title: Novel sulfated polysaccharides disrupt cathelicidins, inhibit RAGE and reduce cutaneous inflammation in a mouse model of rosacea.
abstract: BACKGROUND
  Rosacea is a common disfiguring skin disease of primarily Caucasians characterized by central erythema of the face, with telangiectatic blood vessels, papules and pustules, and can produce skin thickening, especially on the nose of men, creating rhinophyma. Rosacea can also produce dry, itchy eyes with irritation of the lids, keratitis and corneal scarring. The cause of rosacea has been proposed as over-production of the cationic cathelicidin peptide LL-37.
  
  
  RESULTS
  We tested a new class of non-anticoagulant sulfated anionic polysaccharides, semi-synthetic glycosaminoglycan ethers (SAGEs) on key elements of the pathogenic pathway leading to rosacea. SAGEs were anti-inflammatory at ng/ml, including inhibition of polymorphonuclear leukocyte (PMN) proteases, P-selectin, and interaction of the receptor for advanced glycation end-products (RAGE) with four representative ligands. SAGEs bound LL-37 and inhibited interleukin-8 production induced by LL-37 in cultured human keratinocytes. When mixed with LL-37 before injection, SAGEs prevented the erythema and PMN infiltration produced by direct intradermal injection of LL-37 into mouse skin. Topical application of a 1% (w/w) SAGE emollient to overlying injected skin also reduced erythema and PMN infiltration from intradermal LL-37.
  
  
  CONCLUSIONS
  Anionic polysaccharides, exemplified by SAGEs, offer potential as novel mechanism-based therapies for rosacea and by extension other LL-37-mediated and RAGE-ligand driven skin diseases.
authors.affiliation: Center for Therapeutic Biomaterials, University of Utah, Salt Lake City, Utah, United States of America.
authors.forename: Jianxing
authors.initials: J
authors.lastname: Zhang
authors.forename: Xiaoyu
authors.initials: X
authors.lastname: Xu
authors.forename: Narayanam V
authors.initials: NV
authors.lastname: Rao
authors.forename: Brian
authors.initials: B
authors.lastname: Argyle
authors.forename: Lindsi
authors.initials: L
authors.lastname: McCoard
authors.forename: William J
authors.initials: WJ
authors.lastname: Rusho
authors.forename: Thomas P
authors.initials: TP
authors.lastname: Kennedy
authors.forename: Glenn D
authors.initials: GD
authors.lastname: Prestwich
authors.forename: Gerald
authors.initials: G
authors.lastname: Krueger
mesh_terms: D000287:Administration, Topical; D000818:Animals; D023181:Antimicrobial Cationic Peptides / Q000378:metabolism; D054804:Cathelicidins / Q000378:metabolism*; D003436:Croton Oil / Q000009:adverse effects; D004195:Disease Models, Animal; D006025:Glycosaminoglycans / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D006801:Humans; D007249:Inflammation / Q000139:chemically induced / Q000188:drug therapy / Q000378:metabolism; D008024:Ligands; D016177:Macrophage-1 Antigen / Q000378:metabolism; D051379:Mice; D009504:Neutrophils / Q000187:drug effects / Q000201:enzymology; D019007:P-Selectin / Q000378:metabolism; D010447:Peptide Hydrolases / Q000378:metabolism; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic / Q000037:antagonists & inhibitors*; D012393:Rosacea / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism*; D013431:Sulfates / Q000737:chemistry*
chemical_list: D023181:Antimicrobial Cationic Peptides; D054804:Cathelicidins; D006025:Glycosaminoglycans; D008024:Ligands; D016177:Macrophage-1 Antigen; D019007:P-Selectin; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic; D013431:Sulfates; D003436:Croton Oil; D010447:Peptide Hydrolases