title: A novel post-exposure medical countermeasure L-97-1 improves survival and acute lung injury following intratracheal infection with Yersinia pestis.
abstract: Yersinia pestis, a Gram-negative bacillus causing plague and Centers for Disease Control and Prevention (CDC) classified Category A pathogen, has high potential as a bioweapon. Lipopolysaccharide, a virulence factor for Y. pestis, binds to and activates A(1) adenosine receptor (AR)s and, in animals, A(1)AR antagonists block induced acute lung injury (ALI) and increase survival following cecal ligation and perforation. In this study, rats were infected intratracheally with viable Y. pestis [CO99 (pCD1(                  +               )/Δpgm) 1 × 10(                  8               ) CFU/animal] and treated daily for 3 d with ciprofloxacin (cipro), the A(1)AR antagonist L-97-1, or cipro plus L-97-1 starting at 0, 6, 24, 48, or 72 h post-Y. pestis. At 72 h post-Y. pestis, cipro plus L-97-1 significantly improved 6-d survival to 60-70% vs 28% for cipro plus H(2)O and 33% for untreated Y. pestis controls (P = 0.02, logrank test). Lung edema, hemorrhage and leukocyte infiltration index (LII) were evaluated histologically to produce ALI scores. Cipro plus L-97-1 significantly reduced lung edema, as well as aggregate lung injury scores vs controls or cipro plus H(2)O, and LII vs controls (P < 0.05, Student's unpaired t test). These results support efficacy for L-97-1 as a post-exposure medical countermeasure, adjunctive therapy to antibiotics for Y. pestis.
authors.affiliation: Endacea Inc., Research Triangle Park, NC 27709-2076, USA. cwilson@endacea.com
authors.forename: Constance N
authors.initials: CN
authors.lastname: Wilson
authors.forename: Constance O
authors.initials: CO
authors.lastname: Vance
authors.forename: Timothy M
authors.initials: TM
authors.lastname: Doyle
authors.forename: David S
authors.initials: DS
authors.lastname: Brink
authors.forename: George M
authors.initials: GM
authors.lastname: Matuschak
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Lechner
mesh_terms: D055371:Acute Lung Injury / Q000209:etiology / Q000517:prevention & control*; D000818:Animals; D002939:Ciprofloxacin / Q000008:administration & dosage / Q000009:adverse effects; D004195:Disease Models, Animal; D004359:Drug Therapy, Combination; D006801:Humans; D008070:Lipopolysaccharides; D008168:Lung / Q000187:drug effects* / Q000276:immunology / Q000382:microbiology / Q000473:pathology; D010930:Plague / Q000150:complications / Q000188:drug therapy* / Q000276:immunology; D011485:Protein Binding / Q000187:drug effects; D011687:Purines / Q000008:administration & dosage* / Q000009:adverse effects; D051381:Rats; D043682:Receptor, Adenosine A1 / Q000378:metabolism; D037521:Virulence Factors; D015010:Yersinia pestis / Q000187:drug effects / Q000276:immunology* / Q000472:pathogenicity
chemical_list: C505457:3-(2-(4-aminophenyl)ethyl)-8-benzyl-7-(2-ethyl(2-hydroxyethyl)aminoethyl)-1-propyl-3,7-dihydropurine-2,6-dione; D008070:Lipopolysaccharides; D011687:Purines; D043682:Receptor, Adenosine A1; D037521:Virulence Factors; D002939:Ciprofloxacin