Reza Golestani1,2, Mahmoud Razavian1,2, Yunpeng Ye1,2, Jiasheng Zhang1,2, Jae-Joon Jung1,2, Jakub Toczek1,2, Kiran Gona1,2, Hye-Yeong Kim1,2, Jack A Elias3, Chun Geun Lee3, Robert J Homer2,4, Mehran M Sadeghi5,2. 1. Section of Cardiovascular Medicine and Cardiovascular Research Center, Yale School of Medicine, New Haven, Connecticut. 2. VA Connecticut Healthcare System, West Haven, Connecticut. 3. Brown University, Providence, Rhode Island; and. 4. Department of Pathology, Yale School of Medicine, New Haven, Connecticut. 5. Section of Cardiovascular Medicine and Cardiovascular Research Center, Yale School of Medicine, New Haven, Connecticut mehran.sadeghi@yale.edu.
Abstract
Imaging techniques for detection of molecular and cellular processes that precede or accompany lung diseases are needed. Matrix metalloproteinases (MMPs) play key roles in the development of pulmonary pathology. The objective of this study was to investigate the feasibility of in vivo MMP-targeted molecular imaging for detection of lung inflammation and remodeling. METHODS: Lung-specific IL-13 transgenic (Club cell 10-kDa protein [CC10]-IL-13 Tg) mice and wild-type littermates were used in this study. Lung structure, gene expression, and MMP activity were assessed by histology, real-time reverse transcription polymerase chain reaction, Western blotting, and zymography. MMP activation was imaged by in vivo small-animal SPECT/CT followed by ex vivo planar imaging. Signal specificity was addressed using a control tracer. The correlation between in vivo MMP signal and gene expression was addressed. RESULTS: CC10-IL-13 Tg mice developed considerable pulmonary tissue remodeling and inflammation. CD68, MMP-12, and MMP-13 were significantly higher in CC10-IL-13 Tg lungs. On in vivo small-animal SPECT/CT and ex vivo planar images, the MMP signal was significantly higher in the lungs of CC10-IL-13 Tg mice than wild-type animals. Furthermore, a nonbinding analog tracer showed significantly lower accumulation in CC10-IL-13 Tg lungs relative to the specific tracer. There was a significant correlation between small-animal SPECT/CT-derived MMP signal and CD68 expression in the lungs (r = 0.70, P < 0.01). CONCLUSION: Small-animal SPECT/CT-based MMP-targeted imaging of the lungs is feasible and reflects pulmonary inflammation. If validated in humans, molecular imaging of inflammation and remodeling can potentially help early diagnosis and monitoring of the effects of therapeutic interventions in pulmonary diseases.
Imaging techniques for detection of molecular and cellular processes that precede or accompany lung diseases are needed. Matrix metalloproteinases (MMPs) play key roles in the development of pulmonary pathology. The objective of this study was to investigate the feasibility of in vivo MMP-targeted molecular imaging for detection of lung inflammation and remodeling. METHODS: Lung-specific IL-13transgenic (Club cell 10-kDa protein [CC10]-IL-13 Tg) mice and wild-type littermates were used in this study. Lung structure, gene expression, and MMP activity were assessed by histology, real-time reverse transcription polymerase chain reaction, Western blotting, and zymography. MMP activation was imaged by in vivo small-animal SPECT/CT followed by ex vivo planar imaging. Signal specificity was addressed using a control tracer. The correlation between in vivo MMP signal and gene expression was addressed. RESULTS:CC10-IL-13 Tg mice developed considerable pulmonary tissue remodeling and inflammation. CD68, MMP-12, and MMP-13 were significantly higher in CC10-IL-13 Tg lungs. On in vivo small-animal SPECT/CT and ex vivo planar images, the MMP signal was significantly higher in the lungs of CC10-IL-13 Tg mice than wild-type animals. Furthermore, a nonbinding analog tracer showed significantly lower accumulation in CC10-IL-13 Tg lungs relative to the specific tracer. There was a significant correlation between small-animal SPECT/CT-derived MMP signal and CD68 expression in the lungs (r = 0.70, P < 0.01). CONCLUSION: Small-animal SPECT/CT-based MMP-targeted imaging of the lungs is feasible and reflects pulmonary inflammation. If validated in humans, molecular imaging of inflammation and remodeling can potentially help early diagnosis and monitoring of the effects of therapeutic interventions in pulmonary diseases.
Authors: Miranda Kirby; Sarah Svenningsen; Nikhil Kanhere; Amir Owrangi; Andrew Wheatley; Harvey O Coxson; Giles E Santyr; Nigel A M Paterson; David G McCormack; Grace Parraga Journal: J Appl Physiol (1985) Date: 2012-12-13
Authors: Wei Li; Jianchang Li; Yuchuan Wu; Junjun Wu; Rajeev Hotchandani; Kristina Cunningham; Iain McFadyen; Joel Bard; Paul Morgan; Franklin Schlerman; Xin Xu; Steve Tam; Samuel J Goldman; Cara Williams; Joseph Sypek; Tarek S Mansour Journal: J Med Chem Date: 2009-04-09 Impact factor: 7.446
Authors: Shaoping Xie; Razao Issa; Maria B Sukkar; Ute Oltmanns; Pankaj K Bhavsar; Alberto Papi; Gaetano Caramori; Ian Adcock; K Fan Chung Journal: Respir Res Date: 2005-12-16