Glycine Attenuates Lipopolysaccharide-Induced Acute Lung Injury by Regulating NLRP3 Inflammasome and NRF2 Signaling

Yunchang Zhang,In Ho Kim,Hai Jia,Jingqing Chen,Zhenlong Wu,Da Jiang,Ying Yang,Xiaoshi Ma

doi:10.3390/nu12030611

Abstract

Glycine supplementation has been reported to alleviate lipopolysaccharide (LPS)-induced lung injury in mice. However, the underlying mechanisms responsible for this beneficial effect remain unknown. In the present study, male C57BL/6 mice were treated with aerosolized glycine (1000 mg in 5 mL of 0.9% saline) or vehicle (0.9% saline) once daily for 7 continuous days, and then were exposed to aerosolized LPS (5 mg in 5 mL of 0.9% saline) for 30 min to induce lung injury. Sera and lung tissues were collected 24 h post LPS challenge. Results showed that glycine pretreatment attenuated LPS-induced decreases of mucin at both protein and mRNA levels, reduced LPS-triggered upregulation of pro-inflammatory cytokines, such as tumor necrosis factor-α (TNF-α), interferons, granulocyte-macrophage colony-stimulating factor (GM-CSF), and interleukins. Further study showed that glycine-reduced LPS challenge resulted in the upregulation of nuclear factor κB (NF-κB), nucleotide binding domain (NOD)-like receptor protein 3 (NLRP3) inflammasome. In addition, LPS exposure led to the downregulation of NRF2 and downstream targets, which were significantly improved by glycine administration in the lung tissues. Our findings indicated that glycine pretreatment prevented LPS-induced lung injury by regulating both NLRP3 inflammasome and NRF2 signaling.

Highlights

Acute lung injury is a common and severe pulmonary complication of critical illness caused by multiple factors, such as pneumonia, sepsis, shock, and respiratory bacteria or viruses infection [1].Under physiological conditions, an intracellular homeostasis and a normal function of the lungs are maintained by the host defense systems, including mucus layer and immune response
Is associated with the reduction of mucin and upregulation of pro‐inflammatory cytokines. This beneficial effect ofis inhibition of the nuclear factor κB (NF-κB) and nucleotide-binding domain-like receptor protein 3 (NLRP3) inflammasome signaling pathway, as well as the restoration associated with the inhibition of the
Our results indicated that the glycine-induced downregulation of NF-κB was mediated, at least partially, via nuclear factor erythroid-2 related factor 2 (NRF2) signaling

Summary

Introduction

An intracellular homeostasis and a normal function of the lungs are maintained by the host defense systems, including mucus layer and immune response. Mucus layer, which is mainly consisted of secreted mucins, including MUC5AC and MUC5B, is the first defense line that prevents the contact of host cells with lumen contents, such as chemicals, toxins, and pathogens [2]. The dysfunction of mucus is associated with bacteria invasion, which in turn activates immune response, infiltration of macrophage, and the secretion of pro-inflammatory cytokines, such as Nutrients 2020, 12, 611; doi:10.3390/nu12030611 www.mdpi.com/journal/nutrients. An increased level of lipopolysaccharides (LPS), a cell wall component of Gram-negative bacteria, has been observed in the plasma and lung tissues of clinical patients and experimental animals. A series of pathogen recognition receptors (PRRs), such as Toll-like receptors (TLR), RIG-I-like receptors (RLR), protease-activated receptors (PAR), Nod-like receptors (NLR), C-type lectin receptors, have been reported to sense the pathogens in contact with the airway epithelium and activate host response [5]

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Discussion

Conclusion