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Participation of Functionally Different Macrophage Populations and Monocyte Chemoattractant Protein-1 in Early Stages of Thioacetamide-induced Rat Hepatic Injury

Laboratories of Veterinary Pathology and Molecular Science, Life and Environmental Sciences, Osaka Prefecture University, Nakaku, Sakai, Osaka, Japan

Correspondence: Dr. Jyoji Yamate, D.V.M., Ph.D., Laboratory of Veterinary Pathology, Life and Environmental Sciences, Osaka Prefecture University, Nakaku, Sakai, Osaka, 599-8531, Japan; e-mail:yamate{at}vet.osakafu-u.ac.jp.

Macrophages are crucial in hepatic fibrogenesis. In acute hepatic necrosis induced in rats by a single injection of 300 mg/kg body weight (BW) of thioacetamide (TAA), macrophage properties were investigated using single or double immunohistochemistry. Macrophages reacting with anti-CD68, anti-CD163, or major histocompatibility complex (anti-MHC) class II antibody appeared in injured centrilobular areas on days 1-5 after injection. Increased expression of CD68 and CD163 reflect phagocytosis and production of pro-inflammatory factors, respectively. There were also macrophages double-positive to CD68/CD163, CD68/MHC class II, or CD163/MHC class II; of these, macrophages double-positive to CD68/MHC class II were most frequent, indicating that macrophages with enhanced phagocytic activity came to express MHC class II. The appearance of these macrophages corresponded to increased expression of mRNAs of monocyte chemoattractant protein-1 (MCP-1), a chemokine, on day 1, and TGF-β1, a fibrogenic factor, on day 3. Some hepatic stellate cells (HSCs) in injured areas reacted with anti-MCP-1 antibody. To investigate the effects of MCP-1, we added MCP-1 to HS-P, a rat macrophage line. Addition of MCP-1 increased immunoexpression for CD68 and CD163 and up-regulated TGF-β1 mRNA expression. Collectively, macrophages in acute hepatic necrosis may express different properties such as phagocytosis, MHC class II expression, and TGF-β1 production; such expression may be influenced by MCP-1 produced by HSCs.

Key Words: acute hepatic necrosis • immunohistochemistry • macrophage function • MCP-1 • thioacetamide • rat

Abbreviations: ABC, avidin-biotin complex; • ANOVA, analysis of variance; • BW, body weight; • DAB, 3,3'-diaminobenzidine; • DAPI, 4'6 diamidino-2-phenylindole; • FBS, fetal bovine serum; • HE, hematoxylin and eosin; • HSC, hepatic stellate cell; • IL, interleukin; • MCP-1, monocyte chemoattractant protein-1; • MHC class II, major histocompatibility complex class II; • PBS, phosphate buffered saline; • PFA, paraformaldehyde; • PI, post-injection; • RT-PCR, reverse transcriptase-polymerase chain reaction; • SD, standard deviation; • TAA, thioacetamide; • TGF-β1, transforming growth factor-β1; • TNF-, tumor necrosis factor-.

This version was published on June 1, 2009

Toxicologic Pathology, Vol. 37, No. 4, 463-473 (2009)
DOI: 10.1177/0192623309335634


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