Molecular mechanisms of perfluorocarbon activity

Every year about 79.000 children are born in Austria, about 10% of them are preterm infants. Whereas acute pulmonary diseases significantly contribute to neonatal mortality, morbidity is mainly determined by chronic lung diseases, mainly bronchopulmonary dysplasia (BPD). About 40-70% of extremely preterm infants have a "mild BPD" and between 16 and 55 % develop a "severe BPD". BPD is associated with severe long-term problems, such as respiratory problems during childhood, but also neurological sequels. The cost for subsequent ambulatory therapy equals one million Euro per affected child. Current therapies improve acute respiratory insufficiency, but do not always prevent chronic lung disease. Pulmonary inflammation and oxygen toxicity represent two important factors for the development of BPD. Perfluorocarbons (PFC) with surfactant-like and anti-inflammatory properties are potentially useful for prevention or therapy of neonatal lung disease. Prior to a clinical application mechanisms of PFC activity should be investigated at a cellular and molecular level. The present project will study two aspects of PFC activity on isolated alveolar type II (ATII-) cells and in the lungs of newborn rats. Specific Aim #1: PFC effects on C.pneumoniae (Cpn)-induced inflammation of type II-cells. Contact of Cpn with ATII-cells induces an inflammatory cascade that causes alterations of ATII-cell cytoskeleton and the surfactant metabolism. A similar inflammatory pathway leads to development of BPD in preterm infants. The Cpn-induced inflammatory cascade in ATII-cells was studied by the group of the applicant in the past. That cellular model of inflammation is now used to study the anti-inflammatory properties of PFC in detail. Specific Aim #2: PFC effect on hyperoxia-induced changes in lung of newborn rats. The premature lung is very vulnerable against oxygen. Whereas "absolute hyperoxia" is associated with acute lung injury, the "relative hyperoxia" in preterms rather affects lung development. Hyperoxia induces a cascade of changes in the lung that subsequently leads to the development of BPD. Data from the literature suggest, that PFC could prevent oxygen-induced changes in the lung. The present proposal will study in a stepwise approach how the PFC effect is mediated. A well established model of newborn rats that are exposed to hyperoxia is used. The applicant worked in Berlin until last year. His working group and co-operation partners have long lasting and well-documented experience with the topic and methods of the present project. After the applicant and a co-worker moved to Innsbruck, the knowledge and experience is now made available for his new working site. The established international co-operations and the expertise of the applicant are a guarantee for a successful completion of the present project. The proposal is mainly dedicated to basic research. It will provide the base to prepare a clinical application of PFC therapy. With the present grant a working group will be supported in Innsbruck, that could become one of the leading groups in this field.

Every year about 79.000 children are born in Austria, about 10% of them are preterm infants. Whereas acute pulmonary diseases significantly contribute to neonatal mortality, morbidity is mainly determined by chronic lung diseases, mainly bronchopulmonary dysplasia (BPD). About 40-70% of extremely preterm infants have a "mild BPD" and between 16 and 55 % develop a "severe BPD". BPD is associated with severe long-term problems, such as respiratory problems during childhood, but also neurological sequels. The cost for subsequent ambulatory therapy equals one million Euro per affected child. Current therapies improve acute respiratory insufficiency, but do not always prevent chronic lung disease. Pulmonary inflammation and oxygen toxicity represent two important factors for the development of BPD. Perfluorocarbons (PFC) with surfactant-like and anti-inflammatory properties are potentially useful for prevention or therapy of neonatal lung disease. Prior to a clinical application mechanisms of PFC activity should be investigated at a cellular and molecular level. The present project will study two aspects of PFC activity on isolated alveolar type II (ATII-) cells and in the lungs of newborn rats. Specific Aim #1: PFC effects on C.pneumoniae (Cpn)-induced inflammation of type II-cells. Contact of Cpn with ATII-cells induces an inflammatory cascade that causes alterations of ATII-cell cytoskeleton and the surfactant metabolism. A similar inflammatory pathway leads to development of BPD in preterm infants. The Cpn-induced inflammatory cascade in ATII-cells was studied by the group of the applicant in the past. That cellular model of inflammation is now used to study the anti-inflammatory properties of PFC in detail. Specific Aim #2: PFC effect on hyperoxia-induced changes in lung of newborn rats. The premature lung is very vulnerable against oxygen. Whereas "absolute hyperoxia" is associated with acute lung injury, the "relative hyperoxia" in preterms rather affects lung development. Hyperoxia induces a cascade of changes in the lung that subsequently leads to the development of BPD. Data from the literature suggest, that PFC could prevent oxygen-induced changes in the lung. The present proposal will study in a stepwise approach how the PFC effect is mediated. A well established model of newborn rats that are exposed to hyperoxia is used. The applicant worked in Berlin until last year. His working group and co-operation partners have long lasting and well-documented experience with the topic and methods of the present project. After the applicant and a co-worker moved to Innsbruck, the knowledge and experience is now made available for his new working site. The established international co-operations and the expertise of the applicant are a guarantee for a successful completion of the present project. The proposal is mainly dedicated to basic research. It will provide the base to prepare a clinical application of PFC therapy. With the present grant a working group will be supported in Innsbruck, that could become one of the leading groups in this field.