血清代谢组学特征可区分急性呼吸窘迫综合征宿主反应亚表型的脂肪酸氧化缺陷。

BACKGROUND: Fatty acid oxidation (FAO) defects have been implicated in experimental models of acute lung injury and associated with poor outcomes in critical illness. In this study, we examined acylcarnitine profiles and 3-methylhistidine as markers of FAO defects and skeletal muscle catabolism, respectively, in patients with acute respiratory failure. We determined whether these metabolites were associated with host-response ARDS subphenotypes, inflammatory biomarkers, and clinical outcomes in acute respiratory failure. METHODS: In a nested case-control cohort study, we performed targeted analysis of serum metabolites of patients intubated for airway protection (airway controls), Class 1 (hypoinflammatory), and Class 2 (hyperinflammatory) ARDS patients (N = 50 per group) during early initiation of mechanical ventilation. Relative amounts were quantified by liquid chromatography high resolution mass spectrometry using isotope-labeled standards and analyzed with plasma biomarkers and clinical data. RESULTS: Of the acylcarnitines analyzed, octanoylcarnitine levels were twofold increased in Class 2 ARDS relative to Class 1 ARDS or airway controls (P = 0.0004 and < 0.0001, respectively) and was positively associated with Class 2 by quantile g-computation analysis (P = 0.004). In addition, acetylcarnitine and 3-methylhistidine were increased in Class 2 relative to Class 1 and positively correlated with inflammatory biomarkers. In all patients within the study with acute respiratory failure, increased 3-methylhistidine was observed in non-survivors at 30 days (P = 0.0018), while octanoylcarnitine was increased in patients requiring vasopressor support but not in non-survivors (P = 0.0001 and P = 0.28, respectively). CONCLUSIONS: This study demonstrates that increased levels of acetylcarnitine, octanoylcarnitine, and 3-methylhistidine distinguish Class 2 from Class 1 ARDS patients and airway controls. Octanoylcarnitine and 3-methylhistidine were associated with poor outcomes in patients with acute respiratory failure across the cohort independent of etiology or host-response subphenotype. These findings suggest a role for serum metabolites as biomarkers in ARDS and poor outcomes in critically ill patients early in the clinical course.

背景：脂肪酸氧化 (FAO) 缺陷与急性肺损伤的实验模型有关，并与危重病患者的不良预后相关。在这项研究中，我们分别检测了酰基辅酶 A 谱和 3-甲基组氨酸作为 FAO 缺陷和骨骼肌分解代谢的标志物，以评估急性呼吸衰竭患者。我们还确定了这些代谢物与宿主反应性 ARDS 亚表型、炎症生物标志物以及急性呼吸衰竭患者的临床结局之间的相关性。

方法：在一项嵌套病例对照队列研究中，我们对因气道保护而插管的患者（气道对照）、1 类（低炎症）和 2 类（高炎症）ARDS 患者（每组 50 例）在机械通气早期进行了血清代谢物的靶向分析。采用液相色谱-高分辨质谱法，通过同位素标记标准品进行相对含量的定量分析，并结合血浆生物标志物和临床数据进行分析。

结果：在所分析的酰基辅酶 A 中，与 1 类 ARDS 或气道对照相比，2 类 ARDS 患者的辛酰基辅酶 A 水平增加了两倍（分别为 P<0.0004 和 P<0.0001），并且通过定量分位数计算分析，2 类 ARDS 与辛酰基辅酶 A 呈正相关（P=0.004）。此外，与 1 类 ARDS 相比，2 类 ARDS 患者的乙酰基辅酶 A 和 3-甲基组氨酸水平升高，并与炎症生物标志物呈正相关。在所有患有急性呼吸衰竭的患者中，30 天存活者的 3-甲基组氨酸水平升高（P=0.0018），而需要血管加压支持的患者中辛酰基辅酶 A 水平升高，但存活者中未升高（P=0.0001 和 P=0.28）。

结论：本研究表明，乙酰基辅酶 A、辛酰基辅酶 A 和 3-甲基组氨酸水平的增加可将 2 类 ARDS 与 1 类 ARDS 患者和气道对照区分开来。在整个队列中，无论是病因还是宿主反应亚表型，辛酰基辅酶 A 和 3-甲基组氨酸与急性呼吸衰竭患者的不良预后相关。这些发现提示，在疾病的早期阶段，血清代谢物可作为 ARDS 和危重病患者不良预后的生物标志物。