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. In human neutrophils, propofol competitively reduced the release of elastase, superoxide, and reactive oxygen species induced by fMMYALF, a human mitochondria-derived N-formyl peptide. In addition, propofol significantly inhibited fMMYALF-induced 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. 106-2320-B-255-003-MY3 and MOST Problem: Sedative agents should be selected carefully for anesthetizing critically ill patients who are at high risk of secondary infection and sepsis. Propofol hasanti-inflammatory effects that benefit critically ill patients who require anesthesia.However, the mechanism and therapeutic effect of propofol on neutrophil-dominant acute lung injury remain incompletely understood.Results: Here we found that propofol competitively inhibited various neutrophil activities by blocking the interaction between endogenous N-formyl peptide and its receptor, FPR1, thus inhibiting downstream signaling. Propofol also alleviated the severity of sepsis-associated acute lung injury in mice and improved the survival.Impact: Our in vitro and septic mouse model experiments revealed that the anesthetic agent propofol, an FPR1 antagonist, may be beneficial for treating patients who are critically ill with sepsis and sepsis-associated ALI.

Propofol Improves Survival in a Murine Model of Sepsis via Inhibiting Rab5a-Mediated Intracellular Trafficking of TLR4

“…Propofol inhibits membrane TLR4 expression on macrophages in response to LPS stimulation and CLP Consistent with previous results [7,31], we found that propofol can effectively inhibit the expression of pro-in ammatory cytokines in BMDMs after LPS treatment, and can reduce the level of pro-in ammatory cytokines in the serum of mice challenged with CLP (Figure 1A and 1B). Recent evidence suggests that the amount of TLR4 on the surface of macrophages signi cantly increases following LPS treatment, re ecting involvement in the in ammatory response [32,33].…”

“…Previous studies by our group and others have revealed that propofol possesses anti-in ammatory and antioxidant properties in many conditions including ischemia/reperfusion injuries of organs and cardiopulmonary bypass [6]. It is well established that propofol suppresses production of proin ammatory cytokines, reduces expression of nitric oxide, and inhibits the immune activities of macrophages and neutrophils [7]. Moreover, propofol was proved to be bene cial to the survival of mice challenged with CLP [8].…”