Abstract:
Progressive pulmonary fibrosis (PF) is a rare yet fatal disease that causes a rapid reduction of lung function due to the formation and accumulation of extracellular matrix (ECM) fibres. Since progressive PF is an age-related and diffuse disease, improvement in life span and better clinical standards in diagnostics in industrial countries have led to an increased number of accurately diagnosed cases for this disease, while numbers from developing countries remain unreliable. Despite sustained research efforts, many unanswered questions regarding the cause, progression as well as diagnosis and therapy of PF remain unanswered. In addition to the disruption of the ECM, recent findings seem to point at senescence as a promising biomarker and a potential therapeutic target in progressive PF. The role of senescence in disease development and the success of senolytic treatment remains however debated.
To improve the understanding of PF, preclinical molecular imaging was utilized to provide novel insights into the in vivo progression of PF and its treatment monitoring by using novel PET tracers in a bleomycin mouse model. First, ECM disruption was accurately and selectively detected in vivo over a time course of several weeks using the ECM fibre targeting [64Cu]Cu-NOTA-GPVI-Fc tracer. In addition, longitudinal imaging of PF progression using a novel senescence-targeted radiotracer, which targets the senescence-associated (SA) enzyme β-Galactosidase, could show a crucial role of senescence in disease onset and development. While the detection of ECM disruption and senescence yielded encouraging results, therapy monitoring proved to be more challenging. It was not possible to detect a change in the progression of ECM disruption following the administration of either the approved anti-fibrotic and anti-inflammatory drug pirfenidone or of the novel senolytic combination dasatinib/quercetin using our ECM targeting [64Cu]Cu-NOTA-GPVI-Fc tracer.
Through the in-depth evaluation of two new radiotracers for progressive PF, this study provides new perspectives for in vivo PF diagnosis and therapy monitoring in a pre-clinical mouse model of the disease. Furthermore, clinical translation of the research performed during this PhD could be achieved in the short term as both tracers are currently used in clinical studies, albeit in different application fields. This enables the investigation of their diagnostic potential in patients and depicts the implementable “from bench to bedside” feasibility of this study.
PET Imaging