Effects of HSP70.1/3 gene knockout on acute respiratory distress syndrome and the inflammatory response following sepsis

Department of Anesthesiology, University of Colorado Health Sciences Center, Denver, Colorado Submitted 4 November 2005 ; accepted in final form 14 December 2005 Heat shock response has been implicated in attenuating NF- B activation and inflammation following sepsis. Studies utilizing sublethal heat stress or chemical enhancers to induce in vivo HSP70 expression have demonstrated survival benefit after experimental sepsis. However, it is likely these methods of manipulating HSP70 expression have effects on other stress proteins. The aim of this study was to evaluate the role of specific deletion of HSP70.1/3 gene expression on ARDS, NF- B activation, inflammatory cytokine expression, and survival following sepsis. To address this question, we induced sepsis in HSP70.1/3 KO and HSP70.1/3 WT mice via cecal ligation and puncture (CLP). We evaluated lung tissue NF- B activation and TNF- protein expression at 1 and 2 h, IL-6 protein expression at 1, 2, and 6, and lung histopathology 24 h after sepsis initiation. Survival was assessed for 5 days post-CLP. NF- B activation in lung tissue was increased in HSP70.1/3 (–/–) mice at all time points after sepsis initiation. Deletion of HSP70.1/3 prolonged NF- B binding/activation in lung tissue. Peak expression of lung TNF- at 1 and 2 h was also significantly increased in HSP70.1/3 (–/–) mice. Expression of IL-6 was significantly increased at 2 and 6 h, and histopathology revealed a significant increase in lung injury in HSP70.1/3 (–/–) mice. Last, deletion of the HSP70 gene led to increased mortality 5 days after sepsis initiation. These data reveal that absence of HSP70 alone can significantly increase ARDS, activation of NF- B, and inflammatory cytokine response. The specific absence of HSP70 gene expression also leads to increased mortality after septic insult. nuclear factor- B; heat shock protein 70.1/3; cecal ligation and puncture Address for reprint requests and other correspondence: K. D. Singleton, Univ. of Colorado Health Science Center, Dept. of Anesthesiology, Campus Box B113, 4200 E. 9th Ave., Denver, CO 80262 (e-mail: Kristen.Singleton{at}uchsc.edu )