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首页> 美国卫生研究院文献>American Journal of Physiology - Lung Cellular and Molecular Physiology >Translational Research in Acute Lung Injury and Pulmonary Fibrosis: Imatinib attenuates inflammation and vascular leak in a clinically relevant two-hit model of acute lung injury
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Translational Research in Acute Lung Injury and Pulmonary Fibrosis: Imatinib attenuates inflammation and vascular leak in a clinically relevant two-hit model of acute lung injury

机译：急性肺损伤和肺纤维化的转化研究：伊马替尼在临床相关的两次急性肺损伤模型中减轻炎症和血管渗漏

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Acute lung injury/acute respiratory distress syndrome (ALI/ARDS), an illness characterized by life-threatening vascular leak, is a significant cause of morbidity and mortality in critically ill patients. Recent preclinical studies and clinical observations have suggested a potential role for the chemotherapeutic agent imatinib in restoring vascular integrity. Our prior work demonstrates differential effects of imatinib in mouse models of ALI, namely attenuation of LPS-induced lung injury but exacerbation of ventilator-induced lung injury (VILI). Because of the critical role of mechanical ventilation in the care of patients with ARDS, in the present study we pursued an assessment of the effectiveness of imatinib in a “two-hit” model of ALI caused by combined LPS and VILI. Imatinib significantly decreased bronchoalveolar lavage protein, total cells, neutrophils, and TNF-α levels in mice exposed to LPS plus VILI, indicating that it attenuates ALI in this clinically relevant model. In subsequent experiments focusing on its protective role in LPS-induced lung injury, imatinib attenuated ALI when given 4 h after LPS, suggesting potential therapeutic effectiveness when given after the onset of injury. Mechanistic studies in mouse lung tissue and human lung endothelial cells revealed that imatinib inhibits LPS-induced NF-κB expression and activation. Overall, these results further characterize the therapeutic potential of imatinib against inflammatory vascular leak.
机译：急性肺损伤/急性呼吸窘迫综合征（ALI / ARDS）是一种以危及生命的血管泄漏为特征的疾病，是重症患者发病和死亡的重要原因。最近的临床前研究和临床观察表明，化学治疗剂伊马替尼在恢复血管完整性方面具有潜在作用。我们的先前工作证明了伊马替尼在ALI小鼠模型中的不同作用，即减轻LPS诱导的肺损伤，但加重呼吸机诱导的肺损伤（VILI）。由于机械通气在ARDS患者的护理中起着至关重要的作用，因此在本研究中，我们对伊马替尼在LPS和VILI联合引起的ALI“两次打击” ALI模型中的有效性进行了评估。伊马替尼显着降低了暴露于LPS加VILI的小鼠的支气管肺泡灌洗蛋白，总细胞，中性粒细胞和TNF-α的水平，表明在此临床相关模型中它可减弱ALI。在随后的实验中，以伊马替尼在LPS诱导的肺损伤中的保护作用为重点，当在LPS给药4 h后给予伊马替尼减弱ALI，提示在损伤发作后给予伊马替尼可能具有治疗效果。在小鼠肺组织和人肺内皮细胞中的机理研究表明，伊马替尼抑制LPS诱导的NF-κB表达和激活。总体而言，这些结果进一步表征了伊马替尼抗炎性血管渗漏的治疗潜力。

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