Investigating the impact of RF saturation-pulse parameters on compartment-selective gas-phase depolarization with xenon polarization transfer contrast MRI.

PURPOSE: To demonstrate the utility of continuous-wave (CW) saturation pulses in xenon-polarization transfer contrast (XTC) MRI and MRS, to investigate the selectivity of CW pulses applied to dissolved-phase resonances, and to develop a correction method for measurement biases from saturation of the nontargeted dissolved-phase compartment. METHODS: Studies were performed in six healthy Sprague-Dawley rats over a series of end-exhale breath holds. Discrete saturation schemes included a series of 30 Gaussian pulses (8 ms FWHM), spaced 25 ms apart; CW saturation schemes included single block pulses, with variable flip angle and duration. In XTC imaging, saturation pulses were applied on both dissolved-phase resonance frequencies and off-resonance, to correct for other sources of signal loss and compromised selectivity. In spectroscopy experiments, saturation pulses were applied at a set of 19 frequencies spread out between 185 and 200 ppm to map out modified z-spectra. RESULTS: Both modified z-spectra and imaging results showed that CW RF pulses offer sufficient depolarization and improved selectivity for generating contrast between presaturation and postsaturation acquisitions. A comparison of results obtained using a variety of saturation parameters confirms that saturation pulses applied at higher powers exhibit increased cross-contamination between dissolved-phase resonances. CONCLUSION: Using CW RF saturation pulses in XTC contrast preparation, with the proposed correction method, offers a potentially more selective alternative to traditional discrete saturation. The suppression of the red blood cell contribution to the gas-phase depolarization opens the door to a novel way of quantifying exchange time between alveolar volume and hemoglobin.

Pulmonary pyruvate metabolism as an index of inflammation and injury in a rat model of acute respiratory distress syndrome.

Increased pulmonary lactate production is correlated with severity of lung injury and outcome in acute respiratory distress syndrome (ARDS) patients. This study was conducted to investigate the relative contributions of inflammation and hypoxia to the lung's metabolic shift to glycolysis in an experimental animal model of ARDS using hyperpolarized (HP) 13 C MRI. Fifty-three intubated and mechanically ventilated male rats were imaged using HP 13 C MRI before, and 1, 2.5 and 4 hours after saline (sham) or hydrochloric acid (HCl; 0.5 ml/kg) instillation in the trachea, followed by protective and nonprotective mechanical ventilation (HCl-PEEP and HCl-ZEEP) or the start of moderate or severe hypoxia (Hyp90 and Hyp75 groups). Pulmonary and cardiac HP lactate-to-pyruvate ratios were compared among groups for different time points. Postmortem histology and immunofluorescence were used to assess lung injury severity and quantify the expression of innate inflammatory markers and local tissue hypoxia. HP pulmonary lactate-to-pyruvate ratio progressively increased in rats with lung injury and moderate hypoxia (HCl-ZEEP), with no significant change in pulmonary lactate-to-pyruvate ratio in noninjured but moderately hypoxic rats (Hyp90). Pulmonary lactate-to-pyruvate ratio was elevated in otherwise healthy lung tissue only in severe systemic hypoxia (Hyp75 group). ex vivo histological and immunopathological assessment further confirmed the link between elevated glycolysis and the recruitment into and presence of activated neutrophils in injured lungs. HP lactate-to-pyruvate ratio is elevated in injured lungs predominantly as a result of increased glycolysis in activated inflammatory cells, but can also increase due to severe inflammation-induced hypoxia.

Investigating biases in the measurement of apparent alveolar septal wall thickness with hyperpolarized 129Xe MRI.

PURPOSE: To investigate biases in the measurement of apparent alveolar septal wall thickness (SWT) with hyperpolarized xenon-129 (HXe) as a function of acquisition parameters. METHODS: The HXe MRI scans with simultaneous gas-phase and dissolved-phase excitation were performed using 1-dimensional projection scans in mechanically ventilated rabbits. The dissolved-phase magnetization was periodically saturated, and the dissolved-phase xenon uptake dynamics were measured at end inspiration and end expiration with temporal resolutions up to 10 ms using a Look-Locker-type acquisition. The apparent alveolar septal wall thickness was extracted by fitting the signal to a theoretical model, and the findings were compared with those from the more commonly use chemical shift saturation recovery MRI spectroscopy technique with several different delay time arrangements. RESULTS: It was found that repeated application of RF saturation pulses in chemical shift saturation recovery acquisitions caused exchange-dependent gas-phase saturation that heavily biased the derived SWT value. When this bias was reduced by our proposed method, the SWT dependence on lung inflation disappeared due to an inherent insensitivity of HXe dissolved-phase MRI to thin alveolar structures with very short T2∗ . Furthermore, perfusion-based macroscopic gas transport processes were demonstrated to cause increasing apparent SWTs with TE (2.5 µm/ms at end expiration) and a lung periphery-to-center SWT gradient. CONCLUSION: The apparent SWT measured with HXe MRI was found to be heavily dependent on the acquisition parameters. A method is proposed that can minimize this measurement bias, add limited spatial resolution, and reduce measurement time to a degree that free-breathing studies are feasible.

Measurement of Regional 2D Gas Transport Efficiency in Rabbit Lung Using Hyperpolarized 129Xe MRI.

While hyperpolarized xenon-129 (HXe) MRI offers a wide array of tools for assessing functional aspects of the lung, existing techniques provide only limited quantitative information about the impact of an observed pathology on overall lung function. By selectively destroying the alveolar HXe gas phase magnetization in a volume of interest and monitoring the subsequent decrease in the signal from xenon dissolved in the blood inside the left ventricle of the heart, it is possible to directly measure the contribution of that saturated lung volume to the gas transport capacity of the entire lung. In mechanically ventilated rabbits, we found that both xenon gas transport and transport efficiency exhibited a gravitation-induced anterior-to-posterior gradient that disappeared or reversed direction, respectively, when the animal was turned from supine to prone position. Further, posterior ventilation defects secondary to acute lung injury could be re-inflated by applying positive end expiratory pressure, although at the expense of decreased gas transport efficiency in the anterior volumes. These findings suggest that our technique might prove highly valuable for evaluating lung transplants and lung resections, and could improve our understanding of optimal mechanical ventilator settings in acute lung injury.

Assessment of flip angle-TR equivalence for standardized dissolved-phase imaging of the lung with hyperpolarized 129Xe MRI.

PURPOSE: To investigate the feasibility of describing the impact of any flip angle-TR combination on the resulting distribution of the hyperpolarized xenon-129 (HXe) dissolved-phase magnetization in the chest using a single virtual parameter, TR90°,equiv . METHODS: HXe MRI scans with simultaneous gas- (GP) and dissolved-phase (DP) excitation were performed using 2D projection scans in mechanically ventilated rabbits. Measurements with DP flip angles ranging from 6-90° and TRs ranging from 8.3-500 ms were conducted. DP maps based on acquisitions of similar radio frequency pulse-induced relaxation rates were compared. RESULTS: The observed distribution of the DP magnetization was strongly affected by acquisition flip angle and TR. However, for flip angles up to 60°, measurements with the same radio frequency pulse-induced relaxation rates, resulted in very similar DP images despite the presence of significant macroscopic gas transport processes. For flip angles approaching 90°, the downstream signal component decreased noticeably relative to acquisitions with lower flip angles. Nevertheless, the total DP signal continued to follow an empirically verified conversion equation over the entire investigated parameter range, which yields the equivalent TR of a hypothetical 90° measurement for any experimental flip angle-TR combination. CONCLUSION: We have introduced a method for converting the flip angle and TR of a given HXe DP measurement to a standardized metric based on the virtual quantity, TR90°,equiv , using their equivalent RF relaxation rates. This conversion permits the comparison of measurements obtained with different pulse sequence types or by different research groups using various acquisition parameters.

Assessment of Pulmonary Gas Transport in Rabbits Using Hyperpolarized Xenon-129 Magnetic Resonance Imaging.

Many forms of lung disease manifest themselves as pathological changes in the transport of gas to the circulatory system, yet the difficulty of imaging this process remains a central obstacle to the comprehensive diagnosis of lung disorders. Using hyperpolarized xenon-129 as a surrogate marker for oxygen, we derived the temporal dynamics of gas transport from the ratio of two lung images obtained with different timing parameters. Additionally, by monitoring changes in the total hyperpolarized xenon signal intensity in the left side of the heart induced by depletion of xenon signal in the alveolar airspaces of interest, we quantified the contributions of selected lung volumes to the total pulmonary gas transport. In a rabbit model, we found that it takes at least 200 ms for xenon gas to enter the lung tissue and travel the distance from the airspaces to the heart. Additionally, our method shows that both lungs contribute fairly equally to the gas transport in healthy rabbits, but that this ratio changes in a rabbit model of acid aspiration. These results suggest that hyperpolarized xenon-129 MRI may improve our ability to measure pulmonary gas transport and detect associated pathological changes.

Rapid assessment of pulmonary gas transport with hyperpolarized 129Xe MRI using a 3D radial double golden-means acquisition with variable flip angles.

PURPOSE: To demonstrate the feasibility of using a 3D radial double golden-means acquisition with variable flip angles to monitor pulmonary gas transport in a single breath hold with hyperpolarized xenon-129 MRI. METHODS: Hyperpolarized xenon-129 MRI scans with interleaved gas-phase and dissolved-phase excitations were performed using a 3D radial double golden-means acquisition in mechanically ventilated rabbits. The flip angle was either held fixed at 15 ° or 5 °, or it was varied linearly in ascending or descending order between 5 ° and 15 ° over a sampling interval of 1000 spokes. Dissolved-phase and gas-phase images were reconstructed at high resolution (32 × 32 × 32 matrix size) using all 1000 spokes, or at low resolution (22 × 22 × 22 matrix size) using 400 spokes at a time in a sliding-window fashion. Based on these sliding-window images, relative change maps were obtained using the highest mean flip angle as the reference, and aggregated pixel-based changes were tracked. RESULTS: Although the signal intensities in the dissolve-phase maps were mostly constant in the fixed flip-angle acquisitions, they varied significantly as a function of average flip angle in the variable flip-angle acquisitions. The latter trend reflects the underlying changes in observed dissolve-phase magnetization distribution due to pulmonary gas uptake and transport. CONCLUSION: 3D radial double golden-means acquisitions with variable flip angles provide a robust means for rapidly assessing lung function during a single breath hold, thereby constituting a particularly valuable tool for imaging uncooperative or pediatric patient populations.

Lung Metabolism and Inflammation during Mechanical Ventilation; An Imaging Approach.

Acute respiratory distress syndrome (ARDS) is a major cause of mortality in critically ill patients. Patients are currently managed by protective ventilation and alveolar recruitment using positive-end expiratory pressure (PEEP). However, the PEEP's effect on both pulmonary metabolism and regional inflammation is poorly understood. Here, we demonstrate the effect of PEEP on pulmonary anaerobic metabolism in mechanically ventilated injured rats, using hyperpolarized carbon-13 imaging. Pulmonary lactate-to-pyruvate ratio was measured in 21 rats; 14 rats received intratracheal instillation of hydrochloric-acid, while 7 rats received sham saline. 1 hour after acid/saline instillation, PEEP was lowered to 0 cmH2O in 7 injured rats (ZEEP group) and in all sham rats; PEEP was continued in the remaining 7 injured rats (PEEP group). Pulmonary compliance, oxygen saturation, histological injury scores, ICAM-1 expression and myeloperoxidase expression were measured. Lactate-to-pyruvate ratio progressively increased in the dependent lung during mechanical ventilation at ZEEP (p < 0.001), but remained unchanged in PEEP and sham rats. Lactate-to-pyruvate ratio was correlated with hyaline membrane deposition (r = 0.612), edema severity (r = 0.663), ICAM-1 (r = 0.782) and myeloperoxidase expressions (r = 0.817). Anaerobic pulmonary metabolism increases during lung injury progression and is contained by PEEP. Pulmonary lactate-to-pyruvate ratio may indicate in-vivo neutrophil activity due to atelectasis.

Unstable Inflation Causing Injury. Insight from Prone Position and Paired Computed Tomography Scans.

RATIONALE: It remains unclear how prone positioning improves survival in acute respiratory distress syndrome. Using serial computed tomography (CT), we previously reported that "unstable" inflation (i.e., partial aeration with large tidal density swings, indicating increased local strain) is associated with injury progression. OBJECTIVES: We prospectively tested whether prone position contains the early propagation of experimental lung injury by stabilizing inflation. METHODS: Injury was induced by tracheal hydrochloric acid in rats; after randomization to supine or prone position, injurious ventilation was commenced using high tidal volume and low positive end-expiratory pressure. Paired end-inspiratory (EI) and end-expiratory (EE) CT scans were acquired at baseline and hourly up to 3 hours. Each sequential pair (EI, EE) of CT images was superimposed in parametric response maps to analyze inflation. Unstable inflation was then measured in each voxel in both dependent and nondependent lung. In addition, five pigs were imaged (EI and EE) prone versus supine, before and (1 hour) after hydrochloric acid aspiration. MEASUREMENTS AND MAIN RESULTS: In rats, prone position limited lung injury propagation and increased survival (11/12 vs. 7/12 supine; P = 0.01). EI-EE densities, respiratory mechanics, and blood gases deteriorated more in supine versus prone rats. At baseline, more voxels with unstable inflation occurred in dependent versus nondependent regions when supine (41 ± 6% vs. 18 ± 7%; P < 0.01) but not when prone. In supine pigs, unstable inflation predominated in dorsal regions and was attenuated by prone positioning. CONCLUSIONS: Prone position limits the radiologic progression of early lung injury. Minimizing unstable inflation in this setting may alleviate the burden of acute respiratory distress syndrome.

Hyperpolarized gas diffusion MRI of biphasic lung inflation in short- and long-term emphysema models.

During lung inflation, airspace dimensions are affected nonlinearly by both alveolar expansion and recruitment, potentially confounding the identification of emphysematous lung by hyperpolarized helium-3 diffusion magnetic resonance imaging (HP MRI). This study aimed to characterize lung inflation over a broad range of inflation volume and pressure values in two different models of emphysema, as well as in normal lungs. Elastase-treated rats (n = 7) and healthy controls (n = 7) were imaged with HP MRI. Gradual inflation was achieved by incremental changes to both inflation volume and airway pressure. The apparent diffusion coefficient (ADC) was measured at each level of inflation and fitted to the corresponding airway pressures as the second-order response equation, with minimizing residue (χ2 < 0.001). A biphasic ADC response was detected, with an initial ADC increase followed by a decrease at airway pressures >18 cmH2O. Discrimination between treated and control rats was optimal when airway pressure was intermediate (between 10 and 11 cmH2O). Similar findings were confirmed in mice following long-term exposure to cigarette smoke, where optimal discrimination between treated and healthy mice occurred at a similar airway pressure as in the rats. We subsequently explored the evolution of ADC measured at the intermediate inflation level in mice after prolonged smoke exposure and found a significant increase (P < 0.01) in ADC over time. Our results demonstrate that measuring ADC at intermediate inflation enhances the distinction between healthy and diseased lungs, thereby establishing a model that may improve the diagnostic accuracy of future HP gas diffusion studies.

In vivo imaging of the progression of acute lung injury using hyperpolarized [1-13 C] pyruvate.

PURPOSE: To investigate pulmonary metabolic alterations during progression of acute lung injury. METHODS: Using hyperpolarized [1-13 C] pyruvate imaging, we measured pulmonary lactate and pyruvate in 15 ventilated rats 1, 2, and 4 h after initiation of mechanical ventilation. Lung compliance was used as a marker for injury progression. 5 untreated rats were used as controls; 5 rats (injured-1) received 1 ml/kg and another 5 rats (injured-2) received 2 ml/kg hydrochloric acid (pH 1.25) in the trachea at 70 min. RESULTS: The mean lactate-to-pyruvate ratio of the injured-1 cohort was 0.15 ± 0.02 and 0.15 ± 0.03 at baseline and 1 h after the injury, and significantly increased from the baseline value 3 h after the injury to 0.23 ± 0.02 (P = 0.002). The mean lactate-to-pyruvate ratio of the injured-2 cohort decreased from 0.14 ± 0.03 at baseline to 0.08 ± 0.02 1 h after the injury and further decreased to 0.07 ± 0.02 (P = 0.08) 3 h after injury. No significant change was observed in the control group. Compliance in both injured groups decreased significantly after the injury (P < 0.01). CONCLUSIONS: Our findings suggest that in severe cases of lung injury, edema and hyperperfusion in the injured lung tissue may complicate interpretation of the pulmonary lactate-to-pyruvate ratio as a marker of inflammation. However, combining the lactate-to-pyruvate ratio with pulmonary compliance provides more insight into the progression of the injury and its severity. Magn Reson Med 78:2106-2115, 2017. © 2017 International Society for Magnetic Resonance in Medicine.

Mild loss of lung aeration augments stretch in healthy lung regions.

Inspiratory stretch by mechanical ventilation worsens lung injury. However, it is not clear whether and how the ventilator damages lungs in the absence of preexisting injury. We hypothesized that subtle loss of lung aeration during general anesthesia regionally augments ventilation and distension of ventilated air spaces. In eight supine anesthetized and intubated rats, hyperpolarized gas MRI was performed after a recruitment maneuver following 1 h of volume-controlled ventilation with zero positive end-expiratory pressure (ZEEP), FiO2 0.5, and tidal volume 10 ml/kg, and after a second recruitment maneuver. Regional fractional ventilation (FV), apparent diffusion coefficient (ADC) of (3)He (a measurement of ventilated peripheral air space dimensions), and gas volume were measured in lung quadrants of ventral and dorsal regions of the lungs. In six additional rats, computed tomography (CT) images were obtained at each time point. Ventilation with ZEEP decreased total lung gas volume and increased both FV and ADC in all studied regions. Increases in FV were more evident in the dorsal slices. In each lung quadrant, higher ADC was predicted by lower gas volume and by increased mean values (and heterogeneity) of FV distribution. CT scans documented 10% loss of whole-lung aeration and increased density in the dorsal lung, but no macroscopic atelectasis. Loss of pulmonary gas at ZEEP increased fractional ventilation and inspiratory dimensions of ventilated peripheral air spaces. Such regional changes could help explain a propensity for mechanical ventilation to contribute to lung injury in previously uninjured lungs.

Visualizing the Propagation of Acute Lung Injury.

BACKGROUND: Mechanical ventilation worsens acute respiratory distress syndrome, but this secondary "ventilator-associated" injury is variable and difficult to predict. The authors aimed to visualize the propagation of such ventilator-induced injury, in the presence (and absence) of a primary underlying lung injury, and to determine the predictors of propagation. METHODS: Anesthetized rats (n = 20) received acid aspiration (hydrochloric acid) followed by ventilation with moderate tidal volume (V(T)). In animals surviving ventilation for at least 2 h, propagation of injury was quantified by using serial computed tomography. Baseline lung status was assessed by oxygenation, lung weight, and lung strain (V(T)/expiratory lung volume). Separate groups of rats without hydrochloric acid aspiration were ventilated with large (n = 10) or moderate (n = 6) V(T). RESULTS: In 15 rats surviving longer than 2 h, computed tomography opacities spread outward from the initial site of injury. Propagation was associated with higher baseline strain (propagation vs. no propagation [mean ± SD]: 1.52 ± 0.13 vs. 1.16 ± 0.20, P < 0.01) but similar oxygenation and lung weight. Propagation did not occur where baseline strain was less than 1.29. In healthy animals, large V(T) caused injury that was propagated inward from the lung periphery; in the absence of preexisting injury, propagation did not occur where strain was less than 2.0. CONCLUSIONS: Compared with healthy lungs, underlying injury causes propagation to occur at a lower strain threshold and it originates at the site of injury; this suggests that tissue around the primary lesion is more sensitive. Understanding how injury is propagated may ultimately facilitate a more individualized monitoring or management.

Ascorbic acid prolongs the viability and stability of isolated perfused lungs: A mechanistic study using 31P and hyperpolarized 13C nuclear magnetic resonance.

Ex vivo lung perfusion (EVLP) has recently shown promise as a means of more accurately gauging the health of lung grafts and improving graft performance post-transplant. However, reperfusion of ischemic lung promotes the depletion of high-energy compounds and a progressive loss of normal mitochondrial function, and it remains unclear how and to what extent the EVLP approach contributes to this metabolic decline. Although ascorbate has been used to mitigate the effects of ischemia-reperfusion injury, the nature of its effects during EVLP are also not clear. To address these uncertainties, this study monitored the energy status of lungs during EVLP and after the administration of ascorbate using (31)P and hyperpolarized (13)C NMR (nuclear magnetic resonance). Our experiments demonstrated that the oxidative phosphorylation capacity and pyruvate dehydrogenase flux of lungs decline during ex vivo perfusion. The addition of ascorbate to the perfusate prolonged lung viability by 80% and increased the hyperpolarized (13)C bicarbonate signal by a factor of 2.7. The effect of ascorbate is apparently due not to its antioxidant quality but rather to its ability to energize cellular respiration given that it increased the lung's energy charge significantly, whereas other antioxidants (glutathione and α-lipoic acid) did not alter energy metabolism. During ascorbate administration, inhibition of mitochondrial complex I with rotenone depressed energy charge and shifted the metabolic state of the lung toward glycolysis; reenergizing the electron transport chain with TMPD (N,N,N',N'-tetramethyl-p-phenylenediamine) recovered metabolic activity. This indicates that ascorbate slows the decline of the ex vivo perfused lung's mitochondrial activity through an independent interaction with the electron transport chain complexes.

Semiautomatic segmentation of longitudinal computed tomography images in a rat model of lung injury by surfactant depletion.

Quantitative analysis of computed tomography (CT) is essential to the study of acute lung injury. However, quantitative CT is made difficult by poor lung aeration, which complicates the critical step of image segmentation. To overcome this obstacle, this study sought to develop and validate a semiautomated, multilandmark, registration-based scheme for lung segmentation that is effective in conditions of poor aeration. Expiratory and inspiratory CT images were obtained in rats (n = 8) with surfactant depletion of incremental severity to mimic worsening aeration. Trained operators manually delineated the images to provide a comparative landmark. Semiautomatic segmentation originated from a single, previously segmented reference image obtained at healthy baseline. Deformable registration of the target images (after surfactant depletion) was performed using the symmetric diffeomorphic transformation model with B-spline regularization. Registration used multiple landmarks (i.e., rib cage, spine, and lung parenchyma) to minimize the effect of poor aeration. Then target images were automatically segmented by applying the calculated transformation function to the reference image contour. Semiautomatically and manually segmented contours proved to be highly similar in all aeration conditions, including those characterized by more severe surfactant depletion and expiration. The Dice similarity coefficient was over 0.9 in most conditions, confirming high agreement, irrespective of poor aeration. Furthermore, CT density-based measurements of gas volume, tissue mass, and lung aeration distribution were minimally affected by the method of segmentation. Moving forward, multilandmark registration has the potential to streamline quantitative CT analysis by enabling semiautomatic image segmentation of lungs with a broad range of injury severity.

The effect of exogenous substrate concentrations on true and apparent metabolism of hyperpolarized pyruvate in the isolated perfused lung.

Although relatively metabolically inactive, the lung has an important role in maintaining systemic glycolytic intermediate and cytosolic redox balance. Failure to perform this function appropriately may lead to lung disease progression, including systemic aspects of these disorders. In this study, we experimentally probe the response of the isolated, perfused organ to varying glycolytic intermediate (pyruvate and lactate) concentrations, and the effect on the apparent metabolism of hyperpolarized 1-(13)C pyruvate. Twenty-four separate conditions were studied, from sub-physiological to super-physiological concentrations of each metabolite. A three-compartment model is developed, which accurately matches the full range of experiments and includes a full account of evolution of agent concentration and polarization. The model is then refined using a series of approximations which are shown to be applicable to cases of physiological relevance, and which facilitate an intuitive understanding of the saturation and scaling behavior. Perturbations of the model assumptions are used to determine the sensitivity to input parameter estimates, and finally the model is used to examine the relationship between measurements accessible by NMR and the underlying physiological parameters of interest. Based on the observed scaling of lactate labeling with lactate and pyruvate concentrations, we conclude that the level of hyperpolarized lactate signal in the lung is primarily determined by the rate at which NAD(+) is reduced to NADH. Further, although weak dependences on other factors are predicted, the modeled NAD(+) reduction rate is largely governed by the intracellular lactate pool size. Conditions affecting the lactate pool can therefore be expected to display the highest contrast in hyperpolarized (13)C-pyruvate imaging. The work is intended to serve as a basis both to interpret the signal dynamics of hyperpolarized measurements in the normal lung and to understand the cause of alterations seen in a variety of disease and exposure models.

Metabolic spectroscopy of inflammation in a bleomycin-induced lung injury model using hyperpolarized 1-(13) C pyruvate.

Metabolic activity in the lung is known to change in response to external insults, inflammation, and cancer. We report measurements of metabolism in the isolated, perfused rat lung of healthy controls and in diseased lungs undergoing acute inflammation using hyperpolarized 1-(13) C-labeled pyruvate. The overall apparent activity of lactate dehydrogenase is shown to increase significantly (on average by a factor of 3.3) at the 7 day acute stage and to revert substantially to baseline at 21 days, while other markers indicating monocarboxylate uptake and transamination rate are unchanged. Elevated lung lactate signal levels correlate well with phosphodiester levels as determined with (31) P spectroscopy and with the presence of neutrophils as determined by histology, consistent with a relationship between intracellular lactate pool labeling and the density and type of inflammatory cells present. We discuss several alternate hypotheses, and conclude that the most probable source of the observed signal increase is direct uptake and metabolism of pyruvate by inflammatory cells and primarily neutrophils. This signal is seen in high contrast to the low baseline activity of the lung.

Hyperpolarized (3)He diffusion MRI and histology of secreted frizzled related protein-1 (SFRP1) deficient lungs in a Murine model.

Secreted frizzled related protein-1 (SFRP1) plays a key role in many diverse processes, including embryogenesis, tissue repair, bone formation, and tumor genesis. Previous studies have shown the effects of the SFRP1 gene on lung development using the SFRP1 knockout mouse model via histological and physiological studies. In this study, the feasibility of ADC (acquired via HP (3)He) to detect altered lung structure in the SFRP1 knockout (SFRP1(-/-)) mice was investigated, and compared to analysis by histology. This study consisted of two groups, the wild-type (WT) mice and the knockout (KO) mice with n=6 mice for each group. (3)He ADC MRI and histology were performed on all of the animals. The global Lm values of WT and KO mice were 35.0±0.8µm and 38.4±3.8µm, respectively, which translated to an increase of 9.58% in the Lm of KO mice. The mean global ADCs for the WT and KO mice were 0.12±0.01cm(2)/s and 0.13±0.01cm(2)/s, respectively, which equated to a relative increase of 8.0% in the KO mice compared to the WT mice. In the sub-analysis of the anterior, medial and posterior lung regions, Lm increased by 10.50%, 6.66% and 11.84% in the KO mice, respectively, whereas the differences in ADC between the two groups in the anterior, medial, and posterior regions were 7.3%, 8.3%, and 4.6%, respectively. These results suggest that HP MRI measurements can be used as a suitable substitute for histology to obtain valuable information about lung geometry non-invasively. This technique is also advantageous as regional measurements can be performed, which can identify lung destruction more precisely. Most importantly, this approach extends far beyond the specific pathology analyzed in this study, as it can be applied to many other pathological conditions in the lung tissue, as well to many other embryonic studies.

Is higher lactate an indicator of tumor metastatic risk? A pilot MRS study using hyperpolarized (13)C-pyruvate.

RATIONALE AND OBJECTIVES: Cancer cells generate more lactate than normal cells under both aerobic and hypoxic conditions-exhibiting the so-called Warburg effect. However, the relationship between the Warburg effect and tumor metastatic potential remains controversial. We intend to investigate whether the higher lactate reflects higher tumor metastatic potential. MATERIALS AND METHODS: We used hyperpolarized (13)C-pyruvate magnetic resonance spectroscopy (MRS) to compare lactate (13)C-labeling in vivo in mouse xenografts of the highly metastatic (MDA-MB-231) and the relatively indolent (MCF-7) human breast cancer cell lines. We obtained the kinetic parameters of the lactate dehydrogenase (LDH)-catalyzed reaction by three methods of data analysis including the differential equation fit, q-ratio fit, and ratio fit methods. RESULTS: Consistent results from the three methods showed that the highly metastatic tumors exhibited a smaller apparent forward rate constant (k(+) = 0.060 ± 0.004 s(-1)) than the relatively indolent tumors (k(+) = 0.097 ± 0.013 s(-1)). The ratio fit generated the greatest statistical significance for the difference (P = .02). No significant difference in the reverse rate constant was found between the two tumor lines. CONCLUSIONS: The result indicates that the less metastatic breast tumors may produce more lactate than the highly metastatic ones from the injected (13)C-pyruvate and supports the notion that breast tumor metastatic risk is not necessarily associated with the high levels of glycolysis and lactate production. More studies are needed to confirm whether and how much the measured apparent rate constants are affected by the membrane transporter activity and whether they are primarily determined by the LDH activity.

Positive end-expiratory pressure increments during anesthesia in normal lung result in hysteresis and greater numbers of smaller aerated airspaces.

BACKGROUND: 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. METHODS: Following a recruitment maneuver, rats were ventilated with constant tidal volumes and imaged during ascending and descending ramps of PEEP. RESULTS: 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. CONCLUSIONS: 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.