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Intraperitoneal Injection of Acetate Protects Mice Against Lipopolysaccharide (LPS)?Induced Acute Lung Injury Through Its Anti-In?ammatory and Anti-Oxidative Ability.

ABSTRACT: BACKGROUND As a member of short-chain fatty acids, acetate exhibits anti-inflammatory capacity. The present study aimed to investigate the effect of acetate on lipopolysaccharide (LPS)-induced acute lung injury (ALI) and explored its underlying mechanism. MATERIAL AND METHODS Acetate (250 mM, 400 µL) was given intraperitoneally 30 minutes after LPS (5 mg/kg) intratracheal injection. Lung tissues and bronchoalveolar lavage fluid (BALF) were collected 6 hours after the challenge of LPS. The histopathology scores, wet-to-dry weight ratios, protein content, and cytokine levels in BALF were assessed. RESULTS The acetate treatment resulted in improved lung pathological score, alleviated LPS-induced microvascular permeability, and suppressed the production of reactive oxygen species. Furthermore, acetate decreased the level of pro-inflammatory cytokines and chemokines in the lungs and BALF, consistent with the declined immune cell counting found in BALF. In addition, phosphorylation levels of mitogen-activated protein kinase (MAPK) pathway in lung tissues were downregulated by acetate. CONCLUSIONS These results suggested that acetate exerts its protective effects via anti-inflammatory and anti-oxidant activities on LPS-induced ALI.

SUBMITTER: Xu M

PROVIDER: S-EPMC6450300 | biostudies-literature | 2019 Mar

REPOSITORIES: biostudies-literature

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Intraperitoneal Injection of Acetate Protects Mice Against Lipopolysaccharide (LPS)‑Induced Acute Lung Injury Through Its Anti-Inﬂammatory and Anti-Oxidative Ability.

Xu Mengda M Wang Changli C Li Na N Wang Jun J Zhang Yan Y Deng Xiaoming X

Medical science monitor : international medical journal of experimental and clinical research 20190328

BACKGROUND As a member of short-chain fatty acids, acetate exhibits anti-inflammatory capacity. The present study aimed to investigate the effect of acetate on lipopolysaccharide (LPS)-induced acute lung injury (ALI) and explored its underlying mechanism. MATERIAL AND METHODS Acetate (250 mM, 400 µL) was given intraperitoneally 30 minutes after LPS (5 mg/kg) intratracheal injection. Lung tissues and bronchoalveolar lavage fluid (BALF) were collected 6 hours after the challenge of LPS. The histop ...[more]

PMID: 30921298

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Project description:Background:Sepsis-induced cardiomyopathy (SIC) is a common severe complication of sepsis that contributes to mortality. SIC is closely associated with excessive inflammatory responses, failed inflammation resolution, and apoptotic damage. Resolvin E1 (RvE1), an omega-3 polyunsaturated fatty acid (PUFA)-derived metabolite, has been reported to exert anti-inflammatory or proresolving activity in multiple animal models of inflammatory disease. However, the therapeutic potential of RvE1 in SIC remains undetermined, which was, therefore, the aim of the present study. Methods:C57BL/6J mice were randomly divided into three groups: control, lipopolysaccharide (LPS), and LPS + RvE1. Echocardiography, Western blotting (WB), quantitative real-time (QRT)-PCR, histological analyses, and flow cytometry were used to evaluate cardiac function, myocardial inflammation, and the underlying mechanisms. Results:The RvE1-injected group showed improved left ventricular (LV) function and reduced serum lactate dehydrogenase (LDH) and creatine kinase myocardial bound (CK-MB) levels. Compared to LPS treatment alone, RvE1 treatment inhibited the infiltration of neutrophils and macrophages into the heart and spleen and suppressed the secretion of pro-inflammatory cytokines, including interleukin (IL)-1?, IL-6, and monocyte chemoattractant protein (MCP)-1, in the heart. We also observed that the activation of the mitogen-activated protein kinase (MAPK) and nuclear factor (NF)-?B signaling pathways was blocked by RvE1 treatment, and this inhibition contributed to the improvement in the inflammatory response induced by LPS. RvE1 inhibited LPS-induced M1 macrophage polarization and promoted macrophage polarization toward the M2-like phenotype in both the heart and spleen. In addition, LPS administration dysregulated cyclooxygenase (COX) and lipoxygenase (LOX) in the heart, which were rectified by RvE1 treatment. RvE1 also reduced myocardial apoptosis rate in response to LPS-induced heart injury. Conclusion:RvE1 protects the heart against SIC possibly through the inhibition of the MAPK and NF-?B inflammatory signaling pathways, modulation of macrophage polarization, and reduction in myocardial apoptosis. RvE1 may be a novel lipid mediator for the treatment of SIC.

Project description:ObjectiveSudden unexpected death in epilepsy (SUDEP) is the cause of premature death of 50% patients with chronic refractory epilepsy. Respiratory failure during seizures is regarded as an important mechanism of SUDEP. Previous studies have shown that abnormal serotonergic neurotransmission is involved in the pathogenesis of seizure-induced respiratory failure, while enhancing serotonergic neurotransmission in the brainstem suppresses it. Because peripheral inflammation is known to enhance serotonergic neuron activation and 5-HT synthesis and release, we investigated the effect of intraperitoneal lipopolysaccharide (LPS)-induced inflammation on the S-IRA susceptibility during audiogenic seizures in DBA/1 mice.MethodsAfter DBA/1 mice were primed by exposing to sound stimulation for three consecutive days, they were tested for seizure severity and seizure-induced respiratory arrest (S-IRA) induced by sound stimulation under different conditions. We determined the dose and time course of the effects of intraperitoneal administration of LPS on audiogenic seizures and S-IRA. The effects of blocking TLR4 or RAGE receptors and blocking 5-HT receptors on the LPS-induced effect on S-IRA were investigated. Statistical significance was evaluated using the Kruskal-Wallis test.ResultsIntraperitoneal injection of LPS significantly had dose-dependent effects in reducing the incidence of S-IRA as well as seizure severity in DBA/1 mice. The protective effect of LPS on S-IRA peaked at 8-12 hours after LPS injection and was related to both reducing seizure severity and enhancing autoresuscitation. Blocking TLR4 or RAGE receptor with TAK-242 or FPS-ZM1, respectively, prior to LPS injection attenuated its effects on S-IRA and seizure severity. Injection of a nonselective 5-HT receptor antagonist, cyproheptadine, or a 5-HT3 receptor antagonist, ondansetron, was effective in blocking LPS-induced effect on S-IRA. Immunostaining results showed a significant increase in c-Fos-positive serotonergic neurons in the dorsal raphe.SignificanceThis is the first study that demonstrates the effect of intraperitoneal LPS injection-induced inflammation on reducing S-IRA susceptibility and provides additional evidence supporting the serotonin hypothesis on SUDEP. Our study suggests that inflammation may enhance brainstem 5-HT neurotransmission to promote autoresuscitation during seizure and prevent SUDEP.

Project description:The NAD+-dependent 15-hydroxyprostaglandin dehydrogenase (15-PGDH) catalyzes the oxidation of the 15(S)-hydroxyl group of prostaglandin E2 (PGE2), converting the pro-inflammatory PGE2 to the anti-inflammatory 15-keto-PGE2 (an endogenous ligand for peroxisome proliferator-activated receptor-gamma [PPAR-γ]). To evaluate the significance of 15-PGDH/15-keto-PGE2 cascade in liver inflammation and tissue injury, we generated transgenic mice with targeted expression of 15-PGDH in the liver (15-PGDH Tg) and the animals were subjected to lipopolysaccharide (LPS)/Galactosamine (GalN)-induced acute liver inflammation and injury. Compared to the wild type mice, the 15-PGDH Tg mice showed lower levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST), less liver tissue damage, less hepatic apoptosis/necrosis, less macrophage activation, and lower inflammatory cytokine production. In cultured Kupffer cells, treatment with 15-keto-PGE2 or the conditioned medium (CM) from 15-PGDH Tg hepatocyes inhibited LPS-induced cytokine production, in vitro. Both 15-keto-PGE2 and the CM from15-PGDH Tg hepatocyes also up-regulated the expression of PPAR-γ downstream genes in Kupffer cells. In cultured hepatocytes, 15-keto-PGE2 treatment or 15-PGDH overexpression did not influence TNF-α-induced hepatocyte apoptosis. These findings suggest that 15-PGDH protects against LPS/GalN-induced liver injury and the effect is mediated via 15-keto-PGE2, which activates PPAR-γ in Kupffer cells and thus inhibits their ability to produce inflammatory cytokines. Accordingly, we observed that the PPAR-γ antagonist, GW9662, reversed the effect of 15-keto-PGE2 in Kupffer cell in vitro and restored the susceptibility of 15-PGDH Tg mice to LPS/GalN-induced acute liver injury in vivo. Collectively, our findings suggest that 15-PGDH-derived 15-keto-PGE2 from hepatocytes is able to activate PPAR-γ and inhibit inflammatory cytokine production in Kupffer cells and that this paracrine mechanism negatively regulates LPS-induced necro-inflammatory response in the liver. Therefore, induction of 15-PGDH expression or utilization of 15-keto-PGE2 analogue may have therapeutic benefits for the treatment of endotoxin-associated liver inflammation/injury.

Project description:BackgroundSepsis is a high-mortality disease without effective therapeutic options. The hyperactivation of the monocyte-macrophage system, especially M1 macrophages, triggers the onset of septic shock. Gentiopicroside (GENT), the main active component in the traditional Chinese medicinal herb Radix Gentianae, has been shown to have anti-inflammatory properties. Nevertheless, this anti-inflammatory effect has not been fully elucidated.MethodsIn vitro, we stimulated primary bone marrow-derived macrophages (BMMs) or peritoneal elucidated macrophages (PEMs) by lipopolysaccharide (LPS) and interferon (IFN)-γ and pre-treated with GENT and we tested the cytokines such as interleukin (IL)-1β, IL-6 and tumor necrosis factor (TNF) α production by enzyme linked immunosorbent assay (ELISA) or real-time quantitative PCR (qPCR). Further, we determined the NF-κB-mediated inflammatory pathway such as IKKα/β and p65 phosphorylation by Western blot. Then we detected the p65 nuclear localization by immunofluorescent staining. Moreover, NF-κB inhibitor and p65-targeted siRNAs were further used to validate the anti-inflammatory mechanism of GENT. In vivo, GENT (50 mg/kg) was administered intragastrically before and after LPS (40 mg/kg) injection. The death time were recorded and the serum levels of IL-1β, IL-6 and TNFα were tested by ELISA, and the IL-1β, IL-6 and TNFα mRNA expression in the lung were test by qPCR and the M1 infiltration in the lung were determined by F4/80 and INOS immunofluorescent staining.ResultsIn vitro, we observed that GENT reduced the inflammatory cytokine production of BMMs stimulated by (LPS)/IFN-γ and ameliorated the phosphorylation of IKKα/β and p65, the degradation of IκBα, and the translocation of p65 into the nucleus. We did not find GENT has any effect on MAPK signaling under LPS/IFN-γ stimulation. NF-κB inhibitor and p65 siRNAs eliminated the inhibition effect of GENT. In vivo, we observed GENT prevented mice from dying in the LPS-induced shock model and decreased the serum levels of IL-1β and IL-6, the mRNA expression of IL-1β, IL-6 and TNFα in lung tissue, and the amount of M1 macrophage infiltration in the lung.ConclusionsGENT prevented LPS/IFN-γ-induced inflammatory cytokine production by macrophages through the NF-κB signaling pathway in vitro and protected against the endotoxin shock induced by LPS in vivo.

Dataset Information

Intraperitoneal Injection of Acetate Protects Mice Against Lipopolysaccharide (LPS)?Induced Acute Lung Injury Through Its Anti-In?ammatory and Anti-Oxidative Ability.

Publications

Intraperitoneal Injection of Acetate Protects Mice Against Lipopolysaccharide (LPS)‑Induced Acute Lung Injury Through Its Anti-Inﬂammatory and Anti-Oxidative Ability.

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