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BACKGROUND: The impact of chronic obstructive pulmonary disease (COPD) on outcome in perioperative organ injury (POI) has not yet been investigated sufficiently. METHODS: This retrospective cohort study analysed data of surgical patients with POI, namely delirium, stroke, acute myocardial infarction, acute respiratory distress syndrome, acute liver injury (ALI), or acute kidney injury (AKI), in Germany between 2015 and 2019. We compared in-hospital mortality, hospital length of stay (HLOS) and perioperative ventilation time (VT) in patients with and without COPD. RESULTS: We analysed the data of 1,642,377 surgical cases with POI of which 10.8% suffered from COPD. In-hospital mortality was higher (20.6% vs. 15.8%, p < 0.001) and HLOS (21 days (IQR, 12-34) vs. 16 days (IQR, 10-28), p < 0.001) and VT (199 h (IQR, 43-547) vs. 125 h (IQR, 32-379), p < 0.001) were longer in COPD patients. Within the POI examined, AKI was the most common POI (57.8%), whereas ALI was associated with the highest mortality (54.2%). Regression analysis revealed that COPD was associated with a slightly higher risk of in-hospital mortality (OR, 1.19; 95% CI:1.18-1.21) in patients with any POI. CONCLUSIONS: COPD in patients with POI is associated with higher mortality, longer HLOS and longer VT. Especially patients suffering from ALI are susceptible to the detrimental effects of COPD on adverse outcome.
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Mortalidad Hospitalaria , Complicaciones Posoperatorias , Enfermedad Pulmonar Obstructiva Crónica , Humanos , Estudios Retrospectivos , Masculino , Femenino , Alemania/epidemiología , Enfermedad Pulmonar Obstructiva Crónica/mortalidad , Enfermedad Pulmonar Obstructiva Crónica/epidemiología , Enfermedad Pulmonar Obstructiva Crónica/diagnóstico , Anciano , Mortalidad Hospitalaria/tendencias , Persona de Mediana Edad , Complicaciones Posoperatorias/mortalidad , Complicaciones Posoperatorias/epidemiología , Estudios de Cohortes , Anciano de 80 o más Años , Tiempo de Internación/estadística & datos numéricos , Tiempo de Internación/tendencias , Resultado del Tratamiento , Factores de RiesgoRESUMEN
Heat stroke is a perilous condition marked by severe hyperthermia and extensive multiorgan dysfunction, posing a considerable risk of mortality if not promptly identified and treated. Furthermore, the complex biological mechanisms underlying heat stroke-induced tissue and cell damage across organ systems remain incompletely understood. This knowledge gap has hindered the advancement of effective preventive and therapeutic strategies against this condition. In this narrative review, we synthesize key insights gained over a decade using a translational baboon model of heat stroke. By replicating heat stroke pathology in a non-human primate species that closely resembles humans, we have unveiled novel insights into the pathways of organ injury and cell death elicited by this condition. Here, we contextualize and integrate the lessons learned concerning heat stroke pathophysiology and recovery, areas that are inherently challenging to investigate directly in human subjects. We suggest novel research directions to advance the understanding of the complex mechanisms underlying cell death and organ injury. This may lead to precise therapeutic strategies that benefit individuals suffering from this debilitating condition.
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Golpe de Calor , Animales , Humanos , Papio , Golpe de Calor/terapia , FiebreRESUMEN
Doxorubicin (DOX) is a potent chemotherapeutic agent known for its multi-organ toxicity, especially in the heart, which limits its clinical application. The toxic side effects of DOX, including DNA damage, oxidative stress, mitochondrial dysfunction and cell apoptosis, are intricately linked to the involvement of nicotinamide adenine dinucleotide (NAD+). To assess the effectiveness of the NAD+ precursor nicotinamide mononucleotide (NMN) in counteracting the multi-organ toxicity of DOX, a mouse model was established through DOX administration, which led to significant reductions in NAD+ in tissues with evident injury, including the heart, liver and lungs. NMN treatment alleviated both multi-organ fibrosis and mortality in mice. Mechanistically, tissue fibrosis, macrophage infiltration and DOX-related cellular damage, which are potentially implicated in the development of multi-organ fibrosis, could be attenuated by NAD+ restoration. Our findings provide compelling evidence for the benefits of NMN supplementation in mitigating the adverse effects of chemotherapeutic drugs on multiple organs.
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Doxorrubicina , Fibrosis , Mononucleótido de Nicotinamida , Animales , Doxorrubicina/efectos adversos , Mononucleótido de Nicotinamida/farmacología , Ratones , Suplementos Dietéticos , Masculino , NAD/metabolismo , Estrés Oxidativo/efectos de los fármacos , Hígado/efectos de los fármacos , Hígado/metabolismo , Hígado/patologíaRESUMEN
Extracellular histones have been shown to act as DAMPs in a variety of inflammatory diseases. Moreover, they have the ability to induce cell death. In this study, we show that M6229, a low-anticoagulant fraction of unfractionated heparin (UFH), rescues rats that were challenged by continuous infusion of calf thymus histones at a rate of 25 mg histones/kg/h. Histone infusion by itself induced hepatic and homeostatic dysfunction characterized by elevated activity of hepatic enzymes (ASAT and ALAT) and serum lactate levels as well as by a renal dysfunction, which contributed to the significantly increased mortality rate. M6229 was able to restore normal levels of both hepatic and renal parameters at 3 and 9 mg M6229/kg/h and prevented mortality of the animals. We conclude that M6229 is a promising therapeutic agent to treat histone-mediated disease.
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Lesión Renal Aguda , Enfermedad Hepática Crónica Inducida por Sustancias y Drogas , Ratas , Animales , Histonas/metabolismo , Heparina/farmacología , Anticoagulantes/farmacología , Riñón/metabolismo , Lesión Renal Aguda/tratamiento farmacológicoRESUMEN
Food-grade titanium dioxide (E171) and zinc oxide nanoparticles (ZnO NPs) are common food additives for human consumption. We examined multi-organ toxicity of both compounds on Wistar rats orally exposed for 90 days. Rats were divided into three groups: (1) control (saline solution), (2) E171-exposed, and (3) ZnO NPs-exposed. Histological examination was performed with hematoxylin-eosin (HE) staining and transmission electron microscopy (TEM). Ceramide (Cer), 3-nitrotyrosine (NT), and lysosome-associated membrane protein 2 (LAMP-2) were detected by immunofluorescence. Relevant histological changes were observed: disorganization, inflammatory cell infiltration, and mitochondrial damage. Increased levels of Cer, NT, and LAMP-2 were observed in the liver, kidney, and brain of E171- and ZnO NPs-exposed rats, and in rat hearts exposed to ZnO NPs. E171 up-regulated Cer and NT levels in the aorta and heart, while ZnO NPs up-regulated them in the aorta. Both NPs increased LAMP-2 expression in the intestine. In conclusion, chronic oral exposure to metallic NPs causes multi-organ injury, reflecting how these food additives pose a threat to human health. Our results suggest how complex interplay between ROS, Cer, LAMP-2, and NT may modulate organ function during NP damage.
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Ceramidas , Nanopartículas del Metal , Ratas Wistar , Titanio , Óxido de Zinc , Animales , Óxido de Zinc/toxicidad , Titanio/toxicidad , Titanio/efectos adversos , Ratas , Ceramidas/metabolismo , Nanopartículas del Metal/química , Nanopartículas del Metal/toxicidad , Masculino , Administración Oral , Proteína 2 de la Membrana Asociada a los Lisosomas/metabolismo , Tirosina/análogos & derivados , Tirosina/metabolismo , Hígado/efectos de los fármacos , Hígado/metabolismo , Hígado/patología , Riñón/efectos de los fármacos , Riñón/metabolismo , Riñón/patologíaRESUMEN
Sepsis is a multiple organ dysfunction syndrome due to a dysregulated response to infection with unacceptably high mortality. Currently, no effective treatment exists for sepsis. IRG1/itaconate has been considered to play a protective role for various inflammatory diseases. In the present study, we explored the protective role and mechanisms of IRG1/itaconate on lipopolysaccharide (LPS)-induced multi-organ injury. The LPS-induced sepsis model was used. IRG1-/- and wild type mice were used to explore the protective role of IRG1/itaconate on multi-organ injury. GSDMD-/- mice were used to explore the effect of GSDMD-mediated pyroptosis on LPS-induced model. RAW264.7 cells and bone-marrow-derived macrophages (BMDMs) were used for in vitro studies. In vivo experiments, we found IRG1 deficiency aggravated LPS-induced multi-organ injury especially lung injury. 4-Octyl itaconate (4-OI), a derivative of itaconate, significantly ameliorated LPS-induced acute lung, liver, and kidney injury. Furthermore, IRG1/4-OI decreased serum interleukin-1ß (IL-1ß), IL-6, tumor necrosis factor-α (TNF-α) level, macrophage infiltration, and TUNEL-positive cells in lung and liver tissue. Western blot showed IRG1/itaconate decreased the expressions of p-ERK, p-P38, p-JNK, and p-P65 and increased the expression of Nrf2/HO-1 in lung tissue. Meanwhile, 4-OI inhibited the expression of GSDMD-N. In vitro experiments, 4-OI inhibited ROS production and promoted apoptosis under LPS stimulation in RAW264.7 cells. Furthermore, 4-OI inhibited nuclear factor-kappaB/mitogen-activated protein kinase pathways and GSDMD-medicated pyroptosis in BMDMs. Finally, we used GSDMD-/- mice to explore the effect of pyroptosis on LPS-induced multi-organ injury. The results showed that GSDMD deficiency significantly ameliorated lung injury. In conclusion, our data demonstrated that IRG1/itaconate protect against multi-organ injury via inhibiting inflammation response and GSDMD-indicated pyroptosis, which may be a promising agent for protecting against sepsis.
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Lesión Pulmonar , Sepsis , Succinatos , Animales , Ratones , Piroptosis , Gasderminas , Lipopolisacáridos/farmacología , Sepsis/tratamiento farmacológico , InmunidadRESUMEN
Haematitum is a commonly used mineral medicine. It is toxic, as recorded in the second volume of Chinese Materia Medica. Therefore, it should not be taken for a long time. In this study, the effects of Haematitum and calcined Haematitum on multiple organ injuries in mice were investigated, and the mechanism of the toxicity of the related organs was explored by metabolomics. The mice were randomly divided into the control group, Haematitum low-dose group(ZS-L group), Haematitum high-dose group(ZS-H group), and calcined Haematitum high-dose group(DZS-H group), with 12 mice in each group. Haematitum decoction was given by continuous intragastric administration for 10 days. Then the life situation was observed, and samples were taken to detect various indicators. The results showed that the ZS-H group showed obvious toxicity, with different degrees of toxicity damage in the intestinal tract,liver, spleen, and lung. ZS-L group had no toxic reaction. The toxicity of the DZS-H group was significantly reduced, and only the lung was damaged. Metabolomics technology was used to detect the lung tissue of mice in the control group and the ZS-H group, and a total of 15 kinds of significant difference metabolites were detected, mainly involved in choline metabolism in cancer, sphingolipid metabolism, and glycerophospholipid metabolism. Immunohistochemical results showed that the INSIG1 protein expression level in the lung tissue of mice in the ZS-H group was significantly higher than that in the control group. In summary, large doses and long-time use of Haematitum decoction will cause a variety of organ damage, and the same dose of calcined Haematitum is less toxic than Haematitum. In addition, a low dose of Haematitum has no obvious toxic effect. The dysfunction of lipid metabolic pathways such as sphingolipid and glycerophospholipid metabolism may be an important factor in Haematitum-induced pulmonary toxicity. This study provides a reference for further research on the mechanism of Haematitum pulmonary toxicity.
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Medicamentos Herbarios Chinos , Pulmón , Animales , Ratones , Medicamentos Herbarios Chinos/administración & dosificación , Masculino , Pulmón/efectos de los fármacos , Pulmón/metabolismo , Hígado/efectos de los fármacos , Hígado/metabolismo , Bazo/efectos de los fármacos , Bazo/metabolismo , Insuficiencia Multiorgánica/metabolismo , Insuficiencia Multiorgánica/etiología , Insuficiencia Multiorgánica/inducido químicamente , Femenino , Metabolómica , HumanosRESUMEN
The cell surface antigen CD14 is primarily understood to act as a co-receptor for toll-like receptors (TLRs) to activate innate immunity responses to pathogens and tissue injury in macrophages and monocytes. However, roles for CD14 are increasingly being uncovered in disease responses in epithelial and endothelial cells. Consistent with these broader functions, CD14 expression is altered in a variety of non-immune cell types in response to a several of disease states. Moreover, soluble CD14 activated by factors from both pathogens and tissue damage may initiate signalling in a variety of non-immune cells. This review examined the current understanding CD14 in innate immunity as well as its potential functions in nonimmune cells and associated human diseases.
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Células Endoteliales , Receptor Toll-Like 4 , Humanos , Células Endoteliales/metabolismo , Receptor Toll-Like 4/metabolismo , Lipopolisacáridos , Receptores Toll-Like , Macrófagos , Receptores de Lipopolisacáridos/metabolismoRESUMEN
Failure of the lung's endothelial barrier underlies lung injury, which causes the high mortality acute respiratory distress syndrome (ARDS). Multiple organ failure predisposes to the mortality, but mechanisms are poorly understood. Here, we show that mitochondrial uncoupling protein 2 (UCP2), a component of the mitochondrial inner membrane, plays a role in the barrier failure. Subsequent lung-liver cross talk mediated by neutrophil activation causes liver congestion. We intranasally instilled lipopolysaccharide (LPS). Then, we viewed the lung endothelium by real-time confocal imaging of the isolated, blood-perfused mouse lung. LPS caused alveolar-capillary transfer of reactive oxygen species and mitochondrial depolarization in lung venular capillaries. The mitochondrial depolarization was inhibited by transfection of alveolar Catalase and vascular knockdown of UCP2. LPS instillation caused lung injury as indicated by increases in bronchoalveolar lavage (BAL) protein content and extravascular lung water. LPS or Pseudomonas aeruginosa instillation also caused liver congestion, quantified by liver hemoglobin and plasma aspartate aminotransferase (AST) increases. Genetic inhibition of vascular UCP2 prevented both lung injury and liver congestion. Antibody-mediated neutrophil depletion blocked the liver responses, but not lung injury. Knockdown of lung vascular UCP2 mitigated P. aeruginosa-induced mortality. Together, these data suggest a mechanism in which bacterial pneumonia induces oxidative signaling to lung venular capillaries, known sites of inflammatory signaling in the lung microvasculature, depolarizing venular mitochondria. Successive activation of neutrophils induces liver congestion. We conclude that oxidant-induced UCP2 expression in lung venular capillaries causes a mechanistic sequence leading to liver congestion and mortality. Lung vascular UCP2 may present a therapeutic target in ARDS.NEW & NOTEWORTHY We report that mitochondrial injury in lung venular capillaries underlies barrier failure in pneumonia, and venular capillary uncoupling protein 2 (UCP2) causes neutrophil-mediated liver congestion. Using in situ imaging, we found that epithelial-endothelial transfer of H2O2 activates UCP2, depolarizing mitochondria in venular capillaries. The conceptual advance from our findings is that mitochondrial depolarization in lung capillaries mediates liver cross talk through circulating neutrophils. Pharmacologic blockade of UCP2 could be a therapeutic strategy for lung injury.
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Lesión Pulmonar , Neumonía Bacteriana , Síndrome de Dificultad Respiratoria , Ratones , Animales , Lipopolisacáridos/farmacología , Lipopolisacáridos/metabolismo , Capilares/metabolismo , Peróxido de Hidrógeno , Hígado/metabolismo , Mitocondrias/metabolismo , Síndrome de Dificultad Respiratoria/metabolismo , Lesión Pulmonar/metabolismo , Neumonía Bacteriana/metabolismo , Proteínas Mitocondriales/metabolismoRESUMEN
Macrophages represent the first lines of innate defense against pathogenic infections and are poised to undergo multiple forms of regulated cell death (RCD) upon infections or toxic stimuli, leading to multiple organ injury. Triptolide, an active compound isolated from Tripterygium wilfordii Hook F., possesses various pharmacological activities including anti-tumor and anti-inflammatory effects, but its applications have been hampered by toxic adverse effects. It remains unknown whether and how triptolide induces different forms of RCD in macrophages. In this study, we showed that triptolide exhibited significant cytotoxicity on cultured macrophages in vitro, which was associated with multiple forms of lytic cell death that could not be fully suppressed by any one specific inhibitor for a single form of RCD. Consistently, triptolide induced the simultaneous activation of pyroptotic, apoptotic and necroptotic hallmarks, which was accompanied by the co-localization of ASC specks respectively with RIPK3 or caspase-8 as well as their interaction with each other, indicating the formation of PANoptosome and thus the induction of PANoptosis. Triptolide-induced PANoptosis was associated with mitochondrial dysfunction and ROS production. PANoptosis was also induced by triptolide in mouse peritoneal macrophages in vivo. Furthermore, triptolide caused kidney and liver injury, which was associated with systemic inflammatory responses and the activation of hallmarks for PANoptosis in vivo. Collectively, our data reveal that triptolide induces PANoptosis in macrophages in vitro and exhibits nephrotoxicity and hepatotoxicity associated with induction of PANoptosis in vivo, suggesting a new avenue to alleviate triptolide's toxicity by harnessing PANoptosis.
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Diterpenos , Fenantrenos , Ratones , Animales , Apoptosis , Macrófagos/metabolismo , Diterpenos/efectos adversos , Diterpenos/metabolismo , Fenantrenos/toxicidad , Fenantrenos/metabolismo , Compuestos Epoxi/toxicidad , Compuestos Epoxi/metabolismoRESUMEN
OBJECTIVE(S): To evaluate the cross-sectional association of cardiovascular disease risk factors with left atrial (LA) size and function among healthy youth, aged 11-18 years, with a wide range of blood pressures (BPs). STUDY DESIGN: Echocardiographic images of youth enrolled in the Study of High Blood Pressure in Pediatrics: Adult Hypertension Onset in Youth study were analyzed for LA measurements. The association of casual BP, ambulatory BP, and other cardiovascular disease risk factors with LA size and function were determined using descriptive statistics and multivariable regression. Regression models adjusting for age, sex, race, and body mass index z score determined the independent association between ambulatory systolic BP indices (mean systolic BP/50th %ile systolic BP) and BP phenotypes with LA outcomes while exploratory analyses investigated for additional predictors of LA outcomes. RESULTS: The study population consisted of 347 youth: median age 15.7 years, 60% male and 40% non-White. Greater-risk casual systolic BP groups had worse cardiometabolic profiles but no differences in LA size and function. Each 0.1 increase in ambulatory systolic BP day or night index was associated with a 9.9 mL/m2 increase in LA volume/body surface area (LAV/BSA; 95th% CI 2.8-17.0, P = .006) and a 6.8 mL/m2 increase in LAV/BSA (95th% CI 0.8-12.8, P = .03), respectively. Ambulatory hypertension was associated with greater odds of abnormal LAV/BSA, defined as >75th %ile (2014 ambulatory BP monitoring criteria: OR 3.2 [95th% CI 1.4-7.2; P = .002]; 2022 ambulatory BP monitoring criteria: OR 2.1 [95th% CI 1.0-4.1; P = .008]). CONCLUSIONS: Increasing ambulatory systolic BP and ambulatory hypertension are independently associated with LAV/BSA.
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Fibrilación Atrial , Hipertensión , Humanos , Masculino , Adolescente , Niño , Femenino , Presión Sanguínea/fisiología , Estudios Transversales , Hipertensión/epidemiología , Hipertensión/complicaciones , Atrios Cardíacos/diagnóstico por imagen , Monitoreo Ambulatorio de la Presión ArterialRESUMEN
Magnesium sulfate reduces the risk for eclamptic seizures antepartum, intrapartum, and in the immediate postpartum period, however, there are no studies that have evaluated the benefits and risks of magnesium sulfate among women with late postpartum severe hypertension only. Juxtaposed on this clinical uncertainty is the increased incidence of severe hypertension owing to a rise in pregnancies complicated by advanced maternal age, obesity, chronic hypertension, diabetes, and recent protocols for intensive monitoring of blood pressure in the postpartum period. These factors have led to a significant increase in postpartum presentations for the evaluation and management of severe hypertension, in some cases leading to postpartum readmissions for administration of antihypertensive therapy and magnesium sulfate without data demonstrating clear clinical benefit. Postpartum readmissions can have several negative consequences, including interfering with early bonding with a newborn, breastfeeding, and use of scarce healthcare resources. In addition, magnesium sulfate is associated with risks for serious cardiorespiratory depression and bothersome side effects and can delay determining the optimal antihypertensive regimen, which is typically the most pressing clinical need during postpartum presentations of late-postpartum severe hypertension. Eclampsia that occurs more than 48 hours after delivery is rare (constitutes 16% of all cases of eclampsia) and is most commonly preceded by headaches or other cerebral symptoms. In this commentary, we propose an approach to evaluating and managing patients with late postpartum severe hypertension aimed at identifying those women at highest risk for end-organ injury. We recommend that the short- and long-term focus for all patients with severe hypertension should be the optimal management of blood pressures with a goal of close outpatient monitoring when logistically feasible and clinically appropriate. We suggest reserving magnesium sulfate therapy for the subset of patients with neurologic symptoms who may be at highest risk for an eclamptic seizure.
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Eclampsia , Hipertensión , Preeclampsia , Embarazo , Recién Nacido , Humanos , Femenino , Sulfato de Magnesio/uso terapéutico , Eclampsia/diagnóstico , Antihipertensivos/uso terapéutico , Toma de Decisiones Clínicas , Incertidumbre , Periodo Posparto , Convulsiones/tratamiento farmacológico , Convulsiones/etiología , Hipertensión/tratamiento farmacológico , Hipertensión/epidemiologíaRESUMEN
INTRODUCTION: Trauma patients with blunt abdominal solid organ injuries are at high risk for venous thromboembolism (VTE), but the optimal time to safely administer chemical thromboprophylaxis is controversial, especially for patients who are managed nonoperatively due to increased risk of hemorrhage. We sought to compare failure of nonoperative management (NOM) and VTE events based on timing of chemical thromboprophylaxis initiation. METHODS: A systematic review was conducted in PubMed and Embase databases. Studies were included if they evaluated timing of initiation of chemical thromboprophylaxis in trauma patients who underwent NOM of blunt solid organ injuries. Outcomes included failure of NOM and incidence of VTE. A random-effects meta-analysis was performed comparing patients who received late (>48 h) versus early thromboprophylaxis initiation. RESULTS: Twelve retrospective cohort studies, comprising 21,909 patients, were included. Three studies, including 6375 patients, provided data on adjusted outcomes. Pooled adjusted analysis demonstrated no difference in failure of NOM in patients receiving late versus early thromboprophylaxis (odds ratio [OR] 0.92, 95% confidence interval [CI]:0.4-2.14). When including all unadjusted studies, even those at high risk of bias, there remained no difference in failure of NOM (OR 1.16, 95% CI:0.72-1.86). In the adjusted analysis for VTE events, which had 6259 patients between two studies, patients receiving late chemical thromboprophylaxis had a higher risk of VTE compared with those who received early thromboprophylaxis (OR 1.89, 95% CI:1.15-3.12). CONCLUSIONS: Based on current observational evidence, initiation of prophylaxis before 48 h is associated with lower VTE rates without higher risk of failure of NOM.
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Traumatismos Abdominales , Tromboembolia Venosa , Heridas no Penetrantes , Humanos , Tromboembolia Venosa/etiología , Tromboembolia Venosa/prevención & control , Tromboembolia Venosa/epidemiología , Anticoagulantes/uso terapéutico , Estudios Retrospectivos , Heridas no Penetrantes/complicaciones , Heridas no Penetrantes/terapia , Traumatismos Abdominales/complicacionesRESUMEN
Activation of NLR family pyrin domain-containing 3 (NLRP3) inflammasome plays important role in defending against infections, but its aberrant activation is causally linked to many inflammatory diseases, thus being a therapeutic target for these diseases. Theaflavin, one major ingredient of black tea, exhibits potent anti-inflammatory and anti-oxidative activities. In this study, we investigated the therapeutic effects of theaflavin against NLRP3 inflammasome activation in macrophages in vitro and in animal models of related diseases. We showed that theaflavin (50, 100, 200 µM) dose-dependently inhibited NLRP3 inflammasome activation in LPS-primed macrophages stimulated with ATP, nigericin or monosodium urate crystals (MSU), evidenced by reduced release of caspase-1p10 and mature interleukin-1ß (IL-1ß). Theaflavin treatment also inhibited pyroptosis as shown by decreased generation of N-terminal fragment of gasdermin D (GSDMD-NT) and propidium iodide incorporation. Consistent with these, theaflavin treatment suppressed ASC speck formation and oligomerization in macrophages stimulated with ATP or nigericin, suggesting reduced inflammasome assembly. We revealed that theaflavin-induced inhibition on NLRP3 inflammasome assembly and pyroptosis resulted from ameliorated mitochondrial dysfunction and reduced mitochondrial ROS production, thereby suppressing interaction between NLRP3 and NEK7 downstream of ROS. Moreover, we showed that oral administration of theaflavin significantly attenuated MSU-induced mouse peritonitis and improved the survival of mice with bacterial sepsis. Consistently, theaflavin administration significantly reduced serum levels of inflammatory cytokines including IL-1ß and attenuated liver inflammation and renal injury of mice with sepsis, concomitant with reduced generation of caspase-1p10 and GSDMD-NT in the liver and kidney. Together, we demonstrate that theaflavin suppresses NLRP3 inflammasome activation and pyroptosis by protecting mitochondrial function, thus mitigating acute gouty peritonitis and bacterial sepsis in mice, highlighting a potential application in treating NLRP3 inflammasome-related diseases.
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Gota , Peritonitis , Sepsis , Ratones , Animales , Inflamasomas/metabolismo , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Especies Reactivas de Oxígeno , Nigericina/uso terapéutico , Peritonitis/tratamiento farmacológico , Antioxidantes/uso terapéutico , Sepsis/complicaciones , Sepsis/tratamiento farmacológico , Caspasas , Adenosina Trifosfato , Interleucina-1beta/metabolismoRESUMEN
INSTRUCTION: High mobility group box 1 (HMGB1) is a pro-inflammatory cytokine that reportedly causes kidney injury and other organ damage in rodent acute kidney injury (AKI) models. However, it remains unclear whether HMGB1 is associated with clinical AKI and related outcomes. This study aimed to evaluate the association with HMGB1 and prognosis of AKI requiring continuous renal replacement therapy (CRRT). METHODS: AKI patients treated with CRRT in our intensive care unit were enrolled consecutively during 2013-2016. Plasma HMGB1 was measured on initiation. Classic initiation was defined as presenting at least one of the following conventional indications: hyperkalemia (K ≥6.5 mEq/L), severe acidosis (pH <7.15), uremia (UN >100 mg/dL), and diuretics-resistant pulmonary edema. Early initiation was defined as presenting no conventional indications. The primary outcome was defined as 90-day mortality. RESULTS: A total of 177 AKI patients were enrolled in this study. HMGB1 was significantly associated with the primary outcome (hazard ratio, 1.06; 95% CI, 1.04-1.08). When the patients were divided into two-by-two groups by the timing of CRRT initiation and the HMBG1 cutoff value obtained by receiver operating curve (ROC) analysis, the high HMGB1 group (>10 ng/mL) with classic initiation was significantly associated with the primary outcome compared with the others, even after adjusting for other factors including the nonrenal serial organ failure assessment (SOFA) score. CONCLUSION: HMGB1 was associated with 90-day mortality in AKI patients requiring CRRT. Notably, the highest mortality was observed in the high HMGB1 group with classic initiation. These findings suggest that CRRT should be considered for AKI patients with high HMGB1, regardless of the conventional indications.
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Lesión Renal Aguda , Terapia de Reemplazo Renal Continuo , Proteína HMGB1 , Humanos , Pronóstico , Terapia de Reemplazo Renal , Unidades de Cuidados Intensivos , Estudios RetrospectivosRESUMEN
PURPOSE: This study sought to explore whether the experience level of the first assistant surgeon influences perioperative organ injuries (ureteral, bladder, and intestinal injuries) in patients undergoing total laparoscopic hysterectomy (TLH) for benign diseases. We defined an experienced surgeon as a surgeon certified by the Skill Qualification Committee of the Japan Society of Gynecologic and Obstetric Endoscopy and Minimally Invasive Therapy or a surgeon with equivalent surgical skills. METHODS: We reviewed our surgical registry database of TLH for benign indications between 2014 and 2020 and only selected cases performed by an experienced primary surgeon. Patients were divided into two groups based on the experience level of the first assistant. Inverse probability of treatment weighting by propensity score, which was adjusted for patient and procedure characteristics, was used to examine differences in perioperative organ injuries according to the experience level of the first assistant. RESULTS: Among 1682 patients who underwent TLH, 18 organ injuries were found (0.83%). In the propensity score inverse probability of treatment weighting models, less experience of the first assistant had no significant impact on the occurrence of perioperative organ injuries (p = 0.348). CONCLUSION: In TLH for benign indications at our hospital, given an experienced primary surgeon, the inclusion of a less experienced first assistant does not negatively affect the occurrence of perioperative organ injuries.
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Laparoscopía , Cirujanos , Humanos , Femenino , Laparoscopía/efectos adversos , Laparoscopía/métodos , Estudios Retrospectivos , Complicaciones Posoperatorias/epidemiología , Histerectomía/efectos adversos , Histerectomía/métodosRESUMEN
Tightly controlled inflammation is an indispensable mechanism in the maintenance of cellular and organismal homeostasis in living organisms. However, aberrant inflammation is detrimental and has been suggested as a key contributor to organ injury with different etiologies. Substance P (SP) is a neuropeptide with a robust effect on inflammation. The proinflammatory effects of SP are achieved by activating its functional receptors, namely the neurokinin 1 receptor (NK1R) receptor and mas-related G protein-coupled receptors X member 2 (MRGPRX2) and its murine homolog MRGPRB2. Upon activation, the receptors further signal to several cellular signaling pathways involved in the onset, development, and progression of inflammation. Therefore, excessive SP-NK1R or SP-MRGPRX2/B2 signals have been implicated in the pathogenesis of inflammation-associated organ injury. In this review, we summarize our current knowledge of SP and its receptors and the emerging roles of the SP-NK1R system and the SP-MRGPRX2/B2 system in inflammation and injury in multiple organs resulting from different pathologies. We also briefly discuss the prospect of developing a therapeutic strategy for inflammatory organ injury by disrupting the proinflammatory actions of SP via pharmacological intervention.
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Receptores de Neuroquinina-1 , Sustancia P , Ratones , Animales , Sustancia P/metabolismo , Receptores de Neuroquinina-1/metabolismo , Inflamación/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Receptores de Neuropéptido/metabolismoRESUMEN
BACKGROUND AND OBJECTIVE: Umbilical venous catheters (UVC) and peripherally inserted central catheters (PICC) are commonly used in preterm infants but have been associated with a number of serious complications. We performed a survey in Austria and Germany to assess the use of UVCs and PICCs in preterm infants with a birth weight <â¯1250â¯g and associated rates of catheter-related adverse events. METHODS: Electronic survey of participating centers of the NeoVitaA trial. Main outcome parameter was the reported rates of UVC- and PICC-associated complications (infection, thrombosis, emboli, organ injury, arrhythmia, dislocation, miscellaneous). RESULTS: In total, 20 neonatal intensive care units (NICU) providing maximal intensive care in Austria and Germany (level I) were contacted, with a senior neonatologist response rate of 12/20 (60%). The reported rates for UVC with a dwell time of 1-10 days were bacterial infection: 4.2⯱ 3.4% (range 0-10%); thrombosis: 7.3⯱ 7.1% (0-20%); emboli: 0.9⯱ 2.0% (0-5%); organ injury: 1.1⯱ 1.9% (0-5%); cardiac arrhythmia: 2.2⯱ 2.5% (0-5%); and dislocation: 5.4⯱ 8.7% (0-30%); and for PICCs with a dwell time of 1-14 days bacterial infection: 15.0⯱ 3.4% (range 2.5-30%); thrombosis; 4.3⯱ 3.5% (0-10%); emboli: 0.8⯱ 1.6% (0-5%); organ injury: 1.5⯱ 2.3% (0-5%); cardiac arrhythmia: 1.5⯱ 2.3% (0-5%), and dislocation: 8.5⯱ 4.6% (0-30%). CONCLUSION: The catheter-related complication rates reported in this survey differed between UVCs and PICCs and were higher than those reported in the literature. To generate more reliable data on this clinically important issue, we plan to perform a large prospective multicenter randomized controlled trial investigating the non-inferiority of a prolonged UVC dwell time (up to 10 days) against the early change (up to 5 days) to a PICC.
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Infecciones Bacterianas , Cateterismo Venoso Central , Trombosis , Lactante , Recién Nacido , Humanos , Recien Nacido Prematuro , Peso al Nacer , Cateterismo Venoso Central/efectos adversos , Cateterismo Venoso Central/métodos , Estudios Prospectivos , Austria , Estudios Retrospectivos , Catéteres , Infecciones Bacterianas/etiología , Trombosis/epidemiología , Trombosis/etiología , Recién Nacido de muy Bajo PesoRESUMEN
CONTEXT: Sepsis is a systemic inflammatory response caused by infection, with high morbidity and mortality. Omega-3 polyunsaturated fatty acids (ω-3 PUFAs) have reported biological activities. OBJECTIVE: This study explored the signaling pathways through which ω-3 PUFAs protect against sepsis-induced multiorgan failure. MATERIALS AND METHODS: Septic Sprague-Dawley (SD) rat model was established by the cecum ligation perforation (CLP) method. Rats were divided into control, sham, model, parenteral ω-3 PUFAs (0.5 g/kg) treatment, ω-3 PUFAs (0.5 g/kg) + AMPK inhibitor Compound C (30 mg/kg) treatment, and ω-3 PUFAs (0.5 g/kg) + mTOR activator MHY1485 (10 mg/kg) treatment groups. The serum inflammatory cytokines were measured using ELISA. Organ damage-related markers cTnI, CK, CK-MB, Cr, BUN, ALT, and AST were measured using an automated chemical analyzer. The AMPK/mTOR pathway in liver, kidney, and myocardial tissues was detected using western blot and qRT-PCR methods. RESULTS: CLP treatment enhanced the secretion of pro-inflammatory cytokines and multi-organ related markers, along with increased p-AMPK/AMPK ratio (from 0.47 to 0.87) and decreased p-mTOR/mTOR ratio (from 0.33 to 0.12) in rats. The inflammation response and multi-organ injury induced by CLP treatment could be partially counteracted by 0.5 g/kg parenteral ω-3 PUFA treatment. The activated AMPK/mTOR pathway in CLP-induced rats was further promoted. Finally, Compound C and MHY1485 could reverse the effects of parenteral ω-3 PUFA treatment on sepsis rats. DISCUSSION AND CONCLUSION: ω-3 PUFAs ameliorated sepsis development by activating the AMPK/mTOR pathway, serving as a potent therapeutic agent for sepsis. Further in vivo studies may validate potential clinical use.
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Ácidos Grasos Omega-3 , Sepsis , Ratas , Animales , Ratas Sprague-Dawley , Proteínas Quinasas Activadas por AMP/metabolismo , Ácidos Grasos Omega-3/farmacología , Ácidos Grasos Omega-3/uso terapéutico , Serina-Treonina Quinasas TOR , Citocinas/metabolismo , Sepsis/tratamiento farmacológicoRESUMEN
Subarachnoid hemorrhage (SAH) is a life-threatening condition, and although its two main complications-cerebral vasospasm (CVS)/delayed cerebral ischemia (DCI) and early brain injury (EBI)-have been widely studied, prognosis has not improved over time. The sympathetic nerve (SN) system is important for the regulation of cardiovascular function and is closely associated with cerebral vessels and the regulation of cerebral blood flow and cerebrovascular function; thus, excessive SN activation leads to a rapid breakdown of homeostasis in the brain. In the hyperacute phase, patients with SAH can experience possibly lethal conditions that are thought to be associated with SN activation (catecholamine surge)-related arrhythmia, neurogenic pulmonary edema, and irreversible injury to the hypothalamus and brainstem. Although the role of the SN system in SAH has long been investigated and considerable evidence has been collected, the exact pathophysiology remains undetermined, mainly because the relationships between the SN system and SAH are complicated, and many SN-modulating factors are involved. Thus, research concerning these relationships needs to explore novel findings that correlate with the relevant concepts based on past reliable evidence. Here, we explore the role of the central SN (CSN) system in SAH pathophysiology and provide a comprehensive review of the functional CSN network; brain injury in hyperacute phase involving the CSN system; pathophysiological overlap between the CSN system and the two major SAH complications, CVS/DCI and EBI; CSN-modulating factors; and SAH-related extracerebral organ injury. Further studies are warranted to determine the specific roles of the CSN system in the brain injuries associated with SAH.