title: Activated intestinal macrophages in patients with cirrhosis release NO and IL-6 that may disrupt intestinal barrier function.
abstract: OBJECTIVE
  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 (decompensated 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 duodenal biopsies assessing 84 inflammatory genes. Protein levels of cytokines/chemokines were assessed in serum and supernatant. The duodenal wall was assessed by electron microscopy, tight junction protein expression determined by RT-PCR, immunohistochemistry, and Western blot and, functional analysis performed by transepithelial resistance measurement and permeability 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 demonstrated an intact epithelial barrier. Increased Claudin-2 was detected by Western blot and immunohistochemistry, while decreased transepithelial resistance and increased duodenal permeability 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, suggesting that these cells may produce factors capable of enhancing permeability to bacterial products.
authors: Hepatology and GI Research Laboratory, Department of Immunology, University of Pretoria, South Africa.
authors: Johannie
authors: J
authors: Du Plessis
authors: Hanne
authors: H
authors: Vanheel
authors: Carl E I
authors: CE
authors: Janssen
authors: Leonie
authors: L
authors: Roos
authors: Tomas
authors: T
authors: Slavik
authors: Paraskevi I
authors: PI
authors: Stivaktas
authors: Martin
authors: M
authors: Nieuwoudt
authors: Stefan G
authors: SG
authors: van Wyk
authors: Warren
authors: W
authors: Vieira
authors: Etheresia
authors: E
authors: Pretorius
authors: Mervyn
authors: M
authors: Beukes
authors: Ricard
authors: R
authors: Farré
authors: Jan
authors: J
authors: Tack
authors: Wim
authors: W
authors: Laleman
authors: Johan
authors: J
authors: Fevery
authors: Frederik
authors: F
authors: Nevens
authors: Tania
authors: T
authors: Roskams
authors: Schalk W
authors: SW
authors: Van der Merwe
mesh_terms: D000368:Aged; D005260:Female; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism*; D007413:Intestinal Mucosa / Q000378:metabolism; D007422:Intestines / Q000276:immunology*; D018950:Lipopolysaccharide Receptors / Q000032:analysis; D008103:Liver Cirrhosis / Q000276:immunology*; D008262:Macrophage Activation; D008264:Macrophages / Q000276:immunology* / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009569:Nitric Oxide / Q000378:metabolism*; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D010539:Permeability
chemical_list: C508600:IL6 protein, human; D015850:Interleukin-6; D018950:Lipopolysaccharide Receptors; D009569:Nitric Oxide; D052247:Nitric Oxide Synthase Type II