Identification, characterization, and gene expression profiling of endotoxin-induced myocarditis

Ma-Li Wong, Fiona O'Kirwan, Nadia Khan, Jonas Hannestad, Kwok H. Wu, David Elashoff, Gregory Lawson, Philip W. Gold, Samuel M. McCann, Julio Licinio

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20 Citations (Scopus)

Abstract

In septic shock, reversible cardiac dysfunction starts within 24 h. Myocardial depressant factors are thought to cause myocyte dysfunction, resulting in alterations of intrinsic cardiac function. Nitric oxide is a myocardial depressant factor candidate. Here we identify endotoxin-induced myocarditis (EIM) a previously uncharacterized pathophysiological entity. Features of EIM include differential patterns of inducible NO synthase (NOS2) mRNA induction in the left (LV) and right (RV) ventricles during the systemic response inflammatory syndrome (SIRS) and the presence of myocarditis with focal areas of aseptic necrosis in the RV 24 h after SIRS induction. Even though clinical data lead to the presumption of myocardial injury in sepsis, the underlying pathophysiological mechanisms have not been previously elucidated. Gene expression profiling was used to test the hypothesis of differential LV and RV responses in EIM, and revealed novel patterns of qualitative and quantitative expansion of transcription. Those genes are novel targets for drug development in SIRS and sepsis. Our results demonstrate spatial and temporal heterogeneity of myocardial responses in EIM. These findings justify the design of treatments to ameliorate tissue injury in the RV. Because the complexity of the inflammatory response increases substantially as time elapses, we suggest a stepwise and multitarget therapeutic approach for SIRS and sepsis. Our findings can help identify innate immune pathways that could become targets for immunotherapy in the treatment of disease caused by potential bioterrorism agents.

Original languageEnglish
Pages (from-to)14241-14246
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume100
Issue numberSUPPL. 2
DOIs
Publication statusPublished - 25 Nov 2003

ASJC Scopus subject areas

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