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Winkler, Tilo

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Winkler

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Tilo

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Winkler, Tilo
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    Effects of ventilation strategy on distribution of lung inflammatory cell activity
    (BioMed Central, 2013) de Prost, Nicolas; Costa, Eduardo L; Wellman, Tyler; Musch, Guido; Tucci, Mauro R; Winkler, Tilo; Harris, R Scott; Venegas, Jose; Kavanagh, Brian P; Vidal Melo, Marcos
    Introduction: Leukocyte infiltration is central to the development of acute lung injury, but it is not known how mechanical ventilation strategy alters the distribution or activation of inflammatory cells. We explored how protective (vs. injurious) ventilation alters the magnitude and distribution of lung leukocyte activation following systemic endotoxin administration. Methods: Anesthetized sheep received intravenous endotoxin (10 ng/kg/min) followed by 2 h of either injurious or protective mechanical ventilation (n = 6 per group). We used positron emission tomography to obtain images of regional perfusion and shunting with infused 13N[nitrogen]-saline and images of neutrophilic inflammation with 18F-fluorodeoxyglucose (18F-FDG). The Sokoloff model was used to quantify 18F-FDG uptake (Ki), as well as its components: the phosphorylation rate (k3, a surrogate of hexokinase activity) and the distribution volume of 18F-FDG (Fe) as a fraction of lung volume (Ki = Fe × k3). Regional gas fractions (fgas) were assessed by examining transmission scans. Results: Before endotoxin administration, protective (vs. injurious) ventilation was associated with a higher ratio of partial pressure of oxygen in arterial blood to fraction of inspired oxygen (PaO2/FiO2) (351 ± 117 vs. 255 ± 74 mmHg; P < 0.01) and higher whole-lung fgas (0.71 ± 0.12 vs. 0.48 ± 0.08; P = 0.004), as well as, in dependent regions, lower shunt fractions. Following 2 h of endotoxemia, PaO2/FiO2 ratios decreased in both groups, but more so with injurious ventilation, which also increased the shunt fraction in dependent lung. Protective ventilation resulted in less nonaerated lung (20-fold; P < 0.01) and more normally aerated lung (14-fold; P < 0.01). Ki was lower during protective (vs. injurious) ventilation, especially in dependent lung regions (0.0075 ± 0.0043/min vs. 0.0157 ± 0.0072/min; P < 0.01). 18F-FDG phosphorylation rate (k3) was twofold higher with injurious ventilation and accounted for most of the between-group difference in Ki. Dependent regions of the protective ventilation group exhibited lower k3 values per neutrophil than those in the injurious ventilation group (P = 0.01). In contrast, Fe was not affected by ventilation strategy (P = 0.52). Lung neutrophil counts were not different between groups, even when regional inflation was accounted for. Conclusions: During systemic endotoxemia, protective ventilation may reduce the magnitude and heterogeneity of pulmonary inflammatory cell metabolic activity in early lung injury and may improve gas exchange through its effects predominantly in dependent lung regions. Such effects are likely related to a reduction in the metabolic activity, but not in the number, of lung-infiltrating neutrophils.
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    Allergic Non-Asthmatic Adults Have Regional Pulmonary Responses to Segmental Allergen Challenge
    (Public Library of Science, 2015) Kelly, Vanessa J.; Winkler, Tilo; Venegas, Jose; Kone, Mamary; Hamilos, Daniel; Afshar, Roshi; Cho, Josalyn; Luster, Andrew; Medoff, Benjamin; Harris, R. Scott
    Background: Allergic non-asthmatic (ANA) adults experience upper airway symptoms of allergic disease such as rhinorrhea, congestion and sneezing without symptoms of asthma. The aim of this study was to utilize PET-CT functional imaging to determine whether allergen challenge elicits a pulmonary response in ANA subjects or whether their allergic disease is truly isolated to the upper airways. Methods: In 6 ANA subjects, bronchoalveolar lavages (BAL) were performed at baseline and 24h after instillation of an allergen and a diluent in separate lung lobes. After instillation (10h), functional imaging was performed to quantify and compare regional perfusion, ventilation, fractional gas content (Fgas), and glucose uptake rate (Ki) between the baseline, diluent and allergen lobes. BAL cell counts were also compared. Results: In ANA subjects, compared to the baseline and diluent lobes, perfusion and ventilation were significantly lower in the allergen lobe (median [inter-quartile range], baseline vs. diluent vs. allergen: Mean-normalized perfusion; 0.87 [0.85–0.97] vs. 0.90 [0.86–0.98] vs. 0.59 [0.55–0.67]; p<0.05. Mean-normalized ventilation 0.89 [0.88–0.98] vs. 0.95 [0.89–1.02] vs. 0.63 [0.52–0.67], p<0.05). In contrast, no significant differences were found in Fgas between baseline, diluent and allergen lobes or in Ki. Total cell counts, eosinophil and neutrophil cell counts (cells/ml BAL) were significantly greater in the allergen lobe compared to the baseline lobe (all P<0.05). Conclusions: Despite having no clinical symptoms of a lower airway allergic response (cough and wheeze) allergic non-asthmatic subjects have a pulmonary response to allergen exposure which manifests as reduced ventilation and perfusion.
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    Deep Inspiration and the Emergence of Ventilation Defects during Bronchoconstriction: A Computational Study
    (Public Library of Science, 2014) Golnabi, Amir H.; Harris, R. Scott; Venegas, Jose; Winkler, Tilo
    Deep inspirations (DIs) have a dilatory effect on airway smooth muscle (ASM) that helps to prevent or reduce more severe bronchoconstriction in healthy individuals. However, this bronchodilation appears to fail in some asthmatic patients or under certain conditions, and the reason is unclear. Additionally, quantitative effects of the frequency and magnitude of DIs on bronchodilation are not well understood. In the present study, we used a computational model of bronchoconstriction to study the effects of DI volumes, time intervals between intermittent DIs, relative speed of ASM constriction, and ASM activation on bronchoconstriction and the emergence of ventilation defects (VDefs). Our results showed a synergistic effect between the volume of DIs and the time intervals between them on bronchoconstriction and VDefs. There was a domain of conditions with sufficiently large volumes of DIs and short time intervals between them to prevent VDefs. Among conditions without VDefs, larger volumes of DIs resulted in greater airway dilation. Similarly, the time interval between DIs, during which the activated ASM re-constricts, affected the amplitude of periodic changes in airway radii. Both the relative speed of ASM constriction and ASM activation affected what volume of DIs and what time interval between them could prevent the emergence of VDefs. In conclusion, quantitative characteristics of DIs, such as their volume and time interval between them, affect bronchoconstriction and may contribute to difficulties in asthma. Better understanding of the quantitative aspects of DIs may result in novel or improved therapeutic approaches.
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    Estimation of Noise-Free Variance to Measure Heterogeneity
    (Public Library of Science, 2015) Winkler, Tilo; Melo, Marcos F. Vidal; Degani-Costa, Luiza H.; Harris, R. Scott; Correia, John; Musch, Guido; Venegas, Jose
    Variance is a statistical parameter used to characterize heterogeneity or variability in data sets. However, measurements commonly include noise, as random errors superimposed to the actual value, which may substantially increase the variance compared to a noise-free data set. Our aim was to develop and validate a method to estimate noise-free spatial heterogeneity of pulmonary perfusion using dynamic positron emission tomography (PET) scans. On theoretical grounds, we demonstrate a linear relationship between the total variance of a data set derived from averages of n multiple measurements, and the reciprocal of n. Using multiple measurements with varying n yields estimates of the linear relationship including the noise-free variance as the constant parameter. In PET images, n is proportional to the number of registered decay events, and the variance of the image is typically normalized by the square of its mean value yielding a coefficient of variation squared (CV2). The method was evaluated with a Jaszczak phantom as reference spatial heterogeneity (CVr2) for comparison with our estimate of noise-free or ‘true’ heterogeneity (CVt2). We found that CVt2 was only 5.4% higher than CVr2. Additional evaluations were conducted on 38 PET scans of pulmonary perfusion using 13NN-saline injection. The mean CVt2 was 0.10 (range: 0.03–0.30), while the mean CV2 including noise was 0.24 (range: 0.10–0.59). CVt2 was in average 41.5% of the CV2 measured including noise (range: 17.8–71.2%). The reproducibility of CVt2 was evaluated using three repeated PET scans from five subjects. Individual CVt2 were within 16% of each subject's mean and paired t-tests revealed no difference among the results from the three consecutive PET scans. In conclusion, our method provides reliable noise-free estimates of CVt2 in PET scans, and may be useful for similar statistical problems in experimental data.
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    Modeling \(^{18}F-FDG\) Kinetics during Acute Lung Injury: Experimental Data and Estimation Errors
    (Public Library of Science, 2012) Dittrich, A. Susanne; Winkler, Tilo; Wellman, Tyler James; de Prost, Nicolas; Musch, Guido; Harris, Robert; Vidal Melo, Marcos
    Background: There is increasing interest in Positron Emission Tomography (PET) of 2-deoxy-2-[18F]flouro-D-glucose (\(^{18}F-FDG\)) to evaluate pulmonary inflammation during acute lung injury (ALI). We assessed the effect of extra-vascular lung water on estimates of \(^{18}F-FDG\)-kinetics parameters in experimental and simulated data using the Patlak and Sokoloff methods, and our recently proposed four-compartment model. Methodology/Principal Findings Eleven sheep underwent unilateral lung lavage and 4 h mechanical ventilation. Five sheep received intravenous endotoxin (10 ng/kg/min). Dynamic \(^{18}F-FDG\) PET was performed at the end of the 4 h period. \(^{18}F-FDG\) net uptake rate (Ki), phosphorylation rate (k3), and volume of distribution (Fe) were estimated in three isogravitational regions for each method. Simulations of normal and ALI \(^{18}F-FDG\)-kinetics were conducted to study the dependence of estimated parameters on the transport rate constants to (k5) and from (k6) the extra-vascular extra-cellular compartment. The four-compartment model described 85.7% of the studied \(^{18}F-FDG\)-kinetics better than the Sokoloff model. Relative to the four-compartment model the Sokoloff model exhibited a consistent positive bias in Ki (3.32 [1.30–5.65] 10−4/min, p<0.001) and showed inaccurate estimates of the parameters composing Ki (k3 and Fe), even when Ki was similar for those methods. In simulations, errors in estimates of Ki due to the extra-vascular extra-cellular compartment depended on both k5 and k5/k6, with errors for the Patlak and Sokoloff methods of 0.02 [−0.01–0.18] and 0.40 [0.18–0.60] 10−3/min for normal lungs and of −0.47 [−0.89–0.72] and 2.35 [0.85–3.68] 10−3/min in ALI. Conclusions/Significance: \(^{18}F-FDG\) accumulation in lung extra-vascular fluid, which is commonly increased during lung injury, can result in substantial estimation errors using the traditional Patlak and Sokoloff methods. These errors depend on the extra-vascular extra-cellular compartment volume and its transport rates with other compartments. The four-compartment model provides more accurate quantification of \(^{18}F-FDG\)-kinetics than those methods in the presence of increased extra-vascular fluid.
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    Ventilation Defect Formation in Healthy and Asthma Subjects Is Determined by Lung Inflation
    (Public Library of Science, 2012) Harris, Robert; Fujii-Rios, Hanae; Winkler, Tilo; Musch, Guido; Vidal Melo, Marcos; Venegas, Jose
    Background: Imaging studies have demonstrated that ventilation during bronchoconstriction in subjects with asthma is patchy with large ventilation defective areas (Vdefs). Based on a theoretical model, we postulated that during bronchoconstriction, as smooth muscle force activation increases, a patchy distribution of ventilation should emerge, even in the presence of minimal heterogeneity the lung. We therefore theorized that in normal lungs, Vdefs should also emerge in regions of the lung with reduced expansion. Objective: We studied 12 healthy subjects to evaluate whether Vdefs formed during bronchoconstriction, and compared their Vdefs with those observed in 9 subjects with mild asthma. Methods: Spirometry, low frequency (0.15 Hz) lung elastance and resistance, and regional ventilation by intravenous \(^{13}\)NN-saline positron emission tomography were measured before and after a challenge with nebulized methacholine. Vdefs were defined as regions with elevated residual 13NN after a period of washout. The average location, ventilation, volume, and fractional gas content of the Vdefs, relative to those of the rest of the lung, were calculated for both groups. Results: Consistent with the predictions of the theoretical model, both healthy subjects and those with asthma developed Vdefs. These Vdefs tended to form in regions that, at baseline, had a lower degree of lung inflation and, in healthy subjects, tended to occur in more dependent locations than in subjects with asthma. Conclusion: The formation of Vdefs is determined by the state of inflation prior to bronchoconstriction.
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