Matthew S. Fox

Detection of radiation induced lung injury in rats using dynamic hyperpolarized 129Xe magnetic resonance spectroscopy

PURPOSE Radiation induced lung injury (RILI) is a common side effect for patients undergoing thoracic radiation therapy (RT). RILI can lead to temporary or permanent loss of lung function and in extreme cases, death. Combining functional lung imaging information with conventional radiation treatment plans may lead to more desirable treatment plans that reduce lung toxicity and improve the quality of life for lung cancer survivors. Magnetic Resonance Imaging of the lung following inhalation of hyperpolarized(129)Xe may provide a useful nonionizing approach for probing changes in lung function and structure associated with RILI before, during, or after RT (early and late time-points). METHODS In this study, dynamic(129)Xe MR spectroscopy was used to measure whole-lung gas transfer time constants for lung tissue and red blood cells (RBC), respectively (TTr_tissue and TTr_RBC) in groups of rats at two weeks and six weeks following 14 Gy whole-lung exposure to radiation from a (60)Co source. A separate group of six healthy age-matched rats served as a control group. RESULTS TTr_tissue values at two weeks post-irradiation (51.6 ± 6.8 ms) were found to be significantly elevated (p < 0.05) with respect to the healthy control group (37.2 ± 4.8 ms). TTr_RBC did not show any significant changes between groups. TTr_tissue was strongly correlated with TTr_RBC in the control group (r = 0.9601 p < 0.05) and uncorrelated in the irradiated groups. Measurements of arterial partial pressure of oxygen obtained by arterial blood sampling were found to be significantly decreased (p < 0.05) in the two-week group (54.2 ± 12.3 mm Hg) compared to those from a representative control group (85.0 ± 10.0 mm Hg). Histology of a separate group of similarly irradiated animals confirmed the presence of inflammation due to radiation exposure with alveolar wall thicknesses that were significantly different (p < 0.05). At six weeks post-irradiation, TTr_tissue returned to values (35.6 ± 9.6 ms) that were not significantly different from baseline. CONCLUSIONS Whole-lung tissue transfer time constants for(129)Xe (TTr_tissue) can be used to detect the early phase of RILI in a rat model involving 14 Gy thoracic (60)Co exposure as early as two weeks post-irradiation. This knowledge combined with more sophisticated models of gas exchange and imaging techniques, may allow functional lung avoidance radiation therapy planning to be achievable, providing more beneficial treatment plans and improved quality of life for recovering lung cancer patients.

Detection of radiation-induced lung injury using hyperpolarized 13C magnetic resonance spectroscopy and imaging

Radiation‐induced lung injury limits radiotherapy of thoracic cancers. Detection of radiation pneumonitis associated with early radiation‐induced lung injury (2–4 weeks postirradiation) may provide an opportunity to adjust treatment, before the onset of acute pneumonitis and/or irreversible fibrosis. In this study, localized magnetic resonance (MR) spectroscopy and imaging of hyperpolarized 13C‐pyruvate (pyruvate) and 13C‐lactate (lactate) were performed in the thorax and kidney regions of rats 2 weeks following whole‐thorax irradiation (14 Gy). Lactate‐to‐pyruvate signal ratio was observed to increase by 110% (P < 0.01), 57% (P < 0.02), and 107% (P < 0.01), respectively, in the thorax, lung, and heart tissues of the radiated rats compared with healthy age‐matched rats. This was consistent with lung inflammation confirmed using cell micrographs of bronchioalveolar lavage specimens and decreases in arterial oxygen partial pressure (paO2), indicative of hypoxia. No statistically significant difference was observed in either lactate‐to‐pyruvate signal ratios in the kidney region (P = 0.50) between the healthy (0.215 ± 0.100) and radiated cohorts (0.215 ± 0.054) or in blood lactate levels (P = 0.69) in the healthy (1.255 ± 0.247 mmol/L) and the radiated cohorts (1.325 ± 0.214 mmol/L), confirming that the injury is localized to the thorax. This work demonstrates the feasibility of hyperpolarized 13C metabolic MR spectroscopy and imaging for detection of early radiation‐induced lung injury. Magn Reson Med 70:601–609, 2013.

Early stage radiation-induced lung injury detected using hyperpolarized (129) Xe Morphometry: Proof-of-concept demonstration in a rat model.

Radiation‐induced lung injury (RILI) is still the major dose‐limiting toxicity related to lung cancer radiation therapy, and it is difficult to predict and detect patients who are at early risk of severe pneumonitis and fibrosis. The goal of this proof‐of‐concept preclinical demonstration was to investigate the potential of hyperpolarized 129Xe diffusion‐weighted MRI to detect the lung morphological changes associated with early stage RILI.

In vivo regional ventilation mapping using fluorinated gas MRI with an x-centric FGRE method.

Inert fluorinated gas lung MRI is a new and promising alternative to hyperpolarized gas lung MRI; it is less expensive and does not require expensive isotopes/polarizers. The thermally polarized nature of signal obtained from fluorinated gases makes it relatively easy to use for dynamic lung imaging and for obtaining lung ventilation maps. In this study, we propose that the sensitivity and resolution of fluorine‐19 (19F) in vivo images can be improved using the x‐centric pulse sequence, thereby achieving a short echo time/pulse repetition time. This study is a transitional step for converting to more sustainable gases for lung imaging.

Detection of radiation-induced lung injury using hyperpolarized (13)C magnetic resonance spectroscopy and imaging.

Radiation‐induced lung injury limits radiotherapy of thoracic cancers. Detection of radiation pneumonitis associated with early radiation‐induced lung injury (2–4 weeks postirradiation) may provide an opportunity to adjust treatment, before the onset of acute pneumonitis and/or irreversible fibrosis. In this study, localized magnetic resonance (MR) spectroscopy and imaging of hyperpolarized 13C‐pyruvate (pyruvate) and 13C‐lactate (lactate) were performed in the thorax and kidney regions of rats 2 weeks following whole‐thorax irradiation (14 Gy). Lactate‐to‐pyruvate signal ratio was observed to increase by 110% (P < 0.01), 57% (P < 0.02), and 107% (P < 0.01), respectively, in the thorax, lung, and heart tissues of the radiated rats compared with healthy age‐matched rats. This was consistent with lung inflammation confirmed using cell micrographs of bronchioalveolar lavage specimens and decreases in arterial oxygen partial pressure (paO2), indicative of hypoxia. No statistically significant difference was observed in either lactate‐to‐pyruvate signal ratios in the kidney region (P = 0.50) between the healthy (0.215 ± 0.100) and radiated cohorts (0.215 ± 0.054) or in blood lactate levels (P = 0.69) in the healthy (1.255 ± 0.247 mmol/L) and the radiated cohorts (1.325 ± 0.214 mmol/L), confirming that the injury is localized to the thorax. This work demonstrates the feasibility of hyperpolarized 13C metabolic MR spectroscopy and imaging for detection of early radiation‐induced lung injury. Magn Reson Med 70:601–609, 2013.

Anatomical, functional and metabolic imaging of radiation-induced lung injury using hyperpolarized MRI.

MRI of hyperpolarized 129Xe gas and 13C‐enriched substrates (e.g. pyruvate) presents an unprecedented opportunity to map anatomical, functional and metabolic changes associated with lung injury. In particular, inhaled hyperpolarized 129Xe gas is exquisitely sensitive to changes in alveolar microanatomy and function accompanying lung inflammation through decreases in the apparent diffusion coefficient (ADC) of alveolar gas and increases in the transfer time (Ttr) of xenon exchange from the gas and into the dissolved phase in the lung. Furthermore, metabolic changes associated with hypoxia arising from lung injury may be reflected by increases in lactate‐to‐pyruvate signal ratio obtained by magnetic resonance spectroscopic imaging following injection of hyperpolarized [1‐13C]pyruvate. In this work, the application of hyperpolarized 129Xe and 13C MRI to radiation‐induced lung injury (RILI) is reviewed and results of ADC, Ttr and lactate‐to‐pyruvate signal ratio changes in a rat model of RILI are summarized. These results are consistent with conventional functional (i.e. blood gases) and histological (i.e. tissue density) changes, and correlate significantly with inflammatory cell counts (i.e. macrophages). Hyperpolarized MRI may provide an earlier indication of lung injury associated with radiotherapy of thoracic tumors, potentially allowing adjustment of treatment before the onset of severe complications and irreversible fibrosis. Copyright

Comparison of hyperpolarized 3He and 129Xe MRI for the measurement of absolute ventilated lung volume in rats

MRI using hyperpolarized noble gases, 3He and 129Xe, provides noninvasive assessments of lung structure and function. Previous work demonstrated that absolute ventilated lung volumes (aVLV) measured in rats using hyperpolarized 3He agree well with micro‐CT.

Measurement of alveolar oxygen partial pressure in the rat lung using Carr-Purcell-Meiboom-Gill spin–spin relaxation times of hyperpolarized 3He and 129Xe at 74 mT

Regional measurement of alveolar oxygen partial pressure can be obtained from the relaxation rates of hyperpolarized noble gases, 3He and 129Xe, in the lungs. Recently, it has been demonstrated that measurements of alveolar oxygen partial pressure can be obtained using the spin–spin relaxation rate (R2) of 3He at low magnetic field strengths (<0.1 T) in vivo. R2 measurements can be achieved efficiently using the Carr‐Purcell‐Meiboom‐Gill pulse sequence. In this work, alveolar oxygen partial pressure measurements based on Carr‐Purcell‐Meiboom‐Gill R2 values of hyperpolarized 3He and 129Xe in vitro and in vivo in the rat lung at low magnetic field strength (74 mT) are presented. In vitro spin–spin relaxivity constants for 3He and 129Xe were determined to be (5.2 ± 0.6) ×10−6 Pa−1 sec−1 and (7.3 ± 0.4) ×10−6 Pa−1 s−1 compared with spin‐lattice relaxivity constants of (4.0 ± 0.4) ×10−6 Pa−1 s−1 and (4.3 ± 1.3) × 10−6 Pa−1 s−1, respectively. In vivo experimental measurements of alveolar oxygen partial pressure using 3He in whole rat lung show good agreement (r2 = 0.973) with predictions based on lung volumes and ventilation parameters. For 129Xe, multicomponent relaxation was observed with one component exhibiting an increase in R2 with decreasing alveolar oxygen partial pressure. Magn Reson Med, 2010.

Application of dual 19F and iron cellular MRI agents to track the infiltration of immune cells to the site of a rejected stem cell transplant

Cellular MRI) was used to detect implanted human mesenchymal stem cells (hMSCs) and the resulting macrophage infiltration that occurs in response to xenotransplantation.

Fractional ventilation mapping using inert fluorinated gas MRI in rat models of inflammation and fibrosis

The purpose of this study was to extend established methods for fractional ventilation mapping using 19F MRI of inert fluorinated gases to rat models of pulmonary inflammation and fibrosis. In this study, five rats were instilled with lipopolysaccharide (LPS) in the lungs two days prior to imaging, six rats were instilled with bleomycin in the lungs two weeks prior to imaging and an additional four rats were used as controls. 19F MR lung imaging was performed at 3 T with rats continuously breathing a mixture of sulfur hexafluoride and O2. Fractional ventilation maps were obtained using a wash‐out approach, by switching the breathing mixture to pure O2, and acquiring images following each successive wash‐out breath. The mean fractional ventilation (r) was 0.29 ± 0.05 for control rats, 0.23 ± 0.10 for LPS‐instilled rats and 0.19 ± 0.03 for bleomycin‐instilled rats. Bleomycin‐instilled rats had a significantly decreased mean r value compared with controls (P = 0.010). Although LPS‐instilled rats had a slightly reduced mean r value, this trend was not statistically significant (P = 0.556). Fractional ventilation gradients were calculated in the anterior/posterior (A/P) direction, and the mean A/P gradient was −0.005 ± 0.008 cm−1 for control rats, 0.013 ± 0.005 cm−1 for LPS‐instilled rats and 0.009 ± 0.018 cm−1 for bleomycin‐instilled rats. Fractional ventilation gradients were significantly different for control rats compared with LPS‐instilled rats only (P = 0.016). The ventilation gradients calculated from control rats showed the expected gravitational relationship, while ventilation gradients calculated from LPS‐ and bleomycin‐instilled rats showed the opposite trend. Histology confirmed that LPS‐instilled rats had a significantly elevated alveolar wall thickness, while bleomycin‐instilled rats showed signs of substantial fibrosis. Overall, 19F MRI may be able to detect the effects of pulmonary inflammation and fibrosis using a simple and inexpensive imaging approach that can potentially be translated to humans. Copyright