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The Hsp90 Inhibitor, AUY-922 Reduces Pulmonary Fibrosis and Airway Dysfunction in Mice Exposed to HCl
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A7220 - The Hsp90 Inhibitor, AUY-922 Reduces Pulmonary Fibrosis and Airway Dysfunction in Mice Exposed to HCl
Author Block: J. D. Catravas, N. Barabutis, C. Dimitropoulou; Old Dominion University, Norfolk, VA, United States.
RATIONALE: The incidence of accidental exposure to HCl has been increasing. There is considerable data on the acute, usually reversible pulmonary effects of HCl, but much less is known about, and no antidotes exist to, the potentially lethal chronic effects, pulmonary fibrosis (PF). Inhibitors of heat shock protein 90 (HSP90) inhibit liver, kidney and skin fibrosis. Thus, we tested the hypothesis that the clinically used HSP90 inhibitor, AUY-922, would block HCl-induced PF. METHODS: Mice were exposed to either HCl (0.1M, pH1, 50μl) or saline, i.t. Starting 24 hours later, and subsequently 2x/week, they received AUY-922 (1mg/kg) or vehicle, i.p. We investigated indices of pro-fibrotic signaling in the lung (ERK1/2 phosphorylation), fibroblast activation (α-SMA), PF (collagen levels, histologically) and airway function (Flexi-Vent), at 10 and 30 days post HCl. RESULTS: Mice treated with saline or AUY-922 alone, exhibited normal values in all parameters. HCl caused significant ERK1/2 activation, significant increases in α-SMA and collagen levels and in the Ashcroft value for PF and higher baseline and methacholine-challenged respiratory system resistance and elastance, indicating stimulation of pro-fibrotic signaling and fibroblast activity, followed by development of PF and airway dysfunction. These effects were present at both time points, but were significantly more severe at 30 days post HCl. Post-treatment with AUY-922 significantly reduced- and in most cases returned to baseline values- all aforementioned parameters. CONCLUSOINS: We conclude that HSP90 inhibitors, by regulating the activity of client proteins, reduce pro-fibrotic signaling, PF and chronic lung dysfunction in HCl-exposed mice. Supported by the CounterACT Program, NIEHS Grant ES029309.
Author Block: J. D. Catravas, N. Barabutis, C. Dimitropoulou; Old Dominion University, Norfolk, VA, United States.
RATIONALE: The incidence of accidental exposure to HCl has been increasing. There is considerable data on the acute, usually reversible pulmonary effects of HCl, but much less is known about, and no antidotes exist to, the potentially lethal chronic effects, pulmonary fibrosis (PF). Inhibitors of heat shock protein 90 (HSP90) inhibit liver, kidney and skin fibrosis. Thus, we tested the hypothesis that the clinically used HSP90 inhibitor, AUY-922, would block HCl-induced PF. METHODS: Mice were exposed to either HCl (0.1M, pH1, 50μl) or saline, i.t. Starting 24 hours later, and subsequently 2x/week, they received AUY-922 (1mg/kg) or vehicle, i.p. We investigated indices of pro-fibrotic signaling in the lung (ERK1/2 phosphorylation), fibroblast activation (α-SMA), PF (collagen levels, histologically) and airway function (Flexi-Vent), at 10 and 30 days post HCl. RESULTS: Mice treated with saline or AUY-922 alone, exhibited normal values in all parameters. HCl caused significant ERK1/2 activation, significant increases in α-SMA and collagen levels and in the Ashcroft value for PF and higher baseline and methacholine-challenged respiratory system resistance and elastance, indicating stimulation of pro-fibrotic signaling and fibroblast activity, followed by development of PF and airway dysfunction. These effects were present at both time points, but were significantly more severe at 30 days post HCl. Post-treatment with AUY-922 significantly reduced- and in most cases returned to baseline values- all aforementioned parameters. CONCLUSOINS: We conclude that HSP90 inhibitors, by regulating the activity of client proteins, reduce pro-fibrotic signaling, PF and chronic lung dysfunction in HCl-exposed mice. Supported by the CounterACT Program, NIEHS Grant ES029309.
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