Histological and biochemical evaluation of transforming growth factor-β activation and its clinical significance in patients with chronic liver disease

被引：11

作者：

Yokoyama, Hiroshi ^{[1
,3
]}

Masaki, Takahiro ^{[1
]}

Inoue, Ikuyo ^{[2
]}

Nakamura, Mariko ^{[1
]}

Mezaki, Yoshihiro ^{[1
]}

Saeki, Chisato ^{[3
]}

Oikawa, Tsunekazu ^{[3
]}

Saruta, Masayuki ^{[3
]}

Takahashi, Hiroyuki ^{[4
]}

Ikegami, Masahiro ^{[4
]}

Hano, Hiroshi ^{[4
]}

Ikejima, Kenichi ^{[5
]}

Kojima, Soichi ^{[2
]}

Matsuura, Tomokazu ^{[1
]}

机构：

[1] Jikei Univ, Dept Lab Med, Sch Med, Tokyo, Japan

[2] RIKEN, Ctr Integrat Med Sci, Liver Canc Prevent Res Unit, Saitama, Japan

[3] Jikei Univ, Dept Internal Med, Div Gastroenterol & Hepatol, Sch Med, Tokyo, Japan

[4] Jikei Univ, Dept Pathol, Sch Med, Tokyo, Japan

[5] Juntendo Univ, Dept Gastroenterol, Grad Sch Med, Tokyo, Japan

来源：

HELIYON | 2019年 / 5卷 / 02期

基金：

日本学术振兴会;

关键词：

Internal medicine; Pathology; CHRONIC HEPATITIS-C; INTERFERON-ALPHA; GROWTH-FACTOR-BETA-1; LEVELS; RIBAVIRIN TREATMENT; FIBROSIS MARKERS; STELLATE CELLS; MESSENGER-RNA; SERUM-LEVELS; TGF-BETA; EXPRESSION;

D O I：

10.1016/j.heliyon.2019.e01231

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

Transforming growth factor-beta (TGF-beta) is a key driver for liver fibrogenesis. TGF-beta must be activated in order to function. Plasma kallikrein (PLK) is a TGF-beta activator that cleaves the latency-associated protein (LAP) between arginine(58) and lysine(59) residues and releases active TGF-beta from the latent TGF-beta-LAP complex. Thus, the generation of two LAP degradation products, ending at arginine(58) (R-58/LAPDPs) and beginning from lysine(59) (L-59/LAP-DPs), reflects PLK-dependent TGF-beta activation. However, the significance and details of TGF-beta activation in patients with chronic liver disease (CLD) remain uncertain. We herein examined the PLK-dependent TGF-beta activation in patients by detecting R-58 and L-59/LAP-DPs. A total of 234 patients with CLD were included in this study. Liver biopsy specimens were used for immunostaining to detect R-58/LAP-DPs, while plasma samples were subjected to an enzyme-linked immunosorbent assay to measure the L-59/LAP-DP concentration. R-58/LAP-DP was robustly expressed in and around the sinusoidal cells before the development of the fibrous regions. The R-58/LAP-DP expression at fibrosis stage 1 was higher than at any other stages, and the relationship between the plasma L-59/LAP-DP level and the stage of fibrosis also showed a similar trend. The abundance of plasma L-59/LAP-DP showed no correlation with the levels of direct serum biomarkers of liver fibrosis; however, its changes during interferon-based therapy for chronic hepatitis C were significantly associated with virological responses. Our results suggest that PLK-dependent TGF-beta activation occurs in the early stages of fibrosis and that its unique surrogate markers, R-58 and L-59/LAP-DPs, are useful for monitoring the clinical course of CLD.

引用

页数：30

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