Kupffer cells are associated with apoptosis, inflammation and fibrotic effects in hepatic fibrosis in rats

Abstract

Hepatocellular apoptosis, hepatic inflammation, and fibrosis are prominent features in chronic liver diseases. However, the linkage among these processes remains mechanistically unclear. In this study, we examined the apoptosis and activation of Kupffer cells (KCs) as well as their pathophysiological involvement in liver fibrosis process. Hepatic fibrosis was induced in rats by dimethylnitrosamine (DMN) or carbon tetrachloride (CCl4) treatment. KCs were isolated from normal rats and incubated with lipopolysaccharide (LPS) or from fibrotic rats. The KCs were stained immunohistochemically with anti-CD68 antibody, a biomarker for KC. The level of expression of CD68 was analyzed by western blot and real-time PCR methods. The apoptosis and pathophysiological involvement of KCs in the formation of liver fibrosis were studied using confocal microscopy. The mRNA and protein expression of CD68 were significantly increased in DMNand CCL4-treated rats. Confocal microscopy analysis showed that CD68-positive KCs, but not a-smooth muscle actin (SMA)-positive cells, underwent apoptosis in the liver of DMN-and CCL4-treated rats. It was also revealed that the terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling and CD68-double-positive apoptotic KCs located in the portal or fibrotic septa area were situated next to hepatic stellate cells (HSCs). Tumor necrosis factor-a (TNF-a) and KC co-localized in the liver in the neighbor of HSCs. The double a-SMA-and collagen type I-positive cells predominantly existed in fibrotic septa, and those cells were co-localized clearly with CD68-positive cells. Interestingly, some CD68 and Col (1) double positive, but completely negative for a-SMA, were found in the portal areas and hepatic sinusoids; this phenomenon was also validated in primary isolated KCs after 6 h LPS exposure or fibrotic rats in vitro. These results show that KCs are associated with hepatocellular apoptosis, inflammation, and fibrosis process in a liver fibrosis models.

Transcriptional Repression of the Transforming Growth Factor β (TGF-β) Pseudoreceptor BMP and Activin Membrane-bound Inhibitor (BAMBI) by Nuclear Factor κB (NF-κB) p50 Enhances TGF-β Signaling in Hepatic Stellate Cells

“…There is overwhelming evidence that activated HSCs are the major producers of the fibrotic matrix (1-3). TGF-␤ is the key cytokine that mediates HSC activation, but the current model of TGF-␤-dependent HSC activation does not account for the contribution of inflammatory mediators to hepatic fibrogenesis (6), and extensive studies are aimed to establish a mechanistic link between inflammation and fibrosis in chronic liver disease (6,18). We have shown previously that BAMBI links inflammation and liver fibrosis via TLR4-dependent modification of TGF-␤ signaling in HSC.…”

Liver fibrosis

“…Bacterial lipopolysaccharide is a well-known fibrosis-promoting agent by the activation of Toll-like receptor (TLR) 4 signaling, which is expressed on macrophages and HSCs (33,34). In contrast, Kupffer cell activity increases the activity of nuclear factor-kappa β, which in turn promotes pro-inflammatory cytokine secretion (35).…”

Xiayuxue decoction reduces renal injury by promoting macrophage apoptosis in hepatic cirrhotic rats

“…We previously reported that macrophages underwent apoptosis in dimethylnitrosamineinduced liver fibrosis (Liu et al, 2010). Therefore, in this study, we investigated if macrophages underwent apoptosis in the kidneys during liver cirrhosis.…”

“…Macrophages are known to play an important role in liver fibrosis and cirrhosis (Heinrichs et al, 2011;Zimmermann et al, 2011;Heymann et al, 2012;Ramachandran et al, 2012), which is a central component of the final, common pathway leading to HSC activation and ECM deposition (Liu et al, 2008(Liu et al, , 2010Chiu et al, 2014). However, the macrophage in kidneys with cirrhosis has not been well studied.…”

“…We have previously shown that Kupffer cells (hepatic macrophages) underwent apoptosis and might exert fibrogenic function by producing collogen1 (Col 1) independently during liver fibrosis (Liu et al, 2010). However, renal macrophage function in liver cirrhosis has been rarely reported and requires urgent investigation.…”