Lung Tissue Inflammation Research Articles

Exercise preconditioning and resveratrol reduce the susceptibility of rats with obstructive jaundice to endotoxin and alleviate lung injury

IntroductionEndotoxemia is a common issue for patients with biliary obstruction. The lung is the most affected organ by endotoxins. Exercise training can alleviate lipopolysaccharide (LPS)-induced lung inflammation and resveratrol has biological effects similar to exercise. In this study, we evaluated the protective effects of exercise preconditioning, resveratrol, and their combination on LPS-induced lung injury and mortality in rats with obstructive jaundice.MethodsEndotoxemia was simulated in rats by common bile duct ligation (CBDL) and intraperitoneal injection of low-dose LPS. The treatment groups were pretreated with exercise and/or resveratrol to assess their effects on lung injury and mortality. Immunohistochemistry, immunofluorescence, and ELISA were subsequently used to evaluate the impact of exercise and/or resveratrol on inflammation in lung tissue and bronchoalveolar lavage fluid.ResultsWe found that even in the early stages, compared to sham-LPS rats, low-dose LPS induced excessive systemic inflammatory responses in CBDL rats, as evidenced by a significant increase in TNF-α and IL-6, severe lung inflammation, lung injury, and higher mortality rates, indicating that cholestasis increased rats’ susceptibility to endotoxins. Exercise training reduced neutrophil infiltration in the lungs of model rats and IL-6 levels in bronchoalveolar lavage fluid. Both exercise training and resveratrol exhibited synergistic effects in reducing macrophage accumulation in lung tissues, lowering TNF-α and IL-6 levels in the lungs, and decreasing TNF-α concentration in bronchoalveolar lavage fluid. Additionally, exercise and combined interventions both significantly increased the expression of IL-10. The interventions induced a marked improvement in lung tissue pathological damage and lung edema in model rats and prolonged the survival time of rats with obstructive jaundice.DiscussionThis study demonstrates that exercise preconditioning and/or resveratrol can significantly reduce rats’ susceptibility to endotoxins after CBDL and alleviate lung injuries through their anti-inflammatory effects, thereby decreasing the mortality risk.

Reprint of: M1 Macrophage-Targeted Curcumin Nanocrystals with l-Arginine-Modified for Acute Lung Injury by Inhalation.

Acute Lung Injury/Acute Respiratory Distress Syndrome (ALI/ARDS) with clinical manifestations of respiratory distress and hypoxemia remains a significant cause of respiratory failure, boasting a persistently high incidence and mortality rate. Given the central role of M1 macrophages in the pathogenesis of acute lung injury (ALI), this study utilized the anti-inflammatory agent curcumin as a model drug. l-arginine (L-Arg) was employed as a targeting ligand, and chitosan was initially modified with l-arginine. Subsequently, it was utilized as a surface modifier to prepare inhalable nano-crystals loaded with curcumin (Arg-CS-Cur), aiming for specific targeting of pulmonary M1 macrophages. Compared with unmodified chitosan-curcumin nanocrystals (CS-Cur), Arg-CS-Cur exhibited higher uptake in vitro by M1 macrophages, as evidenced by flow cytometry showing the highest fluorescence intensity in the Arg-CS-Cur group (P < 0.01). In vivo accumulation was greater in inflamed lung tissues, as indicated by small animal imaging demonstrating higher lung fluorescence intensity in the DiR-Arg-CS-Cur group compared to the DiR-CS-Cur group in the rat ALI model (P < 0.05), peaking at 12 h. Moreover, Arg-CS-Cur demonstrated enhanced therapeutic effects in both LPS-induced RAW264.7 cells and ALI rat models. Specifically, treatment with Arg-CS-Cur significantly suppressed NO release and levels of TNF-α and IL-6 in RAW264.7 cells (p < 0.01), while in ALI rat models, expression levels of TNF-α and IL-6 in lung tissues were significantly lower than those in the model group (P < 0.01). Furthermore, lung tissue damage was significantly reduced, with histological scores significantly lower than those in the CS-Cur group (P < 0.01). In conclusion, these findings underscore the targeting potential of l-arginine-modified nanocrystals, which effectively enhance curcumin concentration in inflammatory environments by selectively targeting M1 macrophages. This study thus introduces novel perspectives and theoretical support for the development of targeted therapeutic interventions for acute inflammatory lung diseases, including ALI/ARDS.

NK cell-derived exosomes inhibit survival of Mycobacterium tuberculosis by promoting apoptosis in mice

AimTo investigate anti-Mycobacterium tuberculosis (Mtb) influences exerted by natural killer cell-derived exosomes (NK-exo) on mice and to elucidate underlying immunologic mechanisms. MethodsWe established tuberculosis (TB) model in mouse by injecting Mtb H37Ra (1 × 106 colony counting (CFU), i.v.) into tail vein for 14 days. The survival rate of Mtb was assessed through CFU, apoptosis rates were measured utilizing flow cytometry, and inflammation relief was quantified via HE staining. Expressions of apoptosis, inflammation, and pyroptosis-related proteins were quantified by Western blotting and RT-qPCR. ELISA was utilized for detecting inflammatory cytokines production. Intracellular reactive oxygen species (ROS) levels were assessed through DCFH-DA fluorescent probe assay. ResultsNK-exo treatment reduced Mtb load in lung and spleen tissues and alleviated inflammation in mice lung tissues. NK-exo intervention increased protein levels of markers associated with apoptosis, PARP and caspase-3/8/9, downregulating the concentrations of pro-inflammatory cytokines, comprising IL-1β, TNF-α, IL-6, along with protein expressions of biomarkers, ASC, NLRP3, GSDMD, associated to inflammation and pyroptosis. NK-exo also elevated ROS levels without affecting lactate dehydrogenase (LDH) release from macrophages. ConclusionNK-exo exhibits anti-tuberculosis activity in experimental TB mice. The underlying mechanism involve regulating caspase-dependent apoptotic signaling pathway to promote cell apoptosis, as well as modulating NLRP3 signaling pathway to suppress the inflammatory response.

Intravenous injection of BMSCs modulate tsRNA expression and ameliorate lung remodeling in COPD mice

BackgroundChronic obstructive pulmonary disease (COPD) is characterized by lung remodeling induced by chronic inflammation, presenting challenges for effective treatment. Mesenchymal stem cells (MSCs) and their extracellular vesicles (EVs) have shown promise in mitigating inflammation and tissue repairing in various diseases, including COPD. However, the optimal therapeutic pathways for different stages of COPD remain unclear. Transfer RNA-derived small RNAs (tsRNAs) are emerging as key regulators of cellular processes. However, their role in COPD and MSC therapy remains poorly understood.MethodsThis study explored the optimal administration routes and efficacy of bone marrow mesenchymal stem cells (BMSCs) and their extracellular vesicles (BMSC-EVs) in treating inflammatory or emphysematous COPD stages in mouse models. Male C57BL/6 mice were exposed to cigarette smoke daily for 6 or 16 weeks, with intraperitoneal CSE injections every 10 days, to model different stages of COPD. Mice were then treated with tracheal or intravenous injections of BMSCs or BMSC-EVs. PKH26 fluorescent dye labeled BMSCs and BMSC-EVs for pulmonary distribution observation. Lung tissue inflammation, apoptosis, EMT, and collagen deposition were assessed using HE staining, TUNEL assay, immunohistochemistry, and Sirius Red staining. Gene and tsRNA expression in lung tissues were analyzed by high-throughput sequencing. Differentially expressed tsRNAs (DE-tsRNAs) were validated by RT-qPCR. Statistical analysis was performed using GraphPad Prism 9.0. Data are presented as mean ± standard deviation (SD).ResultsIn 16-week COPD mice characterized by emphysema, tracheal administration of BMSC-EVs showed more significant lung distribution and inhibition of emphysematous pathology. In 6-week COPD mice characterized by inflammation, intravenous injection of BMSCs led to significant pulmonary homing, significantly reduced lung inflammation, apoptosis, EMT, and collagen deposition (P < 0.05). High-throughput sequencing indicated BMSC treatment downregulated genes related to these processes while upregulating mitochondrial function genes. Co-expression networks of DE-tsRNAs and target genes suggested potential roles in COPD. RT-qPCR confirmed significant differential expression of two DE-tsRNAs during COPD progression and BMSC treatment (P < 0.05).ConclusionsOur study provides insights into selecting MSC and MSC-EV administration routes for different COPD stages. High-throughput sequencing supports BMSCs’ inhibitory effects on lung remodeling and identifies the first tsRNA expression profile in a COPD model, warranting further investigation.

Astragaloside IV Inhibits Lung Injury and Fibrosis Induced by PM2.5 by Targeting RUNX1 Through miR-362-3p.

To discover the molecular mechanism of Astragaloside IV (AS IV) in PM2.5-induced lung injury and pulmonary fibrosis (PF). A lung injury rat model was induced by PM2.5 and injected intraperitoneally with AS IV. Lungs were harvested to evaluate lung tissue injury and apoptosis. Rat alveolar epithelial cells L2 were exposed to PM2.5 and treated with AS IV. After cellular transfection, cell proliferation, LDH production, and apoptosis were measured. In both models, inflammatory factors and fibrotic indices were measured by ELISA and Western blot. miR-362-3p and RUNX1 interplay was explored and confirmed. Administration of AS IV attenuated PM2.5-induced lung tissue injury, inflammation, apoptosis, and PF in rats. AS IV enhanced proliferation and reduced LDH release, apoptosis, inflammation, and PF in PM2.5-treated L2 cells. MiR-362-3p upregulation improved PM2.5-induced L2 cell injury. AS IV improved PM2.5-induced lung injury by upregulating miR-362-3p. miR-362-3p had an inhibition effect on RUNX1 expression. RUNX1 upregulation weakened the therapeutic effect of AS IV on PM2.5-induced alveolar epithelial cell injury. AS IV inhibits lung injury and PF induced by PM2.5 by targeting RUNX1 through upregulation of miR-362-3p.

Porcine Nose Atrophy Assessed by Automatic Imaging and Detection of Bordetella bronchiseptica and Other Respiratory Pathogens in Lung and Nose.

The nasal mucosa is a crucial filtering organ to prevent attachment and invasion of pathogens. To assess nasal health in relation to lung health, transverse cross sections of the nasal turbinates of 121 pigs suffering from respiratory disease and sent for diagnostic necropsy were scored visually and by an artificial intelligence (AI) medical diagnostic application (AI DIAGNOS), resulting in a high correlation of both scores (p < 0.001). Nasal samples of the diseased pigs were examined only for Bordetella (B.) bronchiseptica (PCR and bacteriological culture) and Pasteurella (P.) multocida (bacteriological culture). All pigs showed various degrees of inflammatory lung tissue alterations, and 35.5% of the pigs had atrophy of the nasal turbinates with no relation to detection rates of B. bronchiseptica (54.5%) and P. multocida (29.0%) in the nose. All P. multocida strains from nose samples were negative for the toxA gene so non-progressive atrophic rhinitis was diagnosed. Pigs positive for B. bronchiseptica in the nose were more often positive for B. bronchiseptica in the lung (p < 0.001) and for other bacterial species in the lower respiratory tract (p = 0.005). The new diagnostic application for scoring cross sections of nasal turbinates is a valuable tool for a fast and reproducible diagnostic.

Inhibitory Effect of Luteolin on Spike S1 Glycoprotein-Induced Inflammation in THP-1 Cells via the ER Stress-Inducing Calcium/CHOP/MAPK Pathway.

The global SARS-CoV-2 outbreak has escalated into a critical public health emergency, with the spike glycoprotein S1 subunit of SARS-CoV-2 (spike-S1) linked to inflammation in lung tissue and immune cells. Luteolin, a flavone with anti-inflammatory properties, shows promise, but research on its effectiveness against long-COVID-related inflammation and spike protein-induced responses remains limited. This study aims to elucidate the underlying mechanisms of inflammation in THP-1 cells induced by the spike-S1. Additionally, it seeks to assess the potential of luteolin in mitigating inflammatory responses induced by the spike-S1 in a THP-1 macrophage model. The gene expression profiles of spike-S1 in THP-1 cells were analyzed by transcriptome sequencing. The inhibitory effect of luteolin on ER stress and inflammation in spike-S1-induced THP-1 cells was investigated using Western blotting, RT-PCR, and ELISA. The candidate genes (CAMK2A, SIGLEC7, PPARGC1B, SEC22B, USP28, IER2, and TIRAP) were upregulated in the spike-S1-induced THP-1 group compared to the control group. Among these, calcium/calmodulin-dependent protein kinase II alpha (CAMK2A) was identified as the most promising molecule in spike-S1-induced THP-1 cells. Our results indicate that the spike S1 significantly increased the expression of ER-stress markers at both gene and protein levels. Luteolin significantly reduced ER stress by decreasing the expression of ER-stress marker genes and ER-stress marker proteins (p < 0.01). Additionally, luteolin exhibited anti-inflammatory properties upon spike S1-induction in THP-1 cells by significantly suppressing IL-6, IL-8, and IL-1β cytokine secretion in a dose-dependent manner (p < 0.05). Furthermore, our results revealed that luteolin exhibited the downregulation of the MAPK pathway, as evidenced by modulating the phosphorylation of p-ERK1/2, p-JNK and p-p38 proteins (p < 0.05). The results from this study elucidate the mechanisms by which the spike S1 induces inflammation in THP-1 cells and supports the use of naturally occurring bioactive compounds, like luteolin, against inflammation-related SARS-CoV-2 infection.

A Novel Deep Learning Framework Enhanced by Hybrid Optimization Using Dung Beetle and Fick’s Law for Superior Pneumonia Detection

Pneumonia is an inflammation of lung tissue caused by various infectious microorganisms and noninfectious factors. It affects people of all ages, but vulnerable age groups are more susceptible. Imaging techniques, such as chest X-rays (CXRs), are crucial in early detection and prompt action. CXRs for this condition are characterized by radiopaque appearances or sometimes a consolidation in the affected part of the lung caused by inflammatory secretions that replace the air in the infected alveoli. Accurate early detection of pneumonia is essential to avoid its potentially fatal consequences, particularly in children and the elderly. This paper proposes an enhanced framework based on convolutional neural network (CNN) architecture, specifically utilizing a transfer-learning-based architecture (MobileNet V1), which has outperformed recent models. The proposed framework is improved using a hybrid method combining the operation of two optimization algorithms: the dung beetle optimizer (DBO), which enhances exploration by mimicking dung beetles’ navigational strategies, and Fick’s law algorithm (FLA), which improves exploitation by guiding solutions toward optimal areas. This hybrid optimization effectively balances exploration and exploitation, significantly enhancing model performance. The model was trained on 7750 chest X-ray images. The framework can distinguish between healthy and pneumonia, achieving an accuracy of 98.19 ± 0.94% and a sensitivity of 98 ± 0.99%. The results are promising, indicating that this new framework could be used for the early detection of pneumonia with a low cost and high accuracy, especially in remote areas that lack expertise in radiology, thus reducing the mortality rate caused by pneumonia.

Luteolin alleviates airway remodeling in asthma by inhibiting the epithelial-mesenchymal transition via β-catenin regulation

BackgroundAsthma is a prevalent long-term inflammatory condition that causes airway inflammation and remodeling. Increasing evidence indicates that epithelial-mesenchymal transition (EMT) holds a prominent implication in airway reconstruction in patients with asthma. Flavonoids obtained from Chinese Materia Medica (CMM), such as Luteolin (Lut), exhibit various beneficial effects in various asthma models. Lut has been shown to mitigate various asthma symptoms, including airway inflammation, hyperresponsiveness, bronchoconstriction, excessive mucus production, pulmonary autophagy, and neutrophilic asthma. However, whether flavonoids can suppress EMT-associated airway remodeling in asthma and the fundamental mechanisms involved remain unclear, with no studies specifically addressing Lut in this context. PurposeTo evaluate the inhibition of airway remodeling in asthma by Lut and its potential mechanisms, while examining the significance of β-catenin in this process through cellular and animal studies. MethodsA BEAS-2B cell model stimulated by lipopolysaccharide (LPS) was established in vitro. Wound closure and Transwell assays were utilized to assess the cellular migratory ability. EMT- and fibrosis-related markers in LPS-stimulated cells were evaluated using RT-qPCR and western blotting. The status of the β-catenin/E-cadherin and β-catenin destruction complexes was evaluated using western blotting, immunofluorescence (IF) staining, and co-immunoprecipitation (Co-IP) analysis. The regulatory function of Lut in β-catenin-dependent EMT was further validated by β-catenin overexpression with adenovirus transduction and siRNA-mediated knockdown of β-catenin. Moreover, the counts of different types of bronchoalveolar lavage fluid (BALF) inflammatory cells from mice with asthma induced by ovalbumin (OVA) were evaluated in vivo using Congo red staining. Hematoxylin and eosin (H&E), Masson's trichrome, and periodic acid-Schiff (PAS) staining were used to evaluate collagen deposition, mucus production, and inflammation in murine lung tissues. Western blotting and immunohistochemistry (IHC) assays were used to assess EMT- and fibrosis-related markers in the lung tissues in vivo. ResultSix naturally derived flavonoids, including Lut, attenuated cell migration and prevented EMT in LPS-treated BEAS-2B cells. Moreover, Lut suppressed TGF-β1, MMP-9, fibronectin (FN), and α-smooth muscle actin (α-SMA) levels in LPS-stimulated BEAS-2B cells. Additionally, Lut downregulated the levels of β-catenin by modulating the β-catenin/E-cadherin and β-catenin destruction complexes, highlighting the pivotal role of β-catenin in EMT inhibition by Lut in LPS-stimulated BEAS-2B cells. Furthermore, Lut suppressed airway inflammation and attenuated EMT-associated airway remodeling through β-catenin blockade in OVA-induced asthmatic mice. The bronchial wall thickness notably reduced from 37.24 ± 4.00 μm in the asthmatic model group to 30.06 ± 4.40 μm in the Lut low-dose group and 24.69 ± 2.87 μm in the Lut high-dose group. ConclusionAccording to our current understanding, this research is the first to reveal that Lut diminishes airway remodeling in asthma by inhibiting EMT via β-catenin regulation, thereby filling a research gap concerning Lut and flavonoids. These results provide a theoretical basis for treating asthma with anti-asthmatic CMM, as well as a candidate and complementary therapeutic approach to treat asthma.

Sulforaphane attenuates phosgene-induced acute lung injury via the Nrf2-HO-1/NQO1 pathway.

Sulforaphane (SFN) has been demonstrated to exert a protective role in various diseases. However, the role of SFN in phosgene-induced acute lung injury (P-ALI) remains unclear. This study aimed to explore the role and mechanism of SFN in P-ALI and provide a theoretical basis for the clinical prevention and treatment of P-ALI. A mouse model of P-ALI was established followed by phosgene gas inhalation at a dose of 4.17 g/m3 for 5 min. The survival rate, lung coefficient and hematoxylin and eosin (H&E) staining, lung pathology scoring, and bronchoalveolar lavage fluid (BALF) analysis were performed to evaluate lung tissue damage. The real-time quantitative polymerase chain reaction (RT-qPCR) and Western blotting analysis were utilized to evaluate the relative expression levels of inflammation factors and protein expression. Compared with the control group, destruction of alveolar structure, pulmonary edema, lung tissue inflammation and oxidative stress occurred after phosgene exposure. After the administration of SFN, the massive exudation of red blood cells and significant thickening of alveolar interstitium were ameliorated, the lung tissue inflammation was improved, and oxidative stress level was reduced. Mechanically, SFN could increase the expression of nuclear factor erythroid 2 (NFE2)-related factor 2 (Nrf2) protein and the downstream heme oxgenase-1 (HO-1) and NAD(P)H:quinone oxidoreductase 1 (NQO1), thereby improving P-ALI. And the Nrf2 inhibitor ML385 attenuated the lung protective effect of SFN. Phosgene inhalation led to edema, inflammation, and oxidative stress of lung tissue in mice. SFN might ameliorate phosgene-induced lung injury through Nrf2-HO-1/NQO1 signaling pathway.

Phillyrin prevents sepsis-induced acute lung injury through inhibiting the NLRP3/caspase-1/GSDMD-dependent pyroptosis signaling pathway.

Acute lung injury (ALI) is a severe pulmonary disorder of sepsis with high clinical incidence and mortality. Nucleotide-binding oligomerization domain-like receptor family pyrin domain containing 3 (NLRP3)-cysteinyl aspartate specific proteinase 1-gasdermin D (GSDMD)-dependent pyroptosis of alveolar epithelial cells (AECs) has emerged as a crucial contributor to ALI during sepsis. Phillyrin (PHI), a natural lignan isolated from the traditional Chinese herbal medicine Forsythia suspensa, has been shown to have anti-inflammatory, antioxidant and antiviral properties. However, little is known about the protective role and potential mechanism of PHI in sepsis-induced ALI, and it is uncertain whether the protective effect of PHI in sepsis-induced ALI is connected to pyroptosis. This study aims to examine the preventive effects of PHI on sepsis-induced ALI via the inhibition of NLRP3/caspase-1/GSDMD-mediated pyroptosis in AECs. Our findings demonstrate that preadministration of PHI successfully reduces sepsis-induced pulmonary edema, systemic/pulmonary inflammation, and pulmonary histological damage in lung tissues, bronchoalveolar lavage fluid, and the serum of septic mice. Intriguingly, PHI preadministration suppresses sepsis-induced protein expressions of pyroptosis-specific markers, especially their active forms. In vitro assays show that PHI pretreatment also protects type II AECs (MLE-12) from lipopolysaccharide-induced pyroptosis by preventing the activation of the pyroptosis signaling pathway. The results from molecular docking and surface plasmon resonance reveal that PHI has a significant affinity for direct binding to the GSDMD protein, suggesting that GSDMD is a potential pharmacological target for PHI. In conclusion, PHI can prevent sepsis-triggered ALI by effectively suppressing the activation of the canonical pyroptosis signaling pathway and pyroptosis of AECs.

Low dose methotrexate impaired T cell transmigration through down-regulating CXCR4 expression in rheumatoid arthritis (RA)

BackgroundCXC chemokine CXCL12 is involved in the pathological development of rheumatoid arthritis (RA) through abnormal migration of peripheral immune cells in the joint. Although low dose methotrexate (MTX) is clinically used to treat RA patients, CXCL12 signaling responses to MTX-mediated treatments is still not well understood.MethodsIn this study, we examined the expression of CXCR4 (cognatic receptor for CXCL12) in peripheral T cells from RA patients and arthritis mice models received from low dose MTX therapies. The effects of low dose MTX on CXCR4 were further determined via both in vitro CD3+ T cells and Cxcr4 conditional knockout (CKO) arthritis mice models.ResultsOur clinical data shows that low dose MTX treatment was clinically associated with down-regulated expression of chemokine receptor CXCR4 on patient peripheral T cells. In vitro, low dose MTX significantly decreased cell transmigration through down-regulated CXCR4’s expression in CD3+ T cells. Consistently, CD3+ T cells treated with low dose MTX demonstrated an increased genomic hypermethylation across the promoter region of Cxcr4 gene. Furthermore, our preclinical studies showed that low dose MTX-mediated downregulation of CXCR4 significantly improved the pathological development in mouse arthritis models. Conditional disruption of the Cxcr4 gene in peripheral immune cells potentially alleviated inflammation of joints and lung tissue in the arthritis mice, though genetic modification itself overall did not change their clinical scores of arthritis, except for a significant improvement on day 45 in CXCR4 CKO arthritis mice models during the recovery phase.ConclusionOur findings suggest that the effect of low dose MTX treatment could serve to eliminate inflammation in RA patients through impairment of immune cell transmigration mediated by CXCR4.

Development of a dexamethasone-hyaluronic acid conjugate with selective targeting effect for acute lung injury therapy

Acute lung injury (ALI), a critical complication of COVID-19, is characterized by widespread inflammation and severe pulmonary damage, necessitating intensive care for those affected. Although glucocorticoids (GCs), such as dexamethasone (Dex), have been employed clinically to lower mortality, their nonspecific systemic distribution has led to significant side effects, limiting their use in ALI treatment. In this study, we explored the conjugation of Dex to hyaluronic acid (HA) to achieve targeted delivery to inflamed lung tissues. We achieved a conjugation efficiency exceeding 98 % using a cosolvent system, with subsequent ester bond cleavage releasing the active Dex, as verified by liquid chromatography. Biodistribution and cellular uptake studies indicated the potential of the HA conjugate for cluster of differentiation 44 (CD44)-mediated targeting and accumulation. In a lipopolysaccharide-induced ALI mouse model, intravenous (IV) HA-Dex administration showed superior anti-inflammatory effects compared to free Dex administration. Flow cytometry analysis suggested that the HA conjugate preferentially accumulated in lung macrophages, suggesting the possibility of reducing clinical Dex dosages through this targeted delivery approach.

Studies on the role of moderate doses of ionizing radiation-induced cellular senescence in mouse lung tissue

Purpose To investigate the role of moderate doses of ionizing radiation-induced cellular senescence in mouse lung tissue and whole-body inflammation levels. Material and methods Forty-two C57BL/6J mice were randomly divided into the control group, the 1, 3, and 7 days after 2 Gy irradiation group, and the 1, 3, and 7 days after 4 Gy irradiation group, with six mice in each group. The histopathology, cellular senescence, oxidative-antioxidant, DNA damage repair, and inflammation-related indicators of irradiated mice were examined. Results Compared with the control group, the histopathological scores, the positive area of senescence-associated-β-galactosidase (SA-β-Gal) staining, and the mRNA levels of senescence-related genes in the lung tissues in all dose groups increased on 1, 3, and 7 days after irradiation. In peripheral blood, erythrocytes, leukocytes, platelets, hemoglobin, 8-hydroxydeoxyguanosine (8-OHdG), C-reactive protein, and other indicators showed a different trend in all dose groups. The levels of malondialdehyde(MDA), superoxide dismutase (SOD), glutathione (GSH), and 8-OHdG in the lung tissue showed different trends after 2 Gy and 4 Gy irradiation. The 8-Oxoguanine DNA glycosylase 1 (hOGG1) and O-6-methylguanine-DNA methyltransferase (MGMT) mRNA levels showed a trend of increasing and then decreasing. The levels of whole-body inflammation were significantly correlated with the levels of indicators related to cellular senescence and damage repair in the lung tissue of mice. Conclusions The moderate doses of ionizing radiation induce oxidative stress, and DNA damage and increase DNA repair gene expression in mouse lung tissue. The lung tissue cellular senescence correlates with the level of whole-body inflammation.

Rosa roxburghii fermented juice mitigates LPS-induced acute lung injury by modulation of intestinal flora and metabolites.

Acute lung injury (ALI) is a severe pulmonary condition with high mortality and morbidity, lacking effective pharmacotherapeutic options. Rosa roxburghii Tratt, a unique fruit from southwestern China, is valued for its rich nutritional content and functional properties. Fermentation is known to enhance the nutritional value, flavor, and shelf life of foods. In this study, we investigated the effects of fermented Rosa roxburghii juice (RRFJ) on gut microbiota, metabolites, and the levels of short-chain fatty acids in the intestines, as well as its impact on lung tissue and intestine tissue injury, inflammation, and oxidative stress in murine models. The results showed that RRFJ modulated gut microbiota and metabolites, increased short-chain fatty acid levels, and consequently reduced lung tissue injury, inflammation, and oxidative stress in mice with ALI. These findings suggest that RRFJ has the potential to serve as a functional dietary adjunct in the management of acute lung injury, providing a scientific basis for its therapeutic role.

Pyrroloquinoline Quinone Alleviates Mitochondria Damage in Radiation-Induced Lung Injury in a MOTS-c-Dependent Manner.

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.

Inhibiting endothelial cell Mst1 attenuates acute lung injury in mice.

Lung endothelium plays a pivotal role in the orchestration of inflammatory responses to acute pulmonary insults. Mammalian sterile 20-like kinase 1 (Mst1) is a serine/threonine kinase that has been shown to play an important role in the regulation of apoptosis, stress responses, and organ growth. This study investigated the role of Mst1 in lung endothelial activation and acute lung injury (ALI). We found that Mst1 was significantly activated in inflamed lung endothelial cells (ECs) and mouse lung tissues. Overexpression of Mst1 promoted nuclear factor κ-B (NF-κB) activation through promoting JNK and p38 activation in lung ECs. Inhibition of Mst1 by either its dominant negative form (DN-Mst1) or its pharmacological inhibitor markedly attenuated cytokine-induced expression of cytokines, chemokines, and adhesion molecules in lung ECs. Importantly, in a mouse model of lipopolysaccharide-induced (LPS-induced) ALI, both deletion of Mst1 in lung endothelium and treatment of WT mice with a pharmacological Mst1 inhibitor significantly protected mice from LPS-induced ALI. Together, our findings identified Mst1 kinase as a key regulator in controlling lung EC activation and suggest that therapeutic strategies aimed at inhibiting Mst1 activation might be effective in the prevention and treatment of inflammatory lung diseases.

The Effect of Chlorogenic Acid on Methotrexate-Induced Oxidative Stress and Inflammation in Lung Tissue of Rats

Although methotrexate (MTX) is a widely used chemotherapeutic agent, lung toxicity remains a significant problem, limiting its use. The molecular mechanism of MTX-related lung toxicity is not fully understood. However, increased reactive oxygen species (ROS)-induced oxidative stress (OS) and inflammation play an important role in lung injury. Chlorogenic acid (CHA) is a natural phenolic compound that has been shown in recent years to have beneficial effects in many pathologies associated with OS and inflammation. This study focused on investigating for the first time, the potential therapeutic effects of CHA in the lung tissue of rats exposed to MTX. After lung toxicity was induced in rats by MTX (20 mg/kg) injection on the first day, two different doses of CHA (1.5 and 3 mg/kg) were used for treatment for 3 days. The results showed that CHA treatment reduced the level of pulmonary lipid peroxidation, inflammation, and apoptosis and promoted the pulmonary antioxidant system in rats subjected to MTX. Taken together, the antioxidant and anti-inflammatory properties of CHA may play a central role in attenuating MTX-induced lung injury, but the exact mechanism needs to be investigated in more extensive preclinical studies.

VEGFR1 TK signaling protects the lungs against LPS-induced injury by suppressing the activity of alveolar macrophages and enhancing the anti-inflammatory function of monocyte-derived macrophages

Acute lung injury (ALI) is characterized by hyperinflammation followed by vascular leakage and respiratory failure. Vascular endothelial growth factor (VEGF)-A is critical for capillary permeability; however, the role of VEGF receptor 1 (VEGFR1) signaling in ALI progression remains unclear. Here, we show that deletion of VEGFR1 tyrosine kinase (TK) signaling in mice exacerbates lipopolysaccharide (LPS)-induced ALI as evidenced by excessive pro-inflammatory cytokine production and interleukin(IL)-1β-producing neutrophil recruitment to inflamed lung tissues. ALI development involves reduced alveolar macrophage (AM) levels and recruitment of monocyte-derived macrophages (MDMs) in a VEGFR1 TK-dependent manner. VEGFR1 TK signaling reduced pro-inflammatory cytokine levels in cultured AMs. VEGFR1 TK-expressing MDMs displayed an anti-inflammatory macrophage phenotype. Additionally, the transplantation of VEGFR1 TK-expressing bone marrow (BM)-derived macrophages into VEGFR1 TK-deficient mice reduced lung inflammation. Treatment with placental growth factor (PlGF), an agonist for VEGFR1, protected the lung against LPS-induced ALI associated with increased MDMs. These results suggest that VEGFR1 TK signaling prevents LPS-induced ALI by suppressing the pro-inflammatory activity of AMs and enhancing the anti-inflammatory function of MDMs.

The hemostatic activity and Mechanistic roles of glucosyloxybenzyl 2-isobutylmalate extract (BSCE) from Bletilla striata (Thunb.) Rchb.f. in Inhibiting pulmonary hemorrhage

BackgroundHemorrhagic events cause numerous deaths annually worldwide, highlighting the urgent need for effective hemostatic drugs. The glucosyloxybenzyl 2-isobutylmalates Control Extract (BSCE) from the orchid plant Bletilla striata (Thunb.) Rchb.f. has demonstrated significant hemostatic activity in both in vitro and in vivo studies. However, the effect and mechanism of BSCE on non-traumatic bleeding remain unclear. MethodsPulmonary hemorrhage was induced in 40 Sprague-Dawley rats by administering Zingiber officinale Roscoe. for 14 days. These rats were then randomly divided into five groups: model (Mod), positive control (YNBY), and BSCE low, medium, and high-dose groups. An additional 8 rats served as the control group (Con). The BSCE groups received different doses of BSCE for 10 days, while the YNBY group received Yunnan Baiyao suspension. The effects on body weight, food and water intake, red blood cell count (RBC), hemoglobin concentration (HGB), lung tissue pathology, platelet count, coagulation parameters, and fibrinolytic system markers were evaluated. Network pharmacology and molecular docking analyses were also conducted to identify potential targets and pathways involved in BSCE's effects. ResultsBSCE treatment significantly improved body weight, food intake, and water consumption in rats with pulmonary hemorrhage. RBC and HGB levels increased significantly in the BSCE medium and high-dose groups compared to the Mod group (P < 0.05). Pathological examination revealed that BSCE reduced lung tissue hemorrhage and inflammation, with improvements in alveolar structure. BSCE also positively affected platelet count, thrombin time (TT), activated partial thromboplastin time (APTT), fibrinogen (FIB) levels, and fibrinolytic markers (D-dimer, PAI-1, and t-PA). Network pharmacology and molecular docking identified key targets such as MMPs, CASPs, and pathways including IL-17 and TNF signaling, suggesting BSCE's involvement in hemostasis and anti-inflammatory processes. ConclusionsBSCE exhibits significant hemostatic and protective effects on Z.officinale-induced pulmonary hemorrhage in rats by improving hematological parameters, reducing lung tissue damage, and modulating the coagulation and fibrinolytic systems. The study provides evidence supporting the potential of BSCE as a therapeutic agent for hemorrhagic diseases, with its efficacy linked to multi-target and multi-pathway interactions.