Growth hormone-releasing hormone receptor antagonist MIA-602 attenuates cardiopulmonary injury induced by BSL-2 rVSV-SARS-CoV-2 in hACE2 mice.
Growth hormone-releasing hormone receptor antagonist MIA-602 attenuates cardiopulmonary injury induced by BSL-2 rVSV-SARS-CoV-2 in hACE2 mice.
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DOI：
10.1073/pnas.2308342120
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发表时间：
2023-11-28
影响因子：
11.1
通讯作者：
Shehadeh, Lina A.
中科院分区：
文献类型：
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作者：
Capcha, Jose M. Condor;Kamiar, Ali;Robleto, Emely;Saad, Ali G.;Cui, Tengjiao;Wong, Amanda;Villano, Jason;Zhong, William;Pekosz, Andrew;Medina, Edgar;Cai, Renzhi;Sha, Wei;Ranek, Mark J.;Webster, Keith A.;Schally, Andrew V.;Jackson, Robert M.;Shehadeh, Lina A.
抗病毒和抗炎药物已显示出对抗ARDS/COVID的益处，但需要更有效的药理学。坏死性凋亡是包括Z-核酸结合蛋白1（ZBP 1）、受体相互作用蛋白激酶3（RIPK 3）和混合谱系激酶结构域样蛋白（MLKL）的信号级联下游细胞死亡的促炎形式，是ARDS/COVID免疫病理学的一部分。在这里，我们报告了GHRHR拮抗剂MIA-602中和ZBP 1/MLKL信号传导，阻断坏死性凋亡，并在VSV-SARS-CoV-2刺突蛋白驱动的ARDS/COVID小鼠模型中提供肺损伤保护。结果表明，通过靶向免疫失调的中枢途径，MIA-602提供了优于当前抗炎剂的益处，并保证了用于治疗与严重COVID-19感染相关的肺炎/ARDS的临床/转化开发。COVID-19肺炎导致急性肺损伤和急性呼吸窘迫综合征（ALI/ARDS），其特征为早期肺内皮和上皮损伤，伴有肺弥散能力改变和阻塞性或限制性生理学。生长激素释放激素受体（GHRH-R）在肺和心脏中表达。据报道，GHRH-R拮抗剂MIA-602可调节肉芽肿性结节病对博来霉素肺损伤和炎症的免疫反应。我们假设MIA-602将减轻BSL-2小鼠模型中rVSV-SARS-CoV-2诱导的肺功能障碍和心脏损伤。雄性和雌性K18-hACE 2 tg小鼠接种SARS-CoV-2/USA-WA 1/2020、符合BSL-2的重组VSV-eGFP-SARS-CoV-2-Spike（rVSV-SARS-CoV-2）或PBS，并比较肺病毒载量、体重减轻、组织病理学和基因表达。每天用皮下MIA-602或媒介物处理感染rVSV-SARS-CoV-2的K18-hACE 2 tg小鼠，并在第0、3和5天进行有意识的、无限制的体积描记（n = 7至8）。感染后5天，处死小鼠，收集血液和组织用于组织病理学和蛋白质/基因表达。天然SARS-CoV-2和rVSV-SARS-CoV-2在体重减轻、感染性（~60%）和组织病理学变化方面表现出相似的模式。与媒介物相比，用MIA-602每日治疗赋予体重恢复，减少肺血管周围炎症/肺炎，并降低肺/心脏ICAM-1表达。与媒介物相比，MIA-602挽救了改变的呼吸速率、增加的呼气参数（Te、PEF、EEP）和标准化的气流参数（Penh和Rpef），与降低的气道炎症一致。RNASeq随后进行蛋白质分析显示炎症和终末期坏死性凋亡标志物水平升高，包括由rVSV-SARS-CoV-2诱导的ZBP 1和pMLKL，其通过MIA-602治疗正常化，与COVID-19肺炎临床前模型中的抗炎和促生存作用机制一致。
Anti-viral and anti-inflammatory drugs have shown benefit against ARDS/COVID but more effective pharmacology is needed. Necroptosis, a proinflammatory form of cell death downstream of a signalling cascade that includes Z-nucleic acid-binding protein 1 (ZBP1), receptor interacting protein kinase 3 (RIPK3), and mixed lineage kinase domain-like protein (MLKL), is part of the immune pathology of ARDS/COVID. Here we report that GHRHR antagonist MIA-602 neutralizes ZBP1/MLKL signalling, blocks necroptosis and confers protection against lung injury in a mouse model of ARDS/COVID driven by VSV-SARS-CoV-2 spike protein. The results show that by targeting a central pathway of immune dysregulation, MIA-602 provides benefit over current anti-inflammatory agents and warrants clinical/translational development for the treatment of pneumonia/ARDS associated with severe COVID-19 infection. COVID-19 pneumonia causes acute lung injury and acute respiratory distress syndrome (ALI/ARDS) characterized by early pulmonary endothelial and epithelial injuries with altered pulmonary diffusing capacity and obstructive or restrictive physiology. Growth hormone–releasing hormone receptor (GHRH-R) is expressed in the lung and heart. GHRH-R antagonist, MIA-602, has been reported to modulate immune responses to bleomycin lung injury and inflammation in granulomatous sarcoidosis. We hypothesized that MIA-602 would attenuate rVSV-SARS-CoV-2-induced pulmonary dysfunction and heart injury in a BSL-2 mouse model. Male and female K18-hACE2tg mice were inoculated with SARS-CoV-2/USA-WA1/2020, BSL-2-compliant recombinant VSV-eGFP-SARS-CoV-2-Spike (rVSV-SARS-CoV-2), or PBS, and lung viral load, weight loss, histopathology, and gene expression were compared. K18-hACE2tg mice infected with rVSV-SARS-CoV-2 were treated daily with subcutaneous MIA-602 or vehicle and conscious, unrestrained plethysmography performed on days 0, 3, and 5 (n = 7 to 8). Five days after infection mice were killed, and blood and tissues collected for histopathology and protein/gene expression. Both native SARS-CoV-2 and rVSV-SARS-CoV-2 presented similar patterns of weight loss, infectivity (~60%), and histopathologic changes. Daily treatment with MIA-602 conferred weight recovery, reduced lung perivascular inflammation/pneumonia, and decreased lung/heart ICAM-1 expression compared to vehicle. MIA-602 rescued altered respiratory rate, increased expiratory parameters (Te, PEF, EEP), and normalized airflow parameters (Penh and Rpef) compared to vehicle, consistent with decreased airway inflammation. RNASeq followed by protein analysis revealed heightened levels of inflammation and end-stage necroptosis markers, including ZBP1 and pMLKL induced by rVSV-SARS-CoV-2, that were normalized by MIA-602 treatment, consistent with an anti-inflammatory and pro-survival mechanism of action in this preclinical model of COVID-19 pneumonia.
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DOI：
10.1073/pnas.1712612114
发表时间：
2017-11-07
影响因子：
11.1
作者：
Gesmundo I;Miragoli M;Carullo P;Trovato L;Larcher V;Di Pasquale E;Brancaccio M;Mazzola M;Villanova T;Sorge M;Taliano M;Gallo MP;Alloatti G;Penna C;Hare JM;Ghigo E;Schally AV;Condorelli G;Granata R
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Granata R
DOI：
10.3390/antib12010017
发表时间：
2023-02-23
期刊：
Antibodies (Basel, Switzerland)
影响因子：
--
作者：
通讯作者：
--
影响因子：
38.9
作者：
Auriemma, Catherine L.;Zhuo, Hanjing;Calfee, Carolyn S.
通讯作者：
Calfee, Carolyn S.
影响因子：
3.6
作者：
Condor Capcha JM;Lambert G;Dykxhoorn DM;Salerno AG;Hare JM;Whitt MA;Pahwa S;Jayaweera DT;Shehadeh LA
通讯作者：
Shehadeh LA
DOI：
10.3390/molecules28010052
发表时间：
2022-12-21
期刊：
Molecules (Basel, Switzerland)
影响因子：
--
作者：
Chen XY;Dai YH;Wan XX;Hu XM;Zhao WJ;Ban XX;Wan H;Huang K;Zhang Q;Xiong K
通讯作者：
Xiong K