Moussavi-Harami S F, Cleary S J, Magnen M, Seo Y, Conrad C, English B C, Qiu L, Wang K M, Abram C L, Lowell C A, Looney M R
Division of Pulmonary, Critical Care, Allergy and Sleep Medicine, Department of Medicine, University of California, San Francisco.
Division of Pediatric Critical Care Medicine, Department of Pediatrics, University of California, San Francisco.
bioRxiv. 2024 May 28:2024.05.23.595575. doi: 10.1101/2024.05.23.595575.
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 and ameliorated ALI-induced alveolar neutrophilia and NETs . We propose that the pharmacologic activation of Shp1 has the potential to fine-tune neutrophil hyperinflammation that is central to the pathogenesis of ARDS.
急性呼吸窘迫综合征（ARDS）与显著的发病率和死亡率相关，中性粒细胞对其发病机制至关重要。中性粒细胞的激活受包括含Src同源区2结构域的磷酸酶-1（Shp1）在内的抑制性酪氨酸磷酸酶的密切调控。在此，我们报告，在无菌性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缺失通过Syk激酶依赖性机制导致过度炎症和致命性肺出血。我们在中性粒细胞特异性Shp1基因敲除小鼠中观察到大量血管内中性粒细胞聚集、血管周围炎症和过量的中性粒细胞胞外陷阱，提示了观察到的肺出血的潜在机制。通过给予Shp1激活剂（SC43）进行靶向免疫调节可减少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中性粒细胞胞外陷阱形成。我们提出，Shp1的药物激活有可能微调对ARDS发病机制至关重要的中性粒细胞过度炎症。
