Skip to main content
SpringerLink
Log in

Apoptotic PET Imaging of Rat Pulmonary Fibrosis with Small-Molecule Radiotracer

  • Research Article
  • Published:
Molecular Imaging and Biology Aims and scope Submit manuscript

Abstract

Purpose

The purpose of this study was to assess the potential utility of small-molecule apoptotic radiotracer, 2-(5-[18F]fluoropentyl)-2-methyl malonic acid ([18F]ML-10), for positron emission tomography (PET)/computed tomography (CT) monitoring the progression of pulmonary fibrosis in a rat model.

Procedures

Male Sprague-Dawley rats were used to establish a rat model of pulmonary fibrosis by means of bleomycin (BLM) administration; control rats received saline (n = 12 per group). PET/CT with [18F]ML-10 and 2-deoxy-2-[18F]fluoro-d-glucose ([18F]FDG) was performed in two groups at different stages of pulmonary fibrosis. The fibrotic response and the cell apoptosis were assessed with histologic examination. Differences in the apoptosis rate, fibrotic activity, and the lung uptake of [18F]ML-10 and [18F]FDG between two groups were determined with Student t test.

Results

Compared with control group, BLM group showed a higher lung uptake of [18F]ML-10 at all imaging time points (all P < 0.001). During the fibrotic phase of this disease model (days 21 and 28), the lung uptake of [18F]ML-10 was higher than that of [18F]FDG in the BLM group (all P < 0.001). Moreover, accumulation of [18F]ML-10 in the lung tissues increased in proportion to the apoptosis rate (R2 = 0.9863, P < 0.0001) and fibrotic activity (R2 = 0.9631, P < 0.0001) of rat pulmonary fibrosis. Conversely, no correlation between [18F]FDG uptake and fibrotic activity was found.

Conclusions

[18F]ML-10 PET/CT enabled monitoring the progression of rat pulmonary fibrosis, whereas [18F]FDG PET/CT could not. Implications for noninvasive diagnosis of pulmonary fibrosis, assessment of fibrotic activity, and evaluation of antifibrotic therapy are expected.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1.
Fig. 2.
Fig. 3.
Fig. 4.
Fig. 5.
Fig. 6.

Similar content being viewed by others

References

  1. King TE Jr, Pardo A, Selman M (2011) Idiopathic pulmonary fibrosis. Lancet 378:1949–1961

    Article  PubMed  Google Scholar 

  2. Nalysnyk L, Cid-Ruzafa J, Rotella P, Esser D (2012) Incidence and prevalence of idiopathic pulmonary fibrosis: review of the literature. Eur Respir Rev 21:355–361

    Article  PubMed  Google Scholar 

  3. du Bois RM (2010) Strategies for treating idiopathic pulmonary fibrosis. Nat Rev Drug Discov 9:129–140

    Article  CAS  PubMed  Google Scholar 

  4. Raghu G, Collard HR, Egan JJ, Martinez FJ, Behr J, Brown KK, Colby TV, Cordier JF, Flaherty KR, Lasky JA, Lynch DA, Ryu JH, Swigris JJ, Wells AU, Ancochea J, Bouros D, Carvalho C, Costabel U, Ebina M, Hansell DM, Johkoh T, Kim DS, King te Jr, Kondoh Y, Myers J, Müller NL, Nicholson AG, Richeldi L, Selman M, Dudden RF, Griss BS, Protzko SL, Schünemann HJ, ATS/ERS/JRS/ALAT Committee on Idiopathic Pulmonary Fibrosis (2011) An official ATS/ERS/JRS/ALAT statement: idiopathic pulmonary fibrosis: evidence-based guidelines for diagnosis and management. Am J Respir Crit Care Med 183:788–824

    Article  PubMed  PubMed Central  Google Scholar 

  5. Raghu G, Anstrom KJ, King TE Jr et al (2012) Prednisone, azathioprine, and N-acetylcysteine for pulmonary fibrosis. N Engl J Med 366:1968–1977

    Article  CAS  PubMed  Google Scholar 

  6. Bondue B, Sherer F, Van Simaeys G et al (2015) PET/CT with [18F]FDG- and [18F]FBEM-labeled leukocytes for metabolic activity and leukocyte recruitment monitoring in a mouse model of pulmonary fibrosis. J Nucl Med 56:127–132

    Article  CAS  PubMed  Google Scholar 

  7. Blodgett TM, Meltzer CC, Townsend DW (2007) PET/CT: form and function. Radiology 242:360–385

    Article  PubMed  Google Scholar 

  8. Win T, Lambrou T, Hutton BF, Kayani I, Screaton NJ, Porter JC, Maher TM, Endozo R, Shortman RI, Lukey P, Groves AM (2012) [18F]Fluorodeoxyglucose positron emission tomography pulmonary imaging in idiopathic pulmonary fibrosis is reproducible: implications for future clinical trials. Eur J Nucl Med Mol Imaging 39:521–528

    Article  PubMed  Google Scholar 

  9. Ambrosini V, Zompatori M, De Luca F et al (2010) 68Ga-DOTANOC PET/CT allows somatostatin receptor imaging in idiopathic pulmonary fibrosis: preliminary results. J Nucl Med 51:1950–1955

    Article  PubMed  Google Scholar 

  10. Wallace WE, Gupta NC, Hubbs AF et al (2002) Cis-4-[18F]fluoro-L-proline PET imaging of pulmonary fibrosis in a rabbit model. J Nucl Med 43:413–420

    CAS  PubMed  Google Scholar 

  11. Umeda Y, Demura Y, Ishizaki T, Ameshima S, Miyamori I, Saito Y, Tsuchida T, Fujibayashi Y, Okazawa H (2009) Dual-time-point [18F]FDG PET imaging for diagnosis of disease type and disease activity in patients with idiopathic interstitial pneumonia. Eur J Nucl Med Mol Imaging 36:1121–1130

    Article  PubMed  Google Scholar 

  12. El-Chemaly S, Malide D, Yao J et al (2013) Glucose transporter-1 distribution in fibrotic lung disease: association with [18F]-2-fluoro-2-deoxyglucose-PET scan uptake, inflammation, and neovascularization. Chest 143:1685–1691

    Article  CAS  PubMed  Google Scholar 

  13. Groves AM, Win T, Screaton NJ, Berovic M, Endozo R, Booth H, Kayani I, Menezes LJ, Dickson JC, Ell PJ (2009) Idiopathic pulmonary fibrosis and diffuse parenchymal lung disease: implications from initial experience with [18F]FDG PET/CT. J Nucl Med 50:538–545

    Article  PubMed  Google Scholar 

  14. Meissner HH, Soo Hoo GW, Khonsary SA, Mandelkern M, Brown CV, Santiago SM (2006) Idiopathic pulmonary fibrosis: evaluation with positron emission tomography. Respiration 73:197–202

    Article  PubMed  Google Scholar 

  15. Lavalaye J, Grutters JC, van de Garde EM et al (2009) Imaging of fibrogenesis in patients with idiopathic pulmonary fibrosis with cis-4-[18F]-Fluoro-L: -proline PET. Mol Imaging Biol 11:123–127

    Article  PubMed  Google Scholar 

  16. Jones HA, Valind SO, Clark IC, Bolden GE, Krausz T, Schofield JB, Boobis AR, Haslett C (2002) Kinetics of lung macrophages monitored in vivo following particulate challenge in rabbits. Toxicol Appl Pharmacol 183:46–54

    Article  CAS  PubMed  Google Scholar 

  17. Bellani G, Caironi P (2011) Lung imaging during acute respiratory distress syndrome: CT- and PET-scanning. Trends in Anaesthesia and Critical Care 1:203–209

    Article  Google Scholar 

  18. Win T, Screaton NJ, Porter J, Endozo R, Wild D, Kayani I, Dickson J, Shortman RI, Reubi JC, Ell PJ, Groves AM (2012) Novel positron emission tomography/computed tomography of diffuse parenchymal lung disease combining a labeled somatostatin receptor analogue and 2-deoxy-2[18F]fluoro-D-glucose. Mol Imaging 11:91–98

    Article  CAS  PubMed  Google Scholar 

  19. Jones HA, Schofield JB, Krausz T et al (1998) Pulmonary fibrosis correlates with duration of tissue neutrophil activation. Am J Respir Crit Care Med 158:620–628

    Article  CAS  PubMed  Google Scholar 

  20. Taylor RC, Cullen SP, Martin SJ (2008) Apoptosis: controlled demolition at the cellular level. Nat Rev Mol Cell Biol 9:231–241

    Article  CAS  PubMed  Google Scholar 

  21. Fine A, Janssen-Heininger Y, Soultanakis RP, Swisher SG, Uhal BD (2000) Apoptosis in lung pathophysiology. Am J Phys Lung Cell Mol Phys 279:L423–L427

    CAS  Google Scholar 

  22. Barbas-Filho JV, Ferreira MA, Sesso A, Kairalla RA, Carvalho CR, Capelozzi VL (2001) Evidence of type II pneumocyte apoptosis in the pathogenesis of idiopathic pulmonary fibrosis (IFP)/usual interstitial pneumonia (UIP). J Clin Pathol 54:132–138

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Reshef A, Shirvan A, Akselrod-Ballin A, Wall A, Ziv I (2010) Small-molecule biomarkers for clinical PET imaging of apoptosis. J Nucl Med 51:837–840

    Article  CAS  PubMed  Google Scholar 

  24. Zhang K, Si XP, Huang J, Han J, Liang X, Xu XB, Wang YT, Li GY, Wang HY, Wang JH (2016) Preventive effects of Rhodiola rosea L. on bleomycin-induced pulmonary fibrosis in rats. Int J Mol Sci 17:879

    Article  CAS  PubMed Central  Google Scholar 

  25. Tang H, Gao L, Mao J, He H, Liu J, Cai X, Lin H, Wu T (2016) Salidroside protects against bleomycin-induced pulmonary fibrosis: activation of Nrf2-antioxidant signaling, and inhibition of NF-kappaB and TGF-beta1/Smad-2/-3 pathways. Cell Stress Chaperones 21:239–249

    Article  CAS  PubMed  Google Scholar 

  26. Liu S, Nie D, Jiang S, Tang G (2017) Efficient automated synthesis of 2-(5-[18F]fluoropentyl)-2-methylmalonic acid ([18F]ML-10) on a commercial available [18F]FDG synthesis module. Appl Radiat Isot 123:49–53

    Article  CAS  PubMed  Google Scholar 

  27. Ashcroft T, Simpson JM, Timbrell V (1988) Simple method of estimating severity of pulmonary fibrosis on a numerical scale. J Clin Pathol 41:467–470

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Sener G, Topaloglu N, Sehirli AO et al (2007) Resveratrol alleviates bleomycin-induced lung injury in rats. Pulm Pharmacol Ther 20:642–649

    Article  CAS  PubMed  Google Scholar 

  29. Janick-Buckner D, Ranges GE, Hacker MP (1989) Alteration of bronchoalveolar lavage cell populations following bleomycin treatment in mice. Toxicol Appl Pharmacol 100:465–473

    Article  CAS  PubMed  Google Scholar 

  30. Moore BB, Hogaboam CM ((2008)) Murine models of pulmonary fibrosis. Am J Physiol Lung Cell Mol Physiol 294:L152–L160

  31. Kadirvel M, Fairclough M, Cawthorne C, Rowling EJ, Babur M, McMahon A, Birkket P, Smigova A, Freeman S, Williams KJ, Brown G (2014) Detection of apoptosis by PET/CT with the diethyl ester of [18F]ML-10 and fluorescence imaging with a dansyl analogue. Bioorg Med Chem 22:341–349

    Article  CAS  PubMed  Google Scholar 

  32. Chopra A (2004) 2-(5-[18F]Fluoro-pentyl)-2-methyl-malonic acid (ML-10), molecular imaging and contrast agent database (MICAD). National Center for Biotechnology Information (US), Bethesda

    Google Scholar 

Download references

Funding

This work was supported by the National Natural Science Foundation of China (No. 81571704, No. 81371584, No. 81671719), the Science and Technology Foundation of Guangdong Province (No. 2014A020210008, No. 2013B021800264, No. 2016B090920087), the Science and Technology Planning Project Foundation of Guangzhou (No. 201604020169, No. 201510010145), and the Natural Science Foundation of Guangdong Province (No. 2015A030313067).

Author information

Author notes

  1. Ying Xiong and Dahong Nie contributed equally to this work.

Authors and Affiliations

  1. Department of Medical Imaging and Guangdong Engineering Research Center for Translational Application of Medical Radiopharmaceuticals, The First Affiliated Hospital, Sun Yat-sen University, 58 Zhongshan Road II, Guangzhou, 510080, China

    Ying Xiong, Dahong Nie, Shaoyu Liu, Hui Ma, Shu Su, Aixia Sun, Jing Zhao, Zhanwen Zhang, Xianhong Xiang & Ganghua Tang

Authors
  1. Ying Xiong
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Dahong Nie
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Shaoyu Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Hui Ma
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Shu Su
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Aixia Sun
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Jing Zhao
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Zhanwen Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Xianhong Xiang
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Ganghua Tang
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Xianhong Xiang and Ganghua Tang had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Ying Xiong and Dahong Nie contributed to designing this study, collecting samples, carrying out experiments, and writing the manuscript. Shaoyu Liu, Hui Ma, and Shu Su contributed to collecting samples and revising the manuscript. Aixia Sun, Jing Zhao, and Zhanwen Zhang contributed to revising the manuscript. All authors have approved the final article.

Corresponding authors

Correspondence to Xianhong Xiang or Ganghua Tang.

Ethics declarations

Conflict of Interest

The authors declare that they have no conflict of interest.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Xiong, Y., Nie, D., Liu, S. et al. Apoptotic PET Imaging of Rat Pulmonary Fibrosis with Small-Molecule Radiotracer. Mol Imaging Biol 21, 491–499 (2019). https://doi.org/10.1007/s11307-018-1242-7

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11307-018-1242-7

Key words

Search

Navigation