Topical application of a PDE4 inhibitor in a BPD sheep model

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Bronchopulmonary dysplasia (BPD) continues to be a major complication and therapeutic challenge in preterm infants. The pathophysiological sequence leading to BPD are induced by lung immaturity combined with lung injury. The latter is induced by inflammatory and airway remodelling processes, which are in turn caused by mechanical ventilation, oxygen stress and/or ante- or postnatal infections. PDE4 inhibitors could be a potential new therapeutic option for the treatment of BPD because of their protective effects on inflammation and airway remodelling processes. A protective effect of PDE4 inhibitors on BPD development could be demonstrated by systemic administration of PDE4 inhibitors in different small animal (rodent) models in which BPD was mainly induced by hyperoxia in term born animals. However, a major challenge in a treatment using PDE4 inhibitors is that the dose level required for therapeutic activity is about the threshold level for an induction of adverse effects. One option to reduce these systemic adverse effects could be the use of inhaled PDE4 inhibitors, of which the compound GSK256066 yielded the most promising results. During the last years, the applicant and his cooperation partner have used different large animal models of chorioamnionitis, inducing a BPD like phenotype in preterm lambs, to characterize airway remodelling processes. In addition, it could be shown that a PDE4 inhibitor was able to antagonize TGF-b induced Smad signalling and TGF-b regulated genes involved in airway remodelling in BPD. The purpose of this study is to investigate the effect and safety of inhalation-administered GSK256066 in a large (sheep) animal model of BPD, in which lung damage is induced not only by hyperoxia, but also by ventilation and chorioamnionitis in preterm lambs. In contrast to current animal models, the usage of a large animal model may better reflect the pathology of BPD in preterm infants and allows to test the therapeutic approach of inhalation. The effect of GSK256066 on lung function, -damage, -inflammation as well as alveolarization, vascularization, and cAMP metabolism will be studied in BPD damaged lungs. Since pulmonary hypertension can worsen the clinical course of BPD, possible effects of GSK256066 on cardiac function will also be investigated in more detail (hemodynamic measurements; histology; heart function marker). The treatment of BPD with an inhaled PDE4 inhibitor could be a new therapeutic option in BPD treatment, combining anti-inflammatory effects with protective properties on airway remodelling processes, which are the key factors in the pathogenesis of BPD.