Journal article
Mouse Model of Cervicovaginal Toxicity and Inflammation for Preclinical Evaluation of Topical Vaginal Microbicides
Antimicrobial agents and chemotherapy, v 48(5), pp 1837-1847
May 2004
PMID: 15105142
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
Clinical trials evaluating the efficacy of nonoxynol-9 (N-9) as a topical microbicide concluded that N-9 offers no in vivo protection against human immunodeficiency virus type 1 (HIV-1) infection, despite demonstrated in vitro inactivation of HIV-1 by N-9. These trials emphasize the need for better model systems to determine candidate microbicide effectiveness and safety in a preclinical setting. To that end, time-dependent in vitro cytotoxicity, as well as in vivo toxicity and inflammation, associated with N-9 exposure were characterized with the goal of validating a mouse model of microbicide toxicity. In vitro studies using submerged cell cultures indicated that human cervical epithelial cells were inherently more sensitive to N-9-mediated damage than human vaginal epithelial cells. These results correlated with in vivo findings obtained by using Swiss Webster mice in which intravaginal inoculation of 1% N-9 or Conceptrol gel (containing 4% N-9) resulted in selective and acute disruption of the cervical columnar epithelial cells 2 h postapplication accompanied by intense inflammatory infiltrates within the lamina propria. Although damage to the cervical epithelium was apparent out to 8 h postapplication, these tissues resembled control tissue by 24 h postapplication. In contrast, minimal damage and infiltration were associated with both short- and long-term exposure of the vaginal mucosa to either N-9 or Conceptrol. These analyses were extended to examine the relative toxicity of polyethylene hexamethylene biguanide (PEHMB), a polybiguanide compound under evaluation as a candidate topical microbicide. In similar studies, in vivo exposure to 1% PEHMB caused minimal damage and inflammation of the genital mucosa, a finding consistent with the demonstration that PEHMB was >350-fold less cytotoxic than N-9 in vitro. Collectively, these studies highlight the murine model of toxicity as a valuable tool for the preclinical assessment of toxicity and inflammation associated with exposure to candidate topical microbicides.
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Details
- Title
- Mouse Model of Cervicovaginal Toxicity and Inflammation for Preclinical Evaluation of Topical Vaginal Microbicides
- Creators
- Bradley J Catalone - Department of Microbiology and ImmunologyTina M Kish-Catalone - Department of Microbiology and ImmunologyLynn R Budgeon - Department of Microbiology and ImmunologyElizabeth B Neely - Department of Microbiology and ImmunologyMaelee Ferguson - Department of Microbiology and ImmunologyFred C Krebs - Department of Microbiology and ImmunologyMary K Howett - Department of Microbiology and ImmunologyMohamed Labib - Department of Microbiology and ImmunologyRobert Rando - Department of Microbiology and ImmunologyBrian Wigdahl - Department of Microbiology and Immunology
- Publication Details
- Antimicrobial agents and chemotherapy, v 48(5), pp 1837-1847
- Publisher
- American Society for Microbiology
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Microbiology and Immunology
- Web of Science ID
- WOS:000221227900052
- Scopus ID
- 2-s2.0-11144357239
- Other Identifier
- 991014878237304721
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- Collaboration types
- Domestic collaboration
- Web of Science research areas
- Microbiology
- Pharmacology & Pharmacy