Neutrophils play a critical role in acute and chronic inflammatory processes, including myocardial ischemia/reperfusion injury, sepsis, and adult respiratory distress syndrome. Binding of formyl peptide receptor 1 (FPR1) by N-formyl peptides can activate neutrophils and may represent a new therapeutic target in either sterile or septic inflammation. Propofol, a widely used i.v. anesthetic, has been shown to modulate immunoinflammatory responses. However, the mechanism of propofol remains to be established. In this study, we showed that propofol significantly reduced superoxide generation, elastase release, and chemotaxis in human neutrophils activated by fMLF. Propofol did not alter superoxide generation or elastase release in a cell-free system. Neither inhibitors of γ-aminobutyric acid receptors nor an inhibitor of protein kinase A reversed the inhibitory effects of propofol. In addition, propofol showed less inhibitory effects in non-FPR1–induced cell responses. The signaling pathways downstream from FPR1, involving calcium, AKT, and ERK1/2, were also competitively inhibited by propofol. These results show that propofol selectively and competitively inhibits the FPR1-induced human neutrophil activation. Consistent with the hypothesis, propofol inhibited the binding of N-formyl-Nle-Leu-Phe-Nle-Tyr-Lys-fluorescein, a fluorescent analog of fMLF, to FPR1 in human neutrophils, differentiated THP-1 cells, and FPR1-transfected human embryonic kidney-293 cells. To our knowledge, our results identify, for the first time, a novel anti-inflammatory mechanism of propofol by competitively blocking FPR1 in human neutrophils. Considering the importance of N-formyl peptides in inflammatory processes, our data indicate that propofol may have therapeutic potential to attenuate neutrophil-mediated inflammatory diseases by blocking FPR1.

Research from JAMA Surgery — Maneuvers to Decrease Laparoscopy-Induced Shoulder and Upper Abdominal Pain — A Randomized Controlled Study

We sought to determine the minimum effective dose of dexamethasone in preventing postoperative nausea and vomiting in women undergoing thyroidectomy. Two hundred twenty-five women (n = 45 in each of five groups) undergoing thyroidectomy under general anesthesia were enrolled in this randomized, double-blinded, placebo-controlled study. Immediately after the induction of anesthesia, patients received IV dexamethasone at doses of 10 mg (D10), 5 mg (D5), 2.5 mg (D2.5), 1.25 mg (D1.25), or saline (S). We found that Groups D10 and D5 were significantly different from Group S in the total incidences of nausea and vomiting, more than four vomiting episodes, the proportions of patients requiring rescue antiemetics, and the incidences of complete responses. The differences between Groups D10 and D5 were not significant. Dexamethasone 2.5 mg reduced the total incidence of nausea and vomiting. Dexamethasone 1.25 mg was not effective. Dexamethasone 5 mg IV is the minimum effective dose in preventing postoperative nausea and vomiting in women undergoing thyroidectomy. We evaluated four doses of IV dexamethasone in preventing postoperative nausea and vomiting in women undergoing thyroidectomy. We found that dexamethasone 5 mg was as effective as dexamethasone 10 mg, and was more effective than saline control. Dexamethasone 5 mg is suggested to be the minimum effective dose for this purpose.

Dexamethasone is an effective antiemetic drug, but its mechanism of action is unclear. We designed this study to investigate the direct antiemetic action of dexamethasone in the medulla of cats. By using an oscillographic vomiting model, decerebrated cats received microinjections of dexamethasone 100 nL (1 microg, n = 7; 0.1 microg, n = 7) into the bilateral nuclei tractus solitarii, which led to a significant prolongation of the latency (1 microg, 6.4 +/- 1.1 min versus 28.2 +/- 4.9 min, P < 0.05; 0.1 microg, 6.7 +/- 1.1 min versus 27.1 +/- 5.0 min, P < 0.05) of the first emetic episode and significantly decreased the frequency of emetic episodes (1 microg, 2.7 +/- 0.8 versus 0.1 +/- 0.4, P < 0.05; 0.1 microg, 2.9 +/- 0.9 versus 0.3 +/- 0.5, P < 0.05) induced by xylazine. Pretreatment with mifepristone, a glucocorticoid receptor antagonist, blocked the antiemetic effect of dexamethasone in the bilateral nuclei tractus solitarii. However, microinjection of dexamethasone into the unilateral nucleus tractus solitarius alone did not alter the latency of the first emetic episode or the frequency of emetic episodes induced by xylazine. Local application of dexamethasone into the area postrema had no effect on the latency of the first emetic episode or the frequency of emetic episodes induced by xylazine. These results suggest that dexamethasone exerts its central antiemetic action through an activation of the glucocorticoid receptors in the bilateral nuclei tractus solitarii in the medulla.