Anti-Inflammatory Effects and Mechanisms of 2,6-Diisopropylphenol in Activated Human Neutrophils

Neutrophils have long been known to play a major role in acute inflammatory responses, but more recent emerging evidence has extended a role of these cells in chronic inflammatory and autoimmune diseases. Many inflammatory diseases, such as myocardial ischemia/reperfusion injury, sepsis, and chronic obstructive pulmonary disease, are characterized by neutrophil-dominated inflammation. In response to specific stimuli, neutrophils secrete a myriad of proinflammatory mediators and proteolytic enzymes which can damage surrounding tissues. One of the most studied chemoattractants is formyl-L-methionyl-L-leucyl-L-phenylalanine (FMLP), which is a prototype for microbe-derived formylated peptides. Recent studies indicate that formylated peptides are released by damaged mitochondria. Thus, formylated peptides can also be considered as endogenous alarmins. The responses for human neutrophils recognition of N-formyl peptides are their binding to formyl peptide receptors (FPRs), FPR1 and FPR2. FPR1 is a high-affinity receptor for FMLP. Therefore, concerns have been raised about the potential of functional FPR1 as a therapeutic target for the development of new drugs to treat inflammatory diseases. 2,6-Diisopropylphenol (propofol) is a widely used intravenous non-opioid anesthetic, and it is mainly administered for the sedation of surgical or critical ill patients. There is growing evidence that propofol exerts protective effects during inflammatory processes. Despite many years of intensive studies on propofol, outstanding questions remain. Propofol can diminish the oxidative or inflammatory injury induced by neutrophils. For example, in clinical studies, propofol attenuates myocardial reperfusion injury and pulmonary dysfunction following cardiopulmonary bypass by reducing free radical release and modulating the neutrophilic inflammatory process. Conversely, studies showed that propofol increases neutrophil respiratory burst in the bronchoalveolar lavage fluid from patients undergoing tympanoplasty surgery, and it fails to affect neutrophil oxidative response in patients undergoing cataract surgery. Clearly, more in‐depth studies on the regulatory functions and action mechanism of propofol in activated human neutrophils are needed. In the preliminary results, we showed that propofol, at its clinical concentrations, reduced superoxide generation and elastase release in human neutrophils activated by FMLP. Propofol has been shown to display direct scavenging activity for free radical species. However, direct scavenging activity was rule out because propofol failed to alter the superoxide generation in a cell-free system. Interestingly, propofol showed less inhibitory effects in non-FPR1 induced cell responses. Significantly, propofol inhibited the binding of N-formyl-Nle-Leu-Phe-Nle-Tyr-Lys-fluorescein, a fluorescent analogue of FMLP, to FPR1. Based on these preliminary findings, we hypothesize that propofol has a novel anti-inflammatory mechanism by competitively blocking FPR1 in human neutrophils. To the best of our knowledge, this project will be the first study to show that propofol is a FPR1 inhibitor. Therefore, in this three-year project, the detailed effects and mechanisms of propofol in activated human neutrophils and neutrophil-like cells will be further investigated. The outcome of this proposal will not only provide the cellular effects of propofol modulating the inflammatory activities in human neutrophils but also determine the action mechanisms. Considering the importance of N-formylated peptides in inflammatory processes, this project will also suggest that propofol may have therapeutic potential benefits to attenuate FPR1-mediated inflammatory diseases.

Project ID:PC10301-0142
External Project ID:NSC102-2628-B255-003-MY3