Neutrophil-specific Shp1 loss results in lethal pulmonary hemorrhage in mouse models of acute lung injury.

IF 13.3 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL
S Farshid Moussavi-Harami, Simon J Cleary, Mélia Magnen, Yurim Seo, Catharina Conrad, Bevin C English, Longhui Qiu, Kristin M Wang, Clare L Abram, Clifford A Lowell, Mark R Looney
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Abstract

The acute respiratory distress syndrome (ARDS) is associated with significant morbidity and mortality and neutrophils are critical to its pathogenesis. Neutrophil activation is closely regulated by inhibitory tyrosine phosphatases including Src homology region 2 domain containing phosphatase-1 (Shp1). Here, we report that loss of neutrophil Shp1 in mice produced hyperinflammation and lethal pulmonary hemorrhage in sterile inflammation and pathogen-induced models of acute lung injury (ALI) through a Syk kinase-dependent mechanism. We observed large intravascular neutrophil clusters, perivascular inflammation, and excessive neutrophil extracellular traps in neutrophil-specific Shp1 knockout mice suggesting an underlying mechanism for the observed pulmonary hemorrhage. Targeted immunomodulation through the administration of a Shp1 activator (SC43) reduced agonist-induced reactive oxygen species in vitro and ameliorated ALI-induced alveolar neutrophilia and NETs in vivo. We propose that the pharmacologic activation of Shp1 has the potential to fine-tune neutrophil hyperinflammation that is central to the pathogenesis of ARDS.

在急性肺损伤小鼠模型中,中性粒细胞特异性 Shp1 的缺失会导致致命的肺出血。
急性呼吸窘迫综合征(ARDS)与严重的发病率和死亡率有关,而中性粒细胞对其发病机制至关重要。中性粒细胞的活化受到抑制性酪氨酸磷酸酶的密切调控,其中包括含 Src 同源区域 2 结构域的磷酸酶-1(Shp1)。在此,我们报告了在无菌炎症和病原体诱导的急性肺损伤(ALI)模型中,小鼠中性粒细胞 Shp1 的缺失会通过 Syk 激酶依赖机制产生过度炎症和致命的肺出血。我们在中性粒细胞特异性 Shp1 基因敲除小鼠中观察到了大的血管内中性粒细胞集群、血管周围炎症和过多的中性粒细胞胞外捕获物,这表明观察到的肺出血是一种潜在的机制。通过施用 Shp1 激活剂(SC43)进行靶向免疫调节可减少体外激动剂诱导的活性氧,并改善 ALI 诱导的肺泡中性粒细胞增多和体内 NET。我们认为,药理激活 Shp1 有可能微调中性粒细胞的高炎症反应,而这正是 ARDS 发病机制的核心。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Journal of Clinical Investigation
Journal of Clinical Investigation 医学-医学:研究与实验
CiteScore
24.50
自引率
1.30%
发文量
1034
审稿时长
2 months
期刊介绍: The Journal of Clinical Investigation, established in 1924 by the ASCI, is a prestigious publication that focuses on breakthroughs in basic and clinical biomedical science, with the goal of advancing the field of medicine. With an impressive Impact Factor of 15.9 in 2022, it is recognized as one of the leading journals in the "Medicine, Research & Experimental" category of the Web of Science. The journal attracts a diverse readership from various medical disciplines and sectors. It publishes a wide range of research articles encompassing all biomedical specialties, including Autoimmunity, Gastroenterology, Immunology, Metabolism, Nephrology, Neuroscience, Oncology, Pulmonology, Vascular Biology, and many others. The Editorial Board consists of esteemed academic editors who possess extensive expertise in their respective fields. They are actively involved in research, ensuring the journal's high standards of publication and scientific rigor.
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