Abstract

BackgroundAcute lung injury (ALI) is considered to be the major cause of respiratory failure in critically ill patients. Clinical studies have found that in patients with sepsis and after hemorrhage, the elevated level of high mobility group box-1(HMGB-1) in their circulation is highly associated with ALI, but the underlying mechanism remains unclear. Extracellular HMGB-1 has cytokine-like properties and can bind to Toll-like Receptor-4 (TLR4), which was reported to play an important role in the pathogenesis of ALI. The aim of this study was to determine whether HMGB-1 directly contributes to ALI and whether TLR4 signaling pathway is involved in this process.MethodsRecombinant human HMGB-1 (rhHMGB-1) was used to induce ALI in male Sprague-Dawley rats. Lung specimens were collected 2 h after HMGB-1 treatment. The levels of TNF-α, IL-1β, TLR4 protein, and TLR4 mRNA in lungs as well as pathological changes of lung tissue were assessed. In cell studies, the alveolar macrophage cell line, NR8383, was collected 24 h after rhHMGB-1 treatment and the levels of TNF-α and IL-1β in cultured medium as well as TLR4 protein and mRNA levels in the cell were examined. TLR4-shRNA-lentivirus was used to inhibit TLR4 expression, and a neutralizing anti-HMGB1 antibody was used to neutralize rhHMGB-1 both in vitro and in vivo.ResultsFeatures of lung injury and significant elevation of IL-1β and TNF-α levels were found in lungs of rhHMGB-1-treated animals. Cultured NR8383 cells were activated by rhHMGB-1 treatment and resulted in the release of IL-1β and TNF-α. TLR4 expression was greatly up-regulated by rhHMGB-1. Inhibition of TLR4 or neutralization of HMGB1 with a specific antibody also attenuated the inflammatory response induced by HMGB-1 both in vivo and in vitro.ConclusionHMGB-1 can activate alveolar macrophages to produce proinflammatory cytokines and induce ALI through a mechanism that relies on TLR-4.

Highlights

  • Acute lung injury (ALI) is considered to be the major cause of rapid-onset respiratory failure in critically ill patients

  • Once Toll-like Receptor-4 (TLR4) binds with its ligands, it further activates NF-kB through a MyD88-dependent pathway that stimulates the expression of proinflammatory cytokines, such as interleukin (IL)-1, IL-6, and tumor necrosis factor (TNF)-a leading to pathological changes in ALI [9,10]

  • High Mobility Group Box Protein1 (HMGB-1)-Induced ALI To examine whether HMGB-1 contributes to ALI, rats were instilled intratracheally with rhHMGB-1 at the indicated doses and lung histological observation was performed 24 h posttreatment

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Summary

Introduction

Acute lung injury (ALI) is considered to be the major cause of rapid-onset respiratory failure in critically ill patients. TLR4 can be activated by prototypical pathogen-associated molecular pattern (PAMP) and damage-associated molecular pattern (DAMP) proteins, such as HSP70 and High Mobility Group Box Protein (HMGB-1) [11,12]. Acute lung injury (ALI) is considered to be the major cause of respiratory failure in critically ill patients. Clinical studies have found that in patients with sepsis and after hemorrhage, the elevated level of high mobility group box1(HMGB-1) in their circulation is highly associated with ALI, but the underlying mechanism remains unclear. Extracellular HMGB-1 has cytokine-like properties and can bind to Toll-like Receptor-4 (TLR4), which was reported to play an important role in the pathogenesis of ALI. The aim of this study was to determine whether HMGB-1 directly contributes to ALI and whether TLR4 signaling pathway is involved in this process

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