title: Inhibition of Cyclooxygenase-2 Prevents Chronic and Recurrent Cystitis.
abstract: The spread of multidrug-resistant microorganisms globally has created an urgent need for novel therapeutic strategies to combat urinary tract infections (UTIs). Immunomodulatory therapy may provide benefit, as treatment of mice with dexamethasone during acute UTI improved outcome by reducing the development of chronic cystitis, which predisposes to recurrent infection. Here we discovered soluble biomarkers engaged in myeloid cell development and chemotaxis that were predictive of future UTI recurrence when elevated in the sera of young women with UTI. Translation of these findings revealed that temperance of the neutrophil response early during UTI, and specifically disruption of bladder epithelial transmigration of neutrophils by inhibition of cyclooxygenase-2, protected mice against chronic and recurrent cystitis. Further, proteomics identified bladder epithelial remodeling consequent to chronic infection that enhances sensitivity to neutrophil damage. Thus, cyclooxygenase-2 expression during acute UTI is a critical molecular trigger determining disease outcome and drugs targeting cyclooxygenase-2 could prevent recurrent UTI.
authors.affiliation: Department of Pathology & Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA ; Department of Molecular Microbiology and Center for Women's Infectious Disease Research, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Hannan
authors.affiliation: Division of Allergy & Infectious Diseases, Department of Medicine, University of Washington, Seattle, WA 98195, USA.
authors.forename: Pacita L
authors.initials: PL
authors.lastname: Roberts
authors.affiliation: Division of Gastroenterology, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Terrence E
authors.initials: TE
authors.lastname: Riehl
authors.affiliation: Department of Medical Biochemistry, University of Gothenburg, 40530 Gothenburg, Sweden.
authors.forename: Sjoerd
authors.initials: S
authors.lastname: van der Post
authors.affiliation: Department of Molecular Microbiology and Center for Women's Infectious Disease Research, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Jana M
authors.initials: JM
authors.lastname: Binkley
authors.affiliation: Department of Molecular Microbiology and Center for Women's Infectious Disease Research, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Drew J
authors.initials: DJ
authors.lastname: Schwartz
authors.affiliation: Department of Pathology & Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Miyoshi
authors.affiliation: Department of Internal Medicine, University of Regensburg, 93053 Regensburg, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Mack
authors.affiliation: Institute of Molecular Cancer Research, University of Zurich, 8091 Zurich, Switzerland.
authors.forename: Reto A
authors.initials: RA
authors.lastname: Schwendener
authors.affiliation: Division of Infectious Diseases, Department of Medicine, University of Miami Miller School of Medicine, Miami, FL 33136, USA.
authors.forename: Thomas M
authors.initials: TM
authors.lastname: Hooton
authors.affiliation: Department of Pathology & Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Thaddeus S
authors.initials: TS
authors.lastname: Stappenbeck
authors.affiliation: Department of Medical Biochemistry, University of Gothenburg, 40530 Gothenburg, Sweden.
authors.forename: Gunnar C
authors.initials: GC
authors.lastname: Hansson
authors.affiliation: Division of Gastroenterology, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: William F
authors.initials: WF
authors.lastname: Stenson
authors.affiliation: Department of Pathology & Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Marco
authors.initials: M
authors.lastname: Colonna
authors.affiliation: Division of Allergy & Infectious Diseases, Department of Medicine, University of Washington, Seattle, WA 98195, USA.
authors.forename: Ann E
authors.initials: AE
authors.lastname: Stapleton
authors.affiliation: Department of Molecular Microbiology and Center for Women's Infectious Disease Research, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Scott J
authors.initials: SJ
authors.lastname: Hultgren
keywords: ASB, asymptomatic bacteriuria; CD, clusters of differentiation; COX, cyclooxygenase; COX-2; Chronic infection; G-CSF or CSF3, granulocyte colony-stimulating factor; GRO-α or CXCL1, growth-regulated alpha protein; IBC, intracellular bacterial community; IL-8 or CXCL8, interleukin-8; Immunomodulatory therapy; Immunopathology; M-CSF or CSF1, macrophage colony-stimulating factor; MAb, monoclonal antibody; MCP-1 or CCL2, monocyte chemotactic protein 1; Mucosal immunology; NSAID, non-steroidal anti-inflammatory drug; UPEC; UPEC, uropathogenic E. coli; UTI, recurrent infection; UTI, urinary tract infection; Urinary tract infection; Uropathogenic E. coli; rUTI, recurrent urinary tract infection