Grudzinska Frances, Faniyi Aduragbemi A, Belchamber Kylie B R, Chen Celine, Stockley Robert, Jasper Alice, Parekh Dhruv, Sapey Elizabeth, Scott Aaron, Thickett David R
Birmingham Acute Care Research Group, Institute of Inflammation and Ageing, University of Birmingham, Birmingham, UK
School of Translational Medicine, University of Nottingham, Nottingham, UK.
Thorax. 2025 Jan 17;80(2):97-104. doi: 10.1136/thorax-2024-222215.
Community-acquired pneumonia (CAP) is a leading cause of hospitalisation in older adults and is associated with a high likelihood of adverse outcomes. Given the ageing population and lack of therapeutic advances in CAP, new strategies to manage the burden of this disease are needed. Neutrophil dysfunction has been widely demonstrated in CAP and is associated with poor outcomes. We hypothesised that impaired glycolytic metabolism was driving neutrophil dysfunction in older adults with CAP.
To investigate the mechanism underlying neutrophil dysfunction in CAP, we recruited older adults with CAP and sepsis, age-matched controls and healthy young adults to assess neutrophil function and glycolytic metabolism in peripheral blood neutrophils.
We demonstrate that neutrophils from older donors with CAP display a broad range of functional defects, including inaccurate migration to interleukin 8, impaired respiratory burst in response to phorbol 12-myristate 13-acetate and increased spontaneous degranulation compared with age-matched controls. Glycolysis (assessed by extracellular flux and RNA-sequencing) was not significantly altered between age-matched groups; however, basal rates of neutrophil glycolysis were significantly higher in patients with CAP and older adult controls compared with healthy young adults, and stimulated glycolysis was significantly higher in young adults compared with older adults with and without CAP.
Our findings suggest that neutrophil dysfunction in older adults with CAP may be implicated in poor outcomes, irrespective of glycolytic metabolism.
社区获得性肺炎（CAP）是老年人住院的主要原因，且与不良结局的高可能性相关。鉴于人口老龄化以及CAP治疗进展的缺乏，需要新的策略来应对这种疾病的负担。中性粒细胞功能障碍在CAP中已得到广泛证实，且与不良结局相关。我们推测糖酵解代谢受损是导致老年CAP患者中性粒细胞功能障碍的原因。
为了研究CAP中性粒细胞功能障碍的潜在机制，我们招募了患有CAP和脓毒症的老年人、年龄匹配的对照组以及健康的年轻人，以评估外周血中性粒细胞的功能和糖酵解代谢。
我们证明，与年龄匹配的对照组相比，患有CAP的老年供体的中性粒细胞表现出广泛的功能缺陷，包括对白介素8的迁移不准确、对佛波酯12 -肉豆蔻酸酯13 -乙酸酯的呼吸爆发受损以及自发脱颗粒增加。在年龄匹配的组之间，糖酵解（通过细胞外通量和RNA测序评估）没有显著改变；然而，与健康年轻人相比，CAP患者和老年对照组中性粒细胞糖酵解的基础速率显著更高，并且与患有和未患有CAP的老年人相比，年轻人的刺激糖酵解显著更高。
我们的研究结果表明，老年CAP患者的中性粒细胞功能障碍可能与不良结局有关，而与糖酵解代谢无关。
