Non-invasive Imaging of Idiopathic Pulmonary Fibrosis Using Cathepsin Protease Probes.

Abstract

Idiopathic pulmonary fibrosis (IPF) is a lethal, chronic, progressive disease characterized by formation of scar tissue within the lungs. Because it is a disease of unknown etiology, it is difficult to diagnose, to predict disease course and to devise treatment strategies. Recent evidence suggests that activated macrophages play key roles in the pathology of IPF. Therefore, imaging probes that specifically recognize these pools of activated immune cells could provide valuable information about how these cells contribute to the pathobiology of the disease. Here we demonstrate that cysteine cathepsin-targeted imaging probes can be used to monitor the contribution of macrophages to fibrotic disease progression in the bleomycin-induced murine model of pulmonary fibrosis. Furthermore, we show that the probes highlight regions of macrophage involvement in fibrosis in human biopsy tissues from IPF patients. Finally, we present first-in-human results demonstrating non-invasive imaging of active cathepsins in fibrotic lesions of patients with IPF. Together, our findings validate small molecule cysteine cathepsin probes for clinical PET imaging and suggest that they have the potential to be used to generate mechanistically-informative molecular information regarding cellular drivers of IPF disease severity and progression.

• Authors: Nimali P Withana, Xiaowei Ma, Helen M McGuire, Martijn Verdoes, Wouter A van der Linden, Leslie O Ofori, Ruiping Zhang, Hao Li, Laura E Sanman, Ke Wei, Shaobo Yao, Peilin Wu, Fang Li, Hui Huang, Zuojun Xu, Paul J Wolters, Glenn D Rosen, Harold R Collard, Zhaohui Zhu, Zhen Cheng, Matthew Bogyo
• Journal: Scientific reports (Sci Rep) Vol. 6 Pg. 19755 (Jan 22 2016) ISSN: 2045-2322 [Electronic] England
• PMID: 26797565 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Copper Radioisotopes
• Gallium Radioisotopes
• Molecular Probes
• Bleomycin
• Cathepsins

Topics

• Animals
• Bleomycin
• Cathepsins (metabolism)
• Copper Radioisotopes
• Diagnostic Imaging (methods)
• Disease Models, Animal
• Disease Progression
• Gallium Radioisotopes
• Idiopathic Pulmonary Fibrosis (chemically induced, diagnosis, immunology, pathology)
• Lung (pathology)
• Macrophage Activation
• Molecular Probes (chemistry, metabolism)
• Optical Imaging
• Positron-Emission Tomography