Activated intestinal macrophages in patients with cirrhosis release NO and IL-6 that may disrupt intestinal barrier function

Abstract

Background & Aims: Bacterial infections commonly occur in decompensated cirrhosis resulting from bacterial translocation from the intestine. We studied the role of intestinal macrophages and the epithelial barrier in cirrhosis. Methods: Forty-four patients with NASH/ASH cirrhosis (decom-pensated n = 29, compensated n = 15) and nineteen controls undergoing endoscopy were recruited. Serum was obtained and LPS and LBP levels determined. Intestinal macrophages were characterized by flow cytometry, immunohistochemistry, and nitric oxide (NO) production measured in supernatant of cultured duodenal samples. Quantitative RT-PCR was performed on duo-denal biopsies assessing 84 inflammatory genes. Protein levels of cytokines/chemokines were assessed in serum and superna-tant. The duodenal wall was assessed by electron microscopy, tight junction protein expression determined by RT-PCR, immu-nohistochemistry, and Western blot and, functional analysis performed by transepithelial resistance measurement and per-meability studies. Results: Increased plasma LPS, LBP levels and higher numbers of duodenal CD33 + /CD14 + /Trem-1 + macrophages, synthesizing iNOS and secreting NO were present in decompensated cirrhosis. Upregulation of IL-8, CCL2, CCL13 at the transcriptional level, and increased IL-8, and IL-6 were detected in supernatant and serum in cirrhosis. IL-6 and IL-8 co-localised with iNOS + and CD68 + , but not with CD11c + cells. Electron microscopy demon-strated an intact epithelial barrier. Increased Claudin-2 was detected by Western blot and immunohistochemistry, while decreased transepithelial resistance and increased duodenal per-meability were detected in decompensated cirrhosis. Conclusions: Our study shows the presence of activated CD14 +-Trem-1 + iNOS + intestinal macrophages, releasing IL-6, NO, and increased intestinal permeability in patients with cirrhosis, sug-gesting that these cells may produce factors capable of enhancing permeability to bacterial products.

Expression of toll-like receptors in hepatic cirrhosis and hepatocellular carcinoma

“…Many experiments have provided evidence that iNOS-derived NO can play an important role in promoting pathogenic BT in endotoxemia, hemorrhagic shock, and hepatic cirrhosis. The overproduction of NO results in the release of activated intestinal macrophages in decompensated cirrhosis, and may decrease transepithelial resistance and disrupt intestinal barrier function (Du Plessis et al, 2013). Similar results have also been confirmed in iNOS knockout mice exposed to LPS, which exhibited reduced mortality and absent BT.…”

Association of Adipose Tissue Inflammation With Histologic Severity of Nonalcoholic Fatty Liver Disease

“…IL8 is increased in chronic liver disease, and may contribute to hepatic inflammation by activation of Kupffer cells. 24 IL8 levels are increased in NASH 25 and in obese Hispanic pediatric patients in whom serum IL8 correlated with the hepatic fat fraction measured by magnetic resonance imaging. 26 CCL3 has been shown to be a mediator of experimental liver fibrosis in mice.…”

Changes of Intestinal Functions in Liver Cirrhosis

“…Oral administration of antibiotics, polymyxins and neomycins improved intestinal permeability and enhanced TJP expression [101]. On the other hand, Du Plessis et al [102] reported that the structural TJPs ZO-1, occludin and claudin-1 as well as the gap junction protein connexin 43 were not decreased at the mRNA and protein levels in cases of cirrhosis related to NASH and alcoholic steatohepatitis. In that study, electron microscopy further revealed an intact epithelial barrier in patients with decompensated cirrhosis, suggesting that the epithelial barrier is functionally altered but structurally normal in cirrhosis.…”

“…Pathological BT is a contributing factor in the development of complications in cirrhosis, not only in infections but also by exerting a profound inflammatory state and exacerbating the hemodynamic derangement [34,67]. Du Plessis et al [102] showed the presence of activated CD14(+)Trem-1(+) iNOS(+) intestinal macrophages releasing IL-6 and NO as well as increased intestinal permeability in cirrhotics related to NASH and alcoholic steatohepatitis, suggesting that these cells may produce factors capable of enhancing permeability by bacterial products. In our rat model of NASH induced by a CDAA diet, significantly increased immunostaining for TNF-α, TLR4 and macrophage/dendritic cells was demonstrated in the small intestinal submucosa, indicating the activation of innate immune response [125].…”