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Participation of hepatic macrophages and plasma factors in endotoxin-induced liver injury
1First Department of Surgery, Faculty of Medicine, Kyoto University, Japan.
Abstract:
The present study was designed to investigate the mechanism responsible for endotoxin-induced liver injury, based on the working hypothesis that hepatic macrophages activated by endotoxin play a key role in the development of this injury. At both the protein and the transcription levels, the intravenous administration of endotoxin was shown to have increased the capacity of hepatic macrophages to produce chemical mediators. To inhibit the function of hepatic macrophages, gadolinium chloride (GdCl3), a specific inhibitor of resident hepatic macrophages, was preadministered to rats before endotoxin injection. GdCl3 reduced the elevated glutamic oxaloacetic transamiase and lactate dehydrogenase serum levels produced by endotoxin treatment, suppressed the increased mRNA expression of tumor necrosis factor (TNF-alpha) produced in liver nonparenchymal cells by endotoxin, and then improved the survival rate of lipopolysaccharide-injected rats. These results indicated that hepatic macrophages played a crucial role in liver injury and that TNF-alpha was the most likely factor implicated in the development of endotoxin-induced liver injury. Furthermore, we found that liver injury did not progress during perfusion of endotoxin-pretreated extirpated liver with lactate Ringer's solution, whereas liver perfused with plasma developed remarkable hepatic impairment, which was inhibited almost completely by GdCl3-pretreatment; moreover, addition of heparin to the perfusate also prevented this deterioration. Thus, the present study showed that the activation of hepatic macrophages and factors in the plasma were two essential elements in the occurrence and development of endotoxin-induced liver injury.
Insights
Hepatic macrophages activated by endotoxin are key to liver injury. Inhibiting these cells with gadolinium chloride (GdCl3) reduced liver damage and improved survival, implicating tumor necrosis factor-alpha (TNF-alpha).
Area of Science:
- Hepatology
- Immunology
- Toxicology
Background:
- Endotoxin-induced liver injury is a significant clinical concern.
- The precise mechanisms driving this injury require further elucidation.
- Hepatic macrophages are suspected key mediators.
Purpose of the Study:
- To investigate the role of hepatic macrophages in endotoxin-induced liver injury.
- To identify the specific mediators involved in this process.
- To explore potential therapeutic targets for mitigating liver damage.
Main Methods:
- Administered endotoxin intravenously to rats.
- Utilized gadolinium chloride (GdCl3) to inhibit hepatic macrophage function.
- Measured serum enzyme levels (glutamic oxaloacetic transaminase, lactate dehydrogenase).
- Assessed messenger RNA (mRNA) expression of tumor necrosis factor-alpha (TNF-alpha).
- Evaluated rat survival rates post-lipopolysaccharide injection.
- Performed ex vivo liver perfusion experiments with different solutions.
Main Results:
- Endotoxin increased hepatic macrophage mediator production at protein and transcription levels.
- GdCl3 pretreatment reduced elevated liver enzymes and suppressed TNF-alpha mRNA expression.
- GdCl3 administration improved survival rates in endotoxin-treated rats.
- Ex vivo liver perfusion showed plasma exacerbated injury, which GdCl3 and heparin inhibited.
Conclusions:
- Hepatic macrophages play a crucial role in endotoxin-induced liver injury.
- Tumor necrosis factor-alpha (TNF-alpha) is a likely key mediator.
- Plasma factors and hepatic macrophage activation are essential for liver injury development.