Regional function–structure relationship in lungs of an elastase murine model of emphysema
Department of Otolaryngology-Head and Neck Surgery, Johns Hopkins University, Baltimore, Maryland, USA. Journal of Applied Physiology
(Impact Factor: 3.06).
09/2011; 112(1):135-48. DOI: 10.1152/japplphysiol.01181.2010
Changes in lung function and structure were studied using hyperpolarized (3)He MRI in an elastase-induced murine model of emphysema. The combined analysis of the apparent diffusion coefficient (ADC) and fractional ventilation (R) were used to distinguish emphysematous changes and also to develop a model for classifying sections of the lung into diseased and normal. Twelve healthy male BALB/c mice (26 ± 2 g) were randomized into healthy and elastase-induced mice and studied ∼8-11 wk after model induction. ADC and R were measured at a submillimeter planar resolution. Chord length (L(x)) data were analyzed from histology samples from the corresponding imaged slices. Logistic regression was applied to estimate the probability that an imaged pixel came from a diseased animal, and bootstrap methods (1,000 samples) were used to compare the regression results for the morphological and imaging results. Multivariate ANOVA (MANOVA) was used to analyze transformed ADC (ADC(BC)), and R (R(BC)) data and also to control for the experiment-wide error rate. MANOVA and ANOVA showed that elastase induced a statistically measureable change in the average transformed L(x) and ADC(BC) but not in the average R(BC). Marginal mean analysis demonstrated that ADC(BC) was on average 0.19 [95% confidence interval (CI): 0.16, 0.22] higher in the emphysema group, whereas R(BC) was on average 0.05 (95% CI: 0.04, 0.06) lower. Logistic regression supported the hypothesis that ADC(BC) and R(BC), together, were better at differentiating normal from diseased tissue than either measurement alone. The odds ratios for ADC(BC) and R(BC) were 7.73 (95% CI: 5.23, 11.42) and 9.14 × 10(-5) (95% CI: 3.33 × 10(-5), 25.06 × 10(-5)), respectively. Using a 50% probability cutoff, this model classified 70.6% of pixels correctly. The sensitivity and specificity of this model at the 50% cutoff were 74.9% and 65.2%, respectively. The area under the receiver operating characteristic curve was 0.76 (95% CI: 0.74, 0.78). The regression model presented can be used to map MRI data to disease probability maps. These probability maps present a future possibility of using both measurements in a more clinically feasible method of diagnosing this disease.
Available from: Puttisarn Mongkolwisetwara
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ABSTRACT: OBJECTIVE:: Atelectasis and surfactant depletion may contribute to greater distension-and thereby injury-of aerated lung regions; recruitment of atelectatic lung may protect these regions by attenuating such overdistension. However, the effects of atelectasis (and recruitment) on aerated airspaces remain elusive. We tested the hypothesis that during mechanical ventilation, surfactant depletion increases the dimensions of aerated airspaces and that lung recruitment reverses these changes. DESIGN:: Prospective imaging study in an animal model. SETTING:: Research imaging facility. SUBJECTS:: Twenty-seven healthy Sprague Dawley rats. INTERVENTIONS:: Surfactant depletion was obtained by saline lavage in anesthetized, ventilated rats. Alveolar recruitment was accomplished using positive end-expiratory pressure and exogenous surfactant administration. MEASUREMENTS AND MAIN RESULTS:: Airspace dimensions were estimated by measuring the apparent diffusion coefficient of He, using diffusion-weighted hyperpolarized gas magnetic resonance imaging. Atelectasis was demonstrated using computerized tomography and by measuring oxygenation. Saline lavage increased atelectasis (increase in nonaerated tissue from 1.2% to 13.8% of imaged area, p < 0.001), and produced a concomitant increase in mean apparent diffusion coefficient (~33%, p < 0.001) vs. baseline; the heterogeneity of the computerized tomography signal and the variance of apparent diffusion coefficient were also increased. Application of positive end-expiratory pressure and surfactant reduced the mean apparent diffusion coefficient (~23%, p < 0.001), and its variance, in parallel to alveolar recruitment (i.e., less computerized tomography densities and heterogeneity, increased oxygenation). CONCLUSIONS:: Overdistension of aerated lung occurs during atelectasis is detectable using clinically relevant magnetic resonance imaging technology, and could be a key factor in the generation of lung injury during mechanical ventilation. Lung recruitment by higher positive end-expiratory pressure and surfactant administration reduces airspace distension.
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ABSTRACT: Although it is recognized that pulmonary hysteresis can influence the effects of positive end-expiratory pressure (PEEP), the extent to which expansion of previously opened (vs. newly opening) peripheral airspaces contribute to increased lung volume is unknown.
Following a recruitment maneuver, rats were ventilated with constant tidal volumes and imaged during ascending and descending ramps of PEEP.
The authors estimated peripheral airspace dimensions by measuring the apparent diffusion coefficient of He in 10 rats. In a separate group (n = 5) undergoing a similar protocol, the authors used computerized tomography to quantify lung volume. Hysteresis was confirmed by larger end-inspiratory lung volume (mean ± SD; all PEEP levels included): 8.4 ± 2.8 versus 6.8 ± 2.0 ml (P < 0.001) and dynamic compliance: 0.52 ± 0.12 versus 0.42 ± 0.09 ml/cm H2O (P < 0.001) during descending versus ascending PEEP ramps. Apparent diffusion coefficient increased with PEEP, but it was smaller during the descending versus ascending ramps for corresponding levels of PEEP: 0.168 ± 0.019 versus 0.183 ± 0.019 cm/s (P < 0.001). Apparent diffusion coefficient was smaller in the posterior versus anterior lung regions, but the effect of PEEP and hysteresis on apparent diffusion coefficient was greater in the posterior regions.
The authors' study results suggest that in healthy lungs, larger lung volumes due to hysteresis are associated with smaller individual airspaces. This may be explained by opening of previously nonaerated peripheral airspaces rather than expansion of those already aerated. Setting PEEP on a descending ramp may minimize distension of individual airspaces.
Available from: Jeroen Tibboel
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ABSTRACT: Abstract The aim of this study was to characterize the evolution of lung function and -structure in elastase-induced emphysema in adult mice and the effect of mesenchymal stromal cell (MSC) administration on these parameters. Adult mice were treated with intratracheal (4.8 units/100 g bodyweight) elastase to induce emphysema. MSCs were administered intratracheally or intravenously, before or after elastase injection. Lung function measurements, histological and morphometric analysis of lung tissue were performed at 3 weeks, 5 and 10 months after elastase and at 19, 20 and 21 days following MSC administration. Elastase-treated mice showed increased dynamic compliance and total lung capacity, and reduced tissue-specific elastance and forced expiratory flows at 3 weeks after elastase, which persisted during 10 months follow-up. Histology showed heterogeneous alveolar destruction which also persisted during long-term follow-up. Jugular vein injection of MSCs before elastase inhibited deterioration of lung function but had no effects on histology. Intratracheal MSC treatment did not modify lung function or histology. In conclusion, elastase-treated mice displayed persistent characteristics of pulmonary emphysema. Jugular vein injection of MSCs prior to elastase reduced deterioration of lung function. Intratracheal MSC treatment had no effect on lung function or histology.
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