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- Title
Inhibition of Hsp90 attenuates inflammation in endotoxin-induced uveitis.
- Authors
Poulaki, Vassiliki; Iliaki, Eirini; Mitsiades, Nicholas; Mitsiades, Constantine S.; Paulus, Yiannis N.; Bula, Deisy V.; Gragoudas, Evangelos S.; Miller, Joan W.
- Abstract
Heat shock protein (Hsp) 90 inhibitors, such as 17-allylamino-17-demethoxy-geldanamycin (17-AAG), constitute promising novel therapeutic agents. We investigated the anti-inflammatory activity of 17-AAG in endotoxin-induced uveitis (EIU) in rats. After the induction of EIU with a footpad injection of lipopolysaccharide (LPS), female Lewis rats received a single intraperitoneal. (i.p.) injection of 17-AAG or vehicle. Twenty-four hours later, the retinas were extracted and assayed for leukocyte adhesion; blood-retinal barrier breakdown; VEGF, TNF-α, IL-1β, and CD14 protein levels; NF-κB and HIF-1α activity; hsp90 and 70 levels and expression and phosphorylation of the tight junction proteins ZO-1 and occludin. 17-AAG treatment significantly suppressed the LPS-induced increase in retinal leukocyte adhesion; vascular leakage; NF-κB, HIF-1α, p38, and PI-3K activity; and VEGF, TNF-α, and IL-1β levels. 17-AAG also suppressed phosphorylation of ZO-1 and occludin by inhibiting their association with p38 and PI-3K Although 17-AAG treatment did not reduce the LPS-induced increase in total CD14 levels in leukocytes, it significantly decreased membrane CD14 levels. These data suggest that Hsp90 inhibition suppresses several cardinal manifestations of endotoxin-induced uveitis in the rat. 17-AAG has demonstrated a favorable safety profile in clinical trials in cancer patients and represents a promising therapeutic agent for the treatment of inflammatory eye disease.
- Subjects
HEAT shock proteins; UVEITIS; ENDOTOXINS; EYE inflammation; LEUCOCYTES; PHOSPHORYLATION; LABORATORY rats
- Publication
FASEB Journal, 2007, Vol 21, Issue 9, p2113
- ISSN
0892-6638
- Publication type
Article
- DOI
10.1096/fj.06-7637com