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-alpha, IL-1beta, and CD14 protein levels; NF-kappaB and HIF-1alpha 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-kappaB, HIF-1alpha, p38, and PI-3K activity; and VEGF, TNF-alpha, and IL-1beta 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 diseases.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Anti-Inflammatory Agents, Non-Steroidal / pharmacology
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Anti-Inflammatory Agents, Non-Steroidal / therapeutic use*
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Bacterial Toxins / toxicity
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Benzoquinones / therapeutic use*
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Blood-Retinal Barrier / drug effects
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Cell Adhesion / drug effects
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Cell Membrane / chemistry
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Drug Evaluation, Preclinical
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Endotoxins / toxicity
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HSP90 Heat-Shock Proteins / antagonists & inhibitors*
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Hypoxia-Inducible Factor 1, alpha Subunit / metabolism
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Interleukin-1beta / biosynthesis
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Interleukin-1beta / blood
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Lactams, Macrocyclic / therapeutic use*
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Leukocytes / chemistry
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Leukostasis / etiology
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Leukostasis / prevention & control
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Lipopolysaccharide Receptors / blood
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Male
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Membrane Proteins / metabolism
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NF-kappa B / metabolism
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Occludin
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Phosphatidylinositol 3-Kinases / metabolism
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Phosphoproteins / metabolism
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Phosphorylation / drug effects
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Protein Processing, Post-Translational / drug effects
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Rats
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Rats, Long-Evans
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Retinal Vasculitis / chemically induced
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Retinal Vasculitis / prevention & control
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Signal Transduction / drug effects
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Tumor Necrosis Factor-alpha / analysis
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Tumor Necrosis Factor-alpha / biosynthesis
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Up-Regulation / drug effects
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Uveitis, Anterior / chemically induced
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Uveitis, Anterior / drug therapy*
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Vascular Endothelial Growth Factor A / biosynthesis
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Vascular Endothelial Growth Factor A / blood
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Zonula Occludens-1 Protein
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p38 Mitogen-Activated Protein Kinases / metabolism
Substances
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Anti-Inflammatory Agents, Non-Steroidal
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Bacterial Toxins
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Benzoquinones
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Endotoxins
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HSP90 Heat-Shock Proteins
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Hif1a protein, rat
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Hypoxia-Inducible Factor 1, alpha Subunit
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Interleukin-1beta
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Lactams, Macrocyclic
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Lipopolysaccharide Receptors
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Membrane Proteins
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NF-kappa B
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Occludin
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Ocln protein, rat
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Phosphoproteins
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Tjp1 protein, rat
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Tumor Necrosis Factor-alpha
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Vascular Endothelial Growth Factor A
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Zonula Occludens-1 Protein
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salmonella toxin
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vascular endothelial growth factor A, rat
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tanespimycin
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Phosphatidylinositol 3-Kinases
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p38 Mitogen-Activated Protein Kinases