HSP70 Ameliorates Septic Lung Injury via Inhibition of Apoptosis by Interacting with KANK2.

Qing Pei,Jing Yuan,Yihang Yuan,Min Yao,Xiong Zhang,Wei Ni

doi:10.3390/biom12030410

Abstract

Acute lung injury is the most common type of organ damage with high incidence and mortality in sepsis, which is a poorly understood syndrome of disordered inflammation. The aims of this study are to explore whether heat shock protein 70 (HSP70), as a molecular chaperone, attenuates the septic lung injury, and to understand the underlying mechanisms. In our study, treatment with HSP70 ameliorated the survival rate, dysfunction of lung, inflammation, and apoptosis in cecal ligation and puncture (CLP)-treated mice as well as in LPS-treated human alveolar epithelial cells. Furthermore, HSP70 interacted with KANK2, leading to reversed cell viability and reduced apoptosis-inducing factor (AIF) and apoptosis. Additionally, knockdown of KANK2 in epithelial cells and deletion of hsp70.1 gene in CLP mice aggravated apoptosis and tissue damage, suggesting that interaction of KANK2 and HSP70 is critical for protecting lung injury induced by sepsis. HSP70 plays an important role in protection of acute lung injury caused by sepsis through interaction with KANK2 to reduce AIF release and apoptotic cell. HSP70 is a novel potential therapeutic approach for attenuation of septic lung injury.

Highlights

The mice in cecal ligation and puncture (CLP) group were in poor condition, with ruffled fur, lower level of consciousness, reduced activity, weak response to stimulus, and mostly closed eyes with secretions at the corners of their eyes while the sham mice were totally recovered from surgery at 24 h
The mice in the CLP plus heat shock protein 70 (HSP70) group began to die by 32 h, and the survival rate was near 40% at 72 h
We showed that the survival rate, histologic pulmonary damage, cell viability, and apoptosis caused by sepsis or LPS stimulation were attenuated by treatment of recombinant HSP70 and in HSP70-overexpressing cells

Summary

Introduction

Sepsis refers to life-threatening organ dysfunction caused by a dysregulated host response to infection. It is prone to occur after severe burns, surgery, and infection [1,2]. It has been reported that there are more than 19 million sepsis patients worldwide each year, of which 6 million patients die, and the case fatality rate exceeds 1/4 [3,4]. The primary causes of death in septic multiple organ failure are diffuse inflammation of the lung parenchyma and severe pulmonary dysfunction. 50% of patients with severe sepsis can develop acute lung injury (ALI) or even acute respiratory distress syndrome (ARDS). The current treatment for sepsis mainly includes timely elimination of local infection foci, strengthening of circulation and respiratory support, early application of antibiotics, etc.; there is a lack of specific and effective therapies [5–7]

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