Topical application of a PDE4 inhibitor in a BPD sheep model

支气管肺发育不良（BPD）仍然是早产儿的主要并发症和治疗挑战。肺发育不成熟和肺损伤是导致BPD的病理生理过程。后者是由炎症和气道重塑过程引起的，而炎症和气道重塑过程又是由机械通气、氧应激和/或产前或产后感染引起的。PDE 4抑制剂可能是治疗BPD的潜在新治疗选择，因为它们对炎症和气道重塑过程具有保护作用。PDE 4抑制剂对BPD发展的保护作用可以通过在不同的小动物（啮齿动物）模型中全身施用PDE 4抑制剂来证明，其中BPD主要由足月出生的动物中的高氧诱导。然而，使用PDE 4抑制剂治疗的主要挑战是治疗活性所需的剂量水平约为诱导不良反应的阈值水平。减少这些全身性不良反应的一种选择可能是使用吸入性PDE 4抑制剂，其中化合物GSK 256066产生了最有希望的结果。在过去几年中，申请人及其合作伙伴使用了不同的绒毛膜炎大型动物模型，在早产羔羊中诱导BPD样表型，以表征气道重塑过程。此外，可以表明PDE 4抑制剂能够拮抗TGF-β诱导的Smad信号传导和TGF-β调节的参与BPD气道重塑的基因。本研究的目的是在BPD的大型（绵羊）动物模型中研究吸入给药GSK 256066的效果和安全性，其中肺损伤不仅由高氧诱导，还由早产羔羊的通气和绒毛膜炎诱导。与目前的动物模型相比，使用大型动物模型可以更好地反映早产儿BPD的病理学，并允许测试吸入的治疗方法。将在BPD损伤的肺中研究GSK 256066对肺功能、肺损伤、肺炎症以及肺泡形成、血管形成和cAMP代谢的影响。由于肺动脉高压可加重BPD的临床病程，因此还将更详细地研究GSK 256066对心脏功能的可能影响（血液动力学测量;组织学;心脏功能标志物）。用吸入性PDE 4抑制剂治疗BPD可能是BPD治疗中的一种新的治疗选择，其将抗炎作用与对气道重塑过程的保护特性相结合，气道重塑过程是BPD发病机制中的关键因素。

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.