br Acknowledgments This research was supported in

Acknowledgments This research was supported in part by National Institutes of Health IDeA Program COBRE grant GM110732; a USDA National Institute of Food and Agriculture Hatch project; and the Montana State University Agricultural Experiment Station.
Introduction Propofol (2,6-Diisopropylphenol) is a commonly used anesthetic drug that is administered intravenously for the induction and maintenance of anesthesia. The favorable pharmacokinetic characteristics of propofol make it a rapid-onset and short-acting agent. In addition, the anti-inflammatory and antioxidant effects of propofol [1], [2], [3] increase the advantage of its use in clinical practice. Several studies have indicated that propofol can moderate many aspects of inflammatory responses. Propofol suppresses the immune activities of monocytes/macrophages [2], [3], [4], [5], [6], [7] and neutrophils [2], [8], [9], [10], including chemotaxis, extravasation, migration, phagocytosis, and production of reactive oxygen species (ROS). Moreover, propofol attenuates proinflammatory cytokine generation [2], [3], [11], [12] and reduces the biosynthesis of nitric oxide [2], [3], [4], [13], [14], [15] both in vitro and in vivo. The risk of systemic inflammatory response syndrome (SIRS) and infection is higher among critically ill patients who have experienced trauma or cardiac arrest or have undergone surgery. Endogenous damage-associated molecular patterns (DAMPs), which are released in large amounts from damaged AM251 mg or tissues in critically ill patients, activate the innate immune system, and make a contribution to the pathogenesis of septic shock, acute lung injury (ALI), and multi-organ failure. Moreover, once the immune system cannot restrain an invading pathogen sufficiently, the overwhelming inflammatory responses may further deteriorate the immune system's antimicrobial function, engendering a vicious cycle. Recently published protocols for managing critically ill patients proposed that continuous or intermittent sedation should be minimized [16]. However, treating some critically ill patients, such as those who suffer from hypersensitive airway or increased intracranial pressure, requires the use of sedatives for providing bronchodilation [17], [18] and neuroprotective effects [19], [20] as well as minimizing stress responses. Moreover, anesthesia is an essential measure for inducing unconsciousness and analgesia in critically ill patients who required surgery. In summary, sedative agents should be selected cautiously for anesthetizing patients who are severely ill and at high risk of secondary infection and sepsis. The antioxidant and anti-inflammatory properties of propofol may benefit critically ill patients with SIRS. Our previous study demonstrated that propofol is a competitive inhibitor of formyl methionyl-leucyl phenylalamine (fMLF) that functions by blocking formyl peptide receptor 1 (FPR1) [8]. In this study, we hypothesized that propofol has a therapeutic effect through competitive inhibition of human neutrophil activation induced by an endogenous N-formylated peptides. Mitochondria-derived N-formylated peptides are quickly released following tissue or cell damage [21], [22], [23]. These N-formylated peptides are strong chemoattractants and can initiate and aggravate inflammation, resulting in SIRS; thus, they can be considered as DAMPs. We executed the current study with the aim of ascertaining whether propofol inhibits fMMYALF, a human mitochondria-derived N-formylated peptide [21], [23], induced neutrophil activities, including respiratory burst, degranulation, and chemotaxis. Additionally, the pharmacological effects of fMMYALF were analyzed to evaluate whether the inhibitory effects of propofol are attributable to blocking of the interaction between fMMYALF and its receptor, FPR1, which interrupts receptor-mediated downstream signaling. Sepsis is the most common cause of ALI [24], which results in increased lung permeability, enhanced neutrophil recruitment, respiratory failure, and mortality. We further investigated the protective effects of propofol in a murine model of ALI induced by endotoxin.