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The role of macrophages in LPS-induced lethality and tissue injury
P H Groeneveld1, E Claassen, C F Kuper
1Medical Faculty, Department of Histology, Free University, Amsterdam, The Netherlands.
Abstract:
In the present study we investigated the role of mononuclear phagocytes in the pathogenesis of lipopolysaccharide (LPS)-induced lethality and tissue injury. Since hepatic and splenic macrophages are the primary sites of localization of i.v.-injected LPS, we selectively eliminated these macrophages using liposome-encapsulated dichloromethylene diphosphonate (DMDP). After double DMDP-liposome treatment the phagocytic cells in the liver and spleen were completely eliminated, except for the macrophages in the white pulp of the spleen which were affected to a lesser extent by this treatment. An i.v. injection of LPS into DMDP- and saline-pretreated mice showed that the latter animals exhibited febrile-associated symptoms such as lethargy and ruffled fur, but that macrophage elimination abrogated these symptoms. Although after double saline- or DMDP-pretreatment the LD50 appears to be 1 mg and 630 micrograms, respectively, the differences in lethality between both groups of mice were not statistically significant. Therefore, we concluded that hepatic and splenic macrophages are not necessary for LPS-induced lethality. The role of macrophages in LPS-induced local tissue damage was studied by comparing the histopathological changes in hepatic and splenic tissue between DMDP- and saline-pretreated mice. A sublethal dose of LPS induced similar hepatic lesions in macrophage-depleted and saline-pretreated mice, whereas the histopathological changes in the spleen were much more pronounced after DMDP-pretreatment. Particularly in the inner periarteriolar lymphocyte sheath (PALS) of these mice, the number of T cells was considerably reduced and extensive cellular necrosis could be found. These data strongly suggest that the local tissue damage resulting from LPS injection may not be due to its localization in mononuclear phagocytes but rather to interaction with other cell types.
Insights
Mononuclear phagocytes are not essential for lipopolysaccharide (LPS)-induced lethality. However, eliminating these cells exacerbates LPS-induced spleen damage, suggesting other cell types mediate LPS effects.
Area of Science:
- Immunology
- Pathogenesis
- Cell Biology
Background:
- Lipopolysaccharide (LPS) is a potent endotoxin triggering immune responses.
- Mononuclear phagocytes, particularly macrophages in the liver and spleen, are primary sites for LPS localization.
- The precise role of these phagocytes in LPS-induced toxicity and tissue injury remains to be fully elucidated.
Purpose of the Study:
- To investigate the role of mononuclear phagocytes in lipopolysaccharide (LPS)-induced lethality and tissue injury.
- To determine if selective elimination of hepatic and splenic macrophages affects LPS toxicity.
- To elucidate the cellular targets of LPS responsible for local tissue damage.
Main Methods:
- Selective elimination of hepatic and splenic macrophages using liposome-encapsulated dichloromethylene diphosphonate (DMDP).
- Administration of LPS intravenously to macrophage-depleted and control mice.
- Assessment of lethality (LD50) and histopathological changes in liver and spleen tissues.
Main Results:
- Macrophage depletion abrogated LPS-induced febrile symptoms like lethality.
- No statistically significant difference in LD50 was observed between macrophage-depleted and control mice.
- LPS induced similar hepatic lesions in both groups, but significantly more pronounced splenic damage, including T cell reduction and necrosis in the PALS, in macrophage-depleted mice.
Conclusions:
- Hepatic and splenic macrophages are not essential for LPS-induced lethality.
- Local tissue damage induced by LPS may result from interactions with cell types other than mononuclear phagocytes.
- Further research is needed to identify the specific cell types mediating LPS-induced tissue damage.