Bacterial lipopolysaccharide (LPS) induces monocytes/macrophages to express proinflammatory cytokines and tissue factor (TF), the primary activator of the coagulation cascade. Anti-inflammatory signaling pathways including the phosphatidylinositol-3-kinase (PI3K)-Akt pathway inhibit proinflammatory and TF gene expression in macrophages. We determined the role of Akt, the mammalian target of rapamycin (mTOR) and interleukin-10 in the inhibition of LPS-induced proinflammatory cytokine and TF gene expression in peritoneal macrophages (PMs). We used wild type (WT) peritoneal macrophages (PMs), and PMs from PTENflox/flox/LysMCre mice (PTEN−/− PMs), which have increased Akt activity. Pharmacologic inhibition of mTOR with rapamycin inhibited LPS induction of IL-10 mRNA and protein, and enhanced the expression of TF and the proinflammatory cytokine TNFα in WT PMs. Furthermore, neutralizing IL-10 with anti-IL-10 antibody enhanced LPS induction of TNFα and TF expression in WT PMs. The addition of recombinant IL-10 abolished rapamycin enhancement of LPS-induced TNFα and TF expression in WT PMs. Consistent with enhanced Akt activation, LPS-induced IL-10 expression was increased in PTEN−/− PMs compared to WT PMs. In contrast, LPS-induced TNFα and TF expression was significantly reduced in PTEN−/− PMs compared to WT PMs. However, the neutralizing IL-10 antibody did not completely prevent inhibition of LPS-induced TNFα and TF expression in PTEN−/− PMs. The results indicate that mTOR-dependent IL-10 expression leads to inhibition of LPS induction of TF and the proinflammatory cytokine TNFα in WT macrophages. In contrast, the decrease in LPS-induced TNFα and TF expression in PTEN−/− PMs also requires an IL-10-independent pathway.

Bile duct epithelial cells (BDECs) contribute to liver fibrosis by expressing ␣V␤6 integrin, a critical activator of latent transforming growth factor ␤ (TGF-␤). ␤6 integrin (Itg␤6) mRNA induction and ␣V␤6 integrin expression in BDECs are partially TGF-␤-dependent. However, the signaling pathways required for TGF-␤-dependent Itg␤6 mRNA induction in BDECs are not known. We tested the hypothesis that the p38 mitogen-activated protein kinase (MAPK) signaling pathway contributes to TGF-␤1 induction of Itg␤6 mRNA by activating SMAD and activator protein 1 (AP-1) transcription factors. Pretreatment of transformed human BDECs (MMNK-1 cells) with two different p38 MAPK inhibitors, but not a control compound, inhibited TGF-␤1 induction of Itg␤6 mRNA. Inhibition of p38 also reduced TGF-␤1 activation of a SMAD-dependent reporter construct. Expression of a dominant-negative SMAD3 (SMAD3⌬C) significantly reduced TGF-␤1-induced Itg␤6 mRNA expression. Expression of JunB mRNA, but not other AP-1 proteins, increased in TGF-␤1-treated MMNK-1 cells, and induction of JunB expression was p38-dependent. Consistent with a requirement for de novo induction of JunB protein, cycloheximide pretreatment inhibited TGF-␤1 induction of Itg␤6 mRNA. Expression of a dominant-negative AP-1 mutant (TAM67) also inhibited TGF-␤1 induction of Itg␤6 mRNA. Overall, the results suggest that p38 contributes to TGF-␤1-induced Itg␤6 mRNA expression in MMNK-1 cells by regulating activation of both SMAD and AP-1 transcription factors.

Objectives: To determine the frequency of respiratory complications in children admitted to the ICU after adenotonsillectomy and to identify factors associated with the risk of respiratory complications in this cohort. Design: Retrospective observational study. Setting: PICU. Patient Population: All children admitted to the ICU following adenotonsillectomy from September 30, 2009, to March 30, 2014. Measurements and Main Results: Of the 165 children included in the study, 150 (91%) received no respiratory support other than oxygen in the first 2 hours postoperatively. Of the 15 who required support following 2 hours, 14 required nasopharyngeal airways, one required invasive mechanical ventilation, and seven required supplemental oxygen for more than 2 hours. None of the children who received respiratory support for less than 2 hours required subsequent ICU level care. When comparing those who received support for more than 2 hours to those who did not, there were no differences in clinical characteristics except that those who received support were more likely to have chronic neurologic disease including autism, seizures, or cerebral palsy (odds ratio, 3.7; 95% CI, 1.1–11.9; p = 0.04). Intraoperative events were not predictive of need for respiratory support. Most of the children (n = 117/165 or 71%) had sleep studies preoperatively. Abnormal sleep studies (apnea-hypopnea index > 20 [n = 68] or oxygen saturation nadir < 80% [n = 48]) were not associated with need for postoperative respiratory support. Conclusions: Most children admitted to the ICU following adenotonsillectomy in this population required no support after 2 hours. Preoperative factors such as obesity and abnormal sleep studies were not predictive of need for postoperative respiratory support. Need for respiratory support at 2 hours may be a useful criterion for need for ICU level care in this population.

Noninvasive ventilation (NIV) is a common modality employed to treat acute respiratory failure. Most data guiding its use is extrapolated from adult studies. We sought to identify clinical predictors associated with failure of NIV, defined as requiring intubation. This single-center retrospective observational study included children admitted to pediatric intensive care unit (PICU) between July 2014 and June 2016 treated with NIV, excluding postextubation. A total of 148 patients was included. Twenty-seven (18%) failed NIV. There was no difference between the two groups with regard to age, gender, comorbidities, or etiology of acute respiratory failure. Those that failed had higher admission pediatric risk of mortality (p = 0.01) and pediatric logistic organ dysfunction (p = 0.002) scores and higher fraction of inspired oxygen (FiO2; p = 0.009) at NIV initiation. Failure was associated with lack of improvement in tachypnea. At 6 hours of NIV, the failure group had worsening tachypnea with a median increase in respiratory rate of 8%, while the success group had a median reduction of 18% (p = 0.06). Multivariable Cox's proportional hazard models revealed FiO2 at initiation and worsening respiratory rate at 1- and 6-hour significant risks for failure of NIV. Failure was associated with a significantly longer PICU length of stay (success [2.8 days interquartile range (IQR): 1.7, 5.5] vs. failure [10.6 days IQR: 5.6, 13.2], p < 0.001). NIV can be successfully employed to treat acute respiratory failure in pediatric patients. There should be heightened concern for NIV failure in hypoxemic patients whose tachypnea is unresponsive to NIV. A trend toward improvement should be closely monitored.