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1.
Exp Lung Res ; 50(1): 146-159, 2024.
Article in English | MEDLINE | ID: mdl-39243130

ABSTRACT

PURPOSE OF THE STUDY: To observe the dynamic changes in monocyte subsets during septic lung injury and to assess the anti-inflammatory role of the sulfotransferase homolog 2 (ST2) receptor. MATERIALS AND METHODS: Dynamic changes of monocyte subsets from patients with septic lung injury and mice post-cecal ligation and puncture (CLP) were monitored. ST2 receptors on mice monocytes and concentrations of IL-33, IL-1ß, IL-12, and IL-27 from peripheral blood or culture supernatant were detected. RESULTS: CD14lowCD16- (Mo0) and CD14++CD16+ (Mo2) monocyte subsets were significantly expanded in patients with sepsis-related acute respiratory distress syndrome. In sepsis model mice, monocyte counts, particularly of Ly6Cint and CDLy6Cint+hi monocytes, were significantly increased. The mean optical density value of TNF-α after CLP mainly increased after 24 h, whereas that of IL-6 was significantly increased at all time points assessed after CLP. The levels of IL-1ß, IL-12, IL-27, and IL-33 increased to variable degrees at 6, 12, 24, and 48h after CLP, and ST2+ monocytes were significantly expanded in sepsis model mice compared to sham-operated mice. ST2 receptor blockade suppressed IL-1ß and IL-12 production in cell culture. CONCLUSIONS: Changes in monocyte subsets expressing the ST2 receptor play an important role in septic lung injury by modulating inflammatory cytokine secretion.


Subject(s)
Cytokines , Monocytes , Sepsis , Animals , Monocytes/metabolism , Mice , Sepsis/metabolism , Male , Humans , Cytokines/metabolism , Interleukin-1 Receptor-Like 1 Protein/metabolism , Female , Mice, Inbred C57BL , Middle Aged , Interleukin-33/metabolism , Lung Injury/metabolism , Acute Lung Injury/metabolism , Disease Models, Animal , Interleukin-1beta/metabolism , Aged , Interleukin-27/metabolism
2.
FASEB J ; 38(17): e70027, 2024 Sep 15.
Article in English | MEDLINE | ID: mdl-39221615

ABSTRACT

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 ß-hydroxybutyrate (ß-OHB) in ameliorating LIRI was examined. Modulation of ß-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 ß-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, ß-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 ß-OHB in mitigating injury by modulating the SIRT1-FOXO3 signaling pathway.


Subject(s)
3-Hydroxybutyric Acid , Forkhead Box Protein O3 , Macrophages, Alveolar , Mice, Inbred C57BL , Pyroptosis , Reperfusion Injury , Signal Transduction , Sirtuin 1 , Animals , Forkhead Box Protein O3/metabolism , Pyroptosis/drug effects , Sirtuin 1/metabolism , Mice , Macrophages, Alveolar/metabolism , Macrophages, Alveolar/drug effects , Signal Transduction/drug effects , Reperfusion Injury/metabolism , Reperfusion Injury/drug therapy , Male , 3-Hydroxybutyric Acid/pharmacology , Lung/metabolism , Lung/pathology , Carbazoles/pharmacology , Lung Injury/metabolism , Lung Injury/drug therapy
3.
J Biochem Mol Toxicol ; 38(8): e23790, 2024 Aug.
Article in English | MEDLINE | ID: mdl-39108137

ABSTRACT

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.


Subject(s)
Chemoradiotherapy , Epithelial-Mesenchymal Transition , Pulmonary Fibrosis , Humans , Epithelial-Mesenchymal Transition/drug effects , Pulmonary Fibrosis/chemically induced , Pulmonary Fibrosis/metabolism , Pulmonary Fibrosis/pathology , Pulmonary Fibrosis/etiology , Chemoradiotherapy/adverse effects , Animals , Oxidative Stress/drug effects , Lung Injury/etiology , Lung Injury/pathology , Lung Injury/chemically induced , Lung Injury/metabolism
4.
Immun Inflamm Dis ; 12(8): e70001, 2024 Aug.
Article in English | MEDLINE | ID: mdl-39172009

ABSTRACT

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.


Subject(s)
Curcuma , PPAR gamma , Paraquat , Pioglitazone , Plant Extracts , Rats, Wistar , Animals , Pioglitazone/pharmacology , Pioglitazone/therapeutic use , Paraquat/toxicity , Male , Rats , Curcuma/chemistry , PPAR gamma/agonists , PPAR gamma/metabolism , Plant Extracts/pharmacology , Plant Extracts/therapeutic use , Lung/pathology , Lung/drug effects , Lung/metabolism , Lung Injury/chemically induced , Lung Injury/prevention & control , Lung Injury/drug therapy , Lung Injury/pathology , Lung Injury/metabolism , Dexamethasone/pharmacology , Bronchoalveolar Lavage Fluid/cytology , Oxidative Stress/drug effects , Thiazolidinediones/pharmacology , Thiazolidinediones/therapeutic use , Antioxidants/pharmacology , Curcumin/pharmacology , Curcumin/therapeutic use
5.
Mol Biol Rep ; 51(1): 891, 2024 Aug 07.
Article in English | MEDLINE | ID: mdl-39110355

ABSTRACT

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.


Subject(s)
Acetylmuramyl-Alanyl-Isoglutamine , Beclin-1 , Enteral Nutrition , Lung Injury , Nod2 Signaling Adaptor Protein , Peptide Transporter 1 , Rats, Sprague-Dawley , Signal Transduction , Animals , Peptide Transporter 1/metabolism , Peptide Transporter 1/genetics , Rats , Beclin-1/metabolism , Beclin-1/genetics , Nod2 Signaling Adaptor Protein/metabolism , Nod2 Signaling Adaptor Protein/genetics , Signal Transduction/drug effects , Lung Injury/metabolism , Male , Acetylmuramyl-Alanyl-Isoglutamine/pharmacology , Enteral Nutrition/methods , Apoptosis/drug effects , Intestinal Mucosa/metabolism , Intestinal Mucosa/drug effects , Intestinal Mucosa/pathology , Autophagy/drug effects , Lung/metabolism , Lung/pathology , Lung/drug effects , Inflammation/metabolism
6.
In Vivo ; 38(5): 2179-2189, 2024.
Article in English | MEDLINE | ID: mdl-39187362

ABSTRACT

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-1ß) 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.


Subject(s)
Cytokines , Lung Injury , NF-kappa B , Signal Transduction , Silybin , Toll-Like Receptor 4 , Animals , Silybin/pharmacology , Mice , NF-kappa B/metabolism , Male , Signal Transduction/drug effects , Lung Injury/drug therapy , Lung Injury/chemically induced , Lung Injury/metabolism , Lung Injury/pathology , Lung Injury/etiology , Cytokines/metabolism , Toll-Like Receptor 4/metabolism , Disease Models, Animal , Vanadium/pharmacology , Mice, Inbred BALB C , Anti-Inflammatory Agents/pharmacology , Silymarin/pharmacology , Inflammation Mediators/metabolism , Lung/drug effects , Lung/pathology , Lung/metabolism
7.
Sheng Li Xue Bao ; 76(4): 517-525, 2024 Aug 25.
Article in Chinese | MEDLINE | ID: mdl-39192785

ABSTRACT

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-1ß 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-1ß, 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-1ß 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.


Subject(s)
Deoxyglucose , Lung , NLR Family, Pyrin Domain-Containing 3 Protein , Pyroptosis , Rats, Sprague-Dawley , Reperfusion Injury , Animals , NLR Family, Pyrin Domain-Containing 3 Protein/metabolism , Male , Reperfusion Injury/metabolism , Reperfusion Injury/prevention & control , Rats , Lung/metabolism , Lung/pathology , Deoxyglucose/pharmacology , Interleukin-1beta/metabolism , Interleukin-18/metabolism , Lung Injury/metabolism , Lung Injury/prevention & control , Lung Injury/etiology , Oxidative Stress
8.
FASEB J ; 38(16): e70012, 2024 Aug 31.
Article in English | MEDLINE | ID: mdl-39183539

ABSTRACT

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.


Subject(s)
Exosomes , Hyperoxia , Lung Injury , Melatonin , Mesenchymal Stem Cells , MicroRNAs , Signal Transduction , MicroRNAs/genetics , MicroRNAs/metabolism , Animals , Mice , Exosomes/metabolism , Lung Injury/metabolism , Lung Injury/etiology , Mesenchymal Stem Cells/metabolism , Melatonin/pharmacology , Hyperoxia/metabolism , Hyperoxia/complications , Male , Apoptosis , RNA-Binding Proteins/metabolism , RNA-Binding Proteins/genetics , Mice, Inbred C57BL , Oxidative Stress , Membrane Potential, Mitochondrial
9.
Redox Biol ; 75: 103296, 2024 Sep.
Article in English | MEDLINE | ID: mdl-39098263

ABSTRACT

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 % FiO2, 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.


Subject(s)
Animals, Newborn , Hyperoxia , Macrophages, Alveolar , Female , Animals , Male , Macrophages, Alveolar/metabolism , Mice , Hyperoxia/metabolism , Humans , Transcriptome , Bronchopulmonary Dysplasia/metabolism , Bronchopulmonary Dysplasia/pathology , Bronchopulmonary Dysplasia/etiology , Sex Characteristics , Sex Factors , Disease Models, Animal , Infant, Newborn , Lung/metabolism , Lung/pathology , Lung Injury/metabolism , Lung Injury/pathology , Lung Injury/etiology
10.
Int J Immunopathol Pharmacol ; 38: 3946320241272642, 2024.
Article in English | MEDLINE | ID: mdl-39096175

ABSTRACT

Prolonged exposure to different occupational or environmental toxicants triggered oxidative stress and inflammatory reactions mediated lung damage. This study was designed to explore the influence and protective impact of flavone on lung injury in rats intoxicated with nicotine (NIC) and exposed to radiation (IR). Forty rats were divided into four groups; group I control, group II flavone; rats were administered with flavone (25 mg/kg/day), group III NIC + IR; rats were injected intraperitoneally with NIC (1 mg/kg/day) and exposed to γ-IR (3.5 Gy once/week for 2 weeks) while group IV NIC + IR + flavone; rats were injected with NIC, exposed to IR and administered with flavone. Redox status parameters and histopathological changes in lung tissue were evaluated. Nuclear factor-kappa B (NF-κB), forkhead box O-class1 (FoxO1) and nucleotide-binding domain- (NOD-) like receptor pyrin domain-containing-3 (NLRP3) gene expression were measured in lung tissues. Moreover, nuclear factor (erythroid-derived 2)-like 2 (Nrf2) and phosphatidylinositol three kinase (PI3K) were measured using ELISA kits. Our data demonstrates, for the first time, that flavone protects the lung from NIC/IR-associated cytotoxicity, by attenuating the disrupted redox status and aggravating the antioxidant defence mechanism via activation of the PI3K/Nrf2. Moreover, flavone alleviates pulmonary inflammation by inhibiting the inflammatory signaling pathway FOXO1/NF-κB/NLRP3- Inflammasome. Collectively, the obtained results exhibited a notable efficiency of flavone in alleviating lung injury induced by NIC and IR via modulating PI3K/Nrf2 and FoxO1/NLRP3 Inflammasome.


Subject(s)
Flavones , Inflammasomes , Lung Injury , Nicotine , Animals , Male , Rats , Flavones/pharmacology , Forkhead Box Protein O1 , Gamma Rays , Inflammasomes/metabolism , Inflammasomes/drug effects , Lung/drug effects , Lung/metabolism , Lung/pathology , Lung/radiation effects , Lung Injury/metabolism , Lung Injury/prevention & control , NF-E2-Related Factor 2/metabolism , NF-kappa B/metabolism , Nicotine/pharmacology , NLR Family, Pyrin Domain-Containing 3 Protein/metabolism , Oxidative Stress/drug effects , Phosphatidylinositol 3-Kinases/metabolism , Rats, Wistar , Signal Transduction/drug effects
11.
Respir Res ; 25(1): 299, 2024 Aug 07.
Article in English | MEDLINE | ID: mdl-39113018

ABSTRACT

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.


Subject(s)
Alveolar Epithelial Cells , Cellular Senescence , Mice, Inbred C57BL , Mice, Knockout , Animals , Mice , Cellular Senescence/radiation effects , Cellular Senescence/physiology , Alveolar Epithelial Cells/metabolism , Alveolar Epithelial Cells/radiation effects , Alveolar Epithelial Cells/pathology , Lung Injury/metabolism , Lung Injury/genetics , Lung Injury/pathology , Elongation Factor 2 Kinase/metabolism , Elongation Factor 2 Kinase/genetics , Humans , Radiation Injuries, Experimental/metabolism , Radiation Injuries, Experimental/pathology , Radiation Injuries, Experimental/genetics , Cells, Cultured , Male
12.
J Physiol Pharmacol ; 75(3)2024 Jun.
Article in English | MEDLINE | ID: mdl-39042394

ABSTRACT

Bronchopulmonary dysplasia (BPD) is a common serious complication of premature babies. No effective means control it. Hyperoxia damage is one of the important mechanisms of BPD. The reaserach confirmed pyroptosis existed in BPD. Dexmedetomidine is a new, high-specific α2 receptor agonist. Previous research foundation found that dexmedetomidine has a protective effect on BPD. To investigate how dexmedetomidine improves hyperoxic lung injury in neonatal mice by regulating pyroptosis. Neonatal rats were randomly divided into four groups: normal control group, hyperoxic injury group, air plus dexmedetomidine group, and hyperoxia plus dexmedetomidine group. After seven days the lungs of rats in each group were extracted, and the wet-to-dry weight ratio of the lung was measured. The lung injury in rats was observed using hematoxylin-eosin staining. Additionally, the expression and localization of nucleotide-binding oligomerization domain-like receptor thermal protein domain associated protein 3 (NLRP3), apoptosis-associated speck-like protein (ASC), and gasdermin D (GSDMD) proteins were examined in the lungs of rats using immunofluorescence staining. The mRNA levels of NLRP3, ASC, caspase-1, and interleukin 18 (IL-18) in the lungs of rats were determined using real-time PCR. Moreover, the protein levels of NLRP3, ASC, caspase-1/cleaved caspase-1, interleukin 1beta (IL-1ß), IL-18, and tunor necrosis factor alpha (TNF-α) were detected in lungs of rats using Western blot. The extent of mitochondrial damage in lung tissues of each group was observed by transmission electron microscopy. The lung tissue injury of the neonatal rats was significantly improved in the hyperoxia plus dexmedetomidine group compared to the hyperoxic injury group. Furthermore, the expressions of pyroptosis-related proteins such as NLRP3, ASC, cleaved-caspase-1, and GSDMD were significantly decreased, along with the expressions of inflammatory factors in lung tissues. By inhibiting the NLRP3/caspase-1/GSDMD pyroptosis pathway, dexmedetomidine reduces the activation and release of inflammatory factors and provides a protective effect against hyperoxic lung injury in neonatal mice.


Subject(s)
Animals, Newborn , Dexmedetomidine , Hyperoxia , Lung Injury , Lung , NLR Family, Pyrin Domain-Containing 3 Protein , Pyroptosis , Rats, Sprague-Dawley , Animals , Dexmedetomidine/pharmacology , Dexmedetomidine/therapeutic use , Hyperoxia/metabolism , Hyperoxia/complications , Hyperoxia/drug therapy , NLR Family, Pyrin Domain-Containing 3 Protein/metabolism , Lung/drug effects , Lung/pathology , Lung/metabolism , Pyroptosis/drug effects , Lung Injury/metabolism , Lung Injury/prevention & control , Lung Injury/pathology , Lung Injury/drug therapy , Rats , Phosphate-Binding Proteins/metabolism , CARD Signaling Adaptor Proteins/metabolism , Caspase 1/metabolism , Interleukin-18/metabolism , Adrenergic alpha-2 Receptor Agonists/pharmacology , Adrenergic alpha-2 Receptor Agonists/therapeutic use , Male , Gasdermins
14.
Biochem Pharmacol ; 227: 116418, 2024 Sep.
Article in English | MEDLINE | ID: mdl-38996928

ABSTRACT

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.


Subject(s)
Intracellular Signaling Peptides and Proteins , MAP Kinase Kinase Kinases , Mice, Inbred C57BL , NF-kappa B , Sepsis , Ubiquitin-Specific Proteases , Animals , Sepsis/metabolism , MAP Kinase Kinase Kinases/metabolism , MAP Kinase Kinase Kinases/genetics , NF-kappa B/metabolism , Mice , Intracellular Signaling Peptides and Proteins/metabolism , Intracellular Signaling Peptides and Proteins/genetics , Male , Humans , Ubiquitin-Specific Proteases/metabolism , Ubiquitin-Specific Proteases/genetics , Signal Transduction/physiology , Ubiquitination , Lung Injury/metabolism , Lung Injury/etiology , Lung Injury/prevention & control , MAP Kinase Signaling System/physiology
15.
J Ethnopharmacol ; 334: 118584, 2024 Nov 15.
Article in English | MEDLINE | ID: mdl-39019418

ABSTRACT

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.


Subject(s)
Drugs, Chinese Herbal , Lipopolysaccharides , Lung Injury , Metabolomics , Animals , Drugs, Chinese Herbal/pharmacology , Mice , Lung Injury/drug therapy , Lung Injury/metabolism , Lung Injury/chemically induced , Male , Gastrointestinal Microbiome/drug effects , Transcriptome/drug effects , Lung/drug effects , Lung/pathology , Lung/metabolism , Mice, Inbred C57BL , Cytokines/metabolism , Disease Models, Animal , Acute Lung Injury/drug therapy , Acute Lung Injury/chemically induced , Acute Lung Injury/metabolism
16.
Sci Rep ; 14(1): 14231, 2024 06 20.
Article in English | MEDLINE | ID: mdl-38902260

ABSTRACT

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.


Subject(s)
Acute Lung Injury , Apoptosis , Butorphanol , Inflammation , Animals , Butorphanol/pharmacology , Apoptosis/drug effects , Rats , Male , Acute Lung Injury/chemically induced , Acute Lung Injury/metabolism , Acute Lung Injury/pathology , Acute Lung Injury/drug therapy , Acute Lung Injury/prevention & control , Inflammation/drug therapy , Inflammation/metabolism , Inflammation/pathology , Transcription Factor RelA/metabolism , Lipopolysaccharides , Rats, Sprague-Dawley , Lung Injury/chemically induced , Lung Injury/drug therapy , Lung Injury/metabolism , Lung Injury/pathology , Lung Injury/prevention & control , Disease Models, Animal , Cytokines/metabolism , Lung/pathology , Lung/drug effects , Lung/metabolism
17.
Toxicology ; 506: 153869, 2024 Aug.
Article in English | MEDLINE | ID: mdl-38909937

ABSTRACT

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.


Subject(s)
Inflammasomes , MicroRNAs , Plant Extracts , Pyroptosis , Rats, Sprague-Dawley , Signal Transduction , Animals , MicroRNAs/genetics , MicroRNAs/metabolism , Inflammasomes/metabolism , Inflammasomes/drug effects , Inflammasomes/genetics , Rats , Male , Pyroptosis/drug effects , Signal Transduction/drug effects , Plant Extracts/pharmacology , Acrylamide/toxicity , Lung/drug effects , Lung/pathology , Lung/metabolism , Oxidative Stress/drug effects , Pulmonary Fibrosis/chemically induced , Pulmonary Fibrosis/pathology , Pulmonary Fibrosis/genetics , Pulmonary Fibrosis/metabolism , Acrylamides/toxicity , Lung Injury/chemically induced , Lung Injury/pathology , Lung Injury/genetics , Lung Injury/metabolism
18.
Nat Commun ; 15(1): 5449, 2024 Jun 27.
Article in English | MEDLINE | ID: mdl-38937456

ABSTRACT

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.


Subject(s)
Aging , Bleomycin , Endothelial Cells , Lung Injury , Lung , Pulmonary Fibrosis , Animals , Endothelial Cells/metabolism , Endothelial Cells/pathology , Aging/pathology , Bleomycin/toxicity , Humans , Mice , Pulmonary Fibrosis/pathology , Pulmonary Fibrosis/metabolism , Pulmonary Fibrosis/genetics , Lung/pathology , Lung/metabolism , Lung Injury/pathology , Lung Injury/metabolism , Lung Injury/etiology , Receptor, trkB/metabolism , Receptor, trkB/genetics , Mice, Inbred C57BL , Brain-Derived Neurotrophic Factor/metabolism , Brain-Derived Neurotrophic Factor/genetics , YAP-Signaling Proteins/metabolism , Male , Single-Cell Analysis , Adaptor Proteins, Signal Transducing/metabolism , Adaptor Proteins, Signal Transducing/genetics , Female , Disease Models, Animal
19.
Proc Natl Acad Sci U S A ; 121(26): e2319322121, 2024 Jun 25.
Article in English | MEDLINE | ID: mdl-38900789

ABSTRACT

Thymocyte selection-associated high-mobility group box (TOX) is a transcription factor that is crucial for T cell exhaustion during chronic antigenic stimulation, but its role in inflammation is poorly understood. Here, we report that TOX extracellularly mediates drastic inflammation upon severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection by binding to the cell surface receptor for advanced glycation end-products (RAGE). In various diseases, including COVID-19, TOX release was highly detectable in association with disease severity, contributing to lung fibroproliferative acute respiratory distress syndrome (ARDS). Recombinant TOX-induced blood vessel rupture, similar to a clinical signature in patients experiencing a cytokine storm, further exacerbating respiratory function impairment. In contrast, disruption of TOX function by a neutralizing antibody and genetic removal of RAGE diminished TOX-mediated deleterious effects. Altogether, our results suggest an insight into TOX function as an inflammatory mediator and propose the TOX-RAGE axis as a potential target for treating severe patients with pulmonary infection and mitigating lung fibroproliferative ARDS.


Subject(s)
COVID-19 , Receptor for Advanced Glycation End Products , SARS-CoV-2 , Humans , Receptor for Advanced Glycation End Products/metabolism , COVID-19/immunology , COVID-19/metabolism , COVID-19/pathology , COVID-19/complications , COVID-19/virology , Animals , Mice , Inflammation/metabolism , Inflammation/pathology , Respiratory Distress Syndrome/immunology , Respiratory Distress Syndrome/metabolism , Respiratory Distress Syndrome/pathology , Respiratory Distress Syndrome/virology , Lung Injury/immunology , Lung Injury/metabolism , Lung Injury/pathology , High Mobility Group Proteins/metabolism , High Mobility Group Proteins/genetics , Male , Lung/pathology , Lung/metabolism , Lung/immunology , Female
20.
Redox Biol ; 74: 103194, 2024 Aug.
Article in English | MEDLINE | ID: mdl-38852200

ABSTRACT

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.


Subject(s)
Coenzyme A Ligases , Ferroptosis , Methyltransferases , Sepsis , Methyltransferases/metabolism , Methyltransferases/genetics , Animals , Sepsis/metabolism , Sepsis/complications , Mice , Humans , Coenzyme A Ligases/metabolism , Coenzyme A Ligases/genetics , Adenosine/analogs & derivatives , Adenosine/metabolism , Lung Injury/metabolism , Lung Injury/etiology , Lung Injury/pathology , Lung Injury/genetics , Acute Lung Injury/metabolism , Acute Lung Injury/etiology , Acute Lung Injury/pathology , Acute Lung Injury/genetics , Male , Disease Models, Animal , Lactic Acid/metabolism
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