Although transient bacteremia is common during dental and endoscopic procedures, infections developing during sterile diseases like acute pancreatitis (AP) can have grave consequences. We examined how impaired bacterial clearance may cause this transition. Blood samples from patients with AP, normal controls, and rodents with pancreatitis or those administered different nonesterified fatty acids (NEFAs) were analyzed for albumin-unbound NEFAs, microbiome, and inflammatory cell injury. Macrophage uptake of unbound NEFAs using a novel coumarin tracer were done and the downstream effects—NEFA–membrane phospholipid (phosphatidylcholine) interactions—were studied on isothermal titration calorimetry. Patients with infected AP had higher circulating unsaturated NEFAs; unbound NEFAs, including linoleic acid (LA) and oleic acid (OA); higher bacterial 16S DNA; mitochondrial DNA; altered β-diversity; enrichment in ; and increased annexin V–positive myeloid (CD14) and CD3-positive T cells on admission. These, and increased circulating dead inflammatory cells, were also noted in rodents with unbound, unsaturated NEFAs. Isothermal titration calorimetry showed progressively stronger unbound LA interactions with aqueous media, phosphatidylcholine, cardiolipin, and albumin. Unbound NEFAs were taken into protein-free membranes, cells, and mitochondria, inducing voltage-dependent anion channel oligomerization, reducing ATP, and impairing phagocytosis. These were reversed by albumin. In vivo, unbound LA and OA increased bacterial loads and impaired phagocytosis, causing infection. LA and OA were more potent for these amphipathic interactions than the hydrophobic palmitic acid. Release of stored LA and OA can increase their circulating unbound levels and cause amphipathic liponecrosis of immune cells via uptake by membrane phospholipids. This impairs bacterial clearance and causes infection during sterile inflammation.

中文翻译：

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两亲性脂肪坏死会损害细菌清除并在无菌炎症期间引起感染

尽管短暂性菌血症在牙科和内窥镜手术期间很常见，但急性胰腺炎 (AP) 等无菌性疾病期间发生的感染可能会产生严重后果。我们研究了细菌清除受损如何导致这种转变。对来自 AP 患者、正常对照、患有胰腺炎的啮齿动物或施用不同非酯化脂肪酸 (NEFA) 的动物的血液样本进行了分析，以了解未结合白蛋白的 NEFA、微生物组和炎症细胞损伤。使用新型香豆素示踪剂进行巨噬细胞摄取未结合的 NEFA，并通过等温滴定量热法研究下游效应 - NEFA - 膜磷脂（磷脂酰胆碱）相互作用。感染 AP 的患者具有较高的循环不饱和 NEFA；未结合的 NEFA，包括亚油酸 (LA) 和油酸 (OA)；更高的细菌16S DNA；线粒体DNA； β-多样性改变；丰富；入院时膜联蛋白 V 阳性骨髓 (CD14) 和 CD3 阳性 T 细胞增加。在具有未结合、不饱和 NEFA 的啮齿动物中也注意到了这些以及循环死亡炎症细胞的增加。等温滴定量热法显示未结合的 LA 与水介质、磷脂酰胆碱、心磷脂和白蛋白的相互作用逐渐增强。未结合的 NEFA 被带入无蛋白质的膜、细胞和线粒体中，诱导电压依赖性阴离子通道寡聚化、减少 ATP 并损害吞噬作用。这些可被白蛋白逆转。在体内，未结合的 LA 和 OA 会增加细菌负荷并削弱吞噬作用，从而引起感染。 LA 和 OA 对于这些两亲相互作用比疏水性棕榈酸更有效。储存的 LA 和 OA 的释放会增加其循环未结合水平，并通过膜磷脂的摄取导致免疫细胞两亲性脂肪坏死。这会损害细菌清除并在无菌炎症期间引起感染。