Abstract

5-Hydroxymethylfurfural (5-HMF) is a common reaction product during heat processing and the preparation of many types of foods and Traditional Chinese Medicine formulations. The aim of this study was to evaluate the protective effect of 5-HMF on endotoxin-induced acute lung injury (ALI) and the underlying mechanisms. Our findings indicate that 5-HMF attenuated lipopolysaccharide (LPS)-induced ALI in mice by mitigating alveolar destruction, neutrophil infiltration and the release of inflammatory cytokines. Furthermore, the activation of macrophages and human monocytes in response to LPS was remarkably suppressed by 5-HMF in vitro through inhibiting the NF-κB signaling pathway, NLRP3 inflammasome activation and endoplasmic reticulum (ER) stress. The inhibitory effect of 5-HMF on NLRP3 inflammasome was reversed by overexpressing ATF4 or CHOP, indicating the involvement of ER stress in the negative regulation of 5-HMF on NLRP3 inflammasome-mediated inflammation. Consistent with this, the ameliorative effect of 5-HMF on in vivo pulmonary dysfunction were reversed by the ER stress inducer tunicamycin. In conclusion, our findings elucidate the anti-inflammatory and protective efficacy of 5-HMF in LPS-induced acute lung injury, and also demonstrate the key mechanism of its action against NLRP3 inflammasome-related inflammatory disorders via the inhibition of ER stress.

Highlights

  • Acute lung injury (ALI) is a debilitating disease characterized by severe pulmonary lung inflammation and air leak in the upper lobe, which typically lead to hypoxemic respiratory failure in critically ill patients (Moazed and Calfee, 2014)

  • LPS-induced acute lung injury (ALI) is mediated by proinflammatory cytokines and mediators such as nitric oxide (NO), interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), IL-1β and IL-8, which are produced by the alveolar macrophages (Wu et al, 2018) following activation of the mitogen activated protein kinases (MAPK) and NF-κB signaling pathways (Xu et al, 2014; Kim et al, 2015a)

  • It is crucial to identify novel anti-inflammatory compounds for the prevention and treatment of inflammation-relevant lung injury. 5-HMF is an active compound commonly found in sugar-rich heat-processed foods, including honey, coffee, dried fruit and fruit juices (Shapla et al, 2018; Zou et al, 2021)

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Summary

Introduction

Acute lung injury (ALI) is a debilitating disease characterized by severe pulmonary lung inflammation and air leak in the upper lobe, which typically lead to hypoxemic respiratory failure in critically ill patients (Moazed and Calfee, 2014). LPS is recognized by toll-like receptor 4 (TLR4) that is expressed on the cell membrane of various immune cells (Lu et al, 2008), and the ensuing stimulation of TLR4 activates the NF-κB and MAPKs (ERK, JNK and p38 kinases) signaling pathways. Inhibiting these pathways may alleviate LPS-induced inflammation and pulmonary dysfunction

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