ABSTRACT
OBJECTIVE: We sought to evaluate the entire picture of all monocyte chemotactic factors that potentially contribute to adipose tissue macrophage accumulation in obesity. RESEARCH DESIGN AND METHODS: Expression and regulation of members in the entire chemokine superfamily were evaluated in adipose tissue and isolated adipocytes of obese versus lean mice. Kinetics of adipose tissue macrophage infiltration was characterized by fluorescence-activated cell sorting. The effects of fatty acids on stimulation of chemokine expression in adipocytes and underlying mechanisms were investigated. RESULTS: Six monocyte chemotactic factors were found to be predominantly upregulated in isolated adipocytes versus stromal vascular cells in obese mice for the first time, although most of them were previously reported to be upregulated in whole adipose tissue. In diet-induced obese mice, adipose tissue enlargement, increase of adipocyte number, and elevation of multiple chemokine expression precede the initiation of macrophage infiltration. Free fatty acids (FFAs) are found to be inducers for upregulating these chemokines in 3T3-L1 adipocytes, and this effect can be partially blunted by reducing Toll-like receptor 4 expression. FFAs induce expression of monocyte chemotactic factors in adipocytes via both transcription-dependent and -independent mechanisms. In contrast to the reported role of JNK as the exclusive mediator of FFA-induced monocyte chemoattractant protein-1 (MCP-1) expression in macrophages, we show a novel role of inhibitor of kappaB kinase-beta (IKKbeta) in mediating FFA-induced upregulation of all six chemokines and a role of JNK in FFA-induced upregulation of MCP-1 and MCP-3. CONCLUSIONS: Multiple chemokines derived from adipocytes might contribute to obesity-related WAT macrophage infiltration with FFAs as potential triggers and involvement of both IKKbeta and JNK pathways.
Subject(s)
Adaptor Proteins, Signal Transducing/genetics , Adipocytes/metabolism , Monocyte Chemoattractant Proteins/genetics , NF-kappa B/genetics , Obesity/physiopathology , 3T3-L1 Cells , Adipocytes/cytology , Adipocytes/drug effects , Animals , Cells, Cultured , Chemokines/genetics , Fatty Acids, Nonesterified/pharmacology , Gene Expression/drug effects , Gene Expression Profiling , Male , Mice , Mice, Obese , Obesity/metabolism , Reverse Transcriptase Polymerase Chain Reaction , Signal Transduction/drug effects , Signal Transduction/genetics , Signal Transduction/physiologyABSTRACT
BACKGROUND: While the optimal role of spiral CT angiography (CTA) in the diagnosis of pulmonary embolism (PE) remains controversial, this technology is already being widely utilized in the community setting. OBJECTIVES: To assess the impact CTA has had on angiography utilization rates and the overall diagnostic rate of PE. METHODS: All patients evaluated for PE during a 4-year period were studied. PE was defined as either a high-probability V/Q scan, a positive conventional angiogram, or a CTA with emboli in the segmental or larger pulmonary vessels. Diagnostic rates of PE per 1,000 hospital admissions were determined and analyzed for time periods before and after the introduction of CTA. CT reports were compared with their concurrent chest radiograph (CXR) reports and additional findings that were not apparent on CXR were abstracted. RESULTS: The diagnostic rate of PE per 1,000 hospital admissions was 1.8 prior to the introduction of CTA and increased to 2.8 per 1,000 admissions after the introduction of CTA (p < 0.0001). Total costs for diagnostic testing per PE diagnosis made went from US 2,518 dollars to US 2,572 dollars. While the number of PE diagnosed by V/Q scan remained constant, the number of PE diagnosed by conventional angiography decreased while the number diagnosed by CTA increased. In patients with intermediate probability V/Q scan results, the percentage of patients receiving subsequent angiography (conventional or CTA) increased from 17 to 26% (p = 0.043). When conventional angiography was performed, CT imaging of the chest still had to be ordered for other reasons 38% of the time. Additional information was obtained in 78% of cases when CTA was performed. CONCLUSIONS: Increased utilization of CTA was associated with an increase in angiography utilization rates and diagnostic rates of PE, was cost effective, and often provided additional, useful, and unanticipated diagnostic information.
