Doxorubicin-Induced Cardiotoxicity Is Mediated By Neutrophils Through Release of Neutrophil Elastase

<p>Doxorubicin (Dox) is one of the most effective chemotherapy agents that is used for the treatment of childhood cancer. Unfortunately Dox treatment can cause damage to the heart. Indeed, childhood cancer survivors are at a higher risk of developing a cardiovascular disease at an earlier age. The mechanisms by which Dox causes acute and late cardiotoxicity are not completely understood. One understudied area in Dox-induced cardiotoxicity is the contribution of inflammation and innate immune cells, in particular neutrophils. Recognizing that neutrophils have been implicated in a number of heart diseases, we evaluated 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 (as defined by a decrease in ejection fraction and fractional shortening), 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 both in the acute (24 hours after therapy) and late stages (12 weeks after therapy). Furthermore, our data using neutrophil elastase (NE) knock-out mice and the NE inhibitor AZD9668 suggest that neutrophils induce cardiac damage by releasing NE and that inhibiting NE can prevent both acute and late Dox-induced cardiotoxicity. Taken together, this data indicates the contribution of neutrophils and NE in Doxorubicin-induced cardiotoxicity. This is the first demonstration of the importance of neutrophils and NE in heart damage caused by Dox and suggests a potential new therapeutic intervention.</p>

Name thesis:degree_name

Doctor of Philosophy (PhD)

Level thesis:degree_level

Dissertation (PhD)

Year dc:date.available

2022

Authors dc:creator

• Bhagat, Anchit
• <p>https://orcid.org/0000-0003-2392-1489</p>

Contributors dc:contributor

• Dr Eugenie Kleinerman
• Dr Gheath Al-Atrash
• Dr Joya Chandra

• Cardiotoxicity
• Doxorubicin
• Doxorubicin-induced cardiotoxicity
• Neutrophils
• neutrophil elastase
• Immunity
• Immunology and Infectious Disease

Repository record dc:identifier

https://digitalcommons.library.tmc.edu/utgsbs_dissertations/1227

OAI identifier oai:identifier

oai:digitalcommons.library.tmc.edu:utgsbs_dissertations-2284