Identification, characterization, and gene expression profiling of endotoxin-induced myocarditis.
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.
Wong
Ma-Li
ML
Center for Pharmacogenomics, Neuropsychiatric Institute, Department of Psychiatry and Biobehavioral Sciences, David Geffen School of Medicine, University of California, Los Angeles, CA 90095-1761, USA. mali@ucla.edu
O'Kirwan
Fiona
F
Khan
Nadia
N
Hannestad
Jonas
J
Wu
Kwok H
KH
Elashoff
David
D
Lawson
Gregory
G
Gold
Philip W
PW
McCann
Samuel M
SM
Licinio
Julio
J
D000818:Animals; D004731:Endotoxins / Q000633:toxicity*; D020869:Gene Expression Profiling; D006352:Heart Ventricles / Q000378:metabolism; D008070:Lipopolysaccharides / Q000633:toxicity*; D008297:Male; D009205:Myocarditis / Q000209:etiology* / Q000235:genetics* / Q000473:pathology; D019001:Nitric Oxide Synthase / Q000235:genetics; D052247:Nitric Oxide Synthase Type II; D020411:Oligonucleotide Array Sequence Analysis; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D012772:Shock, Septic / Q000150:complications / Q000235:genetics; D018746:Systemic Inflammatory Response Syndrome / Q000150:complications / Q000235:genetics
D004731:Endotoxins; D008070:Lipopolysaccharides; D012333:RNA, Messenger; C044101:endotoxin, Escherichia coli; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat