| Hypoxia-inducible Factor Activation in Myeloid Cells Contributes to the Development of Liver Fibrosis in Cholestatic Mice. | |
| | |
MedLine Citation:
|
PMID: 22271822 Owner: NLM Status: Publisher |
Abstract/OtherAbstract:
|
Macrophages play an integral role in the development of liver fibrosis by releasing mediators, such as platelet-derived growth factor-B (PDGF-B) and transforming growth factor-β1, which stimulate hepatic stellate cell proliferation, chemotaxis, and collagen production. The mechanism by which chronic liver injury stimulates macrophages to release these mediators, however, is not completely understood. We tested the hypothesis that chronic liver injury activates hypoxia-inducible factor (HIF) transcription factors in macrophages that regulate production of mediators that promote fibrosis. To test this hypothesis, Cre/lox technology was used to generate myeloid cell-specific HIF-1α or HIF-1β knockout mice. When these mice were subjected to bile duct ligation (BDL), levels of α-smooth muscle actin and type I collagen in the liver were reduced when compared to mice with normal levels of HIFs. Deficiency of HIFs in macrophages did not affect liver injury or inflammation after BDL, but reduced platelet-derived growth factor-B (PDGF-B) mRNA and protein, suggesting that HIF activation in macrophages may promote fibrosis by regulating production of PDGF-B. Consistent with a role for HIFs in liver fibrosis in cholestatic liver disease, nuclear HIF-1α protein was present in macrophages, hepatocytes, and fibroblasts in livers from patients with primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC). These studies demonstrate that HIFs are important regulators of profibrotic mediator production by macrophages during the development of liver fibrosis, and suggest that HIFs may be a novel therapeutic target for the treatment of chronic liver disease in patients. |
| | |
Authors:
|
Bryan L Copple; Sophia Kaska; Callie Wentling |
Publication Detail:
|
Type: JOURNAL ARTICLE Date: 2012-1-23 |
Journal Detail:
|
Title: The Journal of pharmacology and experimental therapeutics Volume: - ISSN: 1521-0103 ISO Abbreviation: - Publication Date: 2012 Jan |
Date Detail:
|
Created Date: 2012-1-24 Completed Date: - Revised Date: - |
Medline Journal Info:
|
Nlm Unique ID: 0376362 Medline TA: J Pharmacol Exp Ther Country: - |
Other Details:
|
Languages: ENG Pagination: - Citation Subset: - |
Affiliation:
|
University of Kansas Medical Center. |
Export Citation:
|
APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
|
|
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
Previous Document: Studies of the Biogenic Amine Transporters. 14. Identification of Low Efficacy "Partial" Substrates ...
Next Document: Tensor Completion for Estimating Missing Values in Visual Data.