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Kupffer cells promote lead nitrate-induced hepatocyte apoptosis via oxidative stress.

Pagliara P, CarlĂ  EC, Caforio S, Chionna A, Massa S, Abbro L, Dini L - Comp Hepatol (2003)

Bottom Line: RESULTS: The in vivo hepatic apoptosis, induced by Pb(NO3)2 was prevented by a pre-treatment with gadolinium chloride (GdCl3), a Kupffer cells toxicant, that suppresses Kupffer cell activity and reduces to a half the apoptotic rate.In addition, in vivo Pb(NO3)2 administration deprives hepatocytes of reduced glutathione, whereas the loss of this important oxidation-preventing agent is considerably mitigated or abolished by pre-treatment with GdCl3.CONCLUSION: Pb(NO3)2 has, at most, a direct necrotic (but not apoptogenic) effect on hepatocytes and HepG2 cells, giving a clue about the regulatory role of Kupffer cells in the induction of liver apoptosis after a single Pb(NO3)2 injection without pre-treatment with GdCl3, probably via secreting soluble factors that trigger oxidative stress in target cells.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Science and Biological and Environmental Technologies, University of Lecce, via per Monteroni, Lecce, Italy. luciana.dini@unile.it

ABSTRACT
BACKGROUND: Apoptosis and its modulation are crucial factors for the maintenance of liver health, allowing hepatocytes to die without provoking a potential harmful inflammatory response through a tightly controlled and regulated process. Since Kupffer cells play a key role in the maintenance of liver function, the aim of this study was to verify whether Kupffer cells are involved in the induction of liver apoptosis after i.v. injection of Pb(NO3)2 likely by secretion mechanisms. RESULTS: The in vivo hepatic apoptosis, induced by Pb(NO3)2 was prevented by a pre-treatment with gadolinium chloride (GdCl3), a Kupffer cells toxicant, that suppresses Kupffer cell activity and reduces to a half the apoptotic rate. In addition, in vivo Pb(NO3)2 administration deprives hepatocytes of reduced glutathione, whereas the loss of this important oxidation-preventing agent is considerably mitigated or abolished by pre-treatment with GdCl3. However, incubation of isolated hepatocytes and Kupffer cells and HepG2 cells with Pb(NO3)2 for 24 hours induced necrotic but not apoptotic cells. Apoptosis of hepatocytes and HepG2 cells was observed only after the addition of conditioned medium obtained from Kupffer cells cultured for 24 hours with Pb(NO3)2, thus indicating the secretion of soluble mediators of apoptosis by Kupffer cells. Apoptosis in the HepG2 cells was observed upon 24-hours incubation of HepG2 cells with 1 mM buthionine sulfoximine, a glutathione depleting agent, thus showing that there is an oxidative apoptogenic pathway in HepG2 cells. CONCLUSION: Pb(NO3)2 has, at most, a direct necrotic (but not apoptogenic) effect on hepatocytes and HepG2 cells, giving a clue about the regulatory role of Kupffer cells in the induction of liver apoptosis after a single Pb(NO3)2 injection without pre-treatment with GdCl3, probably via secreting soluble factors that trigger oxidative stress in target cells.

No MeSH data available.


Related in: MedlinePlus

Scheme of the role of Kupffer cells during Pb(NO3)2-induced hepatic apoptosis. Pb(NO3)2 particles induce, as an early event, Kupffer cells (KC) to secrete molecules (probably cytokines such as TNF alpha) which stimulate hepatocytes (HEP) to proliferate; the increased level of secreted molecules could initiate hepatocyte apoptosis. Activated Kupffer cells may release other molecules prompting endothelial cells (EC) to release additional cytokines, promoting apoptosis of hepatocytes. At the same time, EC can release cytokines that could promote hepatocyte apoptosis as well as activation of KC. As a late event, Pb(NO3)2 particles induce KC death. GdCl3 particles could inhibit the effects of Pb(NO3)2 by depleting Kupffer cells, likely by inducing apoptosis.
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Figure 5: Scheme of the role of Kupffer cells during Pb(NO3)2-induced hepatic apoptosis. Pb(NO3)2 particles induce, as an early event, Kupffer cells (KC) to secrete molecules (probably cytokines such as TNF alpha) which stimulate hepatocytes (HEP) to proliferate; the increased level of secreted molecules could initiate hepatocyte apoptosis. Activated Kupffer cells may release other molecules prompting endothelial cells (EC) to release additional cytokines, promoting apoptosis of hepatocytes. At the same time, EC can release cytokines that could promote hepatocyte apoptosis as well as activation of KC. As a late event, Pb(NO3)2 particles induce KC death. GdCl3 particles could inhibit the effects of Pb(NO3)2 by depleting Kupffer cells, likely by inducing apoptosis.

Mentions: Our hypothesis indicating the crucial and pre-eminent role of Kupffer cells in the onset of liver apoptosis after Pb(NO3)2 injection is summarized in Fig. 5. In vivo Pb(NO3)2 injection induces Kupffer cells to release factors that can act directly on hepatocytes or indirectly throughout stimulation of other cells (i.e., endothelial liver cells) inducing the death programme in hepatocytes, probably throughout oxidative stress. GdCl3 can block the Pb(NO3)2-induced cascade by destroying Kupffer cells, and in turn, can modify extracellular concentration of molecules released by macrophages (most probably cytokines), which are able to induce depletion of intracellular GSH levels and oxidative apoptotic signalling in hepatocytes.


Kupffer cells promote lead nitrate-induced hepatocyte apoptosis via oxidative stress.

Pagliara P, CarlĂ  EC, Caforio S, Chionna A, Massa S, Abbro L, Dini L - Comp Hepatol (2003)

Scheme of the role of Kupffer cells during Pb(NO3)2-induced hepatic apoptosis. Pb(NO3)2 particles induce, as an early event, Kupffer cells (KC) to secrete molecules (probably cytokines such as TNF alpha) which stimulate hepatocytes (HEP) to proliferate; the increased level of secreted molecules could initiate hepatocyte apoptosis. Activated Kupffer cells may release other molecules prompting endothelial cells (EC) to release additional cytokines, promoting apoptosis of hepatocytes. At the same time, EC can release cytokines that could promote hepatocyte apoptosis as well as activation of KC. As a late event, Pb(NO3)2 particles induce KC death. GdCl3 particles could inhibit the effects of Pb(NO3)2 by depleting Kupffer cells, likely by inducing apoptosis.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC184445&req=5

Figure 5: Scheme of the role of Kupffer cells during Pb(NO3)2-induced hepatic apoptosis. Pb(NO3)2 particles induce, as an early event, Kupffer cells (KC) to secrete molecules (probably cytokines such as TNF alpha) which stimulate hepatocytes (HEP) to proliferate; the increased level of secreted molecules could initiate hepatocyte apoptosis. Activated Kupffer cells may release other molecules prompting endothelial cells (EC) to release additional cytokines, promoting apoptosis of hepatocytes. At the same time, EC can release cytokines that could promote hepatocyte apoptosis as well as activation of KC. As a late event, Pb(NO3)2 particles induce KC death. GdCl3 particles could inhibit the effects of Pb(NO3)2 by depleting Kupffer cells, likely by inducing apoptosis.
Mentions: Our hypothesis indicating the crucial and pre-eminent role of Kupffer cells in the onset of liver apoptosis after Pb(NO3)2 injection is summarized in Fig. 5. In vivo Pb(NO3)2 injection induces Kupffer cells to release factors that can act directly on hepatocytes or indirectly throughout stimulation of other cells (i.e., endothelial liver cells) inducing the death programme in hepatocytes, probably throughout oxidative stress. GdCl3 can block the Pb(NO3)2-induced cascade by destroying Kupffer cells, and in turn, can modify extracellular concentration of molecules released by macrophages (most probably cytokines), which are able to induce depletion of intracellular GSH levels and oxidative apoptotic signalling in hepatocytes.

Bottom Line: RESULTS: The in vivo hepatic apoptosis, induced by Pb(NO3)2 was prevented by a pre-treatment with gadolinium chloride (GdCl3), a Kupffer cells toxicant, that suppresses Kupffer cell activity and reduces to a half the apoptotic rate.In addition, in vivo Pb(NO3)2 administration deprives hepatocytes of reduced glutathione, whereas the loss of this important oxidation-preventing agent is considerably mitigated or abolished by pre-treatment with GdCl3.CONCLUSION: Pb(NO3)2 has, at most, a direct necrotic (but not apoptogenic) effect on hepatocytes and HepG2 cells, giving a clue about the regulatory role of Kupffer cells in the induction of liver apoptosis after a single Pb(NO3)2 injection without pre-treatment with GdCl3, probably via secreting soluble factors that trigger oxidative stress in target cells.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Science and Biological and Environmental Technologies, University of Lecce, via per Monteroni, Lecce, Italy. luciana.dini@unile.it

ABSTRACT
BACKGROUND: Apoptosis and its modulation are crucial factors for the maintenance of liver health, allowing hepatocytes to die without provoking a potential harmful inflammatory response through a tightly controlled and regulated process. Since Kupffer cells play a key role in the maintenance of liver function, the aim of this study was to verify whether Kupffer cells are involved in the induction of liver apoptosis after i.v. injection of Pb(NO3)2 likely by secretion mechanisms. RESULTS: The in vivo hepatic apoptosis, induced by Pb(NO3)2 was prevented by a pre-treatment with gadolinium chloride (GdCl3), a Kupffer cells toxicant, that suppresses Kupffer cell activity and reduces to a half the apoptotic rate. In addition, in vivo Pb(NO3)2 administration deprives hepatocytes of reduced glutathione, whereas the loss of this important oxidation-preventing agent is considerably mitigated or abolished by pre-treatment with GdCl3. However, incubation of isolated hepatocytes and Kupffer cells and HepG2 cells with Pb(NO3)2 for 24 hours induced necrotic but not apoptotic cells. Apoptosis of hepatocytes and HepG2 cells was observed only after the addition of conditioned medium obtained from Kupffer cells cultured for 24 hours with Pb(NO3)2, thus indicating the secretion of soluble mediators of apoptosis by Kupffer cells. Apoptosis in the HepG2 cells was observed upon 24-hours incubation of HepG2 cells with 1 mM buthionine sulfoximine, a glutathione depleting agent, thus showing that there is an oxidative apoptogenic pathway in HepG2 cells. CONCLUSION: Pb(NO3)2 has, at most, a direct necrotic (but not apoptogenic) effect on hepatocytes and HepG2 cells, giving a clue about the regulatory role of Kupffer cells in the induction of liver apoptosis after a single Pb(NO3)2 injection without pre-treatment with GdCl3, probably via secreting soluble factors that trigger oxidative stress in target cells.

No MeSH data available.


Related in: MedlinePlus