Vascular endothelial growth factor accelerates compensatory lung growth after unilateral pneumonectomy.

We hypothesize that compensatory lung growth after unilateral pneumonectomy in a murine model is, in part, angiogenesis dependent and can be altered using angiogenic agents, possibly through regulation of endothelial cell proliferation and apoptosis. Left pneumonectomy was performed in mice. Mice were then treated with proangiogenic factors [vascular endothelial growth factor (VEGF); basic fibroblast growth factor (bFGF)], VEGF receptor antibodies (MF-1, DC101), and VEGF receptor small molecule chemical inhibitors. Lung volume and mass were measured. The lungs were analyzed using immunohistochemistry by CD31 staining, terminal deoxynucleotidyl transferase biotin-dUTP nick end labeling, type II pneumocytes staining, and proliferating cell nuclear antigen. Compensatory lung growth was complete by postoperative day 10 and was associated with diffuse apoptosis of endothelial cells and pneumocytes. This process was accelerated by VEGF, such that growth was complete by postoperative day 4 with similar associated apoptosis. bFGF had no effect on lung growth. MF-1 and DC101 had no effect. The VEGF receptor small molecule chemical inhibitors also had no effect. VEGF, but not bFGF, accelerates growth. VEGF receptor inhibitors do not block growth, suggesting that other proangiogenic factors play a role or can compensate for VEGF receptor blockade. Diffuse apoptosis, endothelial cell and pneumocyte, occurs at cessation of both normal compensatory and VEGF-accelerated growth. Angiogenesis modulators may control growth via regulation of endothelial cell proliferation and apoptosis, although the exact relationship between endothelial cells and pneumocytes has yet to be determined. The fact that bFGF did not accelerate growth in our model when it did accelerate regeneration in the liver model suggests that angiogenesis during organ regeneration is regulated in an organ-specific manner.

Pneumonectomy in the mouse: technique and perioperative management.

Thoracic surgery in mice is challenging due to difficult intubation and ventilation, lack of intravenous access, and the risk of hemorrhage. We developed a rapid and safe technique for murine unilateral pneumonectomy in order to study compensatory lung growth. Under general anesthesia, 81 mice were intubated with an angiocatheter using a 2.7-mm, 0-degree endoscope. A left thoracotomy was performed. The lung was gently extracted from the thoracic cavity, ligated at the hilum, and resected. Postoperatively, warming lights and subcutaneous saline injections were used to ensure minimal morbidity. The survival rate for the scope-assisted intubation and pneumonectomy was 88%. Perioperative mortality was due to technical error. Minimal long-term morbidity was appreciated. This general operative technique and perioperative management may be applied to all types of murine thoracic procedures used for surgical research.