The aim of the studies presented in this thesis is to test potential treatment options in an animal model of bronchopulmonary dysplasia (BPD). BPD is a chronic lung disease in very preterm infants... Show moreThe aim of the studies presented in this thesis is to test potential treatment options in an animal model of bronchopulmonary dysplasia (BPD). BPD is a chronic lung disease in very preterm infants who were mechanically ventilated for respiratory distress syndrome (RDS). BPD is characterized by an arrest in alveolar and vascular lung development, complicated by inflammation, abnormal coagulation, oxidative stress, and at later stages by pulmonary hypertension (PAH). The inflammatory process is one of the major players in experimental BPD and we explored the effect of phospohodiesterase type 4 (PDE4) inhibitors on this process. We investigated the effect of PDE4 inhibition on the cardiopulmonary aspect of experimental BPD. The arrest in alveolar development is currently lack effective therapy, therefore we explored the therapeutic potential on alveologenesis of apelin and PDE5 inhibitor sildenafil, both very potent pro-angiogenic and vasodilative agents. We investigated the therapeutic potential of stem cell therapy in an animal model of PAH by mimicking autologous MSC therapy. Our data warrant clinical investigation of sildenafil as a potential drug to prevent or treat PAH and RVH, and the arrest in lung development, which plays a pivotal role in poor outcome in the neonatal intensive care nursery. Show less
Cleuren, A.C.A.; Linden, I.K. van der; Visser, Y.P. de; Wagenaar, G.T.M.; Reitsma, P.H.; Vlijmen, B.J.M. van 2010
Background: Oral estrogen use is associated with changes in plasma levels of many coagulation proteins. Objective: To gain more insight into the underlying mechanism of estrogen-induced changes in... Show moreBackground: Oral estrogen use is associated with changes in plasma levels of many coagulation proteins. Objective: To gain more insight into the underlying mechanism of estrogen-induced changes in coagulation. Methods: Ovariectomized female mice were used to study the impact of oral 17 alpha-ethinylestradiol (EE) on plasma coagulation, hepatic coagulation gene transcript levels, and dependence on estrogen receptor (ER) alpha and ER beta. Results: Ten days of oral EE treatment resulted in significantly reduced plasma activity levels of factor (F)VIII, FXII, combined FII/FVII/FX and antithrombin, whereas FIX activity significantly increased. Regarding hepatic transcript levels, oral EE caused significant decreases in fibrinogen-gamma, FII, FV, FVII, FX, FXII, antithrombin, protein C, protein Z, protein Z inhibitor and heparin cofactor II mRNA levels, whereas FXI levels significantly increased and transcript levels of FVIII, FIX, protein S and alpha(2)-antiplasmin remained unaffected. All EE-induced coagulation-related changes were neutralized by coadministration of the non-specific ER antagonist ICI182780. In addition, ER alpha-deficient mice lacked the EE-induced changes in plasma coagulation and hepatic transcript profile, whereas ER beta-deficient mice responded similarly to non-deficient littermate controls. A crucial role for the ER was further demonstrated by its rapid effects on transcription, within 2.5-5 h after EE administration, suggesting a short chain of events leading to its final effects. Conclusions: Oral EE administration has a broad impact on the mouse coagulation profile at the level of both plasma and hepatic mRNA levels. The effects on transcription are rapidly induced, mostly downregulatory, and principally mediated by ER alpha. Show less
Cleuren, A.C.A.; Linden, I.K. van der; Visser, Y.P. de; Wagenaar, G.T.M.; Reitsma, P.H.; Vlijmen, B.J.M. van 2010
BACKGROUND Oral estrogen use is associated with changes in plasma levels of many coagulation proteins. OBJECTIVE To gain more insight into the underlying mechanism of estrogen-induced changes in... Show moreBACKGROUND Oral estrogen use is associated with changes in plasma levels of many coagulation proteins. OBJECTIVE To gain more insight into the underlying mechanism of estrogen-induced changes in coagulation. METHODS Ovariectomized female mice were used to study the impact of oral 17α-ethinylestradiol (EE) on plasma coagulation, hepatic coagulation gene transcript levels, and dependence on estrogen receptor (ER) α and ERβ. RESULTS Ten days of oral EE treatment resulted in significantly reduced plasma activity levels of factor (F)VIII, FXII, combined FII/FVII/FX and antithrombin, whereas FIX activity significantly increased. Regarding hepatic transcript levels, oral EE caused significant decreases in fibrinogen-γ, FII, FV, FVII, FX, FXII, antithrombin, protein C, protein Z, protein Z inhibitor and heparin cofactor II mRNA levels, whereas FXI levels significantly increased and transcript levels of FVIII, FIX, protein S and α(2) -antiplasmin remained unaffected. All EE-induced coagulation-related changes were neutralized by coadministration of the non-specific ER antagonist ICI182780. In addition, ERα-deficient mice lacked the EE-induced changes in plasma coagulation and hepatic transcript profile, whereas ERβ-deficient mice responded similarly to non-deficient littermate controls. A crucial role for the ER was further demonstrated by its rapid effects on transcription, within 2.5-5 h after EE administration, suggesting a short chain of events leading to its final effects. CONCLUSIONS Oral EE administration has a broad impact on the mouse coagulation profile at the level of both plasma and hepatic mRNA levels. The effects on transcription are rapidly induced, mostly downregulatory, and principally mediated by ERα. Show less
