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

Withana, Nimali P.; Ma, Xiaowei; McGuire, Helen M.; Verdoes, Martijn; Linden, Wouter A. van der; Ofori, Leslie O.; Zhang, Ruiping; Li, Hao; Sanman, Laura E.; Wei, Ke; Yao, Shaobo; Wu, Pei‐Lin; Fang, Li; Huang, Hui; Xu, Zuojun; Wolters, Paul J.; Rosen, Glenn D.; Collard, Harold R.; Zhu, Zhaohui; Cheng, Zhen; Bogyo, Matthew

doi:10.1038/srep19755

Cited by 99 publications

(81 citation statements)

References 40 publications

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“…The activation of macrophages occupies a pivotal role in the translation of injury to aberrant repair in IPF, but the reasons for macrophage accumulation in lung fibrosis are not always clear [28,29]. Migration of neutrophils to the site of injury allows them to exhibit a range of functions, including the release of neutrophil elastase (NE), where they may then impact the fibrotic process.…”

Section: Discussionmentioning

confidence: 99%

Nrf2 Regulates the Risk of a Diesel Exhaust Inhalation-Induced Immune Response during Bleomycin Lung Injury and Fibrosis in Mice

Shimizu

Shinkai

et al. 2017

IJMS

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Abstract:The present study investigated the effects of diesel exhaust (DE) on an experimental model of bleomycin (BLM)-induced lung injury and fibrosis in mice. BLM was intravenously administered to both Nrf2 +/+ and Nrf2 −/− C57BL/6J mice on day 0. The mice were exposed to DE for 56 days from 28 days before the BLM injection to 28 days after the BLM injection. Inhalation of DE induced significant inhibition of airway clearance function and the proinflammatory cytokine secretion in macrophages, an increase in neutrophils, and severe lung inflammatory injury, which were greater in Nrf2 −/− mice than in Nrf2 +/+ mice. In contrast, inhalation of DE was observed to induce a greater increase of hydroxyproline content in the lung tissues and significantly higher pulmonary antioxidant enzyme mRNA expression in the Nrf2 +/+ mice than in Nrf2 −/− mice. DE is an important risk factor, and Nrf2 regulates the risk of a DE inhalation induced immune response during BLM lung injury and fibrosis in mice.

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Section: Discussionmentioning

confidence: 99%

Nrf2 Regulates the Risk of a Diesel Exhaust Inhalation-Induced Immune Response during Bleomycin Lung Injury and Fibrosis in Mice

Shimizu

Shinkai

et al. 2017

IJMS

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“…1A), has enhanced in vivo properties and broad reactivity toward cathepsins X, B, S, and L (35,36). Given the success of this optical probe in detecting cysteine cathepsins, and the reported role that these proteases have in atherosclerosis, we investigated the use of this probe to detect plaques in an experimental atherosclerotic murine model.…”

Section: Fluorescence Imaging Of Murine Carotid Arteries Using Fluorementioning

confidence: 99%

“…1A) that we recently showed to be an effective label of activated macrophages in mouse models and human clinical studies of lung fibrosis (Fig. 3A) (35). This reagent contains both the optical fluorophore and a chelator group that can be used for labeling with radionuclides.…”

Section: Imaging Of Carotid Arteries Using Dual-modality Optical and mentioning

confidence: 99%

Dual-Modality Activity-Based Probes as Molecular Imaging Agents for Vascular Inflammation

Withana

Saito

et al. 2016

J Nucl Med

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Macrophages are cellular mediators of vascular inflammation and are involved in the formation of atherosclerotic plaques. These immune cells secrete proteases such as matrix metalloproteinases and cathepsins that contribute to disease formation and progression. Here, we demonstrate that activity-based probes (ABPs) targeting cysteine cathepsins can be used in murine models of atherosclerosis to noninvasively image activated macrophage populations using both optical and PET/CT methods. The probes can also be used to topically label human carotid plaques demonstrating similar specific labeling of activated macrophage populations. Methods: Macrophage-rich carotid lesions were induced in FVB mice fed on a high-fat diet by streptozotocin injection followed by ligation of the left common carotid artery. Mice with carotid atherosclerotic plaques were injected with the optical or dual-modality probes BMV109 and BMV101, respectively, via the tail vein and noninvasively imaged by optical and small-animal PET/CT at different time points. After noninvasive imaging, the murine carotid arteries were imaged in situ and ex vivo, followed by immunofluorescence staining to confirm target labeling. Additionally, human carotid plaques were topically labeled with the probe and analyzed by both sodium dodecyl sulfate polyacrylamide gel electrophoresis and immunofluorescence staining to confirm the primary targets of the probe. Results: Quantitative analysis of the signal intensity from both optical and PET/CT imaging showed significantly higher levels of accumulation of BMV109 and BMV101 (P , 0.005 and P , 0.05, respectively) in the ligated left carotid arteries than the right carotid or healthy arteries. Immunofluorescence staining for macrophages in cross-sectional slices of the murine artery demonstrated substantial infiltration of macrophages in the neointima and adventitia of the ligated left carotid arteries compared with the right. Analysis of the human plaque tissues by sodium dodecyl sulfate polyacrylamide gel electrophoresis confirmed that the primary targets of the probe were cathepsins X, B, S, and L. Immunofluorescence labeling of the human tissue with the probe demonstrated colocalization of the probe with CD68, elastin, and cathepsin S, similar to that observed in the experimental carotid inflammation murine model. Conclusion: We demonstrate that ABPs targeting the cysteine cathepsins can be used in murine models of atherosclerosis to noninvasively image activated macrophage populations using both optical and PET/CT methods. The probes could also be used to topically label human carotid plaques demonstrating similar specific labeling of activated macrophage populations. Therefore, ABPs targeting the cysteine cathepsins are potentially valuable new reagents for rapid and noninvasive imaging of atherosclerotic disease progression and plaque vulnerability.

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“…65,96 A discussion of protease-targeted activity-based probes and their clinical applications can be found elsewhere. 97–100 …”

Section: Hydrolases (Ec 3)mentioning

confidence: 99%

Enzyme-Activated Fluorogenic Probes for Live-Cell and in Vivo Imaging

2018

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Fluorogenic probes, small-molecule sensors that unmask brilliant fluorescence upon exposure to specific stimuli, are powerful tools for chemical biology. Those probes that respond to enzymatic catalysis illuminate the complex dynamics of biological processes at a level of spatiotemporal detail and sensitivity unmatched by other techniques. Here, we review recent advances in enzyme-activated fluorogenic probes for biological imaging. We organize our survey by enzyme classification, with emphasis on fluorophore masking strategies, modes of enzymatic activation, and the breadth of current and future applications. Key challenges such as probe selectivity and spectroscopic requirements are described alongside of therapeutic, diagnostic, and theranostic opportunities.

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

Cited by 99 publications

References 40 publications

Nrf2 Regulates the Risk of a Diesel Exhaust Inhalation-Induced Immune Response during Bleomycin Lung Injury and Fibrosis in Mice

Nrf2 Regulates the Risk of a Diesel Exhaust Inhalation-Induced Immune Response during Bleomycin Lung Injury and Fibrosis in Mice

Dual-Modality Activity-Based Probes as Molecular Imaging Agents for Vascular Inflammation

Enzyme-Activated Fluorogenic Probes for Live-Cell and in Vivo Imaging

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