Doxorubicin-induced cardiotoxicity is mediated by neutrophils through release of neutrophil elastase

by Selleckchem | Oct 02 2023

The mechanisms by which Doxorubicin (Dox) causes acute and late cardiotoxicity are not completely understood. One understudied area is the innate immune response, and in particular the role of neutrophils in Dox-induced cardiotoxicity. Here, using echocardiography, flow cytometry and immunofluorescence staining, we demonstrated increased infiltration of neutrophils that correlated with decreased heart function, disruption of vascular structures and increased collagen deposition in the heart after Dox treatment. Depleting neutrophils protected the heart from Dox-induced cardiotoxicity and changes in vascular structure. Furthermore, our data using neutrophil elastase (NE) knock-out mice and the NE inhibitor AZD9668 suggest that neutrophils cause this damage by releasing NE and that inhibiting NE can prevent Dox-induced cardiotoxicity. This work shows the role of neutrophils and NE in Doxorubicin-induced cardiotoxicity for the first time and suggests a new possible therapeutic intervention.

Comments:

The passage you provided describes a study that investigated the role of neutrophils in the development of acute and late cardiotoxicity induced by the chemotherapy drug Doxorubicin (Dox). The study utilized various techniques such as echocardiography, flow cytometry, and immunofluorescence staining to examine the effects of Dox treatment on the heart.

The findings of the study demonstrated increased infiltration of neutrophils into the heart following Dox treatment. This increased neutrophil infiltration was associated with decreased heart function, disruption of vascular structures, and increased collagen deposition in the heart. These changes are characteristic of cardiotoxicity, which refers to the damage inflicted on the heart by certain drugs or treatments.

To further investigate the role of neutrophils in Dox-induced cardiotoxicity, the researchers conducted experiments to deplete neutrophils from the system. The results showed that the depletion of neutrophils protected the heart from Dox-induced cardiotoxicity and prevented changes in vascular structure.

Additionally, the study explored the involvement of neutrophil elastase (NE) in the cardiotoxic effects of Dox. NE is an enzyme released by neutrophils that can contribute to tissue damage. To investigate the role of NE, the researchers used NE knock-out mice and an NE inhibitor called AZD9668. The data from these experiments suggested that neutrophils cause damage in Dox-induced cardiotoxicity by releasing NE. Moreover, inhibiting NE with AZD9668 showed potential in preventing Dox-induced cardiotoxicity.

Overall, this study provides novel insights into the mechanisms underlying Doxorubicin-induced cardiotoxicity. It highlights the involvement of neutrophils and their release of NE in promoting heart damage. The findings suggest that targeting neutrophils or inhibiting NE could be a potential therapeutic strategy to mitigate the cardiotoxic effects of Doxorubicin.