A Comprehensive Murine Model to Evaluate Topical Vaginal Microbicides: Mucosal Inflammation and Susceptibility to Genital Herpes as Surrogate Markers of Safety
A critical gap in microbicide development is the absence of surrogate safety markers. The objective of the present study was to develop a murine model to examine the mucosal response to microbicides and to assess the functional implication of observed changes. Mice received 14 daily intravaginal dos...
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| Veröffentlicht in: | The Journal of infectious diseases 2007-05, Vol.195 (9), p.1332-1339 |
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| container_title | The Journal of infectious diseases |
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| creator | Galen, Benjamin T Martin, Andrea P Hazrati, Ehsan Garin, Alexandre Guzman, Esmeralda Wilson, Sarah S Porter, David D Lira, Sergio A Keller, Marla J Herold, Betsy C |
| description | A critical gap in microbicide development is the absence of surrogate safety markers. The objective of the present study was to develop a murine model to examine the mucosal response to microbicides and to assess the functional implication of observed changes. Mice received 14 daily intravaginal doses of nonoxynol-9, PRO 2000, or placebo gel. Nonoxynol-9 induced an inflammatory response characterized by increases in levels of cytokines and chemokines, recruitment of neutrophils and monocytes into the genital tract, and activation of the transcription factors NF-κB and activator protein-1. Minimal inflammation was observed in response to 2% PRO 2000. Nonoxynol-9-treated mice were significantly more susceptible to challenge with a low dose of herpes simplex virus type 2; the response of PRO 2000-treated mice was similar to the response to placebo. These findings suggest that PRO 2000 has little deleterious effect on mucosal immunity and, if validated by clinical experiences, support the inclusion of this model in the preclinical evaluation of future candidate microbicides. |
| doi_str_mv | 10.1086/513279 |
| format | Article |
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The objective of the present study was to develop a murine model to examine the mucosal response to microbicides and to assess the functional implication of observed changes. Mice received 14 daily intravaginal doses of nonoxynol-9, PRO 2000, or placebo gel. Nonoxynol-9 induced an inflammatory response characterized by increases in levels of cytokines and chemokines, recruitment of neutrophils and monocytes into the genital tract, and activation of the transcription factors NF-κB and activator protein-1. Minimal inflammation was observed in response to 2% PRO 2000. Nonoxynol-9-treated mice were significantly more susceptible to challenge with a low dose of herpes simplex virus type 2; the response of PRO 2000-treated mice was similar to the response to placebo. These findings suggest that PRO 2000 has little deleterious effect on mucosal immunity and, if validated by clinical experiences, support the inclusion of this model in the preclinical evaluation of future candidate microbicides.</description><identifier>ISSN: 0022-1899</identifier><identifier>EISSN: 1537-6613</identifier><identifier>DOI: 10.1086/513279</identifier><identifier>PMID: 17397004</identifier><language>eng</language><publisher>United States: The University of Chicago Press</publisher><subject>Administration, Intravaginal ; Animals ; Anti-Infective Agents - administration & dosage ; Anti-Infective Agents - adverse effects ; Antiinfectives ; Chemokines ; Cytokines ; Disease Susceptibility ; Female ; Gels ; Genitalia ; Herpes Genitalis - prevention & control ; Herpes Genitalis - transmission ; Herpes Genitalis - virology ; HIV ; Human herpesvirus 2 ; Infections ; Mice ; Models, Animal ; NF-kappa B - biosynthesis ; NF-kappa B - genetics ; Nonoxynol - administration & dosage ; Nonoxynol - adverse effects ; Reverse Transcriptase Polymerase Chain Reaction ; RNA, Messenger - analysis ; Sexually Transmitted Diseases, Viral - prevention & control ; Sexually Transmitted Diseases, Viral - transmission ; Sexually Transmitted Diseases, Viral - virology ; Simplexvirus ; Transcription Factor AP-1 - biosynthesis ; Transcription Factor AP-1 - genetics ; Vagina - drug effects ; Vagina - immunology ; Vagina - pathology ; Vaginal Creams, Foams, and Jellies - administration & dosage ; Vaginal Creams, Foams, and Jellies - adverse effects ; Vaginitis - chemically induced ; Vaginitis - pathology ; Viruses</subject><ispartof>The Journal of infectious diseases, 2007-05, Vol.195 (9), p.1332-1339</ispartof><rights>Copyright 2007 Infectious Diseases Society of America</rights><rights>2007 by the Infectious Diseases Society of America 2007</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c426t-971c9054ce07ef9f151ad45405cbef5d284967c27101920f6c969f0282362e683</citedby></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.jstor.org/stable/pdf/30087041$$EPDF$$P50$$Gjstor$$H</linktopdf><linktohtml>$$Uhttps://www.jstor.org/stable/30087041$$EHTML$$P50$$Gjstor$$H</linktohtml><link.rule.ids>314,776,780,799,27903,27904,57995,58228</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/17397004$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Galen, Benjamin T</creatorcontrib><creatorcontrib>Martin, Andrea P</creatorcontrib><creatorcontrib>Hazrati, Ehsan</creatorcontrib><creatorcontrib>Garin, Alexandre</creatorcontrib><creatorcontrib>Guzman, Esmeralda</creatorcontrib><creatorcontrib>Wilson, Sarah S</creatorcontrib><creatorcontrib>Porter, David D</creatorcontrib><creatorcontrib>Lira, Sergio A</creatorcontrib><creatorcontrib>Keller, Marla J</creatorcontrib><creatorcontrib>Herold, Betsy C</creatorcontrib><title>A Comprehensive Murine Model to Evaluate Topical Vaginal Microbicides: Mucosal Inflammation and Susceptibility to Genital Herpes as Surrogate Markers of Safety</title><title>The Journal of infectious diseases</title><addtitle>The Journal of Infectious Diseases</addtitle><addtitle>The Journal of Infectious Diseases</addtitle><description>A critical gap in microbicide development is the absence of surrogate safety markers. The objective of the present study was to develop a murine model to examine the mucosal response to microbicides and to assess the functional implication of observed changes. Mice received 14 daily intravaginal doses of nonoxynol-9, PRO 2000, or placebo gel. Nonoxynol-9 induced an inflammatory response characterized by increases in levels of cytokines and chemokines, recruitment of neutrophils and monocytes into the genital tract, and activation of the transcription factors NF-κB and activator protein-1. Minimal inflammation was observed in response to 2% PRO 2000. Nonoxynol-9-treated mice were significantly more susceptible to challenge with a low dose of herpes simplex virus type 2; the response of PRO 2000-treated mice was similar to the response to placebo. 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Martin, Andrea P ; Hazrati, Ehsan ; Garin, Alexandre ; Guzman, Esmeralda ; Wilson, Sarah S ; Porter, David D ; Lira, Sergio A ; Keller, Marla J ; Herold, Betsy C</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c426t-971c9054ce07ef9f151ad45405cbef5d284967c27101920f6c969f0282362e683</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2007</creationdate><topic>Administration, Intravaginal</topic><topic>Animals</topic><topic>Anti-Infective Agents - administration & dosage</topic><topic>Anti-Infective Agents - adverse effects</topic><topic>Antiinfectives</topic><topic>Chemokines</topic><topic>Cytokines</topic><topic>Disease Susceptibility</topic><topic>Female</topic><topic>Gels</topic><topic>Genitalia</topic><topic>Herpes Genitalis - prevention & control</topic><topic>Herpes Genitalis - transmission</topic><topic>Herpes Genitalis - virology</topic><topic>HIV</topic><topic>Human herpesvirus 2</topic><topic>Infections</topic><topic>Mice</topic><topic>Models, Animal</topic><topic>NF-kappa B - biosynthesis</topic><topic>NF-kappa B - genetics</topic><topic>Nonoxynol - administration & dosage</topic><topic>Nonoxynol - adverse effects</topic><topic>Reverse Transcriptase Polymerase Chain Reaction</topic><topic>RNA, Messenger - analysis</topic><topic>Sexually Transmitted Diseases, Viral - prevention & control</topic><topic>Sexually Transmitted Diseases, Viral - transmission</topic><topic>Sexually Transmitted Diseases, Viral - virology</topic><topic>Simplexvirus</topic><topic>Transcription Factor AP-1 - biosynthesis</topic><topic>Transcription Factor AP-1 - genetics</topic><topic>Vagina - drug effects</topic><topic>Vagina - immunology</topic><topic>Vagina - pathology</topic><topic>Vaginal Creams, Foams, and Jellies - administration & dosage</topic><topic>Vaginal Creams, Foams, and Jellies - adverse effects</topic><topic>Vaginitis - chemically induced</topic><topic>Vaginitis - pathology</topic><topic>Viruses</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Galen, Benjamin T</creatorcontrib><creatorcontrib>Martin, Andrea P</creatorcontrib><creatorcontrib>Hazrati, Ehsan</creatorcontrib><creatorcontrib>Garin, Alexandre</creatorcontrib><creatorcontrib>Guzman, Esmeralda</creatorcontrib><creatorcontrib>Wilson, Sarah S</creatorcontrib><creatorcontrib>Porter, David D</creatorcontrib><creatorcontrib>Lira, Sergio A</creatorcontrib><creatorcontrib>Keller, Marla J</creatorcontrib><creatorcontrib>Herold, Betsy C</creatorcontrib><collection>Istex</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Immunology Abstracts</collection><collection>Industrial and Applied Microbiology Abstracts (Microbiology A)</collection><collection>Virology and AIDS Abstracts</collection><collection>Technology Research Database</collection><collection>Environmental Sciences and Pollution Management</collection><collection>Engineering Research Database</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>Biotechnology and BioEngineering Abstracts</collection><jtitle>The Journal of infectious diseases</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Galen, Benjamin T</au><au>Martin, Andrea P</au><au>Hazrati, Ehsan</au><au>Garin, Alexandre</au><au>Guzman, Esmeralda</au><au>Wilson, Sarah S</au><au>Porter, David D</au><au>Lira, Sergio A</au><au>Keller, Marla J</au><au>Herold, Betsy C</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>A Comprehensive Murine Model to Evaluate Topical Vaginal Microbicides: Mucosal Inflammation and Susceptibility to Genital Herpes as Surrogate Markers of Safety</atitle><jtitle>The Journal of infectious diseases</jtitle><stitle>The Journal of Infectious Diseases</stitle><addtitle>The Journal of Infectious Diseases</addtitle><date>2007-05-01</date><risdate>2007</risdate><volume>195</volume><issue>9</issue><spage>1332</spage><epage>1339</epage><pages>1332-1339</pages><issn>0022-1899</issn><eissn>1537-6613</eissn><abstract>A critical gap in microbicide development is the absence of surrogate safety markers. The objective of the present study was to develop a murine model to examine the mucosal response to microbicides and to assess the functional implication of observed changes. Mice received 14 daily intravaginal doses of nonoxynol-9, PRO 2000, or placebo gel. Nonoxynol-9 induced an inflammatory response characterized by increases in levels of cytokines and chemokines, recruitment of neutrophils and monocytes into the genital tract, and activation of the transcription factors NF-κB and activator protein-1. Minimal inflammation was observed in response to 2% PRO 2000. Nonoxynol-9-treated mice were significantly more susceptible to challenge with a low dose of herpes simplex virus type 2; the response of PRO 2000-treated mice was similar to the response to placebo. These findings suggest that PRO 2000 has little deleterious effect on mucosal immunity and, if validated by clinical experiences, support the inclusion of this model in the preclinical evaluation of future candidate microbicides.</abstract><cop>United States</cop><pub>The University of Chicago Press</pub><pmid>17397004</pmid><doi>10.1086/513279</doi><tpages>8</tpages><oa>free_for_read</oa></addata></record> |
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| issn | 0022-1899 1537-6613 |
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| source | MEDLINE; Jstor Complete Legacy; Oxford University Press Journals All Titles (1996-Current); Alma/SFX Local Collection |
| subjects | Administration, Intravaginal Animals Anti-Infective Agents - administration & dosage Anti-Infective Agents - adverse effects Antiinfectives Chemokines Cytokines Disease Susceptibility Female Gels Genitalia Herpes Genitalis - prevention & control Herpes Genitalis - transmission Herpes Genitalis - virology HIV Human herpesvirus 2 Infections Mice Models, Animal NF-kappa B - biosynthesis NF-kappa B - genetics Nonoxynol - administration & dosage Nonoxynol - adverse effects Reverse Transcriptase Polymerase Chain Reaction RNA, Messenger - analysis Sexually Transmitted Diseases, Viral - prevention & control Sexually Transmitted Diseases, Viral - transmission Sexually Transmitted Diseases, Viral - virology Simplexvirus Transcription Factor AP-1 - biosynthesis Transcription Factor AP-1 - genetics Vagina - drug effects Vagina - immunology Vagina - pathology Vaginal Creams, Foams, and Jellies - administration & dosage Vaginal Creams, Foams, and Jellies - adverse effects Vaginitis - chemically induced Vaginitis - pathology Viruses |
| title | A Comprehensive Murine Model to Evaluate Topical Vaginal Microbicides: Mucosal Inflammation and Susceptibility to Genital Herpes as Surrogate Markers of Safety |
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