Von Willebrand factor protects against acute CCl 4 -induced hepatotoxicity through phospho-p38 MAPK signaling pathway in
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ORIGINAL ARTICLE
Von Willebrand factor protects against acute CCl4-induced hepatotoxicity through phospho-p38 MAPK signaling pathway inhibition Hai-Jian Sun 1,2 & Jian Chen 1 & Hao Zhang 1,3 & Bing Ni 4 & Jennifer C. van Velkinburgh 5 & Yao Liu 6 & Yu-Zhang Wu 1 & Xia Yang 1
# Springer Science+Business Media, LLC 2017
Abstract The blood glycoprotein von Willebrand factor (vWF) is involved in coagulopathy and inflammation; however, its role in the pathogenesis of acute liver failure, as suggested by its higher expression levels in such patients, remains unknown. In this study, vWF-knockout (KO) mice showed more severe carbon tetrachloride (CCl4)-induced liver injury than wild-type mice. Patients with acute liver injury also showed elevated vWF protein activity and expression in liver tissues, as compared to healthy individuals. Using the mouse model and cultured human umbilical vein endothelial cells (HUVECs), CCl4 was found to directly increase vWF protein expression through interaction with the highly expressed vWF receptor, GPIbα. Microarray analysis revealed that the genes
showing the most differential expression in response to CCl4induced liver injury and vWF deficiency were related to the MAPK signaling pathway. Subsequent inhibition of vWF protein activity in HUVECs led to activation of the MAPK signal pathway and elevated production of FGL2, and treatment with a phospho-p38 inhibitor suppressed the CCl4-induced production of FGL2. Exposure of liver sinusoidal endothelial cells isolated from the vWF-KO acute liver injury model mice to phospho-p38 inhibitor also decreased FGL2 expression. The vWF/GPIbα axis plays a protective role against development of acute liver injury by attenuating FGL2 production through the MAPK signaling pathway. Collectively, these data provide insight into the pathogenesis of acute liver injury and a potential novel strategy for its treatment.
Hai-Jian Sun, Jian Chen, and Hao Zhang contributed equally to this study.
Keywords von WillebrandFactor . Acute liver injury . Carbon tetrachloride . Fibrinogen-like protein 2
* Yu-Zhang Wu [email protected] * Xia Yang [email protected] 1
Institute of Immunology, Third Military Medical University (Military Medical University of the Army), PLA, Chongqing 400038, People’s Republic of China
2
Embryology, Nanjing Medical University, Nanjing, Jiangsu 210029, People’s Republic of China
3
Out-patient Department of NO. 75737 Army, PLA, Guangzhou 510800, People’s Republic of China
4
Department of Pathophysiology and High Altitude Pathology, Third Military Medical University (Military Medical University of the Army), Chongqing 400038, People’s Republic of China
5
van Velkinburgh Initiative for Collaboratory BioMedical Research, Santa Fe, NM 87501, USA
6
Department of Pharmacy, Southwestern Hospital, Chongqing 400038, People’s Republic of China
Introduction Acute liver injury syndrome is characterized by hepatocellular necrosis, liver function injury, and severe clinical manifestations, including jaundice, coagulopathy, encephalopat
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