Classical activation of M1 macrophages with lipopolysaccharide (LPS) is associated with a metabolic switch from oxidative phosphorylation to glycolysis. However, the generalizability of such metabolic remodeling to other modes of M1 macrophage stimulation, e.g. type II interferons (IFNs) such as IFNγ, has remained unknown as has the functional significance of aerobic glycolysis during macrophage activation. Here we demonstrate that IFNγ induces a rapid activation of aerobic glycolysis followed by a reduction in oxidative phosphorylation in M1 macrophages. Elevated glycolytic flux sustains cell viability and inflammatory activity, while limiting reliance on mitochondrial oxidative metabolism. Adenosine triphosphate (ATP) distributed by aerobic glycolysis is critical for sustaining IFN-γ triggered JAK (Janus tyrosine kinase)-STAT-1 (Signal Transducer and Activator of Transcription 1) signaling with phosphorylation of the transcription factor STAT-1 as its signature trait. Inhibition of aerobic glycolysis not only blocks the M1 phenotype and pro-inflammatory cytokine/chemokine production in murine macrophages and also human monocytes/macrophages. These findings extend on the potential functional role of immuno-metabolism from LPS- to IFNγ-linked diseases such as atherosclerosis and autoimmune disease.

Introduction: Although nonthyroidal illness syndrome is considered to be associated with adverse outcome in ICU patients, the performance of thyroid hormone levels in predicting clinical outcome in ICU patients is unimpressive. This study was conducted to assess the prognostic value of the complete thyroid indicators (free triiodothyronine (FT3), total triiodothyronine; free thyroxine, total thyroxine, thyroid-stimulating hormone and reverse triiodothyronine) in unselected ICU patients. Methods: A total of 480 consecutive patients without known thyroid diseases were screened for eligibility and followed up during their ICU stay. We collected each patient's baseline characteristics, including the Acute Physiology and Chronic Health Evaluation II (APACHE II) score and thyroid hormone, N-terminal pro-brain natriuretic peptide (NT-proBNP) and C-reactive protein (CRP) levels. The primary outcome was ICU mortality. Potential predictors were analyzed for possible association with outcomes. We also evaluated the ability of thyroid hormones together with APACHE II score to predict ICU mortality by calculation of net reclassification improvement (NRI) and integrated discrimination improvement (IDI) indices. Results: Among the thyroid hormone indicators, FT3 had the greatest power to predict ICU mortality, as suggested by the largest area under the curve (AUC) of 0.762 ± 0.028. The AUC for FT3 level was less than that for APACHE II score (0.829 ± 0.022) but greater than that for NT-proBNP level (0.724 ± 0.030) or CRP level (0.689 ± 0.030). Multiple regression analysis revealed that FT3 level (standardized β = -0.600, P = 0.001), APACHE II score (standardized β = 0.912, P < 0.001), NT-proBNP level (standardized β = 0.459, P = 0.017) and CRP level (standardized β = 0.367, P = 0.030) could independently predict primary outcome. The addition of FT3 level to APACHE II score gave an NRI of 54.29% (P < 0.001) and an IDI of 36.54% (P < 0.001). The level of FT3 was significantly correlated with NT-proBNP levels (r = -0.344, P < 0.001) and CRP levels (r = -0.408, P < 0.001). Conclusion: In unselected ICU patients, FT3 was the most powerful and only independent predictor of ICU mortality among the complete indicators. The addition of FT3 level to the APACHE II score could significantly improve the ability to predict ICU mortality.

Background. The red cell distribution width (RDW) in ICU patients has never been investigated. Methods. A total of 602 consecutive patients were prospectively enrolled. We collected each patient's base-line characteristics including the Acute Physiology and Chronic Health Evaluation II (APACHE-II) score, RDW, and C-reactive protein (CRP). The primary outcome for this analysis was ICU mortality, and secondary outcome was the total length of stay in hospital (TLSH). Potential predictors were analyzed for possible association with outcomes. Results. There was a significantly graded increase in APACHE-II score (tertile I = 10.7 ± 6.5 versus tertile II = 13.3 ± 6.2 versus tertile III = 15.8 ± 7.2; all P < 0.001) and ICU mortality rate (tertile I = 11.2% versus tertile II = 18.8% versus tertile III = 33.8%; all P < 0.001) across increasing of RDW tertile. As compared with APACHE-II score, combination of RDW and APACHE-II score increased the area under the curve (AUC) for predicting ICU mortality from 0.832 ± 0.020 to 0.885 ± 0.017 (P < 0.05). Multivariate analysis demonstrated that RDW, APACHE-II score, and CRP were independent predictors of ICU mortality (P < 0.05). RDW was also independently associated with TLSH in patients alive (P < 0.05). Conclusion. We found a graded independent relation between higher RDW and adverse outcomes in ICU patients. RDW has the potentially clinical utility to predict outcome in ICU patients.