Dissertations / Theses on the topic 'Pulmonary Biomechanics'

Background Right ventricular (RV) diastolic function has been associated with outcomes for patients with pulmonary hypertension; however, the relationship between biomechanics and hemodynamics in the right ventricle has not been studied. Methods and Results Rat models of RV pressure overload were obtained via pulmonary artery banding (PAB; control, n=7; PAB, n=5). At 3 weeks after banding, RV hemodynamics were measured using a conductance catheter. Biaxial mechanical properties of the RV free wall myocardium were obtained to extrapolate longitudinal and circumferential elastic modulus in low and high strain regions (E-1 and E-2, respectively). Hemodynamic analysis revealed significantly increased end-diastolic elastance (E-ed) in PAB (control: 55.1 mm Hg/mL [interquartile range: 44.785.4 mm Hg/mL]; PAB: 146.6 mm Hg/mL [interquartile range: 105.8155.0 mm Hg/mL]; P=0.010). Longitudinal E1 was increased in PAB (control: 7.2 kPa [interquartile range: 6.718.1 kPa]; PAB: 34.2 kPa [interquartile range: 18.144.6 kPa]; P=0.018), whereas there were no significant changes in longitudinal E-2 or circumferential E-1 and E-2. Last, wall stress was calculated from hemodynamic data by modeling the right ventricle as a sphere: (stress = Pressure x radius/2 x thickness Conclusions RV pressure overload in PAB rats resulted in an increase in diastolic myocardial stiffness reflected both hemodynamically, by an increase in E-ed, and biomechanically, by an increase in longitudinal E-1. Modest increases in tissue biomechanical stiffness are associated with large increases in E-ed. Hemodynamic measurements of RV diastolic function can be used to predict biomechanical changes in the myocardium.

Les poumons réalisent leur fonction vitale d'échanges gazeux grâce notamment à leur élasticité et leur porosité. La fibrose pulmonaire idiopathique (FPI), une maladie pulmonaire interstitielle, impacte fortement la mécanique pulmonaire, soulevant des problématiques cliniques. L'objectif de ce travail est d'améliorer la compréhension et le diagnostic de la FPI en s'appuyant sur une modélisation poromécanique du poumon, personnalisée grâce à des données d'imagerie médicale. Dans une première partie, une analyse bibliographique fait l'état de l'art de la physiologie pulmonaire en relation avec les modélisations mécaniques existantes, en insistant sur les caractères multiéchelle, multiphasique et multiphysique de l'organe. Nous proposons ensuite un modèle poromécanique du poumon à l'échelle spatiale de l'organe et à l'échelle temporelle de la respiration, dérivé d'une théorie générale de poromécanique récemment formulée dans l'équipe MΞDISIM. La loi de comportement proposée reproduit notamment le comportement pression-volume du poumon ainsi que la quasi-incompressiblité de la phase solide. Les conditions aux limites prennent en compte l'environnement du poumon (cage thoracique, diaphragme, plèvre) et distinguent les cas de la respiration libre vs ventilée. La configuration déchargée, non observée au cours d'un cycle respiratoire, est estimée, avec une attention particulière apportée pour contraindre la positivité de la porosité. Plusieurs éléments du modèle sont ensuite personnalisés à partir de données cliniques standards, i.e., deux images 3DCT prises en début et en fin d'inspiration. Un problème inverse est notamment formulé pour estimer la compliance pulmonaire en zones saines et fibrosées, la formulation poromécanique permettant de distinguer l’effet de la porosité de celui de la compliance du tissu interstitiel. Appliqué sur trois patients atteints de FPI, le modèle personnalisé permet de retrouver les propriétés pressenties de la FPI, i.e., la rigidification des zones malades. Des surcontraintes sont aussi observées en bordure de la région malade, corroborant ainsi l'hypothèse d'un cercle vicieux mécanique régissant l'évolution de la FPI, où la fibrose entraînerait des contraintes importantes, qui à leur tour favoriseraient la fibrose. Cet outil numérique pourrait servir par la suite au diagnostic objectif et quantitatif de la FPI et, avec des données longitudinales, à l'étude de son remodelage induit par la mécanique
Idiopathic pulmonary fibrosis (IPF), an interstitial lung disease, strongly impacts lung mechanics, which raises clinical issues. The objective of this work is to improve the understanding and diagnosis of IPF based on poromechanical modeling of the lung, personalized with clinical imaging data. In a first part, a literature review analyzes the state of the art of pulmonary physiology in relation to the existing mechanical models, insisting on the multi-scale, multi-phase and multi-physics characteristics of the organ. We then propose a poromechanical model of the lung at the organ spatial scale and breathing time scale, derived from a general poromechanical theory formulated recently in the MΞDISIM team. The constitutive law proposed reproduces mainly the pressure-volume behaviour of the lung as well as the quasi-incompressiblity of the solid phase. The boundary conditions take into account the lung environment (thoracic cage, diaphragm, pleura) and distinguish between free and ventilated breathing. The unloaded configuration, non observed during a breathing cycle, is estimated, with a special attention given to maintain a positive porosity. Various elements of the model are then personalized with standard clinical data, i.e., two 3DCT images acquired at end-exhalation and end-inhalation. In particular, an inverse problem is formulated to estimate the pulmonary compliance of the healthy and fibrotic regions, since the poromechanical formulation allows to distinguish the effect of the porosity from that of the absolute compliance of the interstitial tissue. Applied to three patients suffering from IPF, the personalized model allows to find the foreseen properties of IPF, i.e., the stiffening of the diseased region. Stress concentrations are also observed at the diseased region interface, supporting the hypothesis of a mechanical vicious circle governing the IPF progress, where fibrosis induces large stresses, which in turn favors fibrosis. This numerical tool could later be used for objective and quantitative diagnosis of IPF and, with longitudinal data, to study the mechanics-induced remodeling

Motor vehicle crash (MVC) and its associated injuries remain a major public health problem world wide. In 2005 alone there were 6 million police-reported crashes in the United States resulting in 2.5 million injuries and 46,000 fatalities. The thorax is second only to the head in terms of frequency of injury following MVC, and pulmonary contusion (PC) is the most common intra-thoracic soft tissue injury sustained as a result of blunt chest trauma. The goal of this dissertation research is to mitigate this commonly-sustained and potentially life threatening injury. We have taken a computational approach to solving this problem by developing a predictive injury metric for PC using finite element analysis (FEA). The dissertation begins with an epidemiological examination of the crash modes, vehicles, and patient demographics most commonly associated with PC. This study was conducted using real world crash data from the Crash Injury Research and Engineering Network (CIREN) database and data from government-sponsored vehicle crash tests. The CIREN data showed that a substantial portion of the crashes resulting in PC were lateral impacts (48%). Analysis of the thoracic loading of dummy occupants in lateral crash tests resulted in mean values of medial-lateral chest compression and deflection velocity of 25.3 ± 2.6 % and 4.6 ± 0.42 m⠢s-1 respectively. These data provided quantified loading conditions associated with crash-induced PC and a framework for the remaining research studies, which were focused on blunt impact experiments examining the relationship between insult and outcome in a living model of this injury. A combined experimental and computational approach was used to develop injury metrics for PC. The animal model selected for this research was the Sprague-Dawley male rat. In the remaining studies that comprise this dissertation, an outcome measure of the inflammatory response in the lung parenchyma was correlated with a mechanical analog calculated via a finite element model of the lung. For all studies, a precise and instrumented electronic piston was used to apply prescribed insults directly to the lungs of the subjects. In the first set of experiments, contusion volume was calculated from MicroPET (Micro Positron Emission Tomography) scans and normalized on the basis of liver uptake of 18F-FDG. The subjects were scanned at 24 hours, 7 days, and 28 days (15 scans), and the contused volume was measured. A tentative criteria based on first principal strain in the parenchyma between 9 and 36% was established. In subsequent experiments Computed Tomography was used to acquire volumetric contusion data. The second set of experiments introduced two important aspects of this dissertation; a semi-automated algorithm for CT segmentation and a technique to match the spatial distribution of contusion within the lung to finite element analysis results. The results of this study indicated that the product of first principal strain and strain rate is the most appropriate output variable upon which to base an injury metric for PC. Digital analysis of histology from study subjects that underwent CT scanning prior to sacrifice was conducted and showed good agreement between CT and histology. A final set of experiments was conducted to synthesize the techniques developed in previous studies to determine an injury metric for PC. A concurrent optimization technique was applied to the FEA model to match force vs. deflection traces from four distinct impact cohorts. The resulting predictive injury metrics for PC were exceeding 94.5 sec-1, first principal strain exceeding 0.284 (true strain, dimensionless), and first principal strain rate exceeding 470 sec-1. The method used in this dissertation and the resulting injury metrics for PC are based on quantified inflammatory response observed in a living model, specifically in the organ of interest. This injury metric improves upon current thoracic injury criteria that rely on gross measures of chest loading such as acceleration, or deflection, and are not specific to a particular injury. We anticipate that the findings of this work will lead to more data-driven improvements to vehicular safety systems and ultimately diminish the instance of PC and mitigate its severity.
Ph. D.

Motor vehicle crash (MVC) and its associated injuries remain a major public health problem world wide. In 2005 alone there were 6 million police-reported crashes in the United States resulting in 2.5 million injuries and 46,000 fatalities. The thorax is second only to the head in terms of frequency of injury following MVC, and pulmonary contusion (PC) is the most common intra-thoracic soft tissue injury sustained as a result of blunt chest trauma. The goal of this dissertation research is to mitigate this commonly-sustained and potentially life threatening injury. We have taken a computational approach to solving this problem by developing a predictive injury metric for PC using finite element analysis (FEA). The dissertation begins with an epidemiological examination of the crash modes, vehicles, and patient demographics most commonly associated with PC. This study was conducted using real world crash data from the Crash Injury Research and Engineering Network (CIREN) database and data from government-sponsored vehicle crash tests. The CIREN data showed that a substantial portion of the crashes resulting in PC were lateral impacts (48%). Analysis of the thoracic loading of dummy occupants in lateral crash tests resulted in mean values of medial-lateral chest compression and deflection velocity of 25.3 ± 2.6 % and 4.6 ± 0.42 m⠢s-1 respectively. These data provided quantified loading conditions associated with crash-induced PC and a framework for the remaining research studies, which were focused on blunt impact experiments examining the relationship between insult and outcome in a living model of this injury. A combined experimental and computational approach was used to develop injury metrics for PC. The animal model selected for this research was the Sprague-Dawley male rat. In the remaining studies that comprise this dissertation, an outcome measure of the inflammatory response in the lung parenchyma was correlated with a mechanical analog calculated via a finite element model of the lung. For all studies, a precise and instrumented electronic piston was used to apply prescribed insults directly to the lungs of the subjects. In the first set of experiments, contusion volume was calculated from MicroPET (Micro Positron Emission Tomography) scans and normalized on the basis of liver uptake of 18F-FDG. The subjects were scanned at 24 hours, 7 days, and 28 days (15 scans), and the contused volume was measured. A tentative criteria based on first principal strain in the parenchyma between 9 and 36% was established. In subsequent experiments Computed Tomography was used to acquire volumetric contusion data. The second set of experiments introduced two important aspects of this dissertation; a semi-automated algorithm for CT segmentation and a technique to match the spatial distribution of contusion within the lung to finite element analysis results. The results of this study indicated that the product of first principal strain and strain rate is the most appropriate output variable upon which to base an injury metric for PC. Digital analysis of histology from study subjects that underwent CT scanning prior to sacrifice was conducted and showed good agreement between CT and histology. A final set of experiments was conducted to synthesize the techniques developed in previous studies to determine an injury metric for PC. A concurrent optimization technique was applied to the FEA model to match force vs. deflection traces from four distinct impact cohorts. The resulting predictive injury metrics for PC were exceeding 94.5 sec-1, first principal strain exceeding 0.284 (true strain, dimensionless), and first principal strain rate exceeding 470 sec-1. The method used in this dissertation and the resulting injury metrics for PC are based on quantified inflammatory response observed in a living model, specifically in the organ of interest. This injury metric improves upon current thoracic injury criteria that rely on gross measures of chest loading such as acceleration, or deflection, and are not specific to a particular injury. We anticipate that the findings of this work will lead to more data-driven improvements to vehicular safety systems and ultimately diminish the instance of PC and mitigate its severity.
Ph. D.

Paradoxalement, la sécurité routière est assurée entre autre par la production de particules d’usure ! Ainsi, près de 20 000 tonnes de garnitures de frein sont usées par an en France, dont 9 000 tonnes sous forme de particules d’usure aéroportées. Ces particules posent des problèmes de santé car leur composition chimique et leur morphologie font qu’elles interagissent avec la paroi alvéolaire entrainant des pathologies. Au cours de ces pathologies la phase la plus étudiée est la phase inflammatoire qui s’installe une fois que la particule a passé la première barrière de protection qui est le film de surfactant pulmonaire. En revanche, très peu d’études portent sur l’interaction directe des particules aéroportées avec le film de surfactant pulmonaire à cause de difficultés liées aux résolutions des moyens d’investigations cliniques. Alors-que ces études sont d’un intérêt fondamental puisque, de par ses propriétés physicochimiques de surfactant, ce film contrôle la mécanique respiratoire donc la capacité pulmonaire. Dans ce contexte, cette thèse analyse les mécanismes d’action de particules d’usure aéroportées modèles sur les propriétés physicochimiques et mécaniques des parois alvéolaires et plus particulièrement du film de surfactant pulmonaire. Pour cela, un modèle ex vivo de paroi alvéolaire reproduisant la composition, la microstructure du surfactant ainsi que les sollicitations mécaniques pendant les cycles respiratoires, a été mis au point. L’utilisation de ce modèle et les mesures associées ont permis d’élaborer une démarche d’identification des paramètres significatifs des particules qui déterminent leurs interactions avec le film de surfactant pulmonaire. Cela a permis de montrer que l’électronégativité des particules aéroportées est l’un des paramètres significatifs qui induit des changements couplés à différentes échelles, qui vont de la conformation moléculaire (nano), à la microstructure (micro) et aux propriétés mécaniques (macro) de la paroi alvéolaire, conduisant à la diminution de la capacité respiratoire. Ce modèle et les premiers résultats permettront à court terme, d’identifier les autres paramètres significatifs qui caractérisent les actions de particules d’usure aéroportées sur les propriétés mécaniques et physicochimiques des parois alvéolaires. Ceci permettra de connaitre leurs effets sur la capacité pulmonaire. Par conséquent, à plus long terme, cette connaissance permettra de modifier les matériaux en contact et leurs conditions de frottement pour générer des particules satisfaisant les exigences tribologiques et biologiques, donc tribo-bio-compatibles
Paradoxically, road safety is assured among others by the production of wear particles! Thus, almost 20 000 tons of brake linings are worn each year in France. 9000 tons are airborne wear particles. Due to their size, chemical composition and morphology these particles will interact with the alveolar wall causing pathologies. In these pathologies the most studied is the inflammatory phase that appear after the particle has passed the first protective barrier which is the pulmonary surfactant film. However, very few studies have examined the direct interaction of airborne wear particles with pulmonary surfactant film. These studies are of fundamental interest because, by its physicochemical properties, the pulmonary surfactant film control the respiratory mechanics, hence the pulmonary capacity. In this context, this thesis analyzes the interaction mechanism of model airborne wear particles on the physicochemical and mechanical properties of the alveolar wall and more particularly of pulmonary surfactant film. For this, an ex vivo model of alveolar wall reproducing the composition of the surfactant, its microstructure and the mechanical stresses during the breathing cycles has been developed. This model and the associated measures allowed to develop a method for identifying significant parameters of the particles that determine their interaction with the pulmonary surfactant film. The results showed that the electronegativity of airborne particles is one of the significant parameters which induces changes at different scales ranging from molecular conformation (nano), microstructure (micro) and mechanical properties (macro) of the alveolar wall, leading to the diminution of the pulmonary capacity. This model and the first results will allow, at short term, to identify other significant parameters which characterize the actions of airborne wear particles on mechanical and physicochemical properties of alveolar walls, allowing to know their effects on lung capacity. Therefore, at longer term, this knowledge will permit to change the materials in contact and their friction conditions to generate wear particles satisfying tribological and biological requirements, so tribo-bio-compatibles

La Fibrose Pulmonaire Idiopathique (FPI) est une maladie au pronostic extrêmement sévère, qui affecte directement le parenchyme pulmonaire, et dont les mécanismes d’apparition et d’évolution restent encore mal compris. L’objectif de ce travail de thèse est d’approfondir la compréhension de la FPI en couplant modélisation biomécanique et traitement d’images biomédicales.Tout d'abord, une revue de la littérature relative à la FPI ainsi qu’aux modèles pulmonaires actuels a été effectuée. Un accent particulier est mis sur l’analyse des mécanismes qui pourraient expliquer l’évolution de cette pathologie. En particulier, l’hypothèse d’un lien étroit entre la mécanique, et notamment les concentrations de contraintes, et la progression de la fibrose a été formulée dans la littérature.Le premier axe de ce travail se concentre sur l’amélioration du modèle poromécanique pulmonaire développé dans l’équipe M3DISIM, en y intégrant la gravité et en supprimant le contact avec la cage thoracique. Inclure la gravité dans le modèle permet en effet de reproduire des hétérogénéités physiologiques de contraintes et de déformations lors de la respiration, absentes dans le modèle sans gravité, et permet également la prise en compte de l'orientation (e.g., pronation ou supination) du patient. Le contact avec la cage thoracique, instable et coûteux numériquement, a été remplacé par un champs de pression pleural contraint à vérifier l’équilibre global, modélisant l’ensemble des forces appliquées sur l’extérieur du poumon.De plus, l’identification des paramètres d’un modèle est une étape cruciale pour sa personnalisation. Néanmoins, de nombreuses méthodes existent, chacune présentant ses propres avantages et inconvénients en termes de robustesse et de coût. Cette étude propose donc une méthode de quantification de la robustesse face au bruit et aux erreurs de modèle pour diverses méthodes d’identification. En particulier, une nouvelle formulation de la Méthode d’Écart à l’Équilibre (EGM) en grandes transformations est proposée. Il est démontré que l’EGM, qui est une méthode directe et donc naturellement assez instable, quand couplée à une régularisation par écart à l’équilibre du problème de suivi de mouvement, permet une estimation robuste des paramètres.Le troisième axe de cette étude porte sur la quantification des incertitudes sur l’identification des paramètres du modèle poromécanique pulmonaire à partir d’images cliniques. L’identifiabilité des paramètres, ainsi que leur robustesse aux erreurs de modèle et de mesure, sont analysées afin de déterminer la meilleure paramétrisation du problème d’identification. L’influence du jeu de données utilisé en entrée sur la qualité de l’estimation est également évaluée.Enfin, le dernier axe se concentre sur l’application de l’approche de jumeaux numériques à des jeux de données longitudinales de dix patients atteints de FPI. Pour chaque patient, deux images, l’une en fin d’expiration et l’autre en fin d’inspiration, sont fournies à trois instants d’évolution de la maladie. L’identification de biomarqueurs susceptibles de contribuer à l’explication de l’évolution de la maladie est explorée, notamment en étudiant la corrélation entre certaines quantités d'intérêt et la progression de la fibrose.Ce travail constitue une avancée, en termes de modélisation et personnalisation, du jumeau numérique de poumon développé par l’équipe M3DISIM. Il améliore la physiologie du modèle, sa fiabilité numérique, et quantifie les incertitudes liées aux bruits de mesure et aux erreurs de modèle sur les biomarqueurs calculés. Ces avancées ouvrent la voie à des applications cliniques prometteuses et fournissent des premiers résultats permettant de mieux comprendre l’évolution de la Fibrose Pulmonaire
Idiopathic Pulmonary Fibrosis (IPF) is a disease with an extremely severe prognosis, which directly affects the lung parenchyma, and whose mechanisms of appearance and progression remain poorly understood. The objective of this thesis work is to improve the understanding of IPF by coupling biomechanical modeling and biomedical image processing.Firstly, a review of the literature relating to IPF as well as current pulmonary models was conducted. Particular emphasis is placed on the analysis of the mechanisms that could explain the evolution of this pathology. Notably, the hypothesis of a close link between mechanics, and in particular stress concentrations, and the progression of fibrosis has been formulated in the literature.The first axis of this work focuses on improving the pulmonary poromechanical model developed in the M3DISIM team, by integrating gravity and removing contact with the rib cage. Including gravity in the model indeed allows to reproduce physiological heterogeneities of constraints and deformations during breathing, absent in the model without gravity, and also allows to take into account the orientation (e.g., pronation or supination) of the patient. The contact with the rib cage, unstable and numerically expensive, has been replaced by a pleural pressure field constrained to verify the global equilibrium, modeling all the forces applied on the outside of the lung. In addition, the identification of the parameters of a model is a crucial step for its personalization. Nevertheless, many methods exist, each with its own advantages and drawbacks in terms of robustness and cost. This study therefore proposes a method for quantifying the robustness to noise and model errors for various identification methods. In particular, a new formulation of the Equilibrium Gap Method (EGM) in large transformations is proposed. It is shown that the EGM, which is a direct method and therefore naturally quite unstable, when coupled with a regularization by equilibrium gap of the motion tracking problem, allows a robust estimation of the parameters.The third axis of this study focuses on the quantification of uncertainties on the identification of the parameters of the pulmonary poromechanical model from clinical images. The identifiability of the parameters, as well as their robustness to model and measurement errors, are analyzed in order to determine the best parameterization of the identification problem. The influence of the dataset used as input on the quality of the estimation is also evaluated.Finally, the last axis focuses on the application of the digital twin approach to longitudinal datasets of ten patients with IPF. For each patient, two images, one at the end-exhalation and the other at the end-inhalation, are provided at three different moments of the evolution of the disease. The identification of biomarkers likely to contribute to the explanation of the evolution of the disease is explored, in particular by studying the correlation between certain quantities of interest and the progression of fibrosis.This work constitutes an advance, in terms of modeling and personalization, of the digital twin of the lung developed by the M3DISIM team. It improves the physiology of the model, its numerical reliability, and quantifies the uncertainties related to measurement noise and model errors on the calculated biomarkers. These advances pave the way for promising clinical applications and provide initial results to better understand the evolution of Pulmonary Fibrosis

Nombroses malalties resulten d’una alteració de las propietats mecàniques dels teixits i/o d’una alteració en la resposta cel·lular a les forces (mecanotransducció). La fibrosi es el paradigma de la mecànica tissular alterada, caracterizant-se per una excessiva acumulació de matriu extracel·lular (MEC) que destrueix l’arquitectura de l’òrgan. La fibrosi pulmonar idiopàtica (FPI) és una forma de malaltia pulmonar intersticial (MPI) de causa desconeguda i molt mal pronòstic, amb una supervivència del 30-50% als 5 anys. En aquest treball s’ha desenvolupat una estratègia de cribratge biomecànic que s’ha aplicat l’estudi de la FPI per identificar gens mecanosensibles potencialment rellevants com a dianes terapèutiques. Es van cultivar fibroblasts pulmonars primaris, la cèl·lula responsable del remodelat i enduriment de la MEC, en substrats coberts de col·lagen I de 5 rigideses distintes al llarg del rang fisiopatològic del pulmó, des de la normal (<1 kPa) fins la pròpia de la fibrosi (~30-40 kPa) i en presència de TGF-β. Es van incloure 3 classes de fibroblasts: FPI, control i MPI distintes de la FPI i es va realitzar un perfilat transcripcional mitjançant microarrays d’expressió. S’ha definit el mecanotranscriptoma dels fibroblasts pulmonars, format per 63 gens mecanosensibles, la transcripció dels quals està controlada pels canvis en les propietats mecàniques de la MEC. Un 57% dels gens van ser sobreexpressats amb l’enduriment i 21 gens van discriminar entre la FPI i las altres dos classes de fibroblasts. Para entendre las xarxes reguladores associades al mecanotranscriptoma, es va construir l’interactoma dels seus components, el qual va revelar tres xarxes emergents, les quals poden ser rellevants per entendre l’adaptació de les cèl·lules a l’enduriment del substrat en la FPI i en la mecanobiologia en general: 1) elements del citoesquelet i les fibres d'estrés, 2) quinases MAPK i les seves fosfatases i 3) proteïnes relacionades amb el factor de creixement similar a la insulina (IGF) i proteases del sistema de fibrinòlisi. Després de validar l’expressió a nivell de mRNA i de proteïna de diversos candidats del mecanotranscriptoma, es van caracteritzar diversos aspectes de la proteïna d’unió al factor de creixement similar a la insulina 3 (IGFBP-3). La concentració d’IGFP-3 secretada pels fibroblasts va ser distintivament superior en els fibroblasts de FPI. Per altra banda, amb l’enduriment del substrat es va detectar un factor de mecanosensibilitat de l’odre 3X en totes les classes de fibroblasts, mentre que el TGF-β la va induir 150 vegades. L’efecte dels dos factors va ser independent, mentre que la seva combinació va potenciar sinèrgicament els nivells d’IGFBP-3. L’efecte de la duresa del substrat en l’acumulació d’IGFBP-3 va ser independent de la senyalització a través del receptor de TGF-β. Per altra banda, els efectes van ser dependents del receptor de col·lagen integrina β1. Aquests resultats mostren que la IGFBP-3 es una proteïna important en la fibrogènesi pulmonar mediada por l’enduriment, que portaria a una acumulació de MEC i a la destrucció de l’arquitectura del teixit.
A new strategy based on a biomechanical screening has been developed and it was applied to the study of idiopathic pulmonary fibrosis (IPF) to identify mechanosensitive genes that might be potential therapeutic targets for the disease. The transcriptional profile of lung fibroblasts (control and fibrotic of different types) cultured on substrates of different stiffness spanning the normal to fibrotic (stiffened) range was obtained. The mechanotranscriptome of the cells was established, which consisted of 63 mechanosensitive genes, 57% of which were upregulated by tissue stiffening. It was built an interactome, showing the regulatory networks associated with the mechanotranscriptome, revealing three different subnetworks: 1) elements of the cytoskeleton and stress fibers; 2) MAPK quinases and their phosphatases; 3) proteins associated with insulin-like growth factor and the fibrinolysis pathway. After validating expression at the mRNA and protein levels for different selected candidates from the mechanotranscriptome, different biological aspects of insulin-like growth factor binding protein 3 (IGFBP-3) were analyzed. Concentration of IGFBP-3 secreted by fibroblasts was distinctively higher in IPF fibroblasts. With substrate stiffening, a mechanosensitivity factor of 3X was detected in all classes of lung fibroblasts, while transforming growth factor- β (TGF- β) induced protein levels by 150X. The effect of tissue stiffening on IGFBP-3 accumulation was independent of signaling through the TGF-β receptor and dependent of the collagen receptor integrin β1. These results show that IGFBP-3 is an important protein for lung fibrogenesis mediated through stiffness and that it could lead to an accumulation of extracellular matrix and contribute to the destruction of the lung architecture.

Le modèle cellulaire de magnétostimulation (MTS) développé dans l'équipe a permis d'obtenir des résultats préliminaires sur les essais de perméabilité endothéliale ainsi que sur les reconstructions et modélisation des fibres d'actine. Les premiers résultats en Magnétocytométrie (MTC) montrent une augmentation de rigidité cellulaire suite à une stimulation mécanique du tapis cellulaire. Les images confocales ont permis de mettre en évidence une restructuration des filaments d'actine dans les cellules endothéliales microvasculaires pulmonaires (HPMEC) soumises au stress mécanique, ainsi qu'une relocalisation des VE-Cadhérines nécessaires aux jonctions intercellulaires. Ces deux résultats concordent avec l'apparition de 'gaps' ou trous inter cellulaires qui permettent d'expliquer l'augmentation de perméabilité mesurée entre les cellules soumises au stress mécanique et la situation contrôle. Des difficultés techniques retardent le travail et l'obtention de résultats en nombre important. Par exemple l'emploi de certaines techniques de marquages difficilement compatibles avec certains supports de culture. Cela empêche dans certains cas la confirmation visuelle de résultats obtenus par MTC. La viabilité cellulaire lors des expérimentation ne permet pas d’allonger les temps d’étude d’une même population cellulaire, ce qui limite certains résultats. Les premiers résultats sont à compéter par une étude plus approfondie des niveaux d'expression de facteurs pro-inflammatoires ainsi que des voies de signalisation et de régulation des VE-Cadhérines et des intégrines AlphaV-Beta3. L’effet de différentes molécules utilisées en clinique devrait être étudié sur le modèle de stress mécanique
The cellular model of magnétostimulation ( MTS) developed in the team allowed to obtain preliminary results(profits) on the tries(essays) of endothéliale permeability as well as on the reconstructions and the modelling of the fibers of actine. The first results(profits) in Magnétocytométrie ( MTC) show an increase of cellular rigidity further to a mechanical stimulation of the cellular carpet(mat). The confocal images allowed to highlight a restructuring of the strands of actine in cells(units) microvascular lung endothéliales ( HPMEC) subjected(submitted) to the mechanical stress, as well as a relocation of the VE-Cadhérines necessary for the intercellular junctions. These two results(profits) suit to the appearance of ' gaps ' or holes inter cellular which allow to explain the increase

La ventilation est une fonction complexe, avec des variabilités naturelles intra- et inter-individuelles imprévisibles, parfois inhomogènes dans le volume pulmonaire. La spirométrie standard est l'examen de référence pour évaluer la fonction ventilatoire à partir de courbes débit-volume mesurées à la bouche et en respiration forcée. Cette technique simple et fiable est limité par la nécessaire coopération du patient, ainsi que par la nature globale de sa mesure. Étant donné que la respiration est intrinsèquement un phénomène tridimensionnel et que les maladies pulmonaires sont généralement régionales, la ventilation devrait être sondée localement. Malgré les difficultés inhérentes à l'application de l'IRM au poumon, de récent progrès ont permis de révéler le potentiel de l'IRM fonctionnelle pulmonaire à partir d'acquisitions standards facilement transposables en clinique. Depuis une quinzaine d'années des développements évaluent la ventilation à partir de la variation du signal IRM au cours de la respiration. Ces techniques reposent sur une hypothèse forte de linéarité du signal IRM avec la densité de tissus pulmonaire. Une nouvelle méthode évaluant la ventilation localement et dynamiquement à partir des déformations a été développée : la spirométrie 3D par IRM. A partir d'un cycle respiratoire moyen, le Jacobien des déformations et sa dérivée temporelle permettent d'inférer les courbes débit-volume locales. Cette thèse s'attache à valider la spirométrie 3D par IRM, à l'amener à la recherche clinique, et à approfondir la compréhension de la mécanique ventilatoire. Le caractère multidimensionnel de la spirométrie 3D par IRM intègre la complexité de la fonction respiratoire mais la technique encore neuve doit être développée et éprouvée. Les évolutions méthodologiques entreprises durant cette thèse incluent une reconstruction optimisée de la dynamique pulmonaire, une segmentation précise des structures lobaires, la définition de biomarqueurs quantitatifs, ainsi qu'une normalisation des cartes fonctionnelles pour permettre des comparaison intra- et inter-sujets. Une étude prospective sur 25 volontaires (10 femmes, 45 ± 17 ans) respirant librement a été menée, avec des acquisitions répétées en position allongée. La fiabilité de la technique a été approchée selon deux critères : sa répétabilité et son exactitude. Les mesures de volumes courants locaux intégrés sur le volume pulmonaire correspondent à ce qui peut être mesuré par segmentation des volumes pulmonaires. Une excellente répétabilité globale a été trouvée, avec une variabilité résiduelle induite par celle intrinsèque à la respiration.La sensibilité de la spirométrie 3D par IRM a été d'abord étudiée sur 25 volontaires sains en position allongée sur le dos puis sur le ventre. Les cartes fonctionnelles mettent en évidence un gradient de ventilation vers les régions les plus dépendantes à la gravité, démontrant la sensibilité de la technique à la physiologie. Des atlas fonctionnels ont été établis à partir des cartes individuelles normalisées, révélant les motifs nominaux de la ventilation pulmonaire reproductibles sur la cohorte de volontaire. Les distributions spatiales mettent en évidence l'inhomogénéité de la ventilation en respiration libre.Enfin, la sensibilité de la spirométrie 3D aux pathologies obstructives et restrictives est évaluée à travers plusieurs études de cas de maladies neuromusculaires, COVID-19 longue durée, asthme et bronchopneumopathie chronique obstructive (BPCO). Ces recherches soulignent l'importance de caractériser les modes de respiration avec les contributions des muscles respiratoires. La réversibilité de l'asthme à l'administration d'un bronchodilatateur a été trouvé, avec une augmentation marquée des débits après bronchodilatateurs. Une étude longitudinale sur un cas d'asthme sévère a aussi mis en évidence l'efficacité de la biothérapie pour améliorer la fonction ventilatoire, réduisant le volume résiduel ainsi que l'obstruction
Ventilation is a complex function, with unpredictable natural intra- and inter-individual variabilities, sometimes heterogeneous in lung volume. Standard spirometry is the reference exam to assess the ventilatory function from flow-volume loops measured at the mouth during forced expiration. This simple and reliable technique is limited by the necessary cooperation of the patient, as well as by the global nature of its measurement. Since breathing is inherently a three-dimensional phenomenon and lung diseases are generally regional, ventilation should be probed locally.Despite the inherent difficulties in applying MRI to the lung, recent advancements have revealed the potential of functional pulmonary MRI from easily translatable standard acquisitions in clinical settings. Over the past fifteen years, developments have evaluated ventilation based on MRI signal variation during respiration. These techniques rely on a strong assumption of linearity of the MRI signal with lung tissue density. A new method evaluating ventilation locally and dynamically from deformations has been developed: 3D spirometry by MRI. From an average respiratory cycle, the deformation Jacobian and its temporal derivative allow inference of local flow-volume curves. This thesis aims to validate 3D spirometry by MRI, bring it into clinical research, and deepen the understanding of ventilatory mechanics.The multidimensional nature of 3D spirometry by MRI integrates the complexity of respiratory function, but the new technique must still be developed and tested. Methodological developments undertaken during this thesis include optimized reconstruction of pulmonary dynamics, precise segmentation of lobar structures, definition of quantitative biomarkers, as well as normalization of functional maps to enable intra- and inter-subject comparisons. A prospective study on 25 volunteers (10 females, 45 ± 17 years old) breathing freely was conducted, with repeated acquisitions in the supine position. The reliability of the technique was approached by two criteria: its repeatability and accuracy. Measures of local tidal volumes integrated over the lung volume agreed to the measured lung volumes from segmentation. Excellent overall repeatability was found, with residual variability induced by that intrinsic to respiration.The sensitivity of 3D MR spirometry was first studied in 25 healthy volunteers in lying supine and prone positions. Functional maps highlight a gradient of ventilation toward the more gravity-dependent regions, demonstrating the sensitivity of the technique to physiology. Functional atlases were established from normalized individual maps, revealing reproducible nominal patterns of pulmonary ventilation across the volunteer cohort. Spatial distributions highlight the heterogeneity of ventilation during free breathing.Finally, the sensitivity of 3D MR spirometry to obstructive and restrictive pathologies is evaluated through several case studies of neuromuscular diseases, long COVID-19, asthma, and chronic obstructive pulmonary disease (COPD). These studies emphasize the importance of characterizing breathing patterns with contributions from respiratory muscles. Reversibility of asthma with bronchodilator administration was found, with a marked increase in flow rates after bronchodilators. A longitudinal study on a case of severe asthma also demonstrated the effectiveness of biotherapy in improving ventilatory function and reducing residual volume and obstruction

Thesis (Ph. D.)--Harvard-MIT Division of Health Sciences and Technology, 2005.
Includes bibliographical references (leaves 80-88).
Neutrophils traversing the pulmonary microcirculation are subjected to mechanical stimulation during their deformation into narrow capillaries. To better understand the time- dependant changes caused by this mechanical stimulus, in the first part of the thesis, neutrophils were caused to flow into a microchannel, which allowed simultaneous visualization of cell morphology, and passive rheological measurement by tracking the Brownian motion of endogenous granules. Above a threshold stimulus, mechanical deformation resulted in neutrophil activation with pseudopod projection. The activation time was inversely correlated to the rate of mechanical deformation experienced by the neutrophils. A reduction in shear moduli was observed within seconds after the onset of the mechanical stimulus, suggesting a sudden disruption of the neutrophil cytoskeleton when subjected to mechanical deformation. However, the magnitude of the reduction in moduli was independent of the degree of deformation. Recovery to nearly the initial values of viscoelastic moduli occurred within one minute. These observations confirm that mechanical deformation of neutrophils, similar to conditions encountered in the pulmonary capillaries is not a passive event; rather, it is capable of activating the neutrophils and enhancing their migratory tendencies. The second part of the thesis seeks to understand the changes in the cytoskeletal structure and the extent of biological activation as a result of this deformation process. Neutrophils were passed through narrow polycarbonate filter pores under physiological driving pressures, fixed and stained downstream in order to visualize the F-actin content and distribution.
(cont.) Below a threshold capillary size, the cell remodeled its cytoskeleton through initial F-actin depolymerization, followed by recovery and increase in F-actin content associated with formation of pseudopods. 'This rapid depolymerization and subsequent recovery of F-actin was consistent with our previous observation of an immediate reduction in moduli with eventual recovery when the cells were subjected to deformation. Results also show that neutrophils must be retained in their elongated shape for an extended period of time for pseudopod formation, suggesting that a combination of low driving pressures and small capillary diameters promotes cellular activation. These observations show that mechanical deformation of neutrophils into narrow pulmonary capillaries have the ability to influence cytoskeletal structure, the degree of cellular activation and migrational capabilities of the cells.
by Belinda Yap.
Ph.D.

A avaliação da mecânica respiratória (AMR) busca descrever o comportamento mecânico do sistema respiratório, para melhor entender a sua fisiologia e a sua patofisiologia. O método quasi-estático é caracterizado pela AMR em condições nas quais a aceleração dos tecidos pode ser considerada desprezível. Esta dissertação de mestrado teve como objetivo avaliar a mecânica respiratória pelo método quasi-estático em roedores, utilizando um insuflador pulmonar para pequenos roedores (IPPR) construído no Laboratório de Engenharia Biomédica (LEB) da Escola Politécnica da Universidade de São Paulo (EPUSP). Uma extensa revisão da literatura sobre fisiologia e técnicas de AMR em humanos e roedores é apresentada. Uma documentação bastante detalhada sobre a implementação e o funcionamento do IPPR é fornecida, com o intuito de permitir que o dispositivo seja reproduzido. Testes de bancada foram executados, para avaliar o funcionamento do IPPR, e um protocolo experimental com modelo animal de doença, em ratos Wistar envenenados por Paraquat, foi realizado. Os resultados dos testes de bancada mostraram que o equipamento ainda carece de alguns ajustes, pois apresenta erros na indicação de volume, da ordem de 5%, mas que podem ser compensados na análise dos dados experimentais obtidos. No futuro, pretende-se sanar essa imprecisão, tornando o IPPR independente de um microcomputador com sistema operacional multitarefa. Os resultados da aplicação do modelo matemático exponencial, nos dados obtidos de curvas pressão-volume no protocolo experimental, trouxeram informações que estão de acordo com as características observadas no modelo animal de envenenamento por Paraquat.
The assessment of respiratory mechanics (AMR) aims to describe the mechanical behavior of the respiratory system in order to better understand its physiology and pathophysiology. The quasi-static method is characterized by the AMR under conditions where the tissue\'s acceleration can be considered negligible. The purpose of this master degree dissertation was to assess the respiratory mechanics by quasistatic method in rats using a lung insufflator for small rodents (IPPR) implemented in the Biomedical Engineering Laboratory (LEB) of Escola Politécnica of University of São Paulo (EPUSP). Abroad literature review on AMR techniques and on physiology in humans and rodents was presented. A fairly detailed documentation of the assembly and the operation of the IPPR was provided in order to allow the device to be reproduced. Bench tests were conducted to evaluate the behavior of the IPPR, and an animal disease model by Paraquat poisoning protocol was performed in Wistar rats. The bench tests results showed that the equipment still needs some tweaking, because it presents errors in volume indication of the order of 5%, but these errors can be compensated in the analysis of the experimental data. In the future, there is an intention to correct this inaccuracy turning the IPPR independent of a multitask microcomputer operating system. The results of the mathematical exponential modeling applied on the pressure-volume curves in the experimental protocol are in good agreement with the characteristics observed on Paraquat poisoning animal model.

Este trabalho é uma contribuição importante para o desenvolvimento de um modelo numérico de arênquima pulmonar capaz de simular manobras de ventilação mecânica. O pulmão é um órgão estruturalmente complexo e hierarquizado. Por isso uma revisão bibliográfica multidisciplinar foi realizada. A revisão apresenta as propriedades mecânicas do parênquima, sua morfologia e os efeitos da tensão superficial para a contração e adesão dos septos interalveolares. Um aspecto importante para o modelo de alvéolo é um modelo de contato com adesão causada pela tensão superficial. Um modelo de contato adesivo simplificado foi desenvolvido e simulado em uma estrutura com parâmetros de mesma ordem de grandeza de um alvéolo real. A simulação foi realizada com o método dos elementos finitos não-linear e foi necessário empregar o método da corda para evitar divergência em pontos limites. Os resultados numéricos se aproximaram de resultados experimentais globai no pulmão com pressões de mesma ordem de grandeza.
This work is an important step on the development of a computational model of lung parenchyma capable to simulate mechanical ventilation maneuveres. The lung has a complex and hierarchized structure. Therefore a multidisciplinary literature review was held. The review presents the mechanical properties of the parenchyma, its morphology and the effects of surface tension to septums contraction and adhesion. An important aspect for the alveolus model is a contact model which includes the adhesion caused by surface tension. Thus a simplified model was developed and then simulated in a structure with properties of the same order of magnitude of a real alveolus. The simulation was performed with the nonlinear finite element method. The implementation of the arc-length method was also necessary in order to prevent diversion at limit points. The numerical results were close to whole lung experimental results with pressure levels of the same order of magnitude.

Thesis (M. Eng.)--Massachusetts Institute of Technology, Biological Engineering Division, 2006.
Includes bibliographical references (p. 73-79).
Neutrophils in the pulmonary microcirculation are subjected to mechanical deformation while traveling through capillaries of sizes much smaller than the mean neutrophil diameter. This deformation has been shown to result in significant reductions in both the shear storage and shear loss moduli of the cell, with subsequent recovery towards their initial values. Also, deformation above a threshold stimulus results in neutrophil activation, evidenced by pseudopod projection from the cell. These two events are thought to occur via independent pathways, yet little is known about the mechanosensing signaling involved. Other work has demonstrated that physiological deformation of neutrophils induces a marked increase in the levels of cytosolic calcium, suggesting that this occurrence may trigger the biomechanical response observed in the cell. The aim of this thesis was to elucidate the role of calcium in the neutrophil response to the mechanical deformation experienced during transit through the pulmonary capillaries.
(cont.) Chelating intracellular calcium in neutrophils resulted in (i) decreased deformability of the cells into a microchannel, (ii) attenuation of the drop in shear storage modulus (G') observed in untreated cells upon deformation, and (iii) shorter activation times. These findings suggest that cytosolic calcium holds an important function in the neutrophil transit through the capillaries, and inhibition of normal calcium release within the cell can lead to leukostasis-like conditions.
by Jeffrey J Hsu.
M.Eng.

Pacientes portadores de doença pulmonar obstrutiva crônica (DPOC) podem apresentar assincronia toracoabdominal (ATA). Existem diversos métodos de estimativa da ATA, porém, não há um consenso sobre qual é o mais adequado. O objetivo deste estudo foi comparar dois métodos de estimativa da assincronia toracoabdominal e avaliar a ineficiência ventilatória em pacientes DPOC no repouso e durante o exercício. Foram avaliados 22 pacientes com DPOC (VEF1 40,2±10,5% predito) e 13 indivíduos controle (GC) pareados por idade, gênero e índice de massa corpórea. A cinemática toracoabdominal foi avaliada utilizando pletismografia optoeletrônica no repouso e durante o exercício leve e moderado (70% da carga máxima) no ciclo ergômetro. A ATA foi calculada entre a caixa torácica superior (CTS) e inferior (CTI) e o abdome (ABD) utilizando os métodos de ângulo de fase (AF) e relação de fase (RF). A ineficiência ventilatória foi calculada em cada compartimento como a diferença entre o volume máximo (VM) e o volume calculado (VC) de acordo com o ciclo respiratório (determinado pela soma de volume dos três compartimentos) dividida pelo volume máximo (VM-VC)/VM. Os pacientes com DPOC foram classificados como assíncronos (grupo AT) ou não assíncronos (grupo NA) utilizando como referência os valores do GC. Foi utilizado o teste qui-quadrado ou de Fisher para avaliar a discriminação de pacientes entre os métodos e o ANOVA de dois fatores para comparações entre os grupos. O nível de significância foi ajustado para 5%. O método AF determinou maior número de pacientes com ATA quando comparado com RF no repouso (respectivamente, 15 vs. 7) e no exercício leve (11 vs. 3) e moderado (14 vs. 8). Os valores de assincronia no grupo AT entre CTS-CTI e CTI-ABD foram maiores no repouso (AF: 35,7±45,4° e -42,2±42,5° e RF: 61,8±29,1° e -66,9±27,4°, respectivamente) e no exercício leve (AF: 53,3±35,6° e -55,8±40,4°; RF: 106,1±40,3° e - 124,8±17,2°) e moderado (AF: 61,6±55,1° e -75,9±44,8°; RF: 85,9±23,6° e -81,8±42,2°) quando comparados com os grupos NA (p < 0,05) e GC (p < 0,05). Na análise entre CTSABD não houve diferença entre os grupos. Observou-se que o grupo AT apresentou menor contribuição e maior ineficiência ventilatória da CTI em todos os momentos de avaliação e, durante o exercício moderado, menor volume corrente quando comparado com os grupos NA e GC. Os nossos resultados sugerem que o ângulo de fase apresenta maior detecção de ATA nos pacientes com DPOC. A presença de assincronia parece ocorrer principalmente na caixa torácica inferior e associada com menor contribuição e maior ineficiência ventilatória deste compartimento
Chronic obstructive pulmonary disease (COPD) patients can present thoracoabdominal asynchrony (TAA). There are several TAA estimation techniques, however, there is no consensus about which is the most appropriate. The aim of this study was to compare two thoracoabdominal asynchrony quantification techniques and to assess chest wall ventilatory inefficiency in COPD patients at rest and during exercise. We evaluated 22 COPD patients (FEV1 40,2±10,5% predicted) and 13 healthy controls (CG) matched by age, gender and body mass index. Thoracoabdominal kinematics was assessed via optoelectronic plethysmography at rest and during mild and moderate exercise (70 % maximum workload) in a cycle ergometer. TAA was calculated among upper (URC) and lower ribcage (LRC) and abdomen (ABD) by using the phase angle (PA) and phase relation (PR) approaches. Ventilatory Inefficiency was estimated in each compartment as the difference between the maximal volume (VM) and the volume (VC) calculated according to respiratory timing (sum of volume in the 3 compartments) divided by the maximal volume (VM-VC)/VM. COPD patients were classified as asynchronous (AT group) or not (NA group) by using as reference the values on the controls. Chi-square or Fisher\'s exact test was used for assessing the patients differentiation between the two TAA quantification approaches and two-way ANOVA was used to compare respiratory parameters among groups (CG, AT and NA). Statistical significance was set at 5% level. PA approach determined more patients as asynchronous when compared to RF at rest (respectively, 15 vs. 7) and during mild (11 vs. 3) and moderate (14 vs. 8) exercise. Asynchrony values in AT group among URC-LRC and LRC-ABD were greater at rest (respectively, 35.7±45.4° and -42.2±42.5° with PA and 61.8±29.1° and -66.9±27.4° with PR) and during mild (PA: 53.3±35.6° and -55.8±40.4°; PR: 106.1±40.3° and -124.8±17.2°) and moderate exercise (PA: 61.6±55.1° and - 75.9±44.8°; PR: 85.9±23.6° and -81.8±42.2°) when compared to NA (p < 0.05) and CG (p < 0.05). Analysis among URC-ABD presented no difference between groups. It was observed that AT group presented a smaller LRC contribution and greater ventilatory inefficiency during all assessing moments and, during moderate exercise, had a lower tidal volume when compared to NA and CG. Our results suggest that phase angle approach presents larger TAA detection in COPD patients. This asynchrony seems to occur mainly in the lower ribcage and be associated with decreased contribution and increased ventilatory inefficiency of this compartment

This research utilizes CFD to analyze blood flow through pathways representative of central shunts, commonly used as part of the Fontan procedure to treat cyanotic heart disease. In the first part of this research, a parametric study of steady, Newtonian blood flow through parabolic pathways was performed to demonstrate the effect that flow pathway curvature has on wall shear stress distribution and flow energy losses. In the second part, blood flow through two shunts obtained via biplane angiograms is simulated. Pressure boundary conditions were obtained via catheterization. Results showed that wall shear stresses were of sufficient magnitude to initiate platelet activation, a precursor for thrombus formation. Steady results utilizing time-averaged boundary conditions showed excellent agreement with the time-averaged results obtained from pulsatile simulations. For the points of interest in this research, namely wall shear stress distribution and flow energy loss, the Newtonian viscosity model was found to yield acceptable results.

Las enfermedades pulmonares intersticiales difusas (EPID), constituyen un grupo variado de trastornos inflamatorios difusos de las vías aéreas inferiores causadas por inflamación, fibrosis (cicatritzación) de las paredes alveolares y grosor del espacio intersticial. Como muchas de estas EPID dan lugar a la formación de fibrosis, también se las llama fibrosis pulmonar (FP). Tanto la fisiopatología de la enfermedad como los mecanismos bioquímicos que se desencadenan son poco conocidos. La lesión pulmonar inducida por fármacos como la bleomicina, es heterogénea y rápida en su inicio, con una fase de alveolitis inicial caracterizada por la presencia de edema intersticial y de infiltración de células inflamatorias como los neutrófilos, macrófagos y limfocitos, que a su vez conducirán a una proliferación de los fibroblastos. Después hay una segunda fase, más fibrótica, que se caracteriza por la deposición de colágeno y de otros componentes de la matriz extracelular que resultarán en una distorsión de la arquitectura pulmonar.

Como creemos que los parámetros biomecánicos pueden ser de gran utilidad en el seguimiento de las estrategias terapéuticas así como también del conocimiento general de la historia natural de las EPID, queremos saber cuál es la influencia de la respuesta inflamatoria en las diferentes fases evolutivas de la FP sobre la biomecánica del parénquima. Por eso utilizamos un modelo murino de lesión pulmonar de dos semanas o de un mes de durada, inducida por dosis única o dosis repetidas de bleomicina respectivamente.

En el primer trabajo, utilizamos tiras de paánquima pulmonar para el estudio biomecánico (elastancia, resistencia (R0) e histeresividad (mi(0)) los días 3, 7 y 15 después de una instilación única sub-letal de bleomicina. Se analizaron también el impacto de la inflamación pulmonar (mieloperoxidasa (MPOL), índice de inflamación pulmonar (LI) y el contenido de agua pulmonar (WL)) y de la remodelación pulmonar (hidroxiprolina (HPL) y fibras elásticas) en los mismos días en los que se hizo el estudio mecánico. Los hallazgos más significativos sugieren que este modelo proporciona nuevas evidencias para la comprensión de la fisiopatología de la lesión pulmonar inducida por bleomicina y la relación entre los cambios inflamatorios y la mecánica del tejido pulmonar. Los parámetros disipativos del tejido pulmonar se vieron modificados después de la lesión: tanto R0 como mi(0) estuvieron correlacionadas con la MPOL, WL y LI. No encontramos correlaciones significativas entre HPL y los parámetros mecánicos, pero si de la elastina con mi(0) i el grosor de la paret alveolar.

En el segundo trabajo, usamos tiras de parénquima pulmonar para hacer el estudio mecánico el día 28 después de una instilación única sub-letal o después de tres dosis de bleomicina cada dos semanas. Se analizó el impacto de la inflamación pulmonar (MPOL y LI) y de la remodelación pulmonar (fibras de colágeno) en los mismos días en que se hizo el estudio mecánico. En el modelo de tres dosis repetidas por bleomicina se halló una infiltración de células inflamatorias, un incremento de la MPO y de las fibras de colágeno, la presencia de focos fibroblásticos y un aumento tanto de la elastancia (H) como de la amortiguación tisular (G), 28 dáas después de la última dosis. Sin embargo, en el modelo de dosis única, el colágeno aumentó sin que hubiesen cambios significativos en la mecánica pulmonar.

During the progression of pulmonary arterial hypertension (PAH), the smooth muscle of the pulmonary artery changes phenotypically in several ways. Although many of these changes have been characterized, more remains to be understood about the mechanical properties of pulmonary arterial smooth muscle (PASM) cells and their role in PAH. To address this, PASM cells were studied using traction force microscopy to test their fluidization response to stretch, to determine if changes in contractility occur in the setting of PAH, and to screen a preliminary set of myosin inhibitors for those which relax the cell. As predicted, PASM cells produced a similar fluidization-resolidification response to transient stretch as shown in previous studies of other smooth muscle cell types. Although the statistical significance is not strong (p=0.082), PASM cells incubated in serum from PAH patients did show an increased average baseline contractility compared to cells treated with serum from normal volunteers. Of three myosin inhibitors tested, blebbistatin had a statistically significant (p=0.002) reduction in baseline contractility compared to untreated control cells. Taken together, these results support the hypothesis that stretch-induced fluidization is a feature of the normal PASM cell and suggest that factors in the PAH milieu may cause changes in the PASM cell, yielding a more contractile phenotype. A possible avenue for treating PAH may lie in using myosin inhibitor drugs such as blebbistatin to reduce contractility of the PASM cell.

La procédure de Ross: Propriétés biomécaniques de l'artère pulmonaire en fonction du phénotype valvulaire aortique Pierre Olivier Dionne, Evan Wener, Alexander Emmott, Raymond Cartier, Rosaire Mongrain, Richard Leask et Ismail El-Hamamsy OBJECTIFS: Le but de cette étude est de déterminer si les propriétés des artères pulmonaires des patients bénéficiant d'une procédure de Ross ayant une valve aortique bicuspide sont différentes que celles des patients ayant une valve aortique tricuspide. MÉTHODOLOGIE: Trente-deux artères pulmonaires et 20 aortes ont été prélevées chez des patients subissant une procédure de Ross au moment de la chirurgie, dans une cohorte de 32 patients. L'analyse histologique et l'étude tensile equi-biaxiale ex-vivo complétées dans les 8 heures suivant le prélèvement furent utilisées afin d'évaluer les différences entre les groupes de patients et entre les artères pulmonaires et les aortes ascendantes. RÉSULTATS: Il n'y avait aucune différence d'épaisseur au niveau des artères pulmonaires lorsque comparées en fonction du phénotype valvulaire aortique (P = 0.94). Il n'y avait aucune différence au niveau des propriétés tensiles parmi les aortes et les artères pulmonaires lorsque comparées en fonction du phénotype valvulaire. Lorsque comparées en fonction de leur indication chirurgicale, les artères pulmonaires de patients ayant une régurgitation aortique pure étaient moins rigides que leur contre-partie (P = 0.002). Il n'y avait aucune différence au niveau du nombre de lamelles élastiques entre les spécimens d'artère pulmonaire en fonction du phénotype valvulaire aortique (Tricuspide, bicuspide ou unicuspide), ni entre les spécimens aortiques. CONCLUSION: Aucune différence significative ne fut observée au niveau des propriétés biomécaniques des artères pulmonaires lorsque comparées selon leur phénotype valvulaire aortique associé.
The Ross procedure: biomechanical properties of the pulmonary artery according to aortic valve phenotype Pierre Olivier Dionne, Evan Wener, Alexander Emmott, Raymond Cartier, Rosaire Mongrain, Richard Leask and Ismail El-Hamamsy OBJECTIVES: The aim of this study is to determine whether patients undergoing the Ross procedure with bicuspid aortic valves have different pulmonary artery biomechanical properties from those with tricuspid valves. METHODS: Thirty-two pulmonary arteries and 20 aortas were obtained from patients undergoing the Ross procedure at the time of surgery, from a cohort of 32 patients. Histological analysis and ex vivo equi-biaxial tensile testing completed within 8 hours of surgery were used to evaluate differences in patient groups and between the pulmonary artery and the ascending aorta. RESULTS: There was no difference in thickness among pulmonary arteries when compared according to aortic valve phenotype (P = 0.94). There was no difference in the tensile tissue properties among aortas and pulmonary arteries when compared according to aortic valve phenotype, in either the circumferential or longitudinal axis. When compared according to the main surgical indication, pulmonary artery walls from patients with pure aortic regurgitation were less stiff than their counterparts (P = 0.002). There was no difference in the number of elastic lamellae in pulmonary artery specimens from the three different aortic valve phenotypes (Tricuspid, bicuspid or unicuspid), as well as in the aortic specimens. CONCLUSION: No significant differences were observed in the biomechanical properties of pulmonary arteries when compared according to aortic valve phenotype.

Emphysema is a disease of the lung parenchyma associated with chronic obstructive pulmonary disease (COPD) and characterized by progressive, irreversible tissue destruction. While chronic inflammation due to repeated noxious particle exposure is the most common environmental risk factor, biomechanical stresses are also known to contribute. It is thought that inflammation-related enzymatic weakening predisposes tissue to mechanical failure, leading to self-propagating parenchymal destruction. However, essential questions regarding the underlying disease mechanisms and their link to overall lung decline remain unanswered. The overarching goals of this dissertation were to relate changes at the cell and tissue level to lung structure and function, and to determine how clinical interventions impact the mechanical balance of parenchymal tissue stresses. First, we use a computational network model of lung volume reduction, a palliative treatment for end-stage emphysema, to demonstrate how recent bronchoscopic, biomaterial-based treatments can achieve similar outcomes as traditional surgical procedures. Next, in a cohort of COPD patients with follow-up computed tomography (CT) imaging, we identify a previously unrecognized structural feature of emphysema that suggests a fundamentally new mechanism of disease progression and potential target for tissue engineering solutions. Finally, we describe the design and implementation of an ex vivo platform for cyclic stretching of precision-cut lung slices, demonstrating a stretch-dependent inflammatory response to acute cigarette smoke extract exposure. In summary, this work combines computational modeling, clinical imaging, and ex vivo measurements to characterize the biomechanical stresses driving emphysema progression and provide new insight that may inform more rational, patient-specific treatment strategies.
2020-07-02T00:00:00Z