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Despite intensive research efforts, the aetiology of the majority of chronic lung diseases (CLD) in both, children and adults, remains elusive. Current therapeutic options are limited, providing only symptomatic relief, rather than treating the underlying condition, or preventing its development in the first place. Thus, there is a strong and unmet clinical need for the development of both, novel effective therapies and preventative strategies for CLD. Many studies suggest that modifications of prenatal and/or early postnatal lung development will have important implications for future lung function and risk of CLD throughout life. This view represents a fundamental change of current pathophysiological concepts and treatment paradigms, and holds the potential to develop novel preventative and/or therapeutic strategies. However, for the successful development of such approaches, key questions, such as a clear understanding of underlying mechanisms of impaired lung development, the identification and validation of relevant preclinical models to facilitate translational research, and the development of concepts for correction of aberrant development, all need to be solved. Accordingly, a European Science Foundation Exploratory Workshop was held where clinical, translational and basic research scientists from different disciplines met to discuss potential mechanisms of developmental origins of CLD, and to identify major knowledge gaps in order to delineate a roadmap for future integrative research.

Bronchopulmonary dysplasia is the most common complication when premature birth occurs at less than 28 weeks gestational age. The general aim of this thesis is to explore the therapeutic potential of interventions in signaling pathways, involved in lung development and oxidative stress-induced lung injury, to prevent or attenuate BPD in a neonatal rat model, in which experimental BPD is induced by exposure to hyperoxia. The therapeutic potential of the targeting compounds of signaling pathways was investigated by studying their beneficial effects on contributing factors to severe experimental BPD pathology, including aberrant alveolar and vascular development, inflammation, fibrosis, coagulation, vascular remodeling, pulmonary arterial hypertension and right ventricular hypertrophy. We found ⑴angiotensin II type 2 receptor ligand PD123319 attenuates hyperoxia-induced lung and heart injury at a low dose in newborn rats; ⑵ Metformin attenuates hyperoxia-induced lung injury in neonatal rats by reducing the inflammatory response; ⑶ Deficiency or inhibition of lysophosphatidic acid receptor 1 protects against hyperoxia-induced lung injury in neonatal rats; ⑷Adult lysophosphatidic acid receptor 1-deficient rats with hyperoxia-induced neonatal chronic lung disease are protected against lipopolysaccharide-induced acute lung injury; ⑸ Bone morphogenetic protein 9 protects against neonatal hyperoxia-induced impairment of alveolarization and pulmonary inflammation.