title: Preclinical SPECT/CT imaging of αvβ6 integrins for molecular stratification of idiopathic pulmonary fibrosis.
abstract: Transforming growth factor β activation by the αvβ6 integrin is central to the pathogenesis of idiopathic pulmonary fibrosis. Expression of the αvβ6 integrin is increased in fibrotic lung tissue and is a promising therapeutic target for treatment of the disease. Currently, measurement of αvβ6 integrin levels in the lung requires immunohistochemical analysis of biopsy samples. This procedure is clinically impractical for many patients with pulmonary fibrosis, and a noninvasive strategy for measuring αvβ6 integrin levels in the lungs is urgently required to facilitate monitoring of disease progression and therapeutic responses.
  
  
  METHODS
  Using a murine model of bleomycin-induced lung injury, we assessed the binding of intravenously administered (111)In-labeled αvβ6-specific (diethylenetriamine pentaacetate-tetra [DTPA]-A20FMDV2) or control (DTPA-A20FMDVran) peptide by nanoSPECT/CT imaging. Development of fibrosis was assessed by lung hydroxyproline content, and αvβ6 protein and itgb6 messenger RNA were measured in the lungs.
  
  
  RESULTS
  Maximal binding of (111)In-labeled A20FMDV2 peptide to αvβ6 integrins was detected in the lungs 1 h after intravenous administration. No significant binding was detected in mice injected with control peptide. Integrin binding was increased in the lungs of bleomycin-, compared with saline-, exposed mice and was attenuated by pretreatment with αvβ6-blocking antibodies. Levels of (111)In-labeled A20FMDV2 peptide correlated positively with hydroxyproline, αvβ6 protein, and itgb6 messenger RNA levels.
  
  
  CONCLUSIONS
  We have developed a highly sensitive, quantifiable, and noninvasive technique for measuring αvβ6 integrin levels within the lung. Measurement of αvβ6 integrins by SPECT/CT scanning has the potential for use in stratifying therapy for patients with pulmonary fibrosis.
authors.affiliation: Nottingham Respiratory Research Unit, University of Nottingham, Nottingham, United Kingdom.
authors.forename: Alison E
authors.initials: AE
authors.lastname: John
authors.forename: Jeni C
authors.initials: JC
authors.lastname: Luckett
authors.forename: Amanda L
authors.initials: AL
authors.lastname: Tatler
authors.forename: Ramla O
authors.initials: RO
authors.lastname: Awais
authors.forename: Ami
authors.initials: A
authors.lastname: Desai
authors.forename: Anthony
authors.initials: A
authors.lastname: Habgood
authors.forename: Steve
authors.initials: S
authors.lastname: Ludbrook
authors.forename: Andy D
authors.initials: AD
authors.lastname: Blanchard
authors.forename: Alan C
authors.initials: AC
authors.lastname: Perkins
authors.forename: R Gisli
authors.initials: RG
authors.lastname: Jenkins
authors.forename: John F
authors.initials: JF
authors.lastname: Marshall
mesh_terms: D000818:Animals; D000951:Antigens, Neoplasm / Q000235:genetics / Q000378:metabolism*; D015415:Biomarkers / Q000378:metabolism; D023381:Endpoint Determination; D054990:Idiopathic Pulmonary Fibrosis / Q000000981:diagnostic imaging* / Q000378:metabolism / Q000473:pathology; D007205:Indium Radioisotopes; D016023:Integrins / Q000235:genetics / Q000378:metabolism*; D008168:Lung / Q000000981:diagnostic imaging / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D064847:Multimodal Imaging; D010455:Peptides; D011379:Prognosis; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D015899:Tomography, Emission-Computed, Single-Photon; D014057:Tomography, X-Ray Computed
chemical_list: D000951:Antigens, Neoplasm; D015415:Biomarkers; D007205:Indium Radioisotopes; D016023:Integrins; D010455:Peptides; D012333:RNA, Messenger; C073878:integrin alphavbeta6
keywords: SPECT/CT; fibrosis; integrin αvβ6