3he magnetic resonance imaging for the quantification of disease in the rat lung

Resumen

Lung diseases are the leading cause of death worldwide and the second in Europe, with an expected further increase in annual number of deaths. Existing respiratory disease biomarkers, such as spirometric measures of lung function, are non-sensitive and spatially non-specific, because of their global character. Therefore, they cannot quantify the inhomogeneity of many pulmonary diseases. Imaging based biomarkers are regionally sensitive because they are directly measured in the affected areas. Even though magnetic resonance imaging (MRI) is an excellent technique that uses non-ionizing radiation, the visualization of lung parenchyma by proton lung MRI is difficult because of its low density and of magnetic field inhomogeneities in the chest cavity, which shorten dramatically T2* . 3He lung MRI is an alternative to indirectly probe the lung structure and function. It consists of inhaling 3He and imaging this gas while in the lungs. In 3He MRI the imaged nucleus is not proton but the 3He nucleus, which before experimenting is laser-hyperpolarized. This is a process by which the MRI signal of 3He, a gas with low spin density, is increased up to 5 orders of magnitude over its thermal equilibrium level. Until today 3He lung MRI research has focused in static spin-density-weighted and diffusion-weighted imaging. The apparent diffusion coefficient registered by diffusion-weighted 3He MRI is considered a well-established biomarker of emphysema. In this thesis we experimented with rats to investigate the usefulness of inflation rate, a biomarker based on dynamic spin-density-weighted 3He MRI, also termed ventilation 3He MRI. This technique has the relative advantage that it visualizes the distribution of ventilation, which is expected to be altered in pathologic conditions. In dynamic 3He MRI the precise control and measurement of tracheal flow and pressure is extremely important. This accuracy is normally achieved by any small animal ventilator. However, hyperpolarized gas makes the use of commercial devices impossible. Hyperpolarized gas should not come in contact with metallic parts or cross through magnetic fields, because hyperpolarization is destroyed. The use of a special device is therefore imperative. In this thesis, we used a custom-built ventilator that was readily available in our laboratory. The device was partially redesigned and new features were added for the needs of the dynamic 3He MRI experiment. The imaging biomarker that was quantified is proportional to gas flow. It was therefore critical to ensure reproducibility of 3He inflow. The first objective of this thesis was the design of the ventilator for the needs of the experiment. To verify how inflation rate, measured by dynamic spin-density-weighted 3He MRI, is affected by the presence of disease in the lungs, we executed an experiment with three groups of rats: healthy (n=8), treated with porcine pancreatic elastase (n=9), and one rat unilaterally treated with elastase in the left lung. Porcine pancreatic elastase when instilled in the lungs of rats, provokes a model of emphysema within 3 weeks. This disease is expected to alter the distribution of ventilation. Its effects were also assessed by gold-standard morphological and 3He MRI diffusion measurements. The correlation of inflation rate with these reference parameters was verified. Inflation rate was quantified on a dynamically growing grid, which followed the lung growth during inspiration. The grid also served to regionally compare the different parameters between them. It was proven that 3He MRI regional inflation rate can quantify elastase induced emphysema in the lungs. This technique has the potential to be used in pharmacological studies or to test preclinically the progress of pulmonary diseases, that provoke impaired ventilation.