title: 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.affiliation: Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305 USA.
authors.forename: Nimali P
authors.initials: NP
authors.lastname: Withana
authors.affiliation: Department of Radiology, Stanford University School of Medicine, Stanford, CA 94305 USA.
authors.forename: Xiaowei
authors.initials: X
authors.lastname: Ma
authors.affiliation: Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA 94305 USA.
authors.forename: Helen M
authors.initials: HM
authors.lastname: McGuire
authors.affiliation: Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305 USA.
authors.forename: Martijn
authors.initials: M
authors.lastname: Verdoes
authors.affiliation: Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305 USA.
authors.forename: Wouter A
authors.initials: WA
authors.lastname: van der Linden
authors.affiliation: Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305 USA.
authors.forename: Leslie O
authors.initials: LO
authors.lastname: Ofori
authors.affiliation: Department of Radiology, Stanford University School of Medicine, Stanford, CA 94305 USA.
authors.forename: Ruiping
authors.initials: R
authors.lastname: Zhang
authors.affiliation: Department of Chemical and Systems Biology, Stanford University School of Medicine, Stanford, CA 94305 USA.
authors.forename: Hao
authors.initials: H
authors.lastname: Li
authors.affiliation: Department of Chemical and Systems Biology, Stanford University School of Medicine, Stanford, CA 94305 USA.
authors.forename: Laura E
authors.initials: LE
authors.lastname: Sanman
authors.affiliation: Department of Pulmonary and Critical Care Medicine, Stanford University School of Medicine, Stanford, CA 94305 USA.
authors.forename: Ke
authors.initials: K
authors.lastname: Wei
authors.affiliation: Department of Nuclear Medicine, Beijing, 100730, China.
authors.forename: Shaobo
authors.initials: S
authors.lastname: Yao
authors.affiliation: Department of Nuclear Medicine, Beijing, 100730, China.
authors.forename: Peilin
authors.initials: P
authors.lastname: Wu
authors.affiliation: Department of Nuclear Medicine, Beijing, 100730, China.
authors.forename: Fang
authors.initials: F
authors.lastname: Li
authors.affiliation: Respiratory Disease, Peking Union Medical College Hospital, Chinese Academy of Medical Science &Peking Union Medical College, Beijing, 100730, China.
authors.forename: Hui
authors.initials: H
authors.lastname: Huang
authors.affiliation: Respiratory Disease, Peking Union Medical College Hospital, Chinese Academy of Medical Science &Peking Union Medical College, Beijing, 100730, China.
authors.forename: Zuojun
authors.initials: Z
authors.lastname: Xu
authors.affiliation: Department of Medicine, University of California San Francisco, San Francisco, CA 94143 USA.
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Wolters
authors.affiliation: Department of Pulmonary and Critical Care Medicine, Stanford University School of Medicine, Stanford, CA 94305 USA.
authors.forename: Glenn D
authors.initials: GD
authors.lastname: Rosen
authors.affiliation: Department of Medicine, University of California San Francisco, San Francisco, CA 94143 USA.
authors.forename: Harold R
authors.initials: HR
authors.lastname: Collard
authors.affiliation: Department of Nuclear Medicine, Beijing, 100730, China.
authors.forename: Zhaohui
authors.initials: Z
authors.lastname: Zhu
authors.affiliation: Department of Radiology, Stanford University School of Medicine, Stanford, CA 94305 USA.
authors.forename: Zhen
authors.initials: Z
authors.lastname: Cheng
authors.affiliation: Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305 USA.|Department of Radiology, Stanford University School of Medicine, Stanford, CA 94305 USA.|Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA 94305 USA.
authors.forename: Matthew
authors.initials: M
authors.lastname: Bogyo
mesh_terms: D000818:Animals; D001761:Bleomycin; D002403:Cathepsins / Q000378:metabolism*; D003301:Copper Radioisotopes; D003952:Diagnostic Imaging / Q000379:methods*; D004195:Disease Models, Animal; D018450:Disease Progression; D005710:Gallium Radioisotopes; D054990:Idiopathic Pulmonary Fibrosis / Q000139:chemically induced / Q000175:diagnosis* / Q000276:immunology / Q000473:pathology; D008168:Lung / Q000473:pathology; D008262:Macrophage Activation; D015335:Molecular Probes / Q000737:chemistry / Q000378:metabolism*; D061848:Optical Imaging; D049268:Positron-Emission Tomography
chemical_list: D003301:Copper Radioisotopes; D005710:Gallium Radioisotopes; D015335:Molecular Probes; D001761:Bleomycin; D002403:Cathepsins