Histopathological Analysis of Rat Hepatotoxicity Based on Macrophage Functions: in Particular, an Analysis for Thioacetamide-induced Hepatic Lesions

Abstract

Hepatic macrophages play an important role in homeostasis. The functional abnormalities of hepatic macrophages primarily or secondarily influence chemically induced hepatotoxicity. However, the evaluation system based on their functions has not yet been established. Recently, a new concept (M1-/M2-macrophage polarization) was proposed; M1macropahges are induced by INF-γ, and show high phagocytosis/tissue damage, whereas M2-macropahges are induced by IL-4 and play roles in reparative fibrosis by releasing IL-10 and TGF-β1. In hepatogenesis, CD68-expressing M1macrophages predominantly exist in embryos; in neonates, in contrast, CD163-/CD204-expressing M2-macrophages appear along the sinusoids and mature as Kupffer cells. Activated Kupffer cells by liposome decrease AST and ALT values, whereas AST and ALT values are increased under Kupffer cells depleted with clodronate treatment. Since Kupffer cells may be involved in clearance of liver enzymes, macrophage condition should be taken into consideration when hepatotoxicity is analyzed. In TAA-induced acute hepatic lesions, INF-γ, TNF-α and IL-6 for M1-factors and IL-4 for M2factors are already increased before histopathological change; the appearance of CD68-expressing M1-macrophages and CD163-expressing M2-macrophages follows in injured centrilobular lesions, and TGF-β1 and IL-10 are increased for reparative fibrosis. CD68-expressing M1-macrophages co-express MHC class II and Iba-1, whereas CD163-expressing M2-macrophages also express CD204 and Galectin-3. Under macrophage depletion by clodoronate, TAA-treated rat livers show prolonged coagulation necrosis of hepatocytes, and then develop dystrophic calcification without reparative fibrosis. The depletion of hepatic macrophages influences hepatic lesion development. Collectively, a histopathological analysis method for hepatotoxicity according to M1-/M2-macrophage polarization would lead to the refinement of hazard characterization of chemicals in food and feed.

Antioxidant Potential, Anti-Inflammatory and Hepatoprotective Effect of Curcumin in a Rat Model of Hepatotoxicity

“…IL-6 gene expression was significantly raised in the TAA group as compared with the control group, indicating that TAA induced changes in the IL-6 gene, producing more IL-6 protein than would the normal gene. This result comes in concomitant with recent literature which illustrates that in TAA-induced acute hepatic lesions, INF-γ, TNF-α and IL-6 for M1-factors and IL-4 for M2-factors are already increased before histopathological change (Yamate et al, 2016).This increase in IL-6 gene expression was overcome in the experimental animals who received curcumin with TAA; hence, they seemed to be protected against abnormally increased levels of IL-6 in the liver caused by TAA. This result was confirmed by several previous studies (Bereswill et al, 2010, Tarladacalisir et al, 2013.…”

Histopathological Analysis of Tumor Microenvironment and Angiogenesis in Pheochromocytoma

“…In addition, M2 macrophages were the representative subtypes of macrophages in TME of most human malignancies including breast, urinary bladder, and prostate carcinoma (46,47). Results of our present study did demonstrate that TAMs in PHEOs could be predominantly reprogrammed into CD68 + M1 rather than CD163+M2 macrophages, which exerted potential antitumoral effects by secreting different cytokines (44,48). However further investigations are required to clarify the details.…”

Histochemical and Immunohistochemical Characterizations of Hepatic Trematodiasis in Odontocetes

“…Macrophages migrating to lesion sites are classified into two main types: M1 and M2 macrophages. M1 macrophages are induced in the early stage of inflammation and show high phagocytic capacities while M2 macrophages are involved in tissue repair by inducing fibrosis (46). These macrophages express different antigens, where Iba1-, CD68-, and major histocompatibility complex (MHC) class II-positive cells are considered M1, and CD163-and CD204-positive cells are considered M2 macrophages (46).…”

“…M1 macrophages are induced in the early stage of inflammation and show high phagocytic capacities while M2 macrophages are involved in tissue repair by inducing fibrosis (46). These macrophages express different antigens, where Iba1-, CD68-, and major histocompatibility complex (MHC) class II-positive cells are considered M1, and CD163-and CD204-positive cells are considered M2 macrophages (46). In the current analyses, M2 macrophages were dominant over M1 macrophages especially in the HP regions, suggesting that all analyzed individuals were in the chronic stage of fibrosis rather than in the early stage of infection and injury.…”