This work was supported by NIH grants R01HL159898 and R01HL142258.

Assessing Lung Function with Hyperpolarized Xenon-129 MRI

<ol>
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W., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Large+production+system+for+hyperpolarized+129Xe+for+human+lung+imaging+studies.">Large production system for hyperpolarized 129Xe for human lung imaging studies.</a> Acad Radiol. 15 (6), 683-692 (2008).</li><li>Parnell, S. R., Deppe, M. H., Parra-Robles, J., Wild, J. M. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Enhancement+of+Xe-129+polarization+by+off-resonant+spin+exchange+optical+pumping.">Enhancement of Xe-129 polarization by off-resonant spin exchange optical pumping.</a> J Appl Phys. 108 (6), 064908 (2010).</li><li>Norquay, G., Collier, G. J., Rao, M., Stewart, N. J., Wild, J. M. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=^{129}Xe-Rb+spin-exchange+optical+pumping+with+high+photon+efficiency.">^{129}Xe-Rb spin-exchange optical pumping with high photon efficiency.</a> Phys Rev Lett. 121 (15), 153201 (2018).</li><li>Mugler, J. P., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=MR+imaging+and+spectroscopy+using+hyperpolarized+129Xe+gas:+preliminary+human+results.">MR imaging and spectroscopy using hyperpolarized 129Xe gas: preliminary human results.</a> Magn Reson Med. 37 (6), 809-815 (1997).</li><li>Ruppert, K., Brookeman, J. R., Hagspiel, K. D., Driehuys, B., Mugler, J. 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J., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Reproducibility+of+quantitative+indices+of+lung+function+and+microstructure+from+129+Xe+chemical+shift+saturation+recovery+(CSSR)+MR+spectroscopy.">Reproducibility of quantitative indices of lung function and microstructure from 129 Xe chemical shift saturation recovery (CSSR) MR spectroscopy.</a> Magn Reson Med. 77 (6), 2107-2113 (2017).</li><li>Zhong, J., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Simultaneous+assessment+of+both+lung+morphometry+and+gas+exchange+function+within+a+single+breath-hold+by+hyperpolarized+(129)+Xe+MRI.">Simultaneous assessment of both lung morphometry and gas exchange function within a single breath-hold by hyperpolarized (129) Xe MRI.</a> NMR Biomed. 30 (8), (2017).</li><li>Kern, A. L., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Regional+investigation+of+lung+function+and+microstructure+parameters+by+localized+(129)+Xe+chemical+shift+saturation+recovery+and+dissolved-phase+imaging:+A+reproducibility+study.">Regional investigation of lung function and microstructure parameters by localized (129) Xe chemical shift saturation recovery and dissolved-phase imaging: A reproducibility study.</a> Magn Reson Med. 81 (1), 13-24 (2018).</li><li>Kern, A. L., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Mapping+of+regional+lung+microstructural+parameters+using+hyperpolarized+(129)+Xe+dissolved-phase+MRI+in+healthy+volunteers+and+patients+with+chronic+obstructive+pulmonary+disease.">Mapping of regional lung microstructural parameters using hyperpolarized (129) Xe dissolved-phase MRI in healthy volunteers and patients with chronic obstructive pulmonary disease.</a> Magn Reson Med. 81 (4), 2360-2373 (2018).</li><li>Xie, J., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Single+breath-hold+measurement+of+pulmonary+gas+exchange+and+diffusion+in+humans+with+hyperpolarized+(129)+Xe+MR.">Single breath-hold measurement of pulmonary gas exchange and diffusion in humans with hyperpolarized (129) Xe MR.</a> NMR Biomed. 32 (5), e4068 (2019).</li><li>Zanette, B., Santyr, G. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Accelerated+interleaved+spiral-IDEAL+imaging+of+hyperpolarized+(129)+Xe+for+parametric+gas+exchange+mapping+in+humans.">Accelerated interleaved spiral-IDEAL imaging of hyperpolarized (129) Xe for parametric gas exchange mapping in humans.</a> Magn Reson Med. 82 (3), 1113-1119 (2019).</li><li>Ruppert, K., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Investigating+biases+in+the+measurement+of+apparent+alveolar+septal+wall+thickness+with+hyperpolarized+129Xe+MRI.">Investigating biases in the measurement of apparent alveolar septal wall thickness with hyperpolarized 129Xe MRI.</a> Magn Reson Med. 84 (6), 3027-3039 (2020).</li><li>Zhang, M., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Quantitative+evaluation+of+lung+injury+caused+by+PM(2.5)+using+hyperpolarized+gas+magnetic+resonance.">Quantitative evaluation of lung injury caused by PM(2.5) using hyperpolarized gas magnetic resonance.</a> Magn Reson Med. 84 (2), 569-578 (2020).</li><li>Friedlander, Y., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Hyperpolarized+(129)+Xe+MRI+of+the+rat+brain+with+chemical+shift+saturation+recovery+and+spiral-IDEAL+readout.">Hyperpolarized (129) Xe MRI of the rat brain with chemical shift saturation recovery and spiral-IDEAL readout.</a> Magn Reson Med. 87 (4), 1971-1979 (2022).</li><li>Patz, S., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Diffusion+of+hyperpolarized+(129)Xe+in+the+lung:+a+simplified+model+of+(129)Xe+septal+uptake+and+experimental+results.">Diffusion of hyperpolarized (129)Xe in the lung: a simplified model of (129)Xe septal uptake and experimental results.</a> New J Phys. 13, 015009 (2011).</li><li>Chang, Y. 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S., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Detection+of+radiation+induced+lung+injury+in+rats+using+dynamic+hyperpolarized+(129)Xe+magnetic+resonance+spectroscopy.">Detection of radiation induced lung injury in rats using dynamic hyperpolarized (129)Xe magnetic resonance spectroscopy.</a> Med Phys. 41 (7), 072302 (2014).</li><li>Li, H., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Quantitative+evaluation+of+radiation-induced+lung+injury+with+hyperpolarized+Xenon+magnetic+resonance.">Quantitative evaluation of radiation-induced lung injury with hyperpolarized Xenon magnetic resonance.</a> Magn Reson Med. 76 (2), 408-416 (2016).</li><li>Ruppert, K., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Detecting+pulmonary+capillary+blood+pulsations+using+hyperpolarized+Xenon-129+chemical+shift+saturation+recovery+(CSSR)+MR+spectroscopy.">Detecting pulmonary capillary blood pulsations using hyperpolarized Xenon-129 chemical shift saturation recovery (CSSR) MR spectroscopy.</a> Magn Reson Med. 75 (4), 1771-1780 (2016).</li><li>Walkup, L. L., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Feasibility,+tolerability+and+safety+of+pediatric+hyperpolarized+129Xe+magnetic+resonance+imaging+in+healthy+volunteers+and+children+with+cystic+fibrosis.">Feasibility, tolerability and safety of pediatric hyperpolarized 129Xe magnetic resonance imaging in healthy volunteers and children with cystic fibrosis.</a> Pediatr Radiol. 46 (12), 1651-1662 (2016).</li><li>Willmering, M. 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J., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Utilizing+flip+angle/TR+equivalence+to+reduce+breath+hold+duration+in+hyperpolarized+(129)+Xe+1-point+Dixon+gas+exchange+imaging.">Utilizing flip angle/TR equivalence to reduce breath hold duration in hyperpolarized (129) Xe 1-point Dixon gas exchange imaging.</a> Magn Reson Med. 87 (3), 1490-1499 (2022).</li><li>Chang, Y. V. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Toward+a+quantitative+understanding+of+gas+exchange+in+the+lung.">Toward a quantitative understanding of gas exchange in the lung.</a> arXiv. , (2010).</li><li>Chang, Y. 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The authors have no conflicts of interest to disclose.

HXe CSSR MR spectroscopy is a powerful technique for assessing several pulmonary function metrics that would be difficult or impossible to quantify in vivo using any other existing diagnostic modality24. Nevertheless, the acquisition and subsequent data analysis are based on certain assumptions about physiological conditions and technical parameters that are never entirely achievable in living subjects. These limitations and their impact on the interpretation of the extracted metrics will...

Hyperpolarized Xenon-129 (HXe) magnetic resonance imaging (MRI)1 is a technique that offers unique insights into lung structure, function, and gas exchange processes. By dramatically amplifying the magnetization of Xenon gas through spin-exchange optical pumping, HXe MRI achieves an order-of-magnitude improvement in signal-to-noise ratio compared to thermally polarized Xenon MRI2,3,4,5,6. This hyperpolarization enables the direct visualization and quantification of Xenon gas uptake into lung tissue and blood, which would otherwise be undetectable with conventional thermally polarized MRI7.
Chemical shift saturation recovery (CSSR) MR spectroscopy8,9,10,11,12,13 has proven to be one of the most valuable HXe MRI techniques. CSSR involves selectively saturating the magnetization of Xenon dissolved in lung tissue and blood using frequency-specific radiofrequency (RF) pulses. The subsequent recovery of the dissolved-phase (DP) signal as it exchanges with fresh hyperpolarized Xenon gas in the airspaces on a timescale of ms offers important functional information about the lung parenchyma.
Since its development in the early 2000s, the techniques behind CSSR spectroscopy have been progressively refined14,15,16,17,18,19,20,21,22,23. Further, advances in modeling Xenon uptake curves have enabled the extraction of specific physiological parameters, such as alveolar wall thickness and pulmonary transit times10,24,25,26. Studies have shown CSSR&#39;s sensitivity to subtle changes in lung microstructure and gas exchange efficiency in the form of pulmonary abnormalities found in clinically healthy smokers27, as well as in a range of lung diseases, including chronic obstructive pulmonary disease (COPD)18,27,28, fibrosis29, and radiation-induced lung injury30,31. CSSR spectroscopy has also been demonstrated to be sensitive to detect oscillations in the DP signal corresponding to pulsatile blood flow during the cardiac cycle32.
While significant progress has been made, practical challenges remain in implementing CSSR spectroscopy on clinical MRI systems. Scan times requiring single-dose breath holds approaching 10 s may be too long for pediatric subjects33,34 or patients with severe lung disease35,36. Additionally, the technique is susceptible to measurement biases if acquisition parameters such as the order of the saturation delay times or the efficacy of the dissolved-phase saturation are not properly optimized21. To address these limitations and make CSSR more accessible to the broader research community, clear, step-by-step protocols for both conventional breath hold and free-breathing acquisitions, currently under development, are needed.
The objective of this paper is to present a detailed methodology for performing optimized CSSR MR spectroscopy using HXe gas. The protocol will cover polarization and delivery of the Xenon gas, RF pulse calibration, sequence parameter selection, subject preparation, data acquisition, and key steps in data analysis. Examples of experimental results will be provided. It is hoped that this comprehensive guide will serve as a foundation for CSSR implementations across sites and help realize the full potential of this technique for quantifying lung microstructural changes in a range of pulmonary diseases.

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quantitative measure of lung structure and function obtained from hyperpolarized xenon spectroscopy

Hyperpolarized Xenon-129 (HXe) magnetic resonance imaging (MRI) provides tools for obtaining 2- or 3-dimensional maps of lung ventilation patterns, gas diffusion, Xenon uptake by lung parenchyma, and other lung function metrics. However, by trading spatial for temporal resolution, it also enables tracing of pulmonary Xenon gas exchange on a ms timescale. This article describes one such technique, chemical shift saturation recovery (CSSR) MR spectroscopy. It illustrates how it can be used to assess capillary blood volume, septal wall thickness, and the surface-to-volume ratio in the alveoli. The flip angle of the applied radiofrequency pulses (RF) was carefully calibrated. Single-dose breath-hold and multi-dose free-breathing protocols were employed for administering the gas to the subject. Once the inhaled Xenon gas reached the alveoli, a series of 90&#176; RF pulses was applied to ensure maximum saturation of the accumulated Xenon magnetization in the lung parenchyma. Following a variable delay time, spectra were acquired to quantify the regrowth of the Xenon signal due to gas exchange between the alveolar gas volume and the tissue compartments of the lung. These spectra were then analyzed by fitting complex pseudo-Voigt functions to the three dominant peaks. Finally, the delay time-dependent peak amplitudes were fitted to a one-dimensional analytical gas-exchange model to extract physiological parameters.

Figure 2&#160;illustrates a typical Xenon spectrum observed in the human lung during a breath hold, subsequent to the inhalation of 500 mL of Xenon dose. The spectrum displays two distinct regions, the GP resonance around 0 ppm, and the DP region, which consists of the membrane peak at approximately 197 ppm and the red blood cell peak at approximately 217 ppm. The relative peak amplitudes depend on a number of factors including the shape, duration, and center frequency of the RF excitation p...

Watch this Scientific Journal Video about Author Spotlight: Advancing Lung Disease Research with Free-Breathing Hyperpolarized Xenon-129 MRI at JoVE.com

Author Spotlight: Advancing Lung Disease Research with Free-Breathing Hyperpolarized Xenon-129 MRI

The manuscript presents a detailed protocol for using hyperpolarized Xenon-129 chemical shift saturation recovery (CSSR) to trace pulmonary gas exchange, assess the apparent alveolar septal wall thickness, and measure the surface-to-volume ratio. The method has the potential to diagnose and monitor lung diseases.

Quantitative Measure of Lung Structure and Function Obtained from Hyperpolarized Xenon Spectroscopy

Hyperpolarized Xenon-129 (HXe) magnetic resonance imaging (MRI) provides tools for obtaining 2- or 3-dimensional maps of lung ventilation patterns, gas ...

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562 Views.  University of Pennsylvania. Ons onderzoek richt zich op het gebruik van hyperpolarisatie op 129 MRI-technologie om de longfunctie te beoordelen en longziekten te onderzoeken. Het belangrijkste doel is om te zien hoe deze beeldvormingstechniek kan leiden tot een betere detectie, begrip en tracking van verschillende longaandoeningen. De meeste hypergepolariseerde MR-beeldvorming van de longen wordt uitgevoerd tijdens het inhouden van de adem.Wij zijn van mening dat de longfunctie, gekwantificeerd onder een dergelij...

Video: Auteur in de schijnwerpers: onderzoek naar longziekten bevorderen met vrij ademende hypergepolariseerde Xenon-129 MRI

Assessment of Cardiac Function and Energetics in Isolated Mouse Hearts Using 31P NMR Spectroscopy

Bioengineered mouse models have become powerful research tools in determining causal relationships between molecular alterations and models of cardiovascular disease. Although molecular biology is necessary in identifying key changes in the signaling pathway, it is not a surrogate for functional significance. While physiology can provide answers to the question of function, combining physiology with biochemical assessment of metabolites in the intact, beating heart allows for a complete picture of cardiac function and energetics. For years, our laboratory has utilized isolated heart perfusions combined with nuclear magnetic resonance (NMR) spectroscopy to accomplish this task. Left ventricular function is assessed by Langendorff-mode isolated heart perfusions while cardiac energetics is measured by performing 31P magnetic resonance spectroscopy of the perfused hearts. With these techniques, indices of cardiac function in combination with levels of phosphocreatine and ATP can be measured simultaneously in beating hearts. Furthermore, these parameters can be monitored while physiologic or pathologic stressors are instituted. For example, ischemia/reperfusion or high workload challenge protocols can be adopted. The use of aortic banding or other models of cardiac pathology are apt as well. Regardless of the variants within the protocol, the functional and energetic significance of molecular modifications of transgenic mouse models can be adequately described, leading to new insights into the associated enzymatic and metabolic pathways. Therefore, 31P NMR spectroscopy in the isolated perfused heart is a valuable research technique in animal models of cardiovascular disease.

Assessment of Cardiac Function and Energetics in Isolated Mouse Hearts Using 31P NMR Spectroscopy

Langendorff-mode isolated heart perfusion, in conjunction with 31P NMR spectroscopy, combines the fields of biochemistry and physiology into one experiment. The protocol allows for the dynamic measurement of high energy phosphate content and turnover in the heart while concurrently monitoring physiologic function. When performed correctly, this is a valuable technique in the assessment of cardiac energetics.

Bioengineered mouse models have become powerful research tools in determining causal relationships between molecular alterations and models of ...

Diagnostic Ultrasound Imaging of Mouse Diaphragm Function

Function analysis of rodent respiratory skeletal muscles, particularly the diaphragm, is commonly performed by isolating muscle strips using invasive surgical procedures. Although this is an effective method of assessing in vitro diaphragm activity, it involves non-survival surgery. The application of non-invasive ultrasound imaging as an in vivo procedure is beneficial since it not only reduces the number of animals sacrificed, but is also suitable for monitoring disease progression in live mice. Thus, our ultrasound imaging method may likely assist in the development of novel therapies that alleviate muscle injury induced by various respiratory diseases. Particularly, in clinical diagnoses of obstructive lung diseases, ultrasound imaging has the potential to be used in conjunction with other standard tests to detect the early onset of diaphragm muscle fatigue. In the current protocol, we describe how to accurately evaluate diaphragm contractility in a mouse model using a diagnostic ultrasound imaging technique.

Diagnostic ultrasound imaging has proven to be effective in diagnosing various respiratory diseases in human and animal subjects. We demonstrate a comprehensive ultrasound protocol utilized by Dr. Zuo's lab to analyze diaphragm kinetics specifically in mouse models. This is also a non-invasive research technique which can provide quantitative information on mouse respiratory muscle function.

Function analysis of rodent respiratory skeletal muscles, particularly the diaphragm, is commonly performed by isolating muscle strips using invasive ...

Method of Isolated Ex Vivo Lung Perfusion in a Rat Model: Lessons Learned from Developing a Rat EVLP Program

The number of acceptable donor lungs available for lung transplantation is severely limited due to poor quality. Ex-Vivo Lung Perfusion (EVLP) has allowed lung transplantation in humans to become more readily available by enabling the ability to assess organs and expand the donor pool. As this technology expands and improves, the ability to potentially evaluate and improve the quality of substandard lungs prior to transplant is a critical need. In order to more rigorously evaluate these approaches, a reproducible animal model needs to be established that would allow for testing of improved techniques and management of the donated lungs as well as to the lung-transplant recipient. In addition, an EVLP animal model of associated pathologies, e.g., ventilation induced lung injury (VILI), would provide a novel method to evaluate treatments for these pathologies. Here, we describe the development of a rat EVLP lung program and refinements to this method that allow for a reproducible model for future expansion. We also describe the application of this EVLP system to model VILI in rat lungs. The goal is to provide the research community with key information and &#8220;pearls of wisdom&#8221;/techniques that arose from trial and error and are critical to establishing an EVLP system that is robust and reproducible.

Method of Isolated Ex Vivo Lung Perfusion in a Rat Model: Lessons Learned from Developing a Rat EVLP Program

Ex-Vivo Lung Perfusion (EVLP) has allowed lung transplantation in humans to become more readily available by enabling the ability to assess organs and expand the donor pool. Here, we describe the development of a rat EVLP program and refinements that allow for a reproducible model for future expansion.

The number of acceptable donor lungs available for lung transplantation is severely limited due to poor quality. Ex-Vivo Lung Perfusion (EVLP) has allowed ...

Cardiac Catheterization in Mice to Measure the Pressure Volume Relationship: Investigating the Bowditch Effect

Animal models that mimic human cardiac disorders have been created to test potential therapeutic strategies. A key component to evaluating these strategies is to examine their effects on heart function. There are several techniques to measure in vivo cardiac mechanics (e.g., echocardiography, pressure/volume relations, etc.). Compared to echocardiography, real-time left ventricular (LV) pressure/volume analysis via catheterization is more precise and insightful in assessing LV function. Additionally, LV pressure/volume analysis provides the ability to instantaneously record changes during manipulations of contractility (e.g., &#946;-adrenergic stimulation) and pathological insults (e.g., ischemia/reperfusion injury). In addition to the maximum (+dP/dt) and minimum (-dP/dt) rate of pressure change in the LV, an accurate assessment of LV function via several load-independent indexes (e.g., end systolic pressure volume relationship and preload recruitable stroke work) can be attained. Heart rate has a significant effect on LV contractility such that an increase in the heart rate is the primary mechanism to increase cardiac output (i.e., Bowditch effect). Thus, when comparing hemodynamics between experimental groups, it is necessary to have similar heart rates. Furthermore, a hallmark of many cardiomyopathy models is a decrease in contractile reserve (i.e., decreased Bowditch effect). Consequently, vital information can be obtained by determining the effects of increasing heart rate on contractility. Our and others data has demonstrated that the neuronal nitric oxide synthase (NOS1) knockout mouse has decreased contractility. Here we describe the procedure of measuring LV pressure/volume with increasing heart rates using the NOS1 knockout mouse model.

This article describes the measurement of murine left ventricular function via pressure/volume analysis at different heart rates.

Animal models that mimic human cardiac disorders have been created to test potential therapeutic strategies. A key component to evaluating these ...

Nerve-sparing Mid-urethral Obstruction (NeMO) in Female Small Rodents

Partial bladder outlet obstruction (pBOO) has a high prevalence, causes significant patient burden, and immense health care costs. The most common animal model to investigate bladder remodeling in pBOO are female rodents undergoing partial obstruction at the proximal urethra. Variability in the degree of obstruction and animal mortality are major concerns with proximal obstruction. Furthermore, dissecting around the proximal urethra and bladder neck jeopardizes bladder innervation.
We developed a nerve-sparing mid-urethral obstruction (NeMO) model for pBOO avoiding the disadvantages of the traditional model. We approached the urethra just inferior to the pubic symphysis, which obviated the need for laparotomy as well as for dissection in this area; also, the striated urethral sphincter remained untouched. We performed NeMO in female Sprague-Dawley rats (12 obstructions, 6 sham animals) as well as in female C57/bl6 mice (20 obstructions, 18 sham animals). After two weeks, we evaluated bladder function, bladder mass, and body mass.
We had no mortalities among obstructed- or sham-operated female rats; as described for the traditional proximal pBOO-method, we tied the suture around the proximal urethra and a temporarily placed 0.9 mm metal rod. NeMO induced an 85% increase in bladder mass after two weeks, average residual urine volume was 0.4 mL in partially obstructed rats while only 0.03 mL in sham animals. In mice, we tested 3 sizes of cannulas that we placed along the urethra when tying the suture. We found that using a 27-gauge cannula resulted in over 50% animal mortality; placing the 25-gauge cannula did not yield the desired response in increasing bladder mass; utilizing a 26-gauge cannula yielded favorable results with minimal animal mortality (1/8) yet a significant 2-fold increase in bladder mass.

Nerve-sparing Mid-urethral Obstruction NeMO in Female Small Rodents

Traditional modeling of partial bladder outlet obstruction in rodents is fraught with animal mortality. A denervation injury from dissection around the proximal urethra and bladder neck is also of major concern. We developed and evaluated a safe and reliable mid-urethral obstruction model, avoiding the shortcomings of the traditional model.

Partial bladder outlet obstruction (pBOO) has a high prevalence, causes significant patient burden, and immense health care costs. The most common animal ...

Combining Volumetric Capnography And Barometric Plethysmography To Measure The Lung Structure-function Relationship

Tools to measure lung and airways volume are critical for pulmonary researchers interested in evaluating the impact of disease or novel therapies on the lung. Barometric plethysmography is a classic technique to evaluate the lung volume with a long history of clinical use. Volumetric capnography utilizes the profile of exhaled carbon dioxide to determine the volume of the conducting airways, or dead space, and provides an index of airways homogeneity. These techniques may be used independently, or in combination to evaluate the dependence of airways volume and homogeneity on lung volume. This paper provides detailed technical instructions to replicate these techniques and our representative data demonstrates that the airways volume and homogeneity are highly correlated to lung volume. We also provide a macro for the analysis of capnographic data, which can be modified or adapted to fit different experimental designs. The advantage of these measures is that their advantages and limitations are supported by decades of experimental data, and they can be made repeatedly in the same subject without expensive imaging equipment or technically advanced analysis algorithms. These methods may be particularly useful for investigators interested in perturbations that change both the functional residual capacity of the lung and airways volume.

Here, we describe two measures of pulmonary function &#8211; barometric plethysmography, which allows the measurement of lung volume, and volumetric capnography, a tool to measure the anatomic dead space and airways uniformity. These techniques may be used independently or combined to assess airways function at different lung volumes.

Tools to measure lung and airways volume are critical for pulmonary researchers interested in evaluating the impact of disease or novel therapies on the ...

Quantitative Analysis of Cellular Composition in Advanced Atherosclerotic Lesions of Smooth Muscle Cell Lineage-Tracing Mice

Atherosclerosis remains the leading cause of death worldwide and, despite countless preclinical studies describing promising therapeutic targets, novel interventions have remained elusive. This is likely due, in part, to a reliance on preclinical prevention models investigating the effects of genetic manipulations or pharmacological treatments on atherosclerosis development rather than the established disease. Also, results of these studies are often confounding because of the use of superficial lesion analyses and a lack of characterization of lesion cell populations. To help overcome these translational hurdles, we propose an increased reliance on intervention models that employ investigation of changes in cellular composition at a single cell level by immunofluorescent staining and confocal microscopy. To this end, we describe a protocol for testing a putative therapeutic agent in a murine intervention model including a systematic approach for animal dissection, embedding, sectioning, staining, and quantification of brachiocephalic artery lesions. In addition, due to the phenotypic diversity of cells within late-stage atherosclerotic lesions, we describe the importance of using cell-specific, inducible lineage tracing mouse systems and how this can be leveraged for unbiased characterization of atherosclerotic lesion cell populations. Together, these strategies may assist vascular biologists to more accurately model therapeutic interventions and analyze atherosclerotic disease and will hopefully translate into a higher rate of success in clinical trials.

We propose a standardized protocol to characterize the cellular composition of late-stage murine atherosclerotic lesions including systematic methods of animal dissection, tissue embedding, sectioning, staining, and analysis of brachiocephalic arteries from atheroprone smooth muscle cell lineage tracing mice.

Atherosclerosis remains the leading cause of death worldwide and, despite countless preclinical studies describing promising therapeutic targets, novel ...

Hyperpolarized 129Xe Lung MRI and Spectroscopy in Mechanically Ventilated Mice

Hyperpolarized (HP) xenon-129 (129Xe) is an inhaled magnetic resonance imaging (MRI) contrast agent with unique spectral and physical properties that can be exploited to quantify pulmonary physiology, including ventilation, restricted diffusion (alveolar-airspace size), and gas exchange. In humans, it has been used to evaluate disease severity and progression in a variety of pulmonary disorders and is approved for clinical use in the United States and United Kingdom. Beyond its clinical applications, the ability of 129Xe MRI to noninvasively assess pulmonary pathophysiology and provide spatially resolved information is valuable for preclinical research. Among animal models, mice are the most widely used due to the accessibility of genetically modified disease models. Here, 129Xe MRI is promising as a minimally invasive, radiation-free, and sensitive technique to longitudinally monitor lung disease progression and therapy response (e.g., in drug discovery). This technique can extend to preclinical applications by incorporating an MRI-triggered, free-breathing apparatus or mechanical ventilator to deliver gas. Here, we describe the steps and provide checklists to ensure robust data collection and analysis, including creating a thermally polarized xenon gas phantom for quality control, optimizing polarization, animal handling (sedation, intubation, ventilation, and care for mice), and protocols for ventilation, restricted diffusion, and gas exchange data. While preclinical 129Xe MRI can be applied in various animal models (e.g., rats, pigs, sheep), this protocol focuses on mice due to the challenges posed by their small anatomy, which are balanced by their affordability and the availability of many disease models.

Hyperpolarized xenon MRI can quantify regional lung microstructure (air-space dimensions) and physiology (ventilation and gas exchange) in translational research and clinical care. Although challenging, it can provide comparable pulmonary insights in preclinical studies. This protocol describes the infrastructure and procedures needed to perform routine xenon lung MRI in mice.

Hyperpolarized (HP) xenon-129 (129Xe) is an inhaled magnetic resonance imaging (MRI) contrast agent with unique spectral and physical properties that can ...

Bioengineering

A Standardized Workflow for Hyperpolarized 129Xe MRI to Study Pulmonary Function

Acquiring Hyperpolarized 129Xe Magnetic Resonance Images of Lung Ventilation

Hyperpolarized 129Xe MRI comprises a unique array of structural and functional lung imaging techniques. Technique standardization across sites is increasingly important given the recent FDA approval of 129Xe as an MR contrast agent and as interest in 129Xe MRI increases among research and clinical institutions. Members of the 129Xe MRI Clinical Trials Consortium (Xe MRI CTC) have agreed upon best practices for each of the key aspects of the 129Xe MRI workflow, and these recommendations are summarized in a recent publication. This work provides practical information to develop an end-to-end workflow for collecting 129Xe MR images of lung ventilation according to the Xe MRI CTC recommendations. Preparation and administration of 129Xe for MR studies will be discussed and demonstrated, with specific topics including choice of appropriate gas volumes for entire studies and for individual MR scans, preparation&#160;and delivery of individual 129Xe doses, and best practices for monitoring subject safety and 129Xe tolerability during studies. Key MR technical considerations will also be covered, including pulse sequence types and optimized parameters, calibration of 129Xe flip angle and center frequency, and 129Xe MRI ventilation image analysis.

Author Spotlight: Standardization and Best Practices for Advancing Lung Imaging Using 129Xe MRI

Hyperpolarized 129Xe magnetic resonance imaging (MRI) is a method for studying regionally resolved aspects of pulmonary function. This work presents an end-to-end standardized workflow for hyperpolarized 129Xe MRI of lung ventilation, with specific attention to pulse sequence design, 129Xe dose preparation, scan workflow, and best practices for subject safety monitoring.

Hyperpolarized 129Xe MRI comprises a unique array of structural and functional lung imaging techniques. Technique standardization across sites is ...

Multi-modal Pulmonary Imaging: Using Complementary Information from CT and Hyperpolarized 129Xe MRI to Evaluate Lung Structure-Function

Hyperpolarized 129Xe gas MRI is an emerging technique to evaluate and measure regional lung function including pulmonary gas distribution and gas exchange. Chest computed tomography (CT) still remains the clinical gold standard for imaging of the lungs, though, in part due to the rapid CT protocols that acquire high-resolution images in seconds and the widespread availability of CT scanners. Quantitative approaches have enabled the extraction of structural lung parenchymal, airway and vascular measurements from chest CT that have been evaluated in many clinical research studies. Together, CT and 129Xe MRI provide complementary information that can be used to evaluate regional lung structure and function, resulting in new insights into lung health and disease. 129Xe MR-CT image registration can be performed to measure regional lung structure-function to better understand lung disease pathophysiology, and to perform image-guided pulmonary interventions. Here, a method for 129Xe MRI-CT registration is outlined to support implementation in research or clinical settings. Registration methods and applications that have been employed to date in the literature are also summarized, and suggestions are provided for future directions that may further overcome technical challenges related to 129Xe MR-CT image registration and facilitate broader implementation of regional lung structure-function evaluation.

Multi-modal Pulmonary Imaging: Using Complementary Information from CT and Hyperpolarized 129Xe MRI to Evaluate Lung Structure-Function

CT and 129Xe MRI provide complementary lung structure-function information that can be exploited for regional analysis using image registration. Here, we provide a protocol that builds from the existing literature for 129Xe MR to CT image registration using open-source platforms.

Quantitative Measure of Lung Structure and Function Obtained from Hyperpolarized Xenon Spectroscopy

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