About
173
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Introduction
Please visit my Investigator Profile at the
Pulmonary Imaging and Bioengineering Laboratories (PIBL) | Massachusetts General Hospital (MGH)
https://pibl.mgh.harvard.edu/T.Winkler.html
or my Institutional Profile at
Mass General Research Institute
https://researchers.mgh.harvard.edu/profile/1534995/Tilo-Winkler
Current institution
Additional affiliations
April 2020 - present
Massachusetts General Hospital / Harvard Medical School
Position
- Professor (Associate)
November 2010 - March 2020
Massachusetts General Hospital / Harvard Medical School
Position
- Professor (Assistant)
January 2002 - December 2003
Publications
Publications (173)
Background
Pulmonary capillary blood volume is a major determinant of lung gas transport efficiency, and also potentially related to ventilator-induced lung injury. Yet, knowledge on how lung expansion influences pulmonary blood volume in injured lungs is scant. We hypothesize that lung expansion produced by positive end-expiratory pressure (PEEP)...
Mechanical ventilation exposes the lung to injurious stresses and strains that can negatively affect clinical outcomes in acute respiratory distress syndrome or cause pulmonary complications after general anesthesia. Excess global lung strain, estimated as increased respiratory system driving pressure, is associated with mortality related to mechan...
Regional pulmonary perfusion (Q) has been investigated using blood volume (Fb) imaging as an easier-to-measure surrogate. However, it is unclear if changing pulmonary conditions could affect their relationship. We hypothesized that vascular changes in early acute respiratory distress syndrome (ARDS) affect Q and Fb differently. Five sheep were anes...
Pulmonary functional imaging modalities such as computed tomography, magnetic resonance imaging and nuclear imaging can quantitatively assess regional lung functional parameters and their distributions. These include ventilation, perfusion, gas exchange at the microvascular level and biomechanical properties, among other variables. This review desc...
Background
Positive end-expiratory pressure (PEEP) individualized to a maximal respiratory system compliance directly implies minimal driving pressures with potential outcome benefits, yet, raises concerns on static and dynamic overinflation, strain and cyclic recruitment. Detailed accurate assessment and understanding of these has been hampered by...
Regional pulmonary perfusion (Q) has been investigated using blood volume (Fb) imaging as an easier-to-measure surrogate. However, it is unclear if changing pulmonary conditions could affect their relationship. We hypothesized that vascular changes in early acute respiratory distress syndrome (ARDS) affect Q and Fb differently. Five sheep were anes...
Introduction:
Lung perfusion magnitude and distribution are essential for oxygenation and, potentially, lung inflammation and protection during acute respiratory distress syndrome (ARDS). Yet, perfusion patterns and their relationship to inflammation are unknown pre-ARDS. We aimed to assess perfusion/density ratios and spatial perfusion-density di...
Introduction: Pulmonary perfusion has been poorly characterized in acute respiratory distress syndrome(ARDS). Optimizing protocols to measure pulmonary blood flow(PBF) via dynamic contrast-enhanced(DCE) computed tomography(CT) could improve understanding of how ARDS alters pulmonary perfusion. In this study, comparative evaluations of injection pro...
Background:
Without aggressive treatment, pulmonary arterial hypertension (PAH) has a 5-year mortality of approximately 40%. A patient's response to vasodilators at diagnosis impacts the therapeutic options and prognosis. We hypothesized that analyzing perfusion images acquired before and during vasodilation could identify characteristic differenc...
Background: Without aggressive treatment, pulmonary arterial hypertension (PAH) has a 5-year mortality of approximately 40%. A patient's response to vasodilators at diagnosis impacts the therapeutic options and prognosis. We hypothesized that analyzing perfusion images acquired before and during vasodilation could identify characteristic difference...
Smoking and HIV-1 infection are risk factors for COPD, which is among the most common comorbid conditions in people living with HIV-1. HIV-1 infection leads to persistent expansion of CD8+ T cells, and CD8+ T cell-mediated inflammation has been implicated in COPD pathogenesis. In this study, we investigated the effects of HIV-1 infection and smokin...
Low-dose inhaled carbon monoxide is a novel therapeutic under investigation in acute respiratory distress syndrome. The Coburn-Forster-Kane equation is a well-validated model of carbon monoxide uptake that can accurately predict carboxyhemoglobin levels to ensure safe administration of low-dose inhaled carbon monoxide in patients with acute respira...
Positron emission tomography (PET) with 18F-fluorodeoxyglucose (18F-FDG) has been increasingly applied, predominantly in the research setting, to study drug effects and pulmonary biology and monitor disease progression and treatment outcomes in lung diseases, disorders that interfere with gas exchange through alterations of the pulmonary parenchyma...
Background
We aimed to investigate the physiological mechanism and spatial distribution of increased physiological dead‐space, an early marker of ARDS mortality, in the initial stages of ARDS. We hypothesized that: increased dead‐space results from the spatial redistribution of pulmonary perfusion, not ventilation; such redistribution is not relate...
Background:
Pulmonary atelectasis is frequent in clinical settings. Yet there is limited mechanistic understanding and substantial clinical and biologic controversy on its consequences. The authors hypothesize that atelectasis produces local transcriptomic changes related to immunity and alveolar-capillary barrier function conducive to lung injury...
RATIONALE: COPD is the most common non-infectious pulmonary disease among people living with HIV, independent of smoking. However, the cause for this enhanced susceptibility remains unclear, and the effects of HIV on pulmonary perfusion and ventilation are unknown. METHODS: We used PET-CT in 46 smokers and non-smokers, 23 of whom had documented HIV...
Rationale and Objectives
Pulmonary atelectasis presumably promotes and facilitates lung injury. However, data are limited on its direct and remote relation to inflammation. We aimed to assess regional 2-deoxy-2-[¹⁸F]-fluoro-D-glucose (¹⁸F-FDG) kinetics representative of inflammation in atelectatic and normally aerated regions in models of early lun...
Homeostasis is a cardinal feature of our body’s response to changes in the environment. However, there are circumstances under which seemingly small changes may have much greater impact through emergent phenomena affecting the development of life as well as disease. Revisiting Peter Macklem’s paper “Emergent phenomena and the secrets of life” inspi...
Airway transmural pressure in healthy homogeneous lungs with dilated airways is approximately equal to the difference between intraluminal and pleural pressure. However, bronchoconstriction causes airway narrowing, parenchymal distortion, dynamic hyperinflation, and the emergence of ventilation defects (VDefs) affecting transmural pressure. This st...
Background
Asthma exacerbations cause lung hyperinflation, elevation in load to inspiratory muscles, and decreased breathing capacity that, in severe cases, may lead to inspiratory muscle fatigue and respiratory failure. Hyperinflation has been attributed to a passive mechanical origin; a respiratory system time-constant too long for full exhalatio...
Background:
Acute respiratory distress syndrome (ARDS) is a prevalent disease with significant mortality for which no effective pharmacologic therapy exists. Low-dose inhaled carbon monoxide (iCO) confers cytoprotection in preclinical models of sepsis and ARDS.
Methods:
We conducted a phase I dose escalation trial to assess feasibility and safet...
Introduction:
Spatial heterogeneity of lung aeration and strain (change volume/resting volume) occurs at microscopic levels and contributes to lung injury. Yet, it is mostly assessed with histograms or large regions-of-interest. Spatial heterogeneity could also influence regional gene expression. We used positron emission tomography (PET)/computed...
Rationale:
The contribution of aeration heterogeneity to lung injury during early mechanical ventilation of uninjured lungs is unknown.
Objective:
Test the hypotheses that a strategy consistent with clinical practice does not protect from worsening in lung strains during the first 24h of ventilation of initially normal lungs exposed to mild syst...
Rationale:
Regional hypoventilation in bronchoconstricted asthmatics is spatially associated with reduced perfusion, which is proposed to result from Hypoxic Pulmonary Vasoconstriction (HPV). Our study aimed to determine the role of HPV in the regional perfusion redistribution in bronchoconstricted asthmatics.
Methods:
Eight asthmatics completed...
Background:
Acute respiratory distress syndrome (ARDS) is an inflammatory condition comprising diffuse lung edema and alveolar damage. ARDS frequently results from regional injury mechanisms. However, it is unknown whether detectable inflammation precedes lung edema and opacification and whether topographically differential gene expression consist...
Parenchymal strain is a key determinant of lung injury produced by mechanical ventilation. However, imaging estimates of volumetric tidal strain (e = regional tidal volume/reference volume) present substantial conceptual differences in reference volume computation and consideration of tidally recruited lung. We compared current and new methods to e...
Asthma is a chronic disease resulting in periodic attacks of coughing and wheezing due to temporarily constricted and clogged airways. The pathophysiology of asthma and the process of airway narrowing are not completely understood. Appropriate in vivo imaging modality with sufficient spatial and temporal resolution to dynamically assess the behavio...
Objective:
Volutrauma and atelectrauma promote ventilator-induced lung injury, but their relative contribution to inflammation in ventilator-induced lung injury is not well established. The aim of this study was to determine the impact of volutrauma and atelectrauma on the distribution of lung inflammation in experimental acute respiratory distres...
Background:
Theoretical models suggest that He-O2 as carrier gas may lead to more homogeneous ventilation and aerosol deposition than air. However, these effects have not been clinically consistent and it is unclear why subjects may or may not respond to the therapy. Here we present 3D-imaging data of aerosol deposition and ventilation distributio...
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 di...
This paper presents a novel approach to visualizing regional lung function, through quantitative three-dimensional maps of O2 and CO2 transfer rates. These maps describe the contribution of anatomical regions to overall gas exchange and demonstrate how transfer rates of the two gas species' differ regionally. An algorithm for generating such maps i...
Inhaled carbon monoxide (CO) gas has therapeutic potential for patients with acute respiratory distress syndrome (ARDS) if a safe, evidence-based dosing strategy and a ventilator-compatible CO delivery system can be developed. In this study, we used a clinically-relevant baboon model of S. pneumoniae pneumonia to 1) test a novel, ventilator-compati...
A previous PET-CT imaging study of 14 bronchoconstricted asthmatic subjects showed that peripheral aerosol deposition was highly variable among subjects and lobes. The aim of this work was to identify and quantify factors responsible for this variability.
A theoretical framework was formulated to integrate four factors affecting aerosol deposition:...
18F-FDG-PET is increasingly used to assess pulmonary inflammatory cell activity. However, current models of pulmonary 18F-FDG kinetics do not account for delays in 18F-FDG transport between the plasma sampling site and the lungs. We developed a three-compartment model of 18F-FDG kinetics that includes a delay between the right heart and the local c...
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 spat...
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...
Unlabelled:
PET with (18)F-FDG allows for noninvasive assessment of regional lung metabolism reflective of neutrophilic inflammation. This study aimed at determining during early acute lung injury whether local (18)F-FDG phosphorylation rate and volume of distribution were sensitive to the initial regional inflammatory response and whether they de...
Inhomogeneous inflation or deflation of the lungs can cause dynamic pressure differences between regions and lead to interregional airflows known as pendelluft. This work first uses analytical tools to clarify the theoretical limits of pendelluft at a single bifurcation. It then explores the global and regional pendelluft that may occur throughout...
Background:
This article presents a novel methodological approach to evaluate images of aerosol deposition taken with PET-CT cameras. Traditionally, Black-or-White (BW) Regions of Interest (ROIs) are created to cover Anatomical Regions (ARs) segmented from the high-resolution CT. Such ROIs do not usually consider blurring effects due to limited sp...
Asymmetry and heterogeneity in the branching of the human bronchial tree are well documented but their effects on bronchoconstriction and ventilation distribution in asthma are unclear. In a series of seminal studies, Venegas et al. have shown that bronchoconstriction may lead to self-organized patterns of patchy ventilation in a computational mode...
Regional tidal lung strain may trigger local inflammation during mechanical ventilation, particularly when additional inflammatory stimuli are present. However, it is unclear whether inflammation develops proportionally to tidal strain or only above a threshold. We aimed to 1) assess the relationship between regional tidal strain and local inflamma...
Airway narrowing by smooth muscle constriction is a hallmark of asthma attacks that may cause severe difficulties of breathing. However, the causes of asthma and the underlying mechanisms are not fully understood. Bronchoconstriction within a bronchial tree involves complex interactions among the airways that lead to the emergence of regions of poo...
In most diseases of the lung, both function and structure are spatially heterogeneous. As a result, global measures of lung function obtained from measurements at the mouth may be insensitive to localized pathological changes in the lungs and usually fail to detect the true extent of the functional impairment. With the development of imaging method...
Acute lung injury occurs in a third of patients with smoke inhalation injury. Its clinical manifestations usually do not appear until 48-72 h after inhalation. Identifying inflammatory changes that occur in pulmonary parenchyma earlier than that could provide insight into the pathogenesis of smoke-induced acute lung injury. Furthermore, noninvasive...
An input function indicative of a time-activity curve in pulmonary arterial plasma is produced from a series of PET image frames in lieu of manual blood sampling. Two manually acquired blood samples are input along with pixel values of a blood pool region of interest (ROI) in the PET image frames into a two-parameter model of the ROI's time-activit...
![Sokoloff model for 18F-fluorodeoxyglucose tracer kinetics [13]. The...](profile/Nicolas-De-Prost/publication/255956976/figure/fig1/AS:195878204776456@1423712411615/Sokoloff-model-for-18F-fluorodeoxyglucose-tracer-kinetics-13-The-three-compartments-of_Q320.jpg)
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 adminis...
Omalizumab promotes clinical improvement in patients with allergic asthma, but its effect on pulmonary function is unclear. One possibility is that omalizumab improves asthma symptoms through effects on the regional distributions of ventilation, perfusion, and ventilation/perfusion matching, metrics which can be assessed with Nitrogen-13-saline Pos...
Background: A previous PET-CT imaging study of 14 bronchoconstricted asthmatic subjects showed that peripheral aerosol deposition was highly variable among subjects and lobes. The aim of this work was to identify and quantify factors responsible for this variability. Methods: A theoretical framework was formulated to integrate four factors affectin...
Background:
Lung derecruitment is common during general anesthesia. Mechanical ventilation with physiological tidal volumes could magnify derecruitment, and produce lung dysfunction and inflammation. The authors used positron emission tomography to study the process of derecruitment in normal lungs ventilated for 16 h and the corresponding changes...
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 pres...
Airflow obstruction and heterogeneities in airway constriction and ventilation distribution are well-described prominent features of asthma. However, the mechanistic link between these global and regional features has not been well defined. We speculate that peripheral airway resistance (R(p)) may provide such a link. Structural and functional para...
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 So...
Relative Errors in Net Uptake Rates Estimated by the Patlak and Sokoloff Methods. Relative errors in Ki of the Sokoloff (εKiS = KiS-KiF/KiF·100 [%]) and the Patlak method (εKiP = KiP-KiF/KiF·100 [%]) compared to the four-compartment model (contour lines) as function of k5/k6 and k5 in simulations of a healthy lung (LPS−, Lav−) and of a lung exposed...
Abstract Physiological conditions and pathophysiological changes in the lungs may affect many applications in aerosol medicine and pulmonary drug delivery. In the diseased lung, spatial heterogeneity in function and structure may cause substantial changes in aerosol transport and local deposition among different lung regions. Non-uniform aerosol de...
Purpose:
The aim of the study was to use micro-autoradiography to investigate the lung cell types responsible for 2-deoxy-2-[(18)F]fluoro-D-glucose (FDG) uptake in murine models of acute lung injury (ALI).
Procedures:
C57/BL6 mice were studied in three groups: controls, ventilator-induced lung injury (VILI), and endotoxin. VILI was produced by h...
Heterogeneous, small-airway diameters and alveolar derecruitment in poorly aerated regions of normal lungs could produce ventilation heterogeneity at those anatomic levels. We modeled the washout kinetics of (13)NN with positron emission tomography to examine how specific ventilation (sV) heterogeneity at different length scales is influenced by lu...
Questions
Questions (2)
I'm very interested in scientific data visualization. What are your best sources you use for inspiration or for advancing your design?
There are reference values for different lung volumes based on age, weight, BMI, BSA, etc., e.g., Garcia-Rio F et al (2009), doi:10.1164/rccm.200901-0127oc. Are there equivalent methods that would allow CT-based estimates of reference values? For example, a CT would allow determining the gas volume of a patient at an end-expiratory breath-hold. But, that volume is different from FRC the patient would have if healthy and in an upright position. It would be ideal if the CT could be used for an anatomical measurement that would allow estimating the reference volume, e.g., FRC for that patient and the deviation of gas volume in the CT from the reference value.
