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Role of macrophages in regeneration of liver
Y Shiratori1, S Hongo, Y Hikiba
1Department of Internal Medicine (II), Faculty of Medicine, University of Tokyo, Japan.
Abstract:
In an attempt to clarify the role of macrophages and their mediators during regeneration of the liver, the difference of liver regeneration among C3H/HeN (LPS-responsive strain) and C3H/HeJ (LPS-resistant strain) mice was investigated. After a 67% partial hepatectomy, an increase in the weight of regenerating liver was significantly delayed in the C3H/HeJ mice, as compared with C3H/HeN mice. The number of hepatocytes labeled with antibody against PCNA reached maximum levels 48 hr after partial hepatectomy, but the PCNA labeling index in C3H/HeJ mice was 20% less than that for C3H/HeN mice. In addition, TNF-alpha activities in serum were enhanced shortly after partial hepatectomy in C3H/HeN strain mice, but were not increased in C3H/HeJ strain mice. Serum IL-6 levels were markedly enhanced in both C3H/HeN and C3H/HeJ mice, but a bimodial peak (14 and 48 hr after partial hepatectomy) was demonstrated in C3H/HeN mice, in contrast to a single peak (at 24 hr) in C3H/HeJ mice. Suppression of Kupffer cells by previous administration of gadolinium chloride in C3H/HeN mice reduced the increase in both serum TNF-alpha and IL-6 concentrations, reduced PCNA labeling index of hepatocytes by 20%, and disturbed the regeneration of the liver. Previous administration of antibody against TNF-alpha reduced the PCNA labeling index of hepatocytes by 20% after partial hepatectomy in C3H/HeN strain mice. These results suggest that LPS-responsive macrophages in the liver and their mediators, especially TNF-alpha, could partly play a role in liver regeneration.
Insights
Liver regeneration is impaired in LPS-resistant mice, suggesting macrophages and TNF-alpha play a role. Kupffer cell suppression further hinders liver repair, highlighting their importance in this process.
Area of Science:
- Hepatology
- Immunology
- Regenerative Medicine
Background:
- Macrophages, particularly Kupffer cells, are key immune cells in the liver.
- Their role in liver regeneration following injury is not fully understood.
- Lipopolysaccharide (LPS) responsiveness varies between mouse strains, offering a model to study macrophage function.
Purpose of the Study:
- To investigate the role of macrophages and their mediators in liver regeneration.
- To compare liver regeneration in LPS-responsive (C3H/HeN) and LPS-resistant (C3H/HeJ) mice after partial hepatectomy.
Main Methods:
- Performed 67% partial hepatectomy on C3H/HeN and C3H/HeJ mice.
- Assessed liver regeneration by measuring liver weight gain and PCNA labeling index.
- Measured serum levels of TNF-alpha and IL-6.
- Investigated the effect of Kupffer cell suppression (gadolinium chloride) and anti-TNF-alpha antibody administration.
Main Results:
- Liver regeneration was significantly delayed in LPS-resistant C3H/HeJ mice compared to C3H/HeN mice.
- PCNA labeling index was reduced by 20% in C3H/HeJ mice.
- TNF-alpha serum levels increased in C3H/HeN mice post-hepatectomy but not in C3H/HeJ mice.
- Kupffer cell suppression in C3H/HeN mice reduced TNF-alpha and IL-6, decreased PCNA index, and impaired regeneration.
- Anti-TNF-alpha antibody administration reduced PCNA index in C3H/HeN mice.
Conclusions:
- LPS-responsive macrophages and mediators like TNF-alpha partially contribute to liver regeneration.
- Kupffer cells and TNF-alpha are crucial for efficient liver repair after partial hepatectomy.