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COVID-19: High-JAKing of the Inflammatory “Flight” by Ruxolitinib to Avoid the Cytokine Storm

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 proinfla...

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Autores principales: Botta, Cirino, Indrieri, Alessia, Garofalo, Eugenio, Biamonte, Flavia, Bruni, Andrea, Pasqua, Pino, Cesario, Francesco, Costanzo, Francesco Saverio, Longhini, Federico, Mendicino, Francesco
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7819896/
https://www.ncbi.nlm.nih.gov/pubmed/33489899
http://dx.doi.org/10.3389/fonc.2020.599502
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author Botta, Cirino
Indrieri, Alessia
Garofalo, Eugenio
Biamonte, Flavia
Bruni, Andrea
Pasqua, Pino
Cesario, Francesco
Costanzo, Francesco Saverio
Longhini, Federico
Mendicino, Francesco
author_facet Botta, Cirino
Indrieri, Alessia
Garofalo, Eugenio
Biamonte, Flavia
Bruni, Andrea
Pasqua, Pino
Cesario, Francesco
Costanzo, Francesco Saverio
Longhini, Federico
Mendicino, Francesco
author_sort Botta, Cirino
collection PubMed
description 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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spelling pubmed-78198962021-01-23 COVID-19: High-JAKing of the Inflammatory “Flight” by Ruxolitinib to Avoid the Cytokine Storm Botta, Cirino Indrieri, Alessia Garofalo, Eugenio Biamonte, Flavia Bruni, Andrea Pasqua, Pino Cesario, Francesco Costanzo, Francesco Saverio Longhini, Federico Mendicino, Francesco Front Oncol Oncology 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. Frontiers Media S.A. 2021-01-08 /pmc/articles/PMC7819896/ /pubmed/33489899 http://dx.doi.org/10.3389/fonc.2020.599502 Text en Copyright © 2021 Botta, Indrieri, Garofalo, Biamonte, Bruni, Pasqua, Cesario, Costanzo, Longhini and Mendicino http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Oncology
Botta, Cirino
Indrieri, Alessia
Garofalo, Eugenio
Biamonte, Flavia
Bruni, Andrea
Pasqua, Pino
Cesario, Francesco
Costanzo, Francesco Saverio
Longhini, Federico
Mendicino, Francesco
COVID-19: High-JAKing of the Inflammatory “Flight” by Ruxolitinib to Avoid the Cytokine Storm
title COVID-19: High-JAKing of the Inflammatory “Flight” by Ruxolitinib to Avoid the Cytokine Storm
title_full COVID-19: High-JAKing of the Inflammatory “Flight” by Ruxolitinib to Avoid the Cytokine Storm
title_fullStr COVID-19: High-JAKing of the Inflammatory “Flight” by Ruxolitinib to Avoid the Cytokine Storm
title_full_unstemmed COVID-19: High-JAKing of the Inflammatory “Flight” by Ruxolitinib to Avoid the Cytokine Storm
title_short COVID-19: High-JAKing of the Inflammatory “Flight” by Ruxolitinib to Avoid the Cytokine Storm
title_sort covid-19: high-jaking of the inflammatory “flight” by ruxolitinib to avoid the cytokine storm
topic Oncology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7819896/
https://www.ncbi.nlm.nih.gov/pubmed/33489899
http://dx.doi.org/10.3389/fonc.2020.599502
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