The Heat Shock Protein 70 Plays a Protective Role in Sepsis by Maintenance of the Endothelial Permeability

Abstract

Sepsis is a severe system inflammatory response syndrome in response to infection. The vascular endothelium cells play a key role in sepsis-induced organ dysfunction. The heat shock protein 70 (HSP70) has been reported to play an anti-inflammatory role and protect from sepsis. The present study is aimed at finding the function of HSP70 against sepsis in vascular endothelium cells. Lipopolysaccharide (LPS) and HSP70 agonist and inhibitor were used to treat HUVEC. Cell permeability was measured by transepithelial electrical resistance (TEER) assay and FITC-Dextrans. Cell junction protein levels were measured by western blot. Mice were subjected to cecal ligation and puncture (CLP) to establish a sepsis model and were observed for survival. After LPS incubation, HSP70 expression was decreased in HUVEC. LPS induced the inhibition of cell viability and the increases of IL-1β, IL-6, and TNF-α. Furthermore, cell permeability was increased and cell junction proteins (E-cadherin, occludin, and ZO-1) were downregulated after treatment with LPS. However, HSP70 could reverse these effects induced by LPS in HUVEC. In addition, LPS-induced elevated phosphorylation of p38 can be blocked by HSP70. On the other hand, we found that inhibition of HSP70 had similar effects as LPS and these effects could be alleviated by the inhibitor of p38. Subsequently, HSP70 was also found to increase survival of sepsis mice in vivo. In conclusion, HSP70 plays a protective role in sepsis by maintenance of the endothelial permeability via regulating p38 signaling.

Comparison of the Modulating Effect of Anthocyanin-Rich Sour Cherry Extract on Occludin and ZO-1 on Caco-2 and HUVEC Cultures

“…TNF-α, as an inflammatory inducer, decreases Occludin concentration, which was confirmed by lighter immunostaining. A similar trend was observed in the study in which HUVECs were induced by LPS and the presence of Occludin was examined by Western blot [ 39 ].…”

“…Thus, the analysis of these parameters, in addition to the study of TJ proteins, is unavoidable. Studies examining the barrier function of Caco-2 and HUVEC monolayers confirm the close relationship between these two parameters and Occludin expression [ 39 ]. In our previous study, we reported the protective effects of AC on membrane permeability, in an inflamed Caco-2 monolayer [ 21 ].…”

Regulation of Epithelial and Endothelial Barriers by Molecular Chaperones

“…This barrier-protective effect of HSPA12B overexpression was paralleled by the restoration of VE-cadherin expression and increased levels of myosin light chains [ 47 ]. Similar endothelial-protective activity was described in experiments with a chemical inducer of Hsp70 chaperones, TRC051384 [ 49 ]. This Hsp70 inducer reversed the increased permeability and restored the diminished expression of VE-cadherin, occludin, and ZO-1 in LPS-activated HUVEC monolayers.…”

Transient heat stress protects from severe endothelial damage and dysfunction during prolonged experimental ex-vivo lung perfusion

“…As we did not measure lung tissue ATP, we cannot determine whether possible changes in ATP content during EVLP might have influenced their activities. Previous investigations revealed that both HSP70 and HSP27 could reduce endothelial damage and permeability in non-pulmonary vessels by maintaining the integrity of cell junction proteins ( 27 ) and by preventing actin polymerization ( 28 ). Here, we found that heat-treated lungs displayed a marked reduction of lung edema after 6h reperfusion, an effect translating into preserved oxygenation capacity and static lung compliance ( Figure 3 ).…”