Doxorubicin triggers splenic contraction and irreversible dysregulation of COX and LOX that alters the inflammation-resolution program in the myocardium

Abstract

Doxorubicin (DOX) is a widely used drug for cancer treatment as a chemotherapeutic agent. However, the cellular and integrative mechanism of DOX-induced immunometabolism is unclear. Two-month-old male C57BL/6J mice were divided into high- and low-dose DOX-treated groups with a maintained saline control group. The first group was injected with a high dose of DOX (H-DOX; 15 mg·kg·wk), and the second group was injected with 7.5 mg·kg·wk as a latent low dose of DOX (LL-DOX). H-DOX treatment led to complete mortality in 2 wk and 70% survival in the LL-DOX group compared with the saline control group. Therefore, an additional group of mice was injected with an acute high dose of DOX (AH-DOX) and euthanized at 24 h to compare with LL-DOX and saline control groups. The LL-DOX and AH-DOX groups showed obvious apoptosis and dysfunctional and structural changes in cardiac tissue. Splenic contraction was evident in AH-DOX- and LL-DOX-treated mice, indicating the systems-wide impact of DOX on integrative organs of the spleen, which is essential for cardiac homeostasis and repair. DOX dysregulated splenic-enriched immune-sensitive lipoxygenase and cyclooxygenase in the spleen and left ventricle compared with the saline control group. As a result, lipoxygenase-dependent D- and E-series resolvin precursors, such as 16HDoHE, 4HDoHE, and 12-HEPE, as well as cyclooxygenase-mediated PG species (PGD, PGE and 6-keto-PG) were decreased in the left ventricle, suggestive of defective immunometabolism. Both AH-DOX and LL-DOX induced splenic contraction and expansion of red pulp with decreased CD169 metallophilic macrophages. AH-DOX intoxicated macrophages in the spleen by depleting CD169 cells in the acute setting and sustained the splenic macrophage loss in the chronic phase in the LL-DOX group. Thus, DOX triggers a vicious cycle of splenocardiac cachexia to facilitate defective immunometabolism and irreversible macrophage toxicity and thereby impaired the inflammation-resolution program. NEW & NOTEWORTHY Doxorubicin (DOX) triggered splenic mass loss and decreased CD169 with germinal center contraction in acute and chronic exposure. Cardiac toxicity of DOX is marked with dysregulation of immunometabolism and thereby impaired resolution of inflammation. DOX suppressed physiological levels of cytokines and chemokines with signs of splenocardiac cachexia.

Oxidative stress and inflammation: determinants of anthracycline cardiotoxicity and possible therapeutic targets

“…Furthermore, through transcription factor modulation, ANT increase NLRP3 expression, thus stimulating the release of the proinflammatory interleukins (IL)-1β and IL-6 [ 21 ]. Additionally, ANT-dependent inhibition of cyclooxygenase and lipoxygenases reduces cardiac availability of anti-inflammatory mediators (such as prostacyclins), promoting cardiac damage [ 22 , 23 ].…”

Race‐based and sex‐based differences in bioactive lipid mediators after myocardial infarction

“…aspirin), the magnitude of infarction (minor, major, or massive), or ageing. We did not have data on diet or over‐the‐counter medications and recognize that these factors need to be considered in interpreting levels of lipid mediators in plasma of the individual patient . The influence of SES on CV disease is widely recognized.…”

“…We did not have data on diet or over-the-counter medications and recognize that these factors need to be considered in interpreting levels of lipid mediators in plasma of the individual patient. 37,[46][47][48] The influence of SES on CV disease is widely recognized. Although we collected information on education, income, and health insurance, we could not stratify by SES due to the small sample size.…”

Cardioprotective Effects of Latifolin Against Doxorubicin-Induced Cardiotoxicity by Macrophage Polarization in Mice

“…17 It is known that the M1/M2 macrophage polarization balance regulates the fate of an organ in inflammation or injury. 18 Jadapalli et al 19 reported that the LL-DOX caused myocardial apoptosis and cardiac dysfunction. It has also been shown that DOX triggers splenic contraction and irreversible dysregulation of cyclooxygenase (COX) and lipoxygenase (LOX), which alter the inflammation-resolution program in the myocardium with decreasing CD169 + metallophilic macrophages.…”