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DNA fragmentation in mouse organs during endotoxic shock
I Bohlinger1, M Leist, F Gantner
1Department of Biochemical Pharmacology, Faculty of Biology, University of Konstanz, Germany.
Abstract:
The systemic inflammatory response syndrome has still an unpredictable outcome, and patients often die of multiple organ failure despite circulatory stabilization therapy. The still incompletely understood pathophysiological mechanisms include organ damage due to direct toxic actions of cytokines elicited by overactivation of the host response. To study this process of organ failure in experimental septic shock, we injected mice with a lethal dose of endotoxin and examined apoptotic and necrotic tissue damage biochemically, histologically, and ultrastructurally. Endotoxin administration caused oligonucleosomal as well as random DNA fragmentation in liver, lung, kidney, and intestine. In the liver, DNA fragmentation was not restricted to hepatocytes but also occurred in nonparenchymal cells. The DNA fragmentation was mediated by tumor necrosis factor and attenuated by endogenous nitric oxide release. Unlike the situation in D-galactosamine-sensitized mice, in which injection or release of tumor necrosis factor causes massive hepatocyte apoptosis, liver failure due to high doses of endotoxin was characterized by single-cell necrosis, a low incidence of apoptosis, and simultaneous damage to nonparenchymal cells. We conclude that, even though endotoxin causes cytokine-mediated DNA fragmentation in several organs including the liver, hepatocyte apoptosis itself seems to be a minor phenomenon in high-dose endotoxic shock in mice.
Insights
Systemic inflammatory response syndrome can lead to organ failure. This study shows endotoxin causes DNA fragmentation in multiple organs, but hepatocyte apoptosis is minimal in high-dose endotoxic shock.
Area of Science:
- Pathophysiology
- Immunology
- Toxicology
Background:
- Systemic inflammatory response syndrome (SIRS) has unpredictable outcomes, often resulting in multiple organ failure.
- Pathophysiological mechanisms involve cytokine-induced organ damage from host response overactivation.
- Understanding organ failure in septic shock is crucial for effective treatment.
Purpose of the Study:
- To investigate organ damage mechanisms in experimental septic shock.
- To examine apoptotic and necrotic tissue damage following endotoxin administration.
- To elucidate the role of cytokines and nitric oxide in endotoxin-induced organ failure.
Main Methods:
- Mice were injected with a lethal dose of endotoxin.
- Biochemical, histological, and ultrastructural analyses were performed to assess tissue damage.
- DNA fragmentation patterns were analyzed in liver, lung, kidney, and intestine.
Main Results:
- Endotoxin induced oligonucleosomal and random DNA fragmentation across multiple organs.
- Liver DNA fragmentation occurred in both hepatocytes and nonparenchymal cells.
- Tumor necrosis factor mediated DNA fragmentation, while nitric oxide attenuated it.
Conclusions:
- Endotoxin triggers cytokine-mediated DNA fragmentation in various organs.
- High-dose endotoxic shock in mice is characterized by single-cell necrosis and nonparenchymal cell damage.
- Hepatocyte apoptosis plays a minor role in liver failure during high-dose endotoxic shock.