Protease-anti-protease compartmentalization in SARS-CoV-2 ARDS: Therapeutic implications.
Protease-anti-protease compartmentalization in SARS-CoV-2 ARDS: Therapeutic implications.
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DOI：
10.1016/j.ebiom.2022.103894
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发表时间：
2022-03
期刊：
影响因子：
11.1
通讯作者：
McElvaney NG
中科院分区：
文献类型：
--
作者：
McElvaney OF;Asakura T;Meinig SL;Torres-Castillo JL;Hagan RS;Gabillard-Lefort C;Murphy MP;Thorne LB;Borczuk A;Reeves EP;Zumwalt RE;Mikami Y;Carroll TP;Okuda K;Hogan G;McElvaney OJ;Clarke J;McEvoy NL;Mallon PW;McCarthy C;Curley G;Wolfgang MC;Boucher RC;McElvaney NG
白细胞介素 6 (IL-6) 在 SARS-CoV-2 感染中升高。 IL-6 调节急性期蛋白，例如 α-1 抗胰蛋白酶 (AAT)，一种关键的肺部抗蛋白酶。我们研究了 SARS-CoV-2 急性呼吸窘迫综合征 (ARDS) 与非 SARS-CoV-2 ARDS (nsARDS) 循环和肺室中蛋白酶-抗蛋白酶平衡，以及托珠单抗（IL-6 受体拮抗剂）对 SARS-CoV-2 感染中抗蛋白酶防御的影响。测量了 SARS-CoV-2 ARDS 或 nsARDS 患者血浆、气道组织和气管分泌物 (TA) 中 AAT 和中性粒细胞弹性蛋白酶 (NE) 的水平和活性。在接受标准护理+/-托珠单抗的中度 SARS-CoV-2 感染患者中评估了 AAT 和 IL-6 水平。 SARS-CoV-2 ARDS 中 AAT 血浆水平翻倍。在肺实质中，AAT 水平增加，参与 NET 形成的中性粒细胞百分比也增加。在具有活性 NE 而无活性 AAT 的 TA 中检测到蛋白酶-抗蛋白酶失衡。气道抗蛋白酶、分泌性白细胞蛋白酶抑制剂在 SARS-CoV-2 感染的肺部中减少，并在 TA 中裂解。在 nsARDS 中，血浆 AAT 水平升高，但 TA 样品的 AAT 裂解较少，大多数样品中未检测到活性 NE。 ARDS 中 AAT 的诱导主要通过 IL-6 发生。托珠单抗在 SARS-CoV-2 感染期间下调 AAT。 SARS-CoV-2-ARDS 患者气道中存在蛋白酶-抗蛋白酶失衡。这种不平衡是抗蛋白酶治疗的目标。
Interleukin-6 (IL-6) is elevated in SARS-CoV-2 infection. IL-6 regulates acute-phase proteins, such as alpha-1 antitrypsin (AAT), a key lung anti-protease. We investigated the protease-anti-protease balance in the circulation and pulmonary compartments in SARS-CoV-2 acute respiratory distress syndrome (ARDS) compared to non-SARS-CoV-2 ARDS (nsARDS) and the effects of tocilizumab (IL-6 receptor antagonist) on anti-protease defence in SARS-CoV-2 infection. Levels and activity of AAT and neutrophil elastase (NE) were measured in plasma, airway tissue and tracheal secretions (TA) of people with SARS-CoV-2 ARDS or nsARDS. AAT and IL-6 levels were evaluated in people with moderate SARS-CoV-2 infection who received standard of care +/- tocilizumab. AAT plasma levels doubled in SARS-CoV-2 ARDS. In lung parenchyma AAT levels were increased, as was the percentage of neutrophils involved in NET formation. A protease-anti-protease imbalance was detected in TA with active NE and no active AAT. The airway anti-protease, secretory leukoprotease inhibitor was decreased in SARS-CoV-2-infected lungs and cleaved in TA. In nsARDS, plasma AAT levels were elevated but TA samples had less AAT cleavage, with no detectable active NE in most samples Induction of AAT in ARDS occurred mainly through IL-6. Tocilizumab down-regulated AAT during SARS-CoV-2 infection. There is a protease-anti-protease imbalance in the airways of SARS-CoV-2-ARDS patients. This imbalance is a target for anti-protease therapy.
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影响因子：
64.5
作者：
Hou, Yixuan J.;Okuda, Kenichi;Baric, Ralph S.
通讯作者：
Baric, Ralph S.
DOI：
10.1164/rccm.202005-1583oc
发表时间：
2020-09-15
影响因子：
24.7
作者：
McElvaney, Oliver J.;McEvoy, Natalie L.;McElvaney, Noel G.
通讯作者：
McElvaney, Noel G.
影响因子：
24.3
作者：
Betsuyaku, T;Takeyabu, K;Nishimura, M
通讯作者：
Nishimura, M
影响因子：
--
作者：
Azouz NP;Klingler AM;Callahan V;Akhrymuk IV;Elez K;Raich L;Henry BM;Benoit JL;Benoit SW;Noé F;Kehn-Hall K;Rothenberg ME
通讯作者：
Rothenberg ME
影响因子：
3.7
作者：
Eskandari A;Brojakowska A;Bisserier M;Bander J;Garikipati VNS;Hadri L;Goukassian D;Fish K
通讯作者：
Fish K