Mechano-inflammatory sensitivity of ACE2: Implications for the regional distribution of SARS-CoV-2 injury in the lung.
Mechano-inflammatory sensitivity of ACE2: Implications for the regional distribution of SARS-CoV-2 injury in the lung.
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DOI：
10.1016/j.resp.2021.103804
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发表时间：
2022-03
影响因子：
2.3
通讯作者：
Suki B
中科院分区：
文献类型：
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作者：
Bartolák-Suki E;Mondoñedo JR;Suki B
由SARS-CoV-2引起的冠状病毒病（COVID-19）可导致严重的肺损伤。计算机断层扫描图像显示，该病毒优先影响肺的底部，该底部比顶部经历更大的潮汐伸展。我们假设SARS-CoV-2的血管紧张素转换酶2（ACE 2）受体和跨膜丝氨酸蛋白酶2（TMPRSS 2）的表达对肺中的区域细胞拉伸敏感。为了检验这一假设，我们用以下方案之一拉伸精密切割肺切片（PCLS）12小时：1）未拉伸（US）; 2）低拉伸（LS），5%峰间面积应变模仿肺基底;或3）高拉伸（HS），相同峰间面积应变叠加在10%静态面积拉伸上模仿肺尖。PCLS另外在香烟烟雾提取物（CSE）中拉伸以模拟急性炎症暴露。与HS相比，LS后对照样品中ACE 2的表达更高，而TMPRSS 2的表达更低。CSE诱导的炎症显著改变了ACE 2的表达，HS后ACE 2的表达水平高于LS。这些结果表明，肺细胞中ACE 2和TMPRSS 2的表达是机械敏感性的，这可能对COVID-19介导的肺损伤的空间分布以及活动性吸烟者和COPD患者更严重疾病的风险增加具有影响。
The coronavirus disease (COVID-19) caused by SARS-CoV-2 can result in severe injury to the lung. Computed tomography images have revealed that the virus preferentially affects the base of the lung, which experiences larger tidal stretches than the apex. We hypothesize that the expression of both the angiotensin converting enzyme-2 (ACE2) receptor for SARS-CoV-2 and the transmembrane serine protease 2 (TMPRSS2) are sensitive to regional cell stretch in the lung. To test this hypothesis, we stretched precision cut lung slices (PCLS) for 12 h with one of the following protocols: 1) unstretched (US); 2) low-stretch (LS), 5% peak-to-peak area strain mimicking the lung base; or 3) high-stretch (HS), the same peak-to-peak area strain superimposed on 10% static area stretch mimicking the lung apex. PCLS were additionally stretched in cigarette smoke extract (CSE) to mimic an acute inflammatory exposure. The expression of ACE2 was higher whereas that of TMPRSS2 was lower in the control samples following LS than HS. CSE-induced inflammation substantially altered the expression of ACE2 with higher levels following HS than LS. These results suggest that ACE2 and TMPRSS2 expression in lung cells is mechanosensitive, which could have implications for the spatial distribution of COVID-19-mediated lung injury and the increased risk for more severe disease in active smokers and patients with COPD.