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Prenatal steroids, surfactants and noninvasive ventilation have helped reduce the incidence of the classical form of bronchopulmonary dysplasia characterized by marked fibrosis and emphysema. However, a new form of bronchopulmonary dysplasia, marked by arrest of alveolarization, remains a complication in the postnatal course of extremely low-birth-weight infants.
An attractive therapeutic goal would be the reversal of emphysema through regeneration of alveolar septa. Proper alveolarization involves the temporal and spatial coordination of a number of cells, mediators and genes. Lung interstitial cells derived from the mesenchyme play a crucial role in alveolarization. Myofibroblasts are essential for secondary septation, a critical process of alveolarization and localize to the front lines of alveologenesis. The differentiation and migration of myofibroblasts are strictly controlled by various mediators and genes.
We have developed a transgenic mouse model that impairs alveolar septation. In this mouse model, we inhibit a specific family of growth factors − fibroblast growth factors (FGF). We showed that signaling of this fibroblast growth factor family is required to initiate alveolarization but is not important for the ongoing formation of alveolar septa. Other researchers have shown that retinoic acid treatment causes the induction of septation and re-alveolarization.
Our work demonstrates that alveolar regeneration is dependent on the differentiation of the interstitial myofibroblast and that induction of alveolar myofibroblast during alveolar repair is dependent on fibroblast growth factor signaling.
Our studies focus on lineage relationships, biological function of cells and signaling networks that regulate myofibroblast differentiation in septation after pneumonectomy.
This work has been published in Am J Physiol Lung Cell Mol Physiol. 2009. This project has been funded (2008-2010) by an American Heart Association research grant and is currently funded by an R01 grant NIH HL 104003 (2010-2015).
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