Suppression of Endoplasmic Reticulum Stress by 4-PBA Protects Against Hyperoxia-Induced Acute Lung Injury via Up-Regulating Claudin-4 Expression

Hsin-Ping Pao,Kun-Lun Huang,Shi-Jye Chu,Shih-En Tang,Shu-Yu Wu,Wen-I Liao

doi:10.3389/fimmu.2021.674316

Abstract

Endoplasmic reticulum (ER) stress that disrupts ER function can occur in response to a wide variety of cellular stress factors leads to the accumulation of unfolded and misfolded proteins in the ER. Many studies have shown that ER stress amplified inflammatory reactions and was involved in various inflammatory diseases. However, little is known regarding the role of ER stress in hyperoxia-induced acute lung injury (HALI). This study investigated the influence of ER stress inhibitor, 4-phenyl butyric acid (4-PBA), in mice with HALI. Treatment with 4-PBA in the hyperoxia groups significantly prolonged the survival, decreased lung edema, and reduced the levels of inflammatory mediators, lactate dehydrogenase, and protein in bronchoalveolar lavage fluid, and increased claudin-4 protein expression in lung tissue. Moreover, 4-PBA reduced the ER stress-related protein expression, NF-κB activation, and apoptosis in the lung tissue. In in vitro study, 4-PBA also exerted a similar effect in hyperoxia-exposed mouse lung epithelial cells (MLE-12). However, when claudin-4 siRNA was administrated in mice and MLE-12 cells, the protective effect of 4-PBA was abrogated. These results suggested that 4-PBA protected against hyperoxia-induced ALI via enhancing claudin-4 expression.

Highlights

In critical pulmonary and cardiorespiratory disease, the delivery of oxygen to peripheral tissues is increased with supplemental oxygen treatment
Three specialized ERlocalized protein sensors are involved in unfolded protein response (UPR) initiation: inositolrequiring enzyme 1a (IRE1a), double-stranded RNA-dependent protein kinase (PKR)-like endoplasmic reticulum (ER) kinase (PERK), and activating transcription factor 6 (ATF6), which are released from binding immunoglobulin protein (BiP; known as glucose-regulated protein–78, or GRP78) during ER stress
This study demonstrated that 4-Phenyl butyric acid (4-PBA), a chemical chaperone, significantly improved multiple indices of hyperoxia-induced acute lung injury (HALI), such as prolonging survival, and decreasing Alveolar Fluid Clearance (AFC), lung edema, and disruption of tight junction proteins, production of proinflammatory cytokines, oxidative stress, the pulmonary neutrophil influx, and lung tissue damage

Summary

INTRODUCTION

In critical pulmonary and cardiorespiratory disease, the delivery of oxygen to peripheral tissues is increased with supplemental oxygen treatment. The major mechanism for the action of 4PBA is that the hydrophobic regions of the chaperone interact with exposed hydrophobic segments of the unfolded protein. This interaction protects the protein from aggregation, promotes the folding of proteins, and reduces ER stress. One study reported that dermatophagoides farinae-sensitized mice had increased ER stress and impaired airway epithelial barrier function which was associated with an exaggerated decrease of TJ proteins. It has been demonstrated that hyperoxia exposure decreases the protein expression of claudin-4 in the pulmonary epithelial barrier [28], the contribution of ER stress in HALI to pulmonary TJ barrier dysfunction is still not conclusive. Similar studies were performed in mouse lung epithelial cells exposed to hyperoxia

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ETHICS STATEMENT