Angiopoietin 2 Is Associated with Vascular Necroptosis Induction in Coronavirus Disease 2019 Acute Respiratory Distress Syndrome.
Angiopoietin 2 Is Associated with Vascular Necroptosis Induction in Coronavirus Disease 2019 Acute Respiratory Distress Syndrome.
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DOI：
10.1016/j.ajpath.2022.04.002
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发表时间：
2022-07
影响因子：
6
通讯作者：
Rafii, Shahin
中科院分区：
文献类型：
--
作者：
Price, David R.;Benedetti, Elisa;Hoffman, Katherine L.;Gomez-Escobar, Luis;Alvarez-Mulett, Sergio;Capili, Allyson;Sarwath, Hina;Parkhurst, Christopher N.;Lafond, Elyse;Weidman, Karissa;Ravishankar, Arjun;Cheong, Jin Gyu;Batra, Richa;Buyukozkan, Mustafa;Chetnik, Kelsey;Easthausen, Imaani;Schenck, Edward J.;Racanelli, Alexandra C.;Reed, Hasina Outtz;Laurence, Jeffrey;Josefowicz, Steven Z.;Lief, Lindsay;Choi, Mary E.;Schmidt, Frank;Borczuk, Alain C.;Choi, Augustine M. K.;Krumsiek, Jan;Rafii, Shahin
血管损伤是急性呼吸窘迫综合征 (ARDS) 发病机制中一个公认的疾病缓解因素。最近，2019 冠状病毒病 (COVID-19) 引起的血管室损伤与补体激活、微血管血栓形成和免疫反应失调有关。本研究旨在评估这种促血栓背景下的异常血管激活是否与诱导坏死性血管细胞死亡相关。为了实现这一目标，我们对 ARDS 发病过程中不同时间点的 COVID-19 受试者的血液样本进行了蛋白质组分析（住院风险，N = 59；ARDS，N = 31；康复，N = 12）。对高危人群中循环血管标志物的评估揭示了血管蛋白丰度低的特征，该特征与血小板水平低和死亡率增加有关。这一特征在 ARDS 队列中得到了复制，并与血浆血管生成素 2 水平升高相关。 COVID-19 ARDS 肺尸检免疫染色证实了血管损伤（血管生成素 2）和富含血小板的微血栓 (CD61) 以及诱导坏死性细胞死亡 [磷酸化混合谱系激酶结构域样 (pMLKL)] 之间的联系。在康复受试者中，血管特征识别出功能结果较差的患者。总而言之，这种血管损伤特征与低血小板水平和死亡率增加有关，可用于识别最有可能从血管靶向治疗中受益的 ARDS 患者。
Vascular injury is a well-established, disease-modifying factor in acute respiratory distress syndrome (ARDS) pathogenesis. Recently, coronavirus disease 2019 (COVID-19)–induced injury to the vascular compartment has been linked to complement activation, microvascular thrombosis, and dysregulated immune responses. This study sought to assess whether aberrant vascular activation in this prothrombotic context was associated with the induction of necroptotic vascular cell death. To achieve this, proteomic analysis was performed on blood samples from COVID-19 subjects at distinct time points during ARDS pathogenesis (hospitalized at risk, N = 59; ARDS, N = 31; and recovery, N = 12). Assessment of circulating vascular markers in the at-risk cohort revealed a signature of low vascular protein abundance that tracked with low platelet levels and increased mortality. This signature was replicated in the ARDS cohort and correlated with increased plasma angiopoietin 2 levels. COVID-19 ARDS lung autopsy immunostaining confirmed a link between vascular injury (angiopoietin 2) and platelet-rich microthrombi (CD61) and induction of necrotic cell death [phosphorylated mixed lineage kinase domain-like (pMLKL)]. Among recovery subjects, the vascular signature identified patients with poor functional outcomes. Taken together, this vascular injury signature was associated with low platelet levels and increased mortality and can be used to identify ARDS patients most likely to benefit from vascular targeted therapies.
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