Division of Pediatric Surgery, Department of Surgery, Johns Hopkins University , Baltimore, Maryland.
Department of Pediatrics, Carver College of Medicine, The University of Iowa , Iowa City, Iowa.
Am J Physiol Lung Cell Mol Physiol. 2018 Jan 1;314(1):L17-L31. doi: 10.1152/ajplung.00498.2016. Epub 2017 Sep 21.
Angiotensin-converting enzyme 2 (ACE2) is a terminal carboxypeptidase with important functions in the renin-angiotensin system and plays a critical role in inflammatory lung diseases. ACE2 cleaves single-terminal residues from several bioactive peptides such as angiotensin II. However, few of its substrates in the respiratory tract have been identified, and the mechanism underlying the role of ACE2 in inflammatory lung disease has not been fully characterized. In an effort to identify biological targets of ACE2 in the lung, we tested its effects on des-Arg bradykinin (DABK) in airway epithelial cells on the basis of the hypothesis that DABK is a biological substrate of ACE2 in the lung and ACE2 plays an important role in the pathogenesis of acute lung inflammation partly through modulating DABK/bradykinin receptor B1 (BKB1R) axis signaling. We found that loss of ACE2 function in mouse lung in the setting of endotoxin inhalation led to activation of the DABK/BKB1R axis, release of proinflammatory chemokines such as C-X-C motif chemokine 5 (CXCL5), macrophage inflammatory protein-2 (MIP2), C-X-C motif chemokine 1 (KC), and TNF-α from airway epithelia, increased neutrophil infiltration, and exaggerated lung inflammation and injury. These results indicate that a reduction in pulmonary ACE2 activity contributes to the pathogenesis of lung inflammation, in part because of an impaired ability to inhibit DABK/BKB1R axis-mediated signaling, resulting in more prompt onset of neutrophil infiltration and more severe inflammation in the lung. Our study identifies a biological substrate of ACE2 within the airways, as well as a potential new therapeutic target for inflammatory diseases.
血管紧张素转换酶 2（ACE2）是一种末端羧肽酶，在肾素-血管紧张素系统中具有重要功能，在炎症性肺病中发挥关键作用。ACE2 从几种生物活性肽（如血管紧张素 II）中切割单末端残基。然而，其在呼吸道中的底物很少被鉴定，ACE2 在炎症性肺病中的作用机制尚未完全阐明。为了鉴定 ACE2 在肺部的生物学靶标，我们根据 DABK 是 ACE2 在肺部的生物底物的假设，在气道上皮细胞上测试 ACE2 对去精氨酸缓激肽（DABK）的作用，ACE2 通过调节 DABK/缓激肽受体 B1（BKB1R）轴信号在急性肺炎症的发病机制中发挥重要作用。我们发现，在脂多糖吸入的情况下，小鼠肺中 ACE2 功能的丧失导致 DABK/BKB1R 轴的激活，从气道上皮细胞释放促炎趋化因子，如 C-X-C 基序趋化因子 5（CXCL5）、巨噬细胞炎症蛋白 2（MIP2）、C-X-C 基序趋化因子 1（KC）和 TNF-α，增加中性粒细胞浸润，并加剧肺炎症和损伤。这些结果表明，肺 ACE2 活性的降低导致肺炎症的发病机制，部分原因是抑制 DABK/BKB1R 轴介导的信号的能力受损，导致中性粒细胞更快地浸润和肺部更严重的炎症。我们的研究鉴定了气道内 ACE2 的生物底物，以及炎症性疾病的潜在新治疗靶点。
