Tilo Winkler

Tilo Winkler
Massachusetts General Hospital | MGH · Department of Anesthesia, Critical Care and Pain Medicine

Ph.D.

About

149
Publications
8,008
Reads
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3,095
Citations
Citations since 2016
40 Research Items
1419 Citations
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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_PI-profile.html or my Institutional Profile at Mass General Research Institute https://researchers.mgh.harvard.edu/profile/1534995/Tilo-Winkler
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 (149)
Article
Full-text available
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...
Preprint
Full-text available
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...
Article
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...
Article
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...
Article
Full-text available
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...
Article
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...
Article
Full-text available
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...
Article
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...
Article
Full-text available
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...
Chapter
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...
Article
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...
Article
Full-text available
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 exhalat...
Article
Full-text available
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...
Article
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...
Article
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...
Article
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...
Article
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...
Article
Full-text available
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...
Conference Paper
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...
Article
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...
Article
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...
Article
Full-text available
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...
Article
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...
Article
Full-text available
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...
Article
Full-text available
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:...
Article
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...
Article
Full-text available
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...
Article
Full-text available
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...
Article
Full-text available
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...
Article
Full-text available
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...
Article
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...
Article
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...
Article
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...
Article
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...
Chapter
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...
Article
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...
Patent
Full-text available
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...
Article
Full-text available
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...
Article
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...
Article
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...
Article
Full-text available
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...
Article
Full-text available
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...