TGFB AND PULMONARY ALDEHYDES IN NEWBORN LUNG INJURY

点击翻译按钮获取中文摘要

Our research focuses on the investigation of mechanisms of newborn lung injury. We aim to identify novel therapeutic targets that can prevent pediatric pulmonary disease. Bronchopulmonary dysplasia (BPD) is a chronic lung disease of prematurely born infants. It is largely caused by O2 therapies that are used to sustain premature babies. It is the second most costly pediatric lung disease in the U.S. and the incidence of BPD remains unchanged despite recent advancements in respiratory therapies. The mechanisms by which O2 therapies cause BPD are poorly understood. Moreover, there are no effective biomarkers or imaging methods that detect the early stages of the disease or guide the deployment of mechanism-targeted preventive therapies. Accumulating evidence suggests that abnormal formation of the lung extracellular matrix (ECM) during O2-induced lung injury has a primary role in the development of BPD. O2-induced lung injury in newborns increases the expression of pro-lysyl oxidases (p-LOXs). After cellular secretion and cleavage they become mature LOXs, which have the capability to form aldehydes in ECM proteins. But whether aldehydes are increased in extracellular proteins in the O2-injured newborn lung is unknown. Previously we discovered that TGFβ activation has a direct role in BPD development in mouse pup BPD models. We determined also that TGFβ activation in hyperoxic newborn lungs increases the mRNA levels of LOXs and dysregulates ECM formation. The increased expression of LOXs appears directly triggered by TGFβ. This is because TGFβ increases their mRNA expression in cultured fibroblasts and TGFβ neutralization inhibits their expression in O2-injured mouse pup lungs. However, the mechanisms by which TGFβ increases the expression of LOXs in fibroblasts and whether the TGFβ-stimulated up-regulation of LOXs in the O2-injured newborn lung drives aldehyde formation are unknown. The central hypothesis of this project is that TGFβ-induced expression of LOXs increases aldehyde levels in the O2-injured newborn lung. In Aim 1, we propose to identify for the first time the intracellular pathways by which TGFβ increases the expression of LOXs in lung fibroblasts, to identify signaling elements that might be targeted to mitigate O2-induced newborn lung disease. In Aim 2, we will test how TGFβ and LOXs increase aldehyde levels in hyperoxic mouse pup lung. In Aim 3, we will use a novel aldehyde-sensing molecular probe and MRI to determine how TGFβ-neutralization inhibits in vivo aldehyde generation during O2-induced lung injury in mouse pups. Successful completion of this project will identify new mechanisms for hyperoxic newborn lung disease that might be targeted to decrease the risk of developing BPD in preterm babies. Moreover, it will provide a proof-in-concept of a novel in vivo biomarker of newborn lung disease that could guide the deployment of TGFβ-targeting therapies. Because of the pressing need for theranostics to prevent BPD, the results of this work will likely stimulate rapid development and testing of in vivo aldehyde-sensing molecules in the O2-injured newborn lung.