While idiopathic pulmonary fibrosis (PF) is a devastating lung disease, the management of PF including effective monitoring of disease progression remains a challenge. Our previous study demonstrated that recombinant mouse SCGB3A2 exhibits anti-fibrotic activity in bleomycin-induced pulmonary fibrosis model mouse. We applied this mouse model in conjunction with the use of SCGB3A2 to introduce and validate a novel, fast, and ultrasensitive metalloproteinase (MMP) activatable optical probe, named MMP-P12, to noninvasively monitor pulmonary fibrosis (PF) progression and response to PF treatment. The MMP-P12 probe is a substrate for MMPs and contains a fluorescent dye and a quencher dye, which fluoresces only when the quencher dye is cleaved by MMPs. The use of MMP-P12 in PF model is based on the fact that MMPs such as MMP2 are thought to be highly expressed in fibrotic tissues. A bleomycin (BLM)-induced mouse PF model was subjected noninvasively to optical imaging at various time points after BLM treatment. The mouse PF model developed fibrosis during 21 days of the experimental period, and the progression of PF was well correlated with the stepwise increase of MMP2 expression as examined by quantitative RT-PCR and Western blot analysis on 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, SCGB3A2 was administered intravenously daily for five days starting on day seven of BLM administration, which resulted in reduced MMP2 activity and reduction of PF. Importantly, the fluorescence signal that reflected MMP activity also decreased in intensity. In conclusion, MMPs may play an important role in PF development and the 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. The MMP-P12 may provide a promising tool for detection and/or assessment of PF progression.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Investigator-Initiated Intramural Research Projects (ZIA)
Project #
1ZIABC010449-12
Application #
8763106
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
12
Fiscal Year
2013
Total Cost
$538,137
Indirect Cost
Name
National Cancer Institute Division of Basic Sciences
Department
Type
DUNS #
City
State
Country
Zip Code
Yoneda, Mitsuhiro; Xu, Lei; Kajiyama, Hiroaki et al. (2016) Secretoglobin Superfamily Protein SCGB3A2 Alleviates House Dust Mite-Induced Allergic Airway Inflammation in Mice. Int Arch Allergy Immunol 171:36-44
Naizhen, Xu; Linnoila, R Ilona; Kimura, Shioko (2016) Co-expression of Achaete-Scute Homologue-1 and Calcitonin Gene-Related Peptide during NNK-Induced Pulmonary Neuroendocrine Hyperplasia and Carcinogenesis in Hamsters. J Cancer 7:2124-2131
Cai, Yan; Yoneda, Mitsuhiro; Tomita, Takeshi et al. (2015) Transgenically-expressed secretoglobin 3A2 accelerates resolution of bleomycin-induced pulmonary fibrosis in mice. BMC Pulm Med 15:72
Cai, Yan; Kimura, Shioko (2015) Secretoglobin 3A2 Exhibits Anti-Fibrotic Activity in Bleomycin-Induced Pulmonary Fibrosis Model Mice. PLoS One 10:e0142497
Xu, Ming-Jiang; Cai, Yan; Wang, Hua et al. (2015) Fat-Specific Protein 27/CIDEC Promotes Development of Alcoholic Steatohepatitis in Mice and Humans. Gastroenterology 149:1030-41.e6
Kurotani, Reiko; Shima, Reika; Miyano, Yuki et al. (2015) SCGB3A2 Inhibits Acrolein-Induced Apoptosis through Decreased p53 Phosphorylation. Acta Histochem Cytochem 48:61-8
Yoneda, Mitsuhiro; Molinolo, Alfredo A; Ward, Jerrold M et al. (2015) A Simple Device to Rapidly Prepare Whole Mounts of the Mouse Intestine. J Vis Exp :e53042
Kido, Taketomo; Yoneda, Mitsuhiro; Cai, Yan et al. (2014) Secretoglobin superfamily protein SCGB3A2 deficiency potentiates ovalbumin-induced allergic pulmonary inflammation. Mediators Inflamm 2014:216465
Miyano, Yuki; Tahara, Shigeyuki; Sakata, Ichiro et al. (2014) Regulation of LH/FSH expression by secretoglobin 3A2 in the mouse pituitary gland. Cell Tissue Res 356:253-60
Cheng, Jie; Fang, Zhong-Ze; Nagaoka, Kenjiro et al. (2014) Activation of intestinal human pregnane X receptor protects against azoxymethane/dextran sulfate sodium-induced colon cancer. J Pharmacol Exp Ther 351:559-67

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