Regulation of Mammalian Lung Growth

Our research interests are focused on the cellular and molecular mechanisms controlling mammalian lung growth. Over the past several years, I have worked closely with Dr. Stephen Rannels. We use an in vitro lung explant model to study fetal lung growth and development, with an emphasis on the role of matrix GLA protein (MGP) in the process of branching morphogenesis. MGP is a secreted matrix protein found in many soft tissues, with high expression in the lung. Lung MGP message expression is developmentally regulated, with an initial peak of expression occurring just prior to birth, and a second, much larger, peak occurring in adulthood (Figure 1). While the role of MGP in the lung remains to be determined, recent studies in knockout mice demonstrate that the mature protein acts as a mineral-binding protein that participates in the prevention of calcification in the vascular system. A lung phenotype, however, has not been described in the MGP knockout mouse.

Interestingly, treatment of fetal lung explants with antibodies to MGP severely attenuates epithelial branching morphogenesis (Figure 2) over the 4-day culture interval. Subsequent on-going studies are directed towards MGP's potential role in regulation of expression of genes known to be involved in lung branching morphogenesis.

In some adult species such as rats and mice, compensatory lung growth can be initiated by partial pneumonectomy. This is a fascinating model of growth in which the remaining lung undergoes a rapid hyperplastic growth response to completely replace the amount of resected tissue in as little as 4 days, including the formation of new alveoli. One primary goal of this research program is to determine if similar cellular and molecular mechanisms of growth exist during the process of compensatory growth in the adult rat lung as that seen during fetal lung growth. Are the developmental genetic programs recapitulated in the adult during compensatory growth?

My interest in this question arises from our limited knowledge of lung growth in humans. Hyperplastic compensatory lung growth occurs in infants and young children following partial lung resection, but not in adults. Instead, the compensatory growth response in adult humans occurs by hypertrophy of existing cell populations and enlargement of existing alveoli. Understanding the mechanisms responsible for switching the growth response from hyperplastic to hypertrophic may lead to improved clinical procedures for treatment of various lung diseases. This question is most pertinent to the treatment of lung carcinoma, in which the majority of patients undergo partial lung resection to remove the diseased tissue.