title: A Src family kinase inhibitor improves survival in experimental acute liver failure associated with elevated cerebral and circulating vascular endothelial growth factor levels.
abstract: OBJECTIVE
  Acute liver failure (ALF) is frequently complicated by cerebral oedema, systemic inflammation and multiorgan dysfunction. Vascular endothelial growth factor (VEGF) may stimulate liver regeneration but it can also be pro-inflammatory, activating endothelial cells and increasing permeability, actions mediated through Src kinase signalling. We therefore examined whether a Src inhibitor could have therapeutic potential in ALF.
  
  
  METHODS
  Murine ALF was induced with azoxymethane. Liver pathology was graded by a blinded examiner and apoptosis quantified by immunohistochemistry. Cerebral VEGF expression was imaged using VEGF-green fluorescent protein transgenic mice. Circulating and macrophage-secreted VEGF levels were measured. Experimental animals received a Src inhibitor or vehicle controls.
  
  
  RESULTS
  VEGF was undetectable in normal plasma but reached a mean of 835 pg/ml at grade III encephalopathy (P<0.001). Ammonia, lipopolysaccharide and interferon-gamma acted synergistically to enhance VEGF secretion by macrophages. Production of VEGF by cerebral cortical astrocytes increased with disease progression. Late treatment with inhibitors of Src or VEGF did not improve liver histology, encephalopathy or survival. However, early use of a Src kinase inhibitor significantly reduced hepatic injury, delayed encephalopathy and allowed 25% of mice to survive an otherwise lethal insult.
  
  
  CONCLUSIONS
  Systemic and cerebral VEGF levels are significantly elevated during experimental ALF and may be exacerbated by hyperammonemia and macrophage activation. Early use of a Src inhibitor reduced hepatocellular injury and enabled survival, indicating such agents may have some promise in the treatment of ALF.
authors: Scripps Clinic, La Jolla, CA, USA. r.j.aspinall@doctors.org.uk
authors: Richard J
authors: RJ
authors: Aspinall
authors: Sara M
authors: SM
authors: Weis
authors: Leo
authors: L
authors: Barnes
authors: Kimberly
authors: K
authors: Lutu-Fuga
authors: David J
authors: DJ
authors: Bylund
authors: Paul J
authors: PJ
authors: Pockros
authors: David A
authors: DA
authors: Cheresh
mesh_terms: D000643:Ammonium Chloride / Q000494:pharmacology; D000814:Aniline Compounds / Q000494:pharmacology*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001253:Astrocytes / Q000187:drug effects / Q000201:enzymology; D001397:Azoxymethane; D001921:Brain / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D001929:Brain Edema / Q000139:chemically induced / Q000201:enzymology / Q000473:pathology / Q000517:prevention & control*; D002478:Cells, Cultured; D004195:Disease Models, Animal; D016228:Endothelial Growth Factors / Q000494:pharmacology; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D006501:Hepatic Encephalopathy / Q000201:enzymology / Q000517:prevention & control; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D007371:Interferon-gamma / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D008099:Liver / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D017114:Liver Failure, Acute / Q000139:chemically induced / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D008264:Macrophages / Q000187:drug effects / Q000201:enzymology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009570:Nitriles / Q000494:pharmacology*; D010456:Peptides, Cyclic / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011804:Quinolines / Q000494:pharmacology*; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D013997:Time Factors; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors / Q000097:blood / Q000235:genetics / Q000378:metabolism*; D019061:src-Family Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D000814:Aniline Compounds; D016228:Endothelial Growth Factors; D008070:Lipopolysaccharides; D009570:Nitriles; D010456:Peptides, Cyclic; D047428:Protein Kinase Inhibitors; D011804:Quinolines; D011993:Recombinant Fusion Proteins; D042461:Vascular Endothelial Growth Factor A; C478485:cyclo-VEGI; C440499:lipopolysaccharide, Escherichia coli O111 B4; C467480:vascular endothelial growth factor A, mouse; D000643:Ammonium Chloride; D049452:Green Fluorescent Proteins; C471992:bosutinib; D007371:Interferon-gamma; D019061:src-Family Kinases; D001397:Azoxymethane