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Am J Physiol Lung Cell Mol Physiol (December 16, 2005). doi:10.1152/ajplung.00466.2005
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Submitted on November 4, 2005
Accepted on December 14, 2005

Effects of HSP70.1/3 Gene Knockout on Acute Respiratory Distress Syndrome (ARDS) and the Inflammatory Response Following Sepsis

Kristen D Singleton1* and Paul E Wischmeyer1

1 Department of Anesthesiology, University of Colorado Health Sciences Center, Denver, Colorado, USA

* To whom correspondence should be addressed. E-mail: kristen.singleton{at}uchsc.edu.

The heat shock response has been implicated in attenuating NF-{kappa}B activation and inflammation following sepsis. Studies utilizing sublethal heat stress or chemical enhancers to induce in vivo HSP70 expression have demonstrated a survival benefit following experimental sepsis. However, it is likely that these methods of manipulating HSP70 expression have effects on other stress proteins. The aim of this study was to evaluate the role of a specific deletion of HSP70.1/3 gene expression on ARDS, NF-{kappa}B activation, inflammatory cytokine expression, and survival following sepsis. To address this question, we induced sepsis in HSP70.1/3 knock out (KO) and HSP70.1/3 wild type (WT) mice via cecal-ligation and puncture (CLP). We evaluated lung tissue NF-{kappa}B activation and TNF-{alpha} protein expression at 1h and 2h, IL-6 protein expression at 1h, 2h, and 6h, and lung histopathology 24h following initiation of sepsis. Survival was assessed for 5 days post-CLP. NF-{kappa}B activation in lung tissue was increased in HSP70.1/3 (-/-) mice at all time points following initiation of sepsis. Deletion of HSP70.1/3 prolonged NF-{kappa}B binding/activation in lung tissue (p < 0.01 versus WT). The peak expression of lung TNF-{alpha} at 1 and 2 h and was also significantly increased in HSP70.1/3 (-/-) mice. Expression of IL-6 was significantly increased at 2 and 6h (p < 0.01 versus WT), and histopathology revealed a significant increase in lung injury in HSP70.1/3 (-/-) mice (p < 0.05 versus WT. Lastly, deletion of the HSP70 gene led to increased mortality 5 days following initiation of sepsis. These data reveal that absence of HSP70 alone can significantly increase ARDS, activation of NF-{kappa}B, and the inflammatory cytokine response. The specific absence of HSP70 gene expression also leads to increased mortality following septic insult.




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