The nitric oxide donor, (Z)-1-[N-(2-aminoethyl)-N-(2-ammonioethyl)amino]diazen-1-ium-1,2-diolate (DETA-NONOate/D-NO), increases survival by attenuating hyperoxia-compromised innate immunity in bacterial clearance in a mouse model of ventilator-associated

一氧化氮供体,(Z)-1-[N-(2-氨基乙基)-N-(2-氨乙基) 氨基] diazen-1-ium-1,2-二酯 (DETA-NONOate/D-NO), 在呼吸机相关小鼠模型中通过减弱细菌清除中高氧受损的固有免疫来提高生存率

  • 影响因子:4.42
  • DOI:10.1016/j.bcp.2020.113817
  • 作者列表:"Gore A","Gauthier AG","Lin M","Patel V","Thomas DD","Ashb CR Jr","Mantell LL
  • 发表时间:2020-01-20

:Mechanical ventilation (MV) with supraphysiological levels of oxygen (hyperoxia) is a life-saving therapy for the management of patients with respiratory distress. However, a significant number of patients on MV develop ventilator-associated pneumonia (VAP). Previously, we have reported that prolonged exposure to hyperoxia impairs the capacity of macrophages to phagocytize Pseudomonas aeruginosa (PA), which can contribute to the compromised innate immunity in VAP. In this study, we show that the high mortality rate in mice subjected to hyperoxia and PA infection was accompanied by a significant decrease in the airway levels of nitric oxide (NO). Decreased NO levels were found to be, in part, due to a significant reduction in NO release by macrophages upon exposure to PA lipopolysaccharide (LPS). Based on these findings, we postulated that NO supplementation should restore hyperoxia-compromised innate immunity and decrease mortality by increasing the clearance of PA under hyperoxic conditions. To test this hypothesis, cultured macrophages were exposed to hyperoxia (95% O2) in the presence or absence of the NO donor, (Z)-1-[N-(2-aminoethyl)-N-(2-ammonioethyl)amino]diazen-1-ium-1,2-diolate (DETA-NONOate/D-NO). Interestingly, D-NO (up to 37.5 µM) significantly attenuated hyperoxia-compromised macrophage migratory, phagocytic, and bactericidal function. To determine whether the administration of exogenous NO enhances the host defense in bacteria clearance, C57BL/6 mice were exposed to hyperoxia (99% O2) and intranasally inoculated with PA in the presence or absence of D-NO. D-NO (300 µM - 800 µM) significantly increased the survival of mice inoculated with PA under hyperoxic conditions, and significantly decreased bacterial loads in the lung and attenuated lung injury. These results suggest the NO donor, D-NO, can improve the clinical outcomes in VAP by augmenting the innate immunity in bacterial clearance. Thus, provided these results can be extrapolated to humans, NO supplementation may represent a potential therapeutic strategy for preventing and treating patients with VAP.


: 机械通气 (MV) 超生理水平的氧气 (高氧) 是一种挽救生命的治疗呼吸窘迫患者的管理。然而,相当多的 MV 患者发生呼吸机相关性肺炎 (VAP)。以前,我们报道过长期暴露于高氧会损害巨噬细胞吞噬铜绿假单胞菌 (PA) 的能力,这可能导致 VAP 固有免疫受损。在这项研究中,我们发现高氧和 PA 感染小鼠的高死亡率伴随着气道一氧化氮 (NO) 水平的显著降低。发现 NO 水平降低部分是由于巨噬细胞暴露于 PA 脂多糖 (LPS) 后 NO 释放显著减少。基于这些发现,我们假设补充 NO 应该通过增加高氧条件下 PA 的清除率来恢复高氧损害的先天免疫并降低死亡率。为了验证这一假设,在 NO 供体 (Z)-1-[N-(2-氨基乙基) 存在或不存在的情况下,将培养的巨噬细胞暴露于高氧 (95% O2) -N-(2-氨乙基) 氨基] diazen-1-ium-1,2-二酯 (DETA-NONOate/D-NO)。有趣的是,D-NO (高达 37.5 µ m) 显著减弱高氧损害的巨噬细胞迁移、吞噬和杀菌功能。为了确定给予外源性 NO 是否增强细菌清除中的宿主防御,C57BL/6 小鼠暴露于高氧 (99% O2) 并在有或无 D-NO 的情况下鼻内接种 PA。D-NO (300 µ m-800 µ m) 显著增加了高氧条件下接种 PA 的小鼠的存活率,显著降低了肺部细菌负荷,减弱了肺损伤。这些结果表明 NO 供体 D-NO 可以通过增强细菌清除中的天然免疫来改善 VAP 的临床结局。因此,只要这些结果可以外推到人类,NO 补充剂可能代表预防和治疗 VAP 患者的潜在治疗策略。



作者列表:["Maria Kózka","Aurelia Sega","Katarzyna Wojnar-Gruszka","Agnieszka Tarnawska","Agnieszka Gniadek"]

METHODS:Background: The hospitalization of patients treated in the intensive care unit (ICU) in 5&#8722;15% of cases is associated with the occurrence of a complication in the form of ventilator-associated pneumonia (VAP). Purpose: Retrospective assessment of risk factors of VAP in patients treated at ICUs in the University Hospital in Krakow. Methods: The research involved the medical documentation of 1872 patients treated at the ICU of the University Hospital in Krakow between 2014 and 2017. The patients were mechanically ventilated for at least 48 h. The obtained data were presented by qualitative and quantitative analysis (%). The qualitative variables were compared using the Chi2 test. Statistically significant was the p < 0.05 value. Results: VAP was demonstrated in 23% of all patients treated in ICU during the analyzed period, and this infection occurred in 13% of men and 10% of women. Pneumonia associated with ventilation was found primarily in patients staying in the ward for over 15 days and subjected to intratracheal intubation (17%). A statistically significant was found between VAP and co-morbidities, e.g., chronic obstructive pulmonary disease, diabetes, alcoholism, obesity, the occurrence of VAP and multi-organ trauma, hemorrhage/hemorrhagic shock, and fractures as the reasons for admitting ICU patients. Conclusions: Patients with comorbidities such as chronic obstructive pulmonary disease, obesity, diabetes, and alcoholism are a high-risk group for VAP. Particular attention should be paid to patients admitted to the ICU with multi-organ trauma, fractures, and hemorrhage/hemorrhagic shock as patients predisposed to VAP. There is a need for further research into risk factors for non-modifiable VAP such as comorbidities and reasons for ICU admission in order to allow closer monitoring of these patients for VAP.

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来源期刊:Bioscience reports
作者列表:["Yu H","Luo J","Ni Y","Hu Y","Liu D","Wang M","Liang B","Liang Z"]

METHODS::Backgroud Severe pneumonia is one of the most common causes for mechanical ventilation. We aimed to early identify severe pneumonia patients with high risk of extubation failure in order to improve prognosis. Methods From April 2014 to December 2015, medical records of intubated patients with severe pneumonia in intensive care unit were retrieved from database. Patients were divided into extubation success and failure groups, and multivariate logistic regressions were performed to identify independent predictors for extubation failure. Results A total of 125 eligible patients were included, of which 82 and 43 patients had extubation success and failure, respectively. APACHE II score (odds ration (OR) 1.141, 95% confident interval (CI) 1.022-1.273, P = 0.019, cutoff at 17.5), blood glucose (OR 1.122, 95%CI 1.008-1.249, P = 0.035, cutoff at 9.87mmol/L), dose of fentanyl (OR 3.010, 95%CI 1.100-8.237, P = 0.032, cutoff at 1.135mg/d), and the need for red blood cell (RBC) transfusion (OR 2.774, 95%CI 1.062-7.252, P = 0.037) were independent risk factors for extubation failure. Conclusions In patients with severe pneumonia, APACHE II score > 17.5, blood glucose > 9.87mmol/L, fentanyl usage > 1.135mg/d, and the need for RBC transfusion might be associated with higher risk of extubation failure.

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作者列表:["Lundin A","Karlsson T","Herlitz J","Lundgren P","Rylander C"]

METHODS:PURPOSE:To assess the association between the duration of mechanical ventilation during post resuscitation care and 30-day survival after cardiac arrest. METHODS:We conducted a retrospective observational study using data from two national registries. Comatose cardiac arrest patients admitted to general intensive care in Swedish hospitals between 2011 and 2016 were eligible. Based on the median duration of mechanical ventilation for patients who did not survive to hospital discharge, used as a proxy for the endurance of post resuscitation care, the hospitals were divided into four ordered groups for which association with 30-day survival was analyzed. RESULTS:In total, 5.113 patients in 56 hospitals were included. Median duration of mechanical ventilation for patients who did not survive to hospital discharge ranged from 17 hours in hospital group 1 to 51 hours in hospital group 4. After adjustment for baseline characteristics, 30-day survival in the entire cohort was positively and independently associated with ordered hospital group: (adjusted odds ratio (95%CI); 1.12 (1.02,1.23); p = 0.02). Thus, hospitals with a longer duration of mechanical ventilation among non-survivors had better survival rate among patients admitted to ICU after a cardiac arrest. However, in a secondary analysis restricted to patients with length of stay in the intensive care unit ≥ 48 hours, there was no significant association between 30-day survival and ordered hospital group. CONCLUSION:A tendency for longer duration of post resuscitation care in the ICU was associated with higher 30-day survival in comatose patients admitted to intensive care after cardiac arrest.

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