Mechanostructural adaptations preceding postpneumonectomy lung growth.

In many species, pneumonectomy results in compensatory growth in the remaining lung. Although the late mechanical consequences of murine pneumonectomy are known, little is known about the anatomic adaptations and respiratory mechanics during compensatory lung growth. To investigate the structural and mechanical changes during compensatory growth, mice were studied for 21 days after left pneumonectomy using microCT and respiratory system impedance (FlexiVent). Anatomic changes after left pneumonectomy included minimal mediastinal shift or chestwall remodeling, but significant displacement of the heart and cardiac lobe. Mean displacement of the cardiac lobe centroid was 5.2 ± 0.8 mm. Lung impedance measurements were used to investigate the associated changes in respiratory mechanics. Quasi-static pressure-volume loops demonstrated progressive increase in volumes with decreased distensibility. Measures of quasi-static compliance and elastance were increased at all time points postpneumonectomy (P < .01). Oscillatory mechanics demonstrated a significant change in tissue impedance on the third day after pneumonectomy. The input impedance on day 3 after pneumonectomy demonstrated a significant increase in tissue damping (5.8 versus 4.3 cm H(2)O/mL) and elastance (36.7 versus 26.6 cm H(2)O/mL) when compared to controls. At all points, hysteresivity was unchanged (0.17). We conclude that the timing and duration of the mechanical changes was consistent with a mechanical signal for compensatory growth.

CD34+ progenitor to endothelial cell transition in post-pneumonectomy angiogenesis.

In many species, pneumonectomy triggers compensatory lung growth that results in an increase not only in lung volume, but also in alveolar number. Whether the associated alveolar angiogenesis involves the contribution of blood-borne progenitor cells is unknown. To identify and characterize blood-borne progenitor cells contributing to lung growth after pneumonectomy in mice, we studied wild-type and wild-type/green fluorescence protein (GFP) parabiotic mice after left pneumonectomy. Within 21 days of pneumonectomy, a 3.2-fold increase occurred in the number of lung endothelial cells. This increase in total endothelial cells was temporally associated with a 7.3-fold increase in the number of CD34(+) endothelial cells. Seventeen percent of the CD34(+) endothelial cells were actively proliferating, compared with only 4.2% of CD34(-) endothelial cells. Using wild-type/GFP parabiotic mice, we demonstrated that 73.4% of CD34(+) cells were derived from the peripheral blood. Furthermore, lectin perfusion studies demonstrated that CD34(+) cells derived from peripheral blood were almost uniformly incorporated into the lung vasculature. Finally, CD34(+) endothelial cells demonstrated a similar profile, but had enhanced transcriptional activity relative to CD34(-) endothelial cells. We conclude that blood-borne CD34(+) endothelial progenitor cells, characterized by active cell division and an amplified transcriptional signature, transition into resident endothelial cells during compensatory lung growth.

Angiogenesis gene expression in murine endothelial cells during post-pneumonectomy lung growth.

Although blood vessel growth occurs readily in the systemic bronchial circulation, angiogenesis in the pulmonary circulation is rare. Compensatory lung growth after pneumonectomy is an experimental model with presumed alveolar capillary angiogenesis. To investigate the genes participating in murine neoalveolarization, we studied the expression of angiogenesis genes in lung endothelial cells. After left pneumonectomy, the remaining right lung was examined on days 3, 6, 14 and 21 days after surgery and compared to both no surgery and sham thoracotomy controls. The lungs were enzymatically digested and CD31+ endothelial cells were isolated using flow cytometry cell sorting. The transcriptional profile of the CD31+ endothelial cells was assessed using quantitative real-time polymerase chain reaction (PCR) arrays. Focusing on 84 angiogenesis-associated genes, we identified 22 genes with greater than 4-fold regulation and significantly enhanced transcription (p <.05) within 21 days of pneumonectomy. Cluster analysis of the 22 genes indicated that changes in gene expression did not occur in a single phase, but in at least four waves of gene expression: a wave demonstrating decreased gene expression more than 3 days after pneumonectomy and 3 sequential waves of increased expression on days 6, 14, and 21 after pneumonectomy. These findings indicate that a network of gene interactions contributes to angiogenesis during compensatory lung growth.