Journal
TOXICOLOGIC PATHOLOGY
Volume 33, Issue 4, Pages 465-476Publisher
SAGE PUBLICATIONS INC
DOI: 10.1080/01926230590959866
Keywords
cytokines; HIV/AIDS; inflammation; microbicide; porcine; spermicide; vagina
Categories
Funding
- EUNICE KENNEDY SHRIVER NATIONAL INSTITUTE OF CHILD HEALTH &HUMAN DEVELOPMENT [R43HD042889, R43HD043683, R44HD042889, R44HD042884, R43HD042884] Funding Source: NIH RePORTER
- NICHD NIH HHS [HD 042889, HD 043683, HD 042884] Funding Source: Medline
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A porcine model was established to test the mucosal toxicity potential of a thiophene thiourea (PHI-443)-based anti-HIV microbicide and a vanadocene-based spermicide, vanadocene dithiocarbamate ( VDDTC) in comparison to benzalkonium chloride (BZK). Nine domestic pigs (Duroc) in nonestrus stage received a single intravaginal application of 2% BZK, 2% PHI-443, or 0.1% VDDTC-containing gel. At various times after gel application, cell differentials and levels of inflammatory cytokines (IL-1 beta, IL-4, IL-6, IL-8, IL-10, IL-18, IFN-gamma, and TNF-alpha) in cervicovaginal lavage (CVL) fluid were monitored by flow cytometry and ELISA, respectively. Eight pigs were exposed intravaginally to a gel with and without BZK or VDDTC for 4 consecutive days and vaginal tissues were scored histologically for inflammation using a new scoring system. Only CVL fluid from pigs exposed to BZK showed a significant increase of IL-1 beta, IL-8, and also IL-18 production when compared to the controls, PHI-443 or VDDTC-treated groups. Maximum levels of BZK-induced IL-1 beta (100-fold), IL-8 (2,500-fold), IL-18 (80-fold), and IFN-gamma (10-fold) were found at 24 hours. In the in vivo porcine vaginal irritation model, increased levels of vaginal IL-1 beta, IL-8, and IL-18 were associated with histological changes consistent with vaginal inflammation. These results demonstrate that key cervicovaginal inflammatory cytokines are useful in vivo biomarkers for predicting the mucosal toxicity potential of vaginal products in the physiologically relevant and sensitive porcine model.
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