Post-Pneumonectomy Compensatory Lung Growth

Background

The lung is one of a select few mammalian organs with the capacity to regenerate lost tissue. Pneumonectomy (removal of a lung) induces rapid, hyperplastic, compensatory lung growth (CLG) resulting in complete restoration of total lung mass and function in animal models. An important long-term goal of our laboratory is to generate knowledge that allows induction of pulmonary alveolar regeneration or that rescues failed alveologenesis in humans. Such understanding will facilitate the development of future therapies for patients with end-stage lung disease or broncho-pulmonary dysplasia through the stimulation and control of alveolar regeneration.

Recently we have evaluated the impact of exogenous growth factors (retinoic acid, epidermal growth factor, keratinocyte growth factor) on compensatory lung growth. These studies have shown that compensatory lung growth can be enhanced by exogenous growth factors. Pneumonectomy results in increased flow and shear stress which stimulate endothelial nitric oxide synthase (eNOS). We have demonstrated that compensatory lung growth is impaired in eNOS gene knockout mice. NO is an essential mediator of VEGF-induced angiogenesis, and the mitogenic actions of bFGF and EGF are at least partially mediated by NO. Also, a critical downstream pathway common among these growth factors is activation of the mitogen activated protein kinase (MAPK) cascade, which itself can be mediated by NO via PKG. Thus one hypothesis we are testing is that NO is a key mediator of compensatory lung growth through the modulation of angiogenesis and type II alveolar cell proliferation.

In recent studies we have begun to study and characterize compensatory growth among the lobes of the right lung after left pneumonectomy. Results indicate that the lobes do not grow equally. We are performing experiments that will help understand the differences in flow and ventilation between the lobes and how this may determine the extent of compensatory growth in the individual lobes.

Basic Science Model

This research utilizes both the rat and mouse pneumonectomy model which is a well characterized, established model for the study of compensatory lung growth. This is a technically simple and reproducible model which entails surgical removal of the entire left lung whereby the animals recover quickly with low mortality. We are utilizing many cell & molecular biology protocols to measure the signaling pathways in the lung after pneumonectomy such as: gene array, ELISA, Western blot, real-time PCR, immunohistochemistry, confocal microscopy, and lung morphometry.

More information on our compensatory lung growth research can be found on our Compensatory Lung Growth website.