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Combined pharmacotherapy of different types of pulmonary hypertension
Krása, Kryštof ; Hampl, Václav (advisor) ; Neckář, Jan (referee) ; Al-Hiti, Hikmet (referee)
Pulmonary hypertension is a group of diseases characterized by increased mean pulmonary artery pressure. Especially in group 2, which is associated with heart disease and is the most prevalent of all types, and in group 3, associated with lung disease, no sufficiently effective treatment has yet been developed beyond the treatment of the underlying disease, which is problematic in many cases. Dehydroepiandrosterone sulfate (DHEA S) and statins have different mechanisms of action on pulmonary hypertension in some respects, so the question of the effectiveness of combining them on pulmonary hypertension versus either agent alone has been offered. To test this hypothesis, we induced pulmonary hypertension in adult male rats by three weeks of exposure to hypoxia (10% O2) and treated them with simvastatin (60 mg/L) and DHEA S (100 mg/L) in drinking water, either alone or in combination. Both simvastatin and DHEA S reduced mean pulmonary artery pressure (from a mean ± s.d. value of 34.4 ± 4.4 to 27.6 ± 5.9 and 26.7 ± 4.8 mmHg, respectively), but their combination was not more effective (26.7 ± 7.9 mmHg). Differences in the degree of oxidative stress (as indicated by malondialdehydedehydplasma concentration), the degree of superoxide production (electron paramagnetic resonance) or blood nitric oxide...
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The metabolic role of pulmonary arterial fibroblasts in the activation of immune system during development of pulmonary arterial hypertension
Křivonosková, Monika ; Plecitá, Lydie (advisor) ; Zadražil, Zdeněk (referee)
The development of inflammation in the small distal pulmonary vessels plays an important role in the development of pulmonary arterial hypertension (PAH). One of the cell types found in the pulmonary vessels are fibroblasts, which, according to the "outside-in" theory, may be the first to respond to stimuli in the vessel, modulating remodeling of the pulmonary vessels toward the inner layers of the vessel and attracting other immune cells to the site. In addition to inflammation, the so- called Warburg effect also occurs in vessels affected by PAH, in which metabolism shifts toward glycolysis and lactate production. Among other changes, a pro-oxidative state is induced within the cell by mitochondrial metabolism and NADPH oxidase, leading to an imbalance in reactive oxygen species production. We therefore wanted to test whether calf lung fibroblasts with hypoxia-induced PAH have an active inflammasome, with which they would produce mature interleukin 1β (IL-1β) and to clarify the effect of a pro-oxidant environment on this expression. In our in vitro model we have confirmed IL-1β mRNA expression, but we were unable to detect its expression at the protein level. This was consistent with the inability to detect inflammasome activity. We believe that the inability to detect the protein form of IL-1β...
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Treatment of pulmonary hypertension affect the metabolism of cyclic guanosine monophosphate
Al-Hiti, Hikmet ; Kettner, Jiří (advisor) ; Ošťádal, Petr (referee) ; Goncalvesová, Eva (referee)
Chronic damage to pulmonary vessels leads to pulmonary hypertension (PH). Different forms of PH are quite frequent and are associated with significant morbidity and mortality. The treatment of PH is most successful, if its cause can be identified and removed before irreversible damage to the pulmonary vascular bed occurs. For patients, in whom the elimination of the underlying cause is not possible or where the cause is unknown, the treatment is aimed at reduction of pulmonary vascular resistance and improvement of cardiac and circulatory response to pressure overload of the right ventricle. One option for the PH treatment is modification of metabolism of cyclic guanosine monophosphate (GMP), which is the second messenger of nitric oxide and induces vascular vasodilation. Cyclic GMP is degraded by phosphodiesterases (PDE 5). In the clinical part, we tested the hypothesis that acute inhibition of PDE5 by sildenafil provides more selective pulmonary vasodilation than high doses of prostaglandin E1 (PGE1). The study showed that the vasodilator effects of sildenafil on pulmonary circulation is more pronounced than in the systemic circulation and that sildenafil had a greater ability to detect reversible component precapillary PH due to advanced chronic heart failure than PGE1. The aim of our...
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Treatment of pulmonary hypertension affect the metabolism of cyclic guanosine monophosphate
Al-Hiti, Hikmet ; Kettner, Jiří (advisor) ; Ošťádal, Petr (referee) ; Goncalvesová, Eva (referee)
Chronic damage to pulmonary vessels leads to pulmonary hypertension (PH). Different forms of PH are quite frequent and are associated with significant morbidity and mortality. The treatment of PH is most successful, if its cause can be identified and removed before irreversible damage to the pulmonary vascular bed occurs. For patients, in whom the elimination of the underlying cause is not possible or where the cause is unknown, the treatment is aimed at reduction of pulmonary vascular resistance and improvement of cardiac and circulatory response to pressure overload of the right ventricle. One option for the PH treatment is modification of metabolism of cyclic guanosine monophosphate (GMP), which is the second messenger of nitric oxide and induces vascular vasodilation. Cyclic GMP is degraded by phosphodiesterases (PDE 5). In the clinical part, we tested the hypothesis that acute inhibition of PDE5 by sildenafil provides more selective pulmonary vasodilation than high doses of prostaglandin E1 (PGE1). The study showed that the vasodilator effects of sildenafil on pulmonary circulation is more pronounced than in the systemic circulation and that sildenafil had a greater ability to detect reversible component precapillary PH due to advanced chronic heart failure than PGE1. The aim of our...
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