Experimental acute lung injury induces multi-organ epigenetic modifications in key angiogenic genes implicated in sepsis-associated endothelial dysfunction

Abstract

IntroductionThe 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.MethodsWestern 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).ResultsExperimental 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.ConclusionsOur 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.Electronic supplementary materialThe online version of this article (doi:10.1186/s13054-015-0943-4) contains supplementary material, which is available to authorized users.

Pulmonary vascular inflammation: effect of TLR signalling on angiopoietin/TIE regulation

“…Even when the lung is the organ of interest when regarding increased pulmonary vascular resistance, remote mechanisms may play a significant role. Recently, it has been demonstrated that epigenetic modifications (more precisely decreases in transcription‐permissive histone modifications) in various organs contribute to a downregulation of ANG1 and TIE2 in ALI and sepsis . Moreover, cell types other than EC and SMC such as specialized immune cells should be considered too .…”

“…Recently, it has been demonstrated that epigenetic modifications (more precisely decreases in transcription-permissive histone modifications) in various organs contribute to a downregulation of ANG1 and TIE2 in ALI and sepsis. 40 Moreover, cell types other than EC and SMC such as specialized immune cells should be considered too. 41,42 Future studies should focus on these alternative sources of highly altered angiopoietin balance.…”

Treating the host response to emerging virus diseases: lessons learned from sepsis, pneumonia, influenza and Ebola

“…The molecular biology of the Angpt/Tie2 signaling axis has been revealed in studies spanning more than a decade (25)(26)(27)(28). Angpt-1 is found in platelets, pericytes and especially in endothelial cells, where it acts constitutively to maintain endothelial barrier integrity.…”

“…All rights reserved. Ann Transl Med 2016;4(21):421 atm.amegroups.com involved in the loss of endothelial barrier integrity and the ensuing plasma leakage (26)(27)(28)(29)31).…”

“…In mice (27,28,32) and humans (27)(28)(29)(31)(32)(33)(34)(35)(36)(37), sepsis is associated with increased plasma levels of Angpt-2, increased plasma leakage into the lungs, and increased liver and renal dysfunction (27)(28)(29)(30)(31)(32)(33). Tie2 activation maintains or restores endothelial barrier integrity in experimental sepsis (34).…”