Propofol inhibits endogenous formyl peptide-induced neutrophil activation and alleviates lung injury.

Abstract

Critically ill patients have a high risk of sepsis. Various studies have demonstrated that propofol has anti-inflammatory effects that may benefit critically ill patients who require anesthesia. However, the mechanism and therapeutic effect remain incompletely understood. Our previous data suggest that propofol can act as a formyl peptide receptor 1 (FPR1) antagonist. Here, we hypothesize that propofol mitigates sepsis-induced acute lung injury (ALI) by inhibiting mitochondria-derived N-formyl peptide-mediated neutrophil activation. Oxidative stress caused by activated neutrophils is involved in the pathogenesis of ALI. In human neutrophils, propofol competitively reduced the release of superoxide and associated reactive oxygen species induced by fMMYALF, a human mitochondria-derived N-formyl peptide, suggesting that propofol effectively suppresses neutrophilic oxidative stress. In addition, propofol significantly inhibited fMMYALF-induced elastase release, chemotaxis, calcium mobilization, and phosphorylation of protein kinase B and mitogen-activated protein kinases. These results indicate that propofol suppresses neutrophil activation by blocking the interaction between endogenous N-formyl peptide and its receptor, FPR1, thus inhibiting downstream signaling. Furthermore, propofol alleviated alveolar wall disruption, edematous changes, and neutrophil infiltration in lipopolysaccharide-induced ALI in mice. Noticeably, propofol improved the survival of sepsis mice. This study indicates that the anti-neutrophil effects of propofol may benefit critically ill septic patients.

• Authors: Chun-Yu Chen, Yung-Fong Tsai, Wei-Ju Huang, Shih-Hsin Chang, Tsong-Long Hwang
• Journal: Free radical biology & medicine (Free Radic Biol Med) Vol. 129 Pg. 372-382 (12 2018) ISSN: 1873-4596 [Electronic] United States
• PMID: 30312762 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2018 Elsevier Inc. All rights reserved.

Chemical References

• Chemotactic Factors
• Fpr1 protein, mouse
• Lipopolysaccharides
• Oligopeptides
• Reactive Oxygen Species
• Receptors, Formyl Peptide
• F-chemotactic peptide
• L-Lactate Dehydrogenase
• Peroxidase
• Proto-Oncogene Proteins c-akt
• Mitogen-Activated Protein Kinases
• Leukocyte Elastase
• Propofol

Topics

• Acute Lung Injury (chemically induced, genetics, mortality, prevention & control)
• Animals
• Cell Movement (drug effects)
• Chemotactic Factors (pharmacology)
• Gene Expression Regulation
• Humans
• L-Lactate Dehydrogenase (metabolism)
• Leukocyte Elastase (genetics, metabolism)
• Lipopolysaccharides (administration & dosage)
• Lung (drug effects, immunology, pathology)
• Male
• Mice
• Mice, Inbred BALB C
• Mitogen-Activated Protein Kinases (genetics, metabolism)
• Neutrophil Activation (drug effects)
• Neutrophils (drug effects, immunology, pathology)
• Oligopeptides (pharmacology)
• Peroxidase (genetics, metabolism)
• Primary Cell Culture
• Propofol (pharmacology)
• Proto-Oncogene Proteins c-akt (genetics, metabolism)
• Reactive Oxygen Species (antagonists & inhibitors, metabolism)
• Receptors, Formyl Peptide (genetics, metabolism)
• Sepsis (chemically induced, drug therapy, genetics, mortality)
• Signal Transduction
• Survival Analysis