Molecular Imaging of Very Late Antigen-4 in Acute Lung Injury
Autor: | Shubhanchi Nigam, Joseph D. Latoche, Qin Zhu, Carolyn J. Anderson, Sina Tavakoli, Kathryn Day, Michael C Bellavia, Joseph Haddad, W. B. Edwards |
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Rok vydání: | 2020 |
Předmět: |
Pathology
medicine.medical_specialty Acute Lung Injury Inflammation Lung injury Integrin alpha4beta1 Pathogenesis 03 medical and health sciences Mice 0302 clinical medicine In vivo Positron Emission Tomography Computed Tomography Pulmonary fibrosis Medicine Animals Radiology Nuclear Medicine and imaging Lung business.industry Biological Transport respiratory system medicine.disease Molecular Imaging Mice Inbred C57BL medicine.anatomical_structure 030228 respiratory system Tumor necrosis factor alpha medicine.symptom business Ex vivo 030215 immunology |
Zdroj: | J Nucl Med |
ISSN: | 1535-5667 |
Popis: | Inflammation plays a central role in the pathogenesis of acute lung injury (ALI) during both the acute pneumonitis stage and progression into the chronic fibroproliferative phase, leading to pulmonary fibrosis. Currently, there is an unmet clinical and research need for noninvasive ways to monitor lung inflammation through targeting of immunoregulatory pathways contributing to ALI pathogenesis. In this study, we evaluated the role of targeted imaging of very late antigen-4 (VLA-4), as a key integrin mediating the adhesion and recruitment of immune cells to inflamed tissues, in quantifying lung inflammation in a mouse model of lipopolysaccharide-induced ALI. Methods: ALI was induced by a single intratracheal administration of lipopolysaccharide (10, 20, or 40 μg per mouse) in C57BL/6J mice. Control mice were intratracheally instilled with sterile phosphate-buffered saline. VLA-4–targeted PET/CT was performed 24 h after intravenous injection of a (64)Cu-labeled high-affinity peptidomimetic ligand referred to as (64)Cu-LLP2A, which is conjugated with the chelator (1,4,8,11-tetraazacyclotetradecane-1-(methane phosphonic acid)-8-(methane carboxylic acid) and a polyethylene glycol 4 linker, at day 2 after the induction of ALI. Ex vivo biodistribution of (64)Cu-LLP2A was determined by γ-counting of harvested organs. The severity of lung inflammation was assessed histologically and by measuring the expression of inflammatory markers in the lung tissue lysates using reverse transcription quantitative polymerase chain reaction. Results: Intratracheal lipopolysaccharide instillation led to an acute inflammatory response in the lungs, characterized by increased expression of multiple inflammatory markers and infiltration of myeloid cells, along with a significant and specific increase in (64)Cu-LLP2A uptake, predominantly in a peribronchial distribution. There was a strong correlation between the lipopolysaccharide dose and (64)Cu-LLP2A uptake, as quantified by in vivo PET (R = 0.69, P < 0.01). Expression levels of both subunits of VLA-4, that is, integrins α(4) and β(1), significantly correlated with the expression of multiple inflammatory markers, including tumor necrosis factor-α, interleukin-1β, and nitric oxide synthase-2, highlighting the potential of VLA-4 as a surrogate marker of acute lung inflammation. Notably, in vivo (64)Cu-LLP2A uptake significantly correlated with the expression of multiple inflammatory markers and VLA-4. Conclusion: Our study demonstrates the feasibility of molecular imaging of VLA-4, as a mechanistically relevant target in ALI, and the accuracy of VLA-4–targeted PET in quantification of ongoing lung inflammation in a murine model. |
Databáze: | OpenAIRE |
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