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Possible role of macrophages in the pathogenesis of ethanol-induced bone marrow damage
1Department of Haematology, St Mary's Hospital Medical School, Imperial College of Science, London.
Abstract:
Adherent-cell-depleted human marrow cells (MC) were cultured on their own or co-cultured with monolayers of blood-monocyte-derived macrophages or marrow-derived adherent cells with and without 2 mg ethanol/ml for 24 h. The incorporation of 3H-thymidine and 3H-leucine by MC cultured on their own was not significantly influenced by ethanol. By contrast, the incorporation of both radiolabelled compounds was significantly lower in MC from the co-cultures containing ethanol than from those not containing ethanol. This effect was mediated by a diffusible factor produced by macrophages in the ethanol-containing cultures and was independent of intercellular contact. Supernatants from ethanol-containing cultures of marrow-derived adherent cells displayed cytotoxic activity against A9 cells due to the presence of unstable acetaldehyde-albumin complexes. Ethanol inhibited rather than stimulated nitrite production in the MC/marrow-derived adherent cell co-culture system, suggesting that macrophage-derived nitric oxide did not play a role in causing the observed ethanol-related effects. The data indicate that, in the presence of ethanol, macrophages cause inhibition of the incorporation of 3H-thymidine and 3H-leucine into overlying MC, at least partly by oxidizing ethanol to acetaldehyde and releasing some of the potentially cytotoxic acetaldehyde thus formed extracellularly. Bone marrow macrophages may therefore play an important role in the pathogenesis of alcohol-related marrow damage in vivo.
Insights
Ethanol exposure impairs bone marrow cell growth by affecting macrophages, potentially contributing to alcohol-related marrow damage. Macrophages release cytotoxic acetaldehyde, inhibiting cell proliferation.
Area of Science:
- Hematology
- Toxicology
- Cell Biology
Background:
- Ethanol consumption can lead to bone marrow damage.
- The specific mechanisms by which ethanol affects bone marrow cells, particularly in interaction with macrophages, are not fully understood.
Purpose of the Study:
- To investigate the effects of ethanol on human marrow cells (MC) when co-cultured with macrophages.
- To determine the role of macrophages and their secreted factors in ethanol-induced inhibition of marrow cell proliferation.
Main Methods:
- Human marrow cells were cultured alone or co-cultured with macrophages in the presence or absence of ethanol.
- Incorporation of 3H-thymidine and 3H-leucine was measured to assess cell proliferation and protein synthesis.
- Cytotoxicity of culture supernatants was evaluated using A9 cells.
- Nitrite production was measured to assess the role of nitric oxide.
Main Results:
- Ethanol significantly reduced the incorporation of 3H-thymidine and 3H-leucine in marrow cells co-cultured with macrophages.
- This inhibitory effect was mediated by a diffusible factor produced by macrophages exposed to ethanol.
- Supernatants from ethanol-treated cultures showed cytotoxic activity, linked to acetaldehyde-albumin complexes.
- Ethanol inhibited, rather than stimulated, nitrite production, suggesting nitric oxide was not involved.
Conclusions:
- Macrophages, in the presence of ethanol, inhibit the proliferation of overlying marrow cells.
- Ethanol is oxidized to cytotoxic acetaldehyde by macrophages, which is released extracellularly.
- Bone marrow macrophages may contribute to alcohol-related bone marrow damage in vivo.