Propofol inhibits neutrophilic inflammation induced by mitochondrial-derived DAMP and alleviates lipopolysaccharide-induced acute lung injury

[Speaker] Tsong-Long Hwang:1,2,3
[Co-author] Chun-Yu Chen:1,3, Shih-Hsin Chang:1,2, Shun-Chin Yang:4
1:Chang Gung University, Taiwan, 2:Graduate Institute of Health Industry Technology, Chang Gung University of Science and Technology, Taiwan, 3:Department of Anesthesiology, Chang Gung Memorial Hospital, Taiwan, 4:Department of Anesthesiology, Taipei Veterans General Hospital, Taiwan

Critically ill patients have a high risk of secondary infection and sepsis. Various studies and clinical trials have demonstrated that the anesthetic agent propofol has anti-inflammatory and antioxidant effects that may benefit critically ill patients who requires sedation or anesthesia. Our previous data suggest that propofol can act as a formyl peptide receptor 1 (FPR1) antagonist. However, the mechanism and effect remain incompletely understood. Here, we hypothesize that propofol attenuates sepsis-induced acute lung injury (ALI) via inhibition of mitochondria-derived N-formyl peptide-mediated neutrophil activation. In human neutrophils, propofol competitively inhibited the release of elastase, superoxide anion, and reactive oxygen species induced by fMMYALF, a human mitochondria-derived N-formyl peptide. In addition, propofol significantly inhibited fMMYALF-induced chemotaxis, intracellular calcium ion 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 receptor signaling. Furthermore, propofol alleviated alveolar wall disruption, edematous changes, and neutrophil infiltration in lipopolysaccharide-induce ALI in mice. Noticeably, propofol improved the survival of mice with LPS-induced sepsis. Our results suggest that the anti-neutrophilic inflammatory effects of propofol may benefit critically ill patients with sepsis.
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