Search

Aberrant repair underlies the pathogenesis of pulmonary fibrosis while effective strategies to convert fibrosis to normal regeneration are scarce. Here, we found that thyroid hormone is decreased in multiple models of lung injury but is essential for lung regeneration. Moreover, thyroid hormone receptor α (TRα) promotes cell proliferation, while TRβ fuels cell maturation in lung regeneration. Using a specific TRβ agonist, sobetirome, we demonstrate that the anti-fibrotic effects of thyroid hormone mainly rely on TRβ in mice. Cellularly, TRβ activation enhances alveolar type-2 (AT2) cell differentiation into AT1 cell and constrains AT2 cell hyperplasia. Molecularly, TRβ activation directly regulates the expression of KLF2 and CEBPA, both of which further synergistically drive the differentiation program of AT1 cells and benefit regeneration and anti-fibrosis. Our findings elucidate the modulation function of the TRβ-KLF2/CEBPA axis on AT2 cell fate and provide a potential treatment strategy to facilitate lung regeneration and anti-fibrosis., (© 2024. The Author(s).)

Introduction: Hemorrhagic shock (HS) poses a life-threatening condition with the lungs being one of the most susceptible organs to its deleterious effects. Extracellular cold-inducible RNA binding protein has emerged as a pivotal mediator of inflammation, and its release has been observed as a case of HS-induced tissue injury. Previous studies unveiled a promising engineered microRNA, designated PS-OMe miR130, which inhibits extracellular cold-inducible RNA binding protein, thereby safeguarding vital organs. In this study, we hypothesized that PS-OMe miR130 serves as a protective shield against HS-induced lung injury by curtailing the overzealous inflammatory immune response., Methods: Hemorrhagic shock was induced in male C57BL6 mice by withdrawing blood via a femoral artery cannula to a mean arterial pressure of 30 mm Hg for 90 minutes. The mice were resuscitated with twice the shed blood volume with Ringer's lactate solution. They were then treated intravenously with either phosphate-buffered saline (vehicle) or 62.5 nmol PS-OMe miR130. At 4 hours later, blood and lungs were harvested., Results: Following PS-OMe miR130 treatment in HS mice, a substantial decrease was observed in serum injury markers including aspartate aminotransferase, alanine transaminase, lactate dehydrogenase, and blood urea nitrogen. Serum interleukin (IL)-6 exhibited a similar reduction. In lung tissues, PS-OMe miR130 led to a significant decrease in the messenger RNA expressions of pro-inflammatory cytokines (IL-6, IL-1β, and tumor necrosis factor α), chemokines (keratinocyte-derived chemokine and macrophage inflammatory protein 2), and an endothelial injury marker, E-selectin. PS-OMe miR130 also produced substantial inhibition of lung myeloperoxidase activity and resulted in a marked reduction in lung injury as evidenced by histological evaluation. This was further confirmed by the observation that PS-OMe miR130 significantly reduced the presence of lymphocyte antigen 6 family member G-positive neutrophils and terminal deoxynucleotidyl transferase dUTP nick end labeling-positive apoptotic cells., Conclusion: PS-OMe miR130 emerges as a potent safeguard against HS-induced lung injury by effectively inhibiting pro-inflammation and injuries, offering a promising therapeutic strategy in such critical clinical condition., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Inflammation and oxidative stress are key players in lung injury stemming from cardiac ischemia (LISCI). Cannabidiol (CBD) demonstrates tissue-protective properties through its antioxidant, anti-inflammatory, and anti-apoptotic characteristics. This study aims to assess the preventive (p-CBD) and therapeutic (t-CBD) effects of CBD on LISCI., Methods: Forty male Wistar Albino rats were divided into four groups: control (CON), LISCI, p-CBD, and t-CBD. The left anterior descending coronary artery was ligated for 30 min of ischemia followed by 30 min of reperfusion. Lung tissues were then extracted for histopathological, immunohistochemical, genetic, and biochemical analyses., Results: Histopathologically, marked hyperemia, increased septal tissue thickness, and inflammatory cell infiltrations were observed in the lung tissues of the LISCI group. Spectrophotometrically, total oxidant status and oxidative stress index levels were elevated, while total antioxidant status levels were decreased. Immunohistochemically, expressions of cyclooxygenase-1 (COX1), granulocyte colony-stimulating factor (GCSF), interleukin-6 (IL6) were increased. In genetic analyses, PERK and CHOP expressions were increased, whereas Nuclear factor erythroid 2-related factor 2 (NRF2) and B-cell leukemia/lymphoma 2 protein (BCL2) expressions were decreased. These parameters were alleviated by both prophylactic and therapeutic CBD treatment protocols., Conclusion: In LISCI-induced damage, both endoplasmic reticulum and mitochondrial stress, along with oxidative and inflammatory markers, were triggered, resulting in lung cell damage. However, both p-CBD and t-CBD treatments effectively reversed these mechanisms, normalizing all histopathological, biochemical, and PCR parameters.

Radiation-induced lung injury (RILI) is a prevalent complication of thoracic tumor radiotherapy and accidental radiation exposure. Pyrroloquinoline quinone (PQQ), a novel vitamin B, plays a crucial role in delaying aging, antioxidation, anti-inflammation, and antiapoptosis. This study aims to investigate the protective effect and mechanisms of PQQ against RILI. C57BL/6 mice were exposed to a 20 Gy dose of X-ray radiation on the entire thorax with or without daily oral administration of PQQ for 2 weeks. PQQ effectively mitigated radiation-induced lung tissue damage, inflammation, oxidative stress, and epithelial cell apoptosis. Additionally, PQQ significantly inhibited oxidative stress and mitochondrial damage in MLE-12 cells. Mechanistically, PQQ upregulated the mRNA and protein levels of MOTS-c in irradiated lung tissue and MLE-12 cells. Knockdown of MOTS-c by siRNA substantially attenuated the protective effects of PQQ on oxidative stress, inflammation, and apoptosis. In conclusion, PQQ alleviates RILI by preserving mitochondrial function through a MOTS-c-dependent mechanism, suggesting that PQQ may serve as a promising nutraceutical intervention against RILI.

Background: Macrophage pyroptosis is a pivotal inflammatory mechanism in sepsis-induced lung injury, however, the underlying mechanisms remain inadequately elucidated., Methods: Lipopolysaccharides (LPS)/adenosine triphosphate (ATP)-stimulated macrophages and cecal ligation and puncture (CLP)-induced mouse model for sepsis were established. The levels of key molecules were examined by qRT-PCR, Western blotting, immunohistochemistry (IHC) and ELISA assay. The subcellular localization of circMAPK1 was detected by RNA fluorescence in situ hybridization (FISH). Cell viability, LDH release and caspase-1 activity were monitored by CCK-8, LDH assays, and flow cytometry. The bindings between KDM2B/H3K36me2 and WNK1 promoter was detected by chromatin immunoprecipitation (ChIP) assay and luciferase assay, and associations among circMAPK1, UPF1 and KDM2B mRNA were assessed by RNA pull-down or RNA immunoprecipitation (RIP) assays. The pathological injury of lung tissues was evaluated by lung wet/dry weight ratio and hematoxylin and eosin (H&E) staining., Results: CircMAPK1 was elevated in patients with septic lung injury. Knockdown of circMAPK1 protected against LPS/ATP-impaired cell viability and macrophage pyroptosis via WNK1/NLRP3 axis. Mechanistically, loss of circMAPK1 enhanced the association between KDM2B and WNK1 promoter to promote the demethylation of WNK1 and increase its expression. CircMAPK1 facilitated KDM2B mRNA decay by recruiting UPF1. Functional experiments showed that silencing of KDM2B or WNK1 counteracted circMAPK1 knockdown-suppressed macrophage pyroptosis. In addition, silencing of circMAPK1 alleviated CLP-induced lung injury in mice via KDM2B/WNK1/NLRP3 axis., Conclusion: CircMAPK1 exacerbates sepsis-induced lung injury by destabilizing KDM2B mRNA to suppress WNK1 expression, thus facilitating NLRP3-driven macrophage pyroptosis., (© 2024. The Author(s).)

Hemolysis drives susceptibility to lung injury and predicts poor outcomes in diseases, such as malaria and sickle cell disease (SCD). However, the underlying pathological mechanism remains elusive. Here, we report that major facilitator superfamily domain containing 7 C (MFSD7C) protects the lung from hemolytic-induced damage by preventing ferroptosis. Mechanistically, MFSD7C deficiency in HuLEC-5A cells leads to mitochondrial dysfunction, lipid remodeling and dysregulation of ACSL4 and GPX4, thereby enhancing lipid peroxidation and promoting ferroptosis. Furthermore, systemic administration of MFSD7C mRNA-loaded nanoparticles effectively prevents lung injury in hemolytic mice, such as HbSS-Townes mice and PHZ-challenged 7 C -/- mice. These findings present the detailed link between hemolytic complications and ferroptosis, providing potential therapeutic targets for patients with hemolytic disorders., (© 2024. The Author(s).)

Patients who receive thoracic radiotherapy may suffer from radiation-induced lung injury, but the treatment options are limited as the underlying mechanisms are unclear. Using a mouse model of right thorax irradiation with fractionated doses of X-rays for three consecutive days (8 Gy/per day), this study found that the thoracic irradiation (Th-IR) induced tissue injury with aberrant infiltration of macrophages, and it significantly increased the secretion of TNF-α, IL-1β, IL-6, TGF-β1 and serum amyloid A (SAA) in mice. Interestingly, SAA could activate macrophages and then induce epithelial-mesenchymal transition (EMT) of lung epithelial cells and fibrosis progression in lung tissue. Mechanistically, SAA enhanced the transient binding of FPR2 to Rac1 protein and further activated NF-κB signaling pathway in macrophages. Inhibition of FPR2 significantly reduced pulmonary fibrosis induced by SAA administration in mice. In addition, cimetidine could reduce the level of SAA release after irradiation and attenuate the lung injury induced by SAA or Th-IR. In conclusion, our results demonstrated that SAA activated macrophages via FPR2/Rac1/NF-κB pathway and might contribute to the Th-IR induced lung injury, which may provide a new strategy to attenuate radiation-induced adverse effects during radiotherapy., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

The complex pathogenesis of lung ischemia-reperfusion injury (LIRI) was examined in a murine model, focusing on the role of pyroptosis and its exacerbation of lung injury. We specifically examined the levels and cellular localization of pyroptosis within the lung, which revealed alveolar macrophages as the primary site. The inhibition of pyroptosis by VX-765 reduced the severity of lung injury, underscoring its significant role in LIRI. Furthermore, the therapeutic potential of β-hydroxybutyrate (β-OHB) in ameliorating LIRI was examined. Modulation of β-OHB levels was evaluated by ketone ester supplementation and 3-hydroxybutyrate dehydrogenase 1 (BDH-1) gene knockout, along with the manipulation of the SIRT1-FOXO3 signaling pathway using EX-527 and pCMV-SIRT1 plasmid transfection. This revealed that β-OHB exerts lung-protective and anti-pyroptotic effects, which were mediated through the upregulation of SIRT1 and the enhancement of FOXO3 deacetylation, leading to decreased pyroptosis markers and lung injury. In addition, β-OHB treatment of MH-S cells in vitro showed a concentration-dependent improvement in pyroptosis, linking its therapeutic benefits to specific cell mechanisms. Overall, this study highlights the significance of alveolar macrophage pyroptosis in the exacerbation of LIRI and indicates the potential of β-OHB in mitigating injury by modulating the SIRT1-FOXO3 signaling pathway., (© 2024 Federation of American Societies for Experimental Biology.)

Background: Premature infants requiring mechanical ventilation and supplemental oxygen for respiratory support are at increased risk for bronchopulmonary dysplasia (BPD), wherein inflammation have been proposed as a driver of hyperoxia-induced injuries, including persistent loss of endothelial progenitor cells (EPCs), impaired vascularization and eventual alveolar simplification in BPD lungs. However, the underlying mechanisms linking these phenomena remain poorly defined., Methods: We used clodronate liposomes to deplete macrophages in a mouse model of neonatal hyperoxia-induced lung injury to evaluate if EPC loss in BPD lungs could be an effect of macrophage infiltration. We further generated in vitro culture systems initiated with cord blood (CB)-derived CD34 + EPCs and neonatal macrophages either polarized from CB-derived monocytes or isolated from tracheal aspirates of human preterm infants requiring mechanical ventilation and oxygen supplementation, to identify EV-transmitted molecular mechanism that is critical for inhibitory actions of hyperoxic macrophages on EPCs., Results: Initial experiments using mouse model identified the crucial role of macrophage infiltration in eliciting significant reduction of c-Kit + EPCs in BPD lungs. Further examination of this concept in human system, we found that hyperoxia-exposed neonatal macrophages hamper human CD34 + EPC maintenance and impair endothelial function in the differentiated progeny via the EV transmission of miR-23a-3p. Notably, treatment with antagomiR-23a-3p to silence miR-23a-3p in vivo enhances c-Kit + EPC maintenance, and increases capillary density, and consequently mitigates simplified alveolarization in BPD lungs., Conclusion: Our findings highlight the importance of pulmonary intercellular communication in the pathophysiology of BPD, by identifying a linkage through vesicle transfer of miR-23a-3p from hyperoxic macrophages to EPCs, and thus demonstrating potential for novel therapeutic target in BPD., (© 2024. The Author(s).)

Background: Sepsis-induced pulmonary injury (SPI) is a common complication of sepsis with a high rate of mortality. N4-acetylcytidine (ac 4 C) is mediated by the ac 4 C "writer", N-acetyltransferase (NAT)10, to regulate the stabilization of mRNA. This study aimed to investigate the role of NAT10 in SPI and the underlying mechanism., Methods: Twenty-three acute respiratory distress syndrome (ARDS) patients and 27 non-ARDS volunteers were recruited. A sepsis rat model was established. Reverse transcription-quantitative polymerase chain reaction was used to detect the expression of NAT10 and transferrin receptor (TFRC). Cell viability was detected by cell counting kit-8. The levels of Fe 2+ , glutathione, and malondialdehyde were assessed by commercial kits. Lipid reactive oxygen species production was measured by flow cytometric analysis. Western blot was used to detect ferroptosis-related protein levels. Haematoxylin & eosin staining was performed to observe the pulmonary pathological symptoms., Results: The results showed that NAT10 was increased in ARDS patients and lipopolysaccharide-treated human lung microvascular endothelial cell line-5a (HULEC-5a) cells. NAT10 inhibition increased cell viability and decreased ferroptosis in HULEC-5a cells. TFRC was a downstream regulatory target of NAT10-mediated ac 4 C acetylation. Overexpression of TFRC decreased cell viability and promoted ferroptosis. In in vivo study, NAT10 inhibition alleviated SPI., Conclusion: NAT10-mediated ac 4 C acetylation of TFRC aggravated SPI through promoting ferroptosis., (© 2024. The Author(s).)

Fine particulate matter (PM2.5) is a significant cause of respiratory diseases and associated cellular damage. The mechanisms behind this damage have not been fully explained. This study investigated two types of cellular damage (inflammation and pyroptosis) induced by PM2.5, focusing on their relationship with two organelles (the endoplasmic reticulum and mitochondria). Animal models have demonstrated that PM2.5 induces excessive endoplasmic reticulum stress (ER stress), which is a significant cause of lung damage in rats. This was confirmed by pretreatment with an ER stress inhibitor (4-Phenylbutyric acid, 4-PBA). We found that, in vitro, the intracellular Ca 2+ ([Ca 2+ ]i) dysregulation induced by PM2.5 in rat alveolar macrophages was associated with ER stress. Changes in mitochondria-associated membranes (MAMs) result in abnormal mitochondrial function. This further induced the massive expression of NLRP3 and GSDMD-N, which was detrimental to cell survival. In conclusion, our findings provide valuable insights into the relationship between [Ca 2+ ]i dysregulation, mitochondrial damage, inflammation and pyroptosis under PM2.5-induced ER stress conditions. Their interactions ultimately have an impact on respiratory health.

Radiation-induced lung injury (RILI) frequently occurs as a complication following radiotherapy for chest tumors like lung and breast cancers. However, the precise underlying mechanisms of RILI remain unclear. In this study, we generated RILI models in rats treated with a single dose of 20 Gy and examined lung tissues by single-cell RNA sequencing (scRNA-seq) 2 weeks post-radiation. Analysis of lung tissues revealed 18 major cell populations, indicating an increase in cell-cell communication following radiation exposure. Neutrophils, macrophages, and monocytes displayed distinct subpopulations and uncovered potential for pro-inflammatory effects. Additionally, endothelial cells exhibited a highly inflammatory profile and the potential for reactive oxygen species (ROS) production. Furthermore, smooth muscle cells (SMC) showed a high propensity for extracellular matrix (ECM) deposition. Our findings broaden the current understanding of RILI and highlight potential avenues for further investigation and clinical applications.

Background and Purpose: Nicorandil, a selective opener of potassium channels, used to treat angina, has drawn attention for its potential in mitigating lung injury, positioning it as a promising therapeutic approach to treat drug-induced lung toxicity. This study aimed to explore the protective role of nicorandil in arsenic trioxide (ATO)-induced lung injury and to elucidate the underlying mechanistic pathways., Experimental Approach: We assessed the effects of nicorandil (15 mg·kg -1 , p.o.) in a rat model of pulmonary injury induced by ATO (5 mg·kg -1 , i.p.). The assessment included oxidative stress biomarkers, inflammatory cytokine levels, and other biomarkers, including sirtuin-1, sirtuin-3, STAT3, TFAM, and JAK in lung tissue. Histological examination using H&E staining and molecular investigations using western blotting and PCR techniques were conducted., Key Results: In our model of lung injury, treatment with nicorandil ameliorated pathological changes as seen with H&E staining, reduced tissue levels of toxicity markers, and exerted significant antioxidant and anti-inflammatory actions. On a molecular level, treatment with nicorandil down-regulated JAK, STAT3, PPARγ, Nrf2, VEGF, p53, and micro-RNA 132 while up-regulating Sirt1, 3, TFAM, AMPK, and ERR-α in lung tissue., Conclusions and Implications: The results presented here show nicorandil as a significant agent in attenuating lung injury induced by ATO in a rodent model. Nonetheless, further clinical studies are warranted to strengthen these findings., (© 2024 British Pharmacological Society.)

The lung macrophages play a crucial role in health and disease. Sexual dimorphism significantly impacts the phenotype and function of tissue-resident macrophages. The primary mechanisms responsible for sexually dimorphic outcomes in bronchopulmonary dysplasia (BPD) remain unidentified. We tested the hypothesis that biological sex plays a crucial role in the transcriptional state of alveolar macrophages, using neonatal murine hyperoxia-induced lung injury as a relevant model for human BPD. The effects of neonatal hyperoxia exposure (95 % FiO 2 , PND1-5: saccular stage) on the lung myeloid cells acutely after injury and during normoxic recovery were measured. Alveolar macrophages (AM) from room air- and hyperoxia exposed from male and female neonatal murine lungs were subjected to bulk-RNA Sequencing. AMs are significantly depleted in the hyperoxia-exposed lung acutely after injury, with subsequent recovery in both sexes. The transcriptome of the alveolar macrophages is impacted by neonatal hyperoxia exposure and by sex as a biological variable. Pathways related to DNA damage and interferon-signaling were positively enriched in female AMs. Metabolic pathways related to glucose and carbohydrate metabolism were positively enriched in the male AMs, while oxidative phosphorylation was negatively enriched. These pathways were shared with monocytes and airway macrophages from intubated male and female human premature neonates., 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 B.V. All rights reserved.)

Ovarian tumor domain-containing protease 1 (OTUD1) is a critical negative regulator that promotes innate immune homeostasis and is extensively involved in the pathogenesis of sepsis. In this study, we performed a powerful integration of multiomics analysis and an experimental mechanistic investigation to elucidate the immunoregulatory role of OTUD1 in sepsis at the clinical, animal and cellular levels. Our study revealed the upregulation of OTUD1 expression and the related distinctive alterations observed via multiomics profiling in clinical and experimental sepsis. Importantly, in vivo and in vitro, OTUD1 was shown to negatively regulate inflammatory responses and play a protective role in sepsis-induced pathological lung injury by mechanistically inhibiting the activation of the transforming growth factor-beta-activated kinase 1 (TAK1)-mediated mitogen-activated protein kinase (MAPK) and nuclear factor kappa-B (NF-κB) signaling pathways in the present study. Subsequently, we probed the molecular mechanisms underlying OTUD1's regulation of NF-κB and MAPK pathways by pinpointing the target proteins that OTUD1 can deubiquitinate. Drawing upon prior research conducted in our laboratory, it has been demonstrated that tumor necrosis factor-α-induced protein 8-like 2 (TIPE2) performs a protective function in septic lung injury and septic encephalopathy by suppressing the NF-κB and MAPK pathways. Hence, we hypothesized that TIPE2 might be a target protein of OTUD1. Additional experiments, including Co-IP, immunofluorescence co-localization, and Western blotting, revealed that OTUD1 indeed has the ability to deubiquitinate TIPE2. In summary, OTUD1 holds potential as an immunoregulatory and inflammatory checkpoint agent, and could serve as a promising therapeutic target for sepsis-induced 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 Elsevier Inc. All rights reserved.)

Background/aim: Silibinin, has been investigated for its potential benefits and mechanisms in addressing vanadium pentoxide (V2O5)-induced pulmonary inflammation. This study explored the anti-inflammatory activity of silibinin and elucidate the mechanisms by which it operates in a mouse model of vanadium-induced lung injury., Materials and Methods: Eight-week-old male BALB/c mice were exposed to V2O5 to induce lung injury. Mice were pretreated with silibinin at doses of 50 mg/kg and 100 mg/kg. Histological analyses were performed to assess cell viability and infiltration of inflammatory cells. The expression of pro-inflammatory cytokines (TNF-α, IL-6, IL-1β) and activation of the MAPK and NF-[Formula: see text]B signaling pathways, as well as the NLRP3 inflammasome, were evaluated using real-time PCR, western blot analysis, and immunohistochemistry. Whole blood analysis was conducted to measure white blood cell counts., Results: Silibinin treatment significantly improved cell viability, reduced inflammatory cell infiltration, and decreased the expression of pro-inflammatory cytokines in V2O5-induced lung injury. It also notably suppressed the activation of the MAPK and NF-[Formula: see text]B signaling pathways, along with a marked reduction in NLRP3 inflammasome expression levels in lung tissues. Additionally, silibinin-treated groups exhibited a significant decrease in white blood cell counts, including neutrophils, lymphocytes, and eosinophils., Conclusion: These findings underscore the potent anti-inflammatory effects of silibinin in mice with V2O5-induced lung inflammation, highlighting its therapeutic potential. The study not only confirms the efficacy of silibinin in mitigating inflammatory responses but also provides a foundational understanding of its role in modulating key inflammatory pathways, paving the way for future therapeutic strategies against pulmonary inflammation induced by environmental pollutants., (Copyright © 2024, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

With the increasing use of vaping devices that deliver high levels of nicotine (NIC) to the lungs, sporadic lung injury has been observed. Commercial vaping solutions can contain high NIC concentrations of 150 mM or more. With high NIC levels, its metabolic products may induce toxicity. NIC is primarily metabolized to form NIC iminium (NICI) which is further metabolized by aldehyde oxidase (AOX) to cotinine. We determine that NICI in the presence of AOX is a potent trigger of superoxide generation. NICI stimulated superoxide generation from AOX with K m  = 2.7 μM and V max  = 794 nmol/min/mg measured by cytochrome-c reduction. EPR spin-trapping confirmed that NICI in the presence of AOX is a potent source of superoxide. AOX is expressed in the lungs and chronic e-cigarette exposure in mice greatly increased AOX expression. NICI or NIC stimulated superoxide production in the lungs of control mice with an even greater increase after chronic e-cigarette exposure. This superoxide production was quenched by AOX inhibition. Furthermore, e-cigarette-mediated NIC delivery triggered oxidative lung damage that was blocked by AOX inhibition. Thus, NIC metabolism triggers AOX-mediated superoxide generation that can cause lung injury. Therefore, high uncontrolled levels of NIC inhalation, as occur with e-cigarette use, can induce oxidative lung damage., Competing Interests: Conflict of interest The authors declare that they have no conflicts of interest with the contents of this article., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Bronchopulmonary dysplasia (BPD), caused by hyperoxia exposure, is the most common complication affecting preterm infants. The C-X-C motif chemokine ligand 17 (CXCL17) belongs to the chemokine family that plays important roles in various processes, but the function in BPD is unknown. Elevated serum CXCL17 levels were observed in human premature infants with hyperoxia-induced lung injury, suggesting that CXCL17 might be involved in BPD. To further validate our speculation, studies were conducted in a hyperoxia-induced lung injury mouse model and primary murine alveolar epithelial cells Type II (T2AEC) cells exposed to hyperoxia. RT-qPCR and western blot were used to validate CXCL17 expression in newborn mice. Hyperoxia exposure-induced lung injury was determined by assessing the lung wet-weight/dry-weight ratio and histological changes. Oxidative stress and inflammatory factors were examined by ELISA assay and RT-qPCR. Reactive oxygen species (ROS) level was evaluated by DHE staining. Apoptosis was assessed by TUNEL staining and western blot. The results showed that hyperoxia exposure increased CXCL17 levels in newborn mice pups. Hyperoxia exposure increased lung wet-weight/dry-weight ratio, increased alveolar diameter and enlarged alveoli, and reduced surfactant protein C expression. However, recombinant CXCL17 (rCXCL17) treatment alleviated hyperoxia-induced lung injury. rCXCL17 treatment inhibited hyperoxia-induced inflammation, oxidative stress, and apoptosis in neonatal mice. These results were further verified in T2AEC cells. Additionally, rCXCL17 treatment activated the AKT pathway, which is a protective pathway in BPD. Collectively, rCXCL17 alleviates hyperoxia-induced lung injury in neonatal mice by activating the AKT pathway, indicating that CXCL17 may be a promising target for BPD therapy., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Pulmonary vascular remodeling and inflammation play an important role in the hypoxic-induced lung diseases. Our previous investigations showed that peptide from yak milk residues could alleviate inflammation. In this study, our results suggest that peptide (LV) from yak milk residues peptide had protective effect of lung in the animal models of hypoxic-induced lung injury. LV Gavage could improve pulmonary vascular remodeling in the lung tissues of hypoxic mice. A comprehensive analysis of metabolomics and transcriptomics revealed that 5-KETE, 8,9-EET, and 6-keto-prostaglandin F1a might be potential targets to prevent lung injury in the hypoxic mice. These metabolites can be regulated by MAPK/VEGF and inflammatory pathways. Our data indicated that LV treatment could inhibit apoptosis and inflammation via Nrf2/NF-κB/MAPK/PHD-2 pathway and protected hypoxic-induced lung epithelial cells injury. Taken together, our results suggest that LV provides a novel therapeutic clue for the prevention of hypoxia-induced lung injury and inflammation-related 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 © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Mesenchymal stem cells (MSC)-derived exosomes (Exo) are a possible option for hyperoxia-induced lung injury (HLI). We wanted to see if melatonin (MT)-pretreated MSC-derived exosomes (MT-Exo) were more effective against HLI, and we also tried to figure out the underlying mechanism. HLI models were established by hyperoxia exposure. HE staining was adopted to analyze lung pathological changes. MTT and flow cytometry were used to determine cell viability and apoptosis, respectively. The mitochondrial membrane potential (MMP) was analyzed using the JC-1 probe. LDH, ROS, SOD, and GSH-Px levels were examined by the corresponding kits. The interactions between miR-18a-5p, PUM2, and DUB3 were analyzed by molecular interaction experiments. MT-Exo could effectively inhibit hyperoxia-induced oxidative stress, inflammatory injury, and apoptosis in lung epithelial cells, while these effects of MT-Exo were weakened by miR-18a-5p knockdown in MSCs. miR-18a-5p reduced PUM2 expression in MLE-12 cells by directly targeting PUM2. In addition, PUM2 inactivated the Nrf2/HO-1 signaling pathway by promoting DUB3 mRNA decay post-transcriptionally. As expected, PUM2 overexpression or DUB3 knockdown abolished the protective effect of MT-Exo on hyperoxia-induced lung epithelial cell injury. MT-Exo carrying miR-18a-5p reduced hyperoxia-mediated lung injury in mice through activating Nrf2/HO-1 pathway. MT reduced PUM2 expression and subsequently activated the DUB3/Nrf2/HO-1 signal axis by increasing miR-18a-5p expression in MSC-derived exosomes to alleviate HLI., (© 2024 Federation of American Societies for Experimental Biology.)

Objective: The present study aims to investigate the protective potential of salidroside in both lung ischemia/reperfusion injury (LIRI) mice model and cell hypoxia/reoxygenation (H/R)model and the involvement of ferroptosis and JAK2/STAT3 pathway., Materials and Methods: After we established the IR-induced lung injury model in mice, we administered salidroside and the ferroptosis inhibitor, ferrostatin-1, then assessed the lung tissue injury, ferroptosis (levels of reactive oxygen species level, malondialdehyde and glutathione), and inflammation in lung tissues. The levels of ferroptosis-related proteins (glutathione peroxidase 4, fibroblast-specific protein 1, solute carrier family 1 member 5 and glutaminase 2) in the lung tissue were measured with Western blotting. Next, BEAS-2B cells were used to establish an H/R cell model and treated with salidroside or ferrostatin-1 before the cell viability and the levels of lactate dehydrogenase (LDH), inflammatory factor, ferroptosis-related proteins were measured. The activation of the JAK2/STAT3 signaling pathway was measured with Western blotting, then its role was confirmed with STAT3 knockdown., Results: Remarkably, salidroside was found to alleviate ferroptosis, inflammation, and lung injury in LIRI mice and the cell injury in H/R cell model. Severe ferroptosis were observed in LIRI mice models and H/R-induced BEAS-2B cells, which was alleviated by salidroside. Furthermore, salidroside could inhibit JAK2/STAT3 activation induced by LIRI. STAT3 knockdown could enhance the effect of salidroside treatment on H/R-induced cell damage and ferroptosis in vitro., Conclusions: Salidroside inhibits ferroptosis to alleviate lung ischemia reperfusion injury via the JAK2/STAT3 signaling pathway., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2024 Elsevier Inc. All rights reserved.)

The aim of this study was to investigate whether the protective effect of 2-deoxyglucose (2-DG) on lung ischemia/reperfusion (I/R) injury is mediated by inhibiting nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3)-mediated pyroptosis in rats. Male Sprague-Dawley rats were randomly divided into control group, 2-DG group, lung I/R injury group (I/R group) and 2-DG+I/R group. 2-DG (0.7 g/kg) was intraperitoneally injected 1 h prior to lung ischemia. The tissue structure was measured under light microscope. Lung injury parameters were detected. The contents of malondialdehyde (MDA), myeloperoxidase (MPO) and lactate were determined by commercially available kits. ELISA was used to detect the levels of IL-1β and IL-18. Western blot, qRT-PCR and immunofluorescence staining were used to measure the expression changes of glycolysis and pyroptosis related indicators. The results showed that there was no significant difference in the parameters between the control group and the 2-DG group. However, the lung injury parameters, oxidative stress response, lactic acid content, IL-1β, and IL-18 levels were significantly increased in the I/R group. The protein expression levels of glycolysis and pyroptosis related indicators including hexokinase 2 (HK2), pyruvate kinase 2 (PKM2), NLRP3, Gasdermin superfamily member GSDMD-N, cleaved-Caspase1, cleaved-IL-1β and cleaved-IL-18, and the gene expression levels of HK2, PKM2 and NLRP3 were markedly up-regulated in the I/R group compared with those in the control group. The expression of HK2 and NLRP3 was also increased detected by immunofluorescence staining. Compared with the I/R group, the 2-DG+I/R group exhibited significantly improved alveolar structure and inflammatory infiltration, reduced lung injury parameters, and decreased expression of glycolysis and pyroptosis related indicators. These results suggest that 2-DG protects against lung I/R injury possibly by inhibiting NLRP3-mediated pyroptosis in rats.

Inflammation, apoptosis and oxidative stress play crucial roles in the deterioration of severe acute pancreatitis-associated acute respiratory distress syndrome (SAP-ARDS). Unfortunately, despite a high mortality rate of 45 %[1], there are limited treatment options available for ARDS outside of last resort options such as mechanical ventilation and extracorporeal support strategies[2]. This study investigated the potential therapeutic role and mechanisms of AQP9 inhibitor RG100204 in two animal models of severe acute pancreatitis, inducing acute respiratory distress syndrome: 1) a sodium-taurocholate induced rat model, and 2) and Cerulein and lipopolysaccharide induced mouse model. RG100204 treatment led to a profound reduction in inflammatory cytokine expression in pancreatic, and lung tissue, in both models. In addition, infiltration of CD68 + and CD11b + cells into these tissues were reduced in RG100204 treated SAP animals, and edema and SAP associated tissue damage were improved. Moreover, we demonstrate that RG100204 reduced apoptosis in the lungs of rat SAP animals, and reduces NF-κB signaling, NLRP3, expression, while profoundly increasing the Nrf2-dependent anti oxidative stress response. We conclude that AQP9 inhibition is a promising strategy for the treatment of pancreatitis and its systemic complications, such as ARDS., 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: Although recent studies provide mechanistic understanding to the pathogenesis of radiation induced lung injury (RILI), rare therapeutics show definitive promise for treating this disease. Type II alveolar epithelial cells (AECII) injury in various manner results in an inflammation response to initiate RILI., Results: Here, we reported that radiation (IR) up-regulated the TNKS1BP1, causing progressive accumulation of the cellular senescence by up-regulating EEF2 in AECII and lung tissue of RILI mice. Senescent AECII induced Senescence-Associated Secretory Phenotype (SASP), consequently activating fibroblasts and macrophages to promote RILI development. In response to IR, elevated TNKS1BP1 interacted with and decreased CNOT4 to suppress EEF2 degradation. Ectopic expression of EEF2 accelerated AECII senescence. Using a model system of TNKS1BP1 knockout (KO) mice, we demonstrated that TNKS1BP1 KO prevents IR-induced lung tissue senescence and RILI., Conclusions: Notably, this study suggested that a regulatory mechanism of the TNKS1BP1/CNOT4/EEF2 axis in AECII senescence may be a potential strategy for RILI., (© 2024. The Author(s).)

Background: Peptide transporter 1 (PepT1) transports bacterial oligopeptide products and induces inflammation of the bowel. Nutritional peptides compete for the binding of intestinal bacterial products to PepT1. We investigated the mechanism of short-peptide-based enteral nutrition (SPEN) on the damage to the gut caused by the bacterial oligopeptide product muramyl dipeptide (MDP), which is transported by PepT1. The gut-lung axis is a shared mucosal immune system, and immune responses and disorders can affect the gut-respiratory relationship., Methods and Results: Sprague-Dawley rats were gavaged with solutions containing MDP, MDP + SPEN, MDP + intact-protein-based enteral nutrition (IPEN), glucose as a control, or glucose with GSK669 (a NOD2 antagonist). Inflammation, mitochondrial damage, autophagy, and apoptosis were explored to determine the role of the PepT1-nucleotide-binding oligomerization domain-containing protein 2 (NOD2)-beclin-1 signaling pathway in the small intestinal mucosa. MDP and proinflammatory factors of lung tissue were explored to determine that MDP can migrate to lung tissue and cause inflammation. Induction of proinflammatory cell accumulation and intestinal damage in MDP gavage rats was associated with increased NOD2 and Beclin-1 mRNA expression. IL-6 and TNF-α expression and apoptosis were increased, and mitochondrial damage was severe, as indicated by increased mtDNA in the MDP group compared with controls. MDP levels and expression of proinflammatory factors in lung tissue increased in the MDP group compared with the control group. SPEN, but not IPEN, eliminated these impacts., Conclusions: Gavage of MDP to rats resulted in damage to the gut-lung axis. SPEN reverses the adverse effects of MDP. The PepT1-NOD2-beclin-1 pathway plays a role in small intestinal inflammation, mitochondrial damage, autophagy, and apoptosis., (© 2024. The Author(s).)

Pulmonary injury is one of the key restricting factors for the therapy of malignancies with chemotherapy or following radiotherapy for chest cancers. The lung is a sensitive organ to some severely toxic antitumor drugs, consisting of bleomycin and alkylating agents. Furthermore, treatment with radiotherapy may drive acute and late adverse impacts on the lung. The major consequences of radiotherapy and chemotherapy in the lung are pneumonitis and fibrosis. Pneumonitis may arise some months to a few years behind cancer therapy. However, fibrosis is a long-term effect that appears years after chemo/or radiotherapy. Several mechanisms such as oxidative stress and severe immune reactions are implicated in the progression of pulmonary fibrosis. Epithelial-mesenchymal transition (EMT) is offered as a pivotal mechanism for lung fibrosis behind chemotherapy and radiotherapy. It seems that pulmonary fibrosis is the main consequence of EMT after chemo/radiotherapy. Several biological processes, consisting of the liberation of pro-inflammatory and pro-fibrosis molecules, oxidative stress, upregulation of nuclear factor of κB and Akt, epigenetic changes, and some others, may participate in EMT and pulmonary fibrosis behind cancer therapy. In this review, we aim to discuss how chemotherapy or radiotherapy may promote EMT and lung fibrosis. Furthermore, we review potential targets and effective agents to suppress EMT and lung fibrosis after cancer therapy., (© 2024 Wiley Periodicals LLC.)

Chronic diabetes mellitus compromises the vascular system, which causes organ injury, including in the lung. Due to the strong compensatory ability of the lung, patients always exhibit subclinical symptoms. Once sepsis occurs, the degree of lung injury is more severe under hyperglycemic conditions. The α7 nicotinic acetylcholine receptor (α7nAChR) plays an important role in regulating inflammation and metabolism and can improve endothelial progenitor cell (EPC) functions. In the present study, lung injury caused by sepsis was compared between diabetic rats and normal rats. We also examined whether α7nAChR activation combined with EPC transplantation could ameliorate lung injury in diabetic sepsis rats. A type 2 diabetic model was induced in rats via a high-fat diet and streptozotocin. Then, a rat model of septic lung injury was established by intraperitoneal injection combined with endotracheal instillation of LPS. The oxygenation indices, wet-to-dry ratios, and histopathological scores of the lungs were tested after PNU282987 treatment and EPC transplantation. IL-6, IL-8, TNF-α, and IL-10 levels were measured. Caspase-3, Bax, Bcl-2, and phosphorylated NF-κB (p-NF-κB) levels were determined by blotting. Sepsis causes obvious lung injury, which is exacerbated by diabetic conditions. α7nAChR activation and endothelial progenitor cell transplantation reduced lung injury in diabetic sepsis rats, alleviating inflammation and decreasing apoptosis. This treatment was more effective when PNU282987 and endothelial progenitor cells were administered together. p-NF-κB levels decreased following treatment with PNU282987 and EPCs. In conclusion, α7nAChR activation combined with EPC transplantation can alleviate lung injury in diabetic sepsis rats through the NF-κB signaling pathway., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: The inhalation of paraquat (PQ), one of the most widely used herbicides in the world, can result in lung injury. Curcuma longa (Cl) has long history in traditional and folk medicine for the treatment of a wide range of disorders including respiratory diseases., Aim: The aim of the present work was to evaluate the preventive effect of Cl on inhaled PQ-induced lung injury in rats., Methods: Male Wistar rats were divided into 8 groups (n = 7), one group exposed to saline (control) and other groups exposed to PQ aerosol. Saline (PQ), Cl extract, (two doses), curcumin (Cu), pioglitazone (Pio), and the combination of Cl-L + Pio and dexamethasone (Dex) were administered during the exposure period to PQ. Total and differential white blood cell (WBC) counts, oxidant and antioxidant indicators in the bronchoalveolar lavage (BALF), interleukin (IL)-10, and tumor necrosis alpha (TNF-α) levels in the lung tissues, lung histologic lesions score, and air way responsiveness to methacholine were evaluated., Results: WBC counts (Total and differential), malondialdehyde level, tracheal responsiveness (TR), IL-10, TNF-α and histopathological changes of the lung were markedly elevated but total thiol content and the activities of catalase and superoxide dismutase were decreased in the BALF in the PQ group. Both doses of Cl, Cu, Pio, Cl-L + Pio, and Dex markedly improved all measured variables in comparison with the PQ group., Conclusion: CI, Pio, and Cl-L + Pio improved PQ-induced lung inflammation and oxidative damage comparable with the effects of Dex., (© 2024 The Authors. Immunity, Inflammation and Disease published by John Wiley & Sons Ltd.)

Sepsis is a systemic inflammatory response syndrome caused by the invasion of pathogenic microorganisms. Despite major advances in diagnosis and technology, morbidity and mortality remain high. The level of neutrophil extracellular traps (NETs) is closely associated with the progression and prognosis of sepsis, suggesting the regulation of NET formation as a new strategy in sepsis treatment. Owing to its pleiotropic effects, atorvastatin, a clinical lipid-lowering drug, affects various aspects of sepsis-related inflammation and immune responses. To align closely with clinical practice, we combined it with imipenem for the treatment of sepsis. In this study, we used a cecum ligation and puncture-induced lung injury mouse model and employed techniques including western blot, immunofluorescence, and enzyme-linked immunosorbent assay to measure the levels of NETs and other sepsis-related lung injury indicators. Our findings indicate that atorvastatin effectively inhibited the formation of NETs. When combined with imipenem, it significantly alleviated lung injury, reduced systemic inflammation, and improved the 7-day survival rate of septic mice. Additionally, we explored the inhibitory mechanism of atorvastatin on NET formation in vitro, revealing its potential action through the ERK/NOX2 pathway. Therefore, atorvastatin is a potential immunomodulatory agent that may offer new treatment strategies for patients with sepsis in clinical settings., Competing Interests: Declaration of competing interest All authors declare that they have no competing interests., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

The alveolar type II epithelial cells (AEC2s) act as stem cells in the lung for alveolar epithelial maintenance and repair. Chemokine C-X-C motif chemokine 10 (CXCL10) is expressed in injured tissues, modulating multiple cellular functions. AEC2s, previously reported to release chemokines to recruit leukocytes, were found in our study to secrete CXCL10 after bleomycin injury. We found that Sftpc-Cxcl10 transgenic mice were protected from bleomycin injury. The transgenic mice showed an increase in the AEC2 population in the lung by flow cytometry analysis. Both endogenous and exogenous CXCL10 promoted the colony formation efficiency of AEC2s in a three-dimensional (3-D) organoid growth assay. We identified that the regenerative effect of CXCL10 was CXCR3 independent using Cxcr3 -deficient mice, but it was related to the TrkA pathway. Binding experiments showed that CXCL10 interacted with TrkA directly and reversibly. This study demonstrates a previously unidentified AEC2 autocrine signaling of CXCL10 to promote their regeneration and proliferation, probably involving a CXCR3-independent TrkA pathway. NEW & NOTEWORTHY CXCL10 may aid in lung injury recovery by promoting the proliferation of alveolar stem cells and using a distinct regulatory pathway from the classical one.

Elevated lactate levels are a significant biomarker of sepsis and are positively associated with sepsis-related mortality. Sepsis-associated lung injury (ALI) is a leading cause of poor prognosis in clinical patients. However, the underlying mechanisms of lactate's involvement in sepsis-associated ALI remain unclear. In this study, we demonstrate that lactate regulates N6-methyladenosine (m6A) modification levels by facilitating p300-mediated H3K18la binding to the METTL3 promoter site. The METTL3-mediated m6A modification is enriched in ACSL4, and its mRNA stability is regulated through a YTHDC1-dependent pathway. Furthermore, short-term lactate stimulation upregulates ACSL4, which promotes mitochondria-associated ferroptosis. Inhibition of METTL3 through knockdown or targeted inhibition effectively suppresses septic hyper-lactate-induced ferroptosis in alveolar epithelial cells and mitigates lung injury in septic mice. Our findings suggest that lactate induces ferroptosis via the GPR81/H3K18la/METTL3/ACSL4 axis in alveolar epithelial cells during sepsis-associated ALI. These results reveal a histone lactylation-driven mechanism inducing ferroptosis through METTL3-mediated m6A modification. Targeting METTL3 represents a promising therapeutic strategy for patients with sepsis-associated ALI., 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 B.V. All rights reserved.)

Background and Purpose: It is well acknowledged that tobacco-derived lung carcinogens can induce lung injury and even lung cancer through a complex mechanism. MicroRNAs (MiRNAs) are differentially expressed in tobacco-derived carcinogen nicotine-derived nitrosamine ketone (NNK)-treated A/J mice., Experimental Approach: RNA sequencing was used to detect the level of long non-coding RNAs (lncRNAs). Murine and human lung normal and cancer cells were used to evaluate the function of lncRNA XIST and miR-328-3p in vitro, and NNK-treated A/J mice were used to test their function in vivo. In vivo levels of miR-328-3p and lncRNA XIST were analysed, using in situ hybridization. miR-328-3p agomir and lncRNA XIST-specific siRNA were used to manipulate in vivo levels of miR-328-3p and lncRNA XIST in A/J mice., Key Results: LncRNA XIST was up-regulated in NNK-induced lung injury and dominated the NNK-induced ectopic miRNA expression in NNK-induced lung injury both in vitro and in vivo. Either lncRNA XIST silencing or miR-328-3p overexpression exerted opposing effects in lung normal and cancer cells regarding cell migration. LncRNA XIST down-regulated miR-328-3p levels as a miRNA sponge, and miR-328-3p targeted the 3'-UTR of FZD 7 mRNA, which is ectopically overexpressed in lung cancer patients. Both in vivo lncRNA XIST silencing and miR-328 overexpression could rescue NNK-induced lung injury and aberrant overexpression of the lung cancer biomarker CK19 in NNK-treated A/J mice., Conclusions and Implications: Our results highlight the promotive effect of lncRNA XIST in NNK-induced lung injury and elucidate its post-transcriptional mechanisms, indicating that targeting lncRNA XIST/miR-328-3p could be a potential therapeutic strategy to prevent tobacco carcinogen-induced lung injury in vivo., (© 2024 British Pharmacological Society.)

Exposure to acrylic amide (AD) has garnered worldwide attention due to its potential adverse health effects, prompting calls from the World Health Organization for intensified research into associated risks. Despite this, the relationship between oral acrylic amide (acrylamide) (AD) exposure and pulmonary dysfunction remains poorly understood. Our study aimed to investigate the correlation between internal oral exposure to AD and the decline in lung function, while exploring potential mediating factors such as tissue inflammation, oxidative stress, pyroptosis, and apoptosis. Additionally, we aimed to evaluate the potential protective effect of zinc oxide nanoparticles green-synthesized moringa extract (ZNO-MONPs) (10 mg/kg b.wt) against ACR toxicity and conducted comprehensive miRNA expression profiling to uncover novel targets and mechanisms of AD toxicity (miRNA 223-3 P and miRNA 325-3 P). Furthermore, we employed computational techniques to predict the interactions between acrylic amide and/or MO-extract components and tissue proteins. Using a rat model, we exposed animals to oral acrylamide (20 mg/kg b.wt for 2 months). Our findings revealed that AD significantly downregulated the expression of miRNA 223-3 P and miRNA 325-3 P, targeting NLRP-3 & GSDMD, respectively, indicating the induction of pyroptosis in pulmonary tissue via an inflammasome activating pathway. Moreover, AD exposure resulted in lipid peroxidative damage and reduced levels of GPX, CAT, GSH, and GSSG. Notably, AD exposure upregulated apoptotic, pyroptotic, and inflammatory genes, accompanied by histopathological damage in lung tissue. Immunohistochemical and immunofluorescence techniques detected elevated levels of indicative harmful proteins including vimentin and 4HNE. Conversely, concurrent administration of ZNO-MONPs with AD significantly elevated the expression of miRNA 223-3 P and miRNA 325-3 P, protecting against oxidative stress, apoptosis, pyroptosis, inflammation, and fibrosis in rat lungs. In conclusion, our study highlights the efficacy of ZNO-MONPs NPs in protecting pulmonary tissue against the detrimental impacts of foodborne toxin AD., 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.)

Cyclophosphamide is an anti-neoplastic drug that has shown competence in the management of a broad range of malignant tumors. In addition, it represents a keystone agent for management of immunological conditions. Despite these unique properties, induction of lung toxicity may limit its clinical use. Omarigliptin is one of the dipeptidyl peptidase-4 inhibitors that has proven efficacy in management of diabetes mellitus. Rosinidin is an anthocyanidin flavonoid that exhibited promising results in management of diseases characterized by oxidative stress, inflammation, and apoptosis. The present work investigated the possible effects of omarigliptin with or without rosinidin on cyclophosphamide-induced lung toxicity with an exploration of the molecular mechanisms that contribute to these effects. In a rodent model of cyclophosphamide elicited lung toxicity, the potential efficacy of omarigliptin with or without rosinidin was investigated at both the biochemical and the histopathological levels. Both omarigliptin and rosinidin exhibited a synergistic ability to augment the tissue antioxidant defenses, mitigate the inflammatory pathways, restore glucagon-like peptide-1 levels, modulate high mobility group box 1 (HMGB1)/receptors of advanced glycation end products (RAGE)/nuclear factor kappa B (NF-κB) axis, downregulate the fibrogenic mediators, and create a balance between the pathways involved in apoptosis and the autophagy signals in the pulmonary tissues. In conclusion, omarigliptin/rosinidin combination may be introduced as a novel therapeutic modality that attenuates the different forms of lung toxicities induced by cyclophosphamide., Competing Interests: Declaration of Competing Interest The authors declare that there are no conflicts of interest., (Copyright © 2024 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Background: Emodin, a natural anthraquinone derivative found in various Chinese medicinal herbs, has been proved to be an effective therapeutic agent in the treatment of many diseases. However, its effect on lung injury after intestinal ischemia/reperfusion injury remains unknown. This research was designed to investigate whether emodin protects against intestinal ischemia/reperfusion-induced lung injury and to elucidate the underlying molecular mechanisms in vivo and in vitro., Methods: Intestinal ischemia/reperfusion injury was induced by occluding the superior mesenteric artery in mice, and mouse lung epithelial-12 cells were subjected to oxygen-glucose deprivation and reoxygenation to establish an in vitro model., Results: Our data indicated that emodin treatment reduced intestinal ischemia/reperfusion-induced oxidative stress, inflammation and apoptosis in lung tissues and alleviated lung injury. However, the protective effects of emodin on intestinal ischemia/reperfusion-induced lung injury were reversed by the protein kinase B inhibitor triciribine or the heme oxygenase-1 inhibitor tin protoporphyrin IX. The protein kinase inhibitor triciribine also downregulated the expression of heme oxygenase-1., Conclusion: In conclusion, our data suggest that emodin treatment protects against intestinal ischemia/reperfusion-induced lung injury by enhancing heme oxygenase-1 expression via activation of the PI3K/protein kinase pathway. Emodin may act as a potential therapeutic agent for the prevention and treatment of lung injury induced by intestinal ischemia/reperfusion., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Sepsis is a life-threatening condition characterized by a systemic inflammatory response to infection. Despite extensive research on its pathophysiology, effective therapeutic approaches remain a challenge. This study investigated the potential of resveratrol (RV) and silver nanoparticle-enhanced resveratrol (AgNP-RV) as treatments for sepsis-induced lung injury using a rat model of polymicrobial sepsis induced by cecal ligation and puncture (CLP). The study focused on evaluating changes in oxidative status (TAS, TOS, and OSI) and the expression of inflammatory and apoptotic markers (IL-1β, TNF-α, P2X7R, TLR4, Caspase-3, and Bcl-2) in lung tissue. Both RV and AgNP-RV demonstrated potential in mitigating oxidative stress, inflammation, and apoptosis, with AgNP-RV exhibiting greater efficacy than RV alone (p < 0.05). These findings were corroborated by histopathological analyses, which revealed reduced tissue damage in the RV- and AgNP-RV-treated groups. Our study highlights the therapeutic potential of RV and, particularly, AgNP-RV in combating sepsis-induced oxidative stress, inflammation, and apoptosis. It also underscores the promise of nanoparticle technology in enhancing therapeutic outcomes. However, further investigations are warranted to fully understand the mechanisms of action, especially concerning the role of the P2X7 receptor in the observed effects. Nonetheless, our research suggests that RV and AgNP-RV hold promise as novel strategies for sepsis management., (© 2024. The Author(s).)

Our previous studies indicated that calcitonin gene-related peptide (CGRP) alleviates hyperoxia-induced lung injury and suggested the possible involvement of autophagy in this process. Herein, we aimed to further explore the potential involvement of tumor protein p53 (TP53) and autophagy in the mode of action of CGRP against hyperoxia-induced lung injury in vitro and in vivo. The study conducted tests on type II alveolar epithelial cells (AECII) and rats that were subjected to hyperoxia treatment or combined treatment of hyperoxia with CGRP, CGRP inhibitor, rapamycin (an autophagy agonist), 3-methyladenine (3-MA, an autophagy inhibitor), TP53 silencing/inhibitor (pifithrin-α), or expression vector/activator (PRIMA-1 (2,2-bis(hydroxymethyl)-3-quinuclidinone)) and their corresponding controls. We found that oxidative stress, apoptosis, and autophagy were all increased by hyperoxia treatment in vitro. However, treating AECII cells with CGRP reversed hyperoxia-induced oxidative stress and apoptosis but further promoted autophagy. In addition, the combined treatment with rapamycin or TP53 silencing with CGRP promoted the effect of CGRP, while contrary results were obtained with combined therapy with 3-MA or TP53 overexpression. In vivo, the number of hyperoxia-induced autophagosomes was promoted in the lung tissue of neonatal rats. Furthermore, hyperoxia increased the expression levels of AMP-activated protein kinase (AMPK) alpha 1 (also known as protein kinase AMP-activated catalytic subunit alpha 1 (PRKAA1)) but inhibited TP53 and mechanistic target of rapamycin (MTOR); these expression trends were regulated by CGRP treatment. In conclusion, we showed that CGRP can attenuate hyperoxia-induced lung injury in neonatal rats by enhancing autophagy and regulating the TP53/AMPK/MTOR crosstalk axis., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Injury to internal organs caused by myocardial infarction (MI), although often neglected, is a very serious condition which damages internal organs especially the lungs. Changes in microcirculation can begin with acute lung injury and result in severe respiratory failure. The aim of this study was to create new approaches that will explain the pathophysiology and treatment of the disease by examining the therapeutic effects of vitamin D (VITD) and Nerolidol (NRD) on the injuries of the lungs caused by MI, and their relationship with asprosin / spexin proteins., Methods: Six groups of seven experimental animals each were constituted. Control, VITD (only 50 IU/day during the experiment), NRD (only 100 mg/kg/day during the experiment), MI (200 mg/kg isoproterenol was administered to rats as a single dose subcutaneously), MI+VITD (200 mg/kg isoproterenol +50 IU/day) and MI+NRD (200 mg/kg isoproterenol +100 mg/kg/day) were the six (6) groups constituted. Tissues were analyzed using histopathological and immunohistochemical methods, whereas serum samples were analyzed using ELISA method., Results: The result of the histopathological study for the MI group showed an observed increase in inflammatory cells, congestion, interalveolar septal thickening, erythrocyteloaded macrophages and fibrosis in the lung tissues. The treatment groups however recorded significant differences with regards to these parameters. In the immunohistochemical analysis, expressions of asprosin and spexin were observed in the smooth muscle structures and interalveolar areas of the vessels and bronchioles of the lung, as well as the bronchiole epithelium. There was no significant difference between the groups in terms of asprosin and spexin expression in the bronchiol epithelium. When immunohistochemical and serum ELISA results were examined, it was observed that asprosin levels increased significantly in the lung tissues of the MI group compared to the control group, decreased significantly in the treatment groups treated with Vitamin D and NRD after MI. While spexin decreased significantly in the MI group compared to the control group, it increased significantly in the MI+VİTD group, but did not change in the MI+NRD group., Conclusion: It was observed that serious injuries occurred in the lungs due to myocardial infarction and that, VITD and NRD treatments had a curative effect on those injuries. It was also observed that Asprosin and Speksin proteins can have effect on mechanisms of both injury and therapy of the lung. Furthermore, the curative effects of VITD are dependent on the expression of asprosin and spexin; whereas the observation indicated that nerolidol could be effective through asprosin-dependent mechanisms and specisin by independent mechanisms., Competing Interests: Declaration of Competing Interest The authors declare no conflicts of interest., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

COVID-19, caused by SARS-CoV-2 infection, results in irreversible or fatal lung injury. We assumed that necroptosis of virus-infected alveolar epithelial cells (AEC) could promote local inflammation and further lung injury in COVID-19. Since CD8+ lymphocytes induced AEC cell death via cytotoxic molecules such as FAS ligands, we examined the involvement of FAS-mediated cell death in COVID-19 patients and murine COVID-19 model. We identified the occurrence of necroptosis and subsequent release of HMGB1 in the admitted patients with COVID-19. In the mouse model of COVID-19, lung inflammation and injury were attenuated in Fas-deficient mice compared to Fas-intact mice. The infection enhanced Type I interferon-inducible genes in both groups, while inflammasome-associated genes were specifically upregulated in Fas-intact mice. The treatment with necroptosis inhibitor, Nec1s, improved survival rate, lung injury, and systemic inflammation. SARS-CoV-2 induced necroptosis causes cytokine induction and lung damage, and its inhibition could be a novel therapeutic strategy for COVID-19., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Shinsuke Yasuda reports a relationship with AbbVie Inc. that includes: funding grants and speaking and lecture fees. Shinsuke Yasuda reports a relationship with Asahi Kasei Pharma Corporation that includes: funding grants and speaking and lecture fees. Shinsuke Yasuda reports a relationship with Chugai Pharmaceutical Co Ltd. that includes: funding grants and speaking and lecture fees. Shinsuke Yasuda reports a relationship with CSL Behring that includes: funding grants. Shinsuke Yasuda reports a relationship with Eisai Inc. that includes: funding grants and speaking and lecture fees. Shinsuke Yasuda reports a relationship with ImmunoForge that includes: funding grants. Shinsuke Yasuda reports a relationship with Mitsubishi Tanabe Pharma Corporation that includes: funding grants and speaking and lecture fees. Shinsuke Yasuda reports a relationship with Ono Pharmaceutical Co Ltd. that includes: funding grants and speaking and lecture fees. Shinsuke Yasuda reports a relationship with Eli Lilly that includes: speaking and lecture fees. Shinsuke Yasuda reports a relationship with GlaxoSmithKline that includes: speaking and lecture fees. Shinsuke Yasuda reports a relationship with Pfizer Inc. that includes: speaking and lecture fees. Tadashi Hosoya reports a relationship with Sony Corporation that includes: funding grants. Tadashi Hosoya reports a relationship with Terumo life science foundation that includes: funding grants. Mari Kamiya reports a relationship with GlaxoSmithKline that includes: funding grants. 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.)

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.)

One of the main pathological features of chronic obstructive pulmonary disease (COPD) is the loss of functional alveolar tissue as a consequence of impaired regenerative capacities (emphysema). Recent research suggests that the secretome from mesenchymal cells, particularly extracellular vesicles (EVs), may possess regenerative properties beneficial for lung repair. However, the regenerative potential of the soluble factors (SFs) within the secretome remains largely unexplored in COPD. To this extent, we purified EVs and SFs secreted by lung fibroblasts to generate EV-enriched and SF-enriched fractions, and evaluated their effects on elastase-induced lung injury in both precision-cut lung slices (PCLS) and a mouse model. EV- and SF-enriched fractions were concentrated and purified from the conditioned medium of cultured MRC-5 lung fibroblasts using a combination of ultrafiltration and size exclusion chromatography, and were subsequently characterized according to the MISEV guidelines. Treatment with EV- or SF-enriched concentrates prevented and improved elastase-induced emphysema in PCLS, leading to reduced lung injury and upregulated markers of alveolar epithelial cells (aquaporin 5 and surfactant protein C), indicating potential parenchymal regeneration. Accordingly, prophylactic intratracheal treatment with lung fibroblast-derived EV- and SF-enriched concentrates in vivo attenuated elastase-induced lung tissue destruction, improved lung function, and enhanced gene expression of alveolar epithelial cell markers. Here, alveolar repair not only serves the purpose of facilitating gas exchange, but also by reinstating the essential parenchymal tethering required for optimal airway mechanics. In conclusion, this study highlights the therapeutic potential of both lung fibroblast-derived EV- and SF-enriched concentrates for the treatment of lung injury and emphysema., 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 Author(s). Published by Elsevier B.V. All rights reserved.)

Hydrogen peroxide (H 2 O 2 ) overexpressed in mitochondria has been regarded as a key biomarker in the pathological processes of various diseases. However, there is currently a lack of suitable mitochondria-targetable near-infrared (NIR) probes for the visualization of H 2 O 2 in multiple diseases, such as PM 2.5 exposure-induced lung injury, hepatic ischemia-reperfusion injury (HIRI), nonalcoholic fatty liver (NAFL), hepatic fibrosis (HF), and malignant tumor tissues containing clinical cancer patient samples. Herein, we conceived a novel NIR fluorescent probe ( HCy-H 2 O 2 ) by introducing pentafluorobenzenesulfonyl as a H 2 O 2 sensing unit into the NIR hemicyanine platform. HCy-H 2 O 2 exhibits good sensitivity and selectivity toward H 2 O 2 , accompanied by a remarkable "turn-on" fluorescence signal at 720 nm. Meanwhile, HCy-H 2 O 2 has stable mitochondria-targetable ability and permits monitoring of the up-generated H 2 O 2 level during mitophagy. Furthermore, using HCy-H 2 O 2 , we have successfully observed an overproduced mitochondrial H 2 O 2 in ambient PM 2.5 exposure-induced lung injury, HIRI, NAFL, and HF models through NIR fluorescence imaging. Significantly, the visualization of H 2 O 2 has been achieved in both tumor-bear mice as well as surgical specimens of cancer patients, making HCy-H 2 O 2 a promising tool for cancer diagnosis and imaging-guided surgery.

Investigations into the mechanisms of injury and repair in fibroproliferative disease require consideration of the spatial heterogeneity inherent in the disease. Most scoring of fibrotic remodeling in preclinical animal models relies on the modified Ashcroft score, which is an ordinal rubric of macroscopic resolution. The obvious limitations of manual histopathologic scoring have generated an unmet need for unbiased, repeatable scoring of fibroproliferative burden in tissue. Using computer vision approaches on immunofluorescence imaging of the extracellular matrix component laminin, we generated a robust and repeatable quantitative remodeling scorer. In the bleomycin lung injury model, the quantitative remodeling scorer shows significant agreement with the modified Ashcroft scale. This antibody-based approach is easily integrated into larger multiplex immunofluorescence experiments, which we demonstrate by testing the spatial apposition of tertiary lymphoid structures to fibroproliferative tissue, a poorly characterized phenomenon observed in both human interstitial lung diseases and preclinical models of lung fibrosis. The tool reported in this article is available as a stand-alone application that is usable without programming knowledge.

Alveoli are complex microenvironments composed of various cell types, including epithelial, fibroblast, endothelial, and immune cells, which work together to maintain a delicate balance in the lung environment, ensuring proper growth, development, and an effective response to lung injuries. However, prolonged inflammation or aging can disrupt normal interactions among these cells, leading to impaired repair processes and a substantial decline in lung function. Therefore, it is essential to understand the key mechanisms underlying the interactions among the major cell types within the alveolar microenvironment. We explored the key mechanisms underlying the interactions among the major cell types within the alveolar microenvironment. These interactions occur through the secretion of signaling factors and play crucial roles in the response to injury, repair mechanisms, and the development of fibrosis in the lungs. Specifically, we focused on the regulation of alveolar type 2 cells by fibroblasts, endothelial cells, and macrophages. In addition, we explored the diverse phenotypes of fibroblasts at different stages of life and in response to lung injury, highlighting their impact on matrix production and immune functions. Furthermore, we summarize the various phenotypes of macrophages in lung injury and fibrosis as well as their intricate interplay with other cell types. This interplay can either contribute to the restoration of immune homeostasis in the alveoli or impede the repair process. Through a comprehensive exploration of these cell interactions, we aim to reveal new insights into the molecular mechanisms that drive lung injury toward fibrosis and identify potential targets for therapeutic intervention.

Hyperthyroidism-induced cardiac disease is an evolving health, economic, and social problem affecting well-being. Sodium-glucose cotransporter protein 2 inhibitors (SGLT2-I) have been proven to be cardio-protective when administered in cases of heart failure. This study intended to investigate the potential therapeutic effect of SGLT2-I on hyperthyroidism-related cardiopulmonary injury, targeting the possible underlying mechanisms. The impact of the SGLT2-I, dapagliflozin (DAPA), (1 mg/kg/day, p.o) on LT4 (0.3 mg/kg/day, i.p)-induced cardiopulmonary injury was investigated in rats. The body weight, ECG, and serum hormones were evaluated. Also, redox balance, DNA fragmentation, inflammatory cytokines, and PCR quantification in heart and lung tissues were employed to investigate the effect of DAPA in experimentally induced hyperthyroid rats along with histological and immunohistochemical examination. Coadministration of DAPA with LT4 effectively restored all serum biomarkers to nearly average levels, improved ECG findings, and reinstated the redox balance. Also, DAPA could improve DNA fragmentation, elevate mtTFA, and lessen TNF-α and IGF-1 gene expression in both organs of treated animals. Furthermore, DAPA markedly improved the necro-inflammatory and fibrotic cardiopulmonary histological alterations and reduced the tissue immunohistochemical expression of TNF-α and caspase-3. Although further clinical and deep molecular studies are required before transposing to humans, our study emphasized DAPA's potential to relieve hyperthyroidism-induced cardiopulmonary injury in rats through its antioxidant, anti-inflammatory, and anti-apoptotic effects, as well as via antagonizing the sympathetic over activity., (© 2024. The Author(s).)

Objectives: Lung transplant warm ischemia-reperfusion injury (IRI) results in cellular injury, inflammation, and poor graft function. Mitsugumin 53 (MG53) is an endogenous protein with cell membrane repair properties and the ability to modulate the inflammasome. We hypothesize that the absence of circulating MG53 protein in the recipient increases IRI, and higher levels of circulating MG53 protein mitigate IRI associated with lung transplantation., Methods: To demonstrate protection, wild-type (wt) lung donor allografts were transplanted into a wt background, a MG53 knockout (mg53-/-), or a constitutively overexpressed MG53 (tissue plasminogen activator-MG53) recipient mouse after 1 hour of warm ischemic injury. Mice survived for 5 days after transplantation. Bronchioalveolar lavage, serum, and tissue were collected at sacrifice. Bronchioalveolar lavage, serum, and tissue markers of apoptosis and a biometric profile of lung health were analyzed., Results: mg53-/- mice had significantly greater levels of markers of overall cell lysis and endothelial cell injury. Overexpression of MG53 resulted in a signature similar to that of wt controls. At the time of explant, tissue plasminogen activator-MG53 recipient tissue expressed significantly greater levels of MG53, measured by immunohistochemistry, compared with mg53-/-, demonstrating uptake of endogenous overexpressed MG53 into donor tissue., Conclusions: In a warm IRI model of lung transplantation, the absence of MG53 resulted in increased cell injury and inflammation. Endogenous overexpression of MG53 in the recipient results in protection in the wt donor. Together, these data suggest that MG53 is a potential therapeutic agent for use in lung transplantation to mitigate IRI., Competing Interests: Conflict of Interest Statement J.M. is a founder of TRIM-edicine, Inc, a university spin-off biotechnology company that develops MG53 for regenerative medicine application. B.A.W. serves on the Clinical Events Committee of TransMedics OCS. All other authors reported no conflicts of interest. The Journal policy requires editors and reviewers to disclose conflicts of interest and to decline handling or reviewing manuscripts for which they may have a conflict of interest. The editors and reviewers of this article have no conflicts of interest., (Copyright © 2023. Published by Elsevier Inc.)

Although exogenous calcitonin gene‑related peptide (CGRP) protects against hyperoxia‑induced lung injury (HILI), the underlying mechanisms remain unclear. The present study attempted to elucidate the molecular mechanism by which CGRP protects against hyperoxia‑induced alveolar cell injury. Human alveolar A549 cells were treated with 95% hyperoxia to establish a hyperoxic cell injury model. ELISA was performed to detect the CGRP secretion. Immunofluorescence, quantitative (q)PCR, and western blotting were used to detect the expression and localization of CGRP receptor (CGRPR) and transient receptor potential vanilloid 1 (TRPV1). Cell counting kit‑8 and flow cytometry were used to examine the proliferation and apoptosis of treated cells. Digital calcium imaging and patch clamp were used to analyze the changes in intracellular Ca 2+ signaling and membrane currents induced by CGRP in A549 cells. The mRNA and protein expression levels of Cyclin D1, proliferating cell nuclear antigen (PCNA), Bcl‑2 and Bax were detected by qPCR and western blotting. The expression levels of CGRPR and TRPV1 in A549 cells were significantly downregulated by hyperoxic treatment, but there was no significant difference in CGRP release between cells cultured under normal air and hyperoxic conditions. CGRP promoted cell proliferation and inhibited apoptosis in hyperoxia, but selective inhibitors of CGRPR and TRPV1 channels could effectively attenuate these effects; TRPV1 knockdown also attenuated this effect. CGRP induced Ca 2+ entry via the TRPV1 channels and enhanced the membrane non‑selective currents through TRPV1 channels. The CGRP‑induced increase in intracellular Ca 2+ was reduced by inhibiting the phospholipase C (PLC)/protein kinase C (PKC) pathway. Moreover, PLC and PKC inhibitors attenuated the effects of CGRP in promoting cell proliferation and inhibiting apoptosis. In conclusion, exogenous CGRP acted by inversely regulating the function of TRPV1 channels in alveolar cells. Importantly, CGRP protected alveolar cells from hyperoxia‑induced injury via the CGRPR/TRPV1/Ca 2+ axis, which may be a potential target for the prevention and treatment of the HILI.

Progressive lung fibrosis is associated with poorly understood aging-related endothelial cell dysfunction. To gain insight into endothelial cell alterations in lung fibrosis we performed single cell RNA-sequencing of bleomycin-injured lungs from young and aged mice. Analysis reveals activated cell states enriched for hypoxia, glycolysis and YAP/TAZ activity in ACKR1+ venous and TrkB+ capillary endothelial cells. Endothelial cell activation is prevalent in lungs of aged mice and can also be detected in human fibrotic lungs. Longitudinal single cell RNA-sequencing combined with lineage tracing demonstrate that endothelial activation resolves in young mouse lungs but persists in aged ones, indicating a failure of the aged vasculature to return to quiescence. Genes associated with activated lung endothelial cells states in vivo can be induced in vitro by activating YAP/TAZ. YAP/TAZ also cooperate with BDNF, a TrkB ligand that is reduced in fibrotic lungs, to promote capillary morphogenesis. These findings offer insights into aging-related lung endothelial cell dysfunction that may contribute to defective lung injury repair and persistent fibrosis., (© 2024. The Author(s).)