col1a1,Tgf-β,α-Sma,IL-1β,and Hif1a) in bleomycin-induced idiopathic pulmonary fibrosis., Conclusions: This research highlights the anti-inflammatory and antifibrotic activity of AS-NV, which contributes to plant nanovesicle mechanisms in IPF; however, more AS-NV studies are needed to identify alternative treatments for idiopathic pulmonary fibrosis., Competing Interests: Declarations Ethical approval All the experimental animal studies were performed with the approval of the Ethics Committee of the Faculty of Medicine and Surgery – Autonomous University “Benito Juarez” of Oaxaca with registration number 0047-CEI-2022. Informed consent Not applicable. Competing interests The authors declare no competing interests., (© 2024. The Author(s), under exclusive licence to Springer Nature B.V.)

Primary graft failure occurs 15 to 30 % of the time after transplantation. Although there have been improvements in preserving the lungs in good condition, there have not been studies on the regulation of transcription factors., Methods: We carried out an experimental study involving lung transplantation to indirectly evaluate reactive oxygen species (ROS) production and VEGF expression by competitive blockade of HIF-1alpha with chetomin. There were 5 groups: Group-1: Lung blocks were perfused with 0.9 % SSF, immediately harvested, and preserved. Group-2 (I-T): Immediate transplantation and then reperfusion for 1 h. Group-3 (I-R): Lung blocks were harvested and preserved in LPD solution for 6 h and reperfused for 1 h. Group-4 (DMSO): Lung blocks were treated for 4 h with DMSO, preserved for 6 h and transplanted to a receptor treated with DMSO. Group-5 (chetomin): Lung blocks were treated for 4 h with chetomin, preserved for 6 h and transplanted to a receptor treated with chetomin. ROS, mRNA, and protein levels of HIF-1alpha and EG-VEGF were determined., Results: The DMSO and chetomin groups had significantly lower ROS levels. Compared with those in the I-R group, the chetomin group exhibited the lowest level of HIF-1alpha., Conclusions: Addition of chetomin to the donor and the receptor results in a significant reduction in HIF-1A, VEGF and ROS.

Bacterial pneumonia is one of the most challenging global infectious diseases with high morbidity and mortality. Considering the antibiotic abuse and resistance of bacterial biofilms, a variety of metal-based materials have been developed. However, due to the high oxygen environment of the lungs, some aerobic infection bacteria have high tolerance to oxygen and ROS, and most of the metal-based materials based on ROS may not achieve good therapeutic effects. Inspired by the sensitivity of cuproptosis to aerobic respiratory cells, we designed a copper composite antibacterial nanoparticle and found that it can effectively induce cuproptosis-like death in the aerobic bacteria of the lungs. To address the challenge of in vivo application of cuproptosis, manganese dioxide was first incorporated to deplete protective glutathione, which can interact with copper and thus hinder the interaction of copper with proteins and assist in antibacterial action through immune enhancement. Cuproptosis-like death also requires a large number of copper ions. To meet this demand, we deliver positively hydrophilic modified composite nanoparticles that effectively penetrate the lung mucus layer directly to the lungs through local administration, and the copper ions are further released rapidly by the acidic environment at the infected site, which can further destroy bacterial biofilms in synergy with manganese. This drug-delivery system can effectively treat pneumonia caused by aerobic bacteria and avoid systemic toxicity that can be caused by large doses of copper.

Aims: Idiopathic pulmonary fibrosis (IPF) is a chronic and progressive lung condition, the cause of which remains unknown and for which no effective therapeutic treatment is currently available. Chlorogenic acid (CGA), a natural polyphenolic compound found in different plants and foods, has emerged as a promising agent due to its anti-inflammatory, antioxidant, and antifibrotic properties. However, the molecular mechanisms underlying the therapeutic effect of CGA in IPF remain unclear. The purpose of this study was to analyze the pharmacological impact and underlying mechanisms of CGA in IPF., Main Methods: Using network pharmacology analysis, genes associated with IPF and potential molecular targets of CGA were identified through specialized databases, and a protein-protein interaction (PPI) network was constructed. Molecular docking was performed to accurately select potential therapeutic targets. To investigate the effects of CGA on lung histology and key gene expression, a murine model of bleomycin-induced lung fibrosis was used., Key Findings: Network pharmacology analysis identified 384 were overlapped between CGA and IPF. Key targets including AKT1, TP53, JUN, CASP3, BCL2, MMP9, NFKB1, EGFR, HIF1A, and IL1B were identified. Pathway analysis suggested the involvement of cancer, atherosclerosis, and inflammatory processes. Molecular docking confirmed the stable binding between CGA and targets. CGA regulated the expression mRNA of EGFR, MMP9, AKT1, BCL2 and IL1B and attenuated pulmonary fibrosis in the mouse model., Significance: CGA is a promising multi-target therapeutic agent for IPF, which is supported by its efficacy in reducing fibrosis through the modulation of key pathways. This evidence provides a basis to further investigate CGA as an IPF potential treatment., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Injuries of the respiratory system caused by viral infections (e.g., by influenza virus, respiratory syncytial virus, metapneumovirus, or coronavirus) can lead to long-term complications or even life-threatening conditions. The challenges of treatment of such diseases have become particularly pronounced during the recent pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). One promising drug is the anti-fibrinolytic and anti-inflammatory protease inhibitor aprotinin, which has demonstrated considerable inhibition of the replication of some viruses. Encapsulation of aprotinin in liposomes can significantly improve the effectiveness of the drug, however, the use of nanoparticles as carriers of aprotinin can radically change its biodistribution in the body. Here we show that the liposomal form of aprotinin accumulates more efficiently in the lungs, heart, and kidneys than the molecular form by side-by-side comparison of the ex vivo biodistribution of these two fluorescently labeled formulations in mice using bioimaging. In particular, we synthesized liposomes of different compositions and studied their accumulation in various organs and tissues. Direct comparison of the biodistributions of liposomal and free aprotinin showed that liposomes accumulated in the lungs 1.82 times more effectively, and in the heart and kidneys - 3.56 and 2.00 times, respectively. This suggests that the liposomal formulation exhibits a longer residence time in the target organ and, thus, has the potential for a longer therapeutic effect. The results reveal the great potential of the aprotinin-loaded liposomes for the treatment of respiratory system injuries and heart- and kidney-related complications of viral infections., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests. E.N.M. and M.P.N. are stakeholders of Abisense LLC that manufactures the LumoTrace FLUO bioimaging system. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Non-steroidal anti-inflammatory drugs (NSAID) are not recommended for use against pneumonia in humans, but are commonly utilised against bovine respiratory disease. This study aimed to determine if the use of NSAIDs in the early phase of bovine respiratory syncytial virus (BRSV)-infection limits pulmonary inflammation. Four to nine-week old calves were infected with BRSV by aerosol and were treated with either meloxicam intravenously on day (D)4 (n = 5, MEL), acetylsalicylat-DL-lysin intravenously on D4 and D5 (n = 5, ASA), or were left untreated as controls (n = 5, CTR). Clinical signs were monitored daily until necropsy on D7, BRSV-RNA was detected in nasal swabs and bronchoalveolar lavage (BAL) by RT-qPCR, inflammatory cells and proteins were identified in BAL by cytology and label-free quantitative mass spectrometry-based proteomics, respectively, and oxylipids were quantified in BAL and plasma by liquid chromatography tandem mass spectrometry with triple quadrupole mass detectors. The calves developed mild to moderate signs of respiratory disease and, with the exception of one MEL-treated and one ASA-treated calf, limited lung lesions. None of the treatments had a significant effect on virus replication, clinical signs or lung lesion extent. Relative to controls, both treatments initially induced a downregulation of proteins in BAL. Immunoglobulin (Ig)-related proteins, such as the Ig kappa and lambda locus and the joining chain of IgA and IgM, were downregulated in MEL-treated calves compared to controls. In addition, meloxicam induced an increased neutrophil influx in BAL in response to BRSV, possibly related to a reduction in plasma prostaglandin, and to a downregulation of The Liver X Receptor/ Retinoid X Receptor (LXR/RXR), the Farnesoid X Receptor (FXR)/RXR and the 24-Dehydrocholesterol Reductase (DHC24) signalling pathways in the lung. The risk of NSAIDs to increase neutrophil activity during stimulation with BRSV or other toll-like receptor 4 agonists needs to be investigated further. Since augmented neutrophil responses can be detrimental, the results of the present study do not support the use of NSAIDs to prevent the clinical expression of BRSV-infection., Competing Interests: Dr. Timsit is an Innovation Scientist at Ceva Animal Health and is responsible for early phases of drug discovery. This article reflects the views of the authors and should not be construed as representing the views of Ceva Sante Animale. None of the authors of this paper has a financial or personal relationship with other people or organizations that could inappropriately influence or bias the content of the paper. This does not alter our adherence to PLOS ONE policies on sharing data and materials., (Copyright: © 2024 Hägglund et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Rifampicin (RIF) is commonly used in the treatment of tuberculosis (TB), a bacterium that currently infects one fourth of the world's population. Despite the effectiveness of RIF in treating TB, current RIF treatment regimens require frequent and prolonged dosing, leading to decreased patient compliance and, ultimately, increased mortality rates. This project aims to provide an alternative to oral RIF by means of an inhalable spray-dried formulation. TB uses alveolar macrophages to hide and replicate until the cells rupture, further spreading the bacteria. Therefore, delivering RIF directly to the lungs can increase the drug concentration at the site of infection while reducing off-site side effects. Cyclodextrin (CD) was used to create a RIF-CD inclusion complex to increase RIF solubility and biodegradable RIF-loaded NP (RIF NP) were developed to provide sustained release of RIF. RIF NP and RIF-CD inclusion complex were spray dried to form a dry powder nanocomposite microparticles (nCmP) formulation (RIF-CD nCmP). RIF-CD nCmP displayed appropriate aerosol dispersion characteristics for effective deposition in the alveolar region of the lungs (4.0 µm) with a fine particle fraction of 89 %. The nCmP provided both a burst release of RIF due to the RIF-CD complex and pH-sensitive release of RIF due to the RIF NP incorporated into the formulation. RIF-CD nCmP did not adversely affect lung epithelial cell viability and RIF NP were able to effectively redisperse from the nCmP after spray drying. These results suggest that RIF-CD nCmP can successfully deliver RIF to the site of TB infection while providing both immediate and sustained release of RIF. Overall, the RIF-CD nCmP formulation has the potential to improve the efficacy for the treatment of TB., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: Irreversible pulmonary fibrosis induced by paraquat is the most prevalent cause of death in patients with paraquat poisoning. Pulmonary fibrosis is characterized by abnormal deposition of extracellular matrix (ECM). Currently, the role of fibrotic ECM microenvironment in paraquat-induced pulmonary fibrosis has not been established., Methods: Rat pulmonary fibrosis model was induced by paraquat, ATN-161 (an integrin-β 1 antagonist) was given to investigate their effect on Rat survival and pulmonary fibrosis. Lungs were decellularized to generate normal and fibrotic acellular ECM scaffolds using Triton and SDS. Fibroblasts were cocultured with ECM scaffolds to established 3D culture systems to investigate the relationship between fibrotic ECM and the differentiation of fibroblasts. Then we explored the effect of fibrotic ECM microenvironment systematically promoting on integrin-β1/FAK/ERK1/2 pathway and established 3D culture systems to investigate the relationship between fibrotic ECM and the differentiation of fibroblasts., Results: Antagonism of integrin-β 1 could alleviate paraquat-induced pulmonary fibrosis and ameliorate survival status of rats. Compared to normal ECM, fibrotic extracellular microenvironment promoted the differentiation of fibroblasts to myofibroblasts. Antagonism of integrin-β 1 could also ameliorate the promotion of fibrotic extracellular microenvironment on differentiation of fibroblasts to myofibroblasts. Fibrotic ECM microenvironment promotes fibroblasts transforming into myofibroblasts through integrin-β 1 /FAK/ERK1/2 signaling pathway. Moreover, this phenomenon holds independent on exogenous integrin-β 1 ., Conclusions: Activation of integrin-β 1 /FAK/ERK1/2 pathway aggravates paraquat-induced pulmonary fibrosis depend on fibrotic ECM and integrin-β 1 may be a prospective therapeutic target for paraquat-induced pulmonary fibrosis in the future., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

Turmeric (Curcuma longa L.) extract (CLE) has been shown to elicit several pharmacological properties and is widely used in Asian traditional medicine. Herein, we assessed the impact of CLE on airway inflammation in BALB/c mice and A549 cells to clarify the underlying mechanism. An asthmatic mouse model was established by administering ovalbumin (OVA). CLE (100 or 300 mg/kg/day) was orally administered daily from days 18 to 23, with dexamethasone (3 mg/kg/day) used as the positive control. Human airway epithelial cells, A549, were stimulated using recombinant tumor necrosis factor-α. The CLE100 and CLE400 groups exhibited a significant downregulation in eosinophil counts, cytokine levels, and immunoglobulin-E levels. Moreover, CLE administration dose-dependently suppressed oxidative stress and airway inflammation in the lung tissue. CLE administration inhibited the phosphorylation of mitogen-activated protein kinases (MAPKs) and the expression and activity of matrix metalloproteinase (MMP)-9. In vitro, CLE treatment reduced mRNA levels of proinflammatory cytokines, MAPK phosphorylation, and the expression and activity of MMP-2 and MMP-9. Additionally, 50 µg/mL CLE and 2.5 µg/mL curcumin showed similar anti-inflammatory effects. Collectively, our findings revealed that CLE could suppress airway inflammation in asthmatic mice and A549 cells via oxidative stress-driven MAPK/MMPs signaling, suggesting that CLE could be developed as a potential treatment option for patients with asthma., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Lung inflammation as a result of exposure to toxicants is a major pathological problem. Autophagy (AP) is a process of cell self-digestion and can be disrupted by environmental toxicants, leading to oxidative stress, inflammation and cellular damage. Bryophyllum pinnatum (Lam.) Oken has been used in folklore medicine to manage pathological abnormalities, including inflammation, but mechanisms remain unclear. This work investigated the effects of Bryophyllum pinnatum ethanol leaf extract (BP) on dysfunctional AP in the lungs of Wistar rats exposed to zinc oxide nanoparticles (ZONPs). The experimental rats were orally administered ZONPs for seven days (10 mg/kg). Some exposed rats were post-treated with BP (62.5 and 125 mg/kg) through oral gavage. Oxidative stress, inflammation, and apoptotic and autophagic parameters were assessed using biochemical assay and gene expression methods. Several indices of pulmonary damage were also evaluated. PCR analysis suggested that ZONP downregulated the expression of pro-autophagy-related genes (Beclin 2, ATG5, DAPK, and FOXP3) and upregulated the expression of the TNF-alpha, NF-Kb, LC3 and Bcl2 genes. In contrast, BP significantly (p < 0.0001) reversed ZONP-induced pulmonary toxicity and oxidative stress. It reduced MDA levels and increased SOD, CAT, GSH and GPxD activities. BP significantly (p < 0.0001) downregulated the expressions of proinflammatory genes (IL-6 and JNK) and upregulated the expressions of IL-10, CAT and SOD genes in ZONP-exposed rats. BP restored the lung's histoarchitectural structure after ZNOP-induced distortion. The results suggested that BP has antioxidant and anti-inflammatory properties, and could effectively restore ZNOP-induced dysfunctional AP in the lungs of Wistar rats., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Increasing evidence has demonstrated that coenzyme Q10 (CoQ10) exhibits a range of biological properties. Herein, we explored the protective effect and potential molecular mechanism of CoQ10 on lipopolysaccharide (LPS)-induced acute lung injury (ALI). We found that medium (10 mg/kg) and high (50 mg/kg) doses of CoQ10 ameliorated LPS (50 µg/µL)-induced ALI to varying degrees, as demonstrated by reduced lung coefficient, lower wet/dry weight lung tissue ratio, decreased bronchoalveolar lavage fluid protein concentration, less anatomical and histopathological damage to the lung, and increased expression of proteins related to lung epithelial barrier structure. CoQ10 also alleviated LPS-induced oxidative stress and inflammation mediated by NOD-like receptor protein 3 (NLRP3) by reducing the reactive oxygen species (ROS), malondialdehyde, and mitochondrial ROS concentrations, increasing superoxide dismutase, glutathione, and catalase activity, and decreasing NLRP3 expression at the protein and mRNA levels. Moreover, CoQ10 alleviated structural and functional damage to the mitochondria, inhibited mitochondrial fission, and promoted mitochondrial fusion, mainly by inhibiting phosphorylation of dynamin-related protein 1 (Drp1) at Ser616 and Ser637. Correlation analysis revealed that mitochondrial fission (especially Drp1) was positively correlated with oxidative stress, NLRP3-mediated inflammation, and structural damage to the lung epithelial barrier. Molecular docking analysis showed that CoQ10 binds stably to Drp1, with a binding energy of -5.9 kcal/mol. Furthermore, the use of schaftoside (a Drp1 inhibitor) has further elucidated the mechanism of action of CoQ10. Together, these results suggest that CoQ10 alleviates LPS-induced ALI by regulating mitochondrial dynamics, attenuating oxidative stress, and decreasing NLRP3-medated inflammation, thereby promoting lung epithelial barrier structural remodeling., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

Sepsis, characterized by high mortality rates, causes over 50 % of acute lung injury (ALI) cases, primarily due to the heightened susceptibility of the lungs during this condition. Suppression of the excessive inflammatory response is critical for improving the survival of patients with sepsis; nevertheless, no specific anti-sepsis drugs exist. Huperzine A (HupA) exhibits neuroprotective and anti-inflammatory properties; however, its underlying mechanisms and effects on sepsis-induced ALI have yet to be elucidated. In this study, we demonstrated the potential of HupA for treating sepsis and explored its mechanism of action. To investigate the in vivo impacts of HupA, a murine model of sepsis was induced through cecal ligation and puncture (CLP) in both wild-type (WT) and α7 nicotinic acetylcholine receptor (α7nAChR) knockout mice. Our results showed that HupA ameliorates sepsis-induced acute lung injury by activating the α7nAChR. We used the CLP sepsis model in wild-type and α7nAChR -/- mice and found that HupA significantly increased the survival rate through α7nAChR, reduced the pro-inflammatory cytokine levels and oxidative stress, ameliorated histopathological lung injury, altered the circulating immune cell composition, regulated gut microbiota, and promoted short-chain fatty acid production through α7nAChR in vivo. Additionally, HupA inhibited Toll-like receptor NF-κB signaling by upregulating the α7nAChR/protein kinase B/glycogen synthase kinase-3 pathways. Our data elucidate HupA's mechanism of action and support a "new use for an old drug" in treating sepsis. Our findings serve as a basis for further in vivo studies of this drug, followed by application to humans. Therefore, the findings have the potential to benefit patients with sepsis., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Epidemiologic studies suggest that prenatal exposure to bisphenols may increase the risk of respiratory disease in children. Bisphenol F (BPF), a member of the bisphenol family, is widely used in industrial production. However, the potential pulmonary toxic effects and mechanisms of BPF exposure on offspring remain unclear. In this study, maternal mice were exposed to 0, 40, 400, and 4000 μg/kg BPF during gestation and lactation. The results showed that an inflammatory response was observed in lungs of BPF-exposed female offspring mice, characterized by peribronchial inflammatory cell infiltration and an increase in the number of inflammatory cells in BALF. Subsequent transcriptome analysis identified a total of 685 differentially expressed genes (DEGs) were in lungs of female offspring mice exposed to high-dose BPF, with 526 upregulated genes and 159 downregulated genes. Among upregulated DEGs of top 10, most of the upregulated genes were associated with inflammatory responses. In addition, enrichment analysis showed that immunosuppression and oxidative damage were significantly enriched in lungs of female offspring mice, suggesting that BPF could induce immunosuppression and oxidative stress in lungs of female offspring mice. Overall, our findings provide mechanistic insights into the potential pulmonary toxicity associated with BPF exposure during gestation and lactation., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Ethnopharmacological Relevance: Fuzheng-Qushi decoction (FZQS) is a practical Chinese herbal formula for relieving cough and fever. Therefore, the action and specific molecular mechanism of FZQS in the treatment of lung injury with cough and fever as the main symptoms need to be further investigated., Aims of the Study: To elucidate the protective effects of FZQS against lung injury in mice and reveal its potential targets and key biological pathways for the treatment of lung injury based on transcriptomics, microbiomics, and untargeted metabolomics analyses., Materials and Methods: Lipopolysaccharide (LPS) was used to induce a mouse model of lung injury, followed by the administration of FZQS. ELISA was used to detect IL-1β, IL-6, IL-17A, IL-4, IL-10, and TNF-α, in mouse lung tissues. Macrophage polarization and neutrophil activation were measured by flow cytometry. RNA sequencing (RNA-seq) was applied to screen for differentially expressed genes (DEGs) in lung tissues. RT-qPCR and Western blot assays were utilized to validate key DEGs and target proteins in lung tissues. 16S rRNA sequencing was employed to characterize the gut microbiota of mice. Metabolites in the gut were analyzed using untargeted metabolomics., Results: FZQS treatment significantly ameliorated lung histopathological damage, decreased pro-inflammatory cytokine levels, and increased anti-inflammatory cytokine levels. M1 macrophage levels in the peripheral blood decreased, M2 macrophage levels increased, and activated neutrophils were inhibited in mice with LPS-induced lung injury. Importantly, transcriptomic analysis showed that FZQS downregulated macrophage and neutrophil activation and migration and adhesion pathways by reversing 51 DEGs, which was further confirmed by RT-qPCR and Western blot analysis. In addition, FZQS modulated the dysbiosis of the gut microbiota by reversing the abundance of Corynebacterium, Facklamia, Staphylococcus, Paenalcaligenes, Lachnoclostridium, norank&#95;f&#95;Muribaculaceae, and unclassified&#95;f&#95;Lachnospiraceae. Meanwhile, metabolomics analysis revealed that FZQS significantly regulated tryptophan metabolism by reducing the levels of 3-Indoleacetonitrile and 5-Hydroxykynurenine., Conclusion: FZQS effectively ameliorated LPS-induced lung injury by inhibiting the activation, migration, and adhesion of macrophages and neutrophils and modulating gut microbiota and its metabolites., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

Ethnopharmacological Relevance: In Mongolian medicine, Loulu flower (LLF), the dried inflorescence of Rhaponticum uniflorum (L.) DC. from the Compositae family, has been used to clear heat and relieve toxicity for millennia, particularly in the treatment of pneumonia., Aim of This Study: To reveal the effects of LLF on mice with lipopolysaccharide (LPS)-stimulated acute lung injury (ALI) and elucidate the underlying mechanisms., Materials and Methods: ALI was established in BALB/c mice via nasal drops administration of LPS (5 mg/kg). The mice were then orally administrated with various doses of LLF extracts and the positive drug dexamethasone (DEX, 5 mg/kg), once daily for seven consecutive days. Last day, after being stimulated with LPS for 6h, the mice were closed dislocation of cervical vertebra, the serum, bronchus alveolar lavage fluid (BALF) and lung tissue were put into the EP tube and stored at -80 °C for further analysis. The changes of histopathology were tested by hematoxylin and eosin stain (H&E), the levels of, IL-1β, IL-18, TNF-α and IL-4 in BALF and serum were measured by ELISA. The pathways related to the treatment of ALI were predicted by network pharmacology. The expression levels of TLR4/NF-κB and NLRP3 signaling pathway-associated proteins, COX-2 and ERK were tested by western blotting. The levels of P65 and NLRP3 in lung tissues were determined by immunofluorescence analysis., Results: LLF total extract and the extract parts could alleviate the inflammatory cell infiltration, thicken the alveolar walls in lung tissues, reduce the levels of IL-18, IL-1β in BALF, the TNF-α in both BALF and serum, meantime enhance the level of IL-4 in BALF and serum in mice with LPS-induced ALI. Our network pharmacology and comprehensive gene ontology analyses revealed the active constituents of LLF and the pathways, including TLR4/NF-κB, NLRP3 and MAPK signaling pathways, which play significant roles in ALI. Furthermore, both the total extract and its extraction portions suppressed the expressions of proteins related with the COX-2, p-ERK and TLR4/NF-κB signaling pathway (TLR4, p-IκB, p-p65), as well as the NLRP3 signaling pathway (NLRP3, cleaved caspase-1, caspase-1, IL-1β)., Conclusion: LLF could improve the pathological changes and reducing inflammatory reactions in mice induced by LPS. The mechanism may be related to the modulation of the TLR4/NLRP3 signaling pathways., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Ethnopharmacological Relevance: Sangju Cold Granule (SJCG) is a classical traditional Chinese medicine (TCM) prescription described in "Item Differentiation of Warm Febrile Diseases". Historically, SJCG was employed to treat respiratory illnesses. Despite its popular usage, the alleviating effect of SJCG on influenza A virus infection and its mechanisms have not been fully elucidated., Aim of the Study: Influenza is a severe respiratory disease that threatens human health. This study aims to assess the therapeutic potential of SJCG and the possible molecular mechanism underlying its activity against influenza A virus in vitro and in vivo., Materials and Methods: Ultrahigh-performance liquid chromatography (UPLC)-Q-Exactive was used to identify the components of SJCG. The 50% cytotoxic concentration of SJCG in MDCK and A549 cells were determined using the CCK-8 assay. The activity of SJCG against influenza A virus H1N1 was evaluated in vitro using plaque reduction and progeny virus titer reduction assays. RT-qPCR was performed to obtain the expression levels of inflammatory mediators and the transcriptional regulation of RIG-I and MDA5 in H1N1-infected A549 cells. Then, the mechanism of SJCG effect on viral replication and inflammation was further explored by measuring the expressions of proteins of the RIG-I/NF-kB/IFN(I/III) signaling pathway by Western blot. The impact of SJCG was explored in vivo in an intranasally H1N1-infected BALB/c mouse pneumonia model treated with varying doses of SJCG. The protective role of SJCG in this model was evaluated by survival, body weight monitoring, lung viral titers, lung index, lung histological changes, lung inflammatory mediators, and peripheral blood leukocyte count., Results: The main SJCG chemical constituents were flavonoids, carbohydrates and glycosides, amino acids, peptides, and derivatives, organic acids and derivatives, alkaloids, fatty acyls, and terpenes. The CC 50 of SJCG were 24.43 mg/mL on MDCK cells and 20.54 mg/mL on A549 cells, respectively. In vitro, SJCG significantly inhibited H1N1 replication and reduced the production of TNF-α, IFN-β, IL-6, IL-8, IL-13, IP-10, RANTES, TRAIL, and SOCS1 in infected A549 cells. Intracellularly, SJCG reduced the expression of RIG-I, MDA5, P-NF-κB P65 (P-P65), P-IκBα, P-STAT1, P-STAT2, and IRF9. In vivo, SJCG enhanced the survival rate and decreased body weight loss in H1N1-infected mice. Mice with H1N1-induced pneumonia treated with SJCG showed a lower lung viral load and lung index than untreated mice. SJCG effectively alleviated lung damage and reduced the levels of TNF-α, IFN-β, IL-6, IP-10, RANTES, and SOCS1 in lung tissue. Moreover, SJCG significantly ameliorated H1N1-induced leukocyte changes in peripheral blood., Conclusions: SJCG significantly reduced influenza A virus and virus-mediated inflammation through inhibiting the RIG-I/NF-kB/IFN(I/III) signaling pathway. Thus, SJCG could provide an effective TCM for influenza treatment., Competing Interests: Declaration of Competing interest The authors declare that there are no conflicts of interest., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Ethnopharmacological Relevance: Radix Bupleuri is the root of Bupleurum chinense DC. (BC) and a classic aromatic traditional Chinese medicine. The traditional pharmacological effects of Radix Bupleuri are alleviating bronchial spasms, dilating airways, and promoting the resolution of respiratory inflammation, thereby reducing asthma symptoms., Aim of the Study: Studies have demonstrated the efficacy of water extracts from BC in asthma treatment. However, the potential role of volatile oil, another active constituent in BC, remains unexplored with asthma. Notably, volatile oil is renowned for its ease of absorption and direct targeting of affected areas, offering distinct advantages in alleviating airway inflammation. This study aims to explain the anti-asthmatic mechanism of BC-oil through in vivo and in vitro pharmacological experiments., Materials and Methods: Firstly, the OVA-induced SD rat asthma model was utilized to evaluate the pharmacological effect of BC-oil by lung function monitoring, HE staining, flow cytometry, ELISA, and RT-qPCR. The anti-asthmatic mechanism was further analyzed by combining transcriptomic analysis of lung tissue from rat model and airway smooth muscle tissue from public database. Initially, GC-MS was used to analyze the components of BC-oil. The anti-asthmatic activity was evaluated in 16-HBE, RBL-2H3, and ASMC cells using CAMKII inhibitors to explore of the critical signal transduction regulated by BC-oil. Furthermore, molecular docking and calcium flow assay were utilized to screen and identify the active components from BC-oil., Results: Oral administration of BC-oil significantly enhanced pulmonary function in asthmatic SD rats by reducing airway resistance and elastic resistance. Additionally, BC-oil inhibited inflammatory cytokines, including serum IL-2, pulmonary Il1b, Tnf, and Cxcl13, demonstrating potent anti-inflammatory and immunomodulatory effects. In this study, we analyzed the significant role of OR2W3 in asthma using public transcriptomic data. Furthermore, we indicated that BC-oil regulated the expression of Olr1433 and GNAL in rat lung tissue. BC-oil reduced degranulation and inhibited gene expression of Il3 and Tnf in RBL-2H3 cells and suppressed gene expression of IL8 and TNF in 16-HBE cells. BC-oil also attenuated airway smooth muscle cell proliferation and expression of Acta2 and Ccnd1. Furthermore, BC-oil regulates asthma-related cellular processes by activating CAMKII. GC-MS analysis identified 11 components of BC-oil, and n-hexadecanoic acid, linoleic acid and oleic acid from BC-oil were identified to interact with OR2W3 by molecular docking. The calcium flow assay revealed linoleic acid as a significant activator of OR2W3 and indicated that BC-oil alleviated asthma through the ectopic olfactory signaling pathway., Conclusions: The mechanism of BC-oil in treating asthma through signal transduction of OR2W3 is revealed at the molecular and cellular levels., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Air pollution is one of the leading causes of early deaths worldwide, with particulate matter (PM) as an emerging factor contributing to this trend. PM is classified based on its physical size, which ranges from PM 10 (diameter ≤10 μm) to PM 2.5 (≤2.5 μm) and PM 0.5 (≤0.5 μm). Smaller-sized PM can move freely through the air and readily infiltrate deep into the lungs, intensifying existing health issues and exacerbating complications. Lung complications are the most common issues arising from PM exposure due to the primary site of deposition in the respiratory system. Conditions such as asthma, COPD, idiopathic pulmonary fibrosis, lung cancer and various lung infections are all susceptible to worsening due to PM exposure. PM can epigenetically modify specific target sites, further complicating its impact on these conditions. Understanding these epigenetic mechanisms holds promise for addressing these complications in cases of PM exposure. This involves studying the effect of PM on different gene expressions and regulation through epigenetic modifications, including DNA methylation, histone modifications and microRNAs. Targeting and manipulating these epigenetic modifications and their mechanisms could be promising strategies for future treatments of lung complications. This review mainly focuses on different epigenetic modifications due to PM 2.5 exposure in the various lung complications mentioned above., Competing Interests: Conflict of interest: All the authors have nothing to disclose., (Copyright ©The authors 2024.)

Background: Hypersensitivity to odorants like perfumes can induce or promote asthma with non-type 2 inflammation for which therapeutic options are limited. Cell death of primary bronchial epithelial cells (PBECs) and the release of the pro-inflammatory cytokines interleukin-6 (IL-6) and IL-8 are key in the pathogenesis. Extra-nasal olfactory receptors (ORs) can influence cellular processes involved in asthma. This study investigated the utility of ORs in epithelial cells as potential drug targets in this context., Methods: We used the A549 cell line and primary bronchial epithelial cells using air-liquid interface culture system (ALI-PBECs). OR expression was investigated by RT-PCR, Western blot, and Immunofluorescence. Effects of OR activation by specific ligands on intracellular calcium concentration, cAMP, Phospholipase C (PLC), cell viability, and IL-6 and IL-8 secretion were analyzed by calcium imaging, enzyme immunoassays, Annexin V/ propidium iodide -based fluorescence-activated cell staining or by ELISA, respectively., Results: By screening A549 cells, the OR51B5 agonists Farnesol and Isononyl Alcohol and the OR1G1 agonist Nonanal increased intracellular Ca2 + . OR51B5 and OR1G1 mRNAs and proteins were detected. Both receptors showed a preferential intracellular localization. OR51B5- but not OR1G1-induced Ca2 + dependent on both cAMP and PLC signaling. Farnesol, Isononyl Alcohol, and Nonanal, all reduced cell viability and induced IL-8 and IL-6 release. The data were verified in ALI-PBECs., Conclusion: ORs in the lung epithelium might be involved in airway-sensitivity to odorants. Their antagonism could represent a promising strategy in treatment of odorant-induced asthma with non-type 2 inflammation., Competing Interests: Declarations Ethical approval The primary lung epithelial cells were isolated from postmortem lung transplants (ethics of University Duisburg-Essen 18–8024-BO and 19–8717-BO). Competing interests The authors declare no competing interests., (© 2024. The Author(s).)

Background: Although copper oxide nanoparticles (CuONPs) offer certain benefits to humans, they can be toxic to organs and exacerbate underlying diseases upon exposure. Chronic obstructive pulmonary disease (COPD), induced by smoking, can worsen with exposure to various harmful particles. However, the specific impact of CuONPs on COPD and the underlying mechanisms remain unknown. In this study, we investigated the toxic effects of CuONPs on the respiratory tract, the pathophysiology of CuONPs exposure-induced COPD, and the mechanism of CuONPs toxicity, focusing on thioredoxin-interacting protein (TXNIP) signaling using a cigarette smoke condensate (CSC)-induced COPD model., Results: In the toxicity study, CuONPs exposure induced an inflammatory response in the respiratory tract, including inflammatory cell infiltration, cytokine production, and mucus secretion, which were accompanied by increased TXNIP, NOD-like receptor protein 3 (NLRP3), caspase-1, and interleukin (IL)-1β. In the COPD model, CuONPs exposure induced the elevation of various indexes related to COPD, as well as increased TXNIP expression. Additionally, TNXIP-knockout (KO) mice showed a significantly decreased expression of NLRP3, caspase-1, and IL-1β and inflammatory responses in CuONPs-exposed COPD mice. These results were consistent with the results of an in vitro experiment using H292 cells. By contrast, TNXIP-overexpressed mice had a markedly increased expression of NLRP3, caspase-1, and IL-1β and inflammatory responses in CuONPs-exposed COPD mice., Conclusions: We elucidated the exacerbating effect of CuONPs exposure on the respiratory tract with underlying COPD, as well as related signaling transduction via TXNIP regulation. CuONPs exposure significantly increased inflammatory responses in the respiratory tract, which was correlated with elevated TXNIP-NLRP3 signaling., Competing Interests: Declarations Ethics approval and consent to participate This research was approved by the Institutional Animal Care Use Committee (IACUC) of Chonnam National University (CNU IACUC-YB-2021-146). Consent for publication Not applicable. Competing interests The authors declare no competing interests., (© 2024. The Author(s).)

Exposure to cigarette smoke significantly enhances susceptibility to bacterial infections by inducing physiological and structural alterations, including immune system dysregulation. This exposure also augments bacterial virulence including biofilm formation, leading to severe infectious diseases and antibiotic resistance. Notably, cigarette smoke exposure increases the incidence of pneumonia by up to 2.5-fold and tuberculosis by up to 4.1-fold. Nicotine, a primary constituent of cigarette smoke, has been extensively characterized for its immunomodulatory effects. However, despite the wealth of knowledge on nicotine's impact on the host immune response, there is a paucity of data regarding its direct effects on various pulmonary pathogens. In the present review, we discuss the main findings in this field., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Radiation-induced lung injury (RILI) initiates radiation pneumonitis and progresses to fibrosis as the main side effect experienced by patients with lung cancer treated with radiotherapy. There is no effective drug for RILI. Sustained vascular activation is a major contributor to the establishment of chronic disease. Here, using a whole thoracic irradiation (WTI) mouse model, we investigated the mechanisms and effectiveness of thrombopoietin mimetic (TPOm) for preventing RILI. We demonstrated that administering TPOm 24 hours before irradiation decreased histologic lung injury score, apoptosis, vascular permeability, expression of proinflammatory cytokines, and neutrophil infiltration in the lungs of mice 2 weeks after WTI. We described the expression of c-MPL, a TPO receptor, in mouse primary pulmonary microvascular endothelial cells, showing that TPOm reduced endothelial cell-neutrophil adhesion by inhibiting ICAM-1 expression. Seven months after WTI, TPOm-treated lung exhibited less collagen deposition and expression of MMP-9, TIMP-1, IL-6, TGF-β, and p21. Moreover, TPOm improved lung vascular structure, lung density, and respiration rate, leading to a prolonged survival time after WTI. Single-cell RNA sequencing analysis of lungs 2 weeks after WTI revealed that TPOm shifted populations of capillary endothelial cells toward a less activated and more homeostatic phenotype. Taken together, TPOm is protective for RILI by inhibiting endothelial cell activation.

Pulmonary hypertension (PH) is a devastating disease characterized by vascular remodeling, resulting in right ventricular failure and death. Dysregulation of energy metabolism is linked to PH pathogenesis. Trimetazidine (TMZ), a selective long-chain 3-ketoacyl coenzyme A thiolase inhibitor, is critical in maintaining energy metabolism. Despite the indicated TMZ's inhibitory effect on pulmonary vascular remodeling in PH development, the integrated evaluation of the changes in biomolecules, such as metabolites and transcripts, that TMZ induces in the lung and heart tissues is largely unknown in vivo. For an improved understanding of the molecular mechanism involving the effects of TMZ on PH development, we performed a comprehensive analysis of the changes in cardiac metabolites and pulmonary transcripts of SU5416-Hypoxia (Su/Hx) rats treated with TMZ. Metabolomic analysis of the Su/Hx-induced PH hearts demonstrated that TMZ reduced the long-chain fatty acid concentration. Additionally, TMZ alleviated PH degree and excessive strain on the right heart functions in rats with Su/Hx-induced PH. We identified the candidate target genes for TMZ treatment during PH development. Interestingly, the mRNA levels of the fatty acid transporters were substantially downregulated by TMZ administration in the lungs with Su/Hx-induced PH. Notably, TMZ suppressed excessive proliferation of human pulmonary artery smooth muscle cells under hypoxic conditions. Our study suggests that TMZ ameliorates PH development by involving energy metabolism in the lungs and heart., (© 2024. The Author(s).)

High-dose levofloxacin was explored in a clinical trial against multidrug-resistant tuberculosis and failed to show increased efficacy. In this study, we used a murine model to explore the efficacy of a dose increase in levofloxacin monotherapy beyond the maximum dose evaluated in humans. A total of 120 4-week-old female BALB/c mice were intravenously infected with 10 6 CFU of Mycobacterium tuberculosis H37Rv wild-type (WT) or isogenic H37Rv mutants harboring GyrA A90V or D94G substitutions; the MICs were 0.25, 4, and 6 µg/mL, respectively. Levofloxacin 250 and 500 mg/kg were given every 12 h (q12h) orally for 4 weeks. Pharmacokinetic parameters were determined after five doses. These two regimens decreased lung bacillary load in mice infected with H37Rv WT but not in mice infected with the A90V and D94G mutants. Levofloxacin 250 mg/kg q12h in mice generated pharmacokinetic parameters equivalent to 1,000 mg/d in humans, whereas 500 mg/kg q12h generated a twofold greater exposure than the highest equivalent dose tested in humans (1,500 mg/d). In our dose-response model, the effective concentration at 50% (EC 50 ) produced an AUC/MIC (AUC 0-24h /MIC) ratio of 167.9 ± 27.5, and at EC 80 it was 281.2 ± 97.3. Based on this model, high-dose levofloxacin regimens above 1,000 mg/d are not expected to cause a significant increase in bactericidal activity. This study suggests no benefit of high-dose levofloxacin above 1,000 mg/d in the treatment of fluoroquinolone-susceptible or -resistant tuberculosis., Competing Interests: The authors declare no conflict of interest.

Mycobacterium abscessus (Mab ) is an opportunistic pathogen common in patients with lung comorbidities and immunosuppression. There are no FDA-approved treatments, and current treatment has a failure rate exceeding 50%. The intravenous oxaborole MRX-6038 is active against Mab . This study evaluated MRX-5, the oral prodrug, against five Mab isolates in a mouse lung infection model. MRX-5 showed dose-dependent efficacy, with 15 and 45 mg/kg doses comparable to the standard of care, supporting progression to clinical trial., Competing Interests: Wen Wang is an employee of MicuRx Pharmaceuticals, Inc.

The spectinamides are novel, narrow-spectrum semisynthetic analogs of spectinomycin, modified to avoid intrinsic efflux by Mycobacterium tuberculosis . Spectinamides, including lead MBX-4888A (Lee-1810), exhibit promising therapeutic profiles in mice, as single drugs and as partner agents with other anti-tuberculosis antibiotics including rifampin and/or pyrazinamide. Here, we show that MBX-4888A, given by injection with the front-line standard of care regimen, is treatment shortening in multiple murine tuberculosis infection models. The positive treatment responses to MBX-4888A combination therapy in multiple mouse models, including mice exhibiting advanced pulmonary disease, can be attributed to favorable distribution in tissues and lesions, retention in caseum, along with favorable effects with rifampin and pyrazinamide under conditions achieved in necrotic lesions. This study also provides an additional data point regarding the safety and tolerability of spectinamide MBX-4888A in long-term murine efficacy studies., Competing Interests: The authors declare no conflict of interest.

High-resolution characterization of magnetite nanoparticles (MNPs) derived from coal combustion activities is crucial to better understand their health-related risks. In this study, size distribution and elemental composition of individual MNPs from various coal fly ashes (CFAs) collected from a representative coal-fired power plant were analyzed using a single-particle inductively coupled plasma time-of-flight mass spectrometry technique. Majority (61-80%) of MNPs were identified as multimetal (mm)-MNPs, while the contribution of single metal (sm)-MNPs to the total increased throughout all the CFAs, reaching the highest in fly ash escaped through the stack (EFA). Among Fe-rich MNPs, Fe-sole and Fe-Al matrices were predominant, and Fe-sole MNPs were identified as the important carrier for toxic metals, with the highest mass contributions of toxic metals therein. Toxic potency results showed that the oxidative stress induced by MNPs was 1.2-2.2 times greater than those of <1 μm fractions in CFAs, while the reduction in cell viability showed no significant difference, elucidating that these MNPs can induce more distinct oxidative stress compared to cell toxicity. Based on structural equation model, MNP size can both directly and indirectly regulate the toxic potency, and the indirect regulation is through a size-dependent elemental composition of MNPs, including toxic metals. sm-MNPs and Fe-rich MNPs with Fe-sole, Fe-Cr, and Fe-Zn matrices can regulate the oxidative stress, whereas Cr, Zn, and Pb associated with Fe-sole, Fe-Al, Si-Fe, and Al-Fe MNPs showed significant effects on cell viability.

The persistent challenge of idiopathic pulmonary fibrosis (IPF), characterized by disease progression and high mortality, underscores the urgent need for innovative therapeutic strategies. We have developed a novel small molecule-catechin derivative ABI-171-selectively targeting dual-specificity tyrosine-phosphorylation-regulated kinase 1A (DYRK1A) and proviral integration site for Moloney murine leukemia virus 1 (PIM1) kinases, crucial in the pathogenesis of fibrotic processes. We employed the Bleomycin-induced (intratracheal) mouse model of pulmonary fibrosis (PF) to evaluate the therapeutic efficacy of ABI-171. Mice with induced PF were treated QD with ABI-171, either prophylactically or therapeutically, using oral and intranasal routes. Pirfenidone (100 mg/kg, TID) and Epigallocatechin gallate (EGCG, 100 mg/kg, QD), a natural catechin currently in a Phase 1 clinical trial, were used as reference compounds. ABI-171, administered prophylactically, led to a significant reduction in hydroxyproline levels and fibrotic tissue formation compared to the control group. Treatment with ABI-171 improved body weight, indicating mitigation of disease-related weight loss. Additionally, ABI-171 demonstrated anti-inflammatory activity, reducing lymphocyte and neutrophil infiltration. In the therapeutic setting, ABI-171, administered 7 days post-induction, reduced mortality rates ( p = 0.04) compared with the bleomycin and EGCG control groups. ABI-171 also ameliorated the severity of lung injuries assessed by improved Masson's trichrome scores when administered both orally and intranasally. ABI-171 significantly decreases bleomycin-induced PF and improves survival in mice, showcasing promising therapeutic potential beyond current medications like pirfenidone and EGCG for patients with IPF. Based on these results, further studies with ABI-171 are ongoing in preclinical studies.

Background: Newly approved highly effective modulation therapies (HEMT) have been life-changing for people with CF. Although these drugs have resulted in significant improvements in lung function and exacerbation rate, bacterial populations in the lung have not been eradicated. The mechanisms behind the continued colonization are not completely clear., Methods: We used a humanized rat to assess the effects of ivacaftor therapy on infection outcomes. Rats harbor an insert expressing humanized CFTR cDNA, including the G551D mutation. hG551D rats were treated with ivacaftor either during or before infection with P. aeruginosa. The response to infection was assessed by bacterial burden in the lung and mucus burden in the lung., Results: We found that hG551D rats treated with ivacaftor had reduced bacteria present in the lung in the acute phase of the infection but were not different than vehicle control in the chronic phase of the infection. Similarly, the percentage of neutrophils in the airways were reduced at the acute, but not chronic, timepoints. Overall weight data indicated that the hG551D rats had significantly better weight recovery during the course of infection when treated with ivacaftor. Potentiation of the G551D mutation with ivacaftor resultant in short-circuit current measurements equal to WT, even during the chronic phase of the infection. Despite the persistent infection, hG551D rats treated with ivacaftor had fewer airways with mucus plugs during the chronic infection., Conclusions: The data indicate that the hG551D rats have better outcomes during infection when treated with ivacaftor compared to the vehicle group. Rats have increased weight gain, increased CFTR protein function, and decreased mucus accumulation, despite the persistence of infection and inflammation. These data suggest that ivacaftor improves tolerance of infection, rather than eradication, in this rat model., (© 2024. The Author(s).)

Objectives: This study investigated the potential therapeutic benefits of PNU120596, a positive allosteric modulator of the α7 nicotinic acetylcholine receptor (α7nAChR), in mitigating acute lung injury (ALI) induced by lipopolysaccharide (LPS) in a mouse model. Specifically, we sought to examine the impact of PNU120596 on the PI3K/AKT signaling pathway in the context of ALI., Methods: ALI was induced in mice by LPS administration, and the protective effects of PNU120596 were assessed. Lung injury, lung function, and the inflammatory response were evaluated. Additionally, the activation of the PI3K/AKT signaling pathway was examined, along with the levels of inflammatory factors and oxidative stress markers., Key Findings: PNU120596 significantly ameliorated LPS-induced lung injury, improved lung function, and reduced the inflammatory response in the mouse model of ALI. Furthermore, we observed that PNU120596 inhibited the activation of the PI3K/AKT signaling pathway, which was associated with decreased levels of inflammatory factors and oxidative stress markers., Conclusions: PNU120596 exhibits promising therapeutic potential for the treatment of acute lung injury, potentially by targeting the PI3K/AKT signaling pathway. These findings suggest that modulation of the α7 nicotinic acetylcholine receptor with PNU120596 may offer a viable strategy for the management of ALI, warranting further investigation and potential clinical applications., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Royal Pharmaceutical Society. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Background: Asthma is one of the most prevalent chronic respiratory diseases among children, markedly impairing patient's health and imposing an increasing burden on the healthcare system. Several traditional Chinese medicines have demonstrated efficacy in alleviating asthma symptoms through studies conducted on animal models. Recent studies have shown that the Yunpi Xiefei Huatan Tang decoction (YPD) exhibits significant therapeutic outcomes in treating phlegm-obstructed pulmonary asthma. However, the precise regulatory effects of YPD on the progression of asthma require additional investigation., Objective: To explore the functions of YPD in asthma progression., Material and Methods: The asthma rat model triggered by ovalbumin (OVA) was established successfully. The pathological changes of lung tissues were examined through Hematoxylin and Eosin (H&E) staining. The levels of Interleukin 6 (IL-6) and IL-1β were tested through Enzyme-Linked-Immunosorbent Serologic Assay (ELISA). The number of total cells or eosinophils in bronchoalveolar lavage fluid was confirmed through cell counter. The collagen deposition in bronchi was assessed through Masson staining. The protein expressions were measured through western blot., Results: This study demonstrated that YPD could mitigate airway inflammation in an OVA-triggered asthma rat model. Furthermore, YPD was found to decrease the production of inflammatory cytokines in the lungs and suppress the infiltration of inflammatory cells into bronchoalveolar lavage fluid. Additionally, the airway remodeling stimulated by OVA could be suppressed following YPD treatment. Finally, it was disclosed that YPD inhibited the wingless-related integration site-beta-catenin (Wnt/β-catenin) signaling pathway in the OVA-stimulated asthma rat model., Conclusion: YPD alleviated airway inflammation and remodeling in asthmatic mice via the Wnt/β-catenin signaling pathway. This research offers significant insights into the potential application of YPD in the treatment of asthma., Competing Interests: The authors stated that there were no conflicts of interest to disclose.

Streptozotocin (STZ) is a commonly used compound for the induction of type 2 diabetes (T2D) in animal models, but its effects on non-pancreatic tissues like the lungs are not well understood. This study aimed to examine the histopathological impact of STZ on the lungs using male Sprague-Dawley rats. The rats were divided into two groups: a control group on a normal diet and an STZ-treated group receiving a high-fat diet and 10% sucrose water for 8 weeks, followed by an STZ injection (30 mg/kg body weight). All rats were terminated 9 days after STZ administration, and lung samples were collected for light microscopy, transmission electron microscopy (TEM), and confocal laser scanning microscopy. Light microscopy revealed thickening of alveolar septa, narrowing of alveoli, and inflammatory infiltrates in the STZ group. TEM showed mitochondrial damage in type 2 pneumocytes, including membrane fragmentation, cristae loss, and formation of mitochondrial-derived vesicles. Confocal microscopy revealed significantly higher expression of myeloperoxidase, neutrophil elastase, and citrullinated histone 3 in the STZ group compared to controls. These findings suggest that STZ induces considerable lung damage, emphasizing the need to consider lung toxicity in studies involving STZ.

Due to the ban on the use of traditional brominated flame retardants, new brominated flame retardants, such as Bis (2-ethylhexyl)-2,3,4,5-tetrabromophthalate (TBPH), have been developed as alternatives to traditional brominated flame retardants to replace the old ones, and TBPH has been widely used. Therefore, we need to systematically evaluate the toxicological effects of TBPH. In the current work, we analyzed the effects of TBPH on lung. In vivo model, we found that TBPH treatment caused damage to lung tissues through H&E staining, immunohistochemistry, and western-blot analysis. Furthermore, in vitro model, our study found that TBPH treatment led to a decrease in the proliferative capacity of lung cells. Furthermore, TBPH treatment led to inflammatory responses and oxidative stress in lung cells. Molecular mechanism studies showed that under exposure to TBPH, the biological function of mitochondria was disrupted, leading to the release of endogenous ds-DNA from mitochondria into the cytosol. This released ds-DNA acts as a danger signal molecule, effectively activating the cGAS-STING signaling pathway and subsequent inflammatory responses. Further research showed that the disruption of mitochondrial homeostasis by TBPH is closely related to lung injury. The current research findings not only enrich our understanding of the potential toxicological effects of new brominated flame retardants as environmental pollutants, but also provide a research foundation for further understanding TBPH toxicology., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. Declaration of Competing Interest The authors declare that they have no conflicts of interest., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Maternal asthma is associated with increased rates of neonatal lung disease, and fetuses from asthmatic ewes have fewer surfactant-producing cells and lower surfactant-protein B gene (SFTPB) expression than controls. Antenatal betamethasone increases lung surfactant production in preterm babies, and we therefore tested this therapy in experimental maternal asthma. Ewes were sensitised to house dust mite allergen, and an asthmatic phenotype induced by fortnightly allergen lung challenges; controls received saline. Pregnant asthmatic ewes were randomised to receive antenatal saline (asthma) or 12 mg intramuscular betamethasone (asthma+beta) at 138 and 139 days of gestation (term = 150 days). Lambs were delivered by Caesarean section at 140 days of gestation and ventilated for 45 min before tissue collection. Lung function and structure were similar in control lambs (n = 16, 11 ewes) and lambs from asthma ewes (n = 14, 9 ewes). Dynamic lung compliance was higher in lambs from asthma+beta ewes (n = 12, 8 ewes) compared to those from controls (P = 0.003) or asthma ewes (P = 0.008). Lung expression of surfactant protein genes SFTPA (P = 0.048) and SFTPB (P < 0.001), but not SFTPC (P = 0.177) or SFTPD (P = 0.285), was higher in lambs from asthma+beta than those from asthma ewes. Female lambs had higher tidal volume (P = 0.007), dynamic lung compliance (P < 0.001), and SFTPA (P = 0.037) and SFTPB gene expression (P = 0.030) than males. These data suggest that betamethasone stimulates lung maturation and function of near-term neonates, even in the absence of impairment by maternal asthma., (© 2024 The Author(s). Experimental Physiology published by John Wiley & Sons Ltd on behalf of The Physiological Society. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.)

Acute lung injury (ALI) is a serious respiratory disease characterized by diffuse alveolar injury, and it has emerged as a major concern in clinical practice due to limited treatments. This study aimed to explore the pharmacological effects and regulatory mechanism of sappanone A (SA) on ALI. In vivo, mice were administered with SA followed by intratracheal injection of lipopolysaccharide (LPS) to establish an animal model of ALI. We observed that SA exerted comparable anti-inflammatory effects to dexamethasone, as evidenced by effectively mitigating histopathological abnormalities and suppressing the inflammatory response in the lung tissues of mice with ALI. RNA sequencing analysis revealed that SA significantly inhibited the activation of the nuclear factor kappa B (NF-κB) signaling pathway. In vitro, we found that SA protected BEAS-2B cells against LPS-induced cellular injury and reduced inflammatory cytokine generation. Furthermore, both in vivo and in vitro experiments demonstrated that SA effectively prevented LPS-induced oxidative stress and apoptosis. Consistent with the results of the RNA sequencing analysis, SA significantly inhibited the increased protein expressions of p105, p50, c-REL, as well as the ratios of p-p65/p65 and p-IκBα/IκBα in the lung tissues of mice with ALI and LPS-stimulated BEAS-2B cells. Additionally, SA inhibited the nuclear translocation of p65 in BEAS-2B cells stimulated with LPS. Importantly, specific blockade of the NF-κB signaling pathway using BAY11-7082 was identified to alleviate LPS-induced cellular injury in BEAS-2B cells. Collectively, these findings suggest that SA can ameliorate ALI, at least in part, through the inhibition of NF-κB signaling pathway activation., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Pulmonary fibrosis (PF) is a progressive and debilitating respiratory condition characterized by excessive deposition of extracellular matrix proteins and scarring within the lung parenchyma. Despite extensive research, the pathogenesis of PF remains incompletely understood, and effective therapeutic options are limited. Emerging evidence suggests a potential link between gut microbiota dysbiosis and the development of PF, highlighting the gut-lung axis as a promising therapeutic target. Akkermansia muciniphila (A. muciniphila), a mucin-degrading bacterium residing in the gut mucosal layer, has garnered considerable interest due to its immunomodulatory and anti-inflammatory properties. This study investigates the therapeutic potential of live and pasteurized A. muciniphila, as well as its extracellular vesicles (EVs), in mitigating inflammation and fibrosis in a murine model of carbon tetrachloride (CCl4)-induced PF exacerbated by a high-fat diet (HFD). Male C57BL/6 mice were divided into groups receiving either a normal diet or an HFD, with or without CCl4 administration. The mice were then treated with live or pasteurized A. muciniphila, or its EVs. Lung tissue was analyzed for the expression of inflammatory markers and fibrosis markers using real-time PCR and ELISA. Administration of live and pasteurized A. muciniphila, as well as its EVs, significantly downregulated the expression of inflammatory and fibrosis markers in the lung tissue of CCl4-induced PF mice. Furthermore, these treatments ameliorated the increased production of IL-6 and reduced IL-10 levels observed in the HFD and CCl4-treated groups. These findings suggest that A. muciniphila and its derivatives exert protective effects against pulmonary inflammation and fibrosis, potentially through modulation of the gut-lung axis. The study highlights the therapeutic potential of A. muciniphila and its derivatives as novel interventions for the management of PF, warranting further preclinical and clinical investigations., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Hexavalent chromium (Cr(VI)) has been identified as a Class I human carcinogen, but its carcinogenic mechanism is currently unclear. There is still a lack of understanding of its associations with early pulmonary inflammatory damages. Inflammation is an important stage before the occurrence of tumors, and under the long-term stimulation of inflammation, it can promote the development of tumors. In this study, the aim is to explore the effect of Cr(VI) exposure on pulmonary inflammation and its relationship with the mechanism of inflammation cancer transformation. We established a Cr(VI) exposure model in SD rats using tracheal instillation of potassium dichromate solution, and collected samples at the time of cessation of exposure and 14 days after cessation of exposure. Analyzing the experimental results, it was found that the lung index increased after exposure to Cr(VI), promoting the occurrence of apoptosis in lung tissue cells and exacerbating lung tissue damage. The damage situation improved after exposure termination; Inductively coupled plasma mass (ICPRQ) spectrometer detection found that the exposed group had significantly increased levels of blood chromium, blood manganese, blood copper, blood arsenic, urine chromium, urine copper, and urine lead; After two weeks of repair, blood chromium and blood manganese levels were significantly lower than those in the same dose group of the exposure group, while blood copper levels were significantly higher than those in the same dose group of the exposure group. There was no significant difference in blood arsenic levels between the exposure group and the exposure group. Urine chromium and urine lead levels were significantly lower than those in the same dose group of the exposure group, while urine copper levels only increased. At the same time, it was found that Cr(VI) exposure caused disruption of oxidative stress levels in rat lung tissues. After 14-day exposure, Cr(VI) significantly decreased and oxidative stress levels significantly decreased. Further investigation revealed that Cr(VI) induces activation of inflammasomes NLRP3, AIM2, and their signaling pathways in lung inflammatory injuries, but this condition persists even after cessation of exposure. The study suggested that in hexavalent chromium induced lung tissue injuries in rats, NLRP3 and AIM2 inflammasomes and their signaling pathways activation. Furthermore, the characteristic of sustained activation after cessation of exposure was also indicated. These results provide new ideas and references for further elucidating the mechanisms of Cr(VI), lung inflammation and inflammation cancer transformation., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

The development of multiple targeted biologic therapies over the past two decades has revolutionized the management of asthma. Currently, there are 6 monoclonal antibodies that target specific inflammatory mediators involved in the pathophysiology of asthma, and together, they provide the opportunity for personalized treatment options beyond bronchodilators and inhaled or systemic glucocorticoids in severe and difficult-to-control cases of asthma. These agents are the anti-IgE antibody omalizumab, the anti-IL-5 antibodies mepolizumab and reslizumab, the IL-5 receptor alpha antagonist benralizumab, the IL-4 receptor alpha antagonist dupilumab, and the anti-thymic stromal lymphopoietin antibody tezepelumab., Competing Interests: Disclosures J.D. Salciccioli has no financial disclosures to declare. E. Israel reports the following: grants and contracts: AstraZeneca, Avillion, Gossamer Bio, National Institutes of Health (NIH), Patient-Centered Outcomes Research Institute (PCORI); royalties or licenses: UpToDate; consulting fees: Amgen, Arrowhead Pharmaceuticals, AstraZeneca, GlaxoSmithKline, Merck, Regeneron, Sanofi, TEVA, Guidepoint, Windrose Consulting Group, Reach Market Research, Apogee Therapeutics, Yuhan, Leerink Partners; honoraria: Clearview Health Partners; support for attending meeting/travel: AstraZeneca; participation on a data safety monitoring board: Novartis; receipt of equipment, materials, drugs, medical writing, or other services: Genentech, Sun Pharma, Laurel Pharmaceuticals, Om Pharma, Nestle, CLS Behring, Sanofi-Regeneron., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Paracoccidioidomycosis (PCM) is a systemic mycosis caused by the dimorphic fungus within the genus Paracoccidioides, particularly Paracoccidioides brasiliensis. The traditional approach to treating this pulmonary infection involves prolonged therapy periods, ranging from weeks to years, often resulting in a notable frequency of disease relapse. Nanotechnology has emerged as a promising avenue for developing novel antifungal therapies and effective vaccines. This is attributed to its capability to facilitate targeted drug and antigen delivery, thereby mitigating toxicity and treatment expenses. This study investigates the synergistic properties of the CHO-rPb27 vaccine nanoformulation against experimental PCM. The therapeutic efficacy of CHO-rPb27 treatment is juxtaposed with the prophylactic protocol. Our findings demonstrate that both protocols effectively control P. brasiliensis pulmonary infection by eliciting a robust cellular and humoral immune response. This response attenuates chronic tissue damage and mitigates pulmonary mechanical dysfunction in mice., Competing Interests: Declaration of competing interest The authors declare that they have no conflict of interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)

High-altitude pulmonary edema (HAPE) is a potentially fatal condition that occurs when exposed to high-altitude hypoxia environments. Currently, there is no effective treatment for HAPE, and available interventions focus on providing relief. Notoginsenoside R1 (NGR1), a major active constituent of Panax notoginseng (Burkill) F.H.Chen (sānqī), has demonstrated heart and lung-protective effects under hypobaric hypoxia. However, there is a lack of clarity regarding the precise mechanisms that underlie the protective effects of NGR1 against inflammation. In this study, a rat model of HAPE was developed to assess the effect of NGR1 on this pathology. High-altitude hypoxia corresponding to 6000 m altitude was simulated with a hypobaric chamber. We found that NGR1 dose-dependently alleviated pulmonary oxidative stress damage and inflammatory response, and prevented acid-base balance disruption. In addition, NGR1 restored the expression levels of hypoxia-inducible factor-1 alpha, vascular endothelial growth factor, and aquaporin protein-5, correlated with the development of pulmonary edema induced by hypobaric hypoxia. Furthermore, NGR1 pre-treatment remarkably mitigated NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome-induced pyroptosis, and this effect was partially counteracted by the use of an NLRP3 agonist. Thus, NGR1 may exert a lung-protective effect against HAPE by ameliorating hypoxia-induced lung edema, oxidative damage, and inflammation through inhibition of the NLRP3/Caspase-1/ GSDMD signaling pathway., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Aim: This study aimed to evaluate the protective effect of soybean extract (SE) against uranium-induced lung injury in rats., Materials and Methods: A rat lung injury model was established through nebulized inhalation of uranyl nitrate. Pretreatment with SE or sterile water (control group) by gavage for seven days before uranium exposure and until the experiment endpoints. The levels of uranium in lung tissues were detected by ICP-MS. Paraffin embedding-based hematoxylin & eosin staining and Masson's staining for the lung tissue were performed to observe the histopathological imaging features. A public database was utilized to analyze the network pharmacological association between SE and lung injury. The expression levels of proteins indicating fibrosis were measured by enzyme-linked immunosorbent assay. RNA-seq transcriptomic and LC-MS/MS targeted metabolomics were conducted in lung tissues., Results: Uranium levels in the lung tissues were lower in SE-pretreated rats than in the uranium-treated group. Inflammatory cell infiltration and the deposition of extracellular matrix were attenuated, and the levels of alpha-smooth muscle actin, transforming growth factor beta1, and hydroxyproline decreased in SE-pretreated rats compared to the uranium-treated group. Active ingredients of SE were related to inflammation, oxidative stress, and drug metabolism. A total of 67 differentially expressed genes and 39 differential metabolites were identified in the SE-pretreated group compared to the uranium-treated group, focusing on the drug metabolism-cytochrome P450, glutathione metabolism, IL-17 signaling pathway, complement, and coagulation cascades., Conclusions: These findings suggest that SE may ameliorate uranium-induced pulmonary inflammation and fibrosis by regulating glutathione metabolism, chronic inflammation, and immune regulation., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

There is increasing evidence that thirdhand exposure to e-cigarette vapor (e-vapor) can have detrimental effects on the lungs. However, whether maternal exposure during pregnancy results in harmful changes to the offspring is unknown. Using two different e-cigarette settings (low vs. high power), BALB/c mice were subjected to thirdhand e-vapor (e-vapor deposited onto towels, towels changed daily) in the absence or presence of nicotine, before, during, and after pregnancy. Male adult offspring were then infected with mouse-adapted influenza A virus (A/PR/8/34 H1N1; Flu) and lung and bone marrow immune cell responses were assessed 7 days postinfection. Maternal thirdhand exposure to low-power ( M LP) or high-power ( M HP) e-vapor with nicotine ( M LP + NIC and M HP + NIC, respectively) increased the percentage of lung immune cells and neutrophils in the bone marrow. Interestingly, Flu-infected offspring from M LP + NIC and M HP + NIC groups had lower percentages of lung alveolar macrophages and more pronounced increases in neutrophils in the bone marrow, when compared with offspring from M Sham Flu controls. Flu infection also decreased the percentage of lung CD4+ T cells and increased the percentage of lung CD8+ T cells, irrespective of maternal exposure ( M LP -/+ NIC and M HP -/+ NIC). Significantly, both M LP + NIC and M HP + NIC resulted in blunted activation of lung CD4+ T cells, but only M LP + NIC caused blunted activation of lung CD8+ T cells. Together, we show for the first time that maternal thirdhand exposure to e-vapor results in significant, long-lived effects on lung and bone marrow immune cell responses in offspring at baseline and response to Flu infection. NEW & NOTEWORTHY Maternal exposure to environmental residues of e-cigarette use has significant effects on immune cell responses in the lungs and bone marrow of offspring at both baseline and in response to influenza A virus (Flu) infection.

Increasing resistance to antiviral drugs approved for the treatment of influenza urges the development of novel compounds. Ideally, this should be complemented by a careful consideration of the administration route. 6'siallyllactosamine-functionalized β-cyclodextrin (CD-6'SLN) is a novel entry inhibitor that acts as a mimic of the primary attachment receptor of influenza, sialic acid. In this study, we aimed to develop a dry powder formulation of CD-6'SLN to assess its in vivo antiviral activity after administration via the pulmonary route. By means of spray drying the compound together with trileucine, a dispersion enhancer, we created a powder that retained the antiviral effect of the drug, remained stable under elevated temperature conditions and performed well in a dry powder inhaler. To test the efficacy of the dry powder drug against influenza infection in vivo, infected mice were treated with CD-6'SLN using an aerosol generator that allowed for the controlled administration of powder formulations to the lungs of mice. CD-6'SLN was effective in mitigating the course of the disease compared to the control groups, reflected by lower disease activity scores and by the prevention of virus-induced IL-6 production. Our data show that CD-6'SLN can be formulated as a stable dry powder that is suitable for use in a dry powder inhaler and is effective when administered via the pulmonary route to influenza-infected mice., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Francesco Stellacci is inventor on patent number WO 2018/015465 A1 − Virucidal compounds and uses thereof. Francesco Stellacci and Paulo H. Jacob Silva are co-founders of Asterivir, a start-up company that focuses on developing novel antivirals. The employer of Henderik W. Frijlink holds a license agreement with PureIMS on the Twincer and Cyclops dry powder inhalers. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; nor in the writing of the manuscript or in the decision to submit the article for publication., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Respiratory syncytial virus (RSV) is a significant cause of acute lower respiratory tract infections, particularly in vulnerable populations such as neonates, infants, young children, and the elderly. Among infants, RSV is the primary cause of bronchiolitis and pneumonia, contributing to a notable proportion of child mortality under the age of 5. In this study, we focused on investigating the pathogenicity of a lethal RSV strain, GZ08-18, as a model for understanding mechanisms of hypervirulent RSV. Our findings indicate that the heightened pathogenicity of GZ08-18 stems from compromised activation of intrinsic apoptosis, as evidenced by aberration of mitochondrial membrane depolarization in host cells. We thus hypothesized that enhancing intrinsic apoptosis could potentially attenuate the virulence of RSV strains and explored the effects of Rotenone, a natural compound known to stimulate the intrinsic apoptosis pathway, on inhibiting RSV infection. Our results demonstrate that Rotenone treatment significantly improved mouse survival rates and mitigated lung pathology following GZ08-18 infection. These findings suggest that modulating the suppressed apoptosis induced by RSV infection represents a promising avenue for antiviral intervention strategies., Competing Interests: Declaration of competing interest All authors of this submission declare that they have no competing interests related to the content of this manuscript. To the best of our knowledge, none of the authors have any financial, personal, or professional conflicts of interest that might have influenced the research presented in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Objective: Pro-resolving molecules, including the peptide Angiotensin-(1-7) [Ang-(1-7)], have potential adjunctive therapy for infections. Here we evaluate the actions of Ang-(1-7) in betacoronavirus infection in mice., Methods: C57BL/6J mice were infected intranasally with the murine betacoronavirus MHV-3 and K18-hACE2 mice were infected with SARS-CoV-2. Mice were treated with Ang-(1-7) (30 µg/mouse, i.p.) at 24-, 36-, and 48-hours post-infection (hpi) or at 24, 36, 48, 72, and 96 h. For lethality evaluation, one additional dose of Ang-(1-7) was given at 120 hpi. At 3- and 5-days post- infection (dpi) blood cells, inflammatory mediators, viral loads, and lung histopathology were evaluated., Results: Ang-(1-7) rescued lymphopenia in MHV-infected mice, and decreased airways leukocyte infiltration and lung damage at 3- and 5-dpi. The levels of pro-inflammatory cytokines and virus titers in lung and plasma were decreased by Ang-(1-7) during MHV infection. Ang-(1-7) improved lung function and increased survival rates in MHV-infected mice. Notably, Ang-(1-7) treatment during SARS-CoV-2 infection restored blood lymphocytes to baseline, decreased weight loss, virus titters and levels of inflammatory cytokines, resulting in improvement of pulmonary damage, clinical scores and lethality rates., Conclusion: Ang-(1-7) protected mice from lung damage and death during betacoronavirus infections by modulating inflammation, hematological parameters and enhancing viral clearance., (© 2024. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Acute lung injury (ALI) or acute respiratory distress syndrome (ARDS) is a high-mortality disease caused by multiple disorders such as COVID-19, influenza, and sepsis. Current therapies mainly rely on the inhalation of nitric oxide or injection of pharmaceutical drugs (e.g., glucocorticoids); however, their toxicity, side effects, or administration routes limit their clinical application. In this study, pachypodol (Pac), a hydrophobic flavonol with anti-inflammatory effects, was extracted from Pogostemon cablin Benth and intercalated in liposomes (Pac@liposome, Pac-lipo) to improve its solubility, biodistribution, and bioavailability, aiming at enhanced ALI/ARDS therapy. Nanosized Pac-lipo was confirmed to have stable physical properties, good biodistribution, and reliable biocompatibility. In vitro tests proved that Pac-lipo has anti-inflammatory property and protective effects on endothelial and epithelial barriers in lipopolysaccharide (LPS)-induced macrophages and endothelial cells, respectively. Further, the roles of Pac-lipo were validated on treating LPS-induced ALI in mice. Pac-lipo showed better effects than did Pac alone on relieving ALI phenotypes: It significantly attenuated lung index, improved pulmonary functions, inhibited cytokine expression such as TNF-α, IL-6, IL-1β, and iNOS in lung tissues, alleviated lung injury shown by HE staining, reduced protein content and total cell number in bronchoalveolar lavage fluid, and repaired lung epithelial and vascular endothelial barriers. As regards the underlying mechanisms, RNA sequencing results showed that the effects of the drugs were associated with numerous immune- and inflammation-related signaling pathways. Molecular docking and western blotting demonstrated that Pac-lipo inhibited the activation of the TLR4-MyD88-NF-κB/MAPK signaling pathway. Taken together, for the first time, our new drug (Pac-lipo) ameliorates ALI via inhibition of TLR4-MyD88-NF-κB/MAPK pathway-mediated inflammation and disruption of lung barrier. These findings may provide a promising strategy for ALI treatment in the clinic., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Neonatal bronchopulmonary dysplasia (BPD) is associated with alveolar simplification and airway remodeling. Airway remodeling leads to deformation of airways characterized by peribronchial collagen deposition and hypertrophy of airway smooth muscle, which contribute to the narrowing of airways. Poorly developed lungs contribute to reduced lung function that deteriorates with the passage of time. We have earlier shown that sphingosine kinase 1 (SPHK 1)/sphingosine-1-phosphate (S1P)/S1P receptor1 (S1PR1) signaling plays a role in the pathogenesis of BPD. In this study, we investigated the role of fingolimod or FTY720, a known S1PR1 modulator approved for the treatment of multiple sclerosis in the treatment of BPD. Fingolimod promotes the degradation of S1PR1 by preventing its recycling, thus serving as the equivalent of an inhibitor. Exposure of neonatal mice to hyperoxia enhanced the expression of S1PR1 in both airways and alveoli as compared with normoxia. This increased expression of S1PR1 in the airways persisted into adulthood, accompanied by airway remodeling and airway hyperreactivity (AHR) after neonatal hyperoxia. Intranasal fingolimod at a much lower dose compared with the intraperitoneal route of administration during neonatal hyperoxia improved alveolarization in neonates and reduced airway remodeling and AHR in adult mice associated with improved lung function. The intranasal route was not associated with the lymphopenia seen with the intraperitoneal route of administration of the drug. An increase in S1PR1 expression in the airways was associated with an increase in the expression of enzyme lysyl oxidase (LOX) in the airways following hyperoxia, which was suppressed by fingolimod. This association warrants further investigation. NEW & NOTEWORTHY The role of the S1P receptor1 modulator, fingolimod, as an FDA-approved drug in preventing the recurrence of multiple sclerosis is established. Fingolimod prevented bronchopulmonary dysplasia (BPD) and its sequela of airway remodeling in a neonatal murine model. This protection was associated with the downregulation of lysyl oxidase signaling pathway. Fingolimod could be repurposed for the therapy of BPD.

Alcohol use disorder (AUD) is defined as patterns of alcohol misuse and affects over 30 million people in the US. AUD is a systemic disease with the epidemiology of acute lung injury and excessive alcohol use established in the literature. However, the distinct mechanisms by which alcohol induces the risk of pulmonary inflammation are less clear. A compelling body of evidence shows that cannabinoid receptors (CB1R and CB2R) play a relevant role in AUD. For this study, we investigated the role of CBR signaling in pulmonary immune activation. Using a human macrophage cell line, we evaluated the expression of CBR1 and CBR2 after cells were exposed to EtOH, +/- cannabinoid agonists and antagonists by flow cytometry. We also evaluated the expression of cannabinoid receptors from the lungs of adolescent mice exposed to acute binge EtOH +/- cannabinoid agonists and antagonists at both resting state and after microbial challenge via western blot, rt-PCR, cytokine analysis, and histology. Our results suggest that EtOH exposure modulates the expression of CBR1 and CBR2. Second, EtOH may contribute to the release of DAMPs and other proinflammatory cytokines, Finally, microbial challenge induces pulmonary inflammation in acute binge EtOH-exposed mice, and this observed immune activation may be CBR-dependent. We have shown that adolescent binge drinking primes the lung to subsequent microbial infection in adulthood and this response can be mitigated with cannabinoid antagonists. These novel findings may provide a framework for developing potential novel therapeutics in AUD research., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Vijay Sivaraman reports financial support, article publishing charges, equipment, drugs, or supplies, and travel were provided by National Institutes of Health. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Human tissue-resident memory T (T RM ) cells play a crucial role in protecting the body from infections and cancers. Recent research observed increased numbers of T RM cells in the lung tissues of idiopathic pulmonary fibrosis patients. However, the functional consequences of T RM cells in pulmonary fibrosis remain unclear. Here, we found that the numbers of T RM cells, especially the CD8 + subset, were increased in the mouse lung with bleomycin-induced pulmonary fibrosis. Increasing or decreasing CD8 + T RM cells in mouse lungs accordingly altered the severity of fibrosis. In addition, the adoptive transfer of CD8 + T cells containing a large number of CD8 + T RM cells from fibrotic lungs was sufficient to induce pulmonary fibrosis in control mice. Treatment with chemokine CC-motif ligand (CCL18) induced CD8 + T RM cell expansion and exacerbated fibrosis, whereas blocking C-C chemokine receptor 8 (CCR8) prevented CD8 + T RM recruitment and inhibited pulmonary fibrosis. In conclusion, CD8 + T RM cells are essential for bleomycin-induced pulmonary fibrosis, and targeting CCL18/CCR8/CD8 + T RM cells may be a potential therapeutic approach. NEW & NOTEWORTHY The role of CD8 + T RM cells in the development of pulmonary fibrosis was validated and studied in the classic model of pulmonary fibrosis. It was proposed for the first time that CCL18 has a chemotactic effect on CD8 + T RM cells, thereby exacerbating pulmonary fibrosis.