Noninvasive Monitoring of Pulmonary Fibrosis by Targeting Matrix Metalloproteinases (MMPs)

Abstract

While idiopathic pulmonary fibrosis (PF) is a devastating lung disease, the management of PF including effective monitoring of disease progression remains a challenge. Herein, we introduce a novel, fast and ultra-sensitive metalloproteinase (MMP) activatable optical probe, named MMP-P12, to non-invasively monitor PF progression and response to PF treatment. A bleomycin (BLM)-induced mouse PF model was subjected non-invasively to optical imaging at various time points after BLM treatment. Mouse PF model developed fibrosis during 21 days of experimental period, and the progression of PF was well correlated with the step-wise increase of MMP-2 expression as examined by quantitative RT-PCR and western blot analysis on the 7-, 14-and 21-day post-BLM administration. On these days, MMP-activated fluorescence images were acquired in vivo and ex vivo. Signal quantification showed time-dependent lung-specific incremental increases in fluorescence signals. As a treatment for PF, secretoglobin 3A2 was daily administered intravenously for five days starting day seven of BLM administration, which resulted in reduced MMP-2 activity and reduction of PF as previously demonstrated. Importantly, the fluorescence signal that reflected MMP activity also decreased in intensity. In conclusion, MMPs may play an important role in PF development and MMP-P12 probe could be a promising tool for PF detection, even at an early stage of the disease as well as an indicator of therapy response.

Therapeutic benefits of young, but not old, adipose-derived mesenchymal stem cells in a chronic mouse model of bleomycin-induced pulmonary fibrosis

“…[49] Similarly, increased expression of α v -integrin, a potential activator of MMPs, [50] correlates with increased lung fibrosis in young mice, [36] as seen in the current aged male BLM model. Importantly, we found that expression of α v -integrin mRNA is lower in donor yASCs compared to donor oASCs at baseline.…”

“…[38] Increased activity of MMPs is directly associated with ECM turnover in IPF [13, 44, 45] and in other fibrotic diseases. [46–48] Higher MMP-2/9 activity and expression has been demonstrated in young [49] and aged mice [13] following BLM infusion. Although we focused on MMP-2, it should be pointed out that current studies suggest that multiple MMPs (1, 2, 7, 9, and 13) are important to the pathogenesis of IPF.…”

The Copper Chelator Tetrathiomolybdate Regressed Bleomycin-Induced Pulmonary Fibrosis in Mice, by Reducing Lysyl Oxidase Expressions

“…*p<0.05 day post-BLM administration. In BLM-induced lung fibrosis, a coincidental increase of gelatinase activity and disruption of the alveolar epithelial basement membrane have been found [25]. It was indicated that MMP2 may play a role in a later phase in regard to the formation of the fibrotic foci, thereby facilitating subepithelial myofibroblast migration to the alveolar lumen [1,26,27].…”

Quantitative detection of drug dose and spatial distribution in the lung revealed by Cryoslicing Imaging

“…Radioactive labeling allows for regional dosimetry via X-ray tomography (CT), PET and SPECT, but not for determination of the bioactivity of the substances. On the other hand, fluorescent substances including nanoparticles have been widely used for preclinical dosimetry studies both in vitro and in vivo [7,8] and numerous fluorescent probes are available for studying the bioactivity of drugs in terms of activation/deactivation of complex biological processes in living animals. Consequently, using innovative preclinical strategies of optical imaging has allowed in vivo real-time insight not only in genomics and proteomics ([9] and references 1-6 herein), but also in disease state of animal models such as the size of cancer lesions or of a remodeled bone [10].…”