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1.
Nature ; 455(7210): 183-8, 2008 Sep 11.
Article in English | MEDLINE | ID: mdl-18784718

ABSTRACT

Long-duration gamma-ray bursts (GRBs) release copious amounts of energy across the entire electromagnetic spectrum, and so provide a window into the process of black hole formation from the collapse of massive stars. Previous early optical observations of even the most exceptional GRBs (990123 and 030329) lacked both the temporal resolution to probe the optical flash in detail and the accuracy needed to trace the transition from the prompt emission within the outflow to external shocks caused by interaction with the progenitor environment. Here we report observations of the extraordinarily bright prompt optical and gamma-ray emission of GRB 080319B that provide diagnostics within seconds of its formation, followed by broadband observations of the afterglow decay that continued for weeks. We show that the prompt emission stems from a single physical region, implying an extremely relativistic outflow that propagates within the narrow inner core of a two-component jet.

2.
J Mol Cell Cardiol ; 30(12): 2761-75, 1998 Dec.
Article in English | MEDLINE | ID: mdl-9990546

ABSTRACT

The bacterial endotoxin lipopolysaccharide (LPS) contributes to the cardiovascular collapse and death observed in patients with sepsis. Because LPS has such profound effects on cardiac performance, we speculate that direct effects of LPS could be demonstrated on cardiomyocytes in culture, and that these direct effects are mediated by the LPS receptor, CD14. Accordingly, in this study, we provide evidence for CD14-dependent cardiotoxic effects of LPS including the LPS-stimulated secretion of tumor necrosis factor alpha (TNF-alpha) from cardiomyocytes. TNF-alpha is an inflammatory cytokine which is known for its negative inotropic effects on cardiac performance, but has not until recently been shown to be produced by cardiac cells. In this study, LPS was found to stimulate strongly in a dose-dependent manner the secretion of TNF-alpha from cultured adult rat cardiomyocytes. Further, LPS-induced TNF-alpha secretion was blocked by an inhibitor of TNF-alpha processing, metallomatrix protease inhibitor (TAPI). Molecular and immunological evidence demonstrated the presence of LPS receptors (CD14) on cardiomyocytes. Attenuated TNF-alpha secretion following PI-PLC treatment confirmed the functional importance of CD14 for LPS-mediated myocardial effects. Importantly, LPS also triggered apoptosis in cultured cardiomyocytes as quantified by single-cell gel electrophoresis of nuclei exhibiting DNA fragmentation patterns characteristic of apoptosis (i.e. cardiac comets). Apoptotic cell death was blocked by pre-incubation with the soluble TNF-alpha receptor fragment (TNFRII:Fc), suggesting that LPS-induced apoptosis was TNF-alpha-dependent and probably involved an autocrine function for the TNF-alpha whose secretion was under LPS control. The results of this study suggest that the cardiodepressant effects of LPS are dependent on CD14 signaling and may not only be due to acute negative inotropic effects of TNF-alpha but also may be complicated by TNF-alpha-induced apoptotic cell death which effectively reduces the number of working myocardial cells.


Subject(s)
Apoptosis/physiology , Heart/physiology , Lipopolysaccharide Receptors/physiology , Lipopolysaccharides/pharmacology , Tumor Necrosis Factor-alpha/metabolism , Animals , Blotting, Western , Calcium/metabolism , Dose-Response Relationship, Drug , Electrophoresis, Gel, Two-Dimensional , Enzyme-Linked Immunosorbent Assay , Male , Models, Biological , Muscle, Skeletal/drug effects , Necrosis , Phenylephrine/pharmacology , Phosphatidylinositol Diacylglycerol-Lyase , Phosphoinositide Phospholipase C , Polymerase Chain Reaction , Protease Inhibitors/pharmacology , Rats , Rats, Sprague-Dawley , Tumor Necrosis Factor-alpha/physiology , Type C Phospholipases/pharmacology , Tyrphostins/pharmacology
3.
J Clin Invest ; 98(12): 2854-65, 1996 Dec 15.
Article in English | MEDLINE | ID: mdl-8981934

ABSTRACT

In the present study, it was shown that physiologically relevant levels of the proinflammatory cytokine TNFalpha induced apoptosis in rat cardiomyocytes in vitro, as quantified by single cell microgel electrophoresis of nuclei ("cardiac comets") as well as by morphological and biochemical criteria. It was also shown that TNFalpha stimulated production of the endogenous second messenger, sphingosine, suggesting sphingolipid involvement in TNFalpha-mediated cardiomyocyte apoptosis. Consistent with this hypothesis, sphingosine strongly induced cardiomyocyte apoptosis. The ability of the appropriate stimulus to drive cardiomyocytes into apoptosis indicated that these cells were primed for apoptosis and were susceptible to clinically relevant apoptotic triggers, such as TNFalpha. These findings suggest that the elevated TNFalpha levels seen in a variety of clinical conditions, including sepsis and ischemic myocardial disorders, may contribute to TNFalpha-induced cardiac cell death. Cardiomyocyte apoptosis is also discussed in terms of its potential beneficial role in limiting the area of cardiac cell involvement as a consequence of myocardial infarction, viral infection, and primary cardiac tumors.


Subject(s)
Apoptosis/drug effects , Myocardium/metabolism , Tumor Necrosis Factor-alpha/pharmacology , Analysis of Variance , Animals , Benzoxazoles/metabolism , Cell Nucleus/metabolism , Cells, Cultured , Ceramides/pharmacology , DNA Damage/genetics , Electrophoresis, Agar Gel , Hydrogen Peroxide/pharmacology , Image Processing, Computer-Assisted , Microscopy, Fluorescence , Myocardial Ischemia/metabolism , Quinolinium Compounds/metabolism , Rats , Signal Transduction/physiology , Sphingolipids/metabolism , Sphingolipids/pharmacology , Sphingosine/metabolism , Sphingosine/pharmacology
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