SYNDECANS IN MODELS OF BRONCHOPULMONARY DYSPLASIA

点击翻译按钮获取中文摘要

A major aspect of the pathogenesis of BPD in newborns is the inflammatory response to injury caused by mechanical ventilation at high FiO2. Ventilated fetal baboons develop the pathophysiological, histologic and biochemical features of the infant with BPD, and provide an opportunity to test hypothesis for the pathogenesis of BPD and to evaluate preventative and therapeutic measures. We study the cell surface heparan sulfate proteoglycans (HSPGs) known as the syndecans. These single membrane spanning protein contain extracellular domains (ectodomains) that bear HS chains near the N- termini, distant from the plasma membrane. Syndecans are on the surface of every adherent cell where they act as co-receptors for a variety of growth factors, cytokines, chemokines and cell adhesion molecules, as well as coordinate, in part, the highly complex reparative response to tissue injury. Specifically, syndecan-1 and -4 are induced in response to tissue injury, agents produced during tissue injury cause syndecan ectodomains to be released intact from cell surfaces, yielding soluble effectors that modify the activities of wide variety of proteins and act as dominant negative inhibitors. Mice containing a targeted deletion of the syndecan-1 gene and mice that transgenically over-express syndecan-1 under the broadly acting CMV promoter show major defects in wound repair: the null mice show slow epithelial response to injury and the over-expressing mice shed excessive amounts of the soluble syndecan-1 ectodomains, causing a major disturbance in repair of injury. We hypothesize that the persistent injury of the lung by mechanical ventilation at high FiO2 leads to excessive shedding of the soluble syndecan ectodomains, that the biological activities of these PGs delay the reparative response and contribute to the changes recognized pathologically and clinically as BPD, and reducing the level of these ectodomains will ameliorate, in part, the progression to BPD. Specifically, we aim to (i) to correlate syndecan expression and shedding with histopathological changes in ventilated pre-term baboon lungs; (ii) determine the biological activities of the soluble ectodomains from ventilated lungs; (iii) establish baboon lung cultures to investigate mechanisms of syndecan induction and shedding and to produce syndecan ectodomains; (iv) assess whether the soluble ectodomains are casually related to development of BPD in the baboon models.