Chronic obstructive pulmonary disease (COPD) is a growing health concern associated with high morbidity and mortality, and is currently the third-ranked cause of death in the United States. COPD is characterized by airflow limitation that is not fully reversible and includes chronic bronchitis, functional small airway disease, and emphysema. The interrelationship between emphysema and airway disease in COPD makes it a highly complex and heterogeneous disorder. Appropriate diagnosis of COPD is vital to administer targeted therapy strategies that can improve patient’s quality of life and reduce the frequency of COPD associated exacerbations. Although spirometry or pulmonary function tests are currently the gold standard for the diagnosis and staging of the disease, their lack of reproducibility and minimal information on regional characterization of the lung tissue destruction makes it hard to rely on to phenotype COPD population and predict disease progression. Quantification of COPD, as done by computed tomography (CT) methods has seen significant advancements, helping us understand the complex pathophysiology of this disease. The prospective and established techniques that are derived from CT imaging such as densitometry, texture, airway, and pulmonary vasculature-based analyses have been successful in regional characterization of emphysema related lung tissue destruction and airway disease related morphological changes in COPD patients. Although, these measures enriched our diagnostic and treating capability of COPD, they lack information on patient specific alterations in lung mechanics and regional parenchymal stresses. This valuable information can be achieved through the use of image registration protocols. Our main goal of this research work is to examine and evaluate the role of lung mechanical measures derived from CT image registration techniques in COPD diagnosis, phenotyping, and progression.

This thesis investigates variability in airway caliber and the distribution of ventilation within the human lung as thought to occur in asthma. Currently, the understanding of how an integrated network of airways can lead to temporal and spatial variation as found in the human lung is unclear. Throughout this thesis, a multibranch airway tree model was used in a forward modeling approach. In a variability study, the mean airway resistance (RL) was observed to be proportional to the standard deviation in airway resistance (SDRL) as reported in the literature under several conditions of airway diameter indicating the strong robustness of this behavior. The model predicted previously reported RL distributions and the reported proportionality of SDRL and RL, but only when we included coherency between airways. In a second study, patient specific ventilation was investigated using an image functional approach by closing specific airways (creating defects) identified by hyperpolarized 3He MRI from asthmatic subjects. Impedance predictions from the imposed heterogeneous ventilation were then calculated and correlated to 3He MRI ventilation defect percent (VDP), plethysmography, and spirometry data. These predictions suggest the forced oscillation technique (FOT) to be a superior metric toward the evaluation of the VDP. In a third study, we investigated how asymmetric branching could play a role in ventilation defect emergence and persistence. At high muscle activation levels simulating an asthmatic episode, airway trees with greater asymmetry reached steady state sooner, with defects that were more persistent in location, had lower RL values (~50%), and greater EL values (~25%) after bronchoconstriction. These results suggest the initial formation of ventilation defects was dependent on airway instability; however, the location and persistence of ventilation defects may be due to geometric airway structure. By modeling the contribution of ventilation defects to lung impedance, we were able to show that defects can play a role in governing the relationship between RL and its variation, and the effect of defects through VDP could be better assessed using FOT. Moreover, lung structure contributed to the emergence and persistence of ventilation defects, meaning that defects could be potentially ameliorated through structural intervention.

The aim of this study is to investigate the functional and structural differences between normal subjects and asthmatics via image registration and computational fluid dynamics (CFD), together with pulmonary function test's (PFT) and one-image-based variables. We analyzed three populations of CT images: 50 normal, 42 non-severe asthmatic and 52 severe asthmatic subjects at total lung capacity (TLC) and functional residual capacity (FRC). A mass preserving image registration technique was employed to match CT images at TLC and FRC for assessments of regional volume change and anisotropic deformation. Instead of existing threshold-based air-trapping measure, a fraction-based air-trapping measure was proposed to account for inter-site and inter-subject variations of CT density. We also analyzed structural alterations of asthmatic airways, including bifurcation angle, hydraulic diameter, luminal area and wall area. CFD and particle tracking simulations are employed with physiologically-consistent boundary condition. As compared with normal subjects, severe asthmatics exhibit reduced air volume change (consistent with air-trapping) and more isotropic deformation in the basal lung regions, but increased air volume change associated with increased anisotropic deformation in the apical lung regions. In the multi-center study, the traditional air-trapping measure showed the significant site-variability due to the differences of scanners and coaching methods. The proposed fraction-based air-trapping measure is able to overcome the inter-site and inter-subject variations, allowing analysis of large data sets collected from multiple centers. We further demonstrate alterations of bifurcation angle, constriction, wall thickness and non-circularity at local branch level in severe asthmatics. The bifurcation angle, non-circularity and especially reduced hydraulic diameter significantly affect the increase of particle deposition in severe asthmatics. In summary, the two-image registration-based deformation provides a tool for distinguishing differences in lung mechanics among populations. The new fraction-based air-trapping measure significantly improves the association of air-trapping with the presence and severity of asthma and the correlation with forced expiratory volume in 1 second over forced vital capacity (FEV1/FVC) than existing approaches. The altered functions and structures such as air-volume change, branching angles, non-circular shapes, wall thickness and hydraulic diameters that found in asthmatics are strongly associated with the flow structures and particle depositions.

Mulheres asmáticas na pós-menopausa podem apresentar piora dos sintomas, portanto neste trabalho investigamos o papel dos hormônios sexuais femininos (HSF) sobre a inflamação alérgica pulmonar. A re-exposição ao antígeno exacerbou a inflamação alérgica pulmonar e a liberação de mediadores no pulmão dos animais alérgicos ovariectomizados (OVx). O valor da reatividade traqueal foi semelhante ao observado nos animais alérgicos Sham/OVx. O tratamento com estrógeno exacerbou a inflamação pulmonar, mas atenuou a reatividade das vias aéreas. O tratamento com progesterona não alterou o número de células do lavado broncoalveolar e atenuou a reatividade das vias aéreas, apesar acentuar a produção de muco e de colágeno. O tratamento com estrógeno em associação com a progesterona atenuou a inflamação pulmonar aos valores encontrados nos animais alérgicos Sham/OVx. Nossos estudos apontam para uma possível dissociação entre os efeitos moduladores dos HSF sobre a resposta inflamatória, notadamente no recrutamento celular e as alterações de mecânica respiratória. / Asthmatic postmenopausal women may experience worsening of symptoms, so in this work we investigated the role of female sex hormones (HSF) on pulmonary allergic inflammation. The re-exposure to antigen exacerbated allergic lung inflammation and release of mediators in the lungs of ovariectomized allergic mice (OVX ) . The value of tracheal reactivity was similar to that observed in allergic Sham/OVx . Treatment with estrogen exacerbated pulmonary inflammation but attenuated airways reactivity. Treatment with progesterone did not alter the number of cells in bronchoalveolar lavage and attenuated airways reactivity, although enhance mucus production and collagen. Treatment with estrogen in combination with progesterone attenuated lung inflammation to the values found in allergic animals Sham/OVx. Our studies point to a possible dissociation between the modulatory effects of HSF on the inflammatory response, especially on cell recruitment and alterations in respiratory mechanic.

[Truncated abstract] Respiratory system impedance (Zrs) is commonly measured at low to medium frequencies (0.5 - 40 Hz) to infer structural and physiological information about the respiratory system. Coupled with the use of mathematical models of the lungs, Zrs has been used to partition the behaviour of the conductive airways and the respiratory tissues. High-frequency (HF) Zrs beyond 100 Hz has been comparatively less studied and understood. Past work has revealed spectral features at high frequencies termed antiresonances, marked by peaks in the real part of Zrs, often coinciding with zero-crossings in the imaginary part. It has been shown that the first occurrence of antiresonance in humans primarily reflects the contribution of the airways, and is a property of sound wave propagation in the airways. Also, the first antiresonance is altered in diseases such as chronic airflow obstruction, and wheeze in infants. The main aim of this project is to shed further understanding about the first antiresonance, via the behaviour of two parameters characterising this feature of the HF spectrum: the frequency at which the first antiresonance occurs, far,1, and the magnitude of the real part of Zrs at this frequency, Rrs(far,1). In our studies, Zrs is measured as an input impedance using the forced oscillation technique with a loudspeaker-in-box and wavetube setup, and employing pseudorandom frequency signals. We studied the effects of altered lung conditions, first in an animal model, then progressed on to humans. v vi In the rat, we found that both far,1 and Rrs(far,1) tended to decrease together with increasing lung volume. With methacholine(MCh)-induced bronchoconstriction, rats showed increases in far,1 and Rrs(far,1) with increasing MCh dose, but these occurred at higher doses compared to increases in airway resistance. The changes in these HF parameters were independent of the changes in tissue properties. ... It was found that in a group of patients with emphysema, VDRrs(far,1) was significantly more negative, potentially due to alterations to airway dimensions and wall properties. Furthermore, VDRrs(far,1) was correlated with extent of obstruction and hyperinflation, suggesting a relationship with severity of emphysema. These results show that the first antiresonance reflect changes in the airways, and its measurement shows promise as a clinical tool, in its potential as an easy-to-perform assessor of conditions in which the airways are altered. Keywords: antiresonance, respiratory input impedance, high frequencies, emphysema

Mulheres asmáticas na pós-menopausa podem apresentar piora dos sintomas, portanto neste trabalho investigamos o papel dos hormônios sexuais femininos (HSF) sobre a inflamação alérgica pulmonar. A re-exposição ao antígeno exacerbou a inflamação alérgica pulmonar e a liberação de mediadores no pulmão dos animais alérgicos ovariectomizados (OVx). O valor da reatividade traqueal foi semelhante ao observado nos animais alérgicos Sham/OVx. O tratamento com estrógeno exacerbou a inflamação pulmonar, mas atenuou a reatividade das vias aéreas. O tratamento com progesterona não alterou o número de células do lavado broncoalveolar e atenuou a reatividade das vias aéreas, apesar acentuar a produção de muco e de colágeno. O tratamento com estrógeno em associação com a progesterona atenuou a inflamação pulmonar aos valores encontrados nos animais alérgicos Sham/OVx. Nossos estudos apontam para uma possível dissociação entre os efeitos moduladores dos HSF sobre a resposta inflamatória, notadamente no recrutamento celular e as alterações de mecânica respiratória. / Asthmatic postmenopausal women may experience worsening of symptoms, so in this work we investigated the role of female sex hormones (HSF) on pulmonary allergic inflammation. The re-exposure to antigen exacerbated allergic lung inflammation and release of mediators in the lungs of ovariectomized allergic mice (OVX ) . The value of tracheal reactivity was similar to that observed in allergic Sham/OVx . Treatment with estrogen exacerbated pulmonary inflammation but attenuated airways reactivity. Treatment with progesterone did not alter the number of cells in bronchoalveolar lavage and attenuated airways reactivity, although enhance mucus production and collagen. Treatment with estrogen in combination with progesterone attenuated lung inflammation to the values found in allergic animals Sham/OVx. Our studies point to a possible dissociation between the modulatory effects of HSF on the inflammatory response, especially on cell recruitment and alterations in respiratory mechanic.

No description available.

Many preterm infants require mechanical ventilation as life-saving therapy. However, ventilation-induced overpressure can result in lung diseases. Considering the lung as a viscoelastic material, positive pressure inside the lung results in increased hydrostatic pressure and tissue compression. To elucidate the effect of positive pressure on lung tissue mechanics and cell behavior, we mimic the effect of overpressure by employing an uniaxial load onto fetal and adult rat lungs with different deformation rates. Additionally, tissue expansion during tidal breathing due to a negative intrathoracic pressure was addressed by uniaxial tension. We found a hyperelastic deformation behavior of fetal tissues under compression and tension with a remarkable strain stiffening. In contrast, adult lungs exhibited a similar response only during compression. Young’s moduli were always larger during tension compared to compression, while only during compression a strong deformation-rate dependency was found. In fact, fetal lung tissue under compression showed clear viscoelastic features even for small strains. Thus, we propose that the fetal lung is much more vulnerable during inflation by mechanical ventilation compared to normal inspiration. Electrophysiological experiments with different hydrostatic pressure gradients acting on primary fetal distal lung epithelial cells revealed that the activity of the epithelial sodium channel (ENaC) and the sodium-potassium pump (Na,K-ATPase) dropped during pressures of 30 cmH2O. Thus, pressures used during mechanical ventilation might impair alveolar fluid clearance important for normal lung function.

Allergic asthma is an inflammatory disease of the airways and is characterized by eosinophilic inflammation and increased airway reactivity. In the studies presented in this thesis, lung mechanics and measurements of airway reactivity were assessed in anaesthetized tracheostomized mice by using an animal ventilator (flexiVent®). A forced oscillation technique makes it possible to measure of both airway and tissue mechanics with a potential to distinguish between central and peripheral airways. The results of the experiments on lung mechanics imply that it is important to understand how altered lung mechanics can affect the airway physiology in order to assess the relevance of different animal models of asthma. We have investigated the effects of changing different components of the lung mechanical measurements, such as administering bronchoconstrictive agents via inhalation or intravenously and implementing deep inhalation in animals with airway inflammation. We have also investigated the relation between airway inflammation and oxidative stress. We found that the formation and time-course of F2-isoprostanes, a marker of oxidative stress, and tissue damage were associated with the degree of inflammation and with the degree of heterogeneous airway airflow. Finally we wished to investigate the hypothesis that nitric oxide (NO) may interact with glucocorticoid (GC) treatment because we see a potential for finding new strategies to increase the therapeutic effect in poor responders or patients resistant to GC treatment. NO plays a central role in physiological regulation of the airway function, and is involved in asthma. We found that the concomitant administration of NO and GC attenuated the airway reactivity more than either treatment alone. In conclusion, with the information presented in this thesis, we hope to contribute to the development of better experimental tools and to improved understanding of murine models of asthma for investigating and understanding the underlying pathophysiology of asthma.

Estudo clínico prospectivo, em 11 pacientes com SARA ou LPA, avaliando o comportamento regional da densidade do tecido pulmonar e do colapso alveolar ao longo dos três eixos do espaço. Foram realizadas tomografias seriadas, após manobra de recrutamento inicial e após níveis de PEEP progressivamente decrescentes. Regressão linear múltipla (R2=0.83) mostrou importante gradiente no eixo gravitacional (p<0.001) e não no sentido céfalo-caudal (p<0.001), nem da direita para a esquerda (p<0.05). Isto corrobora o conceito do pulmão líquido, em que a resultante das pressões exercidas pelo diafragma, estruturas mediastinais e derrames seria transmitida uniformemente pelo tecido pulmonar. Cada um destes níveis isogravitacionais tem uma pressão crítica de fechamento (Pclosing), que é maior do que a pressão superimposta calculada. PEEP tem um efeito homogeneizador sobre o parênquima pulmonar. Dentre os parâmetros clínicos estudados, Pflex mostrou a pior correlação com colapso pulmonar documentado enquanto PO2 e a complacência máxima se mostraram equivalentes. / A prospective clinical study performed on 11 patients with ARDS or ALI with the intention of studying the regional behavior of lung tissue density and alveolar collapse along the three spatial axes. An initial recruitment maneuver was followed by multiple semi-complete CT scans at descending levels of PEEP. Multiple linear regression (R2=0.83) showed a gravitational gradient of densities and collapse (p<0.001) and no cephalo-caudal (p<0.001) or right-toleft increase (p<0.05), corroborating the liquid-like behavior of the lung. Pressure exerted by mediastinal structures, chest wall and effusions is transmitted uniformly throughout the lung. PEEP has a homogenizing effect on lung parenchyma. Among commonly used clinical surrogates, Pflex showed the worst correlation with actual lung collapse, while arterial PO2 and compliance were equivalent.