Alipanah-Lechner Narges, Neyton Lucile, Sinha Pratik, Leroux Carolyn, Bardillon Kim, Carrillo Sidney A, Chak Suzanna, Chao Olivia, Hariharan Taarini, Henrickson Carolyn, Kangelaris Kirsten, Langelier Charles R, Lee Deanna, Lin Chelsea, Liu Kathleen, Magee Liam, Ringor Angelika, Sarma Aartik, Schmiege Emma, Spottiswoode Natasha, Sullivan Kathryn, Weingart Melanie F, Willmore Andrew, Zhuo Hanjing, Rogers Angela J, Stringer Kathleen A, Matthay Michael A, Calfee Carolyn S
medRxiv. 2025 Sep 10:2025.05.07.25327117. doi: 10.1101/2025.05.07.25327117.
Critically ill patients with acute respiratory distress syndrome (ARDS) and sepsis exhibit distinct inflammatory phenotypes with divergent clinical outcomes and apparent heterogeneity of treatment effects, but the underlying molecular mechanisms remain poorly understood. These phenotypes, derived from clinical data and protein biomarkers, were associated with metabolic differences in a prior pilot study. This study investigated the metabolomic and transcriptomic differences between Hyperinflammatory and Hypoinflammatory phenotypes through integrative multi-omics analysis of blood samples from ARDS patients in the ROSE trial. Multi-omics integration revealed three molecular signatures strongly associated with the Hyperinflammatory phenotype and with mortality: enhanced innate immune activation coupled with increased glycolysis, hepatic dysfunction and immune dysfunction paired with impaired fatty acid beta-oxidation, and interferon program suppression coupled with altered mitochondrial respiration. A fourth molecular signature, not associated with inflammatory phenotype, identified redox impairment and cell proliferation pathways associated with mortality. Integrated multi-omics analysis within each inflammatory phenotype revealed distinct pathways associated with mortality. All mortality-associated molecular signatures including those within phenotypes were validated in an independent cohort of critically ill patients with sepsis (EARLI). These findings reveal distinct molecular mechanisms underlying ARDS/sepsis phenotypes and suggest potential therapeutic targets for precise treatment strategies in critical illness.
患有急性呼吸窘迫综合征（ARDS）和脓毒症的重症患者表现出不同的炎症表型，临床结局各异，治疗效果存在明显异质性，但其潜在分子机制仍知之甚少。在先前的一项初步研究中，源自临床数据和蛋白质生物标志物的这些表型与代谢差异相关。本研究通过对ROSE试验中ARDS患者血液样本进行综合多组学分析，调查了高炎症和低炎症表型之间的代谢组学和转录组学差异。多组学整合揭示了与高炎症表型及死亡率密切相关的三个分子特征：固有免疫激活增强伴糖酵解增加、肝功能障碍和免疫功能障碍伴脂肪酸β氧化受损，以及干扰素程序抑制伴线粒体呼吸改变。第四个分子特征与炎症表型无关，确定了与死亡率相关的氧化还原损伤和细胞增殖途径。在每种炎症表型内进行的综合多组学分析揭示了与死亡率相关的不同途径。所有与死亡率相关的分子特征，包括表型内的特征，均在脓毒症重症患者独立队列（EARLI）中得到验证。这些发现揭示了ARDS/脓毒症表型背后不同的分子机制，并为危重症的精准治疗策略提出了潜在治疗靶点。
