The tumor suppressor PDCD4 is a proinflammatory protein that promotes activation of the transcription factor NF-kappaB and suppresses interleukin 10 (IL-10). Here we found that mice deficient in PDCD4 were protected from lipopolysaccharide (LPS)-induced death. The induction of NF-kappaB and IL-6 by LPS required PDCD4, whereas LPS enhanced IL-10 induction in cells lacking PDCD4. Treatment of human peripheral blood mononuclear cells with LPS resulted in lower PDCD4 expression, which was due to induction of the microRNA miR-21 via the adaptor MyD88 and NF-kappaB. Transfection of cells with a miR-21 precursor blocked NF-kappaB activity and promoted IL-10 production in response to LPS, whereas transfection with antisense oligonucleotides to miR-21 or targeted protection of the miR-21 site in Pdcd4 mRNA had the opposite effect. Thus, miR-21 regulates PDCD4 expression after LPS stimulation.
ritical illness can lead to hypermetabolism and subsequent malnutrition. 1,2 Malnutrition is strongly associated with increased morbidity and mortality rates among seriously ill patients. 3,4 Thus, standards of care for patients with critical illness include nutritional support. Recent reviews suggest that enteral nutrition (EN) is associated with lower septic morbidity rates and that parenteral nutrition (PN) may be associated with increased rates of complications and death. 5-7 Immune-enhancing diets may be beneficial for elective surgical patients but have no benefit and may harm the critically ill patient. 6 If EN is preferable, starting sooner may be better. Data from the few animal and clinical studies on this topic support this hypothesis. 7 However, recent observational studies have documented low rates of "optimal" use of EN in the critical care setting. 8-10 EN is often started several days after admission, patients do not tolerate adequate amounts of EN, and PN is used excessively in some patients (up to 60% in some countries). 8-10 Using an audit of intensive care units (ICUs) in community and teaching hospitals, our Critical Care Research Network (CCR-Net) also documented delays in the institution of nutritional support that included both enteral and parenteral routes. 11 Several studies have shown that using nurse-directed feeding protocols or algorithms increases the amount of EN delivered daily 12,13 and that enhancing delivery may improve outcomes in some patients. 14 Protocols may improve this process. We report a prospective, cluster-randomized clinical trial in the ICUs of community and teaching hospitals that tested the hypothesis that an evidence-based algorithm for nutritional support in critically ill patients, accompanied by a multifaceted implementation strategy, would improve the provision of nutritional support and patient outcomes. Methods The study consisted of a run-in phase followed by cluster randomization of hospitals to the intervention or control group. Cluster randomization reduces the risk of contamination between groups, but individual patient characteristics can still be evaluated by appropriate analysis. 15 Patient enrolment into both phases of the study occurred from October 1997 to September 1998. Patients were included if they were at least 16 years of age and were expected to stay in the ICU at least 48 hours. Patients were excluded if they were expected to be receiving sufficient nutrition orally to meet their daily energy requirements within 24 hours after ICU admission, were admitted for palliative care, were moribund and not expected to survive for more than 6 hours, or were suspected to be brain dead. The Ethics Review Board at the University of Western Ontario waived the requirement for informed consent on the basis that the intervention was a quality-improvement initiative. The study was conducted in 11 community and 3 teaching hospitals in Ontario. All hospitals that volunteered for the study were Multicentre, cluster-randomized clinical trial of algorithms for...
Preterm birth, the major cause of neonatal mortality in developed countries, is associated with intrauterine infections and inflammation, although the exact mechanisms underlying this event are unclear. In this study, we show that circulating fetal DNA, which is elevated in pregnancies complicated by preterm labor or preeclampsia, triggers an inflammatory reaction that results in spontaneous preterm birth. Fetal DNA activates NF-κB, shown by IκBα degradation in human PBMCs resulting in production of proinflammatory IL-6. We show that fetal resorption and preterm birth are rapidly induced in mice after i.p. injection of CpG or fetal DNA (300 μg/dam) on gestational day 10–14. In contrast, TLR9−/− mice were protected from these effects. Furthermore, this effect was blocked by oral administration of the TLR9 inhibitor chloroquine. Our data therefore provide a novel mechanism for preterm birth and preeclampsia, highlighting TLR9 as a potential therapeutic target for these common disorders of pregnancy.
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