RÉSUMÉ
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.
Sujet(s)
Chimioradiothérapie , Transition épithélio-mésenchymateuse , Fibrose pulmonaire , Humains , Transition épithélio-mésenchymateuse/effets des médicaments et des substances chimiques , Fibrose pulmonaire/induit chimiquement , Fibrose pulmonaire/métabolisme , Fibrose pulmonaire/anatomopathologie , Fibrose pulmonaire/étiologie , Chimioradiothérapie/effets indésirables , Animaux , Stress oxydatif/effets des médicaments et des substances chimiques , Lésion pulmonaire/étiologie , Lésion pulmonaire/anatomopathologie , Lésion pulmonaire/induit chimiquement , Lésion pulmonaire/métabolismeRÉSUMÉ
Paraquat poisoning results in significant pulmonary damage, but current treatments are only minimally effective in repairing the injured lung tissues. Recent research has highlighted the promise of using stem cell therapy, namely mesenchymal stem cells, as a new method for treating paraquat toxicity. These cells have shown effectiveness in decreasing inflammation, apoptosis, and fibrosis in the mice lungs subjected to paraquat. The therapeutic implications of mesenchymal stem cells are believed to arise from their release of bioactive proteins and their capacity to regulate inflammatory responses. However, additional clinical study is required to validate these therapies' efficacy. This review thoroughly explores the pathophysiology of paraquat poisoning and the properties of mesenchymal stem cells. Additionally, it critically assesses the long-term safety and effectiveness of mesenchymal stem cell therapies, which is crucial for developing more dependable and effective treatment protocols. In summary, although mesenchymal stem cells offer promising prospects for treating lung injuries, more investigations are required to optimize their therapeutic promise and ensure their safe clinical application in the context of paraquat poisoning.
Sujet(s)
Lésion pulmonaire , Transplantation de cellules souches mésenchymateuses , Cellules souches mésenchymateuses , Paraquat , Paraquat/toxicité , Animaux , Humains , Transplantation de cellules souches mésenchymateuses/méthodes , Lésion pulmonaire/thérapie , Lésion pulmonaire/induit chimiquement , Poumon/anatomopathologie , SourisRÉSUMÉ
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.
Sujet(s)
Curcuma , Récepteur PPAR gamma , Paraquat , Pioglitazone , Extraits de plantes , Rat Wistar , Animaux , Pioglitazone/pharmacologie , Pioglitazone/usage thérapeutique , Paraquat/toxicité , Mâle , Rats , Curcuma/composition chimique , Récepteur PPAR gamma/agonistes , Récepteur PPAR gamma/métabolisme , Extraits de plantes/pharmacologie , Extraits de plantes/usage thérapeutique , Poumon/anatomopathologie , Poumon/effets des médicaments et des substances chimiques , Poumon/métabolisme , Lésion pulmonaire/induit chimiquement , Lésion pulmonaire/prévention et contrôle , Lésion pulmonaire/traitement médicamenteux , Lésion pulmonaire/anatomopathologie , Lésion pulmonaire/métabolisme , Dexaméthasone/pharmacologie , Liquide de lavage bronchoalvéolaire/cytologie , Stress oxydatif/effets des médicaments et des substances chimiques , Thiazolidinediones/pharmacologie , Thiazolidinediones/usage thérapeutique , Antioxydants/pharmacologie , Curcumine/pharmacologie , Curcumine/usage thérapeutiqueRÉSUMÉ
BACKGROUND: Pulmonary fibrosis is a pathological hallmark of lung injury. It is an aggressive disease that replaces normal lung parenchyma by fibrotic tissue. The transforming growth factor-beta-mothers against decapentaplegic homolog 3 (TGF-ß1-Smad3) signaling pathway plays a key role in regulating lung fibrosis. Decorin (DCN), a small leucine-rich proteoglycan, has a modulatory effect on the immune system by reversibly binding with TGF-ß and reducing its bioavailability. Mesenchymal stem cell (MSC) therapy is a new strategy that has an immune-modulatory capacity. OBJECTIVE: The aim of this study was to introduce a new therapeutic approach to harness remodeling in injured lung. MATERIAL AND METHODS: Bone marrow MSCs were isolated and transduced by decorin gene. Lung injury was induced by bleomycin and mice were treated with MSCs, MSCs-decorin, and decorin. Then, oxidative stress biomarkers, remodeling biomarkers, bronchoalveolar lavage cells, and histopathology study were conducted. RESULTS: Reduced catalase and superoxide dismutase increased due to treatments. Elevated malondialdehyde, hydroxyproline, TGF-ß levels, and polymorphonuclear cells count decreased in the treated groups. Additionally, the histopathology of lung tissues showed controlled inflammation and fibrosis. CONCLUSION: Transfected decorin gene to MSCs and used cell therapy could control remodeling and bleomycin-induced lung injury.
Sujet(s)
Bléomycine , Décorine , Transplantation de cellules souches mésenchymateuses , Cellules souches mésenchymateuses , Fibrose pulmonaire , Décorine/génétique , Décorine/métabolisme , Animaux , Souris , Fibrose pulmonaire/immunologie , Fibrose pulmonaire/induit chimiquement , Fibrose pulmonaire/thérapie , Lésion pulmonaire/induit chimiquement , Lésion pulmonaire/thérapie , Lésion pulmonaire/immunologie , Lésion pulmonaire/génétique , Transduction génétique , Stress oxydatif , Cellules cultivées , Modèles animaux de maladie humaine , Mâle , HumainsRÉSUMÉ
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-1ß, 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_f_Muribaculaceae, and unclassified_f_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.
Sujet(s)
Médicaments issus de plantes chinoises , Lipopolysaccharides , Lésion pulmonaire , Métabolomique , Animaux , Médicaments issus de plantes chinoises/pharmacologie , Souris , Lésion pulmonaire/traitement médicamenteux , Lésion pulmonaire/métabolisme , Lésion pulmonaire/induit chimiquement , Mâle , Microbiome gastro-intestinal/effets des médicaments et des substances chimiques , Transcriptome/effets des médicaments et des substances chimiques , Poumon/effets des médicaments et des substances chimiques , Poumon/anatomopathologie , Poumon/métabolisme , Souris de lignée C57BL , Cytokines/métabolisme , Modèles animaux de maladie humaine , Lésion pulmonaire aigüe/traitement médicamenteux , Lésion pulmonaire aigüe/induit chimiquement , Lésion pulmonaire aigüe/métabolismeRÉSUMÉ
Polyhexamethyleneguanidine phosphate (PHMG-P) is a biocide of guanidine family that can cause a fatal lung damage if exposed directly to the lungs. No reports exist regarding the toxicity of PHMG-P in neonatal animals. Therefore, this study aimed to determine PHMG-P toxicity in neonatal and 8-week-old mice after they were intranasally instilled with 1.5 mg/kg, 3 mg/kg, and 4.5 mg/kg PHMG-P. PHMG-P lung exposure resulted in more severe pulmonary toxicity in adult mice than in newborn mice. In the high-dose group of newborn mice, a minimal degree of inflammatory cell infiltration and fibrosis in the lung were detected, whereas more severe pathological lesions including granulomatous inflammation, fibrosis, and degeneration of the bronchiolar epithelium were observed in adult mice. At day 4, C-C motif chemokine ligand 2 (CCL2), a potent chemokine for monocytes, was upregulated but recovered to normal levels at day 15 in newborn mice. However, increased CCL2 and IL-6 levels were sustained at day 15 in adult mice. When comparing the differentially expressed genes of newborn and adult mice through RNA-seq analysis, there were expression changes in several genes associated with inflammation in neonates that were similar or different from those in adults. Although no significant lung damage occurred in newborns, growth inhibition was observed which was not reversed until the end of the experiment. Further research is needed to determine how growth inhibition from neonatal exposure to PHMG-P affects adolescent and young adult health.
Sujet(s)
Animaux nouveau-nés , Chimiokine CCL2 , Guanidines , Poumon , Animaux , Souris , Guanidines/toxicité , Poumon/effets des médicaments et des substances chimiques , Poumon/anatomopathologie , Poumon/métabolisme , Chimiokine CCL2/métabolisme , Chimiokine CCL2/génétique , Interleukine-6/métabolisme , Interleukine-6/génétique , Souris de lignée C57BL , Femelle , Mâle , Lésion pulmonaire/induit chimiquement , Lésion pulmonaire/anatomopathologieRÉSUMÉ
An earlier study found that respiratory cadmium chloride (CdCl2) exposure caused COPD-like lung injury. This study aimed to explore whether mitochondrial dysfunction-mediated alveolar epithelial senescence is involved in CdCl2-induced COPD-like lung injury. Adult C57BL/6 mice were exposed to CdCl2 (10 mg/L) aerosol for six months. Beta-galactosidase-positive cells, p21 and p16 were increased in CdCl2-exposed mouse lungs. The in vitro experiments showed that γ-H2AX was elevated in CdCl2-exposed alveolar epithelial cells. The cGAS-STING pathway was activated in CdCl2-exposed alveolar epithelial cells and mouse lungs. Cxcl1, Cxcl9, Il-10, Il-1ß and Mmp2, several senescence-associated secretory phenotypes (SASP), were upregulated in CdCl2-exposed alveolar epithelial cells. Mechanistically, CdCl2 exposure caused SIRT3 reduction and mitochondrial dysfunction in mouse lungs and alveolar epithelial cells. The in vitro experiment found that Sirt3 overexpression attenuated CdCl2-induced alveolar epithelial senescence and SASP. The in vivo experiments showed that Sirt3 gene knockout exacerbated CdCl2-induced alveolar epithelial senescence, alveolar structure damage, airway inflammation and pulmonary function decline. NMN, an NAD+ precursor, attenuated CdCl2-induced alveolar epithelial senescence and SASP in mouse lungs. Moreover, NMN supplementation prevented CdCl2-induced COPD-like alveolar structure damage, epithelial-mesenchymal transition and pulmonary function decline. These results suggest that mitochondrial dysfunction-associated alveolar epithelial senescence is involved in CdCl2-induced COPD-like lung injury.
Sujet(s)
Vieillissement de la cellule , Souris de lignée C57BL , Mitochondries , Broncho-pneumopathie chronique obstructive , Animaux , Mitochondries/effets des médicaments et des substances chimiques , Mitochondries/métabolisme , Vieillissement de la cellule/effets des médicaments et des substances chimiques , Broncho-pneumopathie chronique obstructive/anatomopathologie , Broncho-pneumopathie chronique obstructive/induit chimiquement , Broncho-pneumopathie chronique obstructive/métabolisme , Pneumocytes/effets des médicaments et des substances chimiques , Pneumocytes/métabolisme , Mâle , Lésion pulmonaire/induit chimiquement , Lésion pulmonaire/anatomopathologie , Sirtuine-3/métabolisme , Sirtuine-3/génétique , Souris , Souris knockoutRÉSUMÉ
The outbreak of e-cigarette or vaping use-associated lung injury (EVALI) in the United States in 2019 led to a total of 2807 hospitalizations with 68 deaths. While the exact causes of this vaping-related lung illness are still being debated, laboratory analyses of products from victims of EVALI have shown that vitamin E acetate (VEA), an additive in some tetrahydrocannabinol (THC)-containing products, is strongly linked to the EVALI outbreak. Because of its similar appearance and viscosity to pure THC oil, VEA was used as a diluent agent in cannabis oils in illicit markets. A potential mechanism for EVALI may involve VEA's thermal decomposition product, ketene, a highly poisonous gas, being generated under vaping conditions. In this study, a novel approach was developed to evaluate ketene production from VEA vaping under measurable temperature conditions in real-world devices. Ketene in generated aerosols was captured by two different chemical agents and analyzed by gas chromatography-mass spectrometry (GC-MS) and liquid chromatography with tandem mass spectrometry (LC-MS/MS). The LC-MS/MS method takes advantage of the high sensitivity and specificity of tandem mass spectrometry and appears to be more suitable than GC-MS for the analysis of large batches of samples. Our results confirmed the formation of ketene when VEA was vaped. The production of ketene increased with repeat puffs and showed a correlation to temperatures (200 to 500 °C) measured within vaping devices. Device battery power strength, which affects the heating temperature, plays an important role in ketene formation. In addition to ketene, the organic oxidant duroquinone was also obtained as another thermal degradation product of VEA. Ketene was not detected when vitamin E was vaped under the same conditions, confirming the importance of the acetate group for its generation.
Sujet(s)
Dispositifs électroniques d'administration de nicotine , Éthylènes , Cétones , Vapotage , Vapotage/effets indésirables , Cétones/composition chimique , Cétones/analyse , Éthylènes/composition chimique , Humains , Santé publique , Vitamine E/composition chimique , Vitamine E/analyse , Lésion pulmonaire/étiologie , Lésion pulmonaire/induit chimiquement , Chromatographie gazeuse-spectrométrie de masseRÉSUMÉ
Silicosis, caused by silica exposure, is the most widespread and deadliest occupational disease. However, effective treatments are lacking. Therefore, it is crucial to elucidate the mechanisms and targets involved in the development of silicosis. We investigated the basic processes of silicosis development and onset at different exposure durations (2 or 4 weeks) using various techniques such as histopathology, immunohistochemistry, Enzyme linked immunosorbent assay(ELISA),16â¯S rRNA, and untargeted metabolomics.These results indicate that exposure to silica leads to progressive damage to lung tissue with significant deterioration observed over time. Time-dependent cytokines such as the IL-4, IL-13, and IL-6 are detected in lung lavage fluid, the model group consistently exhibited elevated levels of these cytokines, indicating a persistent and worsening inflammatory response in the lungs. Meanwhile, HE and Masson results show that 4-week exposure to silica causes more obvious lung injury and pulmonary fibrosis. Besides, the model group consistently exhibited a distinct lung bacterial population, known as the Lachnospiraceae_NK4A136_group, regardless of exposure duration. However, with increasing exposure duration, specific temporal changes were observed in lung bacterial populations, including Haliangium, Allobaculum, and Sandaracinus (at 4 weeks; p < 0.05). Furthermore, our study revealed a strong correlation between the mechanism of silica-induced lung injury and three factors: oxidative stress, impaired lipid metabolism, and imbalanced amino acid metabolism. We observed a close correlation between cytokine levels, changes in lung microbiota, and metabolic disturbances during various exposure periods. These findings propose that a possible mechanism of silica-induced lung injury involves the interplay of cytokines, lung microbiota, and metabolites.
Sujet(s)
Cytokines , Lésion pulmonaire , Poumon , Microbiote , Silice , Silice/toxicité , Animaux , Poumon/microbiologie , Poumon/effets des médicaments et des substances chimiques , Poumon/anatomopathologie , Microbiote/effets des médicaments et des substances chimiques , Lésion pulmonaire/induit chimiquement , Lésion pulmonaire/microbiologie , Lésion pulmonaire/anatomopathologie , Cytokines/métabolisme , Mâle , Silicose/métabolisme , Liquide de lavage bronchoalvéolaire/composition chimiqueRÉSUMÉ
Nanoplastics (NPs) are a common type of degraded plastic material associated with adverse health effects such as pulmonary injury. However, the molecular mechanism(s) underlying lung injury as caused by NPs remains uncertain. Thus, we herein investigated the pulmonary toxicity of NPs on RAW264.7 cells and C57BL/6 mice. Our in vitro study indicated that NPs induced oxidative stress, cell death, inflammation, and the activation of the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING)-signaling pathway. Mice in our in vivo study displayed significant pulmonary fibrosis, inflammation, apoptosis, necrosis, and excessive double-stranded DNA release into serum and bronchoalveolar lavage fluid. Our mechanistic exploration uncovered cGAS-STING-signaling activation as the leading cause of NPs-induced pulmonary fibrosis. The current study opens an avenue toward elucidating the role of the cGAS-STING-signaling pathway in NPs-induced pulmonary injury.
Sujet(s)
ADN mitochondrial , Lésion pulmonaire , Nucleotidyltransferases , Transduction du signal , Animaux , Souris , Lésion pulmonaire/induit chimiquement , Protéines membranaires/métabolisme , Protéines membranaires/génétique , Souris de lignée C57BL , Nanoparticules/toxicité , Nucleotidyltransferases/métabolisme , Nucleotidyltransferases/génétique , Cellules RAW 264.7 , Transduction du signal/effets des médicaments et des substances chimiquesRÉSUMÉ
Pentoxifylline (PTX), a non-selective phosphodiesterase inhibitor, has demonstrated protective effects against lung injury in animal models. Given the significance of pulmonary toxicity resulting from paraquat (PQ) exposure, the present investigation was designed to explore the impact of PTX on PQ-induced pulmonary oxidative impairment in male mice.Following preliminary studies, thirty-six mice were divided into six groups. Group 1 received normal saline, group 2 received a single dose of PQ (20 mg/kg; i.p.), and group 3 received PTX (100 mg/kg/day; i.p.). Additionally, treatment groups 4-6 were received various doses of PTX (25, 50, and 100 mg/kg/day; respectively) one hour after a single dose of PQ. After 72 hours, the animals were sacrificed, and lung tissue was collected.PQ administration caused a significant decrease in hematocrit and an increase in blood potassium levels. Moreover, a notable increase was found in the lipid peroxidation (LPO), nitric oxide (NO), and myeloperoxidase (MPO) levels, along with a notable decrease in total thiol (TTM) and total antioxidant capacity (TAC) contents, catalase (CAT) and superoxide dismutase (SOD) enzymes activity in lung tissue. PTX demonstrated the ability to improve hematocrit levels; enhance SOD activity and TTM content; and decrease MPO activity, LPO and NO levels in PQ-induced pulmonary toxicity. Furthermore, these findings were well-correlated with the observed lung histopathological changes.In conclusion, our results suggest that the high dose of PTX may ameliorate lung injury by improving the oxidant/antioxidant balance in animals exposed to PQ.
Sujet(s)
Antioxydants , Peroxydation lipidique , Poumon , Paraquat , Pentoxifylline , Superoxide dismutase , Animaux , Pentoxifylline/pharmacologie , Pentoxifylline/usage thérapeutique , Paraquat/toxicité , Souris , Mâle , Poumon/effets des médicaments et des substances chimiques , Poumon/anatomopathologie , Poumon/métabolisme , Peroxydation lipidique/effets des médicaments et des substances chimiques , Antioxydants/pharmacologie , Superoxide dismutase/métabolisme , Stress oxydatif/effets des médicaments et des substances chimiques , Catalase/métabolisme , Inhibiteurs de la phosphodiestérase/pharmacologie , Inhibiteurs de la phosphodiestérase/usage thérapeutique , Monoxyde d'azote/métabolisme , Myeloperoxidase/métabolisme , Lésion pulmonaire/induit chimiquement , Lésion pulmonaire/traitement médicamenteux , Phosphodiesterases/métabolismeRÉSUMÉ
Ferrate (Fe(VI)) is an environmentally friendly disinfectant that is widely used to eradicate microbes in reclaimed water. However, the potential health risks associated with inhalation of Fe(VI)-treated bacteria-laden reclaimed water remains uncertain. We aimed to explore the inhalation hazards and potential mechanisms of K2FeO4-treated Escherichia coli (E. coli, ATCC 25922). Our findings indicated that Fe(VI) disinfection induced a dose- and time-dependent E. coli inactivation, accompanied by a rapid release of the bacterial endotoxin, lipopolysaccharide (LPS). Scanning electron microscopy (SEM) observations indicate that Fe(VI)-induced endotoxin production consists of at least two stages: initial binding of endotoxin to bacteria and subsequent dissociation to release free endotoxin. Furthermore, Fe(VI) disinfection was not able to effectively eliminate pure or E. coli-derived endotoxins. The E. coli strain used in this study lacks lung infection capability, thus the inhalation of bacteria alone failed to induce severe lung injury. However, mice inhaled exposure to Fe(VI)-treated E. coli showed severe impairment of lung structure and function. Moreover, we observed an accumulation of neutrophil/macrophage recruitment, cell apoptosis, and ROS generation in the lung tissue of mice subjected to Fe(VI)-treated E. coli. RNA sequencing (RNA-seq) and PCR results revealed that genes involved with endotoxin stimuli, cell apoptosis, antioxidant defence, inflammation response, chemokines and their receptors were upregulated in response to Fe(VI)-treated E. coli. In conclusion, Fe(VI) is ineffective in eliminating endotoxins and can trigger secondary hazards owing to endotoxin release from inactivated bacteria. Aerosol exposure to Fe(VI)-treated E. coli causes considerable damage to lung tissue by inducing oxidative stress and inflammatory responses.
Sujet(s)
Endotoxines , Escherichia coli , Inflammation , Lésion pulmonaire , Stress oxydatif , Escherichia coli/effets des médicaments et des substances chimiques , Souris , Animaux , Lésion pulmonaire/induit chimiquement , Lésion pulmonaire/microbiologie , Fer/métabolisme , Désinfection/méthodes , Désinfectants/toxicitéRÉSUMÉ
Butorphanol is widely used as an anesthetic drug, whether butorphanol could reduce organ injury and protecting lung tissue is unknown. This study explored the effects of butorphanol on ALI and investigated its underlying mechanisms. We established a "two-hit" rat model and "two-hit" cell model to prove our hypothesis. Rats were divided into four groups [control, "two-hit" (OA + LPS), "two-hit" + butorphanol (4 mg/kg and 8 mg/kg) (OA + LPS + B1 and OA + LPS + B2)]. RPMVE cells were divided into four groups [control, "two-hit" (OA + LPS), "two-hit" + butorphanol (4 µM and 8 µM) (OA + LPS + 4 µM and OA + LPS + 8 µM)]. Inflammatory injury was assessed by the histopathology and W/D ratio, inflammatory cytokines, and arterial blood gas analysis. Apoptosis was assessed by Western blotting and flow cytometry. The effect of NF-κB p65 was detected by ELISA. Butorphanol could relieve the "two-hit" induced lung injury, the expression of TNF, IL-1ß, IL-6, and improve lung ventilation. In addition, butorphanol decreased Bax and cleaved caspase-3, increased an antiapoptotic protein (Bcl-2), and inhibited the "two-hit" cell apoptosis ratio. Moreover, butorphanol suppressed NF-κB p65 activity in rat lung injury. Our research showed that butorphanol may attenuate "two-hit"-induced lung injury by regulating the activity of NF-κB p65, which may supply more evidence for ALI treatment.
Sujet(s)
Lésion pulmonaire aigüe , Apoptose , Butorphanol , Inflammation , Animaux , Butorphanol/pharmacologie , Apoptose/effets des médicaments et des substances chimiques , Rats , Mâle , Lésion pulmonaire aigüe/induit chimiquement , Lésion pulmonaire aigüe/métabolisme , Lésion pulmonaire aigüe/anatomopathologie , Lésion pulmonaire aigüe/traitement médicamenteux , Lésion pulmonaire aigüe/prévention et contrôle , Inflammation/traitement médicamenteux , Inflammation/métabolisme , Inflammation/anatomopathologie , Facteur de transcription RelA/métabolisme , Lipopolysaccharides , Rat Sprague-Dawley , Lésion pulmonaire/induit chimiquement , Lésion pulmonaire/traitement médicamenteux , Lésion pulmonaire/métabolisme , Lésion pulmonaire/anatomopathologie , Lésion pulmonaire/prévention et contrôle , Modèles animaux de maladie humaine , Cytokines/métabolisme , Poumon/anatomopathologie , Poumon/effets des médicaments et des substances chimiques , Poumon/métabolismeRÉSUMÉ
Hydrogen peroxide (H2O2) 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 H2O2 in multiple diseases, such as PM2.5 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-H2O2) by introducing pentafluorobenzenesulfonyl as a H2O2 sensing unit into the NIR hemicyanine platform. HCy-H2O2 exhibits good sensitivity and selectivity toward H2O2, accompanied by a remarkable "turn-on" fluorescence signal at 720 nm. Meanwhile, HCy-H2O2 has stable mitochondria-targetable ability and permits monitoring of the up-generated H2O2 level during mitophagy. Furthermore, using HCy-H2O2, we have successfully observed an overproduced mitochondrial H2O2 in ambient PM2.5 exposure-induced lung injury, HIRI, NAFL, and HF models through NIR fluorescence imaging. Significantly, the visualization of H2O2 has been achieved in both tumor-bear mice as well as surgical specimens of cancer patients, making HCy-H2O2 a promising tool for cancer diagnosis and imaging-guided surgery.
Sujet(s)
Colorants fluorescents , Peroxyde d'hydrogène , Mitochondries , Imagerie optique , Colorants fluorescents/composition chimique , Colorants fluorescents/synthèse chimique , Peroxyde d'hydrogène/métabolisme , Animaux , Mitochondries/métabolisme , Mitochondries/composition chimique , Souris , Humains , Lésion pulmonaire/imagerie diagnostique , Lésion pulmonaire/induit chimiquement , Lésion pulmonaire/métabolisme , Rayons infrarougesRÉSUMÉ
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.
Sujet(s)
Cyclophosphamide , Glucagon-like peptide 1 , Inflammasomes , Protéine-3 de la famille des NLR contenant un domaine pyrine , Phosphatidylinositol 3-kinases , Protéines proto-oncogènes c-akt , Pyrannes , Transduction du signal , Animaux , Cyclophosphamide/toxicité , Protéine-3 de la famille des NLR contenant un domaine pyrine/métabolisme , Mâle , Inflammasomes/métabolisme , Inflammasomes/effets des médicaments et des substances chimiques , Protéines proto-oncogènes c-akt/métabolisme , Transduction du signal/effets des médicaments et des substances chimiques , Rats , Phosphatidylinositol 3-kinases/métabolisme , Glucagon-like peptide 1/métabolisme , Pyrannes/pharmacologie , Poumon/effets des médicaments et des substances chimiques , Poumon/métabolisme , Poumon/anatomopathologie , Anthocyanes/pharmacologie , Stress oxydatif/effets des médicaments et des substances chimiques , Inhibiteurs de la dipeptidyl-peptidase IV/pharmacologie , Rat Wistar , Pyrimidines/pharmacologie , Lésion pulmonaire/induit chimiquement , Lésion pulmonaire/traitement médicamenteux , Lésion pulmonaire/métabolisme , Lésion pulmonaire/anatomopathologie , Protéine O1 à motif en tête de fourche , Composés hétérobicycliquesRÉSUMÉ
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) (10â¯mg/kg b.wt) against ACR toxicity and conducted comprehensive miRNA expression profiling to uncover novel targets and mechanisms of AD toxicity (miRNA 223-3â¯P and miRNA 325-3â¯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 (20â¯mg/kg b.wt for 2 months). Our findings revealed that AD significantly downregulated the expression of miRNA 223-3â¯P and miRNA 325-3â¯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 223-3â¯P and miRNA 325-3â¯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.
Sujet(s)
Inflammasomes , microARN , Extraits de plantes , Pyroptose , Rat Sprague-Dawley , Transduction du signal , Animaux , microARN/génétique , microARN/métabolisme , Inflammasomes/métabolisme , Inflammasomes/effets des médicaments et des substances chimiques , Inflammasomes/génétique , Rats , Mâle , Pyroptose/effets des médicaments et des substances chimiques , Transduction du signal/effets des médicaments et des substances chimiques , Extraits de plantes/pharmacologie , Acrylamide/toxicité , Poumon/effets des médicaments et des substances chimiques , Poumon/anatomopathologie , Poumon/métabolisme , Stress oxydatif/effets des médicaments et des substances chimiques , Fibrose pulmonaire/induit chimiquement , Fibrose pulmonaire/anatomopathologie , Fibrose pulmonaire/génétique , Fibrose pulmonaire/métabolisme , Acrylamides/toxicité , Lésion pulmonaire/induit chimiquement , Lésion pulmonaire/anatomopathologie , Lésion pulmonaire/génétique , Lésion pulmonaire/métabolismeRÉSUMÉ
Microplastics (MPs) have been found in the air, human nasal cavity, and lung, suggesting that the respiratory tract is one of the important exposure routes for MPs. The lung is a direct target organ for injury from inhaled MPs, but data on lung injury from longer-term exposure to environmental doses of MPs are limited, and the mechanisms remain unclear. Here, C57BL/6 J mice were treated with 5 µm polystyrene (PS)-MPs by intratracheal instillation (0.6, 3, and 15 mg/kg) for 60 days to establish MPs exposure model. We found that PS-MPs lead to increased collagen fibers and decreased lung barrier permeability and lung function in lung tissue. Mechanistically, the abundance of gram-negative bacteria in the pulmonary flora increased after inhalation of PS-MPs, causing lipopolysaccharide (LPS) release. The expression of Toll-like receptor 4 (TLR4), the key receptor of LPS, was increased, and ferroptosis occurred in lung tissue cells. Further in vitro intervention experiments were performed, pulmonary flora/TLR4-induced imbalance of lung iron homeostasis is an important mechanism of PS-MPs-induced lung injury. Our study provides new evidence for lung injury caused by environmental doses of MPs and strategies to prevent it through longer-term dynamic observation.
Sujet(s)
Homéostasie , Fer , Poumon , Souris de lignée C57BL , Microplastiques , Polystyrènes , Récepteur de type Toll-4 , Animaux , Polystyrènes/toxicité , Souris , Poumon/effets des médicaments et des substances chimiques , Microplastiques/toxicité , Récepteur de type Toll-4/métabolisme , Homéostasie/effets des médicaments et des substances chimiques , Fer/métabolisme , Lésion pulmonaire/induit chimiquement , Exposition par inhalation/effets indésirablesRÉSUMÉ
Ricin, an extremely potent toxin produced from the seeds of castor plant, Ricinus communis, is ribosome-inactivating protein that blocks cell-protein synthesis. It is considered a biological threat due to worldwide availability of castor beans, massive quantities as a by-product of castor oil production, high stability and ease of production. The consequence of exposure to lethal dose of ricin was extensively described in various animal models. However, it is assumed that in case of aerosolized ricin bioterror attack, the majority of individuals would be exposed to sublethal doses rather than to lethal ones. Therefore, the purpose of current study was to assess short- and long-term effects on physiological parameters and function following sublethal pulmonary exposure. We show that in the short-term, sublethal exposure of mice to ricin resulted in acute lung injury, including interstitial pneumonia, cytokine storm, neutrophil influx, edema and cellular death. This damage was manifested in reduced lung performance and physiological function. Interestingly, although in the long-term, mice recovered from acute lung damage and restored pulmonary and physiological functionality, the reparative process was associated with lasting fibrotic lesions. Therefore, restriction of short-term acute phase of the disease and management of long-term pulmonary fibrosis by medical countermeasures is expected to facilitate the quality of life of exposed survivors.
Sujet(s)
Ricine , Animaux , Ricine/toxicité , Souris , Poumon/effets des médicaments et des substances chimiques , Poumon/anatomopathologie , Cytokines/métabolisme , Lésion pulmonaire/induit chimiquement , Lésion pulmonaire/anatomopathologie , Femelle , Modèles animaux de maladie humaineRÉSUMÉ
BACKGROUND: Bleomycin (BLM)-induced lung injury is characterized by mixed histopathologic changes with inflammation and fibrosis, such as observed in human patients with bronchopulmonary dysplasia, idiopathic pulmonary fibrosis, and chronic obstructive pulmonary disease. Although no curative therapies for these lung diseases exist, stem cell therapy has emerged as a potential therapeutic option. Multilineage-differentiating stress-enduring (Muse) cells are endogenous pluripotent- and macrophage-like stem cells distributed in various adult and fetal tissues as stage-specific embryonic antigen-3-positive cells. They selectively home to damaged tissue by sensing sphingosine-1-phosphate and replace the damaged/apoptotic cells by in vivo differentiation. Clinical trials for some human diseases suggest the safety and therapeutic efficacy of intravenously injected human leukocyte antigen-mismatched allogenic Muse cells from adult bone marrow (BM) without immunosuppressant. Here, we evaluated the therapeutic effects of human Muse cells from preterm and term umbilical cord (UC), and adult BM in a rat BLM-induced lung injury model. METHODS: Rats were endotracheally administered BLM to induce lung injury on day 0. On day 3, human preterm UC-Muse, term UC-Muse, or adult BM-Muse cells were administered intravenously without immunosuppressants, and rats were subjected to histopathologic analysis on day 21. Body weight, serum surfactant protein D (SP-D) levels, and oxygen saturation (SpO2) were monitored. Histopathologic lung injury scoring by the Ashcroft and modified American Thoracic Society document scales, quantitative characterization of engrafted Muse cells, RNA sequencing analysis, and in vitro migration assay of infused Muse cells were performed. RESULTS: Rats administered preterm- and term-UC-Muse cells exhibited a significantly better recovery based on weight loss, serum SP-D levels, SpO2, and histopathologic lung injury scores, and a significantly higher rate of both Muse cell homing to the lung and alveolar marker expression (podoplanin and prosurfactant protein-C) than rats administered BM-Muse cells. Rats receiving preterm-UC-Muse cells showed statistically superior results to those receiving term-UC-Muse cells in many of the measures. These findings are thought to be due to higher expression of genes related to cell migration, lung differentiation, and cell adhesion. CONCLUSION: Preterm UC-Muse cells deliver more efficient therapeutic effects than term UC- and BM-Muse cells for treating BLM-induced lung injury in a rat model.
Sujet(s)
Bléomycine , Modèles animaux de maladie humaine , Lésion pulmonaire , Cordon ombilical , Animaux , Humains , Rats , Lésion pulmonaire/thérapie , Lésion pulmonaire/induit chimiquement , Lésion pulmonaire/anatomopathologie , Cordon ombilical/cytologie , Rat Sprague-Dawley , Mâle , Différenciation cellulaire , FemelleRÉSUMÉ
Significant impairment of pulmonary function has been demonstrated through long-term exposure to neonicotinoid insecticides, such as imidacloprid (IMI). However, the underlying mechanisms of lung injury induced by IMI remain unclear. In this study, a mouse model of IMI-induced pulmonary injury was established, and the toxicity and lung damage were assessed through mouse body weight, organ index, hematological parameters, and histopathological analysis of lung tissues. Furthermore, metabolomics and transcriptomics techniques were employed to explore the mechanistic aspects. Results from the toxicity assessments indicated that mouse body weight was significantly reduced by IMI, organ index was disturbed, and hematological parameters were disrupted, resulting in pulmonary injury. The mechanistic experimental results indicate that the differences in metabolites and gene expression in mouse lungs could be altered by IMI. Validation of the results through combined analysis of metabolomics and transcriptomics revealed that the mechanism by which IMI induces lung injury in mice might be associated with the activation of the TLR4 receptor, thereby activating the PI3K/AKT/NF-κB signaling pathway to induce inflammation in mouse lungs. This study provided valuable insights into the mechanisms underlying IMI-induced pulmonary damage, potentially contributing to the development of safer pest control strategies. The knowledge gained served as a robust scientific foundation for the prevention and treatment of IMI-related pulmonary injuries.