title: Effects of HSP70.1/3 gene knockout on acute respiratory distress syndrome and the inflammatory response following sepsis.
abstract: Heat shock response has been implicated in attenuating NF-kappaB 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-kappaB 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-kappaB activation and TNF-alpha 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-kappaB 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-kappaB binding/activation in lung tissue. Peak expression of lung TNF-alpha 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-kappaB, and inflammatory cytokine response. The specific absence of HSP70 gene expression also leads to increased mortality after septic insult.
authors.affiliation: Department of Anesthesiology, University of Colorado Health Sciences Center, Campus Box B113, 4200 E. 9th Avenue, Denver, CO 80262, USA. Kristen.Singleton@uchsc.edu
authors.forename: Kristen D
authors.initials: KD
authors.lastname: Singleton
authors.forename: Paul E
authors.initials: PE
authors.lastname: Wischmeyer
mesh_terms: D000818:Animals; D018840:HSP70 Heat-Shock Proteins / Q000172:deficiency* / Q000235:genetics; D007249:Inflammation / Q000209:etiology / Q000503:physiopathology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D012128:Respiratory Distress Syndrome / Q000150:complications*; D018805:Sepsis / Q000209:etiology
chemical_list: D018840:HSP70 Heat-Shock Proteins