Gastroenterology

Gastroenterology

Volume 123, Issue 1, July 2002, Pages 291-300
Gastroenterology

Basic–Liver, Pancreas, and Biliary Tract
Thalidomide prevents alcoholic liver injury in rats through suppression of Kupffer cell sensitization and TNF-α production

https://doi.org/10.1053/gast.2002.34161Get rights and content

Abstract

Background & Aims: Sensitization of Kupffer cells (KCs) to lipopolysaccharide (LPS) and overproduction of tumor necrosis factor (TNF) α are critical for progression of alcoholic liver injury. Thalidomide has been shown to suppress TNF-α production from macrophages. Accordingly, the purpose of this study was to determine whether thalidomide could prevent alcohol-induced liver injury. Methods: Rats were given ethanol (5 g/kg body wt) and thalidomide (5 mg/kg) once every 24 hours intragastrically. To assess the sensitization of Kupffer cells, LPS (5 mg/kg intravenously) was administered and liver histology was evaluated 24 hours later. KCs were isolated after 4 weeks of ethanol treatment and intracellular Ca2+ ([Ca2+]i) was measured using fura-2, whereas TNF-α was evaluated by reverse-transcription polymerase chain reaction and enzyme-linked immunosorbent assay. CD14 was determined by Western and fluorescence staining. Results: Treatment with ethanol for 8 weeks caused marked steatosis, necrosis, and inflammation in the liver. These pathologic parameters were diminished markedly by treatment with thalidomide. In the 4-week ethanol group, the LPS-induced liver damage was aggravated and KCs were sensitized to LPS. Coadministration of thalidomide with ethanol prevented the KC sensitization completely. Furthermore, thalidomide abolished the LPS-induced increase in CD14 expression and [Ca2+]i elevation in KCs. Gut permeability was increased about 10-fold after 4 weeks of ethanol exposure, which was not affected by thalidomide. Moreover, thalidomide reduced the LPS-induced TNF-α production by KCs by decreasing TNF-α messenger RNA. Conclusions: These results collectively indicate that thalidomide prevents alcoholic liver injury through suppression of TNF-α production and abolishment of KC sensitization.

GASTROENTEROLOGY 2002;123:291-300

Section snippets

Animals and treatments

In this study, a model of alcoholic liver injury based on the sensitization of Kupffer cells, in which rats are given ethanol (5 g/kg body weight) once every 24 hours,22 was used. This model achieves inflammatory and necrotic changes in the liver only in 8 weeks, which mimics features of clinical alcohol liver injury.22 Liver damage was evaluated after 8 weeks of treatment with ethanol because histologic manifestations are preceded by sensitization of Kupffer cells to LPS treatment, and Kupffer

Effect of thalidomide on alcoholic liver injury

There were no differences in body weight growth among the control, thalidomide, ethanol, and ethanol plus thalidomide groups during 8 weeks of ethanol treatment. All rats survived for 8 weeks. Animals treated with thalidomide only showed completely normal liver histology (Figure 1B).

. Effect of thalidomide on ethanol-induced liver injury. Photomicrographs of H&E sections of livers from rats treated as described in Materials and Methods. (A) No treatment, (B) 8 weeks of treatment with thalidomide

Thalidomide prevents alcohol-induced liver injury

In this study, we used a model of alcohol-induced liver injury based on sensitization of Kupffer cells22 because it has been established that sensitization of Kupffer cells to LPS and consequent overproduction of TNF-α play a central role in the pathogenesis of alcohol liver disease.1, 2, 31 This model makes it possible to achieve pathologic changes in the liver (e.g., steatosis, inflammation, and necrosis) that resemble alterations that occur in the enteral-feeding model without surgery (

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    Address requests for reprints to: Nobuhiro Sato, M.D., Department of Gastroenterology, Juntendo University School of Medicine, 2-1-1, Hongo, Bunkyo-ku, Tokyo, 113-8421, Japan. e-mail: [email protected]; fax: (81) 3-3813-8862.

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