Inflammatory tissue injury such as acute lung injury (ALI) is a disorder that leads to respiratory failure, a major cause of morbidity and mortality worldwide. Excessive neutrophil influx is a critical pathogenic factor in the development of ALI. Here, we identify the subset of neutrophils that is responsible for ALI and lethality in polymicrobial sepsis. The pro-inflammatory neutrophil subpopulation was characterized by its unique ability to endocytose albumin nanoparticles (ANP), upregulation of pro-inflammatory cytokines and chemokines as well as the excessive production of reactive oxygen species (ROS) in models of endotoxemia and septicemia. ANP delivery of the drug piceatannol, a spleen tyrosine kinase (Syk) inhibitor, to the susceptible subset of neutrophils, prevented ALI and mortality in mice subjected to polymicrobial infection. Targeted inhibition of Syk in ANP-susceptible neutrophils had no detrimental effect on neutrophil-dependent host defense because the subset of ANPlow neutrophils effectively controlled polymicrobial infection. The results show that neutrophil heterogeneity can be leveraged therapeutically to prevent ALI without compromising host defense.

中文翻译：

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嗜中性粒细胞亚群介导炎性损伤的选择性Nanotherapeutic靶向。

炎性组织损伤，例如急性肺损伤（ALI），是导致呼吸衰竭的疾病，呼吸衰竭是全球发病率和死亡率的主要原因。中性粒细胞大量涌入是ALI发生的关键致病因素。在这里，我们确定了嗜中性粒细胞的亚群，该亚群是导致ALI和致死性的微生物败血症。促炎性中性粒细胞亚群的特征在于其在内毒素血症和败血病模型中内吞酶白蛋白纳米颗粒（ANP）的独特能力，促炎性细胞因子和趋化因子的上调以及活性氧（ROS）的过量产生。ANP将药物皮卡季诺醇（一种脾酪氨酸激酶（Syk）抑制剂）向嗜中性粒细胞的易感亚群递送，可防止ALI和致死微生物的小鼠死亡。在ANP敏感的中性粒细胞中有针对性地抑制Syk对中性粒细胞依赖的宿主防御没有不利影响，因为ANPlow中性粒细胞的亚群有效控制了微生物感染。结果表明，嗜中性粒细胞异质性可在治疗上利用以预防ALI而不会损害宿主防御。