Effects of dexamethasone on hepatic macrophages in normal livers and thioacetamide-induced acute liver lesions in rats

Abstract

Resident and infiltrative macrophages play important roles in the development of pathological lesions. M1/M2 macrophage polarization with respective CD68 and CD163 expression remains unclear in chemically induced liver injury. This study was aimed at investigating the influence of macrophages on normal and chemically induced liver injury. For this, dexamethasone (DX), an immunosuppressive drug, was administered in normal rats and thioacetamide (TAA)-treated rats. Liver samples were collected and analyzed with immunohistochemical methods. Repeated injections of DX (0.5 or 1.0 mg/kg BW) for 3, 7 and 11 days reduced the number of CD163 positive hepatic resident macrophages (Kupffer cells) in normal livers, while increasing AST and ALT levels. In TAA (300 mg/kg BW)-treated rats injected with DX (0.5 mg/kg BW) pretreatment, the number of M1 and M2 macrophages showed a significant decrease compared with that of TAA-treated rats without DX treatment. Additionally, reparative fibrosis resulting from hepatocyte injury induced by TAA injection was suppressed by DX pretreatment. Our data suggested that macrophages could influence not only normal hepatic homeostasis (reflected by AST and ALT levels) but also chemically induced hepatic lesion development (reduced reparative fibrosis).

Macrophage pathology in hepatotoxicity

“…In rats injected with TAA under the pretreatment of Dex and subsequent discontinuation 70 , M1 macrophages continuously decrease by approximately 70%, compared to the rats injected TAA alone; M2 macrophages also decrease by approximately 50%, but quickly recover to normal levels after discontinuation. Of interest, reparative fibrosis, that should occur in the late stage by TAA alone injection, is considerably reduced by the co-treatment with Dex/TAA.…”

“…1 ; II), have been extensively evaluated 4 . The depletion of M1/M2 macrophages by clodronate exacerbates liver lesions 73 ; in contrast, Dex treatment, despite decreasing M1/M2 macrophages, improves the liver lesions through appropriate regulation of macrophages 70 . In spite of no histopathological changes, the initial induction for M1/M2 macrophages in liver lesions may be caused by Kupffer cells/interstitial dendritic cells existing in and around the Glisson’s sheath; these cells act as the “portal vein-liver barrier” 32 ( Fig.…”

“…Therefore, the reparative fibrosis by M2 macrophages is thought to function in a timely manner. The clinical dose of Dex results in the improvement of hepatic fibrosis through appropriate suppression of M1/M2 macrophages 70,71 .…”

“…Therefore, the reparative fibrosis by M2 macrophages is thought to function in a timely manner. The clinical dose of Dex results in the improvement of hepatic fibrosis through appropriate suppression of M1/M2 macrophages 70 , 71 . The improvement of TAA-induced liver lesions are also confirmed by using gadolinium chloride which can appropriately reduce the hepatic macrophages including Kupffer cells 72 .…”

Immunophenotypic analysis of the distribution of hepatic macrophages, lymphocytes and hepatic stellate cells in the adult rat liver

“…Increasing evidence implicates the role of hepatic macrophages as an important factor in developing different forms of liver injury. Macrophages play a key role in alcohol‐induced (Ju & Mandrekar, 2015) as well as chemical‐induced (D‐galactosamine and thioacetamide) liver injury (Hada et al., 2020; Rahman et al., 2018; Wijesundera et al., 2015). The hepatic stellate cells have participated in hepatic lesions induced by D‐galactosamine (Rahman et al., 2018) and thioacetamide (Tennakoon et al.,2015).…”