Abstract 269: The Role of Neutrophils in Doxorubicin-induced Cardiotoxicity

Abstract

Doxorubicin (Dox) is one of the most effective chemotherapy agents for treating childhood cancer. Unfortunately, Dox also causes damage to the heart which leads to reduced heart function and heart failure in >50% of survivors. Understanding the mechanisms by which Dox induces cardiotoxicity is crucial to identifying preventive interventions. Inflammation, in particular: neutrophils and monocytes has been linked to other form of cardiac disease. However, the role of these immune cells in Dox-induced cardiotoxicity has not been examined. We hypothesize that neutrophils are responsible for the early damage caused by Dox treatment. Using our mouse cardiotoxicity model, mice were treated with Doxorubicin for 2 weeks. Neutrophil infiltration in the heart 24 hours after therapy were evaluated by flow cytometry. There was an increase in neutrophils in heart tissue of Dox-treated mice as compared to controls and a decrease in heart function as quantified by echocardiography (ejection fraction [EF] and fractional shortening [FS]). Next, we depleted neutrophils using an anti-Ly6G antibody. Neutrophil depletion was confirmed by flow cytometry in the blood and hearts of Dox-treated mice. We found that neutrophil depletion prevented Dox-induced decrease in both ejection fraction and fractional shortening. Additionally, we also observed by flow cytometry that infiltration of monocytes was unaffected by the neutrophil depletion antibody. Based on this data we concluded that neutrophils and not monocytes are integral contributors to acute heart damage caused by Dox. These data indicate that targeting neutrophils may be a preventive strategy against Dox-induced cardiotoxicity.