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Importance: In adults undergoing hip fracture surgery, regional anesthesia may reduce postoperative delirium, but there is uncertainty about its effectiveness. Objective: To investigate, in older adults undergoing surgical repair for hip fracture, the effects of regional anesthesia on the incidence of postoperative delirium compared with general anesthesia. Design, Setting, and Participants: A randomized, allocation-concealed, open-label, multicenter clinical trial of 950 patients, aged 65 years and older, with or without preexisting dementia, and a fragility hip fracture requiring surgical repair from 9 university teaching hospitals in Southeastern China. Participants were enrolled between October 2014 and September 2018; 30-day follow-up ended November 2018. Interventions: Patients were randomized to receive either regional anesthesia (spinal, epidural, or both techniques combined with no sedation; n = 476) or general anesthesia (intravenous, inhalational, or combined anesthetic agents; n = 474). Main Outcomes and Measures: Primary outcome was incidence of delirium during the first 7 postoperative days. Secondary outcomes analyzed in this article include delirium severity, duration, and subtype; postoperative pain score; length of hospitalization; 30-day all-cause mortality; and complications. Results: Among 950 randomized patients (mean age, 76.5 years; 247 [26.8%] male), 941 were evaluable for the primary outcome (6 canceled surgery and 3 withdrew consent). Postoperative delirium occurred in 29 (6.2%) in the regional anesthesia group vs 24 (5.1%) in the general anesthesia group (unadjusted risk difference [RD], 1.1%; 95% CI, -1.7% to 3.8%; P = .48; unadjusted relative risk [RR], 1.2 [95% CI, 0.7 to 2.0]; P = .57]). Mean severity score of delirium was 23.0 vs 24.1, respectively (unadjusted difference, -1.1; 95% CI, -4.6 to 3.1). A single delirium episode occurred in 16 (3.4%) vs 10 (2.1%) (unadjusted RD, 1.1%; 95% CI, -1.7% to 3.9%; RR, 1.6 [95% CI, 0.7 to 3.5]). Hypoactive subtype in 11 (37.9%) vs 5 (20.8%) (RD, 11.5; 95% CI, -11.0% to 35.7%; RR, 2.2 [95% CI, 0.8 to 6.3]). Median worst pain score was 0 (IQR, 0 to 20) vs 0 (IQR, 0 to 10) (difference 0; 95% CI, 0 to 0). Median length of hospitalization was 7 days (IQR, 5 to 10) vs 7 days (IQR, 6 to 10) (difference 0; 95% CI, 0 to 0). Death occurred in 8 (1.7%) vs 4 (0.9%) (unadjusted RD, -0.8%; 95% CI, -2.2% to 0.7%; RR, 2.0 [95% CI, 0.6 to 6.5]). Adverse events were reported in 106 episodes in the regional anesthesia group and 102 in the general anesthesia group; the most frequently reported adverse events were nausea and vomiting (47 [44.3%] vs 34 [33.3%]) and postoperative hypotension (13 [12.3%] vs 10 [9.8%]). Conclusions and Relevance: In patients aged 65 years and older undergoing hip fracture surgery, regional anesthesia without sedation did not significantly reduce the incidence of postoperative delirium compared with general anesthesia. Trial Registration: ClinicalTrials.gov Identifier: NCT02213380.
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Anestesia por Condução/efeitos adversos , Anestesia Geral/efeitos adversos , Delírio do Despertar/etiologia , Fraturas do Quadril/cirurgia , Complicações Pós-Operatórias/etiologia , Idoso , Idoso de 80 Anos ou mais , Delírio do Despertar/epidemiologia , Delírio do Despertar/prevenção & controle , Feminino , Humanos , Incidência , Masculino , Complicações Pós-Operatórias/epidemiologia , Método Simples-CegoRESUMO
Acute respiratory distress syndrome (ARDS), a common and fatal clinical condition, is characterized by the destruction of epithelium and augmented permeability of the alveolar-capillary barrier. Resolvin conjugates in tissue regeneration 1 (RCTR1) is an endogenous lipid mediator derived from docosahexaenoic acid , exerting proresolution effects in the process of inflammation. In our research, we evaluated the role of RCTR1 in alveolar fluid clearance (AFC) in lipopolysaccharide-induced ARDS/acute lung injury (ALI) rat model. Rats were injected with RCTR1 (5 µg/kg) via caudal veins 8 hours after lipopolysaccharide (LPS) (14 mg/kg) treatment, and then AFC was estimated after 1 hour of ventilation. Primary type II alveolar epithelial cells were incubated with LPS (1 ug/ml) with or without RCTR1 (10 nM) for 8 hours. Our results showed that RCTR1 significantly enhanced the survival rate, promoted the AFC, and alleviated LPS-induced ARDS/ALI in vivo. Furthermore, RCTR1 remarkably elevated the protein expression of sodium channels and Na, K-ATPase and the activity of Na, K-ATPase in vivo and in vitro. Additionally, RCTR1 also decreased neural precursor cell expressed developmentally downregulated 4-2 (Nedd4-2) level via upregulating Ser473-phosphorylated-Akt expression. Besides this, inhibitors of receptor for lipoxin A4 (ALX), cAMP, and phosphatidylinositol 3-kinase (PI3K) (BOC-2, KH-7, and LY294002) notably inhibited the effects of RCTR1 on AFC. In summary, RCTR1 enhances the protein levels of sodium channels and Na, K-ATPase and the Na, K-ATPase activity to improve AFC in ALI through ALX/cAMP/PI3K/Nedd4-2 pathway, suggesting that RCTR1 may become a therapeutic drug for ARDS/ALI. SIGNIFICANCE STATEMENT: RCTR1, an endogenous lipid mediator, enhanced the rate of AFC to accelerate the resolution of inflammation in the LPS-induced murine lung injury model. RCTR1 upregulates the expression of epithelial sodium channels (ENaCs) and Na, K-ATPase in vivo and in vitro to accelerate the AFC. The efficacy of RCTR1 on the ENaC and Na, K-ATPase level was in an ALX/cAMP/PI3K/Nedd4-2-dependent manner.
Assuntos
Lesão Pulmonar Aguda/metabolismo , Ácidos Docosa-Hexaenoicos/farmacologia , Agonistas do Canal de Sódio Epitelial/farmacologia , Canais Epiteliais de Sódio/metabolismo , Alvéolos Pulmonares/metabolismo , ATPase Trocadora de Sódio-Potássio/metabolismo , Lesão Pulmonar Aguda/induzido quimicamente , Lesão Pulmonar Aguda/tratamento farmacológico , Animais , Ácidos Docosa-Hexaenoicos/análogos & derivados , Ácidos Docosa-Hexaenoicos/uso terapêutico , Lipopolissacarídeos/toxicidade , Masculino , Alvéolos Pulmonares/efeitos dos fármacos , Ratos , Ratos Sprague-DawleyRESUMO
Acute respiratory distress syndrome (ARDS) is a fatal disease characterized by excessive infiltration of inflammatory cells. MCTR1 is an endogenously pro-resolution lipid mediator. We tested the hypothesis that MCTR1 accelerates inflammation resolution through resident M2 alveolar macrophage polarization. The mice received MCTR1 via intraperitoneal administration 3 days after LPS stimulation, and then, the bronchoalveolar lavage (BAL) fluid was collected 24 hours later to measure the neutrophil numbers. Flow cytometry was used to sort the resident and recruited macrophages. Post-treatment with MCTR1 offered dramatic benefits in the resolution phase of LPS-induced lung injury, including decreased neutrophil numbers, reduced BAL fluid protein and albumin concentrations and reduced histological injury. In addition, the expression of the M2 markers Arg1, FIZZ1, Remlα, CD206 and Dectin-1 was increased on resident macrophages in the LPS + MCTR1 group. Resident macrophage depletion abrogated the therapeutic effects of MCTR1, and reinjection of the sorted resident macrophages into the lung decreased neutrophil numbers. Finally, treatment with MCTR1 increased STAT6 phosphorylation. The STAT6 inhibitor AS1517499 abolished the beneficial effects of MCTR1. In conclusion, MCTR1 promotes resident M2 alveolar macrophage polarization via the STAT6 pathway to accelerate resolution of LPS-induced lung injury.
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Lesão Pulmonar Aguda/induzido quimicamente , Lesão Pulmonar Aguda/metabolismo , Polaridade Celular/fisiologia , Lipopolissacarídeos/farmacologia , Macrófagos Alveolares/metabolismo , Proteínas Oncogênicas/metabolismo , Fator de Transcrição STAT6/metabolismo , Animais , Líquido da Lavagem Broncoalveolar , Inflamação/metabolismo , Pulmão/metabolismo , Ativação de Macrófagos/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Neutrófilos/metabolismo , Síndrome do Desconforto Respiratório/metabolismo , Transdução de Sinais/fisiologiaRESUMO
Maresin Conjugates in Tissue Regeneration 1 (MCTR1) is a newly identified macrophage-derived sulfido-conjugated mediator that stimulates the resolution of inflammation. This study assessed the role of MCTR1 in alveolar fluid clearance (AFC) in a rat model of acute lung injury (ALI) induced by lipopolysaccharide (LPS). Rats were intravenously injected with MCTR1 at a dose of 200 ng/rat, 8 hours after administration of 14 mg/kg LPS. The level of AFC was then determined in live rats. Primary rat ATII (Alveolar Type II) epithelial cells were also treated with MCTR1 (100 nmol/L) in a culture medium containing LPS for 8 hours. MCTR1 treatment improved AFC (18.85 ± 2.07 vs 10.11 ± 1.08, P < .0001) and ameliorated ALI in rats. MCTR1 also significantly promoted AFC by up-regulating epithelial sodium channel (ENaC) and Na+ -K+ -adenosine triphosphatase (Na, K-ATPase) expressions in vivo. MCTR1 also activated Na, K-ATPase and elevated phosphorylated-Akt (P-Akt) by up-regulating the expression of phosphorylated Nedd4-2 (P-Nedd4-2) in vivo and in vitro. However, BOC-2 (ALX inhibitor), KH7 (cAMP inhibitor) and LY294002 (PI3K inhibitor) abrogated the improved AFC induced by MCTR1. Based on the findings of this study, MCTR1 may be a novel therapeutic approach to improve reabsorption of pulmonary oedema during ALI/acute respiratory distress syndrome (ARDS).
Assuntos
Lesão Pulmonar Aguda/terapia , Células Epiteliais Alveolares/efeitos dos fármacos , Proteínas de Ciclo Celular/farmacologia , Proteínas Oncogênicas/farmacologia , Alvéolos Pulmonares/efeitos dos fármacos , Lesão Pulmonar Aguda/induzido quimicamente , Lesão Pulmonar Aguda/etiologia , Lesão Pulmonar Aguda/genética , Células Epiteliais Alveolares/metabolismo , Animais , Proteínas de Ciclo Celular/genética , Canais Epiteliais de Sódio/genética , Regulação da Expressão Gênica/efeitos dos fármacos , Lipopolissacarídeos/toxicidade , Proteínas Oncogênicas/genética , Fosfatidilinositol 3-Quinases/genética , Fosforilação , Alvéolos Pulmonares/metabolismo , Ratos , Transdução de Sinais/efeitos dos fármacos , ATPase Trocadora de Sódio-Potássio/genéticaRESUMO
Acute respiratory distress syndrome (ARDS) is a lethal clinical syndrome characterized by damage of the epithelial barriers and accumulation of pulmonary edema fluid. Protectin conjugates in tissue regeneration 1 (PCTR1), an endogenously produced lipid mediator, are believed to exert anti-inflammatory and pro-resolution effects. PCTR1 (1 µg/kg) was injected at 8 hr after lipopolysaccharide (LPS; 14 mg/kg) administration, and the rate of pulmonary fluid clearance was measured in live rats at 1 hr after PCTR1 treatment. The primary type II alveolar epithelial cells were cultured with PCTR1 (10 nmol/ml) and LPS (1 µg/ml) for 8 hr. PCTR1 effectively improved pulmonary fluid clearance and ameliorated morphological damage and reduced inflammation of lung tissue, as well as improved the survival rate in the LPS-induced acute lung injury (ALI) model. Moreover, PCTR1 markedly increased sodium channel expression as well as Na, K-ATPase expression and activity in vivo and in vitro. In addition, PCTR1i also upregulated the expression of LYVE-1 in vivo. Besides that, BOC-2, HK7, and LY294002 blocked the promoted effect of PCTR1 on pulmonary fluid clearance. Taken together, PCTR1 upregulates sodium channels' expression via activating the ALX/cAMP/P-Akt/Nedd4-2 pathway and increases Na, K-ATPase expression and activity to promote alveolar fluid clearance. Moreover, PCTR1 also promotes the expression of LYVE-1 to recover the lymphatic drainage resulting in the increase of lung interstitial fluid clearance. In summary, these results highlight a novel systematic mechanism for PCTR1 in pulmonary edema fluid clearance after ALI/ARDS, suggesting its potential role in a therapeutic approach for ALI/ARDS.
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Lesão Pulmonar Aguda/tratamento farmacológico , Antígenos CD59/farmacologia , Canais Epiteliais de Sódio/genética , Edema Pulmonar/tratamento farmacológico , Síndrome do Desconforto Respiratório/tratamento farmacológico , Lesão Pulmonar Aguda/induzido quimicamente , Lesão Pulmonar Aguda/patologia , Células Epiteliais Alveolares/efeitos dos fármacos , Células Epiteliais Alveolares/patologia , Animais , Anti-Inflamatórios/farmacologia , Líquidos Corporais/efeitos dos fármacos , Antígenos CD59/química , Antígenos CD59/genética , Inibidor p16 de Quinase Dependente de Ciclina , Modelos Animais de Doenças , Ácidos Docosa-Hexaenoicos/química , Ácidos Docosa-Hexaenoicos/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Lipopolissacarídeos/toxicidade , Pulmão/efeitos dos fármacos , Pulmão/patologia , Fosfatidilinositol 3-Quinases/genética , Alvéolos Pulmonares/efeitos dos fármacos , Alvéolos Pulmonares/patologia , Edema Pulmonar/induzido quimicamente , Edema Pulmonar/patologia , Ratos , Síndrome do Desconforto Respiratório/induzido quimicamente , Síndrome do Desconforto Respiratório/genética , Transdução de Sinais/efeitos dos fármacos , ATPase Trocadora de Sódio-Potássio/genéticaRESUMO
Endothelial glycocalyx degradation, critical for increased pulmonary vascular permeability, is thought to facilitate the development of sepsis into the multiple organ failure. Maresin conjugates in tissue regeneration 1 (MCTR1), a macrophage-derived lipid mediator, which exhibits potentially beneficial effects via the regulation of bacterial phagocytosis, promotion of inflammation resolution, and regeneration of tissue. In this study, we show that MCTR1 (100 ng/mouse) enhances the survival of mice with lipopolysaccharide (LPS)-induced (15 mg/kg) sepsis. MCTR1 alleviates LPS (10 mg/kg)-induced lung dysfunction and lung tissue inflammatory response by decreasing inflammatory cytokines (tumor necrosis factor-α, interleukin-1ß [IL-1ß], and IL-6) expression in serum and reducing the serum levels of heparan sulfate (HS) and syndecan-1. In human umbilical vein endothelial cells (HUVECs) experiments, MCTR1 (100 nM) was added to the culture medium with LPS for 6 hr. MCTR1 treatment markedly inhibited HS degradation by downregulating heparanase (HPA) protein expression in vivo and in vitro. Further analyses indicated that MCTR1 upregulates sirtuin 1 (SIRT1) expression and decreases NF-κB p65 phosphorylation. In the presence of BOC-2 or EX527, the above effects of MCTR1 were abolished. These results suggest that MCTR1 protects against LPS-induced sepsis in mice by attenuating pulmonary endothelial glycocalyx injury via the ALX/SIRT1/NF-κB/HPA pathway.
Assuntos
Lesão Pulmonar Aguda/tratamento farmacológico , Ácidos Docosa-Hexaenoicos/farmacologia , Lesão Pulmonar Aguda/sangue , Lesão Pulmonar Aguda/induzido quimicamente , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Animais , Citocinas/sangue , Endotélio/efeitos dos fármacos , Endotélio/patologia , Glucuronidase/metabolismo , Glicocálix/efeitos dos fármacos , Glicocálix/patologia , Células Endoteliais da Veia Umbilical Humana , Humanos , Mediadores da Inflamação/sangue , Lipopolissacarídeos/toxicidade , Pulmão/efeitos dos fármacos , Pulmão/fisiologia , Pulmão/fisiopatologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Sepse/tratamento farmacológico , Sepse/patologia , Sepse/fisiopatologia , Transdução de Sinais , Sirtuína 1/metabolismo , Fator de Transcrição RelA/metabolismoRESUMO
INTRODUCTION: Good analgesia has been shown to reduce the risk of pneumonia, chronic pain, and mortality in patients with multiple rib fractures (MRFs). This survey explores the current analgesic practice in the UK, protocol use, barriers to provision, and physician preferences. MATERIALS AND METHODS: A web-based survey was distributed nationally to an enriched cohort of clinicians working in UK trauma units with an interest in MRF management. RESULTS: Seventy-nine healthcare professionals responded. A third (31.4%) reported that their department had a rib fracture pain protocol, 52.9% did not, and 15.7% were unsure. Significantly more respondents reported adequate pain control when a hospital protocol was present compared to when not (χ 2, p < 0.01). Inadequate analgesia, a poor cough, and inability to breathe deeply were the commonest complications reported by 81.4, 78.6, and 65.7%, respectively. Patient-controlled analgesia (PCA) was the most commonly used form of analgesia (38.6%) followed by thoracic epidural (TEA) (30.0%) and continuous opioid infusion (18.6%). However, TEA was the preferred method of analgesia among respondents (37.1%) followed by serratus block (21.4%), paravertebral block (17.1%), and PCA (14.3%). DISCUSSION: There is considerable variation among physicians in their current use of analgesic modalities, with opiate-based methods predominating despite a physician preference for regional techniques. Thoracic epidurals are preferred by physicians but of limited use as a result of contraindications, time pressures, and staff skill mix. Pain control is reported to be better handled when protocols are present. Further research focusing on currently utilized regional techniques is required in order to produce a validated standardized national protocol that is informed by the current practice, the evidence base, and limitations to service provision. KEY MESSAGES: There is considerable variation among physicians in their current use of analgesic modalities. Opiate-based methods dominate for thoracic trauma despite a physician preference for regional techniques, which can be challenging in this cohort due to contraindications, staff skill mix, and time pressures. Inadequate analgesia is common but is better managed when pain management protocols are available. HOW TO CITE THIS ARTICLE: Beard L, Holt B, Snelson C, Parcha C, Smith FG, Veenith T. Analgesia of Patients with Multiple Rib Fractures in Critical Care: A Survey of Healthcare Professionals in the UK. Indian J Crit Care Med 2020;24(3):184-189.
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Maresin1 (MaR1), a new anti-inflammatory and proresolving lipid mediator, has been proven to exert organ-protective effects in septic animal models. However, the potential mechanisms are still not fully elucidated. In this study, we sought to explore the impact of MaR1 on metabolic dysfunction in cecal ligation and puncture- (CLP-) induced septic mice. We found that MaR1 significantly increased the overall survival rate and attenuated lung and liver injuries in septic mice. In addition, MaR1 markedly reduced the levels of proinflammatory cytokines (TNF-α and IL-6) and alleviated mitochondrial damage. Based on a 1H NMR-based metabolomics analysis, CLP-induced septic mice had increased levels of acetate, pyruvate, and lactate in serum and decreased levels of alanine, aspartate, glutamate, and fumarate in lungs. However, these metabolic disorders, mainly involving energy and amino acid metabolism, can be recovered by MaR1 treatment. Therefore, our results suggest that the protective effects of MaR1 on sepsis could be related to the recovery of metabolic dysfunction and the alleviation of inflammation and mitochondrial damage.
Assuntos
Ácidos Docosa-Hexaenoicos/uso terapêutico , Imageamento por Ressonância Magnética/métodos , Metabolômica/métodos , Sepse/tratamento farmacológico , Sepse/metabolismo , Animais , Ceco , Doença Hepática Induzida por Substâncias e Drogas/tratamento farmacológico , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Modelos Animais de Doenças , Inflamação/tratamento farmacológico , Inflamação/imunologia , Inflamação/metabolismo , Interleucina-6/metabolismo , Ligadura/efeitos adversos , Lesão Pulmonar/tratamento farmacológico , Lesão Pulmonar/etiologia , Lesão Pulmonar/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Microscopia Eletrônica de Transmissão , Análise Multivariada , Fator de Necrose Tumoral alfa/metabolismoRESUMO
Inflammation always accompanies infection during sepsis. Mitochondrial dysfunction and the role of reactive oxygen species (ROS) produced by mitochondria have been proposed in the pathogenesis of sepsis. Maresins have protective and resolving effects in experimental models of infection. In the present study, we investigated the effects of maresin 1 (MaR1) on mitochondrial function in cecal ligation and puncture (CLP)-induced sepsis and sepsis patients to identify mechanisms underlying maresin 1-mediated stimulation of ROS in mitochondria. We found that treatment with MaR1 significantly inhibited production of cytokines, decreased bacterial load in the peritoneal lavage fluid, reduced the number of neutrophils, decreased lactic acid level and upregulated cyclic AMP (cAMP) concentration, with the outcome of decreased lung injury in CLP-induced sepsis in mice. The effects of MaR1 on downregulation nitric oxide (NOX) activity, improvement CAT and SOD activity to inhibit ROS production in mitochondria was dependent on lipoxin receptor (ALX) and cAMP. Survival rates were significantly increased after the treatment of mice with MaR1. In BMDM stimulated with LPS, MaR1 inhibited the ROS production, downregulated enzyme activity, reduced mtO2 production, increased mitochondrial membrane potential, improved adenosine triphosphate (ATP) content and mitochondrial DNA (mtDNA) copy number. Finally, the effects of MaR1 on ROS production in the blood of healthy volunteers stimulated with LPS or sepsis patients were associated with ALX and cAMP. Taken together, these data suggest that treatment with MaR1 could attenuate mitochondrial dysfunction during sepsis through regulating ROS production.
Assuntos
AMP Cíclico/fisiologia , Ácidos Docosa-Hexaenoicos/farmacologia , Mitocôndrias/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Receptores de Lipoxinas/fisiologia , Sepse/tratamento farmacológico , Transdução de Sinais/fisiologia , Animais , Catalase/metabolismo , Células Cultivadas , Citocinas/metabolismo , Modelos Animais de Doenças , Humanos , Masculino , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Camundongos , Mitocôndrias/fisiologia , Óxido Nítrico/fisiologia , Oligopeptídeos/farmacologia , Sepse/imunologia , Sepse/mortalidade , Transdução de Sinais/efeitos dos fármacosAssuntos
Anestesia por Condução , Anestesia Geral , Delírio , Fraturas do Quadril , Idoso , Anestesia por Condução/efeitos adversos , Anestesia Geral/efeitos adversos , Delírio/epidemiologia , Delírio/etiologia , Fraturas do Quadril/epidemiologia , Fraturas do Quadril/cirurgia , Humanos , Incidência , Complicações Pós-Operatórias/epidemiologia , Complicações Pós-Operatórias/etiologiaRESUMO
Resolvin D1 (7S,8R,17S-trihydroxy-4Z,9E,11E,13Z,15E,19Z-docosahexaenoic acid) (RvD1), generated from ω-3 fatty docosahexaenoic acids, is believed to exert anti-inflammatory properties including inhibition of neutrophil activation and regulating inflammatory cytokines. In this study, we sought to investigate the effect of RvD1 in modulating alveolar fluid clearance (AFC) on LPS-induced acute lung injury. In vivo, RvD1 was injected i.v. (5 µg/kg) 8 h after LPS (20 mg/kg) administration, which markedly stimulated AFC in LPS-induced lung injury, with the outcome of decreased pulmonary edema. In addition, rat lung tissue protein was isolated after intervention and we found RvD1 improved epithelial sodium channel (ENaC) α, γ, Na,K-adenosine triphosphatase (ATPase) α1, ß1 subunit protein expression and Na,K-ATPase activity. In primary rat alveolar type II epithelial cells stimulated with LPS, RvD1 not only upregulated ENaC α, γ and Na,K-ATPase α1 subunits protein expression, but also increased Na+ currents and Na,K-ATPase activity. Finally, protein kinase A and cGMP were not responsible for RvD1's function because a protein kinase A inhibitor (H89) and cGMP inhibitor (Rp-cGMP) did not reduce RvD1's effects. However, the RvD1 receptor (formyl-peptide receptor type 2 [FPR2], also called ALX [the lipoxin A4 receptor]) inhibitor (BOC-2), cAMP inhibitor (Rp-cAMP), and PI3K inhibitor (LY294002) not only blocked RvD1's effects on the expression of ENaC α in vitro, but also inhibited the AFC in vivo. In summary, RvD1 stimulates AFC through a mechanism partly dependent on alveolar epithelial ENaC and Na,K-ATPase activation via the ALX/cAMP/PI3K signaling pathway.
Assuntos
Lesão Pulmonar Aguda/imunologia , Lesão Pulmonar Aguda/metabolismo , Células Epiteliais Alveolares/metabolismo , AMP Cíclico/metabolismo , Ácidos Docosa-Hexaenoicos/farmacologia , Fosfatidilinositol 3-Quinases/metabolismo , Receptores de Lipoxinas/metabolismo , Transdução de Sinais/efeitos dos fármacos , ATPase Trocadora de Sódio-Potássio/metabolismo , Lesão Pulmonar Aguda/genética , Células Epiteliais Alveolares/efeitos dos fármacos , Células Epiteliais Alveolares/imunologia , Animais , Ácidos Docosa-Hexaenoicos/administração & dosagem , Ativação Enzimática/efeitos dos fármacos , Canais Epiteliais de Sódio/genética , Canais Epiteliais de Sódio/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Lipopolissacarídeos/imunologia , Pulmão/efeitos dos fármacos , Pulmão/imunologia , Pulmão/metabolismo , Pulmão/patologia , Masculino , Ratos , ATPase Trocadora de Sódio-Potássio/genéticaRESUMO
The lymphatic vasculature is the natural pathway for the resolution of inflammation, yet the role of pulmonary lymphatic drainage function in sepsis-induced acute respiratory distress syndrome (ARDS) remains poorly characterized. In this study, indocyanine green-near infrared lymphatic living imaging was performed to examine pulmonary lymphatic drainage function in septic mouse models. We found that the pulmonary lymphatic drainage was impaired owing to the damaged lymphatic structure in sepsis-induced ARDS. Moreover, prior lymphatic defects by blocking vascular endothelial growth factor receptor-3 (VEGFR-3) worsened sepsis-induced lymphatic dysfunction and inflammation. Posttreatment with vascular endothelial growth factor-C (Cys156Ser) (VEGF-C156S), a ligand of VEGFR-3, ameliorated lymphatic drainage by rejuvenating lymphatics to reduce the pulmonary edema and promote draining of pulmonary macrophages and neutrophils to pretracheal lymph nodes. Meanwhile, VEGF-C156S posttreatment reversed sepsis-inhibited CC chemokine ligand 21 (CCL21), which colocalizes with pulmonary lymphatic vessels. Furthermore, the advantages of VEGF-C156S on the drainage of inflammatory cells and edema fluid were abolished by blocking VEGFR-3 or CCL21. These results suggest that efficient pulmonary lymphatic drainage is necessary for inflammation resolution in ARDS. Our findings offer a therapeutic approach to sepsis-induced ARDS by promoting lymphatic drainage function.
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Vasos Linfáticos , Síndrome do Desconforto Respiratório , Sepse , Camundongos , Animais , Fator C de Crescimento do Endotélio Vascular/metabolismo , Receptor 3 de Fatores de Crescimento do Endotélio Vascular/metabolismo , Fator A de Crescimento do Endotélio Vascular/metabolismo , Ligantes , Vasos Linfáticos/patologia , Inflamação/metabolismo , Síndrome do Desconforto Respiratório/patologia , Sepse/metabolismoRESUMO
Proton pump inhibitors (PPIs) are commonly used for gastric acid-related disorders, but their safety profile and risk stratification for high-burden diseases need further investigation. Analyzing over 2 million participants from five prospective cohorts from the US, the UK, and China, we found that PPI use correlated with increased risk of 15 leading global diseases, such as ischemic heart disease, diabetes, respiratory infections, and chronic kidney disease. These associations showed dose-response relationships and consistency across different PPI types. PPI-related absolute risks increased with baseline risks, with approximately 82% of cases occurring in those at the upper 40% of the baseline predicted risk, and only 11.5% of cases occurring in individuals at the lower 50% of the baseline risk. While statistical association does not necessarily imply causation, its potential safety concerns suggest that personalized use of PPIs through risk stratification might guide appropriate decision-making for patients, clinicians, and the public.
Assuntos
Inibidores da Bomba de Prótons , Inibidores da Bomba de Prótons/efeitos adversos , Inibidores da Bomba de Prótons/uso terapêutico , Humanos , Medição de Risco , Masculino , Feminino , Pessoa de Meia-Idade , China/epidemiologia , Reino Unido/epidemiologia , Idoso , Estudos Prospectivos , Estados Unidos/epidemiologia , Adulto , Medicina de Precisão , Insuficiência Renal Crônica/induzido quimicamente , Isquemia Miocárdica/induzido quimicamente , Isquemia Miocárdica/epidemiologia , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/epidemiologia , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/prevenção & controle , Infecções Respiratórias/epidemiologia , Diabetes Mellitus/induzido quimicamente , Diabetes Mellitus/epidemiologia , Fatores de RiscoRESUMO
Edema fluid resorption is critical for gas exchange, and both alveolar epithelial sodium channel (ENaC) and Na,K-ATPase are accredited with key roles in the resolution of pulmonary edema. Alveolar fluid clearance (AFC) was measured in in situ ventilated lungs by instilling isosmolar 5% BSA solution with Evans Blue-labeled albumin tracer (5 ml/kg) and measuring the change in Evans Blue-labeled albumin concentration over time. Treatment with lipoxin A4 and lipoxin receptor agonist (5(S), 6(R)-7-trihydroxymethyl 17 heptanoate) significantly stimulated AFC in oleic acid (OA)-induced lung injury, with the outcome of decreased pulmonary edema. Lipoxin A4 and 5(S), 6(R)-7-trihydroxymethyl 17 heptanoate not only up-regulated the ENaC α and ENaC γ subunits protein expression, but also increased Na,K-ATPase α1 subunit protein expression and Na,K-ATPase activity in lung tissues. There was no significant difference of intracellular cAMP level between the lipoxin A4 treatment and OA group. However, the intracellular cGMP level was significantly decreased after lipoxin A4 treatment. The beneficial effects of lipoxin A4 were abrogated by butoxycarbonyl-Phe-Leu-Phe-Leu-Ph (lipoxin A4 receptor antagonist) in OA-induced lung injury. In primary rat alveolar type II epithelial cells stimulated with LPS, lipoxin A4 increased ENaC α and ENaC γ subunits protein expression and Na,K-ATPase activity. Lipoxin A4 stimulated AFC through activation of alveolar epithelial ENaC and Na,K-ATPase.
Assuntos
Agonistas do Canal de Sódio Epitelial/administração & dosagem , Canais Epiteliais de Sódio/metabolismo , Lipoxinas/administração & dosagem , ATPase Trocadora de Sódio-Potássio/metabolismo , Lesão Pulmonar Aguda/tratamento farmacológico , Lesão Pulmonar Aguda/imunologia , Lesão Pulmonar Aguda/metabolismo , Células Epiteliais Alveolares/efeitos dos fármacos , Células Epiteliais Alveolares/imunologia , Animais , Células Cultivadas , AMP Cíclico/metabolismo , GMP Cíclico/metabolismo , Agonistas do Canal de Sódio Epitelial/farmacologia , Bloqueadores do Canal de Sódio Epitelial/farmacologia , Canais Epiteliais de Sódio/genética , Expressão Gênica/efeitos dos fármacos , Ácidos Heptanoicos/farmacologia , Lipopolissacarídeos/farmacologia , Lipoxinas/farmacologia , Masculino , Depuração Mucociliar , Oligopeptídeos/farmacologia , Peroxidase/metabolismo , Alvéolos Pulmonares/efeitos dos fármacos , Alvéolos Pulmonares/metabolismo , Alvéolos Pulmonares/fisiopatologia , Ratos , Ratos Sprague-Dawley , Fator de Necrose Tumoral alfa/metabolismoRESUMO
Fibroblasts, far from being merely bystander cells, are known to play a specific role in inflammation resolution after an acute injury. As the endogenous "braking signal," resolvins possess potent anti-inflammatory and pro-resolution actions. We demonstrated that the expression of COX-2 protein was significantly peaked initially at 6 hours but then also at 48 hours after LPS stimulation in lung fibroblasts. PGE2 levels also peaked at 6 hours, and PGD2 levels were increased and peaked at 48 hours. However, no significant change in the protein expression of COX-1 was observed after treatment with LPS in lung fibroblasts. Exogenous resolvin D1 inhibited the first peak of COX-2 expression as well as the production of PGE2 induced by LPS. In contrast, exogenous resolvin D1 increased the second peak of COX-2 expression as well as the production of PGD2 induced by LPS. In addition, resolvin D1 inhibited COX-2 expression at 6 hours, which was partly through PI3K/AKT and ERK2 signalling pathways.
Assuntos
Ciclo-Oxigenase 2/metabolismo , Ácidos Docosa-Hexaenoicos/farmacologia , Fibroblastos/metabolismo , Pulmão/patologia , Sistema de Sinalização das MAP Quinases , Animais , Linhagem Celular , Quimiocina CCL2/metabolismo , Dinoprostona/metabolismo , Regulação da Expressão Gênica , Humanos , Interleucina-8/metabolismo , Lipopolissacarídeos , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Prostaglandina D2/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ratos , Transdução de SinaisRESUMO
The lipoxins are the first proresolution mediators to be recognized and described as the endogenous "braking signals" for inflammation. We evaluated the anti-inflammatory and proresolution bioactions of lipoxin A4 in our lipopolysaccharide (LPS-)induced lung injury model. We demonstrated that lipoxin A4 significantly improved histology of rat lungs and inhibited IL-6 and TNF- α in LPS-induced lung injury. In addition, lipoxin A4 increased alveolar fluid clearance (AFC) and the effect of lipoxin A4 on AFC was abolished by CFTRinh-172 (a specific inhibitor of CFTR). Moreover, lipoxin A4 could increase cystic fibrosis transmembrane conductance regulator (CFTR) protein expression in vitro and in vivo. In rat primary alveolar type II (ATII) cells, LPS decreased CFTR protein expression via activation of PI3K/Akt, and lipoxin A4 suppressed LPS-stimulated phosphorylation of Akt. These results showed that lipoxin A4 enhanced CFTR protein expression and increased AFC via PI3K/Akt pathway. Thus, lipoxin A4 may provide a potential therapeutic approach for acute lung injury.
Assuntos
Lesão Pulmonar Aguda/induzido quimicamente , Lesão Pulmonar Aguda/metabolismo , Anti-Inflamatórios não Esteroides/uso terapêutico , Regulador de Condutância Transmembrana em Fibrose Cística/metabolismo , Lipopolissacarídeos/toxicidade , Lipoxinas/uso terapêutico , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Lesão Pulmonar Aguda/tratamento farmacológico , Animais , Western Blotting , Células Cultivadas , Regulador de Condutância Transmembrana em Fibrose Cística/genética , Imunofluorescência , Imuno-Histoquímica , Interleucina-6/metabolismo , Masculino , Ratos , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos , Fator de Necrose Tumoral alfa/metabolismoRESUMO
BACKGROUND: Thoracotomy is considered one of the most painful surgical procedures and can cause debilitating chronic post-surgical pain lasting months or years postoperatively. Aggressive management of acute pain resulting from thoracotomy may reduce the likelihood of developing chronic pain. This trial compares the two most commonly used modes of acute analgesia provision at the time of thoracotomy (thoracic epidural blockade (TEB) and paravertebral blockade (PVB)) in terms of their clinical and cost-effectiveness in preventing chronic post-thoracotomy pain. METHODS: TOPIC 2 is a multi-centre, open-label, parallel group, superiority, randomised controlled trial, with an internal pilot investigating the use of TEB and PVB in 1026 adult (≥ 18 years old) patients undergoing thoracotomy in up to 20 thoracic centres throughout the UK. Patients (N = 1026) will be randomised in a 1:1 ratio to receive either TEB or PVB. During the first year, the trial will include an integrated QuinteT (Qualitative Research Integrated into Trials) Recruitment Intervention (QRI) with the aim of optimising recruitment and informed consent. The primary outcome is the incidence of chronic post-surgical pain at 6 months post-randomisation defined as 'worst chest pain over the last week' equating to a visual analogue score greater than or equal to 40 mm indicating at least a moderate level of pain. Secondary outcomes include acute pain, complications of regional analgesia and surgery, health-related quality of life, mortality and a health economic analysis. DISCUSSION: Both TEB and PVB have been demonstrated to be effective in the prevention of acute pain following thoracotomy and nationally practice is divided. Identification of which mode of analgesia is both clinically and cost-effective in preventing chronic post-thoracotomy pain could ameliorate the debilitating effects of chronic pain, improving health-related quality of life, facilitating return to work and caring responsibilities and resulting in a cost saving to the NHS. TRIAL REGISTRATION: NCT03677856 [ClinicalTrials.gov] registered September 19, 2018. https://clinicaltrials.gov/ct2/show/NCT03677856 . First patient recruited 8 January 2019.
Assuntos
Dor Aguda , Analgesia Epidural , Dor Crônica , Bloqueio Nervoso , Adulto , Humanos , Adolescente , Toracotomia/efeitos adversos , Dor Crônica/diagnóstico , Dor Crônica/etiologia , Dor Crônica/prevenção & controle , Analgesia Epidural/efeitos adversos , Analgesia Epidural/métodos , Dor Aguda/diagnóstico , Dor Aguda/etiologia , Dor Aguda/prevenção & controle , Qualidade de Vida , Bloqueio Nervoso/efeitos adversos , Bloqueio Nervoso/métodos , Dor Pós-Operatória/diagnóstico , Dor Pós-Operatória/etiologia , Dor Pós-Operatória/prevenção & controle , Ensaios Clínicos Controlados Aleatórios como Assunto , Estudos Multicêntricos como AssuntoRESUMO
Sepsis, a life-threatening organ dysfunction, is not caused by direct damage of pathogens and their toxins but by the host's severe immune and metabolic dysfunction caused by the damage when the host confronts infection. Previous views focused on the damage-associated molecular patterns (DAMPs) and pathogen-associated molecular patterns (PAMPs), including metabolic proinflammatory factors in sepsis. Recently, new concepts have been proposed to group free fatty acids (FFAs), glucose, advanced glycation end products (AGEs), cholesterol, mitochondrial DNA (mtDNA), oxidized phospholipids (OxPLs), ceramides, and uric acid into metabolism-associated molecular patterns (MAMPs). The concept of MAMPs will bring new guidance to the research and potential treatments of sepsis. Nowadays, sepsis is regarded as closely related to metabolic disorders, and MAMPs play an important role in the pathogenesis and development of sepsis. According to this view, we have explained MAMPs and their possible roles in the pathogenesis of sepsis. Next, we have further explained the specific functions of different types of MAMPs in the metabolic process and their interactional relationship with sepsis. Finally, the therapeutic prospects of MAMPs in sepsis have been summarized.
Assuntos
Sepse , Alarminas , Humanos , Mitocôndrias/metabolismo , Moléculas com Motivos Associados a PatógenosRESUMO
The uncontrolled inflammatory response caused by a disorder in inflammation resolution is one of the reasons for acute respiratory distress syndrome (ARDS). The macrophage pool markedly expands when inflammatory monocytes, known as recruited macrophages, migrate from the circulation to the lung. The persistent presence of recruited macrophages leads to chronic inflammation in the resolution phase of inflammation. On the contrary, elimination of the recruited macrophages at the injury site leads to the rapid resolution of inflammation. Resolvin D1 (RvD1) is an endogenous lipid mediator derived from docosahexaenoic acid. Mice were administered RvD1 via the tail vein 3 and 4 days after stimulation with lipopolysaccharide. RvD1 reduced the levels of the inflammatory factors in the lung tissue, promoted the anti-inflammatory M2 phenotype, and enhanced the phagocytic function of recruited macrophages to alleviate acute lung injury. We also found that the number of macrophages was decreased in BAL fluid after treatment with RvD1. RvD1 increased the apoptosis of recruited macrophages partly via the FasL-FasR/caspase-3 signaling pathway, and this effect could be blocked by Boc-2, an ALX/PRP2 inhibitor. Taken together, our findings reinforce the concept of therapeutic targeting leading to the apoptosis of recruited macrophages. Thus, RvD1 may provide a new therapy for the resolution of ARDS.