Magnetic Resonance Imaging of Protease-Mediated Lung Tissue Inflammation and Injury

Abstract

Pulmonary inflammation usually involves strong neutrophil recruitment with a marked release of proteases such as neutrophil elastase (NE). Noninvasive in vivo assessment of unregulated elastase activity in the lungs would provide a valuable diagnostic tool. Here, it is proposed to use Overhauser-enhanced magnetic resonance imaging (OMRI) in mice where inflammation was induced by the instillation of lipopolysaccharide (LPS). OMRI contrast in the lungs was generated by a dedicated NE free radical substrate. The free radical decayed more rapidly in LPS-treated mouse lungs than in control mice, indicating the occurrence of increased proteolysis under inflammation. Preclinical detection of abnormal proteolysis opens the way for new diagnosis modality and antiprotease testing in vivo.

Figure 1

(a) Chemical structure of the nitroxide substrate. (b) Overhauser-enhanced chest MRI of NE substrate nitroxide in representative untreated and LPS-treated mice. Coronal images were taken 3 min and 30 min postnitroxide substrate instillation. Lung area in control images appears as a hyposignal, and the liver appears brighter in the bottom part. Arrows and arrowhead indicate the areas of effect in the presence of EPR. No significant Overhauser effect was observed in the lung of the LPS-treated mouse 30 min postinstillation. Scale bar is 1 cm. The displayed slices are extracted from 3D matrices in all cases (matrix size: 64 × 32 × 32; field of view: 64 mm × 32 mm × 32 mm. Acquisition parameters : repetition time (TR) : 600 ms, inter echo time : 9 ms ; and number of echoes per TR : 8. (c) Maximal magnitude of the DNPF measured in mouse lungs in control and LPS-treated mice at 3, 15, and 30 min postnitroxide substrate instillation. Error bars represent standard deviation.