title: Experimental acute lung injury induces multi-organ epigenetic modifications in key angiogenic genes implicated in sepsis-associated endothelial dysfunction.
abstract: BACKGROUND
  The Tie2/angiopoietin (Tie2/Ang) and vascular endothelial growth factor receptor-ligand systems (VEGFR/VEGF) are recognized to play important roles in the regulation of microvascular endothelial function. Downregulation of these genes during sepsis has been implicated in the pathogenesis of sepsis-related microvascular leak and multiple organ dysfunction syndrome. Mechanisms responsible for dysregulation of angiogenic genes in sepsis are poorly defined.
  
  
  METHODS
  Western blot, reverse transcription-polymerase chain reaction, and multiplex chromatin immunoprecipitation platform (Matrix ChIP) were used to investigate serum albumin leak, changes in gene expression, and associated epigenetic alterations in a murine model of acute lung injury-induced sepsis (ALI-sepsis).
  
  
  RESULTS
  Experimental ALI-sepsis induced microvascular leak and downregulation of expression of Angpt1 (Ang1), Tek (Tie2), and Kdr (Vegfr2 or Flk-1) genes in the lung, kidney, and liver. These changes correlate with a decrease in RNA polymerase II density at these genes, and the greatest response was observed in the lung. ALI-sepsis reduced levels of transcription-permissive histone H3 lysine acetylation (H3KAc) at these loci in all examined tissues. Decreases in permissive H3K4m3 and H3Km2 marks were detected only in the lung. In contrast, only minimal alterations in transcription-repressive histone modifications (H3K27m3, H3K9m2, H3K9m3, and H4K20m3) were observed in all tissues.
  
  
  CONCLUSIONS
  Our results demonstrate that decreases in transcription-permissive, but not increases in transcription-repressive, histone modifications at Angpt1, Tek, and Kdr are a systemic, rather than a lung-restricted, response, involving key end-organs in experimental ALI-sepsis. Given that ventilator-associated pneumonia is a major cause of sepsis in critically ill patients, elucidation of mechanisms mediating epigenetic alterations during sepsis provides fundamental new insights into the pathogenesis of sepsis-induced microvascular leak and subsequent end-organ injury/dysfunction.
authors.affiliation: UW Medicine South Lake Union, University of Washington, 850 Republican Street, 98109, Seattle, WA, USA. karolb@u.washington.edu.|Department of Medicine, University of Washington, 850 Republican Street, 98195, Seattle, WA, USA. karolb@u.washington.edu.
authors.forename: Karol
authors.initials: K
authors.lastname: Bomsztyk
authors.affiliation: UW Medicine South Lake Union, University of Washington, 850 Republican Street, 98109, Seattle, WA, USA. danmar@uw.edu.
authors.forename: Daniel
authors.initials: D
authors.lastname: Mar
authors.affiliation: UW Medicine South Lake Union, University of Washington, 850 Republican Street, 98109, Seattle, WA, USA. dowon@u.washington.edu.
authors.forename: Dowon
authors.initials: D
authors.lastname: An
authors.affiliation: UW Medicine South Lake Union, University of Washington, 850 Republican Street, 98109, Seattle, WA, USA. roya_sharifian@yahoo.com.
authors.forename: Roya
authors.initials: R
authors.lastname: Sharifian
authors.affiliation: UW Medicine South Lake Union, University of Washington, 850 Republican Street, 98109, Seattle, WA, USA. mikula.michal@gmail.com.
authors.forename: Michal
authors.initials: M
authors.lastname: Mikula
authors.affiliation: UW Medicine South Lake Union, University of Washington, 850 Republican Street, 98109, Seattle, WA, USA. sagharib@u.washington.edu.|Department of Medicine, University of Washington, 850 Republican Street, 98195, Seattle, WA, USA. sagharib@u.washington.edu.|Center for Lung Biology, University of Washington, 850 Republican Street, 98109, Seattle, WA, USA. sagharib@u.washington.edu.
authors.forename: Sina A
authors.initials: SA
authors.lastname: Gharib
authors.affiliation: UW Medicine South Lake Union, University of Washington, 850 Republican Street, 98109, Seattle, WA, USA. billa@u.washington.edu.|Department of Medicine, University of Washington, 850 Republican Street, 98195, Seattle, WA, USA. billa@u.washington.edu.|Center for Lung Biology, University of Washington, 850 Republican Street, 98109, Seattle, WA, USA. billa@u.washington.edu.
authors.forename: William A
authors.initials: WA
authors.lastname: Altemeier
authors.affiliation: UW Medicine South Lake Union, University of Washington, 850 Republican Street, 98109, Seattle, WA, USA. wcliles@uw.edu.|Department of Medicine, University of Washington, 850 Republican Street, 98195, Seattle, WA, USA. wcliles@uw.edu.|Center for Lung Biology, University of Washington, 850 Republican Street, 98109, Seattle, WA, USA. wcliles@uw.edu.
authors.forename: W Conrad
authors.initials: WC
authors.lastname: Liles
authors.affiliation: UW Medicine South Lake Union, University of Washington, 850 Republican Street, 98109, Seattle, WA, USA. odenis@u.washington.edu.|Department of Medicine, University of Washington, 850 Republican Street, 98195, Seattle, WA, USA. odenis@u.washington.edu.
authors.forename: Oleg
authors.initials: O
authors.lastname: Denisenko
mesh_terms: D055371:Acute Lung Injury / Q000235:genetics* / Q000473:pathology; D042501:Angiogenic Proteins / Q000235:genetics*; D000818:Animals; D004730:Endothelium, Vascular / Q000473:pathology; D044127:Epigenesis, Genetic / Q000235:genetics*; D007668:Kidney / Q000473:pathology; D008099:Liver / Q000473:pathology; D008168:Lung / Q000473:pathology; D051379:Mice; D055806:Microvessels / Q000473:pathology; D018805:Sepsis / Q000235:genetics* / Q000473:pathology
chemical_list: D042501:Angiogenic Proteins