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.

• Authors: Liang Chen, Lingling Li, Yong Song, Tangfeng Lv
• Journal: Inflammation (Inflammation) Vol. 44 Issue 6 Pg. 2170-2179 (Dec 2021) ISSN: 1573-2576 [Electronic] United States
• PMID: 34109517 (Publication Type: Journal Article)
• Copyright: © 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.

Chemical References

• Cytokines
• Enzyme Inhibitors
• Inflammation Mediators
• Lysophospholipids
• PF-543
• Pyrrolidines
• Sphingosine-1-Phosphate Receptors
• Sulfones
• sphingosine 1-phosphate
• Phosphotransferases (Alcohol Group Acceptor)
• Sphk1 protein, mouse
• Sphingosine
• Methanol

Topics

• Alcoholic Intoxication (complications)
• Animals
• Apoptosis (drug effects)
• Cytokines (metabolism)
• Disease Models, Animal
• Enzyme Inhibitors (pharmacology)
• Inflammation Mediators (metabolism)
• Lung (drug effects, enzymology, pathology)
• Lung Injury (enzymology, etiology, pathology, prevention & control)
• Lysophospholipids (metabolism)
• Male
• Methanol (pharmacology)
• Mice, Inbred C57BL
• Neutrophil Infiltration (drug effects)
• Oxidative Stress (drug effects)
• Phosphotransferases (Alcohol Group Acceptor) (antagonists & inhibitors, metabolism)
• Pneumonia (enzymology, etiology, pathology, prevention & control)
• Pulmonary Edema (enzymology, etiology, pathology, prevention & control)
• Pyrrolidines (pharmacology)
• Sepsis (complications, drug therapy, enzymology)
• Signal Transduction
• Sphingosine (analogs & derivatives, metabolism)
• Sphingosine-1-Phosphate Receptors (metabolism)
• Sulfones (pharmacology)
• Mice