Doxorubicin triggers splenic contraction and irreversible dysregulation of COX and LOX that alters the inflammation-resolution program in the myocardium
| العنوان: | Doxorubicin triggers splenic contraction and irreversible dysregulation of COX and LOX that alters the inflammation-resolution program in the myocardium |
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| المؤلفون: | Nabiha Yusuf, Mohammad Asif Sherwani, Vasundhara Kain, Jeevan Kumar Jadapalli, Griffin W. Wright, Ravi Sonkar, Ganesh V. Halade |
| المصدر: | American Journal of Physiology-Heart and Circulatory Physiology. 315:H1091-H1100 |
| بيانات النشر: | American Physiological Society, 2018. |
| سنة النشر: | 2018 |
| مصطلحات موضوعية: | Male, 0301 basic medicine, Cachexia, Time Factors, Contraction (grammar), Physiology, Lipoxygenase, Apoptosis, 030204 cardiovascular system & hematology, Ventricular Function, Left, 0302 clinical medicine, Cardiac toxicity, polycyclic compounds, Medicine, Antibiotics, Antineoplastic, Ventricular Remodeling, biology, Organ Size, Cytokines, Cardiology and Cardiovascular Medicine, Signal Transduction, Research Article, medicine.drug, Chronic exposure, Heart Diseases, Heart Ventricles, macromolecular substances, Gene Expression Regulation, Enzymologic, 03 medical and health sciences, Inflammation resolution, Physiology (medical), Animals, Doxorubicin, Splenic Diseases, Dose-Response Relationship, Drug, business.industry, Macrophages, Myocardium, organic chemicals, technology, industry, and agriculture, Germinal center, Fibrosis, Cardiotoxicity, Mice, Inbred C57BL, carbohydrates (lipids), 030104 developmental biology, Prostaglandin-Endoperoxide Synthases, Cancer research, biology.protein, Cyclooxygenase, business, Spleen |
| الوصف: | 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−1·wk−1), and the second group was injected with 7.5 mg·kg−1·wk−1 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 (PGD2, PGE2, and 6-keto-PG2α) 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. |
| تدمد: | 1522-1539 0363-6135 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::8c9ec3861df965a0f5671cf707f6d769Test https://doi.org/10.1152/ajpheart.00290.2018Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....8c9ec3861df965a0f5671cf707f6d769 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 15221539 03636135 |
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