title: The accumulation of circulating histones on heparan sulphate in the capillary glycocalyx of the lungs.
abstract: Recent findings on the role of circulating histone proteins in mediating acute lung injury prompted us to investigate whether there is a specific mechanism for accumulation of histones in the lungs. Binding sites for polycations are already known in the vasculature of the lungs, and we postulated that these could also be involved in histone accumulation, since histones have a high content of positively charged amino acids. Using a histone-coated colloid of a radiolabelled nanocomposite to track histone biodistribution with imaging techniques, it was found that histones bind avidly in the lungs of rabbits after intravenous injection. Blocking experiments with competing polycations in vivo characterised histone lung binding as dependent on a charge interaction with microvessel polyanions. Pretreatment of rabbits with a specific heparinase confirmed that the lung binding sites consist of heparan sulphate in the endothelial glycocalyx. A range of heparan sulphate analogues was accordingly shown to prevent histone accumulation in the lungs by neutralising histones in blood. These findings provide a rational basis for the design of polyanions that can prevent accumulation of cytotoxic histones in the lungs and thereby intervene at an early key step in the development of acute lung injury.
authors.affiliation: Vascular Biology Laboratory, Immunology and Genetics Division, John Curtin School of Medical Research, Australian National University, Canberra ACT, Australia.
authors.forename: Craig G
authors.initials: CG
authors.lastname: Freeman
authors.forename: Christopher R
authors.initials: CR
authors.lastname: Parish
authors.forename: Karen J
authors.initials: KJ
authors.lastname: Knox
authors.forename: Jessica L
authors.initials: JL
authors.lastname: Blackmore
authors.forename: Sergei A
authors.initials: SA
authors.lastname: Lobov
authors.forename: David W
authors.initials: DW
authors.lastname: King
authors.forename: Tim J
authors.initials: TJ
authors.lastname: Senden
authors.forename: Ross W
authors.initials: RW
authors.lastname: Stephens
mesh_terms: D000818:Animals; D057134:Antibodies, Neutralizing / Q000378:metabolism; D001665:Binding Sites; D002196:Capillaries / Q000378:metabolism*; D002417:Cattle; D004591:Electrophoresis, Polyacrylamide Gel; D019276:Glycocalyx / Q000378:metabolism*; D019763:Heparin Lyase / Q000378:metabolism; D006497:Heparan Sulfate / Q000378:metabolism*; D006657:Histones / Q000378:metabolism*; D008168:Lung / Q000098:blood supply* / Q000378:metabolism*; D053758:Nanoparticles; D011073:Polyamines / Q000378:metabolism; D000071228:Polyelectrolytes; D011134:Polysaccharides / Q000378:metabolism; D011485:Protein Binding; D011817:Rabbits; D014018:Tissue Distribution
chemical_list: D057134:Antibodies, Neutralizing; D019763:Heparin Lyase; D006497:Heparan Sulfate; D006657:Histones; D011073:Polyamines; D000071228:Polyelectrolytes; D011134:Polysaccharides