Analysis of AT7519 and acetaminophen in a mouse model of acute inflammation by LC-MS/MS

This dataset is the LC-MS/MS analysis of quantities of acetaminophen (APAP) and the drug AT7519 in a preclinical study, as described. Neutrophils are crucial innate immune cells required for host pathogen defense, with multifaceted roles, recognized both in disease pathogenesis and increasingly during tissue repair. Neutrophil actions during acetaminophen (APAP)-induced acute liver injury (ALI), the leading cause of acute liver failure-induced death in the western world, are controversial. Most publications indicate neutrophils contribute to APAP-ALI, but recent reports highlight their reparative function, and no studies evaluate both injury and repair times. Through a combination of pharmacological (AT7519) neutrophil depletion and genetic prevention of formylated peptide receptor 1 induction of neutrophil activation and chemotaxis, we show that they contribute both to hepatic damage and repair during APAP-ALI. We highlight APAP-ALI neutrophil reparative roles include hepatic extracellular matrix remodeling, angiogenesis and an anti-inflammatory monocyte/macrophage phenotype. This study resolves the time dependent dichotomous role of neutrophils in APAP-ALI, and informs future therapeutic strategies to modulate neutrophil function in APAP-ALI.

本数据集源自一项临床前研究，包含对乙酰氨基酚（acetaminophen, APAP）与药物AT7519的液相色谱-串联质谱（Liquid Chromatography-Tandem Mass Spectrometry, LC-MS/MS）定量分析数据。中性粒细胞（Neutrophils）是宿主抵御病原体的关键固有免疫细胞，兼具多重功能，其在疾病发病机制中的作用已得到广泛认知，近年来在组织修复过程中的功能也日益受到关注。对乙酰氨基酚诱导的急性肝损伤（acetaminophen-induced acute liver injury, ALI）是西方世界急性肝衰竭致死的首要诱因，目前学界对中性粒细胞在此病理过程中的作用尚存争议。多数现有研究认为中性粒细胞会加重对乙酰氨基酚诱导的急性肝损伤，但近期研究则指出其具有修复功能，且目前尚无研究同时评估中性粒细胞在损伤期与修复期的作用。本研究通过药物（AT7519）介导的中性粒细胞耗竭，以及联合基因手段抑制甲酰肽受体1（formylated peptide receptor 1）介导的中性粒细胞活化与趋化作用，证实中性粒细胞在对乙酰氨基酚诱导的急性肝损伤过程中，同时参与了肝损伤与组织修复两个进程。本研究进一步明确，中性粒细胞在对乙酰氨基酚诱导的急性肝损伤中的修复功能包括：肝组织细胞外基质重塑、血管生成，以及介导抗炎型单核细胞/巨噬细胞表型的形成。本研究阐明了中性粒细胞在对乙酰氨基酚诱导的急性肝损伤中随时间变化的双重作用，可为未来调控该疾病中中性粒细胞功能的治疗策略提供理论依据。