Der Einfluss von Xenon auf das pulmonale System und die Untersuchung von Vasodilatoren, Argon und Platelet-derived growth factor in der akuten und chronischen pulmonalen Hypertonie

Suleiman, Said; Martin, Christian (Thesis advisor); Pradel, Gabriele (Thesis advisor); Fabry, Marlies (Thesis advisor)

Aachen (2020)
Dissertation / PhD Thesis

Dissertation, RWTH Aachen University, 2020

Abstract

Pulmonary hypertension is a chronic and progressive disease of the pulmonary system. The use of isolated, perfused lungs (IPL), precision cut lung slices (PCLS) and the hypoxia-induced increase of the pulmonary vasotonus were selected for the investigations of responsible signal mechanisms and possible therapy options. We were able to show that both perfusion of levosimendan and ventilation of argon significantly reduced endothelin-1-induced increase of the pulmonary vasotonus in healthy rat lungs. Ventilation of xenon, on the other hand, increased the pulmonary vascular and precapillary resistance and could be a potential additional stress factor for patients who would inhale xenon due to its neuro- and organo protective properties. Furthermore, by inhibiting GABAA/B receptors, we showed that argon-induced vasodilation could be inhibited in PCLS and thus showed a possible interaction of argon and pulmonary GABA receptors. At the same time, we were able to show in guinea pig lungs that perfusion of the Platelet-derived Growth Factor BB (PDGF-BB) led to broncho constriction and vasoconstriction and increased thromboxane expression. These effects were subsequently successfully inhibited by perfusion of the tyrosine kinase inhibitor imatinib. Nebulisation of imatinib as a topical application also proved to be a suitable alternative therapy option and could allow the avoidance of imatinib-induced side effects after systemic perfusion. The extension of the experiments using hypoxic-treated lungs also demonstrated that chronic hypoxia led to a significant increase in the media of the small pulmonary arteries and to an increase in PDGF-BB-induced vasoconstriction of the central pulmonary arteries in PCLS. The use of the PDGFR-β inhibitor SU6668 successfully induced inhibition of PDGF-BB-induced vasoconstriction in PDGF-BB-treated healthy and hypoxic lungs. Argon and imatinib also reduced the hypoxia-induced development of pulmonary edema. These results could be of clinical relevance for the treatment of pulmonary hypertension.

Institutions

• Department of Biology [160000]
• Department of Cellular and Applied Infection Biology [164020]
• [528500-2]