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Einleitung: Circulating fibrocytes (CFs) comprise a recently described new cell type of blood born derived fibroblast like cells that are recruited from the circulation to sites of wound repair, vascular remodelling or fibrotic tissue remodelling. A role of these cells in the pulmonary vascular remodelling in pulmonary hypertension has been proposed. Hence, we focussed on these cells type to decipher their role in pulmonary hypertension. Methoden: FACS, confocal laser scanning microscopy; Western blot, qPCR, Rap pull down assay and in vivo hypoxia induced pulmonary hypertension murine model. Ergebnisse: We observed that freshly isolated human peripheral mononuclear cells (PBMCs) upon treatment with treprostinil exhibited poor cell adhesion and subsequently reduction of cell differentiation in ex-vivo expansion. Our further investigations indicated a cAMP induced integrin impairment that was a PKA independent process transduced via an alternative cAMP-RAP-ERK axis. We created blood chimeric animals by bone marrow transplantation of wild type C57 mice with bone marrow derived from eGFP mice. We found a significant contribution of these cells to pulmonary vascular remodelling of the chronic hypoxic mouse and this cellular recruitment was inhibited upon treatment with continuous treprostinil infusion in the mouse directed by an implanted minipump. Diskussion: We could show that prostanoids, which are approved for clinical therapy of pulmonary hypertension, potently inhibit the in vitro differentiation of CF from blood as well as the in vivo recruitment and integration into pulmonary resistance arteries. We thereby showed that CFs are a new therapeutic target in this devastating disease. The further aims are now to more precisely dissect the pathway of prostanoids action on circulating fibrocytes by introducing mutated Rap, Raf and ERK proteins.

Over the last decade the pathophysiology of obstructive sleep apnea (OSA)-related cardiovascular disease has been further elucidated in animal models employing dogs and rats/mice. It was demonstrated that, under the conditions of chronic intermittent hypoxia (CIH), endothelial dysfunction, i. e., a reduction in endothelial-dependent vasorelaxation, occurs. Furthermore, animals were shown to develop arterial hypertension when subjected to CIH for some weeks. Other aspects of the cardiovascular morbidity linked to OSA such as pulmonary hypertension, heart failure and atherosclerosis were also found in these animal models. The common result of these studies is that, apart from sympathetic over-activity, an increased oxidative stress seems to play a key role in the development of OSA-associated cardiovascular disease. It is anticipated that animal studies will continue to enhance our understanding of the pathogenesis of these disorders.

Rechtsventrikulares Remodelling (RVR) und Rechtsherzversagen konnen durch isolierte pulmonale Erkrankungen oder sekundare Rechtsherzbelastung induziert werden. Die Mechanismen, welche ein myokardiales Remodelling, sowohl im linken als auch rechten Ventrikel induzieren, sind noch nicht vollstandig geklart. Beide Ventrikel reagieren auf Druck- und/oder Volumen-Belastung weitgehend identisch, es wurden jedoch bereits viele funktionelle Unterschiede nachgewiesen, welche auch auf der transkiptionalen Ebene zu finden sind. Es ist wahrscheinlich, dass die unterschiedliche embryonale Herkunft des rechten Ventrikels, sowie dessen besondere funktionelle Anforderung und die Prasenz spezieller myokardialer Progenitor-Zellen in einer ventrikelspezifischen pathophysiologischen Adaptation munden. Derzeit liegt kein detailliertes molekularbiologisches Wissen um rechtsventrikulare Hypertrophie und Dysfunktion vor, welches fur die Entwicklung spezieller Strategien zur Reversion des Remodelling notig ware. Zur genaueren Untersuchung des RVR wurden Mause verschiedenen Modalitaten der Rechtsherzbelastung ausgesetzt: Direktes RVR wurde zunachst unabhangig von Anderungen der intrapulmonalen Strombahn durch ein pulmonal-arterielles Banding erreicht. Sekundare RVR unter Beteiligung der intrapulmonalen Strombahn wurde zum einen durch Langzeitexposition gegenuber Hypoxie mit konsekutiver pulmonaler hypoxischer Vasokonstriktion, zum anderen durch transaortales Banding, einem bi-ventrikularen Belastungsmodel, herbeigefuhrt. Basierend auf diesen experimentellen Modellen konnte rechts- und linksventrikulares Remodelling auf funktioneller Ebene durch Kleintier MRT und Druck-Volumenkurven und auf molekularer Ebene durch 'Proteomics' (2D-Gelelektrophorese, Massenspektrometrie, Western-Blot Analyse) verglichen werden. Praliminare Evidenzen deuten auf signifikante molekulare Unterschiede des rechts- und linksventrikularen Remodelling als Folge der pathophysiologischen Stimuli hin.

Pulmonary hypertension (PH), i. e. an increase of mean pulmonary artery pressure above 20 mm Hg under resting conditions, can be observed in different forms of sleep-disordered breathing (SDB). In obstructive sleep apnea (OSA) the apnea-associated triggers of hypoxia and intrathoracic pressure swings lead to repetitive rises of pulmonary artery pressure during sleep. In 20 - 30 % of these patients daytime PH occurs. PH in the setting of OSA is usually mild and rarely causes clinically evident cor pulmonale. Effective CPAP therapy has a beneficial influence on pulmonary hemodynamics in OSA. Severe congestive heart failure (i. e. with a LVEF40 %) might provoke pulmonary venous hypertension and thereby stimulation of pulmonary stretch and irritant receptors. The ensuing hyperventilation leads to a decrease of pCO (2) levels below the apneic threshold and thus contributes to the emergence of Cheyne Stokes respiration (CSR) in up to one half of the affected patients. Patients suffering from advanced idiopathic pulmonary arterial hypertension (IPAH) might show a similar breathing pattern while asleep. Possible pathogenetic factors of the nocturnal periodic breathing occurring in end-stage IPAH are prolonged circulation times and hypocapnia. In conclusion, SDB might cause PH (OSA-associated PH). On the other hand, PH might lead to the development of SDB (CSR in congestive heart failure, periodic breathing in IPAH).

The goal of this study was to assess atrial natriuretic peptide (ANP) levels during inhalation of iloprost in severe primary (PPH) and nonprimary pulmonary hypertension (NPPH).The ANP system is activated in pulmonary hypertension and may help protect from right ventricular (RV) decompensation. It is unknown if ANP regulation is the same in severe PPH and NPPH and if the dynamic regulation is intact in a highly activated ANP system.In 11 patients with PPH and seven patients with NPPH, right heart catheter investigations were performed. Pulmonary and systemic artery ANP and cyclic guanosine monophosphate (cGMP) levels as well as hemodynamics were measured before and after iloprost inhalation.The baseline hemodynamics of patients with PPH and patients with NPPH were comparable (mean pulmonary artery pressure [mPAP]: 61 +/- 5 mm Hg vs. 52 +/- 5 mm Hg, pulmonary vascular resistance [PVR]: 1,504 +/- 153 dyne.s.cm(-5) vs. 1,219 +/- 270 dyne.s.cm(-5). Atrial natriuretic peptide and cGMP levels were increased about tenfold and fivefold compared with controls in both PPH and NPPH. Iloprost inhalation significantly decreased mPAP (-9.1 +/- 2.5 mm Hg vs. -7.9 +/- 1.5 mm Hg), PVR (-453 +/- 103 dyne.s.cm(-5) vs. -381 +/- 114 dyne.s.cm(-5)), ANP (-99 +/- 63 pg/ml vs. -108 +/- 47 pg/ml) and cGMP (-4.6 +/- 0.9 nM vs. -4.2 +/- 1.6 nM). Baseline ANP including all patients significantly correlated with PVR, right atrial pressure, cardiac index, RV ejection fraction, mixed venous oxygen saturation and cGMP.The ANP system is highly activated in patients with severe PPH and NPPH. Atrial natriuretic peptide levels are significantly correlated with parameters of RV function and pre- and afterload. Iloprost inhalation causes a rapid decrease in ANP and cGMP in parallel with pulmonary vasodilation and hemodynamic improvement.

Chronic pulmonary hypertension and septic lung failure display different clinical features resulting in severe disturbances in the pulmonary circulation. In these diseases, the pulmonary bloodflow is impaired by a pathologic constriction of blood vessels that may lead to right ventricular overloading as well as serious worsening of gas exchange mainly caused by ventilation/perfusion mismatch. Various mechanisms deteriorating the vascular function may induce both an irreversible and a reversible contraction of pulmonary vessels, respectively. Two pharmacological approaches exist to reduce the vascular resistance: Reduction of the increased vascular tone by relaxation of vascular smooth muscle cells (effect of vasodilators). Inhibition of thrombus-mediated obliteration of the lung perfusion by use of anticoagulant and fibrinolytic drugs. Prevention of the structural reorganization of pulmonary vessels (vascular remodeling) by use of vasodilators with anti-inflammatory and anti-proliferative potency such as prostanoids. The systemic (intravenous or oral) application of vasodilative agents in sepsis and chronic pulmonary hypertension has, however, important side effects: Antagonism of the hypoxic pulmonary vasoconstriction aggravates the ventilation/perfusion mismatch (decrease in arterial oxygenation). Side effects of these vasodilators (systemic hypotension). The inhalative route of application is superior because of the pulmonary enrichment of the applied agent (pulmonary selectivity). Furthermore, a preferential deposition in the well-ventilated areas of the lung is achieved (intrapulmonary selectivity). Thus, the decrease in pulmonary-vascular resistance is paralleled by both optimized ventilation-perfusion matching and subsequently improved gas exchange. First clinical studies with inhaled nitric oxide and aerosolized prostacyclin have been performed in intubated and mechanically ventilated patients with septic lung failure. At present, the use of the long-acting prostacyclin analogue ilomedin for ambulant treatment of patients with chronic pulmonary hypertension is under investigation.

Aerosolized prostacyclin (PGI(2)) has been suggested for selective pulmonary vasodilation, but its effect rapidly levels off after termination of nebulization. Stabilization of the second-messenger cAMP by phosphodiesterase (PDE) inhibition may offer a new strategy for amplification of the vasodilative response to nebulized PGI(2). In perfused rabbit lungs, continuous infusion of the thromboxane mimetic U46619 was used to establish stable pulmonary hypertension [increase in pulmonary arterial pressure (pPA) from approximately 7 to approximately 32 mm Hg], which is accompanied by progressive edema formation and severe disturbances in gas exchange with a predominance of shunt flow (increase from2 to approximately 58%, as assessed by the multiple inert gas elimination technique). In the absence of PGI(2), dose-effect curves for intravascular and aerosol administration of the specific PDE3 inhibitor motapizone, the PDE4 inhibitor rolipram, and the dual-selective PDE3/4 inhibitor tolafentrine on pulmonary hemodynamics were established (potency rank order: rolipramtolafentrine approximately motapizone; highest efficacy on coapplication of rolipram and motapizone). Ten-minute aerosolization of PGI(2) was chosen to effect a moderate pPA decrease (approximately 4 mm Hg; rapidly returning to prenebulization values within 10-15 min) with only a slight reduction in shunt flow (approximately 49%). Prior application of subthreshold doses of i.v. or inhaled PDE3 or PDE4 inhibitors, which per se did not affect pulmonary hemodynamics, caused prolongation of the post-PGI(2) decrease in pPA. The most effective approach, rolipram plus motapizone, amplified the maximum pPA decrease in response to PGI(2) to approximately 9 to 10 mm Hg, prolonged the post-PGI(2) vasorelaxation to60 min, reduced the extent of lung edema formation by 50%, and decreased the shunt flow to approximately 19% (i.v. rolipram/motapizone) and 28% (aerosolized rolipram/motapizone). We conclude that lung PDE3/4 inhibition, achieved by intravascular or transbronchial administration of subthreshold doses of specific PDE inhibitors, synergistically amplifies the pulmonary vasodilatory response to inhaled PGI(2), concomitant with an improvement in ventilation-perfusion matching and a reduction in lung edema formation. The combination of nebulized PGI(2) and PDE3/4 inhibition may thus offer a new concept for selective pulmonary vasodilation, with maintenance of gas exchange in respiratory failure and pulmonary hypertension.