Lung Tissue Mechanics Research Articles

Changes in lung mechanics and ventilation-perfusion match: comparison of pulmonary air- and thromboembolism in rats

BackgroundPulmonary air embolism (AE) and thromboembolism lead to severe ventilation-perfusion defects. The spatial distribution of pulmonary perfusion dysfunctions differs substantially in the two pulmonary embolism pathologies, and the effects on respiratory mechanics, gas exchange, and ventilation-perfusion match have not been compared within a study. Therefore, we compared changes in indices reflecting airway and respiratory tissue mechanics, gas exchange, and capnography when pulmonary embolism was induced by venous injection of air as a model of gas embolism or by clamping the main pulmonary artery to mimic severe thromboembolism.MethodsAnesthetized and mechanically ventilated rats (n = 9) were measured under baseline conditions after inducing pulmonary AE by injecting 0.1 mL air into the femoral vein and after occluding the left pulmonary artery (LPAO). Changes in mechanical parameters were assessed by forced oscillations to measure airway resistance, lung tissue damping, and elastance. The arterial partial pressures of oxygen (PaO2) and carbon dioxide (PaCO2) were determined by blood gas analyses. Gas exchange indices were also assessed by measuring end-tidal CO2 concentration (ETCO2), shape factors, and dead space parameters by volumetric capnography.ResultsIn the presence of a uniform decrease in ETCO2 in the two embolism models, marked elevations in the bronchial tone and compromised lung tissue mechanics were noted after LPAO, whereas AE did not affect lung mechanics. Conversely, only AE deteriorated PaO2, and PaCO2, while LPAO did not affect these outcomes. Neither AE nor LPAO caused changes in the anatomical or physiological dead space, while both embolism models resulted in elevated alveolar dead space indices incorporating intrapulmonary shunting.ConclusionsOur findings indicate that severe focal hypocapnia following LPAO triggers bronchoconstriction redirecting airflow to well-perfused lung areas, thereby maintaining normal oxygenation, and the CO2 elimination ability of the lungs. However, hypocapnia in diffuse pulmonary perfusion after AE may not reach the threshold level to induce lung mechanical changes; thus, the compensatory mechanisms to match ventilation to perfusion are activated less effectively.

Comparison of the respiratory effects of commonly utilized general anaesthesia regimes in male Sprague-Dawley rats.

Background: Respiratory parameters in experimental animals are often characterised under general anaesthesia. However, anaesthesia regimes may alter the functional and mechanical properties of the respiratory system. While most anaesthesia regimes have been shown to affect the respiratory system, the effects of general anaesthesia protocols commonly used in animal models on lung function have not been systematically compared. Methods: The present study comprised 40 male Sprague-Dawley rats divided into five groups (N = 8 in each) according to anaesthesia regime applied: intravenous (iv) Na-pentobarbital, intraperitoneal (ip) ketamine-xylazine, iv propofol-fentanyl, inhaled sevoflurane, and ip urethane. All drugs were administered at commonly used doses. End-expiratory lung volume (EELV), airway resistance (Raw) and tissue mechanics were measured in addition to arterial blood gas parameters during mechanical ventilation while maintaining positive end-expiratory pressure (PEEP) values of 0, 3, and 6cm H2O. Respiratory mechanics were also measured during iv methacholine (MCh) challenges to assess bronchial responsiveness. Results: While PEEP influenced baseline respiratory mechanics, EELV and blood gas parameters (p < 0.001), no between-group differences were observed (p > 0.10). Conversely, significantly lower doses of MCh were required to achieve the same elevation in Raw under ketamine-xylazine anaesthesia compared to the other groups. Conclusion: In the most frequent rodent model of respiratory disorders, no differences in baseline respiratory mechanics or function were observed between commonly used anaesthesia regimes. Bronchial hyperresponsiveness in response to ketamine-xylazine anaesthesia should be considered when designing experiments using this regime. The findings of the present study indicate commonly used anaesthetic regimes allow fair comparison of respiratory mechanics in experimental animals undergoing any of the examined anaesthesia protocols.

Mechanical properties of the premature lung: From tissue deformation under load to mechanosensitivity of alveolar cells.

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.

Respiratory effects caused by exposure to diesel exhaust particles during moderate exercise: a murine model.

Aerobic exercise is an increasing trend worldwide. However, people are increasingly exercising outdoors, alongside roadways where heavy vehicles release diesel exhaust. We analyzed respiratory effects caused by inhaled diesel particulate emitted by vehicles adhering to Brazilian legislation, PROCONVE Phase P7 (equivalent to EURO 5), as well the effects of exposure during moderate-intensity aerobic exercise. Male C57BL/6 mice were divided into four groups for a 4-wk treadmill protocol: CE (n = 8) received intranasal sterile physiological saline and then performed moderate-intensity exercise (control), CS (n = 10) received saline and then remained stationary on the treadmill (control), DS (n = 9) received intranasal diesel exhaust particles and then remained stationary, and DE (n = 10) was exposed to diesel exhaust and then exercised at moderate intensity. Mice were subsequently connected to a mechanical ventilator (SCIREQ flexiVent, Canada) to analyze the following respiratory mechanics parameters: tissue resistance, elastance, inspiratory capacity, static compliance, Newtonian resistance, and pressure-volume loop area. After euthanasia, peripheral pulmonary tissue strips were extracted and subjected to force-length tests to evaluate parenchymal elastic and mechanical properties, using oscillations applied by a computer-controlled force transducer system; parameters obtained were tissue resistance, elastance, and hysteresivity. DS displayed impaired respiratory mechanics for all parameters, in comparison with CS. DE exhibited significantly reduced inspiratory capacity and static compliance, and increased Newtonian resistance when compared with CE. Exposure to diesel exhaust, both during exercise and rest, still exerts harmful pulmonary effects, even at current legislation limits. These results justify further changes in environmental standards, to reduce the health risks caused by traffic-related pollution.NEW & NOTEWORTHY Exercise, while beneficial, is often performed in areas of greater inhaled particulates. Here we show this effect using mice exposed to controlled diesel particle inhalation and moderate aerobic exercise. Diesel particle inhalation, without or with exercise, worsened both respiratory mechanical properties associated with changes in lung tissue mechanics and morphometry.

Lung and chest wall mechanical properties in metformin-treated and untreated models of type 2 diabetes

The adverse respiratory consequences of type 2 diabetes mellitus (T2DM) may reflect compromised lung function and/or alterations of the chest wall because of skeletal muscle stiffening. We assessed the separate contributions of these compartments to respiratory complications in diabetes and explored the effects of metformin on respiratory abnormalities. Experiments were performed in untreated rats (control, n = 7), high-fat diet-fed rats receiving streptozotocin (T2DM, n = 7), and metformin-treated diabetic rats (MET, n = 6). Newtonian resistance, tissue damping, and elastance were separately assessed for lung and chest wall components by measuring the esophageal pressure during forced oscillations at low (0 cmH2O), medium (3 cmH2O), and high positive end-expiratory pressure (PEEP) (6 cmH2O). Tissue hysteresivity was calculated as damping/elastance. Blood gas parameters were used to assess gas exchange, and lung histology was performed to characterize collagen expression. T2DM at low PEEP compromised airway and lung tissue mechanics in association with gas-exchange defects and collagen overexpression. Abnormal chest wall mechanics in T2DM was indicated only by decreased tissue hysteresivity. No difference in lung or chest wall mechanics, gas exchange, or lung histology was observed between the MET and control groups. These findings suggest the primary involvement of the pulmonary system in the respiratory consequences of T2DM, with chest wall properties only disturbed by a shift toward the dominance of elastic forces at low PEEP. The adequacy of metformin to treat the adverse respiratory consequences of diabetes was also revealed, in addition to its well-established beneficial effects on other organs.NEW & NOTEWORTHY The present study examined the contributions of the lungs and chest wall to respiratory complications in a rat model of diabetes and clarified the effects of metformin on these changes. At low positive end-expiratory pressure, type 2 diabetes was linked to dysfunctional airway and lung tissue mechanics in relation with gas-exchange defects and collagen overexpression, whereas decreased tissue hysteresivity was manifested in the chest wall abnormalities. Metformin treated all adverse respiratory consequences of diabetes.

Non-destructive vacuum-assisted measurement of lung elastic modulus

In living tissues, mechanical stiffness and biological function are intrinsically linked. Alterations in the stiffness of tissues can induce pathological interactions that affect cellular activity and tissue function. Underlying connections between tissue stiffness and disease highlights the importance of accurate quantitative characterizations of soft tissue mechanics, which can improve our understanding of disease and inform therapeutic development. In particular, accurate measurement of lung mechanical properties has been especially challenging due to the anatomical and mechanobiological complexities of the lung. Discrepancies between measured mechanical properties of dissected lung tissue samples and intact lung tissues in vivo has limited the ability to accurately characterize integral lung mechanics. Here, we report a non-destructive vacuum-assisted method to evaluate mechanical properties of soft biomaterials, including intact tissues and hydrogels. Using this approach, we measured elastic moduli of rat lung tissue that varied depending on stress-strain distribution throughout the lung. We also observed that the elastic moduli of enzymatically disrupted lung parenchyma increased by at least 64%. The reported methodology enables assessment of the nonlinear viscoelastic characteristics of intact lungs under normal and abnormal (i.e., injured, diseased) conditions and allows measurement of mechanical properties of tissue-mimetic biomaterials for use in therapeutics or in vitro models. Statement of significanceAccurate quantification of tissue stiffness is critical for understanding mechanisms of disease and developing effective therapeutics. Current modalities to measure tissue stiffness are destructive and preclude accurate assessment of lung mechanical properties, as lung mechanics are determined by complex features of the intact lung. To address the need for alternative methods to assess lung mechanics, we report a non-destructive vacuum-based approach to quantify tissue stiffness. We applied this method to correlate lung tissue mechanics with tissue disruption, and to assess the stiffness of biomaterials. This method can be used to inform the development of tissue-mimetic materials for use in therapeutics and disease models, and could potentially be applied for in-situ evaluation of tissue stiffness as a diagnostic or prognostic tool.

Lung and fissure shape is associated with age in healthy never-smoking adults aged 20\u201390 years

Lung shape could hold prognostic information for age-related diseases that affect lung tissue mechanics. We sought to quantify mean lung shape, its modes of variation, and shape associations with lung size, age, sex, and Body Mass Index (BMI) in healthy subjects across a seven-decade age span. Volumetric computed tomography from 83 subjects (49 M/34 F, BMI 24.7 pm 2.7) was used to derive two statistical shape models using a principal component analysis. One model included, and the other controlled for, lung volume. Volume made the strongest contribution to shape when it was included. Shape had a strong relationship with age but not sex when volume was controlled for, and BMI had only a small but significant association with shape. The first principal shape mode was associated with decrease in the antero-posterior dimension from base to apex. In older subjects this was rapid and obvious, whereas younger subjects had relatively more constant dimension. A shift of the fissures of both lungs in the basal direction was apparent for the older subjects, consistent with a change in tissue elasticity with age. This study suggests a quantifiable structure-function relationship for the healthy adult lung that can potentially be exploited as a normative description against which abnormal can be compared.

A Microfluidic System to Measure Neonatal Lung Compliance Over Late Stage Development as a Functional Measure of Lung Tissue Mechanics.

Premature birth interrupts the development of the lung, resulting in functional deficiencies and the onset of complex pathologies, like bronchopulmonary dysplasia (BPD), that further decrease the functional capabilities of the immature lung. The dysregulation of molecular targets has been implicated in the presentation of BPD, but there is currently no method to correlate resultant morphological changes observed in tissue histology with these perturbations to differences in function throughout saccular and alveolar lung development. Lung compliance is an aggregate measure of the lung's mechanical properties that is highly sensitive to a number of molecular, cellular, and architectural characteristics, but little is known about compliance in the neonatal mouse lung due to measurement challenges. We have developed a novel method to quantify changes in lung volume and pressure to determine inspiratory and expiratory compliance throughout neonatal mouse lung development. The compliance measurements obtained were validated against compliance values from published studies using mature lungs following enzymatic degradation of the extracellular matrix (ECM). The system was then used to quantify changes in compliance that occurred over the entire span of neonatal mouse lung development. These methods fill a critically important gap connecting powerful mouse models of development and disease to measures of functional lung mechanics critical to respiration and enable insights into the genetic, molecular, and cellular underpinnings of BPD pathology to improve lung function in premature infants.

Reversing Cholinergic Bronchoconstriction by Common Inotropic Agents: A Randomized Experimental Trial on Isolated Perfused Rat Lungs.

The ability of inotropic agents to alter airway reactivity and lung tissue mechanics has not been compared in a well-controlled experimental model. Therefore, we compared the potential to alter lung tissue viscoelasticity and bronchodilator effects of commonly used inotropic agents in an isolated perfused rat lung model. After achieving steady state lung perfusion, sustained bronchoconstriction was induced by acetylcholine (ACh). Isolated rat lungs were then randomly allocated to 6 groups treated with either saline vehicle (n = 8) or incremental concentrations of inotropes (adrenaline, n = 8; dopamine, n = 7; dobutamine, n = 7; milrinone, n = 8; or levosimendan, n = 6) added to the whole-blood perfusate. Airway resistance (Raw), lung tissue damping (G), and elastance were measured under baseline conditions, during steady-state ACh-induced constriction and for each inotrope dose. No change in Raw was observed after addition of the saline vehicle. Raw was significantly lower after addition of dopamine (maximum difference [95% CI] of 29 [12-46]% relative to the saline control, P = .004), levosimendan (58 [39-77]%, P < .001), and adrenaline (37 [21-53]%, P < .001), whereas no significant differences were observed at any dose of milrinone (5 [-12 to 22]%) and dobutamine (4 [-13 to 21]%). Lung tissue damping (G) was lower in animals receiving the highest doses of adrenaline (difference: 22 [7-37]%, P = .015), dobutamine (20 [5-35]%, P = .024), milrinone (20 [6-34]%, P = .026), and levosimendan (36 [19-53]%, P < .001) than in controls. Although dobutamine and milrinone did not reduce cholinergic bronchoconstriction, they reversed the ACh-induced elevations in lung tissue resistance. In contrast, adrenaline, dopamine, and levosimendan exhibited both potent bronchodilatory action against ACh and diminished lung tissue damping. Further work is needed to determine whether these effects are clinically relevant in humans.

Do Pulmonary Cavity Shapes Influence Lung Function?

Distribution of lung tissue within the chest cavity is a key contributor to delivery of both blood and air to the gas exchange regions of the lung. This distribution is multifactorial with influences from parenchyma, gravity, and level of inflation. We hypothesize that the manner in which lung inflates, for example, the primarily diaphragmatic nature of normal breathing, is an important contributor to regional lung tissue distribution. To investigate this hypothesis, we present an organ-level model of lung tissue mechanics, which incorporates pleural cavity change due to change in lung volume or posture. We quantify the changes using shape and density metrics in ten healthy subjects scanned supine at end-inspiratory and end-expiratory volumes and ten subjects scanned at both supine and prone end-inspiratory volumes. Comparing end-expiratory to end-inspiratory volume, we see primarily a change in the cranial-caudal dimension of the lung, reflective of movement of diaphragm. In the diaphragmatic region, there is greater regional lung expansion than in the cranial aspect, which is restricted by the chest wall. When moving from supine to prone, a restriction of lung was observed anteriorly, resulting in a generally reduced lung volume and a redistribution of air volume posteriorly. In general, we see the highest in lung tissue density heterogeneity in regions of the lung that are most inflated. Using our computational model, we quantify the impact of pleural cavity shape change on regional lung distribution and predict the impact on regional elastic recoil pressure.

A multi-scale model of gas transport in the lung to study heterogeneous lung ventilation during the multiple-breath washout test.

The multiple-breath washout (MBW) is a lung function test that measures the degree of ventilation inhomogeneity (VI). The test is used to identify small airway impairment in patients with lung diseases like cystic fibrosis. However, the physical and physiological factors that influence the test outcomes and differentiate health from disease are not well understood. Computational models have been used to better understand the interaction between anatomical structure and physiological properties of the lung, but none of them has dealt in depth with the tracer gas washout test in a whole. Thus, our aim was to create a lung model that simulates the entire MBW and investigate the role of lung morphology and tissue mechanics on the tracer gas washout procedure. To this end, we developed a multi-scale lung model to simulate the inert gas transport in airways of all size. We then applied systematically different modifications to geometrical and mechanical properties of the lung model (compliance, residual airway volume and flow resistance) which have been associated with VI. The modifications were applied to distinct parts of the model, and their effects on the gas distribution within the lung and on the gas concentration profile were assessed. We found that variability in compliance and residual volume of the airways, as well as the spatial distribution of this variability in the lung had a direct influence on gas distribution among airways and on the MBW pattern (washout duration, characteristic concentration profile during each expiration), while the effects of variable flow resistance were negligible. Based on these findings, it is possible to classify different types of inhomogeneities in the lung and relate them to specific features of the MBW pattern, which builds the basis for a more detailed association of lung function and structure.

Different contributions from lungs and chest wall to respiratory mechanics in mice, rats, and rabbits.

Changes in lung mechanics are frequently inferred from intact-chest measures of total respiratory system mechanics without consideration of the chest wall contribution. The participation of lungs and chest wall in respiratory mechanics has not been evaluated systematically in small animals commonly used in respiratory research. Thus, we compared these contributions in intact-chest mice, rats, and rabbits and further characterized the influence of positive end-expiratory pressure (PEEP). Forced oscillation technique was applied to anesthetized mechanically ventilated healthy animals to obtain total respiratory system impedance (Zrs) at 0, 3, and 6 cmH2O PEEP levels. Esophageal pressure was measured by a catheter-tip micromanometer to separate Zrs into pulmonary (ZL) and chest wall (Zcw) components. A model containing a frequency-independent Newtonian resistance (RN), inertance, and a constant-phase tissue damping (G) and elastance (H) was fitted to Zrs, ZL, and Zcw spectra. The contribution of Zcw to RN was negligible in all species and PEEP levels studied. However, the participation of Zcw in G and H was significant in all species and increased significantly with increasing PEEP and animal size (rabbit > rat > mice). Even in mice, the chest wall contribution to G and H was still considerable, reaching 47.0 ± 4.0(SE)% and 32.9 ± 5.9% for G and H, respectively. These findings demonstrate that airway parameters can be assessed from respiratory system mechanical measurements. However, the contribution from the chest wall should be considered when intact-chest measurements are used to estimate lung parenchymal mechanics in small laboratory models (even in mice), particularly at elevated PEEP levels. NEW & NOTEWORTHY In species commonly used in respiratory research (rabbits, rats, mice), esophageal pressure-based estimates revealed negligible contribution from the chest wall to the Newtonian resistance. Conversely, chest wall participation in the viscoelastic tissue mechanical parameters increased with body size (rabbit > rat > mice) and positive end-expiratory pressure, with contribution varying between 30 and 50%, even in mice. These findings demonstrate the potential biasing effects of the chest wall when lung tissue mechanics are inferred from intact-chest measurements in small laboratory animals.

Cross-platform mechanical characterization of lung tissue.

Published data on the mechanical strength and elasticity of lung tissue is widely variable, primarily due to differences in how testing was conducted across individual studies. This makes it extremely difficult to find a benchmark modulus of lung tissue when designing synthetic extracellular matrices (ECMs). To address this issue, we tested tissues from various areas of the lung using multiple characterization techniques, including micro-indentation, small amplitude oscillatory shear (SAOS), uniaxial tension, and cavitation rheology. We report the sample preparation required and data obtainable across these unique but complimentary methods to quantify the modulus of lung tissue. We highlight cavitation rheology as a new method, which can measure the modulus of intact tissue with precise spatial control, and reports a modulus on the length scale of typical tissue heterogeneities. Shear rheology, uniaxial, and indentation testing require heavy sample manipulation and destruction; however, cavitation rheology can be performed in situ across nearly all areas of the lung with minimal preparation. The Young’s modulus of bulk lung tissue using micro-indentation (1.4±0.4 kPa), SAOS (3.3±0.5 kPa), uniaxial testing (3.4±0.4 kPa), and cavitation rheology (6.1±1.6 kPa) were within the same order of magnitude, with higher values consistently reported from cavitation, likely due to our ability to keep the tissue intact. Although cavitation rheology does not capture the non-linear strains revealed by uniaxial testing and SAOS, it provides an opportunity to measure mechanical characteristics of lung tissue on a microscale level on intact tissues. Overall, our study demonstrates that each technique has independent benefits, and each technique revealed unique mechanical features of lung tissue that can contribute to a deeper understanding of lung tissue mechanics.

Integrated lung tissue mechanics one piece at a time: Computational modeling across the scales of biology

The lung is a delicately balanced and highly integrated mechanical system. Lung tissue is continuously exposed to the environment via the air we breathe, making it susceptible to damage. As a consequence, respiratory diseases present a huge burden on society and their prevalence continues to rise. Emergent function is produced not only by the sum of the function of its individual components but also by the complex feedback and interactions occurring across the biological scales – from genes to proteins, cells, tissue and whole organ - and back again. Computational modeling provides the necessary framework for pulling apart and putting back together the pieces of the body and organ systems so that we can fully understand how they function in both health and disease. In this review, we discuss models of lung tissue mechanics spanning from the protein level (the extracellular matrix) through to the level of cells, tissue and whole organ, many of which have been developed in isolation. This is a vital step in the process but to understand the emergent behavior of the lung, we must work towards integrating these component parts and accounting for feedback across the scales, such as mechanotransduction. These interactions will be key to unlocking the mechanisms occurring in disease and in seeking new pharmacological targets and improving personalized healthcare.

Quantification of Age-Related Lung Tissue Mechanics under Mechanical Ventilation.

Elderly patients with obstructive lung diseases often receive mechanical ventilation to support their breathing and restore respiratory function. However, mechanical ventilation is known to increase the severity of ventilator-induced lung injury (VILI) in the elderly. Therefore, it is important to investigate the effects of aging to better understand the lung tissue mechanics to estimate the severity of ventilator-induced lung injuries. Two age-related geometric models involving human bronchioles from generation G10 to G23 and alveolar sacs were developed. The first is for a 50-year-old (normal) and second is for an 80-year old (aged) model. Lung tissue mechanics of normal and aged models were investigated under mechanical ventilation through computational simulations. Results obtained indicated that lung tissue strains during inhalation (t = 0.2 s) decreased by about 40% in the alveolar sac (G23) and 27% in the bronchiole (G20), respectively, for the 80-year-old as compared to the 50-year-old. The respiratory mechanics parameters (work of breathing per unit volume and maximum tissue strain) over G20 and G23 for the 80-year-old decreased by about 64% (three-fold) and 80% (four-fold), respectively, during the mechanical ventilation breathing cycle. However, there was a significant increase (by about threefold) in lung compliance for the 80-year-old in comparison to the 50-year-old. These findings from the computational simulations demonstrated that lung mechanical characteristics are significantly compromised in aging tissues, and these effects were quantified in this study.

Metformin influences on respiratory system in obese mice induced by postnatal overnutrition

Many studies have confirmed the merits of metformin to treat type 2 diabetes, but few studies have addressed its effect on the respiratory system. Moreover, vascular endothelial growth factor (VEGF) is critical to many lung functions. In this way, we evaluated the metformin impact on the lung in treated obese Swiss mice, induced by postnatal overnutrition. Glucose and insulin were detected and the insulin resistance index (HOMA) was calculated; inflammatory cells and nitrite/nitrate concentration (NOx) was quantified from bronchoalveolar lavage, collagen and lung VEGF-a was analysed in the lung tissue and lung mechanics were evaluated by methacholine-induced bronchoconstriction. Values of glucose, insulin, HOMA; VEGF-a and collagen demonstrate the partial ability of metformin to improve the effects of obesity. However, metformin is ineffective in re-establishing the inflammation, shows no effects on NOx and does not restore bronchoconstriction in obese mice. In conclusion, metformińs beneficial effects on lung are questionable in the postnatal overnutrition model of obesity.

Quantification of regional deformation of the lungs by non-rigid registration of three-dimensional contrast-enhanced magnetic resonance imaging.

Assessment of lung function is vital for the diagnosis of a variety of pathological conditions. Research has been proposed to study pulmonary mechanics and kinematics using two-dimensional (2D) magnetic resonance imaging (MRI). This allows estimation of regional lung tissue mechanics but is limited to 2D information. An approach based on three-dimensional (3D) contrast-enhanced MR angiogram of pulmonary blood vessels and a non-rigid image registration technique is proposed for quantification of lung regional deformations, which can potentially be used for assessment of pulmonary parenchymal mechanics and regional ventilation for disease diagnosis without ionizing radiation. On three volunteers, an end-expiration scan and end-inspiration scan was acquired successively for each volunteer using a 3D breath-hold contrast-enhanced MRI sequence several minutes after gadolinium injection. Subsequently, a rectangle box lung mask is manually selected for each end-expiration scan, applying non-rigid registration algorithms using cubic B-splines as transformations to align each pair of images. This incorporates the Normalized Correlation Coefficient similarity with the bending energy term as cost function with a multi-resolution multi-grid approach. Finally, the lung regional 3D deformations were obtained using the transformations obtained by registration. The alignment accuracy after non-rigid registration was estimated by using a set of branch points of pulmonary blood vessels as anatomical landmarks for each pair of images. With contrast enhancement, the pulmonary blood vessel signal was enhanced, which greatly facilitated the non-rigid registration in the lung parenchyma. The average landmarks distances in three pairs of datasets are reduced from 17.9, 20.3 and 16.3 mm, to 1.0, 1.6 and 1.2 mm, respectively, by non-rigid registration. After registration, the average distances error of each pair of datasets was less than 0.6 mm in the right-to-left (RL) direction, less than 0.9 mm in the inferior-to-superior (IS) direction, and less than 1.2 mm in the anterior-to-posterior (AP) direction. Results demonstrated that the proposed method can accurately register lungs with large deformations to evaluate lung regional deformation. It may be used for quantitative assessment of 3D lung regional ventilation avoiding ionizing radiation.

Sevoflurane Relieves Lung Function Deterioration After Cardiopulmonary Bypass

To investigate sevoflurane's potential to alleviate the detrimental pulmonary changes after cardiopulmonary bypass (CPB). Prospective, randomized clinical investigation. University hospital. One hundred ninety patients undergoing elective cardiac surgery. Ninety-nine patients under intravenous anesthesia were administered 1 minimal alveolar concentration of sevoflurane for 5 minutes after being weaned from CPB (group SEV); intravenous anesthesia was maintained in the other 91 patients (group CTRL). Measurements were performed with open chest: before CPB, after CPB, and after intervention. The lungs' mechanical impedance and capnogram traces were recorded, arterial and central venous blood samples were analyzed, and lung compliance was documented. Airway resistance, tissue damping, and elastance were obtained from the impedance spectra. The capnogram phase III slope was determined using linear regression. The partial pressure of oxygen in the arterial blood/fraction of inspired oxygen ratio and shunt fraction were calculated from blood gas parameters. After CPB, sevoflurane induced bronchodilation, reflected in marked drops in airway resistance and smaller improvements in lung tissue viscoelasticity indicated by decreases in tissue damping and elastance. These changes were reflected in a decreased capnogram phase III slope and shunt fraction and increased partial pressure of oxygen in the arterial blood/fraction of inspired oxygen ratio and lung compliance. The more severe deteriorations that occurred after CPB, the greater improvements by sevoflurane were observed. Sevoflurane can alleviate CPB-induced bronchoconstriction, compromised lung tissue mechanics, and enhanced intrapulmonary shunt. This benefit has particular importance in patients with severe CPB-induced lung function deterioration.

Capnographic Parameters in Ventilated Patients: Correspondence with Airway and Lung Tissue Mechanics

Although the mechanical status of the lungs affects the shape of the capnogram, the relations between the capnographic parameters and those reflecting the airway and lung tissue mechanics have not been established in mechanically ventilated patients. We, therefore, set out to characterize how the mechanical properties of the airways and lung tissues modify the indices obtained from the different phases of the time and volumetric capnograms and how the lung mechanical changes are reflected in the altered capnographic parameters after a cardiopulmonary bypass (CPB). Anesthetized, mechanically ventilated patients (n = 101) undergoing heart surgery were studied in a prospective consecutive cross-sectional study under the open-chest condition before and 5 minutes after CPB. Forced oscillation technique was applied to measure airway resistance (Raw), tissue damping (G), and elastance (H). Time and volumetric capnography were performed to assess parameters reflecting the phase II (SII) and phase III slopes (SIII), their transition (D2min), the dead-space indices according to Fowler, Bohr, and Enghoff and the intrapulmonary shunt. Before CPB, SII and D2min exhibited the closest (P = 0.006) associations with H (0.65 and -0.57; P < 0.0001, respectively), whereas SIII correlated most strongly (P < 0.0001) with Raw (r = 0.63; P < 0.0001). CPB induced significant elevations in Raw and G and H (P < 0.0001). These adverse mechanical changes were reflected consistently in SII, SIII, and D2min, with weaker correlations with the dead-space indices (P < 0.0001). The intrapulmonary shunt expressed as the difference between the Enghoff and Bohr dead-space parameters was increased after CPB (95% ± 5% [SEM] vs 143% ± 6%; P < 0.001). In mechanically ventilated patients, the capnographic parameters from the early phase of expiration (SII and D2min) are linked to the pulmonary elastic recoil, whereas the effect of airway patency on SIII dominates over the lung tissue stiffness. However, severe deterioration in lung resistance or elastance affects both capnogram slopes.

Increased TGF-β: a drawback of tracheal occlusion in human and experimental congenital diaphragmatic hernia?

Survivors of severe congenital diaphragmatic hernia (CDH) present significant respiratory morbidity despite lung growth induced by fetal tracheal occlusion (TO). We hypothesized that the underlying mechanisms would involve changes in lung extracellular matrix and dysregulated transforming growth factor (TGF)-β pathway, a key player in lung development and repair. Pulmonary expression of TGF-β signaling components, downstream effectors, and extracellular matrix targets were evaluated in CDH neonates who died between birth and the first few weeks of life after prenatal conservative management or TO, and in rabbit pups that were prenatally randomized for surgical CDH and TO vs. sham operation. Before tissue harvesting, lung tissue mechanics in rabbits was measured using the constant-phase model during the first 30 min of life. Human CDH and control fetal lungs were also collected from midterm onwards. Human and experimental CDH did not affect TGF-β/Smad2/3 expression and activity. In human and rabbit CDH lungs, TO upregulated TGF-β transcripts. Analysis of downstream pathways indicated increased Rho-associated kinases to the detriment of Smad2/3 activation. After TO, subtle accumulation of collagen and α-smooth muscle actin within alveolar walls was detected in rabbit pups and human CDH lungs with short-term mechanical ventilation. Despite TO-induced lung growth, mediocre lung tissue mechanics in the rabbit model was associated with increased transcription of extracellular matrix components. These results suggest that prenatal TO increases TGF-β/Rho kinase pathway, myofibroblast differentiation, and matrix deposition in neonatal rabbit and human CDH lungs. Whether this might influence postnatal development of sustainably ventilated lungs remains to be determined.