Blocking SphK1/S1P/S1PR1 Signaling Pathway Alleviates Lung Injury Caused by Sepsis in Acute Ethanol Intoxication Mice

Abstract

Acute ethanol intoxication increases the risk of sepsis and aggravates the symptoms of sepsis and lung injury. Therefore, this study aimed to explore whether sphingosine kinase 1 (SphK1)/sphingosine-1-phosphate (S1P)/S1P receptor 1 (S1PR1) signaling pathway functions in lung injury caused by acute ethanol intoxication-enhanced sepsis, as well as its underlying mechanism. The acute ethanol intoxication model was simulated by intraperitoneally administering mice with 32% ethanol solution, and cecal ligation and puncture (CLP) was used to construct the sepsis model. The lung tissue damage was observed by hematoxylin-eosin (H&E) staining, and the wet-to-dry (W/D) ratio was used to evaluate the degree of pulmonary edema. Inflammatory cell counting and protein concentration in bronchoalveolar lavage fluid (BALF) were, respectively, detected by hemocytometer and bicinchoninic acid (BCA) method. The levels of tumor necrosis factor (TNF)-α, interleukin (IL)-6, IL-1β, and IL-18 in BALF were detected by their commercial enzyme-linked immunosorbent assay (ELISA) kits. The myeloperoxidase (MPO) activity and expression of apoptosis-related proteins and SphK1/S1P/S1PR1 pathway-related proteins were, respectively, analyzed by MPO ELISA kit and Western blot analysis. The cell apoptosis in lung tissues was observed by TUNEL assay. Acute ethanol intoxication (EtOH) decreased the survival rate of mice and exacerbated the lung injury caused by sepsis through increasing pulmonary vascular permeability, neutrophil infiltration, release of inflammatory factors, and cell apoptosis. In addition, EtOH could activate the SphK1/S1P/S1PR1 pathway in CLP mice. However, PF-543, as a specific inhibitor of SphK1, could partially reverse the deleterious effects on lung injury of CLP mice. PF-543 alleviated lung injury caused by sepsis in acute ethanol intoxication rats by suppressing the SphK1/S1P/S1PR1 signaling pathway.

MicroRNA-28-5p as a potential diagnostic biomarker for chronic periodontitis and its role in cell proliferation and inflammatory response

“…SPHK1, a kinase in sphingolipid metabolism, is recognized as a critical factor in the regulation of inflammatory response and cellular immunity. 27 For example, SPHK1 promoted inflammatory responses in renal clear cell carcinoma 28 and cerebral ischemia/reperfusion injury, 29 and its reduced levels alleviated inflammatory factor release in ethanol-intoxicated septic mice 30 and was involved in the ameliorative effect of atractylenolide-1 in mice with colitis. 31 The transcriptional activation of pro-inflammatory cytokines (IL-6), chemokines, and adhesion molecules requires the activation of SPHK1.…”

Therapeutic Potential of SphK1 Inhibitors Based on Abnormal Expression of SphK1 in Inflammatory Immune Related-Diseases

“…However, PF-543 had no effect on Cer level, suggesting that the lack of the ability to induce apoptosis ( Byun et al, 2013 ; Wang et al, 2013 ). A recent study has proved that PF-543 reduces apoptosis in the lungs of mice after acute ethanol intoxication, and inhibits neutrophil infiltration and the release of inflammatory cytokines to reduce lung injury ( Chen et al, 2021b ). As the most effective SphK1 inhibitor so far, PF-543 can inhibit inflammation in RA model ( Deng et al, 2021 ), ulcerative colitis model ( Liu and Jiang, 2020 ) and mouse pulmonary hypertension hypoxia model ( Ha et al, 2020 ) in vivo and in vitro , mainly by inhibiting the release of inflammatory cytokines and the change of cell biological function.…”

Targeting SPHK1/PBX1 Axis Induced Cell Cycle Arrest in Non-Small Cell Lung Cancer

“…PF-543, a novel and selective inhibitor of SPHK1 among all the SK inhibitors, exerted potent antiproliferation and cytotoxic effects applied in multiple cancer treatments [ 24 ]. A study demonstrated that PF-543 alleviated lung injury caused by sepsis in acute ethanol intoxication rats by suppressing the SPHK1/S1P/S1PR1 signaling pathway [ 25 ]. To further characterize the oncogenic role of SPHK1 in NSCLC cells, MTT assay was performed to test the effect of PF-543 on cell survival.…”