Mechanisms of Compensatory Lung Growth

PI:  Victor Laubach, PhD

Summary: In experimental animals, 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 project focuses 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, we are utilizing the post-PNX CLG model in mice. Aim 1 tests the hypothesis that CLG requires EGF-mediated angiogenic signaling through the use of various loss- and gain-of-function mouse models. Aim 2 tests the hypothesis that failed CLG in eNOS-deficient mice is due to loss of angiogenic potential which can be rescued by angiogenic therapy. We are testing whether 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 tests 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.

Compensatory growth of the right lung after left pneumonectomy (right) in mice compared to normal left+right lungs (left). The time point shown is two weeks after pneumonectomy.

Barium arteriograms of rat left lungs 21 days after right pneumonectomy. Arrows indicate visible areas of arterial remodeling (i.e. new branches).