ABSTRACT
Aberrant high-density lipoprotein (HDL) function is implicated in inflammation-associated pathologies. While HDL ABCA1-mediated reverse cholesterol and phospholipid transport are well described, the movement of pro-/anti-inflammatory lipids has not been explored. HDL phospholipids are the largest reservoir of circulating arachidonic acid-derived oxylipins. Endotoxin-stimulation activates inflammatory cells leading to hydroxyeicosatetraenoic acid (HETE) production, oxylipins which are involved in inflammatory response coordination. Active signaling in the non-esterified (NE) pool is terminated by sequestration of HETEs as esterified (Es) forms and degradation. We speculate that an ABCA1-apoA-I-dependent efflux of HETEs from stimulated cells could regulate intracellular HETE availability. Here we test this hypothesis both in vitro and in vivo. In endotoxin-stimulated RAW-264.7 macrophages preloaded with d8-arachidonic acid we use compartmental tracer modeling to characterize the formation of HETEs, and their efflux into HDL. We found that in response to endotoxin: I) Cellular NE 12-HETE is positively associated with MCP-1 secretion (p<0.001); II) HETE transfer from NE to Es pools is ABCA1-depedent (p<0.001); III) Cellular Es HETEs are transported into media when both apoA-I and ABCA1 are present (p<0.001); IV) The stimulated efflux of HETEs >> arachidonate (p<0.001). Finally, in endotoxin challenged humans (n=17), we demonstrate that intravenous lipopolysaccharide (0.6 ng/kg body weight) resulted in accumulation of 12-HETE in HDL over a 168-hour follow-up. Therefore, HDL can suppress inflammatory responses in macrophages by regulating intracellular HETE content in an apoA-I/ABCA1 dependent manner. The described mechanism may apply to other oxylipins and explain anti-inflammatory properties of HDL. This newly defined HDL property opens new doors for the study of lipoprotein interactions in metabolic diseases.
ABSTRACT
OBJECTIVE: The aim of this study was to evaluate the outcomes of implementing a sepsis screening (SS) tool based on the quick Sequential [Sepsis-Related] Organ Failure Assessment (qSOFA) and the presence of confirmed/suspected infection. The implementation of the 6-h bundle was also evaluated. DESIGN: Interrupted times series with prospective data collection. SETTING: Five hospital wards in a developing nation, Argentina. PARTICIPANTS: A total of 1151 patients (≥18 years) recruited within 24-48 h of hospital admission. INTERVENTION: The qSOFA-based SS tool and the 6-h bundle. MAIN OUTCOME MEASURES: The primary outcome was the timing of implementation of the first 6-h bundle element. Secondary outcomes were related to the adherence to the screening procedures. RESULTS: Of 1151 patients, 145 (12.6%) met the qSOFA-based SS tool criteria, among them intervention (39/64) patients received the first 6-h bundle element earlier (median 8 h; 95% confidence interval (CI): 0.1-16) than baseline (48/81) patients (median 22 h; 95% CI: 3-41); these times, however, did not differ significantly (P = 0.525). Overall, 47 (4.1%) patients had sepsis; intervention patients (18/25) received the first 6-h bundle element sooner (median 5 h; 95% CI: 4-6) than baseline patients (15/22) did (median 12 h; 95% CI: 0-33); however, times were not significantly different (P = 0.470). While intervention patients were screened regularly, only one-third of patients who required sepsis alerts had them activated. CONCLUSION: The implementation of the qSOFA-based SS tool resulted in early, but not significantly improved, provision of 6-h bundle care. Screening procedures were regularly conducted, but sepsis alerts rarely activated. Further research is needed to better understand the implementation of sepsis care in developing settings.