Role of TGFbeta superfamily in Broncopulmonary Dysplasia

Indiana University Indianapolis, Indianapolis IN

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Abstract

DESCRIPTION (provided by applicant): Bronchopulmonary Dysplasia (BPD) continues to affect the majority of infants born extremely premature and is primarily a disease of arrested alveolarization resulting from injury to the developing saccular lung. Protective strategies have been ineffective in reducing BPD, underscoring the need to better understand the underlying pathogenesis to enable development of novel therapies. Transforming Growth Factor-ß superfamily signaling regulates ECM deposition, which is critical to normal lung development, and is dynamically regulated during the saccular stage of lung development. Utilizing a clinically-relevant murine model of BPD that limits hyperoxic lung injury to the saccular stage (day 0-4 in mice) to persistently simplify adult alveolar structure, we determined TGFß2 (but not TGFß1 or 3 ligands) is uniquely suppressed by O2 by day 4. Although excessive TGFß has been implicated in BPD pathogenesis, it is often following prolonged O2 exposure coincident with late-onset fibrosis (when BPD phenotype is already well-established); it is unclear if ligand-specific TGFß signaling within the acute phase of arrested saccular development contributes to BPD pathogenesis. In addition to TGFß2, we show during saccular lung development that hyperoxia down-regulates the complete mechanistic pathway of TGFß signaling, including intracellular TGFß signal transducer, pSmad3 (which predominates in lung), as well as a novel TGFß downstream ECM effector, ßigH3. Similar to hyperoxia, genetic knockout of ßigH3 impairs saccular lung development. Through targeted genetic analysis of TGFß signaling pathways in both our physiologic (hyperoxia) and novel genetic (ßigH3 null) mouse models of arrested saccular development, we identified known and novel biomarkers of BPD pathogenesis: Follistatin and Msx2 (negatively regulates myofibroblast differentiation), Cdkn1a (negatively regulates cell proliferation), and IL6 (important modulator of inflammation). We hypothesize that acute, short-lived suppression of TGFß signaling within the saccular stage is sufficient to cause BPD, and that Tgfß2 downregulation is the key ligand responsible and acts via suppression of Smad3 activation resulting in down-regulation of the ECM-modulating protein, ßigH3. By comparing our physiologic and genetic models of BPD, we will determine whether TGFß mis-regulation is an active participant in the mechanism of arrested alveolarization or merely a compensatory response to lung injury. Aim 1 will examine whether early phase BPD is characterized by suppressed TGFß signaling while subsequent upregulation following prolonged hyperoxia is a compensatory response to 2nd reparative mechanisms. Aim 2 will test whether TGFß suppression via specific loss of TGFß2 ligand alone is able to phenocopy BPD. Aim 3 will determine the mechanism(s) by which absence of the downstream TGFß2 effector ECM protein, ßigH3, is sufficient to cause BPD.