The most vital function of the lung is gas-exchange. The site of this critical function, the alveolus, must harbor robust mechanisms for both the maintenance and survival of resident cells and the preservation of functional morphology. When these mechanisms are compromised, diseases such as chronic obstructive pulmonary disease, bronchopulmonary dysplasia and pulmonary fibrosis result. Trophic signaling by growth factors in the lung epithelium induces molecular programs that promote cell survival and suppress the intrinsic cell death machinery. These programs utilize a restricted set of proximal and distal intracellular signaling mediators that integrate the coordinated balance of proliferative/antiproliferative and apoptotic/anti- apoptotic agendas. This integration allows for maintenance of alveolar homeostasis and controlled growth and maturation of the lung. Inappropriate trophic signaling can result in either airspace hypoplasia (emphysema, bronchopulmonary dysplasia) or neoplastic disease. Despite the introduction of therapies aimed at enhancing trophic signaling to treat hematologic, neural and endocrine disorders, these approaches remain mostly underexplored in hypoplastic lung disease. In this proposal, we examine the utility of HGF/c- met mediated trophic signaling to reduce airspace injury and maintain or restore normal airspace morphology in murine models of destructive airspace enlargement.
In Specific Aim 1, we target gain of HGF function with a detailed dose-response analysis of HGF supplementation in the TSK model of emphysema. We also establish whether transgenic overexpression of c-met in alveolar type II cells is sufficient to ameliorate airspace enlargement in two models of emphysema.
In Specific Aim 2, we utilize our tri- transgenic mice that are inducibly deficient in c-met in alveolar epithelial cells to determine whether the absence of c-met in the TSK and cigarette-smoke exposed lung worsens the airspace phenotype and the indices of cellular survival.
In Specific Aim 3, using genetic and pharmacologic loss-of-function strategies, we establish the roles of akt1 and stat 3, known mediators of epithelial cell survival whose activation is altered in the studied models, in HGF/c-met promoted airspace repair. If successful, these studies will provide an extensive therapeutic armamentarium to support regenerative alveolarization for a wide range of pulmonary disorders.
| Calvi, Carla; Podowski, Megan; Lopez-Mercado, Armando et al. (2013) Hepatocyte growth factor, a determinant of airspace homeostasis in the murine lung. PLoS Genet 9:e1003228 |
| Podowski, Megan; Calvi, Carla; Metzger, Shana et al. (2012) Angiotensin receptor blockade attenuates cigarette smoke-induced lung injury and rescues lung architecture in mice. J Clin Invest 122:229-40 |
| Calvi, Carla L; Podowski, Megan; D'Alessio, Franco R et al. (2011) Critical transition in tissue homeostasis accompanies murine lung senescence. PLoS One 6:e20712 |
| Podowski, Megan; Calvi, Carla L; Cheadle, Christopher et al. (2009) Complex integration of matrix, oxidative stress, and apoptosis in genetic emphysema. Am J Pathol 175:84-96 |
