RESUMO
Hemolysis drives susceptibility to lung injury and predicts poor outcomes in diseases, such as malaria and sickle cell disease (SCD). However, the underlying pathological mechanism remains elusive. Here, we report that major facilitator superfamily domain containing 7 C (MFSD7C) protects the lung from hemolytic-induced damage by preventing ferroptosis. Mechanistically, MFSD7C deficiency in HuLEC-5A cells leads to mitochondrial dysfunction, lipid remodeling and dysregulation of ACSL4 and GPX4, thereby enhancing lipid peroxidation and promoting ferroptosis. Furthermore, systemic administration of MFSD7C mRNA-loaded nanoparticles effectively prevents lung injury in hemolytic mice, such as HbSS-Townes mice and PHZ-challenged 7 C-/- mice. These findings present the detailed link between hemolytic complications and ferroptosis, providing potential therapeutic targets for patients with hemolytic disorders.
Assuntos
Ferroptose , Hemólise , Camundongos Knockout , Fosfolipídeo Hidroperóxido Glutationa Peroxidase , Animais , Feminino , Humanos , Masculino , Camundongos , Anemia Falciforme/complicações , Anemia Falciforme/genética , Coenzima A Ligases/metabolismo , Coenzima A Ligases/genética , Modelos Animais de Doenças , Ferroptose/efeitos dos fármacos , Ferroptose/genética , Hemólise/efeitos dos fármacos , Peroxidação de Lipídeos/efeitos dos fármacos , Pulmão/patologia , Pulmão/metabolismo , Lesão Pulmonar/metabolismo , Lesão Pulmonar/patologia , Lesão Pulmonar/prevenção & controle , Lesão Pulmonar/genética , Camundongos Endogâmicos C57BL , Mitocôndrias/metabolismo , Mitocôndrias/efeitos dos fármacos , Nanopartículas/química , Fosfolipídeo Hidroperóxido Glutationa Peroxidase/metabolismo , Fosfolipídeo Hidroperóxido Glutationa Peroxidase/genéticaRESUMO
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.
Assuntos
Apoptose , Lesão Pulmonar , Camundongos Endogâmicos C57BL , Mitocôndrias , Estresse Oxidativo , Cofator PQQ , Animais , Camundongos , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Mitocôndrias/efeitos da radiação , Cofator PQQ/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Estresse Oxidativo/efeitos da radiação , Lesão Pulmonar/metabolismo , Lesão Pulmonar/etiologia , Lesão Pulmonar/genética , Lesão Pulmonar/prevenção & controle , Lesão Pulmonar/tratamento farmacológico , Humanos , Apoptose/efeitos dos fármacos , Masculino , Lesões por Radiação/metabolismo , Lesões por Radiação/genética , Lesões por Radiação/tratamento farmacológico , Lesões por Radiação/prevenção & controle , Pulmão/efeitos da radiação , Pulmão/metabolismo , Pulmão/efeitos dos fármacosRESUMO
BACKGROUND: Radiation-induced lung injury (RILI), a serious side effect of thoracic radiotherapy, can lead to acute radiation pneumonitis (RP) and chronic pulmonary fibrosis (PF). Despite various interventions, no effective protocol exists to prevent pneumonitis. Oxytocin (OT), known for its anti-inflammatory, antiapoptotic, and antioxidant properties, has not been explored for its potential in mitigating RILI. MATERIALS AND METHODS: This study involved 24 female Wistar albino rats, divided into three groups: control group, radiation (RAD) + saline, and RAD + OT. The RAD groups received 18 Gy of whole-thorax irradiation. The RAD + OT group was treated with OT (0.1 mg/kg/day) intraperitoneally for 16 weeks. Computerizing tomography (CT) imaging and histopathological, biochemical, and blood gas analyses were performed to assess lung tissue damage and inflammation. RESULTS: Histopathological examination showed significant reduction in alveolar wall thickening, inflammation, and vascular changes in the RAD + OT group compared to the RAD + saline group. Biochemical analysis revealed decreased levels of TGF-beta, VEGF, and PDGF, and increased BMP-7 and prostacyclin in the RAD + oxytocin group (p < 0.05). Morphometric analysis indicated significant reductions in fibrosis, edema, and immune cell infiltration. CT imaging demonstrated near-normal lung parenchyma density in the RAD + oxytocin group (p < 0.001). CONCLUSION: Oxytocin administration significantly mitigates radiation-induced pneumonitis in rats, implying that is has potential as a therapeutic agent for preventing and treating RILI.
Assuntos
Ocitocina , Ratos Wistar , Animais , Ocitocina/farmacologia , Ocitocina/uso terapêutico , Feminino , Ratos , Tomografia Computadorizada por Raios X/métodos , Pulmão/efeitos da radiação , Pulmão/patologia , Pulmão/diagnóstico por imagem , Pneumonite por Radiação/patologia , Pneumonite por Radiação/tratamento farmacológico , Lesões Experimentais por Radiação/patologia , Lesões Experimentais por Radiação/diagnóstico por imagem , Lesão Pulmonar/etiologia , Lesão Pulmonar/diagnóstico por imagem , Lesão Pulmonar/patologia , Lesão Pulmonar/prevenção & controle , Protetores contra Radiação/farmacologia , Protetores contra Radiação/uso terapêuticoRESUMO
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.
Assuntos
Curcuma , PPAR gama , Paraquat , Pioglitazona , Extratos Vegetais , Ratos Wistar , Animais , Pioglitazona/farmacologia , Pioglitazona/uso terapêutico , Paraquat/toxicidade , Masculino , Ratos , Curcuma/química , PPAR gama/agonistas , PPAR gama/metabolismo , Extratos Vegetais/farmacologia , Extratos Vegetais/uso terapêutico , Pulmão/patologia , Pulmão/efeitos dos fármacos , Pulmão/metabolismo , Lesão Pulmonar/induzido quimicamente , Lesão Pulmonar/prevenção & controle , Lesão Pulmonar/tratamento farmacológico , Lesão Pulmonar/patologia , Lesão Pulmonar/metabolismo , Dexametasona/farmacologia , Líquido da Lavagem Broncoalveolar/citologia , Estresse Oxidativo/efeitos dos fármacos , Tiazolidinedionas/farmacologia , Tiazolidinedionas/uso terapêutico , Antioxidantes/farmacologia , Curcumina/farmacologia , Curcumina/uso terapêuticoRESUMO
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.
Assuntos
Desoxiglucose , Pulmão , Proteína 3 que Contém Domínio de Pirina da Família NLR , Piroptose , Ratos Sprague-Dawley , Traumatismo por Reperfusão , Animais , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Masculino , Traumatismo por Reperfusão/metabolismo , Traumatismo por Reperfusão/prevenção & controle , Ratos , Pulmão/metabolismo , Pulmão/patologia , Desoxiglucose/farmacologia , Interleucina-1beta/metabolismo , Interleucina-18/metabolismo , Lesão Pulmonar/metabolismo , Lesão Pulmonar/prevenção & controle , Lesão Pulmonar/etiologia , Estresse OxidativoRESUMO
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.
Assuntos
Flavonas , Inflamassomos , Lesão Pulmonar , Nicotina , Animais , Masculino , Ratos , Flavonas/farmacologia , Proteína Forkhead Box O1 , Raios gama , Inflamassomos/metabolismo , Inflamassomos/efeitos dos fármacos , Pulmão/efeitos dos fármacos , Pulmão/metabolismo , Pulmão/patologia , Pulmão/efeitos da radiação , Lesão Pulmonar/metabolismo , Lesão Pulmonar/prevenção & controle , Fator 2 Relacionado a NF-E2/metabolismo , NF-kappa B/metabolismo , Nicotina/farmacologia , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Fosfatidilinositol 3-Quinases/metabolismo , Ratos Wistar , Transdução de Sinais/efeitos dos fármacosRESUMO
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.
Assuntos
Peptídeos e Proteínas de Sinalização Intracelular , MAP Quinase Quinase Quinases , Camundongos Endogâmicos C57BL , NF-kappa B , Sepse , Proteases Específicas de Ubiquitina , Animais , Humanos , Masculino , Camundongos , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/genética , Lesão Pulmonar/metabolismo , Lesão Pulmonar/etiologia , Lesão Pulmonar/prevenção & controle , MAP Quinase Quinase Quinases/metabolismo , MAP Quinase Quinase Quinases/genética , Sistema de Sinalização das MAP Quinases/fisiologia , NF-kappa B/metabolismo , Sepse/metabolismo , Transdução de Sinais/fisiologia , Proteases Específicas de Ubiquitina/metabolismo , Proteases Específicas de Ubiquitina/genética , UbiquitinaçãoRESUMO
BACKGROUND: Inflammation and oxidative stress are key players in lung injury stemming from cardiac ischemia (LISCI). Cannabidiol (CBD) demonstrates tissue-protective properties through its antioxidant, anti-inflammatory, and anti-apoptotic characteristics. This study aims to assess the preventive (p-CBD) and therapeutic (t-CBD) effects of CBD on LISCI. METHODS: Forty male Wistar Albino rats were divided into four groups: control (CON), LISCI, p-CBD, and t-CBD. The left anterior descending coronary artery was ligated for 30 min of ischemia followed by 30 min of reperfusion. Lung tissues were then extracted for histopathological, immunohistochemical, genetic, and biochemical analyses. RESULTS: Histopathologically, marked hyperemia, increased septal tissue thickness, and inflammatory cell infiltrations were observed in the lung tissues of the LISCI group. Spectrophotometrically, total oxidant status and oxidative stress index levels were elevated, while total antioxidant status levels were decreased. Immunohistochemically, expressions of cyclooxygenase-1 (COX1), granulocyte colony-stimulating factor (GCSF), interleukin-6 (IL6) were increased. In genetic analyses, PERK and CHOP expressions were increased, whereas Nuclear factor erythroid 2-related factor 2 (NRF2) and B-cell leukemia/lymphoma 2 protein (BCL2) expressions were decreased. These parameters were alleviated by both prophylactic and therapeutic CBD treatment protocols. CONCLUSION: In LISCI-induced damage, both endoplasmic reticulum and mitochondrial stress, along with oxidative and inflammatory markers, were triggered, resulting in lung cell damage. However, both p-CBD and t-CBD treatments effectively reversed these mechanisms, normalizing all histopathological, biochemical, and PCR parameters.
Assuntos
Canabidiol , Lesão Pulmonar , Isquemia Miocárdica , Fator 2 Relacionado a NF-E2 , Proteínas Proto-Oncogênicas c-bcl-2 , Ratos Wistar , Fator de Transcrição CHOP , Animais , Canabidiol/farmacologia , Masculino , Ratos , Fator 2 Relacionado a NF-E2/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Fator de Transcrição CHOP/metabolismo , Lesão Pulmonar/prevenção & controle , Lesão Pulmonar/tratamento farmacológico , Lesão Pulmonar/metabolismo , Lesão Pulmonar/patologia , Isquemia Miocárdica/tratamento farmacológico , Isquemia Miocárdica/patologia , Isquemia Miocárdica/metabolismo , Isquemia Miocárdica/prevenção & controle , eIF-2 Quinase/metabolismo , Modelos Animais de Doenças , Transdução de Sinais/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacosRESUMO
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.
Assuntos
Animais Recém-Nascidos , Dexmedetomidina , Hiperóxia , Lesão Pulmonar , Pulmão , Proteína 3 que Contém Domínio de Pirina da Família NLR , Piroptose , Ratos Sprague-Dawley , Animais , Dexmedetomidina/farmacologia , Dexmedetomidina/uso terapêutico , Hiperóxia/metabolismo , Hiperóxia/complicações , Hiperóxia/tratamento farmacológico , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Pulmão/efeitos dos fármacos , Pulmão/patologia , Pulmão/metabolismo , Piroptose/efeitos dos fármacos , Lesão Pulmonar/metabolismo , Lesão Pulmonar/prevenção & controle , Lesão Pulmonar/patologia , Lesão Pulmonar/tratamento farmacológico , Ratos , Proteínas de Ligação a Fosfato/metabolismo , Proteínas Adaptadoras de Sinalização CARD/metabolismo , Caspase 1/metabolismo , Interleucina-18/metabolismo , Agonistas de Receptores Adrenérgicos alfa 2/farmacologia , Agonistas de Receptores Adrenérgicos alfa 2/uso terapêutico , Masculino , GasderminasRESUMO
INTRODUCTION: It has been hypothesized that piperine, the main alkaloid component of black pepper, possesses a unique radioprotective effect. This study aimed to investigate the protective effect of piperine against Radiation-Induced Lung Injury (RILI) in mice. METHODS: Firstly, eighty male mice were divided into eight groups; the control group did not receive any dosage of piperine and radiation (6 Gy), and the other groups received piperine alone at doses 10, 25, and 50 mg/kg, radiation, and radiation-piperine combination (6 Gy + 10, 25, and 50 mg/kg). Animals received piperine by gavage for 7 consecutive days. To investigate the effect of piperine pretreatment in mice that were exposed to radiation, histopathological and biochemical evaluations (markers of oxidative stress) were performed. Irradiation led to an increase in oxidative stress (increase in MDA and PC). Pretreatment of piperine in all three doses in irradiated mice was able to reduce oxidative stress compared to mice that were only exposed to radiation. RESULTS: Piperine at a dose of 25 mg/kg exhibited the highest protective effect as compared to other doses. Also, in the histopathological examination, it was seen that pretreatment with piperine was able to improve the infiltration of inflammatory cells and reduce the thickness of the alveolar septum and air sac damage. CONCLUSION: The outcomes completely proved significant lung protection by piperine in mice through reducing oxidative stress. This natural compound could be considered a protective agent against lung injury induced by ionizing radiation.
Assuntos
Alcaloides , Benzodioxóis , Estresse Oxidativo , Piperidinas , Alcamidas Poli-Insaturadas , Protetores contra Radiação , Animais , Alcamidas Poli-Insaturadas/farmacologia , Alcaloides/farmacologia , Benzodioxóis/farmacologia , Piperidinas/farmacologia , Masculino , Camundongos , Protetores contra Radiação/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Lesão Pulmonar/prevenção & controle , Lesão Pulmonar/patologia , Lesão Pulmonar/tratamento farmacológico , Lesão Pulmonar/etiologia , Relação Dose-Resposta a Droga , Lesões Experimentais por Radiação/prevenção & controle , Lesões Experimentais por Radiação/patologia , Lesões Experimentais por Radiação/tratamento farmacológicoRESUMO
ABSTRACT: Using a blind insertion technique to insert small-bore feeding tubes can result in inadvertent placement in the lungs, leading to lung perforation and even mortality. In a Magnet-designated, 500-bed, level 2 trauma center, two serious patient safety events occurred in a four-week period due to nurses blindly inserting a small-bore feeding tube. A patient safety event review team convened and conducted an assessment of reported small-bore feeding tube insertion events that occurred between March 2019 and July 2021. The review revealed six lung perforations over this two-year period. These events prompted the creation of a multidisciplinary team to evaluate alternative small-bore feeding tube insertion practices. The team reviewed the literature and evaluated several evidence-based small-bore feeding tube placement methods, including placement with fluoroscopy, a two-step X-ray, electromagnetic visualization, and capnography. After the evaluation, capnography was selected as the most effective method to mitigate the complications of blind insertion. In this article, the authors describe a quality improvement project involving the implementation of capnography-guided small-bore feeding tube placement to reduce complications and the incidence of lung perforation. Since the completion of the project, which took place from December 13, 2021, through April 18, 2022, no lung injuries or perforations have been reported. Capnography is a relatively simple, noninvasive, and cost-effective technology that provides nurses with a means to safely and effectively insert small-bore feeding tubes, decrease the incidence of adverse events, and improve patient care.
Assuntos
Lesão Pulmonar , Humanos , Lesão Pulmonar/prevenção & controle , Lesão Pulmonar/etiologia , Nutrição Enteral/instrumentação , Nutrição Enteral/métodos , Nutrição Enteral/enfermagem , Capnografia , Intubação Gastrointestinal/efeitos adversos , Intubação Gastrointestinal/métodos , Intubação Gastrointestinal/enfermagem , Melhoria de Qualidade , Segurança do Paciente , Centros de TraumatologiaRESUMO
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.
Assuntos
Lesão Pulmonar Aguda , Apoptose , Butorfanol , Inflamação , Animais , Butorfanol/farmacologia , Apoptose/efeitos dos fármacos , Ratos , Masculino , Lesão Pulmonar Aguda/induzido quimicamente , Lesão Pulmonar Aguda/metabolismo , Lesão Pulmonar Aguda/patologia , Lesão Pulmonar Aguda/tratamento farmacológico , Lesão Pulmonar Aguda/prevenção & controle , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Inflamação/patologia , Fator de Transcrição RelA/metabolismo , Lipopolissacarídeos , Ratos Sprague-Dawley , Lesão Pulmonar/induzido quimicamente , Lesão Pulmonar/tratamento farmacológico , Lesão Pulmonar/metabolismo , Lesão Pulmonar/patologia , Lesão Pulmonar/prevenção & controle , Modelos Animais de Doenças , Citocinas/metabolismo , Pulmão/patologia , Pulmão/efeitos dos fármacos , Pulmão/metabolismoRESUMO
BACKGROUND: Emodin, a natural anthraquinone derivative found in various Chinese medicinal herbs, has been proved to be an effective therapeutic agent in the treatment of many diseases. However, its effect on lung injury after intestinal ischemia/reperfusion injury remains unknown. This research was designed to investigate whether emodin protects against intestinal ischemia/reperfusion-induced lung injury and to elucidate the underlying molecular mechanisms in vivo and in vitro. METHODS: Intestinal ischemia/reperfusion injury was induced by occluding the superior mesenteric artery in mice, and mouse lung epithelial-12 cells were subjected to oxygen-glucose deprivation and reoxygenation to establish an in vitro model. RESULTS: Our data indicated that emodin treatment reduced intestinal ischemia/reperfusion-induced oxidative stress, inflammation and apoptosis in lung tissues and alleviated lung injury. However, the protective effects of emodin on intestinal ischemia/reperfusion-induced lung injury were reversed by the protein kinase B inhibitor triciribine or the heme oxygenase-1 inhibitor tin protoporphyrin IX. The protein kinase inhibitor triciribine also downregulated the expression of heme oxygenase-1. CONCLUSION: In conclusion, our data suggest that emodin treatment protects against intestinal ischemia/reperfusion-induced lung injury by enhancing heme oxygenase-1 expression via activation of the PI3K/protein kinase pathway. Emodin may act as a potential therapeutic agent for the prevention and treatment of lung injury induced by intestinal ischemia/reperfusion.
Assuntos
Emodina , Heme Oxigenase-1 , Fosfatidilinositol 3-Quinases , Proteínas Proto-Oncogênicas c-akt , Traumatismo por Reperfusão , Transdução de Sinais , Regulação para Cima , Animais , Emodina/farmacologia , Emodina/uso terapêutico , Traumatismo por Reperfusão/prevenção & controle , Traumatismo por Reperfusão/metabolismo , Traumatismo por Reperfusão/etiologia , Traumatismo por Reperfusão/tratamento farmacológico , Camundongos , Proteínas Proto-Oncogênicas c-akt/metabolismo , Heme Oxigenase-1/metabolismo , Masculino , Fosfatidilinositol 3-Quinases/metabolismo , Transdução de Sinais/efeitos dos fármacos , Regulação para Cima/efeitos dos fármacos , Intestinos/irrigação sanguínea , Intestinos/patologia , Intestinos/efeitos dos fármacos , Camundongos Endogâmicos C57BL , Lesão Pulmonar/etiologia , Lesão Pulmonar/prevenção & controle , Lesão Pulmonar/metabolismo , Lesão Pulmonar/tratamento farmacológico , Lesão Pulmonar/patologia , Modelos Animais de Doenças , Estresse Oxidativo/efeitos dos fármacos , Proteínas de MembranaRESUMO
BACKGROUND AND PURPOSE: Nicorandil, a selective opener of potassium channels, used to treat angina, has drawn attention for its potential in mitigating lung injury, positioning it as a promising therapeutic approach to treat drug-induced lung toxicity. This study aimed to explore the protective role of nicorandil in arsenic trioxide (ATO)-induced lung injury and to elucidate the underlying mechanistic pathways. EXPERIMENTAL APPROACH: We assessed the effects of nicorandil (15 mg·kg-1, p.o.) in a rat model of pulmonary injury induced by ATO (5 mg·kg-1, i.p.). The assessment included oxidative stress biomarkers, inflammatory cytokine levels, and other biomarkers, including sirtuin-1, sirtuin-3, STAT3, TFAM, and JAK in lung tissue. Histological examination using H&E staining and molecular investigations using western blotting and PCR techniques were conducted. KEY RESULTS: In our model of lung injury, treatment with nicorandil ameliorated pathological changes as seen with H&E staining, reduced tissue levels of toxicity markers, and exerted significant antioxidant and anti-inflammatory actions. On a molecular level, treatment with nicorandil down-regulated JAK, STAT3, PPARγ, Nrf2, VEGF, p53, and micro-RNA 132 while up-regulating Sirt1, 3, TFAM, AMPK, and ERR-α in lung tissue. CONCLUSIONS AND IMPLICATIONS: The results presented here show nicorandil as a significant agent in attenuating lung injury induced by ATO in a rodent model. Nonetheless, further clinical studies are warranted to strengthen these findings.
Assuntos
Trióxido de Arsênio , Janus Quinase 1 , Lesão Pulmonar , MicroRNAs , Nicorandil , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo , Fator de Transcrição STAT3 , Transdução de Sinais , Sirtuína 1 , Animais , Nicorandil/farmacologia , Fator de Transcrição STAT3/metabolismo , Sirtuína 1/metabolismo , Sirtuína 1/genética , Masculino , Transdução de Sinais/efeitos dos fármacos , Ratos , Trióxido de Arsênio/farmacologia , Trióxido de Arsênio/toxicidade , MicroRNAs/metabolismo , MicroRNAs/genética , Janus Quinase 1/metabolismo , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/genética , Lesão Pulmonar/induzido quimicamente , Lesão Pulmonar/metabolismo , Lesão Pulmonar/tratamento farmacológico , Lesão Pulmonar/patologia , Lesão Pulmonar/prevenção & controle , Fatores de Transcrição/metabolismo , Proteínas de Ligação a DNA/metabolismo , Proteínas de Ligação a DNA/genética , Ratos Wistar , Ratos Sprague-Dawley , Estresse Oxidativo/efeitos dos fármacosRESUMO
Particulate matter (PM) is considered the fundamental component of atmospheric pollutants and is associated with the pathogenesis of many respiratory diseases. Fibroblast growth factor 10 (FGF10) mediates mesenchymal-epithelial signaling and has been linked with the repair process of PM-induced lung injury (PMLI). However, the pathogenic mechanism of PMLI and the specific FGF10 protective mechanism against this injury are still undetermined. PM was administered in vivo into murine airways or in vitro to human bronchial epithelial cells (HBECs), and the inflammatory response and ferroptosis-related proteins SLC7A11 and GPX4 were assessed. The present research investigates the FGF10-mediated regulation of ferroptosis in PMLI mice models in vivo and HBECs in vitro. The results showed that FGF10 pretreatment reduced PM-mediated oxidative damage and ferroptosis in vivo and in vitro. Furthermore, FGF10 pretreatment led to reduced oxidative stress, decreased secretion of inflammatory mediators, and activation of the Nrf2-dependent antioxidant signaling. Additionally, silencing of Nrf2 using siRNA in the context of FGF10 treatment attenuated the effect on ferroptosis. Altogether, both in vivo and in vitro assessments confirmed that FGF10 protects against PMLI by inhibiting ferroptosis via the Nrf2 signaling. Thus, FGF10 can be used as a novel ferroptosis suppressor and a potential treatment target in PMLI.
Assuntos
Ferroptose , Fator 10 de Crescimento de Fibroblastos , Lesão Pulmonar , Camundongos Endogâmicos C57BL , Fator 2 Relacionado a NF-E2 , Estresse Oxidativo , Material Particulado , Transdução de Sinais , Ferroptose/efeitos dos fármacos , Fator 2 Relacionado a NF-E2/metabolismo , Animais , Material Particulado/toxicidade , Humanos , Transdução de Sinais/efeitos dos fármacos , Fator 10 de Crescimento de Fibroblastos/metabolismo , Fator 10 de Crescimento de Fibroblastos/genética , Camundongos , Estresse Oxidativo/efeitos dos fármacos , Lesão Pulmonar/induzido quimicamente , Lesão Pulmonar/metabolismo , Lesão Pulmonar/patologia , Lesão Pulmonar/prevenção & controle , Masculino , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/metabolismo , Linhagem Celular , Fosfolipídeo Hidroperóxido Glutationa Peroxidase/metabolismo , Fosfolipídeo Hidroperóxido Glutationa Peroxidase/genética , Modelos Animais de Doenças , Sistema y+ de Transporte de AminoácidosRESUMO
Numerous cases of lung injury caused by viral infection were reported during the coronavirus disease-19 pandemic. While there have been significant efforts to develop drugs that block viral infection and spread, the development of drugs to reduce or reverse lung injury has been a lower priority. This study aimed to identify compounds from a library of compounds that prevent viral infection that could reduce and prevent lung epithelial cell damage. We investigated the cytotoxicity of the compounds, their activity in inhibiting viral spike protein binding to cells, and their activity in reducing IL-8 production in lung epithelial cells damaged by amodiaquine (AQ). We identified N-(4-(4-methoxyphenoxy)-3-methylphenyl)-N-methylacetamide (MPoMA) as a non-cytotoxic inhibitor against viral infection and AQ-induced cell damage. MPoMA inhibited the expression of IL-8, IL-6, IL-1ß, and fibronectin induced by AQ and protected against AQ-induced morphological changes. However, MPoMA did not affect basal IL-8 expression in lung epithelial cells in the absence of AQ. Further mechanistic analysis confirmed that MPoMA selectively promoted the proteasomal degradation of inflammatory mediator p65, thereby reducing intracellular p65 expression and p65-mediated inflammatory responses. MPoMA exerted potent anti-inflammatory and protective functions in epithelial cells against LPS-induced acute lung injury in vivo. These findings suggest that MPoMA may have beneficial effects in suppressing viral infection and preventing lung epithelial cell damage through the degradation of p65 and inhibition of the production of inflammatory cytokines.
Assuntos
Células Epiteliais , Animais , Humanos , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/metabolismo , Células Epiteliais/patologia , Camundongos , Pulmão/patologia , Pulmão/efeitos dos fármacos , Pulmão/metabolismo , Fator de Transcrição RelA/metabolismo , Tratamento Farmacológico da COVID-19 , Células A549 , SARS-CoV-2/efeitos dos fármacos , COVID-19/prevenção & controle , Proteólise/efeitos dos fármacos , Lesão Pulmonar/prevenção & controle , Lesão Pulmonar/patologia , Lesão Pulmonar/metabolismo , Lesão Pulmonar/virologia , Masculino , Lesão Pulmonar Aguda/prevenção & controle , Lesão Pulmonar Aguda/patologia , Lesão Pulmonar Aguda/metabolismo , Acetamidas/farmacologiaRESUMO
BACKGROUND: Diabetes mellitus (DM) can aggravate lung ischemia-reperfusion (I/R) injury and is a significant risk factor for recipient mortality after lung transplantation. Metformin protects against I/R injury in a variety of organs. However, the effect of metformin on diabetic lung I/R injury remains unclear. Therefore, this study aimed to observe the effect and mechanism of metformin on lung I/R injury following lung transplantation in type 2 diabetic rats. METHODS: Sprague-Dawley rats were randomly divided into the following six groups: the control + sham group (CS group), the control + I/R group (CIR group), the DM + sham group (DS group), the DM + I/R group (DIR group), the DM + I/R + metformin group (DIRM group) and the DM + I/R + metformin + Compound C group (DIRMC group). Control and diabetic rats underwent the sham operation or left lung transplantation operation. Lung function, alveolar capillary permeability, inflammatory response, oxidative stress, necroptosis and the p-AMPK/AMPK ratio were determined after 24 h of reperfusion. RESULTS: Compared with the CIR group, the DIR group exhibited decreased lung function, increased alveolar capillary permeability, inflammatory responses, oxidative stress and necroptosis, but decreased the p-AMPK/AMPK ratio. Metformin improved the function of lung grafts, decreased alveolar capillary permeability, inflammatory responses, oxidative stress and necroptosis, and increased the p-AMPK/AMPK ratio. In contrast, the protective effects of metformin were abrogated by Compound C. CONCLUSIONS: Metformin attenuates lung I/R injury and necroptosis through AMPK pathway in type 2 diabetic lung transplant recipient rats.
Assuntos
Proteínas Quinases Ativadas por AMP , Diabetes Mellitus Experimental , Diabetes Mellitus Tipo 2 , Transplante de Pulmão , Metformina , Necroptose , Traumatismo por Reperfusão , Animais , Ratos , Proteínas Quinases Ativadas por AMP/efeitos dos fármacos , Proteínas Quinases Ativadas por AMP/metabolismo , Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/metabolismo , Hipoglicemiantes/farmacologia , Pulmão/patologia , Pulmão/efeitos dos fármacos , Pulmão/metabolismo , Lesão Pulmonar/prevenção & controle , Lesão Pulmonar/etiologia , Lesão Pulmonar/metabolismo , Metformina/farmacologia , Necroptose/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Ratos Sprague-Dawley , Traumatismo por Reperfusão/tratamento farmacológico , Traumatismo por Reperfusão/prevenção & controle , Transdução de Sinais/efeitos dos fármacosAssuntos
Ferroptose , Fator 2 Relacionado a NF-E2 , Material Particulado , Transdução de Sinais , Fator 2 Relacionado a NF-E2/metabolismo , Ferroptose/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Animais , Material Particulado/toxicidade , Humanos , Lesão Pulmonar/metabolismo , Lesão Pulmonar/induzido quimicamente , Lesão Pulmonar/prevenção & controle , Lesão Pulmonar/tratamento farmacológicoRESUMO
INTRODUCTION: Hemorrhagic shock (HS) poses a life-threatening condition with the lungs being one of the most susceptible organs to its deleterious effects. Extracellular cold-inducible RNA binding protein has emerged as a pivotal mediator of inflammation, and its release has been observed as a case of HS-induced tissue injury. Previous studies unveiled a promising engineered microRNA, designated PS-OMe miR130, which inhibits extracellular cold-inducible RNA binding protein, thereby safeguarding vital organs. In this study, we hypothesized that PS-OMe miR130 serves as a protective shield against HS-induced lung injury by curtailing the overzealous inflammatory immune response. METHODS: Hemorrhagic shock was induced in male C57BL6 mice by withdrawing blood via a femoral artery cannula to a mean arterial pressure of 30 mm Hg for 90 minutes. The mice were resuscitated with twice the shed blood volume with Ringer's lactate solution. They were then treated intravenously with either phosphate-buffered saline (vehicle) or 62.5 nmol PS-OMe miR130. At 4 hours later, blood and lungs were harvested. RESULTS: Following PS-OMe miR130 treatment in HS mice, a substantial decrease was observed in serum injury markers including aspartate aminotransferase, alanine transaminase, lactate dehydrogenase, and blood urea nitrogen. Serum interleukin (IL)-6 exhibited a similar reduction. In lung tissues, PS-OMe miR130 led to a significant decrease in the messenger RNA expressions of pro-inflammatory cytokines (IL-6, IL-1ß, and tumor necrosis factor α), chemokines (keratinocyte-derived chemokine and macrophage inflammatory protein 2), and an endothelial injury marker, E-selectin. PS-OMe miR130 also produced substantial inhibition of lung myeloperoxidase activity and resulted in a marked reduction in lung injury as evidenced by histological evaluation. This was further confirmed by the observation that PS-OMe miR130 significantly reduced the presence of lymphocyte antigen 6 family member G-positive neutrophils and terminal deoxynucleotidyl transferase dUTP nick end labeling-positive apoptotic cells. CONCLUSION: PS-OMe miR130 emerges as a potent safeguard against HS-induced lung injury by effectively inhibiting pro-inflammation and injuries, offering a promising therapeutic strategy in such critical clinical condition.