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Hepatic toll‐like receptor 4 expression is associated with portal inflammation and fibrosis in patients with NAFLD
Author(s) -
VespasianiGentilucci Umberto,
Carotti Simone,
Perrone Giuseppe,
Mazzarelli Chiara,
Galati Giovanni,
OnettiMuda Andrea,
Picardi Antonio,
Morini Sergio
Publication year - 2015
Publication title -
liver international
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.873
H-Index - 110
eISSN - 1478-3231
pISSN - 1478-3223
DOI - 10.1111/liv.12531
Subject(s) - cytokeratin , hepatic stellate cell , progenitor cell , myofibroblast , inflammation , pathology , fibrosis , medicine , immunohistochemistry , hepatic fibrosis , biology , stem cell , genetics
Background & Aims Notwithstanding evidences implicating the lipopolysaccharides ( LPS )/toll‐like receptor‐4 ( TLR 4) axis in the pathogenesis of NAFLD , there are no studies aimed to characterize hepatic TLR 4 expression in NAFLD patients. We aimed to analyse hepatic TLR 4 expression and to verify its relationship with disease activity/evolution in NAFLD patients. Methods Liver tissue from 74 patients with NAFLD and 12 controls was analysed by immunohistochemistry ( IHC ) for TLR 4, α–smooth muscle actin (α– SMA ) and cytokeratin‐7. IHC for α– SMA was used to evaluate activation of fibrogenic cells (hepatic stellate cells and portal/septal myofibroblasts), that for cytokeratin‐7 to count hepatic progenitor cells and bile ducts/ductules, and that for CD 68, in a subgroup of 27 patients, for detecting macrophages. Serum LPS ‐binding protein ( LBP ), a sensitive marker of LPS activity, was determined in 36 patients and 32 controls. Results As confirmed by double‐labelling experiments, the highest level of TLR 4 expression was observed in hepatic progenitor cells, biliary cells and portal/septal macrophages. TLR 4‐positive hepatic progenitor cells and bile ducts/ductules correlated with portal/interface inflammation, activity of fibrogenic cells and fibrosis ( P < 0.001). Also the score of TLR 4 positivity of porto‐septal inflammatory infiltrate correlated with number of hepatic progenitor cells and bile ducts/ductules, activity of fibrogenic cells and fibrosis ( P < 0.01). Serum LBP was increased in patients compared to controls ( P < 0.001), and correlated with portal/interface inflammation, activity of portal/septal myofibroblasts and fibrosis (all P < 0.05). Conclusions TLR 4 expression by regenerating and inflammatory cells at the porto‐septal and interface level, favoured by increased LPS activity, is associated with activation of fibrogenic cells and the degree of fibrosis.