COVID-19: High-JAKing of the Inflammatory "Flight" by Ruxolitinib to Avoid the Cytokine Storm.
COVID-19: High-JAKing of the Inflammatory "Flight" by Ruxolitinib to Avoid the Cytokine Storm.
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DOI：
10.3389/fonc.2020.599502
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发表时间：
2020
影响因子：
4.7
通讯作者：
Mendicino F
中科院分区：
文献类型：
--
作者：
Botta C;Indrieri A;Garofalo E;Biamonte F;Bruni A;Pasqua P;Cesario F;Costanzo FS;Longhini F;Mendicino F
自2019年12月SARS-CoV-2爆发以来，世界卫生系统受到严重影响，住院人数增加，重症监护病房（ICU）的使用和高死亡率，主要是由于严重急性呼吸衰竭和多器官衰竭。促炎细胞因子的过度和不受控制的释放（细胞因子释放/风暴综合征，CRS）与这些事件的发生有关。用于治疗血液和实体肿瘤的免疫疗法的最新进展揭示了这种现象背后的许多分子机制，从而提供了改善COVID-19患者结局的多学科方法。事实上，目前可用的治疗策略，以克服CRS，应紧急评估其降低COVID-19死亡率的能力。值得注意的是，COVID-19与急性移植物抗宿主病（aGVHD）、噬血细胞淋巴组织细胞增多症（HLH）、骨髓纤维化和CAR-T相关CRS具有不同的致病性。具体而言，与aGVHD相似，诱导的组织损伤（由病毒引起）导致细胞因子释放（TNFα和IL-6）增加，进而导致树突状细胞、巨噬细胞（如HLH）和淋巴细胞（如CAR-T）活化过度，免疫细胞迁移和组织损伤（包括晚期纤维化，类似于骨髓纤维化）。Janus激酶（JAK）信号传导代表连接所有这些事件的分子枢纽，使得JAK抑制剂适合于限制压倒性炎症反应的有害作用。因此，ruxolitinib是唯一被批准用于治疗骨髓纤维化和aGVHD的选择性JAK 1和JAK 2抑制剂。在这里，我们从分子和血液学的角度讨论了在COVID-19患者管理中靶向JAK信号传导的基本原理，并报告了意大利首次接受鲁索替尼治疗的ICU患者的临床结果。
Since SARS-CoV-2 outbreak in December 2019, world health-system has been severely impacted with increased hospitalization, Intensive-Care-Unit (ICU) access and high mortality rates, mostly due to severe acute respiratory failure and multi-organ failure. Excessive and uncontrolled release of proinflammatory cytokines (cytokine release/storm syndrome, CRS) have been linked to the development of these events. The recent advancements of immunotherapy for the treatment of hematologic and solid tumors shed light on many of the molecular mechanisms underlying this phenomenon, thus rendering desirable a multidisciplinary approach to improve COVID-19 patients’ outcome. Indeed, currently available therapeutic-strategies to overcome CRS, should be urgently evaluated for their capability of reducing COVID-19 mortality. Notably, COVID-19 shares different pathogenic aspects with acute graft-versus-host-disease (aGVHD), hemophagocytic-lymphohistiocytosis (HLH), myelofibrosis, and CAR-T-associated CRS. Specifically, similarly to aGVHD, an induced tissue damage (caused by the virus) leads to increased cytokine release (TNFα and IL-6) which in turn leads to exaggerated dendritic cells, macrophages (like in HLH) and lymphocytes (as in CAR-T) activation, immune-cells migration, and tissue-damage (including late-stage fibrosis, similar to myelofibrosis). Janus Kinase (JAK) signaling represents a molecular hub linking all these events, rendering JAK-inhibitors suitable to limit deleterious effects of an overwhelming inflammatory-response. Accordingly, ruxolitinib is the only selective JAK1 and JAK2-inhibitor approved for the treatment of myelofibrosis and aGVHD. Here, we discuss, from a molecular and hematological point of view, the rationale for targeting JAK signaling in the management of COVID-19 patients and report the clinical results of a patient admitted to ICU among the firsts to be treated with ruxolitinib in Italy.
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