Blocking airway mucous cell metaplasia by inhibiting EGFR antiapoptosis and IL-13 transdifferentiation signals

Epithelial hyperplasia and metaplasia are common features of inflammatory and neoplastic disease, but the basis for the altered epithelial phenotype is often uncertain. Here we show that long-term ciliated cell hyperplasia coincides with mucous (goblet) cell metaplasia after respiratory viral clearance in mouse airways. This chronic switch in epithelial behavior exhibits genetic susceptibility and depends on persistent activation of EGFR signaling to PI3K that prevents apoptosis of ciliated cells and on IL-13 signaling that promotes transdifferentiation of ciliated to goblet cells. Thus, EGFR blockade (using an irreversible EGFR kinase inhibitor designated EKB-569) prevents virus-induced increases in ciliated and goblet cells whereas IL-13 blockade (using s-IL-13Rα2-Fc) exacerbates ciliated cell hyperplasia but still inhibits goblet cell metaplasia. The distinct effects of EGFR and IL-13 inhibitors after viral reprogramming suggest that these combined therapeutic strategies may also correct epithelial architecture in the setting of airway inflammatory disorders characterized by a similar pattern of chronic EGFR activation, IL-13 expression, and ciliated-to-goblet cell metaplasia

[18F]FDG Uptake in Adipose Tissue Is Not Related to Inflammation in Type 2 Diabetes Mellitus

PURPOSE: 2-deoxy-2-[18F]fluoro-D-glucose ([18F]FDG) uptake is a marker of metabolic activity and is therefore used to measure the inflammatory state of several tissues. This radionuclide marker is transported through the cell membrane via glucose transport proteins (GLUTs). The aim of this study is to investigate whether insulin resistance (IR) or inflammation plays a role in [18F]FDG uptake in adipose tissue (AT). PROCEDURES: This study consisted of an in vivo clinical part and an ex vivo mechanistic part. In the clinical part, [18F]FDG uptake in abdominal visceral AT (VAT) and subcutaneous AT (SAT) was determined using PET/CT imaging in 44 patients with early type 2 diabetes mellitus (T2DM) (age 63 [54-66] years, HbA1c [6.3 ± 0.4 %], HOMA-IR 5.1[3.1-8.5]). Plasma levels were measured with ELISA. In the mechanistic part, AT biopsies obtained from 8 patients were ex vivo incubated with [18F]FDG followed by autoradiography. Next, a qRT-PCR analysis was performed to determine GLUT and cytokine mRNA expression levels. Immunohistochemistry was performed to determine CD68+ macrophage infiltration and GLUT4 protein expression in AT. RESULTS: In vivo VAT [18F]FDG uptake in patients with T2DM was inversely correlated with HOMA-IR (r = - 0.32, p = 0.034), and positively related to adiponectin plasma levels (r = 0.43, p = 0.003). Ex vivo [18F]FDG uptake in VAT was not related to CD68+ macrophage infiltration, and IL-1ß and IL-6 mRNA expression levels. Ex vivo VAT [18F]FDG uptake was positively related to GLUT4 (r = 0.83, p = 0.042), inversely to GLUT3 (r = - 0.83, p = 0.042) and not related to GLUT1 mRNA expression levels. CONCLUSIONS: In vivo [18F]FDG uptake in VAT from patients with T2DM is positively correlated with adiponectin levels and inversely with IR. Ex vivo [18F]FDG uptake in AT is associated with GLUT4 expression but not with pro-inflammatory markers. The effect of IR should be taken into account when interpreting data of [18F]FDG uptake as a marker for AT inflammation

Performance Evaluation of a Semi-automated Method for [F-18]FDG Uptake in Abdominal Visceral Adipose Tissue

PurposeSeverity of abdominal obesity and possibly levels of metabolic activity of abdominal visceral adipose tissue (VAT) are associated with an increased risk for cardiovascular disease (CVD). In this context, the purpose of the current study was to evaluate the reproducibility and repeatability of a semi-automated method for assessment of the metabolic activity of VAT using 2-deoxy-2-[F-18]fluoro-D-glucose ([F-18]FDG) positron emission tomography (PET)/x-ray computed tomography (CT).ProceduresTen patients with lung cancer who underwent two baseline whole-body [F-18]FDG PET/low-dose (LD) CT scans within 1week were included. Abdominal VAT was automatically segmented using CT between levels L1-L5. The initial CT-based segmentation was further optimized using PET data with a standardized uptake value (SUV) threshold approach (range 1.0-2.5) and morphological erosion (range 0-5 pixels). The [F-18]FDG uptake in SUV that was measured by the automated method was compared with manual analysis. The reproducibility and repeatability were quantified using intraclass correlation coefficients (ICCs).ResultsThe metabolic assessment of VAT on [F-18]FDG PET/LDCT scans expressed as SUVmean, using an automated method showed high inter and intra observer (all ICCs >0.99) and overall repeatability (ICC=0.98). The manual method showed reproducible inter observer (all ICCs >0.92), but less intra observer (ICC=0.57) and less overall repeatability (ICC=0.78) compared with the automated method.ConclusionsOur proposed semi-automated method provided reproducible and repeatable quantitative analysis of [F-18]FDG uptake in VAT. We expect this method to aid future research regarding the role of VAT in development of CVD.</div

Performance Evaluation of a Semi-automated Method for [F-18]FDG Uptake in Abdominal Visceral Adipose Tissue

PURPOSE: Severity of abdominal obesity and possibly levels of metabolic activity of abdominal visceral adipose tissue (VAT) are associated with an increased risk for cardiovascular disease (CVD). In this context, the purpose of the current study was to evaluate the reproducibility and repeatability of a semi-automated method for assessment of the metabolic activity of VAT using 2-deoxy-2-[18F]fluoro-D-glucose ([18F]FDG) positron emission tomography (PET)/x-ray computed tomography (CT). PROCEDURES: Ten patients with lung cancer who underwent two baseline whole-body [18F]FDG PET/low-dose (LD) CT scans within 1 week were included. Abdominal VAT was automatically segmented using CT between levels L1-L5. The initial CT-based segmentation was further optimized using PET data with a standardized uptake value (SUV) threshold approach (range 1.0-2.5) and morphological erosion (range 0-5 pixels). The [18F]FDG uptake in SUV that was measured by the automated method was compared with manual analysis. The reproducibility and repeatability were quantified using intraclass correlation coefficients (ICCs). RESULTS: The metabolic assessment of VAT on [18F]FDG PET/LDCT scans expressed as SUVmean, using an automated method showed high inter and intra observer (all ICCs > 0.99) and overall repeatability (ICC = 0.98). The manual method showed reproducible inter observer (all ICCs > 0.92), but less intra observer (ICC = 0.57) and less overall repeatability (ICC = 0.78) compared with the automated method. CONCLUSIONS: Our proposed semi-automated method provided reproducible and repeatable quantitative analysis of [18F]FDG uptake in VAT. We expect this method to aid future research regarding the role of VAT in development of CVD

Visceral adipose tissue volume is associated with premature atherosclerosis in early type 2 diabetes mellitus independent of traditional risk factors

BACKGROUND AND AIMS: Type 2 diabetes mellitus (T2DM) is commonly associated with abdominal obesity, predominantly with high visceral adipose tissue (VAT), and is accompanied by premature atherosclerosis. However, the association between VAT and subcutaneous adipose tissue (SAT) with premature atherosclerosis and (i.e. arterial) inflammation is not completely understood. To provide more insight into this association, we investigated the association between arterial 18F-fluordeoxyglucose (FDG) positron emission tomography (PET) uptake, as a measure of arterial inflammation, and metabolic syndrome (MetS) markers in early T2DM patients. METHODS: Forty-four patients with early T2DM, without glucose lowering medication, were studied (median age 63 [IQR 54-66] years, median BMI 30.4 [IQR 27.5-35.8]). Arterial inflammation was quantified using glucose corrected maximum standardized uptake value (SUVmax) FDG of the aorta, carotid, iliac, and femoral arteries, and corrected for background activity (blood pool) as target-to-background ratio (meanTBR). VAT and SAT volumes (cm3) were automatically segmented using computed tomography (CT) between levels L1-L5. Non-alcoholic fatty liver disease (NAFLD) was assessed by liver function test and CT. RESULTS: VAT volume, but not SAT volume, correlated with meanTBR (r = 0.325, p = 0.031). Linear regression models showed a significant association, even after sequential adjustment for potentially influencing MetS components. Interaction term VAT volume * sex and additional components including HbA1c, insulin resistance, NAFLD, adiponectin, leptin, and C- reactive protein (CRP) did not change the independent association between VAT volume and meanTBR. CONCLUSIONS: CT-assessed VAT volume is positively associated with FDG-PET assessed arterial inflammation, independently of factors thought to potentially mediate these effects. These findings suggest that VAT in contrast to SAT is linked to early atherosclerotic changes in T2DM patients

[18F]FDG Uptake in Adipose Tissue Is Not Related to Inflammation in Type 2 Diabetes Mellitus

Purpose: 2-deoxy-2-[18F]fluoro-d-glucose ([18F]FDG) uptake is a marker of metabolic activity and is therefore used to measure the inflammatory state of several tissues. This radionuclide marker is transported through the cell membrane via glucose transport proteins (GLUTs). The aim of this study is to investigate whether insulin resistance (IR) or inflammation plays a role in [18F]FDG uptake in adipose tissue (AT). Procedures: This study consisted of an in vivo clinical part and an ex vivo mechanistic part. In the clinical part, [18F]FDG uptake in abdominal visceral AT (VAT) and subcutaneous AT (SAT) was determined using PET/CT imaging in 44 patients with early type 2 diabetes mellitus (T2DM) (age 63 [54–66] years, HbA1c [6.3 ± 0.4 %], HOMA-IR 5.1[3.1–8.5]). Plasma levels were measured with ELISA. In the mechanistic part, AT biopsies obtained from 8 patients were ex vivo incubated with [18F]FDG followed by autoradiography. Next, a qRT-PCR analysis was performed to determine GLUT and cytokine mRNA expression levels. Immunohistochemistry was performed to determine CD68+ macrophage infiltration and GLUT4 protein expression in AT. Results: In vivo VAT [18F]FDG uptake in patients with T2DM was inversely correlated with HOMA-IR (r = − 0.32, p = 0.034), and positively related to adiponectin plasma levels (r = 0.43, p = 0.003). Ex vivo [18F]FDG uptake in VAT was not related to CD68+ macrophage infiltration, and IL-1ß and IL-6 mRNA expression levels. Ex vivo VAT [18F]FDG uptake was positively related to GLUT4 (r = 0.83, p = 0.042), inversely to GLUT3 (r = − 0.83, p = 0.042) and not related to GLUT1 mRNA expression levels. Conclusions: In vivo [18F]FDG uptake in VAT from patients with T2DM is positively correlated with adiponectin levels and inversely with IR. Ex vivo [18F]FDG uptake in AT is associated with GLUT4 expression but not with pro-inflammatory markers. The effect of IR should be taken into account when interpreting data of [18F]FDG uptake as a marker for AT inflammation

[F-18]FDG Uptake in Adipose Tissue Is Not Related to Inflammation in Type 2 Diabetes Mellitus

Purpose 2-deoxy-2-[F-18]fluoro-d-glucose ([F-18]FDG) uptake is a marker of metabolic activity and is therefore used to measure the inflammatory state of several tissues. This radionuclide marker is transported through the cell membrane via glucose transport proteins (GLUTs). The aim of this study is to investigate whether insulin resistance (IR) or inflammation plays a role in [F-18]FDG uptake in adipose tissue (AT). Procedures This study consisted of anin vivoclinical part and anex vivomechanistic part. In the clinical part, [F-18]FDG uptake in abdominal visceral AT (VAT) and subcutaneous AT (SAT) was determined using PET/CT imaging in 44 patients with early type 2 diabetes mellitus (T2DM) (age 63 [54-66] years, HbA1c [6.3 +/- 0.4 %], HOMA-IR 5.1[3.1-8.5]). Plasma levels were measured with ELISA. In the mechanistic part, AT biopsies obtained from 8 patients wereex vivoincubated with [F-18]FDG followed by autoradiography. Next, a qRT-PCR analysis was performed to determine GLUT and cytokine mRNA expression levels. Immunohistochemistry was performed to determine CD68(+)macrophage infiltration and GLUT4 protein expression in AT. Results In vivoVAT [F-18]FDG uptake in patients with T2DM was inversely correlated with HOMA-IR (r = - 0.32,p = 0.034), and positively related to adiponectin plasma levels (r = 0.43,p = 0.003).Ex vivo[F-18]FDG uptake in VAT was not related to CD68(+)macrophage infiltration, and IL-1ss and IL-6 mRNA expression levels.Ex vivoVAT [F-18]FDG uptake was positively related to GLUT4 (r = 0.83,p = 0.042), inversely to GLUT3 (r = - 0.83,p = 0.042) and not related to GLUT1 mRNA expression levels. Conclusions In vivo[F-18]FDG uptake in VAT from patients with T2DM is positively correlated with adiponectin levels and inversely with IR.Ex vivo[F-18]FDG uptake in AT is associated with GLUT4 expression but not with pro-inflammatory markers. The effect of IR should be taken into account when interpreting data of [F-18]FDG uptake as a marker for AT inflammation