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首页> 外文期刊>American Journal of Physiology >Inhibiting Bruton's tyrosine kinase rescues mice from lethal influenza-induced acute lung injury
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Inhibiting Bruton's tyrosine kinase rescues mice from lethal influenza-induced acute lung injury

机译：抑制Bruton的酪氨酸激酶从致命流感诱导的急性肺损伤救出小鼠

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Infection with seasonal influenza A vims (IAV) leads to lung inflammation and respiratory failure, a main cause of death in influenza-infected patients. Previous experiments in our laboratory indicate that Bruton's tyrosine kinase (Btk) plays a substantial role in regulating inflammation in the respiratory region during acute lung injury in mice; therefore, we sought to determine if blocking Btk activity has a protective effect in the lung during influenza-induced inflammation. The Btk inhibitor ibrutinib (also known as PCI-32765) was administered intranasally to mice starting 72 h after lethal infection with IAV. Our data indicate that treatment with the Btk inhibitor not only reduced weight loss and led to survival, but also had a dramatic effect on morphological changes to the lungs, in IAV-infected mice. Attenuation of lung inflammation indicative of acute lung injury, such as alveolar hemorrhage, interstitial thickening, and the presence of alveolar exudate, together with reduced levels of the inflammatory mediators TNF? IL-1? IL-6, KC, and MCP-1, strongly suggests amelioration of the pathological immune response in the lungs to promote resolution of the infection. Finally, we observed that blocking Btk specifically in the alveolar compartment led to significant attenuation of neutrophil extracellular traps released into the lung in vivo and neutrophil extracellular trap formation in vitro. Our innovative findings suggest that Btk may be a new drug target for influenza-induced lung injury, and, in general, that immunomodulatory treatment may be key in treating kung dysfunction driven by excessive inflammation.
机译：用季节性流感感染vims（IAV）导致肺炎和呼吸衰竭，是流感感染患者死亡的主要原因。我们实验室中的先前实验表明，Bruton的酪氨酸激酶（BTK）在调节小鼠急性肺损伤期间调节呼吸系统区域中的炎症作用很大;因此，我们试图确定在流感诱导的炎症期间阻断BTK活性是否对肺部有保护作用。将BTK抑制剂伊布洛替尼（也称为PCI-32765）鼻内给予72小时在用IAV致死感染后开始的小鼠。我们的数据表明，随着BTK抑制剂的治疗不仅减轻了减肥，导致生存，而且对IAV感染的小鼠的形态学变化也具有显着影响。肺炎的衰减表明急性肺损伤，如肺泡出血，间质增稠和肺泡渗出物的存在，以及炎症介质的降低水平TNF？ IL-1？ IL-6，KC和MCP-1强烈建议改善肺部病理免疫应答，以促进对感染的解决。最后，我们观察到，特异性地在肺泡室中阻断BTK导致中性粒细胞细胞外捕集器的显着衰减在体外体内释放到肺中的肺部和中性粒细胞细胞外捕集器形成。我们的创新研究结果表明，BTK可能是流感肺损伤的新药物靶标，通常，免疫调节治疗可能是治疗通过过度炎症驱动的Kung功能障碍的关键。

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