Background/Purpose:

Interstitial lung disease (ILD) is a life-threatening complication in SSc. In recent years, distinct genomic and molecular subtypes in SSc-ILD were identified and molecular targeted therapies are now within reach. However, personalized medicine approaches are still lacking since clinical tools for individualized patient stratification are not yet available. Here, we aimed to assess nuclear imaging of key molecular markers of inflammation and/or fibrosis as novel biomarkers for the stage-dependent assessment of ILD in the murine model of bleomycin (BLM)-induced lung fibrosis.

Methods:

The expression of folate receptor β (FR-β), integrin α_vβ₃ and somatostatin receptor 2 (SSTR2) were analyzed in lung biopsies from patients with idiopathic pulmonary fibrosis (IPF), SSc-ILD, and healthy subjects as well as from BLM-treated mice and saline-treated controls using immunohistochemistry and RT-PCR (n=4-11). Single Photon Emission Computed Tomography (SPECT) and Positron Emission Tomography (PET) were performed at days 3, 7, and 14 after BLM instillation using the integrin α_vβ₃-specific ¹⁷⁷Lu-c(RGDfK)-ligand, the FR-β-specific ¹⁸F-Azafol and the SSTR2-specific ¹⁷⁷Lu-DOTA-NOC. Additionally, ¹⁸F-FDG-PET and pulmonary CT scans were performed. The specific lung uptake of the radiotracers over time was assessed by ex vivo SPECT or PET/CT scans and quantified by biodistribution studies (n=3-9).

Results:

Expression of integrin α_vβ₃, FR-β and SSTR2 was significantly elevated in lung tissues from patients with SSc-ILD and IPF at the mRNA or protein level (p<0.05). Similarly, FR-β expression increased time-dependently in lungs of BLM-treated mice, but not of controls at the gene and protein level with highest expression at days 3 or 7, the inflammatory stages of BLM-induced lung fibrosis (p<0.01). In contrast, expression of integrin α_vβ₃ and SSTR2 was most strongly upregulated at days 7 and 14 at the protein, but not at the mRNA level in BLM-treated mice, and thus in the inflammatory and in the fibrotic stages (p<0.01). ¹⁸F-FDG-PET and lung CT scans detected changes of glucose metabolism and ILD morphology in BLM-treated mice. However, compared with these routinely employed, yet unspecific imaging techniques, molecular targeted imaging of integrin α_vβ₃, FR-β and SSTR2 specifically detected ILD and discriminated lung inflammation and/or fibrosis in correspondence with the changes at the tissue level. The specific lung uptake of ¹⁷⁷Lu-c(RGDfK)-ligand, ¹⁸F-Azafol, and ¹⁷⁷Lu-DOTA-NOC as compared to the unspecific uptake of ¹⁸F-FDG in diseased lungs over time was shown by biodistribution studies and ex vivo lung scans.

Conclusion:

Our data suggest that stage-dependent visualization of ILD with radiotracers that target key markers of lung inflammation and/or fibrosis shows promise for clinical application. As opposed to unselective imaging techniques such as ¹⁸F-FDG-PET and lung CT scans, the introduction of specific nuclear imaging biomarkers for individualized management of SSc-ILD patients could represent the first step towards precision medicine in SSc-ILD.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/molecular-imaging-biomarkers-for-personalized-medicine-strategies-in-systemic-sclerosis-related-interstitial-lung-disease/