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Introduction: Critical illness is associated with organ failure, in which endothelial hyperpermeability and tissue edema play a major role. The endothelial angiopoietin/Tie2 system, a regulator of endothelial permeability, is dysbalanced during critical illness. Elevated circulating angiopoietin-2 and decreased Tie2 receptor levels are reported, but it remains unclear whether they cause edema independent of other critical illness-associated alterations. Therefore, we have studied the effect of angiopoietin-2 administration and/or reduced Tie2 expression on microvascular leakage and edema under normal conditions., Methods: Transgenic male mice with partial deletion of Tie2 (heterozygous exon 9 deletion, Tie2 +/- ) and wild-type controls (Tie2 +/+ ) received 24 or 72 pg/g angiopoietin-2 or PBS as control (n = 12 per group) intravenously. Microvascular leakage and edema were determined by Evans blue dye (EBD) extravasation and wet-to-dry weight ratio, respectively, in lungs and kidneys. Expression of molecules related to endothelial angiopoietin/Tie2 signaling were determined by ELISA and RT-qPCR., Results: In Tie2 +/+ mice, angiopoietin-2 administration increased EBD extravasation (154 %, p < 0.05) and wet-to-dry weight ratio (133 %, p < 0.01) in lungs, but not in the kidney compared to PBS. Tie2 +/- mice had higher pulmonary (143 %, p < 0.001), but not renal EBD extravasation, compared to wild-type control mice, whereas a more pronounced wet-to-dry weight ratio was observed in lungs (155 %, p < 0.0001), in contrast to a minor higher wet-to-dry weight ratio in kidneys (106 %, p < 0.05). Angiopoietin-2 administration to Tie2 +/- mice did not further increase pulmonary EBD extravasation, pulmonary wet-to-dry weight ratio, or renal wet-to-dry weight ratio. Interestingly, angiopoietin-2 administration resulted in an increased renal EBD extravasation in Tie2 +/- mice compared to Tie2 +/- mice receiving PBS. Both angiopoietin-2 administration and partial deletion of Tie2 did not affect circulating angiopoietin-1, soluble Tie2, VEGF and NGAL as well as gene expression of angiopoietin-1, -2, Tie1, VE-PTP, ELF-1, Ets-1, KLF2, GATA3, MMP14, Runx1, VE-cadherin, VEGFα and NGAL, except for gene and protein expression of Tie2, which was decreased in Tie2 +/- mice compared to Tie2 +/+ mice., Conclusions: In mice, the microvasculature of the lungs is more vulnerable to angiopoietin-2 and partial deletion of Tie2 compared to those in the kidneys with respect to microvascular leakage and edema., Competing Interests: Declaration of competing interest The authors declare that they have no competing interests., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Pulmonary fibrosis is a lung disorder characterized by the accumulation of abnormal extracellular matrix, scar tissue formation, and tissue stiffness. Type II alveolar epithelial cells (AEII) play a critical role in repairing lung tissue after injury, and repeated injury to these cells is a key factor in the development of pulmonary fibrosis. Chronic exposure to PM 2.5 , a type of air pollution, has been shown to increase the incidence and severity of pulmonary fibrosis by enhancing the activation of EMT in lung epithelial cells. Melatonin, a hormone with antioxidant properties, has been shown to prevent EMT and reduce fibrosis in previous studies. However, the mechanism through which melatonin targets EMT to prevent pulmonary fibrosis caused by PM 2.5 exposure has not been extensively discussed before. In this current study, we found that melatonin effectively prevented pulmonary fibrosis caused by prolonged exposure to PM 2.5 by targeting EMT. The study demonstrated changes in cellular morphology and expression of EMT markers. Furthermore, the cell migratory potential induced by prolonged exposure to PM 2.5 was greatly reduced by melatonin treatment. Finally, in vivo animal studies showed reduced EMT markers and improved pulmonary function. These findings suggest that melatonin has potential clinical use for the prevention of pulmonary fibrosis., Competing Interests: Declaration of competing interest The authors state no conflict of interest., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Acute lung injury (ALI) remains a significant clinical challenge due to the absence of effective treatment alternatives. This study presents a new method that employs a screening platform focusing on MyD88 affinity, anti-inflammatory properties, and toxicity. This platform was used to evaluate a 300-compound library known for its anti-inflammatory potential. Among the screened compounds, Bicyclol emerged as a standout, exhibiting MyD88 binding and a significant reduction in LPS-stimulated pro-inflammatory factors production in mouse primary peritoneal macrophages. By targeting MyD88, Bicyclol disrupts the MyD88/TLR4 complex and MyD88 polymer formation, thereby mitigating the MAPKs and NF-κB signaling pathways. In vivo experiments further confirmed Bicyclol's efficacy, demonstrating alleviated ALI symptoms, decreased inflammatory cytokines level, and reduced inflammatory cells presence in lung tissues. These findings were associated with a decrease in mortality in LPS-challenged mice. Overall, Bicyclol represents a promising treatment option for ALI by specifically targeting MyD88 and limiting inflammatory responses., Competing Interests: Declaration of competing interest The authors declare that there is no conflict of interest regarding the publication of this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Nitrogen mustard (NM; mechlorethamine) is a cytotoxic vesicant known to cause acute lung injury which can progress to chronic disease. Due to the complex nature of NM injury, it has been difficult to analyze early responses of resident lung cells that initiate inflammation and disease progression. To investigate this, we developed a model of acute NM toxicity using murine precision cut lung slices (PCLS), which contain all resident lung cell populations. PCLS were exposed to NM (1-100 μM) for 0.5-3 h and analyzed 1 and 3 d later. NM caused a dose-dependent increase in cytotoxicity and a reduction in metabolic activity, as measured by LDH release and WST-1 activity, respectively. Optimal responses were observed with 50 μM NM after 1 h incubation and these conditions were used in further experiments. Analysis of PCLS bioenergetics using an Agilent Seahorse showed that NM impaired both glycolytic activity and mitochondrial respiration. This was associated with injury to the bronchial epithelium and a reduction in methacholine-induced airway contraction. NM was also found to cause DNA damage in bronchial epithelial cells in PCLS, as measured by expression of γ-H2AX, and to induce oxidative stress, which was evident by a reduction in glutathione levels and upregulation of the antioxidant enzyme catalase. Cleaved caspase-3 was also upregulated in airway smooth muscle cells indicating apoptotic cell death. Characterizing early events in NM toxicity is key in identifying therapeutic targets for the development of efficacious countermeasures., 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. The author is an Associate Editor for Toxicology and Applied Pharmacology and was not involved in the editorial review or the decision to publish this article., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

The use of e-cigarettes or vapes is increasingly popular amongst a range of different demographics however the research in this area is surprisingly sparse. Clinical reports of e-cigarette- or vaping use-associated lung injury (EVALI) and vascular disruption, in both nicotine-containing and nicotine-free e-cigarette smokers, prompts the need for further research with a focus on the pulmonary endothelium. Using a common brand of e-cigarette (eVape) and an in vitro model of the human lung microvasculature, we investigated the effect of nicotine-free eVape fluid on pulmonary endothelial barrier integrity, oxidative stress and inflammation profile. Findings demonstrate reactive oxygen species-dependent breakdown of the pulmonary endothelium and release of inflammatory cytokines. These phenotypic changes, following exposure to nicotine-free eVape fluid, were accompanied by dysregulation of a number of adheren junctions-related genes of which ARF6 was most abundantly overexpressed. Further investigation of ARF6 identified it as a key regulator in eVape-induced barrier disruption and ROS accumulation. This study demonstrates, for the first time, the barrier disruptive effect of nicotine-free e-cigarette fluid on the pulmonary microvasculature and the ARF6 and ROS-dependent molecular mechanisms underlying this damage. Whilst these studies focus on a human in vitro model of the pulmonary microvasculature, the results support clinical case studies on EVALI and demonstrate a need for further investigation of the impact of nicotine-free e-cigarettes on the lung., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Idiopathic pulmonary fibrosis (IPF) is an irreversible disease which considered the most fatal pulmonary fibrosis. Pulmonary toxicity including IPF is the most severe adverse effect of bleomycin, the chemotherapeutic agent. Based on the fact that, exogenous surfactants could induce alveolar stabilization in many lung diseases, the aim of this study was to explore the effects of low cost biosurfactants, surfactin (SUR) and sophorolipids (SLs), against bleomycin-induced pulmonary fibrosis in mice due to their antioxidant, and anti-inflammatory properties. Surfactin and sophorolipids were produced by microbial conversion of frying oil and potato peel wastes using Bacillus halotolerans and Candida parapsilosis respectively. These biosurfactants were identified by FTIR, 1 H NMR, and LC-MS/MS spectra. C57BL/6 mice were administered the produced biosurfactants daily at oral dose of 200 mg kg -1 one day after the first bleomycin dose (35 U/kg). We evaluated four study groups: Control, Bleomycin, Bleomycin+SUR, Bleomycin+SLs. After 30 days, lungs from each mouse were sampled for oxidative stress, ELISA, Western blot, histopathological, immunohistochemical analyses. Our results showed that the produced SUR and SLs reduced pulmonary oxidative stress and inflammatory response in the lungs of bleomycin induced mice as they suppressed SOD, CAT, and GST activities also reduced NF-κβ, TNF-α, and CD68 levels. Furthermore, biosurfactants suppressed the expression of TGF-β1, Smad-3, and p-JNK fibrotic signaling pathway in pulmonary tissues. Histologically, SUR and SLs protected against lung ECM deposition caused by bleomycin administration. Biosurfactants produced from microbial sources can inhibit the induced inflammatory and fibrotic responses in bleomycin-induced pulmonary fibrosis., Competing Interests: Declaration of competing interest The authors declare that they have no conflict of interests., (Copyright © 2023. Published by Elsevier Inc.)

Endothelial permeability deterioration is involved in ventilator-induced lung injury (VILI). The integrality of vascular endothelial glycocalyx (EG) is closely associated with endothelial permeability. The hypothesis was that vascular EG shedding participates in VILI through promoting endothelial permeability. In the present study, male Sprague-Dawley (SD) rats were ventilated with high tidal volume (VT =40 ml/kg) or low tidal volume (VT =8 ml/kg) to investigate the effects of different tidal volume and ventilation durations on EG in vivo. We report disruption of EG during the period of high tidal volume ventilation characterized by increased glycocalyx structural components (such as syndecan-1, heparan sulfate, hyaluronan) in the plasma and decreased the expression of syndecan-1 in the lung tissues. Mechanistically, the disruption of EG was associated with increased proinflammatory cytokines and matrix metalloproteinase in the lung tissues. Collectively, these results demonstrate that the degradation of EG is involved in the occurrence and development of VILI in rats, and the inflammatory mechanism mediated by activation of the NF-κB signaling pathway may be partly responsible for the degradation of EG in VILI in rats. This study enhances our understanding of the pathophysiological processes underlying VILI, shedding light on potential therapeutic targets to mitigate VILI., Competing Interests: Declaration of competing interest All authors declare that they have no conflicts of interest to report, financial or otherwise., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Mesenchymal stem cells (MSCs) have been widely used to treat various inflammatory and immune-related diseases in preclinical and clinical settings. Intravital microscopy (IVM) is considered the gold standard for investigating pathophysiological conditions in living animals. However, the potential for real-time monitoring of MSCs in the pulmonary microenvironment remains underexplored. In this study, we first constructed a lung window and captured changes in the lung at the cellular level under both inflammatory and noninflammatory conditions with a microscope. We further investigated the dynamics and effects of MSCs under two different conditions. Meanwhile, we assessed the alterations in the adhesive capacity of vascular endothelial cells in vitro to investigate the underlying mechanisms of MSC retention in an inflammatory environment. This study emphasizes the importance of the "lung window" for live imaging of the cellular behavior of MSCs by vein injection. Moreover, our results revealed that the upregulation of vascular cell adhesion molecule 1 (VCAM1) in endothelial cells post-inflammatory injury could enhance MSC retention in the lung, further ameliorating acute lung injury. In summary, intravital microscopy imaging provides a practical method to investigate the therapeutic effects of MSCs in acute lung injury., Competing Interests: Declaration of competing interest The authors declare that there is no conflict of interest regarding the publication of this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Hexavalent chromium [Cr(VI)] is considered a major environmental health concern and lung carcinogen. However, the exact mechanism by which Cr(VI) causes lung cancer in humans remains unclear. Since several reports have demonstrated a role for inflammation in Cr(VI) toxicity, the present study aimed to apply transcriptomics to examine the global mRNA expression in human lung fibroblasts after acute (24 h) or prolonged (72 and 120 h) exposure to 0.1, 0.2 and 0.3 μg/cm 2 zinc chromate, with a particular emphasis on inflammatory pathways. The results showed Cr(VI) affected the expression of multiple genes and these effects varied according to Cr(VI) concentration and exposure time. Bioinformatic analysis of RNA-Seq data based on the Gene ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) and MetaCore databases revealed multiple inflammatory pathways were affected by Cr(VI) treatment. qRT-PCR data corroborated RNA-Seq findings. This study showed for the first time that Cr(VI) regulates key inflammatory pathways in human lung fibroblasts, providing novel insights into the mechanisms by which Cr(VI) causes lung cancer., 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.)

Bronchopulmonary dysplasia (BPD) is characterized by shortened secondary septa and fewer, larger alveoli. Elastin deposition to the distal tips of the secondary septa is critical for elongation of the secondary septa. Alveolar myofibroblasts, which are thought to migrate to the septal tips during alveolarization, are mainly responsible for elastin production and deposition. Antenatal exposure to inflammation induces abnormal elastin deposition, thereby increasing the risk of developing BPD. Here, we found that lipopolysaccharide (LPS) significantly increased the expression of transforming growth factor-α (TGF-α) in an LPS-induced rat model of BPD and in LPS-treated human pulmonary epithelial cells (BEAS-2B). In addition, in vitro experiments suggested that LPS upregulated TGF-α expression via toll-like receptor 4 (TLR4)/tumor necrosis factor α-converting enzyme (TACE) signaling. Increased TGF-α levels via its receptor epidermal growth factor receptor (EGFR)-induced lysyl oxidase (LOX) overactivation and cell division cycle 42 (Cdc42) activity inhibition of myofibroblasts. Similarly, in vivo LOX overactivation and inhibition of Cdc42 activity were observed in the lungs of LPS-exposed pups. LOX overactivation led to abnormal elastin deposition, and inhibition of Cdc42 activity disturbed the directional migration of myofibroblasts and disrupted elastin localization. Most importantly, the EGFR inhibitor erlotinib partially rescued LOX overactivation and Cdc42 activity inhibition, and improved elastin deposition and alveolar development in antenatal LPS-treated rats. Taken together, our data suggest that TGF-α/EGFR signaling is critically involved in the regulation of elastin deposition and represents a novel therapeutic target., 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.)

Nitrogen mustard (NM) is a toxic vesicant that causes acute injury to the respiratory tract. This is accompanied by an accumulation of activated macrophages in the lung and oxidative stress which have been implicated in tissue injury. In these studies, we analyzed the effects of N-acetylcysteine (NAC), an inhibitor of oxidative stress and inflammation on NM-induced lung injury, macrophage activation and bioenergetics. Treatment of rats with NAC (150 mg/kg, i.p., daily) beginning 30 min after administration of NM (0.125 mg/kg, i.t.) reduced histopathologic alterations in the lung including alveolar interstitial thickening, blood vessel hemorrhage, fibrin deposition, alveolar inflammation, and bronchiolization of alveolar walls within 3 d of exposure; damage to the alveolar-epithelial barrier, measured by bronchoalveolar lavage fluid protein and cells, was also reduced by NAC, along with oxidative stress as measured by heme oxygenase (HO)-1 and Ym-1 expression in the lung. Treatment of rats with NAC attenuated the accumulation of macrophages in the lung expressing proinflammatory genes including Ptgs2, Nos2, Il-6 and Il-12; macrophages expressing inducible nitric oxide synthase (iNOS), cyclooxygenase (COX)-2 and tumor necrosis factor (TNF)α protein were also reduced in histologic sections. Conversely, NAC had no effect on macrophages expressing the anti-inflammatory proteins arginase-1 or mannose receptor, or on NM-induced increases in matrix metalloproteinase (MMP)-9 or proliferating cell nuclear antigen (PCNA), markers of tissue repair. Following NM exposure, lung macrophage basal and maximal glycolytic activity increased, while basal respiration decreased indicating greater reliance on glycolysis to generate ATP. NAC increased both glycolysis and oxidative phosphorylation. Additionally, in macrophages from both control and NM treated animals, NAC treatment resulted in increased S-nitrosylation of ATP synthase, protecting the enzyme from oxidative damage. Taken together, these data suggest that alterations in NM-induced macrophage activation and bioenergetics contribute to the efficacy of NAC in mitigating lung injury., 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.)

Manganese (Mn)-induced pulmonary toxicity and the underlying molecular mechanisms remain largely enigmatic. Further, in recent years, microRNAs (miRNAs) have emerged as regulators of several pollutants-mediated toxicity. In this context, our study aimed at elucidating whether miRNAs are involved in manganese (II) chloride (MnCl 2 ) (Mn 2+ )-induced cytotoxicity in lung epithelial cells. Growth inhibition of Mn 2+ towards normal human bronchial epithelial (BEAS-2B) and adenocarcinomic human alveolar basal epithelial (A549) cells was analyzed by MTT assay following 24 or 48 h treatment. Reactive oxygen species (ROS) generation, mitochondrial membrane potential (ΔΨm), cell cycle arrest, and apoptosis were evaluated by flow cytometry. RT-qPCR and Western blot were performed to analyze the expression of cyclins, anti-oxidant genes, and miRNAs. We used small RNA sequencing to investigate Mn 2+ -induced changes in miRNA expression patterns. In both cell lines, Mn 2+ treatment inhibited growth in a dose-dependent manner. Further, compared with vehicle-treated cells, Mn 2+ (250 μM) treatment induced ROS generation, cell cycle arrest, apoptosis, and decreased ΔΨm as well as altered the expression of cyclins and anti-oxidant genes. Sequencing data revealed that totally 296 miRNAs were differentially expressed in Mn 2+ -treated cells. Among them, miR-221-3p was one of the topmost down-regulated miRNAs in Mn 2+ -treated cells. We further confirmed this association in A549 cells. In addition, transient transfection was performed to study gain-of-function experiments. Forced expression of miR-221-3p significantly improved cell viability and reduced Mn 2+ -induced cell cycle arrest and apoptosis in BEAS-2B cells. In conclusion, miR-221-3p may be the most likely target that accounts for the cytotoxicity of Mn 2+ -exposed lung epithelial cells., Competing Interests: Declaration of competing interest The authors have no relevant financial or non-financial interests to declare., (Copyright © 2023. Published by Elsevier Inc.)

Pulmonary fibrosis is a progressive and debilitating lung disease characterized by the excessive accumulation of extracellular matrix (ECM) components within the lung parenchyma. However, the underlying mechanism remains largely elusive, and the treatment options available for pulmonary fibrosis are limited. Interleukin 5 receptor, alpha (IL5RA) is a well-established regulator of eosinophil activation, involved in eosinophil-mediated anti-parasitic activities and allergic reactions. Recent studies have indicated additional roles of IL5RA in lung epithelium and fibroblasts. Nevertheless, its involvement in pulmonary fibrosis remains unclear. In present study, we employed single-cell analyses alongside molecular and cellular assays to unveil the expression of IL5RA in lung epithelial cells. Moreover, using both in vitro and in vivo models, we demonstrated a notable upregulation of epithelial IL5RA during the progression of pulmonary fibrosis. This upregulated IL5RA expression subsequently promotes epithelial-mesenchymal transition (EMT), leading to the generation of mesenchymal phenotype with augmented capability for ECM production. Importantly, our findings uncovered that the pro-fibrotic function of IL5RA is mediated by Jak2/STAT3 signaling cascades. Inhibiting IL5RA has the potential to deactivate Jak2/STAT3 and suppress the downstream EMT process and ECM production, thereby offering a promising therapeutic strategy for pulmonary fibrosis., Competing Interests: Declaration of competing Interest The authors declare no conflict of interest., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Endothelial hyperpermeability is the hallmark of severe lung injury, including acute respiratory distress syndrome. Despite the fact that Never In Mitosis A (NIMA)-related kinase 2 (NEK2) and NEK9 mediate fundamental cellular processes, our knowledge on their role in barrier function is limited. Herein we show that NEK2 and NEK9 inhibition suppresses LPS-induced paracellular hyperpermeability and myosin light chain 2 activation in endothelial cells. Moreover, the expression levels of both kinases were elevated in inflamed mouse lungs. Based on those findings, we raise the possibility that NEK2 and NEK9 may serve as novel therapeutic targets in lung inflammatory disease., Competing Interests: Declaration of competing interest None., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Bronchopulmonary dysplasia (BPD) is the most common chronic lung disease among neonates, with increasing morbidity and mortality. This study aims to investigate the effect and mechanism of lysine demethylase 3A (KDM3A) on hyperoxia-induced BPD. Hyperoxia-induced BPD mouse and alveolar epithelial cell models were constructed. The effects of hyperoxia on lung development were evaluated by histological and morphological analysis. The levels of KDM3A, E26 transformation specific-1 (ETS1), H3 lysine 9 dimethylation (H3K9me2), and endoplasmic reticulum (ER) stress-related indexes were quantified by RT-qPCR, Western blot, and IF staining. Cell apoptosis was assessed by flow cytometry and TUNEL staining. Transfection of oe-ETS1, oe-KDM3A, and sh-ETS1 was applied in hyperoxia-induced alveolar epithelial cells to explore the mechanism of the KDM3A/ETS1 axis in hyperoxia-induced apoptosis. KDM3A inhibitor IOX1 was applied to validate the in vivo effect of KDM3A in hyperoxia-induced BPD mice. The results displayed that hyperoxia-induced BPD mice showed reduced body weight, severe destruction of alveolar structure, decreased radial alveolar count (RAC), and increased mean linear intercept (MLI) and mean alveolar diameter (MAD). Further, hyperoxia induction down-regulated ETS1 expression, raised ER stress levels, and increased apoptosis rate in BPD mice and alveolar epithelial cells. However, transfection of oe-ETS1 improved the above changes in hyperoxia-induced alveolar epithelial cells. Moreover, transfection of oe-KDM3A up-regulated ETS1 expression, down-regulated H3K9me2 expression, inhibited ER stress, and reduced apoptosis rate in hyperoxia-induced alveolar epithelial cells. In addition, transfection of sh-ETS1 reversed the inhibitory effect of KDM3A on hyperoxia-induced apoptosis by regulating ER stress. In vivo experiments, KDM3A inhibitor IOX1 intervention further aggravated BPD in newborn mice. In a word, KDM3A alleviated hyperoxia-induced BPD in mice by promoting ETS1 expression., 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.)

Lung cancer is the leading cause of mortality worldwide of which non-small cell lung carcinoma constitutes majority of the cases. High mortality is attributed to early metastasis, late diagnosis, ineffective treatment and tumor relapse. Chemotherapy and radiotherapy form the mainstay of its treatment. However, their associated side effects involving kidneys, nervous system, gastrointestinal tract, and liver further adds to dismal outcome. These disadvantages of conventional treatment can be circumvented by use of engineered nanoparticles for improved effectiveness with minimal side effects. In this study we have synthesized silver gold nanocomposite (Ag-Au NC) using polyethylene glycol and l-ascorbic acid as surfactant and reducing agent respectively. Synthesized nanocomposite was characterized by ultraviolet-visible absorption, dynamic light scattering, scanning and transmission electron microscopy. Compositional analysis was carried out by energy dispersive X-ray analysis and average pore diameter was estimated using Barrett-Joyner-Halenda method. In-silico molecular docking analysis of the synthesized NC against active regions of epidermal growth factor receptor revealed good binding energy. Subsequently, we investigated the effect of NC on growth and stem cell attributes of A549 lung cancer cells. Results showed that NC was effective in inhibiting A549 cell proliferation, induced DNA damage, G2/M phase arrest and apoptosis. Further, tumor cell migration and spheroid formation were also negatively affected. NC also enhanced reactive oxygen species generation and mitochondrial depolarization. In addition, the effect of NC on putative cancer stem cells in A549 cells was evaluated. We found that Ag-Au NC at IC50 targeted CD44, CD24, CD166, CD133 and CD326 positive cancer stem cells and induced apoptosis. CD166 positive cells were relatively resistance to apoptosis. Together our results demonstrate the anticancer efficacy of Ag-Au NC mediated by a mechanism involving cell cycle arrest and mitochondrial derangement., Competing Interests: Declaration of competing interest The authors of the manuscript entitled ‘Antitumor efficacy of synthesized Ag–Au nanocomposite loaded with PEG and ascorbic acid in human lung cancer stem cells’ declare that there is no conflict of interest., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Neurogenic pulmonary edema secondary to acute brain injury (ABI) is a common and fatal disease condition. However, the pathophysiology of brain-lung interactions is incompletely understood. This study aims to investigate whether sympathetic activation-mediated high fluid shear stress after ABI would damage pulmonary endothelial glycocalyx thus leading to increased pulmonary capillary permeability. The tricuspid annular plane systolic excursion (TAPSE) was detected in a rat model of controlled cortical impact (CCI) and CCI + transection of the cervical sympathetic trunk (TCST). Changes in pulmonary capillary permeability were assessed by analyzing the Evans blue, measuring the dry/wet weight ratio of the lungs and altering protein levels in the bronchoalveolar lavage fluid (BALF). The parallel-plate flow chamber system was used to simulate the fluid shear stress in vitro. Western blotting and immunofluorescence staining were used to determine the expression levels of hyaluronan-binding protein (CEMIP), syndecan-1 and tight junction proteins (TJPs, including claudin-5 and occludin). TCST could restrain cardiac overdrive and sympathetic activation in a rat model of CCI. Compared to the CCI group, the CCI + TCST group showed a reduction of CEMPI (which degrades hyaluronic acid), along with an increase of syndecan-1 and TJPs. CCI + TCST group presented decreasing pulmonary capillary permeability. In vitro, high shear stress (HSS) increased the expression of CEMIP and reduced syndecan-1 and TJPs, which was coordinated with the results in vivo. Our findings show that sympathetic activation-mediated high fluid shear stress after ABI would damage pulmonary endothelial glycocalyx thus leading to increased pulmonary capillary permeability., 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 © 2023 Elsevier Inc. All rights reserved.)

Correlative microscopy is an important approach for bridging the resolution gap between fluorescence light and electron microscopy. Here, we describe a fast and simple method for correlative immunofluorescence and immunogold labeling on the same section to elucidate the localization of phosphorylated vimentin (P-Vim), a robust feature of pulmonary vascular remodeling in cells of human lung small arteries. The lung is a complex, soft and difficult tissue to prepare for transmission electron microscopy (TEM). Detailing the molecular composition of small pulmonary arteries (<500μm) would be of great significance for research and diagnostics. Using the classical methods of immunochemistry (either hydrophilic resin or thin cryosections), is difficult to locate small arteries for analysis by TEM. To address this problem and to observe the same structures by both light and electron microscopy, correlative microscopy is a reliable approach. Immunofluorescence enables us to know the distribution of P-Vim in cells but does not provide ultrastructural detail on its localization. Labeled structures selected by fluorescence microscope can be identified and further analyzed by TEM at high resolution. With our method, the morphology of the arteries is well preserved, enabling the localization of P-Vim inside pulmonary endothelial cells. By applying this approach, fluorescent signals can be directly correlated to the corresponding subcellular structures in areas of interest., (Copyright © 2024 Elsevier Inc. All rights are reserved, including those for text and data mining, AI training, and similar technologies.)

Arsenic is a carcinogen and chronic exposure to arsenic increases the risk of many cancers, including lung cancer. However, the underlying mechanism is not clear. Using A/J mice as a model, our previous animal study has shown that chronic arsenic exposure up-regulates PD-L1 on lung tumor cells which interacts with PD-1 on T cells and inhibits T cell anti-tumor function resulting in increased lung tumorigenesis. In a subsequent in vitro study, we further found that arsenic up-regulated PD-L1 by activating STAT3 at tyrosine 705 in lung epithelial cells, and inhibition of STAT3 mitigated arsenic-induced PD-L1 up-regulation. The present study aims to determine whether STAT3 regulates PD-L1 in the lung of A/J mice and the type of cells from which lung tumor develops upon arsenic exposure. For that purpose, a mouse line with STAT3 conditional knockout in alveolar type 2 (AT2) cells was developed. Our results indicate that arsenic exposure up-regulates PD-L1 in AT2 cells through activating STAT3 in A/J mice. Conditional knockout of STAT3 in AT2 cells inhibited arsenic-induced PD-L1 up-regulation and lung tumor formation. Thus, our findings reveal that STAT3 is the upstream regulator of arsenic-induced PD-L1 up-regulation in AT2 cells and the inhibition of T cell anti-tumor function in the lung, and that AT2 cells are sensitive to arsenic exposure and from which arsenic-enhanced lung tumor formation in A/J mice., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Gang Chen reports financial support was provided by National Institutes of Health., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Arsenic (As), a highly toxic metalloid, which causes environmental lung diseases and affects millions of people worldwide. Respiratory epithelial cells are essential for maintaining lung homeostasis, aberrant epithelial damage and death due to exposure to a wide range of environmental pollutants, which are considered to be the initial trigger for many pulmonary diseases. Accumulating evidence has shown that microRNAs (miRNAs) appear to be important players in various normal physiological and pathological processes. Therefore, the present study was carried out to examine the cytotoxic effects of a trivalent form of As (As 3+ ) in normal human bronchial (BEAS-2B) and adenocarcinoma alveolar basal (A549) epithelial cells and the role of miR-195-5p. Further, we also explored the protective effects of a natural dietary polyphenol tannic acid (TA). As 3+ (1 μM) treatment in BEAS-2B cells for 24 h induced cytotoxicity by decreasing the cell viability, mitochondrial membrane potential (ΔΨm) and inducing reactive oxygen species (ROS) generation, lipid peroxidation (LPO), cell cycle arrest, and apoptosis, which was associated with a significantly higher level of miR-195-5p expression compared with vehicle control. Forced expression of miR-195-5p alone suppressed cell survival, ΔΨm, regulated cell cycle distribution and induced ROS generation in BEAS-2B cells. As expected, miR-195-5p inhibition effectively rescued BEAS-2B cells from As 3+ -mediated toxicity, confirming the involvement of miR-195-5p in the cytotoxic effects of As 3+ . Further, TA pre-treatment expressively alleviated As 3+ -induced toxicity by suppressing ROS production, miR-195-5p expression, and increasing ΔΨm. These in vitro results indicate that miR-195-5p may be useful as a therapeutic target for treating As 3+ toxicity., Competing Interests: Declaration of Competing Interest The authors have no relevant financial or non-financial interests to declare., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Trionyx sinensis Hemorrhagic Syndrome Virus (TSHSV), the first aquatic arterivirus identified in China, causes severe mortality to T. sinensis. In this study, we sought to determine the functions of T. sinensis mRNAs and non-coding RNAs (ncRNAs) that were differentially expressed (DE) over different periods of TSHSV infection of T. sinensis lung. We used RT-qPCR to validate the sequencing results of select RNAs, confirming their reliable and referable nature. Gene Ontology (GO) annotation and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis were used to predict multiple biological functions and signaling pathways in various comparison groups (1-day versus mock, 3-day versus 1-day, and 5-day versus 3-day). Multiple types of differentially expressed RNA, including mRNA, lncRNA, circRNA, and miRNA, were associated with cardiac dysfunction, coagulation abnormalities, and arachidonic acid metabolism at day 1. Pre-inflammatory cytokines and inflammatory factors such as PLA2G4A, cPLA2, γ-GGT1, TNFRSF14, TCP11L2, PTER CYP2J2 and LTC4S, were noticeably regulated at the same time. On day 3, multiple GO terms and KEGG pathways were implicated, including those related to virus defense, apoptosis, pyroptosis, and inflammatory response. Notably, key genes such as RSAD2, TRIM39, STAT4, CASP1, CASP14, MYD88, CXCL3, CARD11, ZBP1, and ROBO4 exhibited significant regulation. The lncRNAs and circRNAs that targeted the genes involved in viral recognition (TLR5), apoptosis (CARD11), pyroptosis (ZBP1), inflammatory processes (NEK7, RASGRP4, and SELE) and angiogenesis (ROBO4) exhibited significant regulation. Significantly regulated miRNAs were primarily linked to genes involved in apoptosis (Let-7f-3p, miR-1260a, miR-455-3p), and inflammation (miR-146a, miR-125a, miR-17a, miR-301b, and miR-30a-3p). The findings could advance our understanding of the host immunological response to TSHSV and offer new ideas for developing effective strategies to prevent infection of T. sinensis., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Lung cancer (LC) is the primary reason for cancer-associated fatalities globally. Due to both tumor-suppressing and tumor-promoting activities, the TGF-β family of growth factors is extremely essential to tumorigenesis. A non-coding single-stranded short RNA called microRNA (miRNA), which is made up of about 22 nt and is encoded by endogenous genes, can control normal and pathological pathways in various kinds of cancer, including LC. Recent research demonstrated that the TGF-β signaling directly can affect the synthesis of miRNAs through suppressor of mothers against decapentaplegic (SMAD)-dependent activity or other unidentified pathways, which could generate allostatic feedback as a result of TGF-β signaling stimulation and ultimately affect the destiny of cancer tissues. In this review, we emphasize the critical functions of miRNAs in lung cancer progression and, more critically, how they affect the TGF-β signaling pathway, and explore the role of both the TGF-β signaling pathway and miRNAs as potential therapeutic targets for improving the treatments of LC patients., Competing Interests: Declaration of competing interest The authors declare they have no conflict of interest., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Airway epithelial cells epithelial mesenchymal transition (EMT) and lung fibroblasts extracellular matrix (ECM) production are the key steps in airway remodeling. Our previous study demonstrated that miR-143-3p has the ability to impede airway smooth muscle cell proliferation and ECM deposition. However, the function of miR-143-3p in airway epithelial cells and lung fibroblasts remains unclear., Methods: Cell viability was determined using MTT method, while cell migration was evaluated through scratch assay. EMT and ECM proteins were detected by western blot, RT-qPCR, and ELISA. To determine the level of miR-143-3p m 6 A methylation, we employed the meRIP-qPCR assay. Additionally, the binding of miR-143-3p with Smad3 were projected by bioinformatics and validated by dual luciferase reporter assays., Results: It was discovered that the expression of miR-143-3p were lower in both asthma patients and TGF-β1-treated human bronchial epithelial 16HBE cells and human lung fibroblast HPF cells. Upregulation of miR-143-3p restrained 16HBE cell migration, and decreased EMT mesenchymal markers and increased epithelial markers. And upregulation of miR-143-3p impaired cell viability and ECM protein production in HPF cells. Mechanistically, interfering with METTL3 resulted in decreased m 6 A modification of miR-143-3p and led to lower levels of miR-143-3p. Moreover, miR-143-3p were verified to directly target and downregulate Smad3. Upregulation of Smad3 attenuated the effects of miR-143-3p on cell EMT and ECM production., Conclusion: MiR-143-3p inhibits airway epithelial cell EMT as well as lung fibroblast ECM production by downregulating Smad3. Therefore, miR-143-3p may be a promising target to reduce airway remodeling in asthma., Competing Interests: Declaration of competing interest None., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Hexavalent chromium [Cr(VI)] is a human lung carcinogen with widespread exposure risks. Cr(VI) causes DNA double strand breaks that if unrepaired, progress into chromosomal instability (CIN), a key driving outcome in Cr(VI)-induced tumors. The ability of Cr(VI) to cause DNA breaks and inhibit repair is poorly understood in human lung epithelial cells, which are extremely relevant since pathology data show Cr(VI)-induced tumors originate from bronchial epithelial cells. In the present study, we considered immortalized and primary human bronchial epithelial cells. Cells were treated with zinc chromate at concentrations ranging 0.05 to 0.4μg/cm 2 for acute (24 h) and prolonged (120 h) exposures. DNA double strand breaks (DSBs) were measured by neutral comet assay and the status of homologous recombination repair, the main pathway to fix Cr(VI)-induced DSBs, was measured by RAD51 foci formation with immunofluorescence, RAD51 localization with confocal microscopy and sister chromatid exchanges. We found acute and prolonged Cr(VI) exposure induced DSBs. Acute exposure induced homologous recombination repair, but prolonged exposure inhibited it resulting in chromosome instability in immortalized and primary human bronchial epithelial cells., 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 © 2023 Elsevier Inc. All rights reserved.)

The world has witnessed the cruelty of COVID-19 disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The association of COVID-19 with other secondary and bacterial co-infections has tremendously contributed to lung infections. An increased probability of having a secondary lung infection was observed among the post-COVID patients. The treatment of antibiotics has ameliorated the mortality rate. However, the stewardship of antibiotic treatment was linked to increased organ failure. Therefore, the paper discusses the interactions between the virus and host through the ACE2 receptors that contribute to COVID-19 development. Furthermore, the paper provides an invaluable compendium history of SARS-CoV-2 genomic composition. It revolves around most classes of antibiotics used to treat COVID-19 disease and post-COVID lung infections with the complete mechanism. This binds with the exertion of the antibiotics for bacterial infection associated with COVID-19 patients and how beneficial and effective responses have been recorded for the treatment. The application of nanotechnology and possible approaches of nanomedicines is also discussed to its potential usage., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Prakash Chandra reports was provided by Delhi Technological University Department of Biotechnology. Prakash Chandra reports a relationship with Delhi Technological University Department of Biotechnology that includes: employment. Prakash Chandra has patent NA pending to NA. NA., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

The matricellular protein, follistatin-like 1 (FSTL1), regulates lung development and saccular formation. Here, we employed single-cell RNA sequencing (scRNA-seq) to construct a transcriptomic atlas of 22,774 individual cells from wild-type (WT) and Fstl1 -/- lung (E18.5) samples and identified 27 cell subtypes. We observed abnormal population sizes and gene expression profiles in diverse cell subtypes in Fstl1 -/- lung samples. We identified Pdgfra and Tgfbi as genetic markers specifically expressed in postnatal myofibroblasts (MyoFBs). Fstl1 deletion decreased the number of MyoFB cells and downregulated their roles in ECM organization and muscle tissue/vasculature development, partly through the TGF-β1/BMP4 signaling pathway. Our data provide a single-cell view of the cellular heterogeneity and the molecular mechanisms underlying abnormal saccular formation and atelectatic lungs in Fstl1 -/- mice., Competing Interests: Declaration of Competing Interest The authors declare that they have no conflict of interest., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

The unique microbiome found in the lungs has been studied and shown to be associated with both pulmonary homeostasis and lung diseases. The lung microbiome has the potential to produce metabolites that modulate host-microbe interactions. Specifically, short-chain fatty acids (SCFAs) produced by certain strains of the lung microbiota have been shown to regulate immune function and maintain gut mucosal health. In response, this review described the distribution and composition of the microbiota in lung diseases and discussed the impact of the lung microbiota on health and lung disease. In addition, the review further elaborated on the mechanism of microbial metabolites in microbial-host interaction and their application in the treatment of lung diseases. A better understanding of the interaction between the microbiota, metabolites, and host will provide potential strategies for the development of novel methods for the treatment of pulmonary microbial induced lung diseases., 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 © 2023 Elsevier Ltd. All rights reserved.)

Cellular homeostasis requires the use of multiple environmental sensors that can respond to a variety of endogenous and exogenous compounds. The aryl hydrocarbon receptor (AHR) is classically known as a transcription factor that induces genes that encode drug metabolizing enzymes when bound to toxicants such as 2,3,7,8-tetrachlorodibenzo-ρ-dioxin (TCDD). The receptor has a growing number of putative endogenous ligands, such as tryptophan, cholesterol, and heme metabolites. Many of these compounds are also linked to the translocator protein (TSPO), an outer mitochondrial membrane protein. Given a portion of the cellular pool of the AHR has also been localized to mitochondria and the overlap in putative ligands, we tested the hypothesis that crosstalk exists between the two proteins. CRISPR/Cas9 was used to create knockouts for AHR and TSPO in a mouse lung epithelial cell line (MLE-12). WT, AHR-/-, and TSPO-/- cells were then exposed to AHR ligand (TCDD), TSPO ligand (PK11195), or both and RNA-seq was performed. More mitochondrial-related genes were altered by loss of both AHR and TSPO than would have been expected just by chance. Some of the genes altered included those that encode for components of the electron transport system and the mitochondrial calcium uniporter. Both proteins altered the activity of the other as AHR loss caused the increase of TSPO at both the mRNA and protein level and loss of TSPO significantly increased the expression of classic AHR battery genes after TCDD treatment. This research provides evidence that AHR and TSPO participate in similar pathways that contribute to mitochondrial homeostasis., 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 © 2023 Elsevier Inc. All rights reserved.)

Introduction: Obesity is associated with higher mortality following trauma, although the pathogenesis is unclear. Both obesity and trauma are associated with syndecan-1 shedding and metalloproteinase-9 (MMP-9) activation, which can adversely affect endothelial cell function. We recently demonstrated that fibrinogen stabilizes endothelial cell surface syndecan-1 to reduce shedding and maintain endothelial barrier integrity. We thus hypothesized that MMP-9 activation and syndecan-1 shedding would be exacerbated by obesity after trauma but attenuated by fibrinogen-based resuscitation., Materials and Methods: ApoE null ( -/- ) mice were fed a Western diet to induce obesity. Mice were subjected to hemorrhage shock and laparotomy then resuscitated with Lactated Ranger's (LR) or LR containing fibrinogen and compared to null and lean sham wild type mice. Mean arterial pressure (MAP) was monitored. Bronchial alveolar lavage protein as an indicator of permeability and lung histopathologic injury were assessed. Syndecan-1 protein and active MMP-9 protein were measured., Results: MAP was similar between lean sham and ApoE -/- sham mice. However, following hemorrhage, ApoE -/- mice resuscitated with fibrinogen had significantly higher MAP than LR mice. Lung histopathologic injury and permeability were increased in LR compared to fibrinogen resuscitated animals. Compared with lean sham mice, both active MMP-9 and cleaved syndecan-1 level were significantly higher in ApoE -/- sham mice. Resuscitation with fibrinogen but not lactated Ringers largely reduced these changes., Conclusions: Fibrinogen as a resuscitative adjunct in ApoE -/- mice after hemorrhage shock augmented MAP and reduced histopathologic injury and lung permeability, suggesting fibrinogen protects the endothelium by inhibiting MMP-9-mediated syndecan-1 cleavage in obese mice., (Copyright © 2023 Elsevier Inc. All rights reserved.)

The inhalable administration of lipid nanoparticles is an effective strategy for localised delivery of therapeutics against various lung diseases. Of this, improved intracellular delivery of pharmaceuticals for infectious disease and cancer management is of high significance. However, the influence of lipid nanoparticle composition and structure on uptake in pulmonary cell lines, especially in the presence of biologically relevant media is poorly understood. Here, the uptake of lamellar (liposomes) versus non-lamellar (cubosomes) lipid nanoparticles in macrophages and lung epithelial cells was quantified and the influence of bronchoalveolar lavage fluid (BALF), containing native pulmonary protein and surfactant molecules is determined. Cubosome uptake in both macrophages and epithelial cells was strongly mediated by a high percentage of molecular function regulatory and binding proteins present within the protein corona. In contrast, the protein corona did not influence the uptake of liposomes in epithelial cells. In macrophages, the proteins mediated a rapid internalisation, followed by exocytosis of liposomes after 6 h incubation. These findings on the influence of biological fluid in regulating lipid nanoparticle uptake mechanisms may guide future development of optimal intracellular delivery systems for therapeutics via the pulmonary route., 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 © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Lung cancer remains a common malignant tumor causing death due to the rapid industrialization and serious pollution of the environment. The Von Willebrand Factor (vWF) protein is an endothelial marker and is widely used to diagnose cancer and other inflammations, however its exact mechanism of action remains largely unexplored. In particular, how it plays two opposing roles in tumor development is not clear. Our study aimed to the impact of endothelial-derived vWF on tumor development by co-culturing human umbilical vein endothelial cells (HUVECs) with lung cancer cells (95D and A549). A knockdown of endothelial-derived vWF assisted lung cancer cell in proliferation, migration and inhibited apoptosis in vitro, while overexpression of endothelial-derived vWF inhibited the proliferation, migration and induced apoptosis of lung cancer cells. The results of further experiments indicated that the vWF secreted by endothelial cells could affect lung cancer cell migration and apoptosis via its binding to integrin αvβ3 on the surface of lung cancer cells. Furthermore, a novel finding was the fact that endothelial-derived vWF inhibited lung cancer cell apoptosis by phosphorylating ERK1/2. At the same time, we established experimental lung metastasis model and xenograft model in normal mice and vWF -/- mice, and found that knockout of vWF in mice significantly promoted lung cancer growth and metastasis. In conclusion, our research found that endothelial-derived vWF could directly combine to αvβ3 on the exterior of A549 and 95D, thereby mediating lung cancer proliferation, migration and apoptosis and inhibiting the development of lung cancer., Competing Interests: Declaration of Competing Interest The study's authors affirm that there were no financial or commercial ties that might be viewed as having a potential conflict of interest., (Copyright © 2023. Published by Elsevier Inc.)

Excessive proliferation of pulmonary artery smooth muscle cells (PASMCs) is considered a major contributor to elevated pulmonary vascular resistance and a key mechanism of vascular remodeling in hypoxia-induced pulmonary hypertension (HPH). Kaempferol is a natural flavonoid compound and can be derived from numerous common medicinal herbs and vegetables, which exhibit antiproliferative and proapoptotic properties, however, the effects of kaempferol on vascular remodeling in HPH remain unexplored. In this study, SD rats were placed in a hypobaric hypoxia chamber for four weeks to establish a pulmonary hypertension model and given either kaempferol or sildenafil (an inhibitor of PDE-5) during days 1-28, after which the hemodynamic parameter and pulmonary vascular morphometry were assessed. Furthermore, primary rat PASMCs were exposed to hypoxic conditions to generate a cell proliferation model, then incubated with either kaempferol or LY294002 (an inhibitor of PI3K). Immunoblotting and real-time quantitative PCR assessed the protein and mRNA expression levels in HPH rat lungs and PASMCs. We found that kaempferol reduced pulmonary artery pressure and pulmonary vascular remodeling, and alleviated right ventricular hypertrophy in HPH rats. The mechanistic analysis demonstrated that kaempferol reduced the protein levels of phosphorylation of Akt and GSK3β, leading to decreased expression of pro-proliferation (CDK2, CDK4, Cyclin D1, and PCNA) and anti-apoptotic related proteins (Bcl-2) and increased expression of pro-apoptosis proteins (Bax and cleaved caspase 3). These results collectively demonstrate that kaempferol ameliorates HPH in rats by inhibiting PASMC proliferation and pro-apoptosis via modulation of the Akt/GSK3β/CyclinD axis., Competing Interests: Declaration of Competing Interest The authors declare no conflict of interest., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Idiopathic pulmonary fibrosis (IPF) is the most common form of idiopathic interstitial pneumonia, where M2 macrophages play an irreplaceable role in the anti-inflammatory progress. Targeting M2 macrophages and regulating their polarization may be a potential treatment strategy for IPF. Herein, we designed a magnetic liposome based dual-targeting delivery system for the IPF treatment, constructed by mannose-modified magnetic nanoparticles (MAN-MNPs) loaded on the surface of the liposome (MAN-MNPs@LP). The delivery system is capable of responding to a static magnetic field (SMF) and then recognizing in situ of M2 macrophages through the mannose receptor-dependent internalization. Firstly, a series of physical and chemical assays were used to characterize these nanoparticles. Subsequently, magnetic liposomes accumulation in the damaged lung with/without mannose modification and SMF were compared by in vivo imaging system. Finally, the reduction of M2 macrophages and inhibition of their polarization confirmed that the development of IPF was retarded due to the in situ release of encapsulated dexamethasone (Dex) in lungs under the SMF. Further investigation demonstrated that the expression of α-SMA and collagen deposition was reduced. Altogether, this dual-targeting delivery system can effectively deliver Dex into M2 macrophages in the lung, making it a novel and promising therapeutic system for the IPF 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 © 2023 Elsevier Inc. All rights reserved.)

The most commonly diagnosed and most lethal subtype of lung cancer is lung adenocarcinoma (LUAD). Therefore, more detailed understanding of the potential mechanism and identification of potential targets of lung adenocarcinoma is needed. A growing number of reports reveals that long non-coding RNAs (lncRNAs) play crucial roles in cancer progression. In present study, we found that lncRNA LINC00115 was upregulated in LUAD tissues and cells. Functional studies revealed that LINC00115 knockdown inhibits the proliferation, growth, invasion, and migration of LUAD cells. Mechanically, we indicated that miR-154-3p is target microRNA of LINC00115, and the effect of downregulated LINC00115 on LUAD cells was partially reversed by the miR-154-3p antisense oligonucleotide (ASO-miR-154-3p). Further investigation revealed that Specificity protein 3 (Sp3) directly interacted with miR-154-3p, and the Sp3 level was positively correlated with the LINC00115 expression. Rescue experiments further showed that Sp3 overexpression partially restored the effect of downregulated LINC00115 on LUAD cells. Similarly, in vivo experiments confirmed that downregulated LINC00115 inhibited xenograft growth and Sp3 expression. Our results demonstrated that LINC00115 knockdown inhibited LUAD progression via sponging miR-154-3p to modulate Sp3 expression. These data indicate that the LINC00115/miR-154-3p/Sp3 axis can be a potential therapeutic target of LUAD., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Objective: This study aimed to investigate the inhibiting effects of FHL2 and Arbutin on cell fibrosis and their possible mechanisms., Methods: The mRNA expression of FHL2 in pulmonary fibrosis tissues was analyzed by bioinformatics. TGF⁃β1 induced fibrosis of mouse lung fibroblast (Mlg) and mouse primary pulmonary fibroblast (PPF) in rat's lung fibroblasts. FHL2 siRNA was transfected into Mlg and mouse PPF cells to inhibit FHL2. FHL2, α-smooth muscle actin (α-SMA), collagen 1 (Col I), and Fibronectin (Fn) were detected by qRT-PCR. Western blot expression levels of Smad3, p-Smad3, Smad2, and p-Smad2 proteins in cells. High-throughput drug screening for FHL2 inhibitors and the inhibitory effect of Arbutin on pulmonary fibrosis were validated in cellular and animal models of pulmonary fibrosis., Results: The mRNA expression of FHL2 in lung fiber tissue was increased. Meanwhile, the decrease of FHL2 expression significantly inhibited the cellular fibrosis morphological changes of rat's lung fibroblasts (Mlgs) and primary lung fibroblasts (PPFs). The expression levels of α⁃SMA, Col I, and Fn were decreased. High-throughput screening showed that Arbutin targeted FHL2. Arbutin alleviated bleomycin (BLM)-induced pulmonary fibrosis in rats by inhibiting FHL2 and then the TGF-β1/Smad signaling pathway., Conclusion: Inhibition of FHL2 can effectively reduce the fibrosis process induced by TGF⁃β1 and bleomycin, and then inhibit the fibrosis., 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 © 2023 Elsevier Inc. All rights reserved.)

Kruppel-like factor 2 (KLF2) has been linked with fibrosis and neutrophil-associated thromboinflammation; however, its role in COVID-19 remains elusive. We investigated the effect of disease microenvironment on the fibrotic potential of human lung fibroblasts (LFs) and its association with KLF2 expression. LFs stimulated with plasma from severe COVID-19 patients down-regulated KLF2 expression at mRNA/protein and functional level acquiring a pre-fibrotic phenotype, as indicated by increased CCN2/collagen levels. Pre-incubation with the COMBI-treatment-agents (DNase I and JAKs/IL-6 inhibitors baricitinib/tocilizumab) restored KLF2 levels of LFs to normal abolishing their fibrotic activity. LFs stimulated with plasma from COMBI-treated patients at day-7 expressed lower CCN2 and higher KLF2 levels, compared to plasma prior-to-treatment, an effect not observed in standard-of-care treatment. In line with this, COMBI-treated patients had better outcome than standard-of-care group. These data link fibroblast KLF2 with NETosis and JAK/IL-6 signaling, suggesting the potential of combined therapeutic strategies in immunofibrotic diseases, such as COVID-19., Competing Interests: Declaration of Competing Interest The authors have declared that no conflict of interest exists., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Vanadium is a toxic metal listed by the IARC as possibly carcinogenic to humans. Manufactured nanosize vanadium pentoxide (V 2 O 5 ) materials are used in a wide range of industrial sectors and recently have been developed as nanomedicine for cancer therapeutics, yet limited information is available to evaluate relevant nanotoxicity. In this study we used high-resolution metabolomics to assess effects of two V 2 O 5 nanomaterials, nanoparticles and nanofibers, at exposure levels (0.01, 0.1, and 1 ppm) that did not cause cell death (i.e., non-cytotoxic) in a human airway epithelial cell line, BEAS-2B. As prepared, V 2 O 5 nanofiber exhibited a fibrous morphology, with a width approximately 63 ± 12 nm and length in average 420 ± 70 nm; whereas, V 2 O 5 nanoparticles showed a typical particle morphology with a size 36 ± 2 nm. Both V 2 O 5 nanoparticles and nanofibers had dose-response effects on aminosugar, amino acid, fatty acid, carnitine, niacin and nucleotide metabolism. Differential effects of the particles and fibers included dibasic acid, glycosphingolipid and glycerophospholipid pathway associations with V 2 O 5 nanoparticles, and cholesterol and sialic acid metabolism associations with V 2 O 5 nanofibers. Examination by transmission electron microscopy provided evidence for mitochondrial stress and increased lysosome fusion by both nanomaterials, and these data were supported by effects on mitochondrial membrane potential and lysosomal activity. The results showed that non-cytotoxic exposures to V 2 O 5 nanomaterials impact major metabolic pathways previously associated with human lung diseases and suggest that toxico-metabolomics may be useful to evaluate health risks from V 2 O 5 nanomaterials., Competing Interests: Declaration of Competing Interest The authors declare no competing financial interests., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Current therapies to mitigate inflammatory responses involved in airway remodeling and associated pathological features of asthma and chronic obstructive pulmonary disease (COPD) are limited and largely ineffective. Inflammation and the release of cytokines and growth factors activate kinase signaling pathways that mediate changes in airway mesenchymal cells such as airway smooth muscle cells and lung fibroblasts. Proliferative and secretory changes in mesenchymal cells exacerbate the inflammatory response and promote airway remodeling, which is often characterized by increased airway smooth muscle mass, airway hyperreactivity, increased mucus secretion, and lung fibrosis. Thus, inhibition of relevant kinases has been viewed as a potential therapeutic approach to mitigate the debilitating and, thus far, irreversible airway remodeling that occurs in asthma and COPD. Despite FDA approval of several kinase inhibitors for the treatment of proliferative disorders, such as cancer and inflammation associated with rheumatoid arthritis and ulcerative colitis, none of these drugs have been approved to treat asthma or COPD. This review will provide a brief overview of the role kinases play in the pathology of asthma and COPD and an update on the status of kinase inhibitors currently in clinical trials for the treatment of obstructive pulmonary disease. In addition, potential issues associated with the current kinase inhibitors, which have limited their success as therapeutic agents in treating asthma or COPD, and alternative approaches to target kinase functions will be discussed., (Copyright © 2023. Published by Elsevier Inc.)

Environmental arsenic exposure is associated with lung cancer. Arsenic is the first substance known to cause lung cancer by two distinct routes, ingestion and inhalation, in the forms of soluble arsenite and particulate arsenic trioxide, respectively. In comparison to significant progresses in research on mechanisms for lung carcinogenesis of arsenic ingestion, inhalation arsenic exposure route in particulate form and its lung carcinogenic mechanisms are relatively under-investigated. Fundamentally, it remains unclear whether particulate arsenic exposure is in a dissolved form and whether particulate exposure yields higher damage. Utilizing dynamic laser scattering, particulate arsenic trioxide exposure in cellular system was confirmed to be in particulate form instead of dissolved form. Using immunofluorescence, particulate arsenic trioxide was demonstrated to generate dramatically higher oxidative DNA damage and strand break, as well as significantly higher superoxide, in lung epithelial cell lines such as BEAS-2B, HSAEC1-KT, and SAE, comparing to soluble arsenite exposure at similar or lower concentration. This study demonstrated that particulate arsenic trioxide exposure yields higher damage in lung epithelial cells, and indicated that inhalation route of particulate arsenic exposure plays an important role in lung carcinogenesis., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Xixi Zhou reports financial support was provided by National Institute of General Medical Sciences., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Psychosocially-stressed individuals might have exacerbated responses to air pollution exposure. Acute ozone exposure activates the neuroendocrine stress response leading to systemic metabolic and lung inflammatory changes. We hypothesized chronic mild stress (CS) and/or social isolation (SI) would cause neuroendocrine, inflammatory, and metabolic phenotypes that would be exacerbated by an acute ozone exposure. Male 5-week-old Wistar-Kyoto rats were randomly assigned into 3 groups: no stress (NS) (pair-housed, regular-handling); SI (single-housed, minimal-handling); CS (single-housed, subjected to mild unpredicted-randomized stressors [restraint-1 h, tilted cage-1 h, shaking-1 h, intermittent noise-6 h, and predator odor-1 h], 1-stressor/day*5-days/week*8-weeks. All animals then 13-week-old were subsequently exposed to filtered-air or ozone (0.8-ppm) for 4 h and immediately necropsied. CS, but not SI animals had increased adrenal weights. However, relative to NS, both CS and SI had lower circulating luteinizing hormone, prolactin, and follicle-stimulating hormone regardless of exposure (SI > CS), and only CS demonstrated lower thyroid-stimulating hormone levels. SI caused more severe systemic inflammation than CS, as evidenced by higher circulating cytokines and cholesterol. Ozone exposure increased urine corticosterone and catecholamine metabolites with no significant stressor effect. Ozone-induced lung injury, and increases in lavage-fluid neutrophils and IL-6, were exacerbated by SI. Ozone severely lowered circulating thyroid-stimulating hormone, prolactin, and luteinizing hormone in all groups and exacerbated systemic inflammation in SI. Ozone-induced increases in serum glucose, leptin, and triglycerides were consistent across stressors; however, increases in cholesterol were exacerbated by SI. Collectively, psychosocial stressors, especially SI, affected the neuroendocrine system and induced adverse metabolic and inflammatory effects that were exacerbated by ozone exposure., 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., (Published by Elsevier Inc.)

Pulmonary fibrosis (PF) represents the end stage of a broad range of interstitial lung diseases (ILDs). Statins are among the compounds which have been implicated in drug-induced ILD development. However, recent studies (both in vitro and in vivo) have provided evidence that statins may exert anti-inflammatory and anti-fibrotic effects potentially offering benefits to patients with PF. Several protective molecular mechanisms including the suppression of mevalonic acid pathway, the inhibition of NADPH oxidase activation in macrophages and the inhibition of several profibrotic mediators have been proposed to explain the observed in vivo decrease of the oxidative stress in the lung and the preservation of lung function in patients. Earlier clinical studies relating statins with drug-induced ILD development are contradicted by increasing new data showing the beneficial effects of statins in clinical outcomes in ILD patients who receive statins for concomitant cardiovascular indications. Future research may further elucidate the wide spectrum of pathways of IPF pathogenesis, and genetic heterogeneity, identifying clinically applicable biomarkers and specific endotypes thus recognizing in which patients statins could confer benefit and in which they might cause detrimental effects., Competing Interests: Declaration of competing interest None., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Background: As reported, long non-coding RNAs are a pivotal player in lung squamous cell carcinoma (LSCC) progression. We noticed the remarkably upregulated transmembrane-4-l-six-family-19 antisense RNA 1 (TM4SF19-AS1) in LSCC and further demonstrated the function it played in LSCC and the possible molecular mechanism., Methods: Via bioinformatics approach, we evaluated TM4SF19-AS1 and TM4SF19 levels in LSCC tissue, and real-time quantitative polymerase chain reaction (qRT-PCR) and Western blot revealed their mRNA and protein levels in LSCC cells. Cell Counting Kit-8 and colony formation assays analyzed the proliferation ability of LSCC cells, and cell adhesion ability was detected via cell adhesion assay. RNA immunoprecipitation and chromatin immunoprecipitation analyzed the underlying mechanism of TM4SF19-AS1 regulating its target, while methylation-specific PCR indicated the methylation level of TM4SF19-AS1., Results: TM4SF19-AS1 was markedly upregulated in LSCC. Functional assays revealed that TM4SF19-AS1 could facilitate the proliferation and adhesion of LSCC. Besides, we revealed the mechanism of TM4SF19-AS1 regulation that it directly bound to WD repeat-containing protein 5 (WDR5), and was then recruited to TM4SF19 promoter region, which activated DNA demethylation, thereby suppressing malignant LSCC progression., Conclusion: Our research demonstrated that TM4SF19-AS1 affected LSCC cell proliferation by recruiting WDR5 to manipulate transmembrane-4-lsix-family-member-19 (TM4SF19), which offers a new observation on LSCC pathogenesis, indicating that TM4SF19-AS1 is able to be a promising target for LSCC treatment., Competing Interests: Declaration of competing interest The authors report no conflict of interest., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Acute lung injury (ALI) or its most advanced form, acute respiratory distress syndrome (ARDS), is a severe inflammatory pulmonary process triggered by varieties of pathophysiological factors, among which endothelial barrier disruption plays a critical role in the progression of ALI/ARDS. As an inhibitor of myosin II, blebbistatin inhibits endothelial barrier damage. This study aimed to investigate the effect of blebbistatin on lung endothelial barrier dysfunction in LPS induced acute lung injury and its potential mechanism. Mice were challenged with LPS (5 mg/kg) by intratracheal instillation for 6 h to disrupt the pulmonary endothelial barrier in the model group. Blebbistatin (5 mg/kg, ip) was administrated 1 h before LPS challenge. The results showed that blebbistatin could significantly attenuate LPS-induced lung injury and pulmonary endothelial barrier dysfunction. And we observed that blebbistatin inhibited the activation of NMMHC IIA/Wnt5a/β-catenin pathway in pulmonary endothelium after LPS treatment. In murine lung vascular endothelial cells (MLECs) and human umbilical vein endothelial cells (HUVECs), we further confirmed that Blebbistatin (1 μmol/L) markedly ameliorated endothelial barrier dysfunction in MLECs and HUVECs by modulating NMMHC IIA/Wnt5a/β-catenin pathway. Our data demonstrated that blebbistatin could inhibit the development of pulmonary endothelial barrier dysfunction and ALI via NMMHC IIA/Wnt5a/β-catenin signaling pathway., (Copyright © 2022. Published by Elsevier Inc.)

Exosomes participate in intercellular communication by shuttling various small molecules from donor to recipient cells. We aimed to examine the role of exosomes and exosomal miRNAs in influenza virus infection. The results showed that influenza A/H1N1pdm09 infection could promote A549 cells to secrete exosomes, while blocking the generation of exosomes reduced viral RNA production. A total of 97 exosomal miRNAs with significantly altered expression were identified during influenza infection. Of 12 candidate miRNAs chosen for further validation, ten were confirmed by qRT-PCR. Among 5978 predicted target genes，we found 37 interferon pathway-related genes to be the potential targets of 29 differentially expressed miRNAs. Many target genes were annotated to various KEGG signaling pathways, some of which played important roles in influenza infection. These data will help to further understand the mechanism of influenza virus-host interactions, which is important for the development of preventative and therapeutic strategies against influenza virus., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Humans are exposed to carcinogenic chemicals via occupational and environmental exposures. Common chemicals of concern that can occur in exposures together are aromatic amines (e.g., 4-aminobiphenyl [4-ABP] and β-naphthylamine [BNA]) and hexavalent chromium (Cr[VI]). Arylamine N-acetyltransferases 1 and 2 (NAT1 and NAT2) are key to the metabolism of aromatic amines and their genotoxicity. The effects of Cr(VI) on the metabolism of aromatic amines remains unknown as well as how it may affect their ensuing toxicity. The objective of the research presented here is to investigate the effects of Cr(VI) on the metabolism and genotoxicity of 4-ABP and BNA in immortalized human lung epithelial cells (BEP2D) expressing NAT1 and NAT2. Exposure to Cr(VI) for 48 h increased NAT1 activity (linear regression analysis: P < 0.0001) as measured by N-acetylation of para-aminobenzoic acid (PABA) in BEP2D cells but not NAT2 N-acetylation of sulfamethazine, which are prototypic NAT1 and NAT2 substrates respectively. Cr(VI) also increased the N-acetylation of 4-ABP and BNA. In BEP2D cells the N-acetylation of 4-ABP (1-3 μM) exhibited a dose-dependent increase (linear regression analysis: P < 0.05) following co-incubation with 0-3 μM Cr(VI). In BEP2D cells, incubation with Cr(VI) caused dose-dependent increases (linear regression analysis: P < 0.01) in expression of CYP1A1 protein and catalytic activity. For genotoxicity, BEP2D cells were exposed to 4-ABP or BNA with/without Cr(VI) for 48 h. We observed dose-dependent increases (linear regression analysis: P < 0.01) in phospho-γH2AX protein expression for combined treatment of 4-ABP or BNA with Cr(VI). Further using a CYP1A1 inhibitor (α-naphthoflavone) and NAT1 siRNA, we found that CYP1A1 inhibition did not reduce the increased N-acetylation or genotoxicity of BNA by Cr(VI), while NAT1 inhibition did reduce increases in BNA N-acetylation and genotoxicity by Cr(VI). We conclude that during co-exposure of aromatic amines and Cr(VI) in human lung cells, Cr(VI) increased NAT1 activity contributing to increased 4-ABP and BNA genotoxicity., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Inflammation and resolution are dynamic processes comprised of inflammatory activation and neutrophil influx, followed by mediator catabolism and efferocytosis. These critical pathways ensure a return to homeostasis and promote repair. Over the past decade research has shown that diverse mediators play a role in the active process of resolution. Specialized pro-resolving mediators (SPMs), biosynthesized from fatty acids, are released during inflammation to facilitate resolution and are deficient in a variety of lung disorders. Failed resolution results in remodeling and cellular deposition through pro-fibrotic myofibroblast expansion that irreversibly narrows the airways and worsens lung function. Recent studies indicate environmental exposures may perturb and deregulate critical resolution pathways. Environmental xenobiotics induce lung inflammation and generate reactive metabolites that promote oxidative stress, injuring the respiratory mucosa and impairing gas-exchange. This warrants recognition of xenobiotic associated molecular patterns (XAMPs) as new signals in the field of inflammation biology, as many environmental chemicals generate free radicals capable of initiating the inflammatory response. Recent studies suggest that unresolved, persistent inflammation impacts both resolution pathways and endogenous regulatory mediators, compromising lung function, which over time can progress to chronic lung disease. Chronic ozone (O 3 ) exposure overwhelms successful resolution, and in susceptible individuals promotes asthma onset. The industrial contaminant cadmium (Cd) bioaccumulates in the lung to impair resolution, and recurrent inflammation can result in chronic obstructive pulmonary disease (COPD). Persistent particulate matter (PM) exposure increases systemic cardiopulmonary inflammation, which reduces lung function and can exacerbate asthma, COPD, and idiopathic pulmonary fibrosis (IPF). While recurrent inflammation underlies environmentally induced pulmonary morbidity and may drive the disease process, our understanding of inflammation resolution in this context is limited. This review aims to explore inflammation resolution biology and its role in chronic environmental lung disease(s)., (Copyright © 2022. Published by Elsevier Inc.)

Background: Airway hyperresponsiveness (AHR) is a clinical manifestation of airflow limitation due to abnormal tracheal and bronchial sensitivity and is the main basis for the diagnosis of asthma. Patients with AHR are at high risk of perioperative tracheal and bronchospasm, which can lead to hypoxaemia and haemodynamic instability and, in severe cases, to a life-threatening 'silent lung'. It is therefore important to reduce the incidence or intensity of AHR episodes in the perioperative period. The inflammatory response is key to the development and progression of AHR., Hypothesis/purpose: Based on the modulatory role of dexmedetomidine (DEX) in the inflammatory response, we hypothesised that dexmedetomidine (DEX) attenuates inflammatory properties by inhibiting the toll-like receptor 4 (TLR4)/nuclear factor (NF-κB) signalling pathway and can reduce the respiratory parameters of mechanical ventilation in ovalbumin-induced allergic airway hyperresponsiveness., Study Design: BABL/C mice were divided into control and OVA groups (ovalbumin-induced allergy. Ten mice in all OVA models were randomly selected for in vivo invasive lung function monitoring to analyse airway resistance parameters and demonstrate successful model establishment. The remaining OVA mice were treated with dexmedetomidine 25 μg/kg for 5 days (OVA + DEX group) or dexmedetomidine 25 μg/kg + yohimbine 1 mg/kg for 5 days (OVA + DEX + yohimbine). After treatment, bronchoalveolar lavage fluid (BAL) and peripheral blood (ELISA) and lung tissue (H&E and PAS) were collected for analysis of inflammatory factors, and lung tissue was verified by PCR for genes and proteins that do correlate with inflammatory mediators., Results: All airway resistance parameters were increased in OVA mice by invasive lung function monitoring. Proximal airway resistance (parameter Rn) and total respiratory resistance (parameter Rrs) were attenuated after dexmedetomidine intervention treatment. Dexmedetomidine reduced total inflammatory cell count and inflammatory infiltration of lung tissue in BALF and down-regulated IL-4 and IgE levels in BALF and peripheral blood, as shown by Giemsa, H&E, PAS staining and ELISA; this mechanism of action was found to be related to the TLR4/NFκB pathway, but not to TLR4/NFκB, as measured by PCR., Conclusion: Dexmedetomidine reduces hyperresponsiveness and airway inflammatory responses. This mechanism of action may be related to the TLR4/NFκB signalling pathway. Overall conclusions are presented in., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Introduction: EF-hand Ca 2+ -binding proteins such as S100 protein family members are recognized by the receptor for advanced glycation end-products (RAGE) and are involved in the pathogenesis of asthma/allergic airway inflammation (AAI). Venestatin, an EF-hand Ca 2+ -binding protein, which is secreted by the parasitic helminth Strongyloides venezuelensis, binds with RAGE and suppresses RAGE-mediated inflammatory responses after parasite invasion. In this study, we evaluated the effect of venestatin on pathogenesis in a house dust mite (HDM) murine model of asthma/AAI., Methods: Mice were intranasally treated with HDM, HDM with recombinant venestatin, or HDM with synthetic peptides, which were designed based on the EF-hand Ca 2+ -binding domain of venestatin. Pro-inflammatory responses in the lungs of mice were assessed., Results: HDM treatment induced inflammatory cell infiltration, phosphorylation of the mitogen-activated protein kinase and inhibitor κB, and production of the cytokines tumor necrosis factor-α and interleukin-5 in the lungs. Co-administration of recombinant venestatin with HDM suppressed these pro-inflammatory responses. Treatment with synthetic peptides reduced inflammatory cell infiltration in a RAGE-dependent manner., Conclusion: The EF-hand domain of venestatin may have potential therapeutic benefits in asthma., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Various cardiopulmonary pathologies associated with electronic cigarette (EC) vaping have been reported. This study investigated the differential adverse effects of heating-associated by-products versus the intact components of EC aerosol to the lungs and heart of mice. We further dissected the roles of caspase recruitment domain-containing protein 9 (CARD9)-associated innate immune response and NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome in EC exposure-induced cardiopulmonary injury. C57BL/6 wild type (WT), CARD9 -/- , and NLRP3 -/- mice were exposed to EC aerosol 3 h/day, 5 days/week for 6 month with or without heating the e-liquid with exposure to ambient air as the control. In WT mice, EC exposure with heating (EwH) significantly increased right ventricle (RV) free wall thickness at systole and diastole. However, EC exposure without heating (EwoH) caused a significant decrease in the wall thickness at systole. RV fractional shortening was also markedly reduced following EwH in WT and NLRP3 -/- mice. Further, EwH activated NF-κB and p38 MAPK inflammatory signaling in the lungs, but not in the RV, in a CARD9- and NLRP3-dependent manner. Levels of circulatory inflammatory mediators were also elevated following EwH, indicating systemic inflammation. Moreover, EwoH activated TGF-β1/SMAD2/3/α-SMA fibrosis signaling in the lungs but not the RV of WT mice. In conclusion, EC aerosol exposure following EwH or EwoH induced differential cardiopulmonary remodeling and CARD9 innate immune response and NLRP3 inflammasome contributed to the adverse effects., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Objective: To investigate the role and mechanism of microRNAs (miRNAs) in fibrotic processes involved in the pathology of systemic sclerosis (SSc)., Methods: R language and bioinformatics methods were used to identify differential miRNAs and mRNAs and analyze their biological functions. Transfection experiments were performed to evaluate the function and regulatory mechanism of miR-27a-3p in vitro. Levels of fibrosis-related genes, SPP1 and cell proliferation were assessed., Results: MiR-27a-3p is reduced both in SSc lung and skin tissues. Overexpression of miR-27a-3p significantly inhibited fibrosis-related genes expression and protein abundance and cell proliferation, whereas inhibition of miR-27a-3p significantly enhanced these phenomena. Moreover, miR-27a-3p exerts its anti-fibrosis effect by negatively regulating SPP1 and ERK signal, more prominent in fibroblasts., Conclusions: Our findings show that miR-27a-3p regulates a common mechanism in the process of SSc skin and lung fibrosis. MiR-27a-3p/SPP1/ERK1/2 axis may be an important target for delaying the progression of SSc fibrosis., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)