1-Palmitoyl-2-Linoleoyl-3-Acetyl-rac-Glycerol (PLAG) Rapidly Resolves LPS-Induced Acute Lung Injury Through the Effective Control of Neutrophil Recruitment

Abstract

Acute lung injury (ALI) is an acute respiratory failure that is associated with excessive neutrophil recruitment and high mortality. To assess the efficacy of 1-palmitoyl-2-linoleoyl-3-acetyl-rac-glycerol (PLAG) as a therapeutic agent for ALI, this compound was administered orally to mice challenged with an intranasal dose of lipopolysaccharide (LPS). Using this model, we found that PLAG promotes resolution of ALI through effective control of LPS-induced neutrophil infiltration, endothelial permeability, and inflammatory chemokine production. In addition, the Toll like Receptor 4 (TLR4) endocytosis/exocytosis cycle was significantly accelerated in Raw 264.7 cells co-treated with PLAG/LPS, as compared to cells treated only with LPS. During this cycle, a PLAG-induced exotoxin clearance pathway was observed to occur through the prompt assembly of nicotinamide adenine dinucleotide phosphate (NADPH) units and production of reactive oxygen species (ROS), which ultimately lead to earlier LPS clearance. We further detected reduced expression, as well as faster return to homeostatic levels, of macrophage inflammatory protein (MIP)-2, in PLAG/LPS- vs. LPS-treated cells. MIP-2 is a main inducer of neutrophil migration that is mainly controlled by interferon regulatory factor 3 (IRF3) activation and is involved in the TLR4 endosomal-signaling pathway. PLAG induced TLR4-mediated TRIF-related adaptor molecules/Toll-interleukin receptor (TIR) domain-containing adaptor protein including interferon (IFN)-β/IRF3 endosomal signaling, leading to rapid association of TRAM/TRIF and TLR4 and earlier IRF3 phosphorylation in PLAG/LPS-treated vs. LPS-treated cells. PLAG specificity was further verified with PLAG analogs and metabolites known to control excessive neutrophil infiltration, suggesting that this acetylated diacylglycerol has a unique biological role in neutrophil motility. Thus, our data indicate that PLAG may represent a potential therapeutic agent for resolution of LPS-induced lung inflammation through effective MIP-2 modulation.

Hesperetin ameliorates lipopolysaccharide-induced acute lung injury in mice through regulating the TLR4–MyD88–NF-κB signaling pathway

“…Neutrophils are also vital components of the inflammatory response that characterizes ALI, and are considered to be the final effector cells that responsible for lung injury due to their ability to express multiple cytotoxic products (Li et al 2019;Pinheiro et al 2019). Myeloperoxidase (MPO), which is localized in the primary granules of neutrophils (Lee et al 2019), reflects the adhesion and migration of neutrophils in lung tissues. In this study, LPS promoted the level of MPO, but hesperetin and Dex reversed the result.…”

1-Palmitoyl-2-Linoleoyl-3-Acetyl-rac-Glycerol (PLAG) Mitigates Monosodium Urate (MSU)-Induced Acute Gouty Inflammation in BALB/c Mice

“…The selectivity of PLAG in the regulation of MSU-induced CXCL8 expression is associated with its control ability of P2Y6 receptor endocytosis. Previously, we demonstrated that PLAG accelerates the termination of LPS-induced TRAM and TRIF-dependent TLR4 signaling, resulting in the reduced IRF3-dependent CXCL8 expression (49). In the study, PLAG did not affect MyD88-mediated NF-κB activation that induces the transcriptional expression of IL-1β.…”

“…In the previous study, PLAG induced rapid resolution of inflammation in LPS-induced acute lung injury via early elimination of LPS and early termination of endocytosisdependent signaling of TLR4 (49). PLAG remarkably ameliorated LPS-induced acute lung injury, which is a disease caused by a PAMP molecule (49). In this study, we examined a mitigating effect of PLAG on gouty inflammation, one of the sterile inflammations caused by MSU crystal, a substance thought to be DAMP.…”

“…Therefore, we think that CXCL8 is also a good therapeutic target for the treatment of gouty inflammation. In addition, there were no reports of toxicity or adverse effects when high doses of PLAG were administered in the non-clinical toxicity test (49,66). Since PLAG is delivered via oral administration, it has an advantage in the way of drug delivery than other gout drugs.…”

Botanical formulation, TADIOS, alleviates lipopolysaccharide (LPS)-Induced acute lung injury in mice via modulation of the Nrf2-HO-1 signaling pathway

“…Intratracheal injection of LPS stimulates alveolar macrophages’ rapid production of proinflammatory cytokines like TNF-α, IL-6 and IL-1β, which induce the infiltration and activation of neutrophils ( Bosmann et al, 2013 ; Chen et al, 2020 ; Chignard and Balloy, 2000 ; de Souza Xavier Costa et al, 2017 ; Rittirsch et al, 2008 ). Stimulated neutrophils then produce a large quantity of ROS and cytokines, which further aggravate severe lung damage through destructive inflammatory responses ( Dong and Yuan, 2018 ; Lee, H.R. et al, 2019 ; Potey et al, 2019 ).…”