Effect of patient-ventilator asynchrony on lung and diaphragmatic injury in experimental acute respiratory distress syndrome in a porcine model.

BACKGROUND: Patient-ventilator asynchrony during mechanical ventilation may exacerbate lung and diaphragm injury in spontaneously breathing subjects. We investigated whether subject-ventilator asynchrony increases lung or diaphragmatic injury in a porcine model of acute respiratory distress syndrome (ARDS). METHODS: ARDS was induced in adult female pigs by lung lavage and injurious ventilation before mechanical ventilation by pressure assist-control for 12 h. Mechanically ventilated pigs were randomised to breathe spontaneously with or without induced subject-ventilator asynchrony or neuromuscular block (n=7 per group). Subject-ventilator asynchrony was produced by ineffective, auto-, or double-triggering of spontaneous breaths. The primary outcome was mean alveolar septal thickness (where thickening of the alveolar wall indicates worse lung injury). Secondary outcomes included distribution of ventilation (electrical impedance tomography), lung morphometric analysis, inflammatory biomarkers (gene expression), lung wet-to-dry weight ratio, and diaphragmatic muscle fibre thickness. RESULTS: Subject-ventilator asynchrony (median [interquartile range] 28.8% [10.4] asynchronous breaths of total breaths; n=7) did not increase mean alveolar septal thickness compared with synchronous spontaneous breathing (asynchronous breaths 1.0% [1.6] of total breaths; n=7). There was no difference in mean alveolar septal thickness throughout upper and lower lung lobes between pigs randomised to subject-ventilator asynchrony vs synchronous spontaneous breathing (87.3-92.2 µm after subject-ventilator asynchrony, compared with 84.1-95.0 µm in synchronised spontaneous breathing;). There were also no differences between groups in wet-to-dry weight ratio, diaphragmatic muscle fibre thickness, atelectasis, lung aeration, or mRNA expression levels for inflammatory cytokines pivotal in ARDS pathogenesis. CONCLUSIONS: Subject-ventilator asynchrony during spontaneous breathing did not exacerbate lung injury and dysfunction in experimental porcine ARDS.

Finite element simulations of hyperpolarized gas DWI in micro-CT meshes of acinar airways: validating the cylinder and stretched exponential models of lung microstructural length scales.

PURPOSE: This work assesses the accuracy of the stretched exponential (SEM) and cylinder models of lung microstructural length scales that can be derived from hyperpolarized gas DWI. This was achieved by simulating 3 He and 129 Xe DWI signals within two micro-CT-derived realistic acinar airspace meshes that represent healthy and idiopathic pulmonary fibrosis lungs. METHODS: The healthy and idiopathic pulmonary fibrosis acinar airway meshes were derived from segmentations of 3D micro-CT images of excised human lungs and meshed for finite element simulations of the Bloch-Torrey equations. 3 He and 129 Xe multiple b value DWI experiments across a range of diffusion times (3 He Δ = 1.6 ms; 129 Xe Δ = 5 to 20 ms) were simulated in each mesh. Global SEM mean diffusive length scale and cylinder model mean chord length value was derived from each finite element simulation and compared against each mesh's mean linear intercept length, calculated from intercept length measurements within micro-CT segmentation masks. RESULTS: The SEM-derived mean diffusive length scale was within ±10% of the mean linear intercept length for simulations with both 3 He (Δ = 1.6 ms) and 129 Xe (Δ = 7 to 13 ms) in the healthy mesh, and with 129 Xe (Δ = 13 to 20 ms) for the idiopathic pulmonary fibrosis mesh, whereas for the cylinder model-derived mean chord length the closest agreement with mean linear intercept length (11.7% and 22.6% difference) was at 129 Xe Δ = 20 ms for both healthy and IPF meshes, respectively. CONCLUSION: This work validates the use of the SEM for accurate estimation of acinar dimensions and indicates that the SEM is relatively robust across a range of experimental conditions and acinar length scales.

Comparison of in vivo lung morphometry models from 3D multiple b-value 3 He and 129 Xe diffusion-weighted MRI.

PURPOSE: To compare in vivo lung morphometry parameters derived from theoretical gas diffusion models, the cylinder model and stretched exponential model, in a range of acinar microstructural length scales encountered in healthy and diseased lungs with 3 He and 129 Xe diffusion-weighted MRI. METHODS: Three-dimensional multiple b-value 3 He and 129 Xe diffusion-weighted MRI was acquired with compressed sensing at 1.5 T from 51 and 31 subjects, respectively, including healthy volunteers, ex-smokers, idiopathic pulmonary fibrosis, and chronic obstructive pulmonary disease patients. For each subject, the stretched exponential model-derived mean diffusive length scale (LmD ) was calculated from the diffusion signal decay, and was compared with the cylinder model-derived mean chord length (Lm) and mean alveolar diameter (LAlv ) in order to determine the relationships among the different lung morphometry parameters. RESULTS: For both 3 He and 129 Xe diffusion-weighted MRI, the mean global LmD value was significantly related (P < .001) to Lm in a nonlinear power relationship, whereas the LAlv demonstrated excellent linear correlation (P < .001) with LmD . A mean bias of +1.0% and - 2.6% toward LmD was obtained for Bland-Altman analyses of 3 He and 129 Xe LmD and LAlv values, suggesting that the two morphometric parameters are equivalent measures of mean acinar dimensions. CONCLUSION: Within the experimental range of parameters considered here for both 3 He and 129 Xe, the stretched exponential model-derived LmD is related nonlinearly to cylinder model-derived Lm, and demonstrates excellent agreement with the cylinder model-derived LAlv .

3D diffusion-weighted 129 Xe MRI for whole lung morphometry.

PURPOSE: To obtain whole lung morphometry measurements from 129 Xe in a single breath-hold with 3D multiple b-value 129 Xe diffusion-weighted MRI (DW-MRI) with an empirically optimized diffusion time and compressed sensing for scan acceleration. METHODS: Prospective three-fold undersampled 3D multiple b-value hyperpolarized 129 Xe DW-MRI datasets were acquired, and the diffusion time (Δ) was iterated so as to provide diffusive length scale (LmD ) estimates from the stretched exponential model (SEM) that are comparable to those from 3 He. The empirically optimized 129 Xe diffusion time was then implemented with a four-fold undersampling scheme and was prospectively benchmarked against 3 He measurements in a cohort of five healthy volunteers, six ex-smokers, and two chronic obstructive pulmonary disease patients using both SEM-derived LmD and cylinder model (CM)-derived mean chord length (Lm). RESULTS: Good agreement between the mean 129 Xe and 3 He LmD (mean difference, 2.2%) and Lm (mean difference, 1.1%) values was obtained in all subjects at an empirically optimized 129 Xe Δ = 8.5 ms. CONCLUSION: Compressed sensing has facilitated single-breath 3D multiple b-value 129 Xe DW-MRI acquisitions, and results at 129 Xe Δ = 8.5 ms indicate that 129 Xe provides a viable alternative to 3 He for whole lung morphometry mapping with either the SEM or CM. Magn Reson Med 79:2986-2995, 2018. © 2017 The Authors Magnetic Resonance in Medicine published by Wiley Periodicals, Inc. on behalf of International Society for Magnetic Resonance in Medicine. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

Whole lung morphometry with 3D multiple b-value hyperpolarized gas MRI and compressed sensing.

PURPOSE: To demonstrate three-dimensional (3D) multiple b-value diffusion-weighted (DW) MRI of hyperpolarized 3 He gas for whole lung morphometry with compressed sensing (CS). METHODS: A fully-sampled, two b-value, 3D hyperpolarized 3 He DW-MRI dataset was acquired from the lungs of a healthy volunteer and retrospectively undersampled in the ky and kz phase-encoding directions for CS simulations. Optimal k-space undersampling patterns were determined by minimizing the mean absolute error between reconstructed and fully-sampled 3 He apparent diffusion coefficient (ADC) maps. Prospective three-fold, undersampled, 3D multiple b-value 3 He DW-MRI datasets were acquired from five healthy volunteers and one chronic obstructive pulmonary disease (COPD) patient, and the mean values of maps of ADC and mean alveolar dimension (LmD ) were validated against two-dimensional (2D) and 3D fully-sampled 3 He DW-MRI experiments. RESULTS: Reconstructed undersampled datasets showed no visual artifacts and good preservation of the main image features and quantitative information. A good agreement between fully-sampled and prospective undersampled datasets was found, with a mean difference of +3.4% and +5.1% observed in mean global ADC and LmD values, respectively. These differences were within the standard deviation range and consistent with values reported from healthy and COPD lungs. CONCLUSIONS: Accelerated CS acquisition has facilitated 3D multiple b-value 3 He DW-MRI scans in a single breath-hold, enabling whole lung morphometry mapping. Magn Reson Med 77:1916-1925, 2017. © 2016 The Authors Magnetic Resonance in Medicine published by Wiley Periodicals, Inc. on behalf of International Society for Magnetic Resonance in Medicine. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

Lung morphometry: the link between structure and function.

The study of the structural basis of gas exchange function in the lung depends on the availability of quantitative information that concerns the structures establishing contact between the air in the alveoli and the blood in the alveolar capillaries, which can be entered into physiological equations for predicting oxygen uptake. This information is provided by morphometric studies involving stereological methods and allows estimates of the pulmonary diffusing capacity of the human lung that agree, in experimental studies, with the maximal oxygen consumption. The basis for this "machine lung" structure lies in the complex design of the cells building an extensive air-blood barrier with minimal cell mass.

Diffusion lung imaging with hyperpolarized gas MRI.

Lung imaging using conventional 1 H MRI presents great challenges because of the low density of lung tissue, lung motion and very fast lung tissue transverse relaxation (typical T2 * is about 1-2 ms). MRI with hyperpolarized gases (3 He and 129 Xe) provides a valuable alternative because of the very strong signal originating from inhaled gas residing in the lung airspaces and relatively slow gas T2 * relaxation (typical T2 * is about 20-30 ms). However, in vivo human experiments should be performed very rapidly - usually during a single breath-hold. In this review, we describe the recent developments in diffusion lung MRI with hyperpolarized gases. We show that a combination of the results of modeling of gas diffusion in lung airspaces and diffusion measurements with variable diffusion-sensitizing gradients allows the extraction of quantitative information on the lung microstructure at the alveolar level. From an MRI scan of less than 15 s, this approach, called in vivo lung morphometry, allows the provision of quantitative values and spatial distributions of the same physiological parameters as measured by means of 'standard' invasive stereology (mean linear intercept, surface-to-volume ratio, density of alveoli, etc.). In addition, the approach makes it possible to evaluate some advanced Weibel parameters characterizing lung microstructure: average radii of alveolar sacs and ducts, as well as the depth of their alveolar sleeves. Such measurements, providing in vivo information on the integrity of pulmonary acinar airways and their changes in different diseases, are of great importance and interest to a broad range of physiologists and clinicians. We also discuss a new type of experiment based on the in vivo lung morphometry technique combined with quantitative computed tomography measurements, as well as with gradient echo MRI measurements of hyperpolarized gas transverse relaxation in the lung airspaces. Such experiments provide additional information on the blood vessel volume fraction, specific gas volume and length of the acinar airways, and allow the evaluation of lung parenchymal and non-parenchymal tissue. Copyright © 2015 John Wiley & Sons, Ltd.

What makes a good pediatric transplant lung: Insights from in vivo lung morphometry with hyperpolarized 3 He magnetic resonance imaging.

Obtaining information on transplanted lung microstructure is an important part of the current care for monitoring transplant recipients. However, until now this information was only available from invasive lung biopsy. The objective of this study was to evaluate the use of an innovative non-invasive technique, in vivo lung morphometry with hyperpolarized ³He MRI-to characterize lung microstructure in the pediatric lung transplant population. This technique yields quantitative measurements of acinar airways' (alveolar ducts and sacs) parameters, such as acinar airway radii and alveolar depth. Six pediatric lung transplant recipients with cystic fibrosis underwent in vivo lung morphometry MRI, pulmonary function testing, and quantitative CT. We found a strong correlation between lung lifespan and alveolar depth-patients with more shallow alveoli were likely to have a negative outcome sooner than those with larger alveolar depth. Combining morphometric results with CT, we also determined mean alveolar wall thickness and found substantial increases in this parameter in some patients that negatively correlated with DLCO. In vivo lung morphometry uniquely provides previously unavailable information on lung microstructure that may be predictive of a negative outcome and has a potential to aid in lung selection for transplantation.

Parenchymal Airspace Profiling: Sensitive Quantification and Characterization of Lung Structure Evaluating Parenchymal Destruction.

Lung morphometry was introduced over 50 years ago to provide quantitative evaluation of the lung structure. The existing parameters, such as mean linear intercept and destructive index, suffer from simplistic data interpretation and a subjective data acquisition process. To overcome these existing shortcomings, parenchymal airspace profiling (PAP) was developed to provide a more detailed and unbiased quantitative method. Following the standard protocols of fixation, embedding, and sectioning, lung micrographs were: (1) marked with nonparenchymal area, preprocessed, and binarized under the researcher's supervision; (2) analyzed with a statistical learning method, Gaussian mixture model, to provide an unbiased categorization of parenchymal airspace compartments, corresponding to a single alveolus, alveolar sac, and ductal/destructive airspace; and (3) further quantified into morphometric parameters, including reference volume, alveolar count, and ductal/destructive fraction (DF) based on stereological principles. PAP was performed on hematoxylin and eosin-stained lung sections from mice and rabbits. Unbiased categorization revealed differences in alveolar size among several mouse strains (NZW/LacJ

Pulmonary hyperpolarized (129) Xe morphometry for mapping xenon gas concentrations and alveolar oxygen partial pressure: Proof-of-concept demonstration in healthy and COPD subjects.

PURPOSE: Diffusion-weighted (DW) hyperpolarized (129) Xe morphometry magnetic resonance imaging (MRI) can be used to map regional differences in lung tissue micro-structure. We aimed to generate absolute xenon concentration ([Xe]) and alveolar oxygen partial pressure (pA O2 ) maps by extracting the unrestricted diffusion coefficient (D0 ) of xenon as a morphometric parameter. METHODS: In this proof-of-concept demonstration, morphometry was performed using multi b-value (0, 12, 20, 30 s/cm(2) ) DW hyperpolarized (129) Xe images obtained in four never-smokers and four COPD ex-smokers. Morphometric parameters and D0 maps were computed and the latter used to generate [Xe] and pA O2 maps. Xenon concentration phantoms estimating a range of values mimicking those observed in vivo were also investigated. RESULTS: Xenon D0 was significantly increased (P = 0.035) in COPD (0.14 ± 0.03 cm(2) /s) compared with never-smokers (0.12 ± 0.02 cm(2) /s). COPD ex-smokers also had significantly decreased [Xe] (COPD = 8 ± 7% versus never-smokers = 13 ± 8%, P = 0.012) and increased pA O2 (COPD = 18 ± 3% versus never-smokers = 15 ± 3%, P = 0.009) compared with never-smokers. Phantom measurements showed the expected dependence of D0 on [Xe] over the range of concentrations anticipated in vivo. CONCLUSION: DW hyperpolarized (129) Xe MRI morphometry can be used to simultaneously map [Xe] and pA O2 in addition to providing micro-structural biomarkers of emphysematous destruction in COPD. Phantom measurements of D0 ([Xe]) supported the hypotheses that differences in subjects may reflect differences in functional residual capacity.

In vivo lung morphometry with hyperpolarized (3) He diffusion MRI: reproducibility and the role of diffusion-sensitizing gradient direction.

PURPOSE: Lung morphometry with hyperpolarized gas diffusion MRI is a highly sensitive technique for the noninvasive measurement of acinar microstructural parameters traditionally only accessible by histology. The goal of this work is to establish the reproducibility of these measurements in healthy volunteers and their dependence on the direction of the applied diffusion-sensitizing gradient. METHODS: Hyperpolarized helium-3 ((3) He) lung morphometry MRI was performed on a total of five healthy subjects. Two subjects received duplicate imaging on the same day and three subjects received duplicate imaging after a 4-month or 27-month delay to assess reproducibility. Four subjects repeated the measurement during the same session with different diffusion-sensitizing gradient directions to determine the effect on the parameter estimates. RESULTS: The (3) He lung morphometry measurements were reproducible over the short term and long term (e.g., % coefficient of variation [CV] of mean chord length, Lm = 2.1% and 2.9%, respectively) and across different diffusion gradient directions (Lm % CV = 2.6%). Results also show independence of field inhomogeneity effects at 1.5T. CONCLUSION: (3) He lung morphometry is a reproducible technique for measuring acinar microstructure and is effectively independent of the choice of diffusion gradient direction. This provides confidence for the use of this technique to compare populations and treatment efficacy.

In vivo lung morphometry with accelerated hyperpolarized (3) He diffusion MRI: a preliminary study.

PURPOSE: Parallel imaging can be used to reduce imaging time and to increase the spatial coverage in hyperpolarized gas magnetic resonance imaging of the lung. In this proof-of-concept study, we investigate the effects of parallel imaging on the morphometric measurement of lung microstructure using diffusion magnetic resonance imaging with hyperpolarized (3) He. METHODS: Fully sampled and under-sampled multi-b diffusion data were acquired from human subjects using an 8-channel (3) He receive coil. A parallel imaging reconstruction technique (generalized autocalibrating partially parallel acquisitions [GRAPPA]) was used to reconstruct under-sampled k-space data. The morphometric results of the generalized autocalibrating partially parallel acquisitions-reconstructed data were compared with the results of fully sampled data for three types of subjects: healthy volunteers, mild, and moderate chronic obstructive pulmonary disease patients. RESULTS: Morphometric measurements varied only slightly at mild acceleration factors. The results were largely well preserved compared to fully sampled data for different lung conditions. CONCLUSION: Parallel imaging, given sufficient signal-to-noise ratio, provides a reliable means to accelerate hyperpolarized-gas magnetic resonance imaging with no significant difference in the measurement of lung morphometry from the fully sampled images. GRAPPA is a promising technique to significantly reduce imaging time and/or to improve the spatial coverage for the morphometric measurement with hyperpolarized gases.

New insights into lung diseases using hyperpolarized gas MRI.

Hyperpolarized (HP) gases are a new class of contrast agents that permit to obtain high temporal and spatial resolution magnetic resonance images (MRI) of the lung airspaces. HP gas MRI has become important research tool not only for morphological and functional evaluation of normal pulmonary physiology but also for regional quantification of pathologic changes occurring in several lung diseases. The purpose of this work is to provide an introduction to MRI using HP noble gases, describing both the basic principles of the technique and the new information about lung disease provided by clinical studies with this method. The applications of the technique in normal subjects, smoking related lung disease, asthma, and cystic fibrosis are reviewed.

Probing lung microstructure with hyperpolarized 3He gradient echo MRI.

In this paper we demonstrate that gradient echo MRI with hyperpolarized (3)He gas can be used for simultaneously extracting in vivo information about lung ventilation properties, alveolar geometrical parameters, and blood vessel network structure. This new approach is based on multi-gradient-echo experimental measurements of hyperpolarized (3)He gas MRI signal from human lungs and a proposed theoretical model of this signal. Based on computer simulations of (3)He atoms diffusing in the acinar airway tree in the presence of an inhomogeneous magnetic field induced by the susceptibility differences between lung tissue (alveolar septa, blood vessels) and lung airspaces, we derive analytical expressions relating the time-dependent MR signal to the geometrical parameters of acinar airways and the blood vessel network. Data obtained on eight healthy volunteers are in good agreement with literature values. This information is complementary to the information obtained by means of the in vivo lung morphometry technique with hyperpolarized 3He diffusion MRI previously developed by our group, and opens new opportunities to study lung microstructure in health and disease.

Quantifying abnormal alveolar microstructure in cystic fibrosis lung disease via hyperpolarized 129Xe diffusion MRI.

RATIONALE: Cystic Fibrosis (CF) progresses through recurrent infection and inflammation, causing permanent lung function loss and airway remodeling. CT scans reveal abnormally low-density lung parenchyma in CF, but its microstructural nature remains insufficiently explored due to clinical CT limitations. To this end, diffusion-weighted 129Xe MRI is a non-invasive and validated measure of lung microstructure. In this work, we investigate microstructural changes in people with CF (pwCF) relative to age-matched, healthy subjects using comprehensive imaging and analysis involving pulmonary-function tests (PFTs), and 129Xe MRI. METHODS: 38 healthy subjects (age 6-40; 17.2 ± 9.5 years) and 39 pwCF (age 6-40; 15.6 ± 8.0 years) underwent 129Xe-diffusion MRI and PFTs. The distribution of diffusion measurements (i.e., apparent diffusion coefficients (ADC) and morphometric parameters) was assessed via linear binning (LB). The resulting volume percentages of bins were compared between controls and pwCF. Mean ADC and morphometric parameters were also correlated with PFTs. RESULTS: Mean whole-lung ADC correlated significantly with age (P < 0.001) for both controls and CF, and with PFTs (P < 0.05) specifically for pwCF. Although there was no significant difference in mean ADC between controls and pwCF (P = 0.334), age-adjusted LB indicated significant voxel-level diffusion (i.e., ADC and morphometric parameters) differences in pwCF compared to controls (P < 0.05). CONCLUSIONS: 129Xe diffusion MRI revealed microstructural abnormalities in CF lung disease. Smaller microstructural size may reflect compression from overall higher lung density due to interstitial inflammation, fibrosis, or other pathological changes. While elevated microstructural size may indicate emphysema-like remodeling due to chronic inflammation and infection.

Mechanical and morphological characterization of the emphysematous lung tissue.

Irreversible alveolar airspace enlargement is the main characteristic of pulmonary emphysema, which has been extensively studied using animal models. While the alterations in lung mechanics associated with these morphological changes have been documented in the literature, the study of the mechanical behavior of parenchymal tissue from emphysematous lungs has been poorly investigated. In this work, we characterize the mechanical and morphological properties of lung tissue in elastase-induced emphysema rat models under varying severity conditions. We analyze the non-linear tissue behavior using suitable hyperelastic constitutive models that enable to compare different non-linear responses in terms of hyperelastic material parameters. We further analyze the effect of the elastase dose on alveolar morphology and tissue material parameters and study their connection with respiratory-system mechanical parameters. Our results show that while the lung mechanical function is not significantly influenced by the elastase treatment, the tissue mechanical behavior and alveolar morphology are markedly affected by it. We further show a strong association between alveolar enlargement and tissue softening, not evidenced by respiratory-system compliance. Our findings highlight the importance of understanding tissue mechanics in emphysematous lungs, as changes in tissue properties could detect the early stages of emphysema remodeling. STATEMENT OF SIGNIFICANCE: Gas exchange is vital for life and strongly relies on the mechanical function of the lungs. Pulmonary emphysema is a prevalent respiratory disease where alveolar walls are damaged, causing alveolar enlargement that induces harmful changes in the mechanical response of the lungs. In this work, we study how the mechanical properties of lung tissue change during emphysema. Our results from animal models show that tissue properties are more sensitive to alveolar enlargement due to emphysema than other mechanical properties that describe the function of the whole respiratory system.

Computed Tomographic and Histopathologic Studies of Lung Function Immediately Post Natum in Canine Neonates.

BACKGROUND: The lung tissue in newborn canine neonates is still in a morphologically and functionally immature, canalicular-saccular stage. True alveoli are only formed postnatally. The aim of this study was to analyze the spatial and temporal development of the ventilation of the lung tissue in vital canine neonates during the first 24 h post natum (p.n.). METHODS: Forty pups (birth weight Ø 424 g ± 80.1 g) from three litters of large dog breeds (>20 kg live weight) were included in the studies. Thirty-three pups (29 vital, 2 vitally depressed, 2 stillborn neonates) originated from controlled, uncomplicated births (n = 3); moreover, six stillborn pups as well as one prematurely deceased pup were birthed by other dams with delivery complications. Computed tomography (CT) was used in 39 neonates, and histopathologic tissue classification techniques (HALO) were used in 11 neonates (eight stillborn and three neonates died early post natum, respectively) to quantify the degree of aerated neonatal lung tissue. RESULTS: It was shown that, in vital born pups, within the first 10 min p.n., the degree of ventilation reached mean values of -530 (±114) Hounsfield units (HU) in the dorsal and -453.3 (±133) HU in the ventral lung area. This is about 75-80% of the final values obtained after 24 h p.n. for dorsal -648.0 (±89.9) HU and ventral quadrants -624.7 (±76.8) HU. The dorsal lung areas were always significantly better ventilated than the ventral regions (p = 0.0013). CT as well as histopathology are suitable to clearly distinguish the nonventilated lungs of stillborns from neonates that were initially alive after surviving neonatal respiratory distress syndrome but who died prematurely (p = 0.0398). CONCLUSION: The results of this study are clinically relevant since the lung tissue of canine neonates presents an aeration profile as early as 10 min after birth and continues progressively, with a special regard to the dorsal lung areas. This is the basis for resuscitation measures that should be performed, preferably with the pup in the abdomen-chest position.

Morphometric and functional pulmonary changes of premature neonatal puppies after antenatal corticoid therapy.

Among prematurity complications, the most important disorder is structural immaturity and inadequate production of pulmonary surfactant. Betamethasone is the drug of choice to artificially improve pulmonary capacity, thus we aimed to verify the effect of prenatal maternal treatment on lung development of premature puppies. Pregnant bitches were allocated in Term Group (n = 7), Preterm-Treated Group (interrupted pregnancies with maternal administration of betamethasone; n = 7), Preterm-Control Group (untreated interrupted pregnancies; n = 7), Extremely-Preterm Group (interrupted pregnancies at 55d; n = 6). Puppies were subjected to chest radiographic at birth, morphometric description of pulmonary structures and immunohistochemical analysis of surfactant protein B, proliferating cell nuclear antigen and cytokeratin were performed. In Preterm-Treated Group it was possible to more clearly identify cardiac silhouette and lung parenchyma by X-Ray. Saccular formation was higher in Preterm Groups, while Term Group had higher subsaccular development. Lung septation was higher in Treated and Term Groups. Term Group had higher number of cells marked for SP-B, whereas higher proliferation was observed in Extreme-Preterm and Preterm-Control Groups. Preterm Treated and Term Groups had higher tissue differentiation. In conclusion, antenatal maternal corticotherapy in dogs acted by increasing lung morphology and development of areas of gas exchange, regulate metabolism of pulmonary fluids rather than stimulate surfactant production.

Acclimatization of low altitude-bred deer mice ( Peromyscus maniculatus) to high altitude.

A colony of deer mice subspecies ( Peromyscus maniculatus sonoriensis) native to high altitude (HA) has been maintained at sea level for 18-20 generations and remains genetically unchanged. To determine if these animals retain responsiveness to hypoxia, one group (9-11 wk old) was acclimated to HA (3,800 m) for 8 wk. Age-matched control animals were acclimated to a lower altitude (LA; 252 m). Maximal O2 uptake (V̇o2max) was measured at the respective altitudes. On a separate day, lung volume, diffusing capacity for carbon monoxide (DLCO), and pulmonary blood flow were measured under anesthesia using a rebreathing technique at two inspired O2 tensions. The HA-acclimated deer mice maintained a normal V̇o2max relative to LA baseline. Compared with LA control mice, antemortem lung volume was larger in HA mice in a manner dependent on alveolar O2 tension. Systemic hematocrit, pulmonary blood flow, and standardized DLCO did not differ significantly between groups. HA mice showed a higher postmortem alveolar-capillary hematocrit, larger alveolar ducts, and smaller distal conducting structures. In HA mice, absolute volumes of alveolar type I epithelia and endothelia were higher whereas that of interstitia was lower than in LA mice. These structural changes occurred without a net increase in whole-lung septal tissue-capillary volumes or surface areas. Thus, deer mice bred and raised to adulthood at LA retain phenotypic plasticity and adapt to HA without a decrement in V̇o2max via structural (enlarged airspaces, alveolar septal remodeling) and nonstructural (lung expansion under hypoxia) mechanisms and without an increase in systemic hematocrit or compensatory lung growth. NEW & NOTEWORTHY Deer mice ( Peromyscus maniculatus) are robust and very active mammals that are found across the North American continent. They are also highly adaptable to extreme environments. When introduced to high altitude they retain remarkable adaptive ability to the low-oxygen environment via lung expansion and remodeling of existing lung structure, thereby maintaining normal aerobic capacity without generating more red blood cells or additional lung tissue.