Therapeutic potential of vascular adhesion protein in primary sclerosing cholangitis

• Published in: The Lancet (British edition) 2014-02, Vol.383, p.S102-S102
• Main Authors: Trivedi, Palak, Dr, Weston, Christopher, PhD, Corbett, Christopher, MBBS, Liaskou, Evaggelia, PhD, Adams, David, Prof
• Format: Article
• Language: English
• Subjects: Adhesion; Amines; Enzymatic activity; Enzyme inhibitors; Hepatitis; Hydrogen peroxide; Internal Medicine; Liver; Lymphocytes
• ISSN: 0140-6736; 1474-547X
• DOI: 10.1016/S0140-6736(14)60365-2

Abstract Background Vascular adhesion protein 1 (VAP1) is an adhesion molecule that also posseses potent amine oxidase activity; it produces hydrogen peroxide via the deamination of dietary amines. Through this function, VAP1 leads to activation of NFκB in hepatic sinusoidal endothelial cells (HSEC) resulting in expression of mucosal-vascular cell-adhesion molecule 1 (MAdCAM1), a mechanism proposed to contribute to the homing of gut-tropic lymphocytes expressing α4β7 to the liver. In view of the putative role of this pathway in hepatic diseases complicating inflammatory bowel disease, we aimed to quantify circulating or soluble (sVAP1) as well as intrahepatic VAP1 enzyme activity in patients with primary sclerosing cholangitis, and assess the functional consequence of its inhibition on MAdCAM1-dependent lymphocyte recruitment to HSEC. Methods Total VAP1 concentration was measured by ELISA. VAP1 amine oxidase activity was quantified in human serum and explanted liver tissue with the amplex red assay. We used flow-based adhesion assays with human HSEC isolated from liver explants, activated through tumour necrosis factor α and methylamine (VAP1 substrate), before and after treatment with VAP1 antibody or semicarbazide (VAP1 enzyme inhibitor). Fluorescence-activated cell sorted peripheral blood lymphocytes expressing α4β7 were perfused over HSEC under flow rates simulating physiological shear (0·05 kPa) and differences in adhesion and transmigration measured. Findings Patients with primary sclerosing cholangitis had higher circulating median VAP1 enzyme activity (114·5 pmol hydrogen peroxide produced per min/mL serum, IQR 100·6–134·7) than patients with inflammatory bowel disease (60·3, 38·5–73·0; p=0·006), healthy controls (84·0, 77·7–105·7; p=0·02), and individuals with primary biliary cirrhosis (53·9, 33·0–90·9; p=0·006) and autoimmune hepatitis (77·6, 51·0–124·5; p=0·2, Mann-Whitney). Total sVAP1 concentration correlated well with sVAP1 enzyme activity ( r2 =0·75). Intrahepatic median VAP1 activity was also significantly higher in primary sclerosing cholangitis than in primary biliary cirrhosis (97·6 pmol [IQR 69·5–114·5] vs 24·6 [18·7–27·8], p=0·029) and autoimmune hepatitis (32·3 [23·3–35·6], p=0·028). HSEC pretreatment with semicarbazide and antibody led to a reduction in total α4β7+ lymphocyte adhesion (by 50% and 25%, respectively); however, both antibody and enzyme inhibition independently reduced transmigration by about 50% compared with untreated