Downregulation of TNF-α/TNF-R1 Signals by AT-Lipoxin A4 May Be a Significant Mechanism of Attenuation in SAP-Associated Lung Injury.

Suhui Yu,Hongwei Sun,Jianming Xie,Bicheng Chen,Yukai Xiang,Shengjie Dai,Mengtao Zhou,Dinglai Yu

doi:10.1155/2019/9019404

Abstract

Our previous studies verified the potent anti-inflammatory effects against severe acute pancreatitis (SAP) of AT-Lipoxin A4 and their analogues. However, the anti-inflammatory effects of AT-Lipoxin A4 on SAP-associated lung injury are not thoroughly known. We used western blot, polymerase chain reaction (PCR), and immunofluorescence to investigate the downregulation of TNF-α signals in cellular and animal models of SAP-associated lung injury following AT-Lipoxin A4 intervention. In vitro, we found that AT-Lipoxin A4 markedly suppressed protein expression in TNF-α signals in human pulmonary microvascular endothelial cell, such as tumor necrosis factor receptor-associated factor 2 (TRAF2), TNF-R1-associated death domain (TRADD), receptor-interacting protein (RIP), vascular cell adhesion molecule-1 (VCAM-1), and E-selectin. Moreover, AT-Lipoxin A4 inhibited downstream signals activated by TNF-α, including NF-κB/p65, JNK/MAPK, and ERK/MAPK. In vivo, AT-Lipoxin A4 significantly decreased pathological scores of the pancreas and lungs and the serum levels of IL-6 and TNF-α. Immunofluorescence, western blotting, and real-time PCR assay showed that AT-Lipoxin A4 significantly attenuated the expression of TNF-R1, TRADD, TRAF2, and RIP in the lungs of SAP rats. In addition, the activation of NF-κB was also downregulated by AT-Lipoxin A4 administration as compared with SAP rats. AT-Lipoxin A4 could inhibit the production of proinflammatory mediators and activation of TNF-α downstream signals such as NF-κB and MAPK. Downregulation of TNF-α signals by AT-Lipoxin A4 may be a significant mechanism in the attenuation of SAP-associated lung injury.

Highlights

A challenge exists in the early clinical treatment of severe acute pancreatitis (SAP) in terms of how to control the occurrence of pancreatitis-induced multiple organ dysfunction syndrome (MODS), as a common end-stage pathophysiological process of SAP and a major cause of early death of patients with SAP [1]
The cytotoxicity experiments of AT-Lipoxin A4 were performed at 0-70 ng/mL, and the cell viability test showed that ATLipoxin A4 is nontoxic to HPMECs at the dosages used in this study
To investigate whether the inhibition of inflammation by AT-Lipoxin A4 was involved in the regulation of receptor-interacting protein (RIP) and tumor necrosis factor receptor-associated factor 2 (TRAF2), we examined the expressions of RIP and TRAF2 of HPMECs using western blot assay

Summary

Introduction

A challenge exists in the early clinical treatment of severe acute pancreatitis (SAP) in terms of how to control the occurrence of pancreatitis-induced multiple organ dysfunction syndrome (MODS), as a common end-stage pathophysiological process of SAP and a major cause of early death of patients with SAP [1]. MODS often begins with acute lung injury (ALI) and acute respiratory distress syndrome (ARDS). There has been an increasing awareness that systemic inflammatory response syndrome (SIRS) plays a key role in SAP-induced ALI [2]. SIRS and subsequent lung injury as important experimental topics have not been totally resolved. As a barrier between blood circulation and organization, the vascular endothelium plays a pivotal role in the occurrence and development of inflammation.

Methods

Results

Conclusion