Transduced PEP-1-Heme Oxygenase-1 Fusion Protein Attenuates Lung Injury in Septic Shock Rats.

Yan-Lin Wang,Zong-Ze Zhang,Jun-Jiao Tang,Xue-Tao Yan,Xiang-Hu He

doi:10.1155/2018/6403861

Abstract

Oxidative stress and inflammation have been identified to play a vital role in the pathogenesis of lung injury induced by septic shock. Heme oxygenase-1 (HO-1), an effective antioxidant and anti-inflammatory and antiapoptotic substance, has been used for the treatment of heart, lung, and liver diseases. Thus, we postulated that administration of exogenous HO-1 protein transduced by cell-penetrating peptide PEP-1 has a protective role against septic shock-induced lung injury. Septic shock produced by cecal ligation and puncture caused severe lung damage, manifested in the increase in the lung wet/dry ratio, oxidative stress, inflammation, and apoptosis. However, these changes were reversed by treatment with the PEP-1-HO-1 fusion protein, whereas lung injury in septic shock rats was alleviated. Furthermore, the septic shock upregulated the expression of Toll-like receptor 4 (TLR4) and transcription factor NF-κB, accompanied by the increase of lung injury. Administration of PEP-1-HO-1 fusion protein reversed septic shock-induced lung injury by downregulating the expression of TLR4 and NF-κB. Our study indicates that treatment with HO-1 protein transduced by PEP-1 confers protection against septic shock-induced lung injury by its antioxidant, anti-inflammatory, and antiapoptotic effects.

Highlights

Septic shock is a subset of sepsis in which profound circulatory, cellular, and metabolic abnormalities are associated with a greater risk of mortality than in sepsis alone [1]
This study provides evidence that transduced PEP-1-Heme oxygenase-1 (HO-1) fusion protein may reduce the septic shock-induced increase of Toll-like receptor 4 (TLR4) expression and NF-κB activation and alleviate septic shock-induced lung injury through the antioxidant, antiinflammatory, and antiapoptotic properties of transduced HO-1
Our results were in accordance with previous studies, indicating that treatment with PEP-1HO-1 fusion protein reduced septic shock-induced lung injury via inhibition of the production of proinflammatory cytokines regulated by activated NF-κB

Summary

Introduction

Septic shock is a subset of sepsis in which profound circulatory, cellular, and metabolic abnormalities are associated with a greater risk of mortality than in sepsis alone [1]. Accumulating evidence suggests that HO-1 confers protection against a variety of oxidant-induced cell and tissue injuries. Administration of HO-1 by pharmacological induction or gene transfer provided protection in a variety of preclinical models [4,5,6]. Administration of exogenous CO, BV, or BR may substitute for the cytoprotective effects of HO-1 to confer protection in a variety of clinically applicable models [4, 10,11,12]. A variety of signaling molecules has been implicated in the cytoprotection conferred by HO-1, including the transcription factor nuclear factor-kappaB (NF-κB), autophagic proteins, p38 mitogen-activated protein kinase, phosphatidylinositol 3-kinase/Akt, and others [5]

Methods

Results

Discussion

Conclusion