Thoracic Cardiovascular Surgery
Research Opportunities
COMPENSATORY LUNG GROWTH
ANGIOGENESIS IN COMPENSATORY LUNG GROWTH
Abstract: The lung has the ability to regenerate lost tissue after pneumonectomy (PNX, removal of a lung), and the resulting compensatory lung growth (CLG) leads to rapid alveolar regeneration with complete restoration of total lung mass and function in animal models. Our laboratory has shown that CLG requires growth of new blood vessels (angiogenesis). Thus we believe that CLG and angiogenesis are tightly linked, with angiogenesis being a major driving force required for alveolar regeneration. We have shown that epidermal growth factor (EGF), a potent angiogenic factor, and its receptor are induced after PNX, that exogenous EGF augments CLG, and that inhibition of EGF receptor prevents CLG. Endothelial nitric oxide synthase (eNOS) is another angiogenic factor, and we have demonstrated a failure of CLG in eNOS knockout mice which we believe is due to impaired angiogenesis.
EGF can induce eNOS activity, and thus EGF and eNOS may play critical, interdependent angiogenic roles in CLG. Since many angiogenic growth factors are secreted by pulmonary epithelium, we will also study possible cross talk between the epithelium and endothelium in Aim 3. An important long-term goal of our laboratory is to generate knowledge that allows induction of alveolar regeneration or that rescues failed alveologenesis in humans. This proposal will focus on angiogenic mechanisms of CLG and the potential to induced lung growth via angiogenic therapy. Our overall hypothesis is that angiogenesis drives CLG via EGF and eNOS signaling mechanisms.
To test this hypothesis, the proposed studies will utilize the post-PNX CLG model in mice. Aim 1 will test the hypothesis that CLG requires EGF-mediated angiogenic signaling through the use of various loss- and gain-of-function mouse models. Aim 2 will test the hypothesis that failed CLG in eNOS-deficient mice is due to loss of angiogenic potential which can be rescued by angiogenic therapy. We will determine if impaired CLG in eNOS-deficient mice can be rescued by administration of angiogenic agents (inhaled NO or EGF) and if this correlates with restoration of CLG, angiogenesis, and alveolarization. Aim 3 will test the hypothesis that alveolar epithelial cell-derived growth factors induce endothelial cell growth and angiogenesis during CLG. These studies will advance the potential to manipulate lung regeneration with angiogenic agents which translates into therapies for end-stage lung disease, lung volume reduction surgery, premature infant lungs, and transplantation.
MECHANISMS OF UNEQUAL LOBAR GROWTH IN POST-PNEUMONECTOMY LUNG GROWTH
Abstract: Compensatory lung growth is a regenerative growth which occurs after pneumonectomy, but little is known about the mechanisms which regulate this growth. The long-term goal of our research is to understand the mediators that regulate compensatory lung growth. Preliminary data suggests that compensatory lung growth is not uniform in nature, but is lobe specific, occuring mainly in the upper two lobes. Thus our proposed research will test the following hypothesis: that compensatory lung growth is not uniform in nature, is lobe specific, and this is due to superior angiogenesis and perfusion in the growing lobes.
Specific Aim 1A will determine the lobar distribution of compensatory lung growth by comparing growth between the four lobes of the right lung after left pneumonectomy. Specific Aim 1B will compare alveolar and endothelial cell proliferation and angiogenesis between the lobes of the right lung after left pneumonectomy. Specific Aim 1C will measure blood perfusion in the lobes of the right lung and correlate this to compensatory growth in the lung. We will utilize the rat model of compensatory lung growth. The lobes of the right lung, following left pneumonectomy, will be studied and compared for the following parameters: lobe weight and volume indices, alveolar cell and vascular endothelial cell proliferation, expression of VEGF and VEGF receptors, morphometric measurements of alveolar surface density, volume of respiratory region, and vessel density, and measurements of blood perfusion. Finally, we will test if growth can be induced in the lower two lobes of the right lung by removing the upper two lobes.