Detection and treatment of pulmonary vascular disease

Liza Botros

    Research output: PhD ThesisPhD-Thesis - Research and graduation internal

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    Abstract

    A blood vessel or vas sanguineum, is part of the circulatory system. Blood vessels are responsible for exchanging gases such as oxygen and carbon dioxide, and nutrients such as sugars, proteins and lipids to the tissues and organs. The inner lining of each blood vessel is made up of endothelial cells. These are bricks that lie next to each other like a tight chain to enable no fluid leakage out of the blood vessels into the tissues and to regulate blood pressure. This thesis focuses on the endothelium in the lungs. We investigated pulmonary arterial hypertension (PAH). This is a disease of the vascular wall of lung arteries and the lung microvasculature. This wall becomes thicker and stiffer, causing the blood pressure in the lungs to increase. The origin of this disease is still not completely clear, but the loss and damage of blood vessels is a crucial hallmark. Currently, the diagnostic process of PAH is very complex, invasive and time consuming. l. It would be very useful if we could use a simple blood test to discriminate patients. In chapter 2 we try to find substances in the blood, so-called biomarkers, that are specific for PAH. Unfortunately, there are currently no biomarkers in the bloodstream that are specific for PAH, mainly because most biomarkers are non-specific and often increased in people with another heart disease such as heart failure. In chapter 3 we tried another method to detect patients with PAH. By means of a scan with a radioactive substance (PET scan), we compared healthy volunteers and healthy family members with PAH patients. Unfortunately, this method also proved not sensitive enough to diagnose PAH. In chapter 4, we treated 15 patients with an mercaptopurine for four months. We found a lower lung blood pressure after therapy, but there were also a lot of side effects. Therefore, this medicine appears to be effective, but not safe for daily use. In the second part of this thesis, we focus on fluid leakage from the blood vessels into the lung tissue. This hampers gas exchange and patients become very short of breath. To gain more insight into the origin of leaky blood vessels in the lungs, we focused on the effects of a drug called bosutinib on the endothelium. We noticed that the connections between the endothelial cells were reinforced after treatment with bosutinib. As indicated above, the cement between the bricks was strengthened. Second, we tested bosutinib in a mouse with a lung infection that causes fluid to leak into the lungs. We observed a strong protective effect on the endothelium after treatment with bosutinib, and thus a clear reduction in the leakage of the pulmonary blood vessels. Finally, we tested bosutinib in a rat with a trauma and a blood transfusion. Both a trauma and a blood transfusion can also lead to leaky vessels in various organs. By means of dyes that we injected into the bloodstream, we could measure the pulmonary vascular leakage. We therefore conclude that bosutinib is a potential new treatment for patients with vascular leakage syndromes. When the SARS-CoV-2 virus spread across the world in 2019, many people with the Corona virus disease 2019 (COVID-19) were admitted. Remarkably many patients had fluid in the lungs due to leaky vessels. In chapter 7 we tested imatinib, a drug used for leukemia patients, in approximately 400 patients. Half of the patients received imatinib, the other half received a placebo. We did not see an improvement in the oxygen demand of the patients, but we did see a reduction in death and a shorter intensive care (ICU) admission
    Original languageEnglish
    QualificationPhD
    Awarding Institution
    • Vrije Universiteit Amsterdam
    Supervisors/Advisors
    • Bogaard, Herman Jan, Supervisor, External person
    • Hordijk, P.L., Supervisor, External person
    • Aman, Jannes, Co-supervisor, External person
    Award date4 Mar 2022
    Place of PublicationAmsterdam
    Publisher
    Print ISBNs9789464168921
    Publication statusPublished - 4 Mar 2022

    Keywords

    • pulmonary hypertension
    • pulmonary vascular leak

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