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Plasma Mitochondrial DNA Levels Are Associated With ARDS in Trauma and Sepsis Patients.

血浆线粒体 DNA 水平与创伤和脓毒症患者的 ARDS 相关。

  • 影响因子:3.84
  • DOI:10.1016/j.chest.2019.09.028
  • 作者列表:"Faust HE","Reilly JP","Anderson BJ","Ittner CAG","Forker CM","Zhang P","Weaver BA","Holena DN","Lanken PN","Christie JD","Meyer NJ","Mangalmurti NS","Shashaty MGS
  • 发表时间:2020-01-01

BACKGROUND:Critically ill patients who develop ARDS have substantial associated morbidity and mortality. Circulating mitochondrial DNA (mtDNA) released during critical illness causes endothelial dysfunction and lung injury in experimental models. This study hypothesized that elevated plasma mtDNA is associated with ARDS in critically ill patients with trauma and sepsis. METHODS:Plasma mtDNA concentrations were measured at ED presentation and approximately 48 h later in separate prospective cohorts of critically ill patients with trauma and sepsis. ARDS was classified according to the Berlin definition. The association of mtDNA with ARDS was tested by using multivariable logistic regression, adjusted for covariates previously shown to contribute to ARDS risk in each population. RESULTS:ARDS developed in 41 of 224 (18%) trauma patients and in 45 of 120 (38%) patients with sepsis. Forty-eight-hour mtDNA levels were significantly associated with ARDS (trauma: OR, 1.58/log copies/μL; 95% CI, 1.14-2.19 [P = .006]; sepsis: OR, 1.52/log copies/μL; 95% CI, 1.12-2.06 [P = .007]). Plasma mtDNA on presentation was not significantly associated with ARDS in either cohort. In patients with sepsis, 48-h mtDNA was more strongly associated with ARDS among those with a nonpulmonary infectious source (OR, 2.20/log copies/μL; 95% CI, 1.36-3.55 [P = .001], n = 69) than those with a pulmonary source (OR, 1.04/log copies/μL; 95% CI, 0.68-1.59 [P = .84], n = 51; P = .014 for interaction). CONCLUSIONS:Plasma mtDNA levels were associated with incident ARDS in two critical illness populations. Given supportive preclinical data, our findings suggest a potential link between circulating mtDNA and lung injury and merit further investigation as a potentially targetable mediator of ARDS.


背景: 发展为 ARDS 的危重患者有大量相关的发病率和死亡率。在危重病期间释放的循环线粒体 DNA (mtDNA) 在实验模型中引起内皮功能障碍和肺损伤。本研究假设血浆 mtDNA 升高与创伤和脓毒症危重患者的 ARDS 相关。 方法: 在 ED 就诊时和大约 48 h 后,在独立的创伤和脓毒症危重患者前瞻性队列中测量血浆 mtDNA 浓度。ARDS 是根据柏林定义分类的。使用多变量 logistic 回归检测 mtDNA 与 ARDS 的相关性,校正了之前显示在每个人群中有助于 ARDS 风险的协变量。 结果: 224 例创伤患者中有 41 例 (18%) 发生 ARDS,120 例脓毒症患者中有 45 例 (38%) 发生 ARDS。48 小时 mtDNA 水平与 ARDS 显著相关 (创伤: OR,1.58/log 拷贝/μ l; 95% CI,1.14-2.19 [P =。 006]; 脓毒症: OR,1.52/log 拷贝/μ l; 95% CI,1.12-2.06 [P =。 007])。在两个队列中,就诊时的血浆 mtDNA 与 ARDS 无显著相关性。在脓毒症患者中,48 h mtDNA 与非肺传染源 ARDS 的相关性更强 (OR,2.20/log 拷贝/μ l; 95% CI, 1.36-3.55 [P =0.001],n = 69) 比肺源者 (OR,1.04/log 拷贝/μ l; 95% CI,0.68-1.59 [P = 0.84],N = 51; 相互作用 P =.014)。 结论: 血浆 mtDNA 水平与两种危重疾病人群发生 ARDS 相关。鉴于支持性临床前数据,我们的研究结果表明循环 mtDNA 和肺损伤之间存在潜在联系,值得进一步研究作为 ARDS 的潜在靶向介质。



作者列表:["De Cunto G","Brancaleone V","Riemma MA","Cerqua I","Vellecco V","Spaziano G","Cavarra E","Bartalesi B","D'Agostino B","Lungarella G","Cirino G","Lucattelli M","Roviezzo F"]

METHODS:BACKGROUND AND PURPOSE:A critical role for sphingosine kinase/sphingosine-1-phosphate (S1P) pathway in the control of airway function has been demonstrated in respiratory diseases. Here, we address S1P contribution in a mouse model of mild chronic obstructive pulmonary disease (COPD). EXPERIMENTAL APPROACH:C57BL/6J mice have been exposed to room air or cigarette smoke up to 11 months and killed at different time points. Functional and molecular studies have been performed. KEY RESULTS:Cigarette smoke caused emphysematous changes throughout the lung parenchyma coupled to a progressive collagen deposition in both peribronchiolar and peribronchial areas. The high and low airways showed an increased reactivity to cholinergic stimulation and α-smooth muscle actin overexpression. Similarly, an increase in airway reactivity and lung resistances following S1P challenge occurred in smoking mice. A high expression of S1P, Sph-K2 , and S1P receptors (S1P2 and S1P3 ) has been detected in the lung of smoking mice. Sphingosine kinases inhibition reversed the increased cholinergic response in airways of smoking mice. CONCLUSIONS AND IMPLICATIONS:S1P signalling up-regulation follows the disease progression in smoking mice and is involved in the development of airway hyperresponsiveness. Our study defines a therapeutic potential for S1P inhibitors in management of airways hyperresponsiveness associated to emphysema in smokers with both asthma and COPD.

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作者列表:["Bernstein DM","Toth B","Rogers RA","Kling DE","Kunzendorf P","Phillips JI","Ernst H"]

METHODS::The interim results from this 90-day multi-dose, inhalation toxicology study with life-time post-exposure observation has shown an important fundamental difference in persistence and pathological response in the lung between brake dust derived from brake-pads manufactured with chrysotile, TiO2 or chrysotile alone in comparison to the amphiboles, crocidolite and amosite asbestos. In the brake dust exposure groups no significant pathological response was observed at any time. Slight macrophage accumulation of particles was noted. Wagner-scores, were from 1 to 2 (1 = air-control group) and were similar to the TiO2 group. Chrysotile being biodegradable, shows a weakening of its matrix and breaking into short fibers & particles that can be cleared by alveolar macrophages and continued dissolution. In the chrysotile exposure groups, particle laden macrophage accumulation was noted leading to a slight interstitial inflammatory response (Wagner-score 1-3). There was no peribronchiolar inflammation and occasional very slight interstitial fibrosis. The histopathology and the confocal analyses clearly differentiate the pathological response from amphibole asbestos, crocidolite and amosite, compared to that from the brake dust and chrysotile. Both crocidolite and amosite induced persistent inflammation, microgranulomas, and fibrosis (Wagner-scores 4), which persisted through the post exposure period. The confocal microscopy of the lung and snap-frozen chestwalls quantified the extensive inflammatory response and collagen development in the lung and on the visceral and parietal surfaces. The interim results reported here, provide a clear basis for differentiating the effects from brake dust exposure from those following amphibole asbestos exposure. The subsequent results through life-time post-exposure will follow.

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作者列表:["Zaragosi LE","Deprez M","Barbry P"]

METHODS::The respiratory tract is lined by a pseudo-stratified epithelium from the nose to terminal bronchioles. This first line of defense of the lung against external stress includes five main cell types: basal, suprabasal, club, goblet and multiciliated cells, as well as rare cells such as ionocytes, neuroendocrine and tuft/brush cells. At homeostasis, this epithelium self-renews at low rate but is able of fast regeneration upon damage. Airway epithelial cell lineages during regeneration have been investigated in the mouse by genetic labeling, mainly after injuring the epithelium with noxious agents. From these approaches, basal cells have been identified as progenitors of club, goblet and multiciliated cells, but also of ionocytes and neuroendocrine cells. Single-cell RNA sequencing, coupled to lineage inference algorithms, has independently allowed the establishment of comprehensive pictures of cell lineage relationships in both mouse and human. In line with genetic tracing experiments in mouse trachea, studies using single-cell RNA sequencing (RNAseq) have shown that basal cells first differentiate into club cells, which in turn mature into goblet cells or differentiate into multiciliated cells. In the human airway epithelium, single-cell RNAseq has identified novel intermediate populations such as deuterosomal cells, 'hybrid' mucous-multiciliated cells and progenitors of rare cells. Novel differentiation dynamics, such as a transition from goblet to multiciliated cells have also been discovered. The future of cell lineage relationships in the respiratory tract now resides in the combination of genetic labeling approaches with single-cell RNAseq to establish, in a definitive manner, the hallmarks of cellular lineages in normal and pathological situations.

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