Attenuation of pulmonary ACE2 activity impairs inactivation of des-Arg9 bradykinin/BKB1R axis and facilitates LPS-induced neutrophil infiltration
Attenuation of pulmonary ACE2 activity impairs inactivation of des-Arg9 bradykinin/BKB1R axis and facilitates LPS-induced neutrophil infiltration
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DOI：
10.1152/ajplung.00498.2016
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发表时间：
2018-01-01
影响因子：
4.9
通讯作者：
Jia, Hongpeng
中科院分区：
文献类型：
--
作者：
Sodhi, Chhinder P.;Wohlford-Lenane, Christine;Jia, Hongpeng
血管紧张素转换酶2(ACE2)是一种在肾素-血管紧张素系统中具有重要作用的末端羧肽酶，在炎症性肺部疾病中起重要作用。ACE2从血管紧张素Ⅱ等生物活性多肽中切割出单端残基。然而，其在呼吸道中的底物很少被鉴定，ACE2在炎症性肺部疾病中的作用机制尚未完全确定。为了确定ACE2在肺中的生物学靶点，我们在假设DABK是ACE2在肺中的生物底物以及ACE2部分通过调节DABK/缓激肽受体B1(BKB1R)轴信号转导的基础上，检测了ACE2对气道上皮细胞Des-Arg(9)缓激肽(DABK)的影响。我们发现，在内毒素吸入的环境下，小鼠肺内ACE2功能的丧失导致DABK/BKB1R轴的激活，C-X-C基序趋化因子5(CXCL5)、巨噬细胞炎性蛋白-2(MIP2)、C-X-C基序趋化因子1(KC)和肿瘤坏死因子-α(TNF-α)等促炎趋化因子的释放，增加了中性粒细胞的浸润，并加重了肺的炎症和损伤。这些结果表明，肺ACE2活性降低参与了肺部炎症的发病机制，部分原因是抑制DABK/BKB1R轴介导的信号转导的能力受损，导致中性粒细胞更迅速地渗入肺内，导致肺内更严重的炎症。我们的研究确定了ACE2在呼吸道中的生物底物，以及一个潜在的炎症性疾病的新治疗靶点。
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(9) 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-alpha 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.