title: Inflammatory mediators in a short-time mouse model of doxorubicin-induced cardiotoxicity.
abstract: Doxorubicin (DOXO) is commonly used to treat a wide range of malignant tumors, but its clinical use is limited by acute and chronic cardiotoxicity. The precise mechanism underlying DOXO-induced cardiotoxicity is still not completely elucidated, but cardiac inflammation seems to be involved. Effects of DOXO on proinflammatory cytokines, inflammatory cell infiltration, and necrosis have been proven only when a functional impairment has already occurred, so this study aimed to investigate the acute effect of DOXO administration in mouse heart. The results of our study demonstrated alterations in cardiac function parameters assessed by ultrasound within 24h after a single injection of DOXO, with a cumulative effect along the increase of the dose and the number of DOXO administrations. At the same time, DOXO causes a significant production of proinflammatory cytokines (such as TNF-α and IL-6) with a concomitant reduction of IL-10, a well-known antiinflammatory cytokine. Furthermore, overexpression of inducible nitric oxide synthase (iNOS) in heart tissue and increased levels of serum nitrite in DOXO-treated mice were detected. Notably, DOXO administration significantly increased nitrotyrosine expression in mouse heart. Our data support the hypothesis that these early events, could be responsible for the later onset of more severe deleterious remodeling leading to DOXO induced cardiomyopathy.
authors.affiliation: Department of Pharmacy, University of Salerno, Fisciano, SA, Italy.
authors.forename: Michela
authors.initials: M
authors.lastname: Pecoraro
authors.affiliation: Department of Pharmacy, University of Salerno, Fisciano, SA, Italy.
authors.forename: Mariagiovanna
authors.initials: M
authors.lastname: Del Pizzo
authors.affiliation: Department of Pharmacy, University of Salerno, Fisciano, SA, Italy.
authors.forename: Stefania
authors.initials: S
authors.lastname: Marzocco
authors.affiliation: Department of Pharmacy, University of Salerno, Fisciano, SA, Italy.
authors.forename: Rosalinda
authors.initials: R
authors.lastname: Sorrentino
authors.affiliation: Department of Medicine and Surgery, University of Salerno, Baronissi, SA, Italy.
authors.forename: Michele
authors.initials: M
authors.lastname: Ciccarelli
authors.affiliation: Department of Medicine and Surgery, University of Salerno, Baronissi, SA, Italy.
authors.forename: Guido
authors.initials: G
authors.lastname: Iaccarino
authors.affiliation: Department of Pharmacy, University of Salerno, Fisciano, SA, Italy.
authors.forename: Aldo
authors.initials: A
authors.lastname: Pinto
authors.affiliation: Department of Pharmacy, University of Salerno, Fisciano, SA, Italy. Electronic address: apopolo@unisa.it.
authors.forename: Ada
authors.initials: A
authors.lastname: Popolo
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000009:adverse effects*; D066126:Cardiotoxicity / Q000209:etiology / Q000378:metabolism* / Q000473:pathology; D004195:Disease Models, Animal; D004317:Doxorubicin / Q000009:adverse effects*; D004452:Echocardiography; D005260:Female; D016753:Interleukin-10 / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D008810:Mice, Inbred C57BL; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D009573:Nitrites / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D014443:Tyrosine / Q000031:analogs & derivatives / Q000378:metabolism
chemical_list: D000903:Antibiotics, Antineoplastic; C556062:IL10 protein, mouse; D015850:Interleukin-6; D009573:Nitrites; D014409:Tumor Necrosis Factor-alpha; C577686:interleukin-6, mouse; D016753:Interleukin-10; C002744:3-nitrotyrosine; D014443:Tyrosine; D004317:Doxorubicin; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse
keywords: Cardiotoxicity; Cytokines; Doxorubicin; Inflammation; Nitric oxide