title: Prevention of anti-microbial peptide LL-37-induced apoptosis and ATP release in the urinary bladder by a modified glycosaminoglycan.
abstract: Interstitial cystitis (IC), often referred to in combination with painful bladder syndrome, is a chronic inflammatory disease of the bladder. Current therapies primarily focus on replenishing urothelial glycosaminoglycan (GAG) layer using GAG analogs and managing pain with supportive therapies. However, the elusive etiology of IC and the lack of animal models to study the disease have been major hurdles developing more effective therapeutics. Previously, we showed an increased urinary concentration of antimicrobial peptide LL-37 in spina bifida patients and used LL-37 to develop a mouse model of cystitis that mimics important clinical findings of IC. Here we investigate (1) the molecular mechanism of LL-37 induced cystitis in cultured human urothelial cells and in mice, (2) the protective effects of GM-0111, a modified GAG, within the context of this mechanism, (3) the physiological and molecular markers that correlate with the severity of the inflammation, and (4) the protective effects of several GAGs using these biomarkers in our LL-37 induced cystitis model. We find that LL-37 quickly induces release of ATP and apoptosis in the urothelium. These changes can be inhibited by a chemically-modified GAG, GM-0111. Furthermore, we also find that GAG analogs provide varying degrees of protection against LL-37 challenge in mice. These findings suggest that GM-0111 and possibly GAG molecules prevent the development of cystitis by blocking the apoptosis and the concurrent release of ATP from the urothelium.
authors.affiliation: GlycoMira Therapeutics, Inc. Salt Lake City, Utah, United States of America.
authors.forename: Won Yong
authors.initials: WY
authors.lastname: Lee
authors.forename: Justin R
authors.initials: JR
authors.lastname: Savage
authors.forename: Jianxing
authors.initials: J
authors.lastname: Zhang
authors.forename: Wanjian
authors.initials: W
authors.lastname: Jia
authors.forename: Siam
authors.initials: S
authors.lastname: Oottamasathien
authors.forename: Glenn D
authors.initials: GD
authors.lastname: Prestwich
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism*; D000276:Adjuvants, Immunologic / Q000633:toxicity; D000818:Animals; D023181:Antimicrobial Cationic Peptides; D017209:Apoptosis / Q000187:drug effects*; D054804:Cathelicidins / Q000633:toxicity*; D003556:Cystitis / Q000188:drug therapy* / Q000209:etiology / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D005260:Female; D006025:Glycosaminoglycans / Q000737:chemistry / Q000627:therapeutic use*; D006801:Humans; D007124:Immunoenzyme Techniques; D007249:Inflammation / Q000209:etiology / Q000378:metabolism / Q000517:prevention & control*; D051379:Mice; D008810:Mice, Inbred C57BL; D001743:Urinary Bladder / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology
chemical_list: D000276:Adjuvants, Immunologic; D023181:Antimicrobial Cationic Peptides; D054804:Cathelicidins; D006025:Glycosaminoglycans; D000255:Adenosine Triphosphate