O'Sullivan Ryan, Alder Matthew N, Dixon Celeste G, Zhang Donglan, Srivastava Nishi, Yehya Nadir
Department of Anesthesiology and Critical Care Medicine, Children's Hospital of Philadelphia and Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, United States.
Department of Pediatrics, College of Medicine, University of Cincinnati, Cincinnati, Ohio, United States.
Am J Physiol Lung Cell Mol Physiol. 2025 Jul 1;329(1):L172-L182. doi: 10.1152/ajplung.00040.2025. Epub 2025 Jun 11.
Neutrophils play a key role in acute respiratory distress syndrome (ARDS). The neutrophil marker olfactomedin-4 (OLFM4) has been implicated with worse outcomes in pediatric sepsis; however, OLFM4 has not been studied in pediatric ARDS. Therefore, we performed a secondary analysis of a prospective cohort of children with Berlin-defined ARDS with plasma collected on of ARDS, testing for an association between OLFM4 and 28-day mortality, 7-day dialysis-free survival, and 28-day ventilator-free days (VFDs), adjusting for age, ARDS etiology, immunocompromised status, and arterial partial pressure of oxygen ([Formula: see text])/fraction of inspired oxygen ([Formula: see text]). We also tested the ability of LPS and histones to affect OLFM4 expression in vitro. In 333 children with ARDS (21% nonsurvivors), OLFM4 was higher in nonsurvivors, in severe ARDS, in hyperinflammatory ARDS, and in those with multiple organ failures. In multivariable regression, OLFM4 was associated with higher mortality, higher probability of dialysis by , and fewer VFDs. In stratified analyses, the association between OLFM4 and worse outcomes did not differ between infectious and noninfectious ARDS. In vitro, OLFM4 expression increased following H3 exposure in undifferentiated neutrophils, which was partly mitigated by toll-like receptor (TLR) antagonism. Overall, OLFM4 was associated with worse outcomes in pediatric ARDS. Histone H3 could induce OLFM4 expression in neutrophils, thus linking damage-associated molecular patterns to neutrophil polarization, which may represent a possible targetable pathway in pediatric ARDS. Olfactomedin-4 (OLFM4) was associated with higher mortality, higher probability of dialysis by , and fewer ventilator-free days (VFDs) in a pediatric acute respiratory distress syndrome (ARDS) cohort. In vitro, OLFM4 increased following H3 exposure in undifferentiated neutrophils, which was partly mitigated by toll-like receptor (TLR) antagonism. OLFM4 appears to be a marker, and potentially a mediator, of pathological inflammation and end-organ damage in ARDS.
中性粒细胞在急性呼吸窘迫综合征（ARDS）中起关键作用。中性粒细胞标志物嗅觉介质4（OLFM4）与儿童脓毒症的不良预后有关；然而，尚未对儿童ARDS中的OLFM4进行研究。因此，我们对一组符合柏林定义的ARDS儿童的前瞻性队列进行了二次分析，这些儿童在ARDS发病时采集了血浆，检测OLFM4与28天死亡率、7天无透析生存率和28天无呼吸机天数（VFD）之间的关联，并对年龄、ARDS病因、免疫功能低下状态和动脉血氧分压（[公式：见正文]）/吸入氧分数（[公式：见正文]）进行了校正。我们还测试了脂多糖（LPS）和组蛋白在体外影响OLFM4表达的能力。在333例ARDS儿童（21%为非幸存者）中，非幸存者、重度ARDS、高炎症性ARDS以及多器官功能衰竭患儿的OLFM4水平更高。在多变量回归分析中，OLFM4与更高的死亡率、7天内进行透析的更高概率以及更少的VFD相关。在分层分析中，OLFM4与不良预后之间的关联在感染性和非感染性ARDS中无差异。在体外，未分化的中性粒细胞暴露于H3后OLFM4表达增加，而Toll样受体（TLR）拮抗作用可部分减轻这种增加。总体而言，OLFM4与儿童ARDS的不良预后相关。组蛋白H3可诱导中性粒细胞中OLFM4的表达，从而将损伤相关分子模式与中性粒细胞极化联系起来，这可能代表了儿童ARDS中一条可能的可靶向治疗途径。在儿童急性呼吸窘迫综合征（ARDS）队列中，嗅觉介质4（OLFM4）与更高的死亡率、7天内进行透析的更高概率以及更少的无呼吸机天数（VFD）相关。在体外，未分化的中性粒细胞暴露于H3后OLFM4增加，而Toll样受体（TLR）拮抗作用可部分减轻这种增加。OLFM4似乎是ARDS中病理性炎症和终末器官损伤的一个标志物，并且可能是一种介质。
