Ethanol and arachidonic acid synergize to activate Kupffer cells and modulate the fibrogenic response via tumor necrosis factor alpha, reduced glutathione, and transforming growth factor beta-dependent mechanisms.
Ethanol and arachidonic acid synergize to activate Kupffer cells and modulate the fibrogenic response via tumor necrosis factor alpha, reduced glutathione, and transforming growth factor beta-dependent mechanisms.
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DOI：
10.1002/hep.22592
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发表时间：
2008-12
期刊：
影响因子：
13.5
通讯作者：
Nieto, Natalia
中科院分区：
文献类型：
--
作者：
Cubero, Francisco Javier;Nieto, Natalia
because of the contribution of ethanol and polyunsaturated fatty acids (PUFAs) to alcoholic liver disease, we investigated whether chronic ethanol administration and arachidonic acid (AA) could synergistically mediate Kupffer cell (KC) activation and modulate the stellate cell (HSC) fibrogenic response. 1) Ethanol and AA effects on KC and HSC mono-cultures: cell proliferation, lipid peroxidation, H2O2, O2.−, NADPH oxidase activity, and TNFα were higher in KCethanol than in KCcontrol, and were enhanced by AA; HSCethanol proliferated faster, increased collagen, and showed higher GSH than HSCcontrol, with modest effects by AA. 2) AA effects on the control co-culture: we previously reported the ability of KC to induce a pro-fibrogenic response in HSC via ROS-dependent mechanisms; we now show that AA further increases cell proliferation and collagen in the control co-culture. The latter was prevented by vitamin E (an antioxidant) and by diphenyleneiodonium (a NADPH oxidase inhibitor). 3) Ethanol effects on the co-cultures: co-culture with KCcontrol or KCethanol induced HSCcontrol and HSCethanol proliferation; however, the pro-fibrogenic response in HSCethanol was suppressed due to up-regulation of TNFα and GSH, which was prevented by a TNFα neutralizing Ab and by l-buthionine-sulfoximine, a GSH-depleting agent. 4) Ethanol plus AA effects on the co-cultures: AA lowered TNFα in the HSCcontrol co-cultures allowing for enhanced collagen deposition; furthermore, AA restored the pro-fibrogenic response in the HSCethanol co-cultures by counteracting the up-regulation of TNFα and GSH with a significant increase in GSSG and in pro-fibrogenic TGFβ. these results unveil synergism between ethanol and AA to the mechanism whereby KC mediate ECM remodeling, and suggest that even if chronic ethanol consumption sensitizes HSC to up-regulate anti-fibrogenic signals, their effects are blunted by a second ‘hit’ such as AA.
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影响因子：
14.9
作者：
Lindquist, JN;Kauschke, SG;Brenner, DA
通讯作者：
Brenner, DA
影响因子：
13.5
作者：
García-Trevijano, ER;Iraburu, MJ;Rojkind, M
通讯作者：
Rojkind, M
DOI：
10.1152/ajpgi.2000.278.3.g467
发表时间：
2000-03-01
影响因子：
4.5
作者：
Kono, H;Enomoto, N;Thurman, RG
通讯作者：
Thurman, RG
影响因子：
2.3
作者：
Nanji, AA
通讯作者：
Nanji, AA
影响因子：
13.5
作者：
Nieto, Natalia
通讯作者：
Nieto, Natalia