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Small molecule inhibitor CRT0066101 inhibits cytokine storm syndrome in a mouse model of lung injury

Pneumonia is an acute inflammation of the lungs induced by pathogenic microorganisms, immune damage, physical and chemical factors, and other factors, and the latest outbreak of novel coronavirus pneumonia is also an acute lung injury (ALI) induced by viral infection. However, there are currently no...

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Autores principales: Cui, Bomiao, Liu, Yiying, Chen, Jiao, Chen, Hongli, Feng, Yun, Zhang, Ping
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Elsevier B.V. 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10181585/
https://www.ncbi.nlm.nih.gov/pubmed/37182445
http://dx.doi.org/10.1016/j.intimp.2023.110240
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author Cui, Bomiao
Liu, Yiying
Chen, Jiao
Chen, Hongli
Feng, Yun
Zhang, Ping
author_facet Cui, Bomiao
Liu, Yiying
Chen, Jiao
Chen, Hongli
Feng, Yun
Zhang, Ping
author_sort Cui, Bomiao
collection PubMed
description Pneumonia is an acute inflammation of the lungs induced by pathogenic microorganisms, immune damage, physical and chemical factors, and other factors, and the latest outbreak of novel coronavirus pneumonia is also an acute lung injury (ALI) induced by viral infection. However, there are currently no effective treatments for inflammatory cytokine storms in patients with ALI/acute respiratory distress syndrome (ARDS). Protein kinase D (PKD) is a highly active kinase that has been shown to be associated with the production of inflammatory cytokines. Therefore, small-molecule compounds that inhibit PKD may be potential drugs for the treatment of ALI/ARDS. In the present study, we evaluated the ability of the small-molecule inhibitor CRT0066101 to attenuate lipopolysaccharide (LPS)-induced inflammatory cytokine production through in vitro cell experiments and a mouse pneumonia model. We found that CRT0066101 significantly reduced the protein and mRNA levels of LPS-induced cytokines (e.g., IL-6, TNF-α, and IL-1β). CRT0066101 inhibited MyD88 and TLR4 expression and reduced NF-κB, ERK, and JNK phosphorylation. CRT0066101 also reduced NLRP3 activation, inhibited the assembly of the inflammasome complex, and attenuated inflammatory cell infiltration and lung tissue damage. Taken together, our data indicate that CRT0066101 exerts anti-inflammatory effects on LPS-induced inflammation through the TLR4/MyD88 signaling pathway, suggesting that CRT0066101 may have therapeutic value in acute lung injury and other MyD88-dependent inflammatory diseases.
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spelling pubmed-101815852023-05-15 Small molecule inhibitor CRT0066101 inhibits cytokine storm syndrome in a mouse model of lung injury Cui, Bomiao Liu, Yiying Chen, Jiao Chen, Hongli Feng, Yun Zhang, Ping Int Immunopharmacol Article Pneumonia is an acute inflammation of the lungs induced by pathogenic microorganisms, immune damage, physical and chemical factors, and other factors, and the latest outbreak of novel coronavirus pneumonia is also an acute lung injury (ALI) induced by viral infection. However, there are currently no effective treatments for inflammatory cytokine storms in patients with ALI/acute respiratory distress syndrome (ARDS). Protein kinase D (PKD) is a highly active kinase that has been shown to be associated with the production of inflammatory cytokines. Therefore, small-molecule compounds that inhibit PKD may be potential drugs for the treatment of ALI/ARDS. In the present study, we evaluated the ability of the small-molecule inhibitor CRT0066101 to attenuate lipopolysaccharide (LPS)-induced inflammatory cytokine production through in vitro cell experiments and a mouse pneumonia model. We found that CRT0066101 significantly reduced the protein and mRNA levels of LPS-induced cytokines (e.g., IL-6, TNF-α, and IL-1β). CRT0066101 inhibited MyD88 and TLR4 expression and reduced NF-κB, ERK, and JNK phosphorylation. CRT0066101 also reduced NLRP3 activation, inhibited the assembly of the inflammasome complex, and attenuated inflammatory cell infiltration and lung tissue damage. Taken together, our data indicate that CRT0066101 exerts anti-inflammatory effects on LPS-induced inflammation through the TLR4/MyD88 signaling pathway, suggesting that CRT0066101 may have therapeutic value in acute lung injury and other MyD88-dependent inflammatory diseases. Elsevier B.V. 2023-07 2023-05-12 /pmc/articles/PMC10181585/ /pubmed/37182445 http://dx.doi.org/10.1016/j.intimp.2023.110240 Text en © 2023 Elsevier B.V. All rights reserved. Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active.
spellingShingle Article
Cui, Bomiao
Liu, Yiying
Chen, Jiao
Chen, Hongli
Feng, Yun
Zhang, Ping
Small molecule inhibitor CRT0066101 inhibits cytokine storm syndrome in a mouse model of lung injury
title Small molecule inhibitor CRT0066101 inhibits cytokine storm syndrome in a mouse model of lung injury
title_full Small molecule inhibitor CRT0066101 inhibits cytokine storm syndrome in a mouse model of lung injury
title_fullStr Small molecule inhibitor CRT0066101 inhibits cytokine storm syndrome in a mouse model of lung injury
title_full_unstemmed Small molecule inhibitor CRT0066101 inhibits cytokine storm syndrome in a mouse model of lung injury
title_short Small molecule inhibitor CRT0066101 inhibits cytokine storm syndrome in a mouse model of lung injury
title_sort small molecule inhibitor crt0066101 inhibits cytokine storm syndrome in a mouse model of lung injury
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10181585/
https://www.ncbi.nlm.nih.gov/pubmed/37182445
http://dx.doi.org/10.1016/j.intimp.2023.110240
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